Author Report for: Zhang YContact information:Zhang YinaDepartment of Physiological Genomics, Institute for Physiology, Ludwig-Maximilians University, Pettenkoferstrasse 12, 80336, MunichGermanyPhone : Fax :
Cao Y, Zhang Y, Jia Z, Jia H, Sun Y, Yuan H, Bian Y, Xu B, Fu J, Qin F Ref: Physiol Behav, :114077, 2023 : PubMed ESTHER: Cao_2023_Physiol.Behav__114077 PubMedSearch: Cao 2023 Physiol.Behav 114077 PubMedID: 36638877 Abstract Age-related neurodegenerative diseases accompanied by learning and memory deficits are growing in prevalence due to population aging. Cellular oxidative stress is a common pathomechanism in multiple age-related disorders, and various antioxidants have demonstrated therapeutic efficacy in patients or animal models. Many plants and plant extracts possess potent antioxidant activity, but the compounds responsible are frequently unknown. Identification and evaluation of these phytochemicals is necessary for optimal targeted therapy. A recent study identified theaflavin-3,3'-digallate (TFDG) as the most potent among a large series of phytochemical antioxidants. Here we examined if TFDG can mitigate learning and memory impairments in the D-galactose model of age-related neurodegeneration. Experimental mice were injected subcutaneously with D-galactose (120 mg/kg) for 56 days. In treatment groups, different doses of TFDG were administered daily by gavage starting on day 29 of D-galactose injection. Model mice exhibited poor learning and memory in the novel object recognition and Y-maze tests, reduced brain/body mass ratio, increased brain glutamate concentration and acetylcholinesterase activity, decreased brain acetylcholine concentration, and lower choline acetyltransferase, glutaminase, and glutamine synthetase activities. Activities of antioxidant enzymes glutathione peroxidase and superoxide dismutase were also reduced, while the concentration of malondialdehyde, a lipid peroxidation product, was elevated. Further, antioxidant genes Nrf2, Prx2, Gsh-px1, and Sod1 were downregulated in brain. Each one of these changes was dose-dependently reversed by TFDG. TFDG is an effective antioxidant response inducer and neuroprotectant that can restore normal neurotransmitter metabolism and ameliorate learning and memory dysfunction in the D-galactose model of age-related cognitive decline. Title: Genome-wide exploration of the GDSL-type esterase/lipase gene family in rapeseed reveals several BnGELP proteins active during early seedling development Ding Y, Xing L, Xu J, Jiang T, Tang X, Wang Y, Huang S, Hao W, Zhou X and Xie CG <1 more author(s)> Ding Y, Xing L, Xu J, Jiang T, Tang X, Wang Y, Huang S, Hao W, Zhou X, Zhang Y, Xie CG (- 1) Ref: Front Plant Sci, 14:1139972, 2023 : PubMed ESTHER: Ding_2023_Front.Plant.Sci_14_1139972 PubMedSearch: Ding 2023 Front.Plant.Sci 14 1139972 PubMedID: 37008509 Abstract The Gly-Asp-Ser-Leu (GDSL)-type esterase/lipase proteins (GELP) are one of the most important families of lipolytic enzymes and play prominent roles in seed germination and early seedling establishment through mobilizing the lipids stored in seeds. However, there are no comprehensive studies systematically investigating the GELP gene family in Brassica napus (BnGELP), and their biological significance to these physiological processes are far from understood. In the present study, a total of 240 BnGELP genes were identified in B. napus cultivar "Zhongshuang 11" (ZS11), which is nearly 2.3-fold more GELP genes than in Arabidopsis thaliana. The BnGELP genes clustered into 5 clades based on phylogenetic analysis. Ten BnGELPs were identified through zymogram analysis of esterase activity followed by mass spectrometry, among which five clustered into the clade 5. Gene and protein architecture, gene expression, and cis-element analyses of BnGELP genes in clade 5 suggested that they may play different roles in different tissues and in response to different abiotic stresses. BnGELP99 and BnGELP159 were slightly induced by cold, which may be attributed to two low-temperature responsive cis-acting regulatory elements present in their promoters. An increased activity of esterase isozymes by cold was also observed, which may reflect other cold inducible esterases/lipases in addition to the ten identified BnGELPs. This study provides a systemic view of the BnGELP gene family and offers a strategy for researchers to identify candidate esterase/lipase genes responsible for lipid mobilization during seed germination and early seedling establishment. Title: Dual-Mode Ratiometric Electrochemical and Turn-On Fluorescent Detection of Butyrylcholinesterase Utilizing a Single Probe for the Diagnosis of Alzheimer's Disease Dong H, Zhao L, Wang T, Chen Y, Hao W, Zhang Z, Hao Y, Zhang C, Wei X and Xu M <2 more author(s)> Dong H, Zhao L, Wang T, Chen Y, Hao W, Zhang Z, Hao Y, Zhang C, Wei X, Zhang Y, Zhou Y, Xu M (- 2) Ref: Analytical Chemistry, :, 2023 : PubMed ESTHER: Dong_2023_Anal.Chem__ PubMedSearch: Dong 2023 Anal.Chem PubMedID: 37192372 Abstract Biomarkers detection in blood with high accuracy is crucial for the diagnosis and treatment of many diseases. In this study, the proof-of-concept fabrication of a dual-mode sensor based on a single probe (Re-BChE) using a dual-signaling electrochemical ratiometric strategy and a "turn-on" fluorescent method is presented. The probe Re-BChE was synthesized in a single step and demonstrated dual mode response toward butyrylcholinesterase (BChE), a promising biomarker of Alzheimer's disease (AD). Due to the specific hydrolysis reaction, the probe Re-BChE demonstrated a turn-on current response for BChE at -0.28 V, followed by a turn-off current response at -0.18 V, while the fluorescence spectrum demonstrated a turn-on response with an emission wavelength of 600 nm. The developed ratiometric electrochemical sensor and fluorescence detection demonstrated high sensitivity with BChE concentrations with a low detection limit of 0.08 microg mL(-1) and 0.05 microg mL(-1), respectively. Importantly, the dual-mode sensor presents the following advantages: (1) dual-mode readout can correct the impact of systematic or background error, thereby achieving more accurate results; (2) the responses of dual-mode readout originate from two distinct mechanisms and relatively independent signal transduction, in which there is no interference between two signaling routes. Additionally, compared with the reported single-signal electrochemical assays for BChE, both redox potential signals were detected in the absence of biological interference within a negative potential window. Furthermore, it was discovered that the outcomes of direct dual-mode electrochemical and fluorescence quantifications of the level of BChE in serum were in agreement with those obtained from the use of commercially available assay kits for BChE sensing. This method has the potential to serve as a useful point-of-care tool for the early detection of AD. Title: Enhancement degradation efficiency of pyrethroid-degrading esterase (Est816) through rational design and its application in bioremediation Fan X, Zhao M, Wen H, Zhang Y, Zhang J, Liu X Ref: Chemosphere, 319:138021, 2023 : PubMed ESTHER: Fan_2023_Chemosphere_319_138021 PubMedSearch: Fan 2023 Chemosphere 319 138021 PubMedID: 36731665 Gene_locus related to this paper: 9bact-i6yrg4 Abstract The pervasive use of pyrethroids is seriously hazardous to the environment and even human health. Enzymatic bioremediation is potentially a rapid and environmentally friendly technology to combat the pollution of pyrethroid pesticides. The hydrolysis of ester linkages is the initial and critical enzymatic step in microbial degradation pathways. Here, the versatile and thermostable esterase Est816 was cloned and its new function, pyrethroid-hydrolysis activity, was expanded. To further improve its pyrethroid-hydrolysis ability, Est816 was modified by rational design. After two rounds of mutation, the best-performing mutant, Est816(A216V/K238N/M97V,) was obtained, which could completely degrade 1 mg/L lambda-cyhalothrin, cypermethrin, and deltamethrin within 20 min, and efficiently degrade fenvalerate, reaching over 80% conversion. Degradation activity analyses showed that three substitutions (A216V, K238 N and M97V) were beneficial for enhancing the activity of Est816. Enzymatic characterization showed that Est816(A216V/K238N/M97V) inherited broad substrate specificity and possessed excellent stability and adaptability over wide ranges of temperature and pH, which is essential for bioremediation in frequently changing conditions. Furthermore, Est816(A216V/K238N/M97V) had the best degradation effect on all four pyrethroid residues in Panax notoginseng root, with more than 87% conversion after 24 h. Pyrethroid residues in tea, cucumber, and soil were reduced by more than 76%, 80%, and 76%, respectively. Taken together, these findings highlight the great potential of Est816(A216V/K238N/M97V) in the bioremediation of pyrethroid-contaminated soil and agricultural products. Title: Targeting soluble epoxide hydrolase promotes osteogenic-angiogenic coupling via activating SLIT3/HIF-1alpha signalling pathway Gao L, Chen W, Li L, Li J, Kongling W, Zhang Y, Yang X, Zhao Y, Bai J, Wang F Ref: Cell Prolif, :e13403, 2023 : PubMed ESTHER: Gao_2023_Cell.Prolif__e13403 PubMedSearch: Gao 2023 Cell.Prolif e13403 PubMedID: 36636821 Inhibitor(s) related to this paper: TPPU Abstract Type H vessels have recently been identified to modulate osteogenesis. Epoxyeicostrioleic acids (EETs) have an essential contribution to vascular homeostasis. However, whether increased EETs with soluble epoxide hydrolase (sEH) inhibitor TPPU enhance the coupling of angiogenesis and osteogenesis remains largely unknown. The effects of TPPU on cross-talk between co-cultured human umbilical vein endothelial cells (HUVECs) and human dental pulp stem cells (hDPSCs), and on long bone growth and calvarial defect repair in mice were investigated in vitro and in vivo. TPPU enhanced osteogenic differentiation of co-cultured HUVECs and hDPSCs in vitro and increased type H vessels, and long bone growth and bone repair of calvarial defect. Mechanistically, TPPU promoted cell proliferation and angiogenesis, reclined cell apoptosis, and significantly increased CD31(hi) EMCN(hi) endothelial cells (ECs) and SLIT3 and HIF-1alpha expression levels in co-cultured HUVECs and hDPSCs. Knockdown of Slit3 in hDPSCs or Hif-1alpha in HUVECs impaired the formation of CD31(hi) EMCN(hi) ECs and reversed TPPU-induced osteogenesis. We defined a previously unidentified effect of TPPU coupling angiogenesis and osteogenesis. TPPU induced type H vessels by upregulating the expression of hDPSCs-derived SLIT3, which resulted in the activation of ROBO1/YAP1/HIF-1alpha signalling pathway in ECs. Targeting metabolic pathways of EETs represents a new strategy to couple osteogenesis and angiogenesis, sEH is a promising therapeutic target for bone regeneration and repair. Title: Mechanistic analysis of endothelial lipase G promotion of the occurrence and development of cervical carcinoma by activating the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B/mechanistic target of rapamycin kinase signalling pathway Huang J, Liu R, Zhang Y, Sheng X Ref: J Obstet Gynaecol, 43:2151353, 2023 : PubMed ESTHER: Huang_2023_J.Obstet.Gynaecol_43_2151353 PubMedSearch: Huang 2023 J.Obstet.Gynaecol 43 2151353 PubMedID: 36606668 Gene_locus related to this paper: human-LIPG Abstract Lipase G, endothelial type (LIPG) is expressed abundantly in tissues with a high metabolic rate and vascularisation. Research on LIPG has focussed on metabolic syndromes. However, the role of LIPG in providing lipid precursors suggests that it might function in the metabolism of carcinoma cells. Analysis in The Cancer Genome Atlas indicated that patients with cervical carcinoma with high LIPG expression had a lower survival prognosis compared with patients with low LIPG expression. The mechanism underlying the effects of LIPG in cervical carcinoma is unclear. The present study aimed to determine the role of LIPG in cervical carcinoma and its mechanism. The results showed that the LIPG expression level was higher in cervical cancer. Downregulation of LIPG expression inhibited cell migration, invasion, proliferation, and the formation of cell colonies, but increased the rate of apoptosis. The Human papillomavirus E6 protein might reduce the expression of miR-148a-3p, relieve the inhibitory effect of miR-148a-3p on LIPG expression, and promote the progression of cervical cancer through the phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B/mechanistic target of rapamycin kinase signalling pathway.IMPACT STATEMENTWhat is already known on this subject? LIPG provides lipid precursors, suggesting that it might function in the metabolism of carcinoma cellsWhat do the results of this study add? LIPG might be regulated by HPV16 E6/miR-148a-3p and promote cervical carcinoma progression via the PI3K/AKT/mTOR signalling pathway.What are the implications of these finding for clinical practice and/or further research? The results indicated that novel treatment and diagnosis strategies for cervical carcinoma could be developed related to LIPG. However, the detailed relationship between LIPG and cervical carcinoma remains to be fully determined. Title: PGC 1alpha-Mediates Mitochondrial Damage in the Liver by Inhibiting the Mitochondrial Respiratory Chain as a Non-cholinergic Mechanism of Repeated Low-Level Soman Exposure Jin Q, Zhang Y, Cui Y, Shi M, Shi J, Zhu S, Shi T, Zhang R, Chen X and Li L <2 more author(s)> Jin Q, Zhang Y, Cui Y, Shi M, Shi J, Zhu S, Shi T, Zhang R, Chen X, Zong X, Wang C, Li L (- 2) Ref: Biol Pharm Bull, 46:563, 2023 : PubMed ESTHER: Jin_2023_Biol.Pharm.Bull_46_563 PubMedSearch: Jin 2023 Biol.Pharm.Bull 46 563 PubMedID: 37005300 Abstract This work aimed to assess whether mitochondrial damage in the liver induced by subacute soman exposure is caused by peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1alpha) and whether PGC-1alpha regulates mitochondrial respiratory chain damage. Toxicity mechanism research may provide theoretical support for developing anti-toxic drugs in the future. First, a soman animal model was established in male Sprague-Dawley (SD) rats by subcutaneous soman injection. Then, liver damage was biochemically evaluated, and acetylcholinesterase (AChE) activity was also determined. Transmission electron microscopy (TEM) was performed to examine liver mitochondrial damage, and high-resolution respirometry was carried out for assessing mitochondrial respiration function. In addition, complex I-IV levels were quantitatively evaluated in isolated liver mitochondria by enzyme-linked immunosorbent assay (ELISA). PGC-1alpha levels were detected with a Jess capillary-based immunoassay device. Finally, oxidative stress was analyzed by quantifying superoxide dismutase (SOD), malondialdehyde (MDA), glutathione (GSH), oxidized glutathione (GSSG), and reactive oxygen species (ROS) levels. Repeated low-level soman exposure did not alter AChE activity, while increasing morphological damage of liver mitochondria and liver enzyme levels in rat homogenates. Complex I, II and I + II activities were 2.33, 4.95, and 5.22 times lower after treatment compared with the control group, respectively. Among complexes I-IV, I-III decreased significantly (p < 0.05), and PGC-1alpha levels were 1.82 times lower after soman exposure than in the control group. Subacute soman exposure significantly increased mitochondrial ROS production, which may cause oxidate stress. These findings indicated dysregulated mitochondrial energy metabolism involves PGC-1alpha protein expression imbalance, revealing non-cholinergic mechanisms for soman toxicity. Title: Preparation of functional oils rich in diverse medium and long-chain triacylglycerols based on a broadly applicable solvent-free enzymatic strategy Lai Y, Li D, Liu T, Wan C, Zhang Y, Zheng M Ref: Food Res Int, 164:112338, 2023 : PubMed ESTHER: Lai_2023_Food.Res.Int_164_112338 PubMedSearch: Lai 2023 Food.Res.Int 164 112338 PubMedID: 36737931 Abstract To address the problems of long reaction times and limited range of adaptation in enzymatic synthesis medium- and long-chain triacylglycerols (MLCTs), a broadly applicable solvent-free enzymatic interesterification strategy was proposed. Candida sp. lipase (CSL) was immobilized on hydrophobic hollow mesoporous silica spheres (HHSS) to construct a biocatalyst designated as CSL@HHSS with a 15.3 % immobilization yield and a loading amount of 94.0 mg/g. The expressed activity and the specific activity were 20.14 U/g and 173.62 U/g, which were 4.6 and 5.6 times higher than that of free CSL, respectively. This biocatalyst demonstrated higher activity, wider applicability, and excellent reusability. Linseed oil, sunflower oil, perilla seed oil, algal oil, and malania oleifera oil were applied as substrates to produce MLCTs with medium-chain triacylglycerols (MCT) catalyzed by CSL@HHSS through interesterification in yields ranging from 69.6 % to 78.0 % within 20 min. Specific fatty acids, including linolenic acid, oleic acid, DHA, and nervonic acid (the first reported), were introduced into MLCT's skeleton, respectively. The structures were finely analyzed and identified by GC and UPLC-MS. The catalytic efficiency value of CSL@HHSS in catalyzing interesterification between linseed oil and MCT (70 degC, 20 min, lipase 6 wt%) is 0.86 g/gmin, which is the highest ever reported. This paper presents an effective and sustainable strategy for functional MLCTs production. Title: A novel and controllable method for simultaneous preparation of human milk fat substitutes (OPL, OPO and LPL): two-step enzymatic ethanolysis-esterification strategy Li Y, Zhang Y, Zhou Y, Zheng M Ref: Food Res Int, 163:112168, 2023 : PubMed ESTHER: Li_2023_Food.Res.Int_163_112168 PubMedSearch: Li 2023 Food.Res.Int 163 112168 PubMedID: 36596114 Abstract A novel and effective approach based on the two-step ethanolysis-esterification strategy was proposed for the controllable and simultaneous preparation of 1-oleoyl-2-palmitoyl-3-linoleoylglycerol (OPL), 1,3-dioleoyl-2-palmitoyl-glycerol (OPO) and 1,3-dilinoleoyl-2-palmitoyl-glycerol (LPL) with adjustable proportions. Enzymatic ethanolysis of fractionated palm stearin was carried out to yield 2-monopalmitoylglycerol (79.4s+/-s0.6s%) with over 91.0s% purity at the optimal conditions. The immobilized Candida sp. lipase (CSL) on octyl-functionalized ordered mesoporous silica (OMS-C(8)) was applied to re-esterify 2-monopalmitoylglycerol with oleic acid and linoleic acid for the simultaneous production of OPL, OPO, and LPL. The total content in the final products was 81.5s%, with 91.3s% of palmitic acid (PA) content at the sn-2 position. Besides, OPL/OPO/LPL was conveniently prepared with suitable proportions for worldwide infants by adjusting the ratio of acyl donors. This paper provides a novel and effective two-step ethanolysis-esterification strategy for the development of human milk fat substitutes (HMFS). Title: Design and construction of Carboxylesterase 2c Gene knockout Rats by CRISPR/Cas9 Liu J, Shang X, Yao B, Zhang Y, Huang S, Guo Y, Wang X Ref: Curr Drug Metab, :, 2023 : PubMed ESTHER: Liu_2023_Curr.Drug.Metab__ PubMedSearch: Liu 2023 Curr.Drug.Metab PubMedID: 36694315 Gene_locus related to this paper: ratno-pbcxe Abstract BACKGROUND: Carboxylesterase 2 (CES2) is mainly distributed in the human liver and gut, and plays an active role in the metabolic activation of many prodrugs and lipid metabolism. Although CES2 is of great significance, there are still few animal models related to CES2. OBJECTIVES: This research aims to construct Ces2c gene knockout (KO) rats and further study the function of CES2. METHODS: CRISPR/Cas9 gene editing technology was used to target and cleave the rat Ces2c gene. Compensatory effects of major CES subtypes both in the liver and small intestine of KO rats were detected at mRNA levels. Meanwhile, diltiazem and aspirin were used as substrates to test the metabolic capacity of Ces2c in KO rats. RESULTS: This Ces2c KO rat model showed normal growth and breeding without off-target effects. The metabolic function of Ces2c KO rats was verified by the metabolic study of CES2 substrates in vitro. The results showed that the metabolic capacity of diltiazem in KO rats was weakened, while the metabolic ability of aspirin did not change significantly. In addition, the serum physiological indexes showed that the Ces2c deletion did not affect the liver function of rats. CONCLUSION: The Ces2c KO rat model was successfully constructed by CRISPR/Cas9 system. This rat model can not only be used as an important tool to study the drug metabolism mediated by Ces2, but also as an important animal model to study the physiological function of Ces2. Title: Rhynchophylline relieves nonalcoholic fatty liver disease by activating lipase and increasing energy metabolism Liu K, Liu S, Wu C, Wang Y, Zhang Y, Yu J, Li X, Qi X, Su S and Li Y <1 more author(s)> Liu K, Liu S, Wu C, Wang Y, Zhang Y, Yu J, Li X, Qi X, Su S, Zhou L, Li Y (- 1) Ref: Int Immunopharmacol, 117:109948, 2023 : PubMed ESTHER: Liu_2023_Int.Immunopharmacol_117_109948 PubMedSearch: Liu 2023 Int.Immunopharmacol 117 109948 PubMedID: 37012893 Abstract Hepatic fat metabolism may be altered in the context of overnutrition and obesity, often resulting in the accumulation of triglycerides in hepatocytes and leading to nonalcoholic fatty liver disease (NAFLD). Natural plant alkaloids have demonstrated great potential for the prevention and treatment of NAFLD. However, the role of rhynchophylline (RHY) in lipid metabolism is not clear. We explored the role of RHY in lipid metabolism in cells treated with oleic and palmitic acids to mimic high-fat diet (HFD) conditions. RHY attenuated oleic and palmitic acid-induced increases in triglyceride accumulation in HepG2, AML12, and LMH cells. RHY also increased energy metabolism and reduced oxidative stress. We further investigated the effect of RHY on hepatic lipid metabolism in mice fed an HFD including 40 mg/kg RHY. RHY alleviated hepatic steatosis, reduced fat deposition, promoted energy metabolism, and improved glucose metabolism. We investigated the mechanism responsible for this activity by docking with key proteins of lipid metabolism disorders using Discovery Studio software, which showed that RHY interacted well with lipases. Finally, we found that adding RHY promoted lipase activity and lipolysis. In conclusion, RHY ameliorated HFD-induced NAFLD and its complications by increasing lipase activity. Title: Development of biodegradable nanogels for lipase accelerated drug release of 5-aminolevulinic acid Liu X, Zhang Y, Zhang P, Ge K, Zhang R, Sun Y, Sheng Y, Bradley M Ref: Colloids Surf B Biointerfaces, 225:113268, 2023 : PubMed ESTHER: Liu_2023_Colloids.Surf.B.Biointerfaces_225_113268 PubMedSearch: Liu 2023 Colloids.Surf.B.Biointerfaces 225 113268 PubMedID: 36989818 Abstract Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is an important approach for the treatment of some skin diseases and cancers. A major defect of this approach is that it is difficult for 5-ALA to accumulate around lesions in deeper regions of tissue, resulting in poor conversion to the active fluorophore and photodynamic efficiencies. Because of their targeting and controlled release abilities, nanogel carriers could solve this problem. In this paper, nanogels were prepared by using micro-emulsion polymerization with various biodegradable polyester crosslinkers (L-lactide and sigma-caprolactone). The swelling and degradation properties and entrapment efficiency, drug loading and drug release ability of the nanogels were investigated. Nanogels co-cultured with skin cancer cells (A2058) allowed the efficiency of the PDT in vitro to be demonstrated. The results showed that the swelling rate of hydrogels reduced with increasing crosslinker levels, which caused a slow-down in the release of 5-ALA, but lipase accelerated degradation of nanogels increased 5-ALA concentrations in tumor cells and leading to higher PDT efficiency. It was proved by in vivo experiment indicating that the development of skin cancer tissues were efficiently inhibited by the 5-ALA loaded nanogels. Title: Salicylic acid attenuates brassinosteroid signaling via protein de-S-acylation Liu X, Chen Z, Huang L, Ouyang Y, Wang Z, Wu S, Ye W, Yu B, Zhang Y and Lai J <1 more author(s)> Liu X, Chen Z, Huang L, Ouyang Y, Wang Z, Wu S, Ye W, Yu B, Zhang Y, Yang C, Lai J (- 1) Ref: EMBO j, :e112998, 2023 : PubMed ESTHER: Liu_2023_EMBO.J__e112998 PubMedSearch: Liu 2023 EMBO.J e112998 PubMedID: 37211868 Gene_locus related to this paper: arath-AT5G20520 Abstract Brassinosteroids (BRs) are important plant hormones involved in many aspects of development. Here, we show that BRASSINOSTEROID SIGNALING KINASEs (BSKs), key components of the BR pathway, are precisely controlled via de-S-acylation mediated by the defense hormone salicylic acid (SA). Most Arabidopsis BSK members are substrates of S-acylation, a reversible protein lipidation that is essential for their membrane localization and physiological function. We establish that SA interferes with the plasma membrane localization and function of BSKs by decreasing their S-acylation levels, identifying ABAPT11 (ALPHA/BETA HYDROLASE DOMAIN-CONTAINING PROTEIN 17-LIKE ACYL PROTEIN THIOESTERASE 11) as an enzyme whose expression is quickly induced by SA. ABAPT11 de-S-acylates most BSK family members, thus integrating BR and SA signaling for the control of plant development. In summary, we show that BSK-mediated BR signaling is regulated by SA-induced protein de-S-acylation, which improves our understanding of the function of protein modifications in plant hormone cross talk. Title: The screening for marine fungal strains with high potential in alkaloids production by in situ colony assay and LC-MS/MS based secondary metabolic profiling Lu T, Liu Y, Zhou L, Liao Q, Nie Y, Wang X, Lei X, Hong P, Feng Y and Zhang Y <1 more author(s)> Lu T, Liu Y, Zhou L, Liao Q, Nie Y, Wang X, Lei X, Hong P, Feng Y, Hu X, Zhang Y (- 1) Ref: Front Microbiol, 14:1144328, 2023 : PubMed ESTHER: Lu_2023_Front.Microbiol_14_1144328 PubMedSearch: Lu 2023 Front.Microbiol 14 1144328 PubMedID: 37206330 Abstract BACKGROUND: Alkaloids are the second primary class of secondary metabolites (SMs) from marine organisms, most of which have antioxidant, antitumor, antibacterial, anti-inflammatory, and other activities. However, the SMs obtained by traditional isolation strategies have drawbacks such as highly reduplication and weak bioactivity. Therefore, it is significantly important to establish an efficient strategy for screening strains and mining novel compounds. METHODS: In this study, we utilized in situ colony assay combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify the strain with high potential in alkaloids production. The strain was identified by genetic marker genes and morphological analysis. The secondary metabolites from the strain were isolated by the combine use of vacuum liquid chromatography (VLC), ODS column chromatography, and Sephadex LH-20. Their structures were elucidated by 1D/2D NMR, HR-ESI-MS, and other spectroscopic technologies. Finally, these compounds bioactivity were assay, including anti-inflammatory and anti-beta aggregation. RESULTS: Eighteen marine fungi were preliminarily screened for alkaloids production by in situ colony assay using Dragendorff reagent as dye, and nine of them turned orange, which indicated abundant alkaloids. By thin-layer chromatography (TLC), LC-MS/MS, and multiple approaches assisted Feature-Based Molecular Networking (FBMN) analysis of fermentation extracts, a strain ACD-5 (Penicillium mallochii with GenBank accession number OM368350) from sea cucumber gut was selected for its diverse alkaloids profiles especially azaphilones. In bioassays, the crude extracts of ACD-5 in Czapek-dox broth and brown rice medium showed moderate antioxidant, acetylcholinesterase inhibitory, anti-neuroinflammatory, and anti-beta aggregation activities. Three chlorinated azaphilone alkaloids, compounds 1-3 (sclerotioramine, isochromophilone VI, and isochromophilone IX, respectively), were isolated from the fermentation products of ACD-5 in brown rice medium guided by bioactivities and mass spectrometry analysis. Compound 1 had shown remarkable anti-neuroinflammatory activity in liposaccharide induced BV-2 cells. CONCLUSION: In summary, in situ colony screening together with LC-MS/MS, multi-approach assisted FBMN can act as an efficient screening method for strains with potential in alkaloids production. Title: Strategy of In Situ Electrochemical Regulation for Highly Enhanced Nonenzymatic Sensing of Carbaryl Lv Y, Zhang Y, Yang Y, Li J, Wang J, Xiao X, Zhang M Ref: Analytical Chemistry, :, 2023 : PubMed ESTHER: Lv_2023_Anal.Chem__ PubMedSearch: Lv 2023 Anal.Chem PubMedID: 36802553 Abstract Specific and sensitive sensing of most pesticide residues relies on enzymes such as acetylcholinesterase and advanced materials, which need to be loaded on the surface of working electrodes, leading to instability, uneven surface, tedious process, and high cost. Meanwhile, employing certain potential or current in electrolyte solution could also modify the surface in situ and overcome these drawbacks. However, this method is only regarded as electrochemical activation widely applied in the pretreatment of electrodes. In this paper, by means of regulating the electrochemical technique and its parameters, we prepared a proper sensing interface and derivatized the carbaryl (a carbamate pesticide) hydrolyzed form (1-naphthol) to enhance sensing by 100 times within several minutes. After regulation I by chronopotentiometry with 0.2 mA for 20 s or chronoamperometry with 2 V for 10 s, abundant oxygen-containing groups form and the ordered carbon structure is destroyed. Sweeping from -0.5 to 0.9 V through cyclic voltammetry for only one segment, following regulation II, the composition of oxygen-containing groups changes and the disordered structure is alleviated. Finally, on the constructed sensing interface, test by regulation III through differential pulse voltammetry from 0.8 to -0.4 V, resulting in derivatization of 1-naphthol during 0.8-0 V, followed by electroreduction of the derivative at around -0.17 V. Compared with the electro-oxidation peak at 0.5 V in previous reports, it is essential to improve specificity, even toward several other carbamate pesticides with similar structures. Hence, the in situ electrochemical regulation strategy has demonstrated great potential for effective sensing of electroactive molecules. Title: Engineering a Bacillus subtilis esterase for selective hydrolysis of d, l-menthyl acetate in an organic solvent-free system Qiao J, Yang D, Feng Y, Wei W, Liu X, Zhang Y, Zheng J, Ying X Ref: RSC Adv, 13:10468, 2023 : PubMed ESTHER: Qiao_2023_RSC.Adv_13_10468 PubMedSearch: Qiao 2023 RSC.Adv 13 10468 PubMedID: 37021103 Gene_locus related to this paper: 9baci-a0a2m8sv47 Abstract Esterase/lipase-catalyzed selective hydrolysis of d, l-menthyl esters has become one of the promising approaches for producing l-menthol, one of the most important flavoring chemicals with extensive uses. However, the activity and l-enantioselectivity of the biocatalyst are not sufficient for meeting the industrial requirements. Herein, a highly active para-nitrobenzyl esterase from Bacillus subtilis 168 (pnbA-BS) was cloned and then engineered to enhance its l-enantioselectivity. On the basis of the strategy tailoring the steric exclusion effect and structural flexibility of the region adjacent to the substrate, the substitution of Ala400 to Pro caused a remarkable improvement in the E value from 1.0 to 466.6. The variant A400P was purified and further confirmed with strict l-enantioselectivity in the selective hydrolysis of d, l-menthyl acetate, whereas the improved l-enantioselectivity caused decreased activity. To develop an efficient, easy-to-use, and green methodology, organic solvent was omitted and substrate constant feeding was integrated into the whole-cell catalyzed system. During the catalytic process, the selective hydrolysis of 1.0 M d, l-menthyl acetate in 14 h offered a conversion of 48.9%, e.e.(p) value of >99%, and space-time yield of 160.52 g (l d)(-1). Title: Genome-wide association study of 17 serum biochemical indicators in a chicken F(2) resource population Song H, Li W, Li Y, Zhai B, Guo Y, Chen Y, Han R, Sun G, Jiang R and Kang X <6 more author(s)> Song H, Li W, Li Y, Zhai B, Guo Y, Chen Y, Han R, Sun G, Jiang R, Li Z, Yan F, Li G, Liu X, Zhang Y, Tian Y, Kang X (- 6) Ref: BMC Genomics, 24:98, 2023 : PubMed ESTHER: Song_2023_BMC.Genomics_24_98 PubMedSearch: Song 2023 BMC.Genomics 24 98 PubMedID: 36864386 Abstract BACKGROUND: Serum biochemical indicators are often regarded as direct reflections of animal metabolism and health. The molecular mechanisms underlying serum biochemical indicators metabolism of chicken (Gallus Gallus) have not been elucidated. Herein, we performed a genome-wide association study (GWAS) to identify the variation associated with serum biochemical indicators. The aim of this research was to broaden the understanding of the serum biochemical indicators in chickens. RESULTS: A GWAS of serum biochemical indicators was carried out on 734 samples from an F2 Gushix Anka chicken population. All chickens were genotyped by sequencing, 734 chickens and 321,314 variants were obtained after quality control. Based on these variants, a total of 236 single-nucleotide polymorphisms (SNPs) on 9 chicken chromosomes (GGAs) were identified to be significantly (-log(10)(P) > 5.72) associated with eight of seventeen serum biochemical indicators. Ten novel quantitative trait locis (QTLs) were identified for the 8 serum biochemical indicator traits of the F2 population. Literature mining revealed that the ALPL, BCHE, GGT2/GGT5 genes at loci GGA24, GGA9 and GGA15 might affect the alkaline phosphatase (AKP), cholinesterase (CHE) and gamma-glutamyl transpeptidase (GGT) traits, respectively. CONCLUSION: The findings of the present study may contribute to a better understanding of the molecular mechanisms of chicken serum biochemical indicator regulation and provide a theoretical basis for chicken breeding programs. Title: OsLDDT1, encoding a transmembrane structural DUF726 family protein, is essential for tapetum degradation and pollen formation in rice Sun Z, Liu K, Chen C, Chen D, Peng Z, Zhou R, Liu L, He D, Duan W and Sun L <7 more author(s)> Sun Z, Liu K, Chen C, Chen D, Peng Z, Zhou R, Liu L, He D, Duan W, Chen H, Huang C, Ruan Z, Zhang Y, Cao L, Zhan X, Cheng S, Sun L (- 7) Ref: Plant Sci, :111596, 2023 : PubMed ESTHER: Sun_2023_Plant.Sci__111596 PubMedSearch: Sun 2023 Plant.Sci 111596 PubMedID: 36657664 Gene_locus related to this paper: orysj-q10ss2 Abstract Formation of the pollen wall, which is mainly composed of lipid substances secreted by tapetal cells, is important to ensure pollen development in rice. Although several regulatory factors related to lipid biosynthesis during pollen wall formation have been identified in rice, the molecular mechanisms controlling lipid biosynthesis are unclear. We isolated the male-sterile rice mutant oslddt1 (leaked and delayed degraded tapetum 1). oslddt1 plants show complete pollen abortion resulting from delayed degradation of the tapetum and blocked formation of Ubisch bodies and pollen walls. OsLDDT1 (LOC_Os03g02170) encodes a DUF726 containing protein of unknown functionwith highly conserved transmembrane and alpha/beta Hydrolase domains. OsLDDT1 localizes to the endoplasmic reticulum and the gene is highly expressed in rice panicles. Genes involved in regulating fatty acid synthesis and formation of sporopollenin and pollen exine during anther developmentshowed significantly different expression patterns in oslddt1 plants. Interestingly, the wax and cutin contents in mature oslddt1-1 anthers were decreased by 74.07% and 72.22% compared to WT, indicating that OsLDDT1 is involved in fatty acid synthesis and affects formation of the anther epidermis. Our results provide as deeper understanding of the role of OsLDDT1 in regulating male sterility and also provide materials for hybrid rice breeding. Title: Strigolactone and gibberellin signalling coordinately regulates metabolic adaptations to changes in nitrogen availability in rice Sun H, Guo X, Zhu X, Gu P, Zhang W, Tao W, Wang D, Wu Y, Zhao Q and Zhang Y <2 more author(s)> Sun H, Guo X, Zhu X, Gu P, Zhang W, Tao W, Wang D, Wu Y, Zhao Q, Xu G, Fu X, Zhang Y (- 2) Ref: Mol Plant, :, 2023 : PubMed ESTHER: Sun_2023_Mol.Plant__ PubMedSearch: Sun 2023 Mol.Plant PubMedID: 36683328 Abstract Modern semi-dwarf rice varieties of the 'Green Revolution' require a high nitrogen (N) fertilizer supply to obtain a high yield. A better understanding of the interplay between N metabolic and developmental processes is required for improved N use efficiency (NUE) and agricultural sustainability. Here, we show that strigolactones (SLs) modulate root metabolic and developmental adaptations to low N availability, which ensure efficient uptake and translocation of available N. The key repressor DWARF 53 (D53) of the SL signalling interacts with the transcription factor GROWTH-REGULATING FACTOR 4 (GRF4) and prevents GRF4 from binding to its target gene promoters. N limitation induces the accumulation of SLs, which in turn promotes SL-mediated degradation of D53, leading to the release of GRF4 and thus promoting the genes expression associated with N metabolism. N limitation also induces degradation of the rice DELLA protein SLENDER RICE 1 (SLR1) in the D14- and D53-dependent manners, and that is effective for the release of GRF4 from the competitive inhibition caused by SLR1. Our findings reveal a previously unknown mechanism underlying SL and gibberellin crosstalk in response to N availability, which advances our understanding of plant growth-metabolic coordination that can be useful to improve NUE in high-yield crops. Title: Efficient Combination of Complex Chromatography, Molecular Docking and Enzyme Kinetics for Exploration of Acetylcholinesterase Inhibitors from Poria cocos Wu T, Hou W, Liu C, Li S, Zhang Y Ref: Molecules, 28:, 2023 : PubMed ESTHER: Wu_2023_Molecules_28_ PubMedSearch: Wu 2023 Molecules 28 PubMedID: 36770895 Abstract Poria cocos (P. cocos) is a traditional Chinese medicinal product with the same origin as medicine and food. It has diuretic, anti-inflammatory and liver protection properties, and has been widely used in a Chinese medicine in the treatment of Alzheimer's disease (AD). This study was conducted to explore the activity screening, isolation of acetylcholinesterase inhibitors (AChEIs), and in vitro inhibiting effect of P. cocos. The aim was to develop a new extraction process optimization method based on the Matlab genetic algorithm combined with a traditional orthogonal experiment. Moreover, bio-affinity ultrafiltration combined with molecular docking was used to screen and evaluate the activity of the AChEIs, which were subsequently isolated and purified using high-speed counter-current chromatography (HSCCC) and semi-preparative high-performance liquid chromatography (semi-preparative HPLC). The change in acetylcholinesterase (AChE) activity was tested using an enzymatic reaction kinetics experiment to reflect the inhibitory effect of active compounds on AChE and explore its mechanism of action. Five potential AChEIs were screened via bio-affinity ultrafiltration. Molecular docking results showed that they had good binding affinity for the active site of AChE. Meanwhile, the five active compounds had reversible inhibitory effects on AChE: Polyporenic acid C and Tumulosic acid were non-competitive inhibitors; 3-Epidehydrotumulosic acid was a mixed inhibitor; and Pachymic acid and Dehydrotrametenolic acid were competitive inhibitors. This study provided a basis for the comprehensive utilization of P. cocos and drug development for the treatment of AD. Title: Effects of Honeysuckle Varieties on Protective and Detoxifying Enzyme Activities in Heterolocha Jinyinhuaphaga Chu (Lepidoptera: Geometridae) Larvae Xiang Y, Niu H, Jin B, Zhang Y, Yin P Ref: J Chem Ecol, :, 2023 : PubMed ESTHER: Xiang_2023_J.Chem.Ecol__ PubMedSearch: Xiang 2023 J.Chem.Ecol PubMedID: 36862358 Abstract Investigating the effects of various host plants on protective and detoxifying enzyme activities in insects could provide insights into the adaptation mechanisms of insects to host plants. In the present study, we measured superoxide dismutase (SOD), peroxidase (POD), catalase(CAT), carboxylesterase(CarE), acetylcholinesterase (AchE), and glutathione S-transferase (GST) activity levels in Heterolocha jinyinhuaphaga Chu (Lepidoptera: Geometridae) larvae fed on four honeysuckle varieties (wild variety, Jiufeng 1, Xiangshui 1, and Xiangshui 2). The results showed that levels of SOD, POD, CAT, CarE, AchE, and GST activities in H. jinyinhuaphaga larvae fed on the four honeysuckle varieties differed. The enzyme activity levels were the highest when larvae were fed on the wild variety, followed by Jiufeng 1 and Xiangshui 2, and the lowest when fed on Xiangshui 1. Furthermore, the enzyme activity levels increased with an increase in larval age. According to the results of two - way analysis of variance, the interaction between host plants and larval age had no significant effect on SOD, POD, CAT, CarE, AchE, and GST activities in H. jinyinhuaphaga larvae (p >0.05). Title: Efficient Expression of Candida antarctica Lipase B in Pichia pastoris and Its Application in Biodiesel Production Xiao D, Li X, Zhang Y, Wang F Ref: Appl Biochem Biotechnol, :, 2023 : PubMed ESTHER: Xiao_2023_Appl.Biochem.Biotechnol__ PubMedSearch: Xiao 2023 Appl.Biochem.Biotechnol PubMedID: 36723721 Abstract Lipase B from Candida antarctica (CALB) is an important biocatalyst with many potential applications. However, original CALB is usually with lower enzyme activity and also costly to produce from Candida antarctica; hence, it is often necessary to prepare recombinant CALB through gene heterologous expression. In this research, seven promoters and five signal peptides were compared respectively for expressing codon-optimized CALB in Pichia pastoris, and then recombinant P. pastoris containing 3 copies of calb gene were obtained by screening with high concentrations of antibiotics under the condition of the optimal combination. In a 1.3-L bioreactor, the maximum CALB activity and total protein content reached 444.46 +/- 18.81 U/mL and 5.41 +/- 0.1 g/L, respectively, after about 9 days of incubation in FM22 medium, which were 34 times and 20 times higher than the initial strains, respectively. In addition, the obtained CALB was used to catalyze the transesterification of acidified gutter oil with methanol, suggesting a promising pathway to convert waste or low quality of bio-oil feedstocks with high amount of free fatty acids into biodiesel by using recombinant CALB as catalyst. The results can provide with a good reference for efficient expression of CALB and enhancing lipase production in P. pastoris. It is supposed to bring with new possibility for the bio-production of other valuable proteins. Title: Discovery of myrsinane-type Euphorbia diterpene derivatives through a skeleton conversion strategy from lathyrane diterpene for the treatment of Alzheimer's disease Xiao Y, Zhang Y, Ji WS, Jia XN, Shan LH, Li X, Liu YJ, Jiang T, Gao F Ref: Bioorg Chem, 138:106595, 2023 : PubMed ESTHER: Xiao_2023_Bioorg.Chem_138_106595 PubMedSearch: Xiao 2023 Bioorg.Chem 138 106595 PubMedID: 37178652 Abstract A series of novel myrsinane-type Euphorbia diterpene derivatives (1-37) were synthesized from the abundant natural lathyrane-type Euphorbia factor L(3), using a multi-step chemical process guided by a bioinspired skeleton conversion strategy, with the aim of discovering potential anti-Alzheimer's disease (AD) bioactive lead compounds. The synthesis process involved a concise reductive olefin coupling reaction through an intramolecular Michael addition with a free radical, followed by a visible-light-triggered regioselective cyclopropane ring-opening. The cholinesterase inhibitory and neuroprotective activities of the synthesized myrsinane derivatives were evaluated. Most of the compounds showed moderate to strong potency, highlighting the importance of ester groups in Euphorbia diterpene. In particular, derivative 37 displayed the most potent acetylcholinesterase (AChE) inhibition, with an IC(50) value of 8.3 microM, surpassing that of the positive control, tacrine. Additionally, 37 also showed excellent neuroprotective effect against H(2)O(2)-induced injury in SH-SY5Y cells, with a cell viability rate of 124.2% at 50 microM, which was significantly higher than that of the model group (viability rate 52.1%). Molecular docking, reactive oxygen species (ROS) analysis, immunofluorescence, and immunoblotting were performed to investigate the mechanism of action of myrsinane derivative 37. The results indicated that derivative 37 may be a promising myrsinane-type multi-functional lead compound for the treatment of Alzheimer's disease. Furthermore, a preliminary SAR analysis was performed to study the acetylcholinesterase inhibitory and neuroprotective activities of these diterpenes. Title: Computational Insights into the Allosteric Modulation of a Phthalate-Degrading Hydrolase by Distal Mutations Xu R, Bao Y, Li M, Zhang Y, Xi L, Guo J Ref: Biomolecules, 13:, 2023 : PubMed ESTHER: Xu_2023_Biomolecules_13_ PubMedSearch: Xu 2023 Biomolecules 13 PubMedID: 36979378 Abstract Phthalate esters (PAEs) are a ubiquitous kind of environmental endocrine that disrupt chemicals, causing environmental and health issues. EstJ6 is an effective phthalate-degrading hydrolase, and its mutant with a combination of three non-conservative distal mutations has an improved activity against PAEs with unknown molecular mechanisms. Herein, we attempt to fill the significant gap between distal mutations and the activity of this enzyme using computational approaches. We found that mutations resulted in a redistribution of the enzyme's preexisting conformational states and dynamic changes of key functional regions, especially the lid over the active site. The outward motion of the lid upon the mutations made it easier for substrates or products to enter or exit. Additionally, a stronger substrate binding affinity and conformational rearrangements of catalytic reaction-associated residues in the mutant, accompanied by the strengthened communication within the protein, could synergistically contribute to the elevated catalytic efficiency. Finally, an attempt was made to improve the thermostability of EstJ6 upon introducing a distal disulfide bond between residues A23 and A29, and the simulation results were as expected. Together, our work explored the allosteric effects caused by distal mutations, which could provide insights into the rational design of esterases for industrial applications in the future. Title: Rosmarinic acid potentiates and detoxifies tacrine in combination for Alzheimer's disease Yang M, Zhang X, Qiao O, Ji H, Zhang Y, Han X, Wang W, Li X, Wang J and Gao W <2 more author(s)> Yang M, Zhang X, Qiao O, Ji H, Zhang Y, Han X, Wang W, Li X, Wang J, Guo L, Huang L, Gao W (- 2) Ref: Phytomedicine, 109:154600, 2023 : PubMed ESTHER: Yang_2023_Phytomedicine_109_154600 PubMedSearch: Yang 2023 Phytomedicine 109 154600 PubMedID: 36610144 Abstract BACKGROUND: There is no doubt that Alzheimer's disease (AD) is one of the greatest threats facing mankind today. Within the next few decades, Acetylcholinesterase inhibitors (AChEIs) will be the most widely used treatment for Alzheimer's disease. The withdrawal of the first generation AChEIs drug Tacrine (TAC)/ Cognex from the market as a result of hepatotoxicity has always been an interesting case study. Rosmarinic acid (RA) is a natural compound of phenolic acids that has pharmacological activity for inhibiting Alzheimer's disease, as well as liver protection. PURPOSE AND STUDY DESIGN: In this study, we determined that RA can reduce the hepatotoxicity of TAC, and both of them act synergistically to inhibit the progression of AD in mice. METHODS: In addition to the wild type mice (WT) group, the 6-month-old APP/PS1 (APPswe/PSEN1dE9) double-transgenic (Tg) mice were randomly divided into 6 groups: Tg group, TAC group, RA group, TAC+Silymarin (SIL) group, TAC+RA-L (Rosmarinic Acid Low Dose) goup and TAC+RA-H (Rosmarinic Acid High Dose) group. A series of experiments were carried out, including open field test, Morris water maze test, Hematoxylin - Eosin (HE) staining, Nissl staining, biochemical analysis, immunofluorescence analysis, western blotting analysis and so on. RESULTS: RA combined with TAC could enter the brain tissue of AD mice, and the combination of drugs could better improve the cognitive behavior and brain pathological damage of AD mice, reduce the expression of A beta oligomer, inhibit the deposition of A beta, inhibit the activity of AChE and enhance the level of Ach in hippocampus. Both in vivo and in vitro experiments showed that RA could alleviate the hepatotoxicity or liver injury induced by TAC. The Western blot analysis of the liver of AD mice showed that RA combined with TAC might inhibit the apoptosis of Bcl-2/Bax, reduce the programmed apoptosis mediated by caspase-3 and reduce the burden of liver induced by TAC, could inhibit the development of liver apoptosis by alleviating the hepatotoxicity of TAC and inhibiting the phosphorylation of JNK. CONCLUSION: The potential drug combination that combines rosmarinic acid with tacrine could reduce tacrine's hepatotoxicity as well as enhance its therapeutic effect on Alzheimer's disease. Title: Discovery of seven-membered ring berberine analogues as highly potent and specific hCES2A inhibitors Yang Y, Xiong Y, Zhu G, Sun M, Zou K, Zhao Y, Zhang Y, Xu Z, Li Y and Ge G <3 more author(s)> Yang Y, Xiong Y, Zhu G, Sun M, Zou K, Zhao Y, Zhang Y, Xu Z, Li Y, Zhu W, Jia Q, Li B, Ge G (- 3) Ref: Chemico-Biological Interactions, 378:110501, 2023 : PubMed ESTHER: Yang_2023_Chem.Biol.Interact_378_110501 PubMedSearch: Yang 2023 Chem.Biol.Interact 378 110501 PubMedID: 37080375 Abstract Human carboxylesterase 2A (hCES2A) is a key serine hydrolase responsible for the metabolic clearance of large number of compounds bearing the ester- or amide-bond(s). Inhibition of hCES2A can relieve the chemotherapy-induced toxicity and alter the pharmacokinetic bahaviors of some orally administrate esters-containing agents. However, most of the hCES2A inhibitors show poor cell-membrane permeability and poor specificity. Herein, guided by the structure activity relationships (SAR) of fifteen natural alkaloids against hCES2A, fifteen new seven-membered ring berberine analogues were designed and synthesized, and their anti-hCES2A activities were evaluated. Among all tested compounds, compound 28 showed potent anti-hCES2A effect (IC(50) = 1.66 microM) and excellent selectivity over hCES1A (IC(50) > 100 microM). The SAR analysis revealed that the seven-membered ring of these berberine analogues was a crucial moiety for hCES2A inhibition, while the secondary amine group of the ring-C is important for improving their specificity over other serine hydrolases. Inhibition kinetic analyses and molecular dynamic simulation demonstrated that 28 strongly inhibited hCES2A in a mixed-inhibition manner, with an estimated K(i) value of 1.035 microM. Moreover, 28 could inhibit intracellular hCES2A in living HepG2 cells and exhibited suitable metabolic stability. Collectively, the SAR of seven-membered ring berberine analogues as hCES2A inhibitors were studied, while compound 28 acted as a promising candidate for developing highly selective hCES2A inhibitors. Title: The advantages of penehyclidine hydrochloride over atropine in acute organophosphorus pesticide poisoning: A meta-analysis Zeng S, Ma L, Yang L, Hu X, Wang C, Guo X, Li Y, Gou Y, Zhang Y and Luo Q <7 more author(s)> Zeng S, Ma L, Yang L, Hu X, Wang C, Guo X, Li Y, Gou Y, Zhang Y, Li S, Zhang S, Wu X, Li M, Lei J, Li B, Bi C, Luo Q (- 7) Ref: J Intensive Med, 3:171, 2023 : PubMed ESTHER: Zeng_2023_J.Intensive.Med_3_171 PubMedSearch: Zeng 2023 J.Intensive.Med 3 171 PubMedID: 37188113 Abstract BACKGROUND: Penehyclidine hydrochloride (PHC) has been used for many years as an anticholinergic drug for the treatment of acute organophosphorus pesticide poisoning (AOPP). The purpose of this meta-analysis was to explore whether PHC has advantages over atropine in the use of anticholinergic drugs in AOPP. METHODS: We searched Scopus, Embase, Cochrane, PubMed, ProQuest, Ovid, Web of Science, China Science and Technology Journal Database (VIP), Duxiu, Chinese Biomedical literature (CBM), WanFang, and Chinese National Knowledge Infrastructure (CNKI), from inception to March 2022. After all qualified randomized controlled trials (RCTs) were included, we conducted quality evaluation, data extraction, and statistical analysis. Statistics using risk ratios (RR), weighted mean difference (WMD), and standard mean difference (SMD). RESULTS: Our meta-analysis included 20,797 subjects from 240 studies across 242 different hospitals in China. Compared with the atropine group, the PHC group showed decreased mortality rate (RR=0.20, 95% confidence intervals [CI]: 0.16-0.25, P <0.001), hospitalization time (WMD=-3.89, 95% CI: -4.37 to -3.41, P <0.001), overall incidence rate of complications (RR=0.35, 95% CI: 0.28-0.43, P <0.001), overall incidence of adverse reactions (RR=0.19, 95% CI: 0.17-0.22, P <0.001), total symptom disappearance time (SMD=-2.13, 95% CI: -2.35 to -1.90, P <0.001), time for cholinesterase activity to return to normal value 50-60% (SMD=-1.87, 95% CI: -2.03 to -1.70, P <0.001), coma time (WMD=-5.57, 95% CI: -7.20 to -3.95, P <0.001), and mechanical ventilation time (WMD=-2.16, 95% CI: -2.79 to -1.53, P <0.001). CONCLUSION: PHC has several advantages over atropine as an anticholinergic drug in AOPP. Title: Chromone-based monoamine oxidase B inhibitor with potential iron-chelating activity for the treatment of Alzheimer's disease Zhang C, Zhang Y, Lv Y, Guo J, Gao B, Lu Y, Zang A, Zhu X, Zhou T, Xie Y Ref: J Enzyme Inhib Med Chem, 38:100, 2023 : PubMed ESTHER: Zhang_2023_J.Enzyme.Inhib.Med.Chem_38_100 PubMedSearch: Zhang 2023 J.Enzyme.Inhib.Med.Chem 38 100 PubMedID: 36519319 Abstract Based on the multitarget-directed ligands (MTDLs) strategy, a series of chromone-hydroxypyridinone hybrids were designed, synthesised, and evaluated as potential multimodal anti-AD ligands. Prospective iron-chelating effects and favourable monoamine oxidase B (MAO-B) inhibitory activities were observed for most of the compounds. Pharmacological assays led to the identification of compound 17d, which exhibited favourable iron-chelating potential (pFe(3+) = 18.52) and selective hMAO-B inhibitory activity (IC(50) = 67.02 +/- 4.3 nM, SI = 11). Docking simulation showed that 17d occupied both the substrate and the entrance cavity of MAO-B, and established several key interactions with the pocket residues. Moreover, 17d was determined to cross the blood-brain barrier (BBB), and can significantly ameliorate scopolamine-induced cognitive impairment in AD mice. Despite its undesired pharmacokinetic property, 17d remains a promising multifaceted agent that is worth further investigation. Title: Exogenous methyl jasmonate induced cassava defense response and enhanced resistance to Tetranychus urticae Zhang Y, Liu Y, Liang X, Wu C, Liu X, Wu M, Yao X, Qiao Y, Zhan X, Chen Q Ref: Exp Appl Acarol, :, 2023 : PubMed ESTHER: Zhang_2023_Exp.Appl.Acarol__ PubMedSearch: Zhang 2023 Exp.Appl.Acarol PubMedID: 36635606 Abstract Exogenous application of methyl jasmonate (MeJA) could activate plant defense response against the two-spotted spider mite (TSSM), Tetranychus urticae Koch,sin different plants. However, whether MeJA can also serve as an elicitor in cassava (Manihot esculenta Crantz) remains unknown. In this study, induced defense responses were investigated in TSSM-resistant cassava variety C1115 and TSSM-susceptible cassava variety KU50 when applied with MeJA. The performance of TSSM feeding on cassava plants that werespre-treated with various concentrations of MeJA was first evaluated. Subsequently, the activities of antioxidative enzymes (superoxide dismutase and catalase), detoxification enzymes (glutathione S-transferase, cytochrome P450 and carboxylesterase) and digestive enzymes (protease, amylase and invertase) in TSSM were analyzed at days 1, 2, 4 and 8 post-feeding. The results showed that MeJA treatment can induce cassava defense responses to TSSM in terms of reducing egg production and adult longevity as well as slowing development and prolonging thesegg stage. Noticeably, C1115 exhibited stronger inhibition of TSSM development and reproduction than KU50. In addition, the activities of all the tested enzymes were induced in both C1115 and KU50, the most in C1115. We conclude that exogenous methyl jasmonate can induce cassava defense responses and enhance resistance to TSSM. Title: Palladium-Catalyzed Synthesis, Acetylcholinesterase Inhibition, and Neuroprotective Activities of N-Aryl Galantamine Analogues Zhang Y, Xu JB, Xiao Y, Ji WS, Shan LH, Wan LX, Zhou XL, Lei Y, Gao F Ref: Journal of Natural Products, :, 2023 : PubMed ESTHER: Zhang_2023_J.Nat.Prod__ PubMedSearch: Zhang 2023 J.Nat.Prod PubMedID: 36808969 Abstract A series of new N-aryl galantamine analogues (5a-5x) were designed and synthesized by modification of galantamine, using Pd-catalyzed Buchwald-Hartwig cross-coupling reaction in good to excellent yields. The cholinesterase inhibitory and neuroprotective activities of N-aryl derivatives of galantamine were evaluated. Among the synthesized compounds, the 4-methoxylpyridine-galantamine derivative (5q) (IC(50) = 0.19 microM) exhibited excellent acetylcholinesterase inhibition activity, as well as significant neuroprotective effect against H(2)O(2)-induced injury in SH-SY5Y cells. Molecular docking, staining, and Western blotting analyses were performed to demonstrate the mechanism of action of 5q. Derivative 5q would be a promising multifunctional lead compound for the treatment of Alzheimer's disease. Title: Antennal transcriptomic analysis of carboxylesterases and glutathione S-transferases associated with odorant degradation in the tea gray geometrid, Ectropis grisescens (Lepidoptera, Geometridae) Zhang F, Chen Y, Zhao X, Guo S, Hong F, Zhi Y, Zhang L, Zhou Z, Zhang Y and Li X <1 more author(s)> Zhang F, Chen Y, Zhao X, Guo S, Hong F, Zhi Y, Zhang L, Zhou Z, Zhang Y, Zhou X, Li X (- 1) Ref: Front Physiol, 14:1183610, 2023 : PubMed ESTHER: Zhang_2023_Front.Physiol_14_1183610 PubMedSearch: Zhang 2023 Front.Physiol 14 1183610 PubMedID: 37082242 Abstract Introduction: Carboxylesterases (CXEs) and glutathione S-transferases (GSTs) can terminate olfactory signals during chemosensation by rapid degradation of odorants in the vicinity of receptors. The tea grey geometrid, Ectropis grisescens (Lepidoptera, Geometridae), one of the most devastating insect herbivores of tea plants in China, relies heavily on plant volatiles to locate the host plants as well as the oviposition sites. However, CXEs and GSTs involved in signal termination and odorant clearance in E. grisescens remains unknown. Methods: In this study, identification and spatial expression profiles of CXEs and GSTs in this major tea pest were investigated by transcriptomics and qRT-PCR, respectively. Results: As a result, we identified 28 CXEs and 16 GSTs from female and male antennal transcriptomes. Phylogenetic analyses clustered these candidates into several clades, among which antennal CXEs, mitochondrial and cytosolic CXEs, and delta group GSTs contained genes commonly associated with odorants degradation. Spatial expression profiles showed that most CXEs (26) were expressed in antennae. In comparison, putative GSTs exhibited a diverse expression pattern across different tissues, with one GST expressed specifically in the male antennae. Disscussion: These combined results suggest that 12 CXEs (EgriCXE1, 2, 4, 6, 8, 18, 20-22, 24, 26, and 29) and 5 GSTs (EgriGST1 and EgriGST delta group) provide a major source of candidate genes for odorants degradation in E. grisescens. Title: The roles of serine hydrolases and serum albumin in alisol B 23-acetate hydrolysis in humans Zhang T, Zhang F, Zhang Y, Li H, Zhu G, Weng T, Huang C, Wang P, He Y and Ge G <1 more author(s)> Zhang T, Zhang F, Zhang Y, Li H, Zhu G, Weng T, Huang C, Wang P, He Y, Hu J, Ge G (- 1) Ref: Front Pharmacol, 14:1160665, 2023 : PubMed ESTHER: Zhang_2023_Front.Pharmacol_14_1160665 PubMedSearch: Zhang 2023 Front.Pharmacol 14 1160665 PubMedID: 37089921 Abstract Introduction: Alisol B 23-acetate (AB23A), a major bioactive constituent in the Chinese herb Zexie (Rhizoma Alismatis), has been found with multiple pharmacological activities. AB23A can be readily hydrolyzed to alisol B in mammals, but the hydrolytic pathways of AB23A in humans and the key enzymes responsible for AB23A hydrolysis are still unrevealed. This study aims to reveal the metabolic organs and the crucial enzymes responsible for AB23A hydrolysis in human biological systems, as well as to decipher the impact of AB23A hydrolysis on its biological effects. Methods: The hydrolytic pathways of AB23A in human plasma and tissue preparations were carefully investigated by using Q-Exactive quadrupole-Orbitrap mass spectrometer and LC-UV, while the key enzymes responsible for AB23A hydrolysis were studied via performing a set of assays including reaction phenotyping assays, chemical inhibition assays, and enzyme kinetics analyses. Finally, the agonist effects of both AB23A and its hydrolytic metabolite(s) on FXR were tested at the cellular level. Results: AB23A could be readily hydrolyzed to form alisol B in human plasma, intestinal and hepatic preparations, while human butyrylcholinesterase (hBchE) and human carboxylesterases played key roles in AB23A hydrolysis in human plasma and tissue preparations, respectively. It was also found that human serum albumin (hSA) could catalyze AB23A hydrolysis, while multiple lysine residues of hSA were covalently modified by AB23A, suggesting that hSA catalyzed AB23A hydrolysis via its pseudo-esterase activity. Biological tests revealed that both AB23A and alisol B exhibited similar FXR agonist effects, indicating AB23A hydrolysis did not affect its FXR agonist effect. Discussion: This study deciphers the hydrolytic pathways of AB23A in human biological systems, which is very helpful for deep understanding of the metabolic rates of AB23A in humans, and useful for developing novel prodrugs of alisol B with desirable pharmacokinetic behaviors. Title: Characterization of Feruloyl Esterase from Klebsiella oxytoca Z28 and Its Application in the Release of Ferulic Acid from De-Starching Wheat Bran Zhang Y, Feng Z, Xiang H, Zhang X, Yang L Ref: Microorganisms, 11:989, 2023 : PubMed ESTHER: Zhang_2023_Microorganisms_11_989 PubMedSearch: Zhang 2023 Microorganisms 11 989 PubMedID: 37110412 Gene_locus related to this paper: kleox-KoFae Abstract Feruloyl esterase (EC3.1.1.73; FAE) can degrade biomass to release ferulic acid (FA), which has a high application in bioprocessing, food, pharmaceutical, paper, feed, and other industrial fields. A strain of Klebsiella oxytoca Z28 with ferulic esterase activity was screened from Daqu. In addition, the FAE gene was expressed in Escherichia coli BL21 (DE3). The enzyme consists of 340 amino acids with a molecular mass of 37.7 kDa. The FAE enzyme activity was 463 U/L when the substrate was ethyl 4-hydroxy-3-methoxycinnamate and the optimum temperature and pH were 50 degreesC and 8.0, respectively. The enzyme had good stability at temperatures of 25-40 degreesC and a pH of 8.0. Ba(2+), Cu(2+), Mn(2+), and Ca(2+) had a strong inhibitory effect on the enzyme activity, and Na(+) had a promotive effect on the enzyme activity. The de-starching wheat bran was degraded by KoFAE, and the FA release was up to 227.15 microg/g. This indicated that the heterologous expression of KoFAE from Klebsiella oxytoca Z28 in E. coli had a certain potential of biodegradation, which can be applied to the degradation of agricultural waste to obtain high value-added FA products. Title: Efficient decolorization of melanoidin in raw molasses wastewater by thermophilic esterase in actual extreme conditions Zhang Z, Hu W, Xie Q, Shi Y, Zhao Y, Deng Y, He J, Wu X, Zhang Y and Wang W <3 more author(s)> Zhang Z, Hu W, Xie Q, Shi Y, Zhao Y, Deng Y, He J, Wu X, Zhang Y, Zhang W, Liu P, Yang H, Wang W (- 3) Ref: Bioresour Technol, 382:129191, 2023 : PubMed ESTHER: Zhang_2023_Bioresour.Technol_382_129191 PubMedSearch: Zhang 2023 Bioresour.Technol 382 129191 PubMedID: 37196742 Abstract This work was developed to explore the versatility of thermophilic esterase for decolorizing raw molasses wastewater at high temperature and acidic pH. Combining covalent crosslinking method with deep eutectic solvent, a thermophilic esterase from Pyrobaculum calidifontis was immobilized on chitosan/macroporous resin composite carrier. The application of this immobilized thermophilic esterase eliminated 92.35% of colorants in raw molasses wastewater, achieving maximal decolorization efficiency across all the enzymes tested. Strikingly, this immobilized thermophilic esterase was capable of engaging in continuous activity for a 5-day period while removing 76.23% of pigments from samples. It effectively and continuously eliminated BOD(5) and COD, effectively and directly facilitating raw molasses wastewater decolorization under extreme conditions more readily than control group. In addition, this thermophilic esterase was believed to achieve decolorization through an addition reaction that disrupted conjugated system of melanoidins. Together, these results highlight an efficient and practical means of achieving enzyme-based molasses wastewater decolorization. Title: PRDX6: A protein bridging S-palmitoylation and diabetic neuropathy Cao Y, Wang W, Zhan X, Zhang Y Ref: Front Endocrinol (Lausanne), 13:992875, 2022 : PubMed ESTHER: Cao_2022_Front.Endocrinol.(Lausanne)_13_992875 PubMedSearch: Cao 2022 Front.Endocrinol.(Lausanne) 13 992875 PubMedID: 36120430 Abstract Diabetic neuropathy is regarded as one of the most debilitating outcomes of diabetes. It can affect both the peripheral and central nervous systems, leading to pain, decreased motility, cognitive decline, and dementia. S-palmitoylation is a reversible posttranslational lipid modification, and its dysregulation has been implicated in metabolic syndrome, cancers, neurological disorders, and infections. However, the role of S-palmitoylation in diabetic neuropathy remains unclear. Here we demonstrate a potential association between activating protein palmitoylation and diabetic neuropathy. We compared the proteomic data of lumbar dorsal root ganglia (DRG) of diabetes mice and palmitoylome profiling data of the HUVEC cell line. The mapping results identified peroxiredoxin-6 (PRDX6) as a novel target in diabetic neuropathy, whose biological mechanism was associated with S-palmitoylation. Bioinformatic prediction revealed that PRDX6 had two palmitoylation sites, Cys47 and Cys91. Immunofluorescence results indicated PRDX6 translocating between the cytoplasm and cell membrane. Protein function analysis proposed that increased palmitoylation could competitively inhibit the formation of disulfide-bond between Cys47 and Cys91 and change the spatial topology of PRDX6 protein. Cl(-)HCO3(-) anion exchanger 3 (AE3) was one of the AE family members, which was proved to express in DRG. AE3 activity evoked Cl(-) influx in neurons which was generally associated with increased excitability and susceptibility to pain. We demonstrated that the S-palmitoylation status of Cys47 could affect the interaction between PRDX6 and the C-terminal domain of AE3, thereby regulating the activity of AE3 anion exchanger enzyme in the nervous system. The results highlight a central role for PRDX6 palmitoylation in protection against diabetic neuropathy. Title: Effect of dipeptidyl peptidase-4 inhibitors on postprandial glucagon level in patients with type 2 diabetes mellitus: A systemic review and meta-analysis Chai S, Zhang R, Zhang Y, Carr RD, Zheng Y, Rajpathak S, Ji L Ref: Front Endocrinol (Lausanne), 13:994944, 2022 : PubMed ESTHER: Chai_2022_Front.Endocrinol.(Lausanne)_13_994944 PubMedSearch: Chai 2022 Front.Endocrinol.(Lausanne) 13 994944 PubMedID: 36313782 Abstract AIMS: Hyperglucagonemia occurs in the pathogenesis of type 2 diabetes mellitus (T2DM). In this meta-analysis, we summarized the effects of DPP4 inhibitors on glucagon levels in patients with T2DM. MATERIALS AND METHODS: Randomized controlled trials (RCTs) comparing the influence of DPP4 inhibitors on circulating glucagon levels with placebo or other oral antidiabetic drugs (OADs) in patients with T2DM were identified by searches of Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library). Only studies reporting changes in glucagon level presented as total area under the curve (AUC(glucagon)) using a meal or oral glucose tolerance test were included. Results were combined using a random-effects model that incorporated potential heterogeneity among the included studies. RESULTS: A total of 36 RCTs with moderate to high quality were included. Overall, the numbers of T2DM patients included for the meta-analyses comparing DPP4 inhibitors with placebo and other OADs were 4266 and 1652, respectively. Compared to placebo, DPP4 inhibitors significantly reduced circulating glucagon levels (standard mean difference [SMD]: -0.32, 95% CI: -0.40 to -0.24, P<0.001; I(2 =) 28%). Analysis of subgroups revealed that study characteristics had no significant effect on results, such as study design (parallel group or crossover), number of patients, mean patient age, proportion of men, baseline HbA1c, duration of diabetes, background therapy, treatment duration, or methods for glucagon measurement (all P for subgroup differences >0.05). Moreover, DPP4 inhibitors significantly reduced glucagon levels compared to other OADs (SMD: -0.35, 95% CI: -0.53 to -0.16, P<0.001; I(2) = 66%), and the reduction in glucagon was greater in comparison with insulin secretagogues than in comparison with non-insulin secretagogues (P for subgroup difference =0.03). SYSTEMATIC REVIEW REGISTRATION: https://inplasy.com/, identifier INPLASY202280104. CONCLUSIONS: DPP4 inhibitors are effective at reducing the circulating postprandial glucagon level in T2DM patients. Title: Anti-human Glioma Cancer Potentials of Neobavaisoflavone as Natural Antioxidant Compound and Its Inhibition Profiles for Acetylcholinesterase and Butyrylcholinesterase Enzymes with Molecular Modeling and Spin Density Distributions Studies Chen M, Zhao H, Cheng Y, Wang L, Alotaibi SH, Zhang Y Ref: J Oleo Sci, 71:277, 2022 : PubMed ESTHER: Chen_2022_J.Oleo.Sci_71_277 PubMedSearch: Chen 2022 J.Oleo.Sci 71 277 PubMedID: 35110469 Abstract In this study, the carcinogenic potential of Neobavaisoflavone as a natural antioxidant compound and the inhibitory profiles of acetylcholinesterase and butyrylcholinesterase were investigated by molecular modeling and spin density distribution studies. To evaluate the antioxidant properties of neobavaisoflavone, DPPH test was performed in the presence of butyl hydroxytoluene as a control. Neobavaisoflavone cell viability was low compared to normal human glioma cancer cell lines, namely LN-229, U-87 and A-172 cell lines, without any effect of cytotoxicity on normal cell line. Neobavaisoflavone inhibited half of DPPH at 125 microg/mL. The best effects of Neobavaisoflavone antihypertensive glioma against the above cell lines were in the LN-229 cell line. In addition, the significant anti-cancer potential of human glioma Neobavaisoflavone against the popular human glioma cancer cell lines is related in this study. IC(50) values were calculated by Neobavaisoflavone diagrams, 63.87 nM for AChE and 112.98 nM for BuChE, % Activity- [Inhibitor]. According to the above results, Neobavaisoflavone can be used to treat a variety of human glioma cancers in humans. In addition, molecular modeling calculations were performed to compare the biochemical activities of the Neobavaisoflavone molecule with enzymes. After molecular insertion calculations, ADME/T analysis was performed to investigate the properties of the neobavaisoflavone molecule, which will be used as a drug in the future. Then, different parameters for the antioxidant activity of the neobavaisoflavone molecule were calculated. Title: A new benzaldehyde from the coral-derived fungus Aspergillus terreus C23-3 and its anti-inflammatory effects via suppression of MAPK signaling pathway in RAW264.7 cells Chen M, Liang J, Wang Y, Liu Y, Zhou C, Hong P, Zhang Y, Qian ZJ Ref: J Zhejiang Univ Sci B, 23:230, 2022 : PubMed ESTHER: Chen_2022_J.Zhejiang.Univ.Sci.B_23_230 PubMedSearch: Chen 2022 J.Zhejiang.Univ.Sci.B 23 230 PubMedID: 35261218 Abstract Marine fungi are important members of the marine microbiome, which have been paid growing attention by scientists in recent years. The secondary metabolites of marine fungi have been reported to contain rich and diverse compounds with novel structures (Chen et al., 2019). Aspergillus terreus, the higher level marine fungus of the Aspergillus genus (family of Trichocomaceae, order of Eurotiales, class of Eurotiomycetes, phylum of Ascomycota), is widely distributed in both sea and land. In our previous study, the coral-derived A. terreus strain C23-3 exhibited potential in producing other biologically active (with antioxidant, acetylcholinesterase inhibition, and anti-inflammatory activity) compounds like arylbutyrolactones, territrems, and isoflavones, and high sensitivity to the chemical regulation of secondary metabolism (Yang et al., 2019, 2020; Nie et al., 2020; Ma et al., 2021). Moreover, we have isolated two different benzaldehydes, including a benzaldehyde with a novel structure, from A. terreus C23-3 which was derived from Pectinia paeonia of Xuwen, Zhanjiang City, Guangdong Province, China. Title: Carnosic acid ameliorated Abeta-mediated (amyloid-beta peptide) toxicity, cholinergic dysfunction and mitochondrial defect in Caenorhabditis elegans of Alzheimer's Model Chen Y, Wang Y, Qin Q, Zhang Y, Xie L, Xiao J, Cao Y, Su Z Ref: Food Funct, :, 2022 : PubMed ESTHER: Chen_2022_Food.Funct__ PubMedSearch: Chen 2022 Food.Funct PubMedID: 35357374 Abstract Amyloid-beta peptide (Abeta)-induced cholinergic system and mitochondrial dysfunction are major risk factors for Alzheimer's disease (AD). Our previous studies found that carnosic acid (CA), an important polyphenol antioxidant, could significantly delay Abeta(1-42)-mediated acute paralysis. However, many details and underlying mechanisms of CA's neuroprotection against Abeta-induced cholinergic system defects and mitochondrial dysfunction remain unclear. Herein, we deeply investigated the effects and the possible mechanisms of CA-mediated protection against Abeta toxicity in vivo through several AD Caenorhabditis elegans strains. The results showed CA delayed age-related paralysis and Abeta deposition, and significantly protected neurons from Abeta-induced toxicity. CA might downgrade the expression of ace-1 and ace-2 genes, and upregulate cha-1 and unc-17 genes to inhibit acetylcholinesterase activity and relieve Abeta-caused cholinergic system defects. Furthermore, CA might also ameliorate Abeta-induced mitochondrial imbalance and oxidative stress through up-regulating the expression of phb-1, phb-2, eat-3, and drp-1 genes. The enhancements of the cholinergic system and mitochondrial function might be the reasons for the amelioration of Abeta-mediated toxicity and Abeta aggregation mediated by CA. These findings have helped us to understand the CA anti-Abeta activity in C. elegans and the potential mechanism of action. Title: A novel monoacylglycerol lipase-targeted (18)F-labeled probe for positron emission tomography imaging of brown adipose tissue in the energy network Cheng R, Fujinaga M, Yang J, Rong J, Haider A, Ogasawara D, Van RS, Shao T, Chen Z and Liang SH <14 more author(s)> Cheng R, Fujinaga M, Yang J, Rong J, Haider A, Ogasawara D, Van RS, Shao T, Chen Z, Zhang X, Calderon Leon ER, Zhang Y, Mori W, Kumata K, Yamasaki T, Xie L, Sun S, Wang L, Ran C, Shao Y, Cravatt B, Josephson L, Zhang MR, Liang SH (- 14) Ref: Acta Pharmacol Sin, :, 2022 : PubMed ESTHER: Cheng_2022_Acta.Pharmacol.Sin__ PubMedSearch: Cheng 2022 Acta.Pharmacol.Sin PubMedID: 35513432 Gene_locus related to this paper: human-MGLL Inhibitor(s) related to this paper: FEPAD Abstract Monoacylglycerol lipase (MAGL) constitutes a serine hydrolase that orchestrates endocannabinoid homeostasis and exerts its function by catalyzing the degradation of 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA). As such, selective inhibition of MAGL represents a potential therapeutic and diagnostic approach to various pathologies including neurodegenerative disorders, metabolic diseases and cancers. Based on a unique 4-piperidinyl azetidine diamide scaffold, we developed a reversible and peripheral-specific radiofluorinated MAGL PET ligand [(18)F]FEPAD. Pharmacokinetics and binding studies on [(18)F]FEPAD revealed its outstanding specificity and selectivity towards MAGL in brown adipose tissue (BAT) - a tissue that is known to be metabolically active. We employed [(18)F]FEPAD in PET studies to assess the abundancy of MAGL in BAT deposits of mice and found a remarkable degree of specific tracer binding in the BAT, which was confirmed by post-mortem tissue analysis. Given the negative regulation of endocannabinoids on the metabolic BAT activity, our study supports the concept that dysregulation of MAGL is likely linked to metabolic disorders. Further, we now provide a suitable imaging tool that allows non-invasive assessment of MAGL in BAT deposits, thereby paving the way for detailed mechanistic studies on the role of BAT in endocannabinoid system (ECS)-related pathologies. Title: Plin5, a New Target in Diabetic Cardiomyopathy Cui X, Wang J, Zhang Y, Wei J, Wang Y Ref: Oxid Med Cell Longev, 2022:2122856, 2022 : PubMed ESTHER: Cui_2022_Oxid.Med.Cell.Longev_2022_2122856 PubMedSearch: Cui 2022 Oxid.Med.Cell.Longev 2022 2122856 PubMedID: 35509833 Abstract Abnormal lipid accumulation is commonly observed in diabetic cardiomyopathy (DC), which can create a lipotoxic microenvironment and damage cardiomyocytes. Lipid toxicity is an important pathogenic factor due to abnormal lipid accumulation in DC. As a lipid droplet (LD) decomposition barrier, Plin5 can protect LDs from lipase decomposition and regulate lipid metabolism, which is involved in the occurrence and development of cardiovascular diseases. In recent years, studies have shown that Plin5 expression is involved in the pathogenesis of DC lipid toxicity, such as oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and insulin resistance (IR) and has become a key target of DC research. Therefore, understanding the relationship between Plin5 and DC progression as well as the mechanism of this process is crucial for developing new therapeutic approaches and exploring new therapeutic targets. This review is aimed at exploring the latest findings and roles of Plin5 in lipid metabolism and DC-related pathogenesis, to explore possible clinical intervention approaches. Title: Butenolide derivatives from Aspergillus terreus selectively inhibit butyrylcholinesterase Cui X, Deng S, Li G, Zhang Y, Wang L, Wu C, Deng Y Ref: Front Chem, 10:1063284, 2022 : PubMed ESTHER: Cui_2022_Front.Chem_10_1063284 PubMedSearch: Cui 2022 Front.Chem 10 1063284 PubMedID: 36618870 Abstract Two undescribed butenolide derivatives, asperteretal J (1) and K (2), together with 13 known ones (3-15) were isolated from an endophytic fungus Aspergillus terreus SGP-1, the fermentation product of which exhibited selective inhibitory activity toward butyrylcholinesterase. The structures of the new compounds were elucidated based on HRMS and NMR data, and the absolute configurations were determined by specific optical rotation comparison. All compounds were evaluated for cholinesterase inhibitory effects with galantamine as a positive control. Compounds 4-8 selectively inhibited butyrylcholinesterase with IC(50) values of 18.4-45.8smicroM in a competitive manner, with Ki values of 12.3-38.2smicroM. The structure-activity relationship was discussed. Molecular docking and dynamic simulation of the inhibitor-enzyme complex were performed to better understand the interactions. Title: Toxin diversity revealed by de novo transcriptome assembly for venom gland in two species of spiders (Trichonephila clavata and Sinopoda pengi) Ding LJ, Wu XM, Zhang CG, Gao PF, Zhang Y, Yang ZZ, Zhao Y Ref: Comparative Biochemistry & Physiology Part D Genomics Proteomics, 42:100984, 2022 : PubMed ESTHER: Ding_2022_Comp.Biochem.Physiol.Part.D.Genomics.Proteomics_42_100984 PubMedSearch: Ding 2022 Comp.Biochem.Physiol.Part.D.Genomics.Proteomics 42 100984 PubMedID: 35462116 Abstract During long-term predator-prey coevolution, spiders have generated a vast diversity of toxins. Trichonephila clavata is a web-spinning spider whose large, well-constructed webs and venomous arsenal facilitate prey capture. In contrast, Sinopoda pengi is an ambush predator with agile locomotion and strong chelicerae for hunting. In this study, transcriptomic analysis was performed to describe the predicted toxins of S. pengi and T. clavata. A total of 43 and 47 of these unigenes from S. pengi and T. clavata, respectively, were predicted to have toxin activity. Putative neurotoxins were classified to the family level according to cysteine arrangement; 4 and 6 toxin families were produced by S. pengi and T. clavata, respectively. In addition, potential metalloproteases, acetylcholinesterases, serine proteases, hyaluronidases and phospholipases were found by annotation in databases. In summary, molecular templates with potential application value for medical and biological fields were obtained by classifying and characterizing presumed venom components, which established a foundation for further study of venom. Title: Cirrhosinones A-H, 24-hydroxy cevanine-type alkaloids from Fritillariacirrhosa Dong H, Zhang Y, Wai Ming T, Wang S, Li J, Fu S, Zhang Q, Zeng K, Tu P, Liang H Ref: Phytochemistry, 197:113129, 2022 : PubMed ESTHER: Dong_2022_Phytochemistry_197_113129 PubMedSearch: Dong 2022 Phytochemistry 197 113129 PubMedID: 35176308 Abstract Eight undescribed isosteroidal alkaloids cirrhosinones A-H (1-8), along with six known isosteroidal alkaloids (9-14), were isolated from the bulbs of Fritillaria cirrhosa D. Don. Their structures were determined by HRESIMS and 2D NMR analysis, and their absolute configurations were established by X-ray analysis. Compounds 1-8 possessed a typical cevanine-type alkaloid skeleton with a hydroxyl group rarely substituted at C-24 and compounds 4-8 possessed rare 7alpha or 7beta-hydroxyl groups. This was the first report of both C-7 and C-24 hydroxyl groups substituted cevanine-type alkaloids. In addition, an approach for distinguishing D/E cis and trans conformations of cevanine-type alkaloids by (1)H NMR data was developed. Moreover, the correlations between the relative configurations of 3-OH, 7-OH, 22-C, 24-OH, and 25-Me and the (1)H NMR and (13)C NMR data were also summarized. Compounds 1-9 exhibited moderate NO inhibitory activities in LPS-stimulated BV-2 cells at the concentration of 40 microM. The acetylcholinesterase inhibitory activities of compounds 1-7 and 9-10 were also evaluated and none of them showed acetylcholinesterase inhibitory activities at the concentrations of 20-80 microM. Title: CRISPR-Cas12a based fluorescence assay for organophosphorus pesticides in agricultural products Fu R, Wang Y, Liu Y, Liu H, Zhao Q, Zhang Y, Wang C, Li Z, Jiao B, He Y Ref: Food Chem, 387:132919, 2022 : PubMed ESTHER: Fu_2022_Food.Chem_387_132919 PubMedSearch: Fu 2022 Food.Chem 387 132919 PubMedID: 35421656 Abstract Herein, we propose a sensitive fluorescent assay for organophosphorus pesticides (OPs) detection based on a novel strategy of activating the CRISPR-Cas12a system. Specifically, acetylcholinesterase (AChE) hydrolyzes acetylthiocholine into thiocholine (TCh). Subsequently, TCh induces the degradation of MnO(2) nanosheets and generates sufficient Mn(2+) ions to activate the Mn(2+)-dependent DNAzyme. Then, as the catalytic product of activated DNAzyme, the short DNA strand activates the CRISPR-Cas12a system to cleave the fluorophore-quencher-labeled DNA reporter (FQ) probe effectively; thus, increasing the fluorescence intensity (FI) in the solution. However, in the presence of OPs, the activity of AChE is suppressed, resulting in a decrease in FI. Under optimized conditions, the limits of detection for paraoxon, dichlorvos, and demeton were 270, 406, and 218 pg/mL, respectively. Benefiting from the outstanding MnO(2) nanosheets properties and three rounds of enzymatic signal amplification, the proposed fluorescence assay holds great potential for the detection of OPs in agricultural products. Title: Soluble epoxide hydrolase inhibitor, t-AUCB, improves salivary gland function by ameliorating endothelial injury Han WW, Wang XR, He YF, Zhang HS, Cong X, Xiang RL, Wu LL, Yu GY, Liu LM, Zhang Y Ref: Life Sciences, 308:120942, 2022 : PubMed ESTHER: Han_2022_Life.Sci_308_120942 PubMedSearch: Han 2022 Life.Sci 308 120942 PubMedID: 36096247 Abstract AIMS: Inhibitor of soluble epoxide hydrolase (t-AUCB) has been used in the experimental therapy of hypertension. This study aimed to investigate whether the secretion of submandibular glands (SMGs) altered in renal hypertensive rats, and to explore whether t-AUCB could improve the salivary secretion. MAIN METHODS: 2-kidney 1-clip Sprague-Dawley rats were used as renal hypertensive animals. t-AUCB treatment was given for 1 week after 8 weeks modeling. Blood pressure, blood perfusion and the secretion of SMGs, and endothelium-dependent relaxation of external maxillary artery were measured to investigate the effects of t-AUCB on the vascular tone and the secretion of SMGs in renal hypertensive rats. SMGs were collected for histological evaluation and the internal arteries were dissected for primary endothelial cells culture. KEY FINDINGS: The blood perfusion and flow rate of SMGs in the renal hypertensive rats were significantly lower than those in the controls. Endothelium-dependent relaxation of the external maxillary artery and AMPK/Akt/eNOS signaling was impaired in hypertensive rats. The glandular morphology and the concentration of salivary ions did not change obviously. t-AUCB treatment ameliorated the secretion of SMGs, the blood perfusion, and the dysfunction of endothelium-dependent relaxation of the external maxillary artery by activating the AMPK/Akt/eNOS pathway in hypertensive rats. SIGNIFICANCE: t-AUCB increases the blood perfusion through ameliorating dysfunction of endothelium-dependent relaxation of SMGs arteries and thus improves the hyposecretion of SMGs in hypertensive rats. Title: Comprehensive Enantioselectivity Evaluation of Insecticidal Activity and Mammalian Toxicity of Fenobucarb He Z, Li C, Xia W, Wang Z, Li R, Zhang Y, Wang M Ref: Journal of Agricultural and Food Chemistry, :, 2022 : PubMed ESTHER: He_2022_J.Agric.Food.Chem__ PubMedSearch: He 2022 J.Agric.Food.Chem PubMedID: 35451821 Abstract To comprehensively evaluate the efficiency and risk of the chiral pesticide fenobucarb, the bioactivity, toxicity, and environmental behavior of fenobucarb (FNC) enantiomers were investigated. The results showed that R-FNC possesses 1.8-2.7 times more bioactivity than S-FNC but 1.3-3.0 times lower toxicity than S-FNC against four nontarget organisms: Chlorella pyrenoidosa, HepG2, and Danio rerio and its embryos. The corresponding enzyme inhibitory activity showed consistent results; the acetylcholinesterase inhibitory activity of target organisms was ordered as R-FNC > rac-FNC > S-FNC, while the reduction in catalase activity after exposure to R-FNC was 2.5 times that after exposure to S-FNC in zebrafish. The enantioselective bioactivity mechanism of FNC enantiomers was further explored in silico. No significant enantioselective degradation was found in soils or rat liver microsomes. In sum, R-FNC possesses higher insecticidal activity and lower toxicity. The development of R-FNC as a commercial agrochemical is beneficial for reducing pesticide inputs. Title: An efficient strategy based on two-stage chromatography and in vitro evaluation for rapid screening and isolation of acetylcholinesterase inhibitors from Scutellaria baicalensis Georgi Hou W, Liu C, Li S, Zhang Y, Jin Y, Li X, Liu Z, Niu H, Xia J Ref: J Sep Sci, :, 2022 : PubMed ESTHER: Hou_2022_J.Sep.Sci__ PubMedSearch: Hou 2022 J.Sep.Sci PubMedID: 34990521 Abstract The extraction of Scutellaria baicalensis Georgi was investigated using the response surface methodology-genetic algorithm mathematical regression model, and the extraction variables were optimized to maximize the flavonoid yield. Furthermore, a simple and efficient ultrafiltration-liquid chromatography-mass spectrometry and molecular docking methods was developed for the rapid screening and identification of acetylcholinesterase inhibitors present in Scutellaria baicalensis Georgi. Subsequently, four major chemical constituents, namely baicalein, norwogonin, wogonin, and oroxylin A, were identified as potent acetylcholinesterase inhibitors. This novel approach, involving the use of ultrafiltration-liquid chromatography-mass spectrometry and molecular docking methods combined with stepwise flow rate counter-current chromatography and semi-preparative high-performance liquid chromatography, could potentially provide a powerful tool for the screening and extraction of acetylcholinesterase inhibitors from complex matrices and be a useful platform for the production of bioactive and nutraceutical ingredients. This article is protected by copyright. All rights reserved. Title: Development and Validation of a Non-invasive Model to Predict Liver Histological Lesions in Chronic Hepatitis B Patients With Persistently Normal Alanine Aminotransferase and Detectable Viremia Hu Q, Wang Q, Xu W, Huang C, Tao S, Qi X, Zhang Y, Li X, Jiang X and Huang Y <3 more author(s)> Hu Q, Wang Q, Xu W, Huang C, Tao S, Qi X, Zhang Y, Li X, Jiang X, Song J, Li Q, Chen L, Huang Y (- 3) Ref: Front Med (Lausanne), 9:944547, 2022 : PubMed ESTHER: Hu_2022_Front.Med.(Lausanne)_9_944547 PubMedSearch: Hu 2022 Front.Med.(Lausanne) 9 944547 PubMedID: 35911415 Abstract BACKGROUND: A critical and controversial issue is whether antiviral therapy should be recommended in chronic hepatitis B virus (HBV) infection patients with persistently normal alanine aminotransferase (PNALT) and detectable HBV DNA. The study aimed to develop a non-invasive model for predicting significant liver histological changes (SLHC), which is the histological indication for antiviral therapy in chronic hepatitis B (CHB) patients with PNALT and detectable HBV DNA. METHODS: 398 chronic HBV infection patients with PNALT and detectable HBV DNA who underwent liver biopsy were divided into the estimation set (n = 256) and validation set (n = 142). A multivariate logistic regression model was developed to predict SLHC in the estimation set, and the diagnostic performance was further validated in the validation set. RESULTS: 132 patients (33.2%) with PNALT and detectable HBV DNA had SLHC. Aspartate aminotransferase (AST), cholinesterase (ChE), and liver stiffness measurement (LSM) were identified as the independent predictors of SLHC. The AUROC of the SLHC index, which combined AST, ChE, and LSM, was 0.824 and 0.816 in the estimation and validation set, respectively, for the prediction of SLHC. Applying the SLHC index >= 0.15, the presence of SLHC could be excluded with high negative predictive value in the estimation set (93.2%) and in the validation set (90.2%). Applying the SLHC index <= 0.55, the presence of SLHC could be considered with high positive predictive value in the estimation set (79.2%) and in the validation set (76.5%). CONCLUSION: The SLHC index provides a high accuracy in predicting liver histological indication for antiviral therapy in CHB patients with PNALT and detectable HBV DNA. Title: Structure-guided preparation of functional oil rich in 1,3-diacylglycerols and linoleic acid from Camellia oil by combi-lipase Huang C, Lin Z, Zhang Y, Liu Z, Tang X, Li C, Lin L, Huang W, Ye Y Ref: J Sci Food Agric, :, 2022 : PubMed ESTHER: Huang_2022_J.Sci.Food.Agric__ PubMedSearch: Huang 2022 J.Sci.Food.Agric PubMedID: 35810339 Abstract BACKGROUND: The diacylglycerols (DAG) enriched oil has been attracting attention on nutritional benefits and biological functions, but its various free fatty acids (FFA) composition and unclear relationship between substrate and yield make it difficult to be identified and qualified to produce. In this research, the linoleic acid-enriched diacylglycerols (LA-DAG) was synthesized and enriched from Camellia oil by the esterification process using the combi-lipase Lipozyme TL IM/RM IM systems. RESULTS: The relationship between the FFA compositions and the DAG species productivity was revealed. Results showed that heterogeneous FFA with a major constituent (more than 50%) exhibited higher DAG productivity and inhibited TAG productivity than homogeneous constituents. The joint characterization by HPLC-ELSD, GC-MS and UPLC-HESI-MS/MS identified that DAG components contained dilinoleic acid acyl glyceride, linoleyl-oleyl glyceride, and dioleic acid acyl glyceride in esterification products. Under the optimum conditions, 60.4% 1,3-DAG and 61.3% LA-DAG in the crude product at 1 h reaction were obtained, and further purified to 81.7% LA-DAG and 94.7% DAG by the silica column chromatography. CONCLUSION: This research provides a guideline for identification of DAG species, and a structure-guided preparing method of the DAG enriched oils by the cost-effective combi-lipase. This article is protected by copyright. All rights reserved. Title: Narciclasine inhibits phospholipase A2 and regulates phospholipid metabolism to ameliorate psoriasis-like dermatitis Kong Y, Jiang J, Huang Y, Liu X, Jin Z, Li L, Wei F, Yin J, Zhang Y and Chen H <1 more author(s)> Kong Y, Jiang J, Huang Y, Liu X, Jin Z, Li L, Wei F, Yin J, Zhang Y, Tong Q, Chen H (- 1) Ref: Front Immunol, 13:1094375, 2022 : PubMed ESTHER: Kong_2022_Front.Immunol_13_1094375 PubMedSearch: Kong 2022 Front.Immunol 13 1094375 PubMedID: 36700214 Abstract INTRODUCTION: Psoriasis is a common inflammatory skin disease recognized by the World Health Organization as "an incurable chronic, noninfectious, painful, disfiguring and disabling disease." The fact that metabolic syndrome (MetS) is the most common and important comorbidities of psoriasis suggests an important role of lipid metabolism in the pathogenesis of psoriasis. Narciclasine (Ncs) is an alkaloid isolated from the Amaryllidaceae plants. Its biological activities include antitumor, antibacterial, antiinflammatory, anti-angiogenic and promoting energy expenditure to improve dietinduced obesity. Here, we report that Ncs may be a potential candidate for psoriasis, acting at both the organismal and cellular levels. METHODS: The therapeutic effect of Ncs was assessed in IMQ-induced psoriasis-like mouse model. Then, through in vitro experiments, we explored the inhibitory effect of Ncs on HaCaT cell proliferation and Th17 cell polarization; Transcriptomics and lipidomics were used to analyze the major targets of Ncs; Single-cell sequencing data was used to identify the target cells of Ncs action. RESULTS: Ncs can inhibit keratinocyte proliferation and reduce the recruitment of immune cells in the skin by inhibiting psoriasis-associated inflammatory mediators. In addition, it showed a direct repression effect on Th17 cell polarization. Transcriptomic and lipidomic data further revealed that Ncs extensively regulated lipid metabolismrelated genes, especially the Phospholipase A2 (PLA2) family, and increased antiinflammatory lipid molecules. Combined with single-cell data analysis, we confirmed that keratinocytes are the main cells in which Ncs functions. DISCUSSION: Taken together, our findings indicate that Ncs alleviates psoriasiform skin inflammation in mice, which is associated with inhibition of PLA2 in keratinocytes and improved phospholipid metabolism. Ncs has the potential for further development as a novel anti-psoriasis drug. Title: [Characterization of Humicola insolens cutinase-tachystatin A2 fusion protein and its application in treatment of recycled paper stickies] Li G, Liu Z, Zhang Y, Wu J Ref: Sheng Wu Gong Cheng Xue Bao, 38:207, 2022 : PubMed ESTHER: Li_2022_Sheng.Wu.Gong.Cheng.Xue.Bao_38_207 PubMedSearch: Li 2022 Sheng.Wu.Gong.Cheng.Xue.Bao 38 207 PubMedID: 35142131 Abstract With the decrease of forest timber resources, the recycling of waste paper has received increasing attention. However, the stickies produced in the process of waste paper recycling may negatively affect the production of recycled paper. The biological decomposition of stickies, which has the advantages of high efficiency, high specificity and pollution-free, is achieved mainly through the enzymatic cleavage of the ester bond in the stickies components to prevent flocculation. Cutinase is a serine esterase that can degrade some components of the stickies. Previous research indicated that the anchor peptide tachystatin A2 (TA2) is able to bind polyurethane. In this study, the cutinase HiC derived from Humicola insolens was used to construct a fusion protein HiC-TA2 by megaprimer PCR of the whole plasmid (MEGAWHOP). The enzymatic properties and the degradation efficiency of the fusion protein on poly(ethyl acrylate) (PEA), a model substrate of stickies component, were determined. The results showed that the degradation efficiency, the size decrease of PEA particle, and the amount of ethanol produced by HiC-TA2 were 1.5 times, 6.8 times, and 1.4 times of that by HiC, respectively. These results demonstrated that TA2 improved the degradation efficiency of HiC on PEA. This study provides a useful reference for biological decomposition of stickies produced in the process of recycled paper production. Title: Ratiometric fluorescent hydrogel for point-of-care monitoring of organophosphorus pesticide degradation Li H, Zou R, Su C, Zhang N, Wang Q, Zhang Y, Zhang T, Sun C, Yan X Ref: J Hazard Mater, 432:128660, 2022 : PubMed ESTHER: Li_2022_J.Hazard.Mater_432_128660 PubMedSearch: Li 2022 J.Hazard.Mater 432 128660 PubMedID: 35334266 Abstract The residues of organophosphorus pesticides have caused the potential risk in environment and human health, arousing worldwidely great concern. Herein, we fabricated a robust gold nanoclusters/MnO(2) composites-based hydrogel portable kit for accurate monitoring of paraoxon residues and degradation in Chinese cabbages. With the immobilization of gold nanoclusters/MnO(2) composites into a hydrogel, a ratiometric fluorescent signal is generated by catalyzing the oxidation of o-phenylenediamine, which possesses a built-in correction with low background interference. Coupling with acetylcholinesterase catalytic reactions and pesticide inhibition effect, the portable kit can sensitively detect paraoxon residues with a detection limit of 5.0 ng mL(-1). For on-site quantification, the fluorescent color variations of portable kit are converted into digital information that exhibits applicative linear range toward pesticide. Notably, the hydrogel portable kit was successfully applied for precisely monitoring the residue and degradation of paraoxon in Chinese cabbage, providing a potential pathway toward practical point-of-care testing in food safety monitoring. Title: Association between CES1 rs2244613 and the pharmacokinetics and safety of dabigatran: Meta-analysis and quantitative trait loci analysis Li H, Zhang Z, Weng H, Qiu Y, Zubiaur P, Zhang Y, Fan G, Yang P, Vuorinen AL and Wang C <2 more author(s)> Li H, Zhang Z, Weng H, Qiu Y, Zubiaur P, Zhang Y, Fan G, Yang P, Vuorinen AL, Zuo X, Zhai Z, Wang C (- 2) Ref: Front Cardiovasc Med, 9:959916, 2022 : PubMed ESTHER: Li_2022_Front.Cardiovasc.Med_9_959916 PubMedSearch: Li 2022 Front.Cardiovasc.Med 9 959916 PubMedID: 35990949 Abstract OBJECTIVE: To date, the influence of the carboxylesterase 1 (CES1) rs2244613 genotype on the pharmacokinetics (PKs) and safety of dabigatran remains controversial. Hence, a systematic review was performed to study the association between CES1 rs2244613 genotype and the PKs and safety of dabigatran and CES1 relative expression. METHODS: In addition to the three English databases (Web of Science, PubMed, and Embase), two Chinese databases (CNKI and Wanfang) were thoroughly revised. The mean differences (MD) and corresponding 95% confidence intervals (CI) were applied to evaluate the differences in PKs between the CES1 rs2244613 genotype. Odds ratio (OR) was used to study the risk for bleeding events between the CES1 rs2244613 genotypes. Subsequent expression quantitative trait loci (eQTL) analyses were performed to evaluate genotype-specific expressions in human tissues. RESULTS: Ten studies (n = 2,777) were included. CES1 rs2244613 G allele carriers exhibited significantly lower dabigatran trough concentrations compared to T allele carriers (MD: -8.00 ng/mL; 95% CI: -15.08 to -0.92; p = 0.03). The risk for bleeding events was significantly lower in carriers of the G allele compared to T allele carriers (OR: 0.65; 95% CI: 0.44-0.96; p = 0.03). Subsequent eQTL analysis showed significant genome-wide expressions in two human tissues, whole blood (p = 5.1 x 10(-10)) and liver (p = 6.2 x 10(-43)). CONCLUSION: Our meta-analysis indicated a definite relation between the CES1 rs2244613 genotype and tolerability variations or pharmacokinetic fluctuations. The carriers of T allele showed higher dabigatran concentrations; therefore, they would benefit from a dose reduction. SYSTEMATIC REVIEW REGISTRATION: [https://inplasy.com/inplasy-2022-6-0027/], identifier [NPLASY202260027]. Title: Probiotic effect of ferulic acid esterase-producing Lactobacillus plantarum inoculated alfalfa silage on digestion, antioxidant, and immunity status of lactating dairy goats Li F, Zhang B, Zhang Y, Zhang X, Usman S, Ding Z, Hao L, Guo X Ref: Anim Nutr, 11:38, 2022 : PubMed ESTHER: Li_2022_Anim.Nutr_11_38 PubMedSearch: Li 2022 Anim.Nutr 11 38 PubMedID: 36091259 Abstract A feeding experiment was conducted to determine the effects of inoculating alfalfa silage with a ferulic acid esterase-producing inoculum on feed digestibility, rumen fermentation, antioxidant, and immunity status of lactating dairy goats. Twenty dairy goats were distributed into 2 experimental groups consisting of control diet (Lp MTD/1, including Lactobacillus plantarum MTD/1 inoculated silage) against diet containing silage treated with ferulic acid esterase-producing L. plantarum A1 (Lp A1). Alfalfa silage inoculated with a ferulic acid esterase-producing Lp A1 had better fermentation quality than the Lp MTD/1 inoculation. The application of Lp A1 improved silage antioxidant capacity as indicated by greater total antioxidant capacity (T-AOC), superoxide dismutase (SOD) and glutathion peroxidase (GSH-Px) activities in Lp A1 treated silage versus Lp MTD/1 treatment. Compared with Lp MTD/1 treated group, inoculation of silage with Lp A1 increased apparent total tract digestibility of dietary dry matter, organic matter and crude protein, and ruminal concentrations of total volatile fatty acids, acetate, propionate and isobutyrate as well. The results of current study also demonstrated improved antioxidant capacity and immune performance of dairy goats with Lp A1 inoculation. Feeding Lp A1-treated silage increased dairy goats' serum antioxidase activity, such as T-AOC, SOD, GSH-Px and catalase, and the serum concentration of immunoglobulin A, while decreased tumor necrosis factor alpha, interleukin (IL)-2 and IL-6. In addition, compared with Lp MTD/1, diet containing alfalfa silage inoculated with Lp A1 endowed dairy goats' milk with greater fat and protein contents, improved dairy goat milk quality without affecting feed efficiency. Title: Multiple acetylcholinesterases in Pardosa pseudoannulata brain worked collaboratively to provide protection from organophosphorus insecticides Lin X, Zhang Y, Yang B, Zhang L, Chen Y, Liu Z Ref: Ecotoxicology & Environmental Safety, 248:114301, 2022 : PubMed ESTHER: Lin_2022_Ecotoxicol.Environ.Saf_248_114301 PubMedSearch: Lin 2022 Ecotoxicol.Environ.Saf 248 114301 PubMedID: 36410143 Gene_locus related to this paper: 9arac-KU501290, 9arac-KU501289, 9arac-KU501288, 9arac-KU501287, 9arac-v5qqc6, 9arac-v5qqr1 Abstract Acetylcholinesterase (AChE) is an essential neurotransmitter hydrolase in nervous systems of animals and its number varies among species. So far, five AChEs have been identified in the natural enemy Pardosa pseudoannulata. Here we found that Ppace1, Ppace2 and Ppace5 were highly expressed in the spider brain, among which the mRNA level of Ppace5, but not Ppace1 and Ppace2, could be up-regulated by organophosphorus insecticides at their sublethal concentrations. In spider brain, the treatment by organophosphorus insecticides at the sublethal concentrations could increase total AChE activity, although high concentrations inhibited the activity. The activity that increased from the sublethal concentration pretreatment could compensate for the activity inhibition due to subsequent application of organophosphorus insecticides at lethal concentrations, and consequently reduce the mortality of spiders. PpAChE1 and PpAChE2 were highly sensitive to organophosphorus insecticides, and their activities would be strongly inhibited by the insecticides. In contrast, PpAChE5 displayed relative insensitivity towards organophosphorus insecticides, but with the highest catalytic efficiency for ACh. That meant the up-regulation of Ppace5 under insecticide exposure was important for maintaining AChE activity in spider brain, when PpAChE1 and PpAChE2 were inhibited by organophosphorus insecticides. The study demonstrated that multiple AChEs in the spider brain worked collaboratively, with part members for maintaining AChE activity and other members responding to organophosphorus inhibition, to provide protection from organophosphorus insecticides. In fields, high concentration insecticides are often applied when ineffective controls of insect pests occur due to relative-low concentration of insecticides in last round application. This application pattern of organophosphorus insecticides provides more chances for P. pseudoannulata to survive and controlling insect pests as a natural enemy. Title: Enhancement of PET biodegradation by anchor peptide-cutinase fusion protein Liu Z, Zhang Y, Wu J Ref: Enzyme Microb Technol, 156:110004, 2022 : PubMed ESTHER: Liu_2022_Enzyme.Microb.Technol_156_110004 PubMedSearch: Liu 2022 Enzyme.Microb.Technol 156 110004 PubMedID: 35217214 Gene_locus related to this paper: thefu-q6a0i3 Abstract With the increasing production of polyethylene terephthalate (PET) plastic products, the problem of PET waste has become a serious threat to ecosystem. PET enzymatic biodegradation, due to its environmental friendliness and sustainability, has gradually attracted attention. As a multifunctional hydrolase, cutinase (EC 3.1.1.74) can not only degrade fatty acid esters, soluble synthetic esters, and emulsified triglycerides, but also exhibit potential for PET degradation. In order to enhance the PET degradation activity of cutinase, we functionally screened several PET binding domains, e.g. carbohydrate binding module, anchor peptide, and hydrophobin, that promote the absorption of enzyme to PET substrate, selected Dermaseptin SI (DSI) and fused it onto the N-terminus of Thermobifida fusca cutinase mutant D204C/E253C (Tfuc2), and finally achieved the PET degradation rate up to 57.9% at 70 degreesC for 96 h, which was 22.7-fold of that of Tfuc2 itself. These results indicate that the fusion of PET binding domain is a promising strategy to enhance PET enzymatic degradation. Title: The juvenile hormone epoxide hydrolase homolog in Penaeus vannamei plays immune-related functions Liu Z, Huang Z, Zheng X, Zheng Z, Yao D, Zhang Y, Aweya JJ Ref: Dev Comp Immunol, 132:104410, 2022 : PubMed ESTHER: Liu_2022_Dev.Comp.Immunol_132_104410 PubMedSearch: Liu 2022 Dev.Comp.Immunol 132 104410 PubMedID: 35398160 Gene_locus related to this paper: penva-a0a3r7m6s0 Abstract Juvenile hormone epoxide hydrolase (JHEH) participates in the degradation of juvenile hormone and also involved in the development and molting process in insects. Here, the JHEH homolog in Pennaus vannamei was cloned and found to consist of a full-length cDNA of 2543 bp and an open reading frame (ORF) of 1386 bp. Transcripts of PvJHEH1 were expressed in most tissues of healthy shrimp with the highest found in the hepatopancreas and lowest in hemocytes. Both Gram-negative (Vibrio parahaemolyticus) and Gram-positive (Streptococcus iniae) bacteria induced PvJHEH1 expression in shrimp hemocytes and hepatopancreas, suggesting the involvement of PvJHEH1 in P. vannamei immune responses. Moreover, the mRNA levels of ecdysone inducible nuclear transcription factor PvE75 and crustacean hyperglycemic hormone (PvCHH), two endocrine-related genes with roles in shrimp innate immune response, decreased significantly in shrimp hemocytes after PvJHEH1 knockdown. Shrimp survival was also affected after PvJHEH1 knockdown followed by V. parahaemolyticus challenge, indicating that JHEH1 plays an essential role in shrimp survival during bacterial infection. Title: Emerging role of carboxylesterases in nonalcoholic fatty liver disease Liu J, Yao B, Gao L, Zhang Y, Huang S, Wang X Ref: Biochemical Pharmacology, :115250, 2022 : PubMed ESTHER: Liu_2022_Biochem.Pharmacol__115250 PubMedSearch: Liu 2022 Biochem.Pharmacol 115250 PubMedID: 36130649 Abstract Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as a global public health problem. Carboxylesterases (CESs), as potential influencing factors of NAFLD, are very important to improve clinical outcomes. This review aims to deeply understand the role of CESs in the progression of NAFLD and proposes that CESs can be used as potential targets for NAFLD treatment. We first introduced CESs and analyzed the relationship between CESs and hepatic lipid metabolism and inflammation. Then, we further reviewed the regulation of nuclear receptors on CESs, including PXR, CAR, PPARalpha, HNF4alpha and FXR, which may influence the progression of NAFLD. Finally, we evaluated the advantages and disadvantages of existing NAFLD animal models and summarized the application of CES-related animal models in NAFLD research. In general, this review provides an overview of the relationship between CESs and NAFLD and discusses the role and potential value of CESs in the treatment and prevention of NAFLD. Title: Extraction and preparation of 5-lipoxygenase and acetylcholinesterase inhibitors from Astragalus membranaceus stems and leaves Liu R, Zhang Y, Li S, Liu C, Zhuang S, Zhou X, Li Y, Liang J Ref: J Sep Sci, :, 2022 : PubMed ESTHER: Liu_2022_J.Sep.Sci__ PubMedSearch: Liu 2022 J.Sep.Sci PubMedID: 36502278 Abstract In this study, an efficient method that employs 5-lipoxygenase and acetylcholinesterase as biological target molecules in receptor-ligand affinity ultrafiltration-liquid chromatography was developed for the screening of enzyme inhibitors derived from the Astragalus membranaceus stems and leaves. The effects of the extraction time, number of extraction cycles, ethanol concentration, and liquid-solid ratio on the total yield of the target compounds were investigated using response surface methodology, and the bioactive components were isolated using a combination of semi-preparative high-performance liquid chromatography and high-speed countercurrent chromatography via a two-phase solvent system consisting of n-hexane-ethyl acetate-methanol-water (1:6:2:6, v/v/v/v). Subsequently, ten naturally-occurring bioactive components in the Astragalus membranaceus stems and leaves, including wogonin, ononin, isoquercitrin, calycosin-7-glucoside, 3-hydroxy-9,10-dimethoxyptercarpan, hyperoside, 7,2'-dihydroxy-3',4'-dimethoxyisoflavan, baicalein, calycosin, and soyasaponin, were screened using affinity ultrafiltration to determine their potential effects against Alzheimer's disease. Consequently, all target compounds had purities higher than 95.0%, and the potential anti-Alzheimer's disease effect of the obtained bioactive compounds was verified using molecular docking analysis. Based on the results, the back-to-back screening of complex enzyme inhibitors and separation of the target bioactive compounds using complex chromatography could provide a new approach for the discovery and preparation of natural active ingredients. This article is protected by copyright. All rights reserved. Title: Effects of larval exposure to the insecticide flumethrin on the development of honeybee (Apis mellifera) workers Liu C, Wu X, Yang H, Yu L, Zhang Y Ref: Front Physiol, 13:1054769, 2022 : PubMed ESTHER: Liu_2022_Front.Physiol_13_1054769 PubMedSearch: Liu 2022 Front.Physiol 13 1054769 PubMedID: 36589443 Abstract Flumethrin is a widely used acaricide, but its improper use often leads to residue accumulation in honeybee colonies, thus threatening the health of honeybees, especially at the larval stage. Therefore, this study aimed to describe the direct toxicity of flumethrin on honeybee (Apis mellifera) larvae by conducting bioassays for immune and detoxification-related enzymes and transcriptome sequencing to determine the potential effects on newly emerged adults who were exposed to flumethrin during the larval stage. Results showed that the higher the concentration of flumethrin the honeybee larvae were exposed to, the greater the damage to the physiology of honeybee larvae and the newly emerged worker bees. When honeybee larvae were exposed to flumethrin concentrations higher than 0.01smg/L, the activities of glutathione sulfur transferase and carboxylesterase were affected, and the metabolism-related genes in the head of newly emerged honeybees exposed to flumethrin during the larval stage were down-regulated. Flumethrin concentration higher than 0.1smg/L significantly increased mixed-functional oxidase content in honeybee larvae, reduced the larval survival rate, and down-regulated the expression levels of olfactory-related and antioxidant-related genes in newly emerged honeybees. Furthermore, a flumethrin concentration of 1smg/L significantly down-regulated the expression levels of immune and detoxification-related genes in newly emerged honeybees. These findings provide a comprehensive understanding of the response of honeybee larvae to sublethal flumethrin toxicity and could be used to further investigate the complex molecular mechanisms in honeybees under pesticide stress. Title: Machine learning-aided engineering of hydrolases for PET depolymerization Lu H, Diaz DJ, Czarnecki NJ, Zhu C, Kim W, Shroff R, Acosta DJ, Alexander BR, Cole HO and Alper HS <3 more author(s)> Lu H, Diaz DJ, Czarnecki NJ, Zhu C, Kim W, Shroff R, Acosta DJ, Alexander BR, Cole HO, Zhang Y, Lynd NA, Ellington AD, Alper HS (- 3) Ref: Nature, 604:662, 2022 : PubMed ESTHER: Lu_2022_Nature_604_662 PubMedSearch: Lu 2022 Nature 604 662 PubMedID: 35478237 Gene_locus related to this paper: idesa-peth Abstract Plastic waste poses an ecological challenge(1-3) and enzymatic degradation offers one, potentially green and scalable, route for polyesters waste recycling(4). Poly(ethylene terephthalate) (PET) accounts for 12% of global solid waste(5), and a circular carbon economy for PET is theoretically attainable through rapid enzymatic depolymerization followed by repolymerization or conversion/valorization into other products(6-10). Application of PET hydrolases, however, has been hampered by their lack of robustness to pH and temperature ranges, slow reaction rates and inability to directly use untreated postconsumer plastics(11). Here, we use a structure-based, machine learning algorithm to engineer a robust and active PET hydrolase. Our mutant and scaffold combination (FAST-PETase: functional, active, stable and tolerant PETase) contains five mutations compared to wild-type PETase (N233K/R224Q/S121E from prediction and D186H/R280A from scaffold) and shows superior PET-hydrolytic activity relative to both wild-type and engineered alternatives(12) between 30 and 50 degreesC and a range of pH levels. We demonstrate that untreated, postconsumer-PET from 51 different thermoformed products can all be almost completely degraded by FAST-PETase in 1 week. FAST-PETase can also depolymerize untreated, amorphous portions of a commercial water bottle and an entire thermally pretreated water bottle at 50 C. Finally, we demonstrate a closed-loop PET recycling process by using FAST-PETase and resynthesizing PET from the recovered monomers. Collectively, our results demonstrate a viable route for enzymatic plastic recycling at the industrial scale. Title: Isolation and Identification of Efficient Malathion-Degrading Bacteria from Deep-Sea Hydrothermal Sediment Ma L, Dai X, Ai G, Zheng X, Zhang Y, Pan C, Hu M, Jiang C, Wang L, Dong Z Ref: Microorganisms, 10:, 2022 : PubMed ESTHER: Ma_2022_Microorganisms_10_ PubMedSearch: Ma 2022 Microorganisms 10 PubMedID: 36144399 Abstract The genetic and metabolic diversity of deep-sea microorganisms play important roles in phosphorus and sulfur cycles in the ocean, distinguishing them from terrestrial counterparts. Malathion is a representative organophosphorus component in herbicides, pesticides, and insecticides and is analogues of neurotoxic agent. Malathion has been one of the best-selling generic organophosphate insecticides from 1980 to 2012. Most of the sprayed malathion has migrated by surface runoff to ocean sinks, and it is highly toxic to aquatic organisms. Hitherto, there is no report on bacterial cultures capable of degrading malathion isolated from deep-sea sediment. In this study, eight bacterial strains, isolated from sediments from deep-sea hydrothermal regions, were identified as malathion degradators. Two of the tested strains, Pseudidiomarina homiensis strain FG2 and Pseudidiomarina sp. strain CB1, can completely degrade an initial concentration of 500 mg/L malathion within 36 h. Since the two strains have abundant carboxylesterases (CEs) genes, malathion monocarboxylic acid (MMC alpha and MMC beta) and dibasic carboxylic acid were detected as key intermediate metabolites of malathion degradation, and the pathway of malathion degradation between the two strains was identified as a passage from malathion monocarboxylic acid to malathion dicarboxylic acid. Title: Silencing of MsD14 Resulted in Enhanced Forage Biomass through Increasing Shoot Branching in Alfalfa (Medicago sativa L.) Ma L, Zhang Y, Wen H, Liu W, Zhou Y, Wang X Ref: Plants (Basel), 11:, 2022 : PubMed ESTHER: Ma_2022_Plants.(Basel)_11_ PubMedSearch: Ma 2022 Plants.(Basel) 11 PubMedID: 35406919 Abstract Branching is one of the key determinants of plant architecture that dramatically affects crop yield. As alfalfa is the most important forage crop, understanding the genetic basis of branching in this plant can facilitate breeding for a high biomass yield. In this study, we characterized the strigolactone receptor gene MsD14 in alfalfa and demonstrated that MsD14 was predominantly expressed in flowers, roots, and seedpods. Furthermore, we found that MsD14 expression could significantly respond to strigolactone in alfalfa seedlings, and its protein was located in the nucleus, cytoplasm, and cytomembrane. Most importantly, transformation assays demonstrated that silencing of MsD14 in alfalfa resulted in increased shoot branching and forage biomass. Significantly, MsD14 could physically interact with AtMAX2 and MsMAX2 in the presence of strigolactone, suggesting a similarity between MsD14 and AtD14. Together, our results revealed the conserved D14-MAX2 module in alfalfa branching regulation and provided candidate genes for alfalfa high-yield molecular breeding. Title: Effect of lentivirus-mediated peroxiredoxins 6 gene silencing on the phenotype of human gastric cancer BGC-823 cells Mu R, Li Y, Xing J, Lin R, Ye S, Zhang Y, Mu H, Guo X, An L Ref: J Cancer Research Ther, 18:411, 2022 : PubMed ESTHER: Mu_2022_J.Cancer.Res.Ther_18_411 PubMedSearch: Mu 2022 J.Cancer.Res.Ther 18 411 PubMedID: 35645108 Abstract AIMS: Peroxiredoxins (PRDX6) regulates the occurrence and progression of cancer. The aim of this study is to investigate the effect of PRDX6 knockdown on the biological behavior of human gastric cancer cell line BGC-823 cells. SETTINGS AND DESIGN: Research article. SUBJECTS AND METHODS: The differential expression of PRDX6 in gastric cancer and normal gastric tissues was tested by immunohistochemistry. Ribonucleic acid plasmid of PRDX6 gene was packaged using a lentivirus, and BGC-823 cells were transfected with the lentivirus to obtain a BGC-823 cell line in which the expression of PRDX6 was stably silenced. STATISTICAL ANALYSIS USED: The proliferation activity of BGC-823 cells was detected using the cell counting kit-8 method. The effect of PRDX6 on the migration and invasion of BGC-823 cells was evaluated using the scratch test and Transwell assay, and the expression of related proteins was detected by western blot. RESULTS: The expression of PRDX6 in gastric cancer was significantly increased (P < 0.05). Compared with those in the untransfected and negative control groups. The proliferation, migration, and invasion of gastric cancer BGC-823 cells were significantly inhibited, and the apoptotic rates were significantly increased in the lentivirus-transfected (short hairpin-PRDX6) group. Western blot analysis showed that the expression of Bax protein increased, whereas that of proliferating cell nuclear antigen, Bcl-2, PI3K, phospho (p-Akt), and phosphorylated-mammalian target of rapamycin (mTOR) decreased significantly compared with that in WT and vector groups (P < 0.05). CONCLUSION: The knockdown of PRDX6 gene expression in BGC-823 cells can inhibit the proliferation, migration, and invasion of gastric cancer cells and promote apoptosis, thereby affecting gastric cancer cells. Title: Cloning and Molecular Characterization of HSL and Its Expression Pattern in HPG Axis and Testis during Different Stages in Bactrian Camel Nan J, Wang Q, Yan Q, Wang J, Zhang Y, Zhao X Ref: Curr Issues Mol Biol, 44:3779, 2022 : PubMed ESTHER: Nan_2022_Curr.Issues.Mol.Biol_44_3779 PubMedSearch: Nan 2022 Curr.Issues.Mol.Biol 44 3779 PubMedID: 36005155 Abstract Hormone-sensitive lipase (HSL) is a key enzyme in animal fat metabolism and is involved in the rate-limiting step of catalyzing the decomposition of fat and cholesterol. It also plays an important regulatory role in maintaining seminiferous epithelial structure, androgen synthesis and primordial germ cell differentiation. We previously reported that HSL is involved the synthesis of steroids in Bactrian camels, although it is unclear what role it plays in testicular development. The present study was conducted to characterize the biological function and expression pattern of the HSL gene in the hypothalamic pituitary gonadal (HPG) axis and the development of testis in Bactrian camels. We analyzed cloning of the cDNA sequence of the HSL gene of Bactrian camels by RT-PCR, as well as the structural features of HSL proteins, using bioinformatics software, such as ProtParam, TMHMM, Signal P 4.1, SOPMA and MEGA 7.0. We used qRT-PCR, Western blotting and immunofluorescence staining to clarify the expression pattern of HSL in the HPG axis and testis of two-week-old (2W), two-year-old (2Y), four-year-old (4Y) and six-year-old (6Y) Bactrian camels. According to sequence analysis, the coding sequence (CDS) region of the HSL gene is 648 bp in length and encodes 204 amino acids. According to bioinformatics analysis, the nucleotide and amino acid sequence of Bactrian camel HSL are most similar to those of Camelus pacos and Camelusdromedarius, with the lowest sequence similarity with Mus musculus. In adult Bactrian camel HPG axis tissues, both HSL mRNA and protein expression were significantly higher in the testis than in other tissues (hypothalamus, pituitary and pineal tissues) (p < 0.05). The expression of mRNA in the testis increased with age and was the highest in six-year-old testis (p < 0.01). The protein expression levels of HSL in 2Y and 6Y testis were clearly higher than in 2W and 4Y testis tissues (p < 0.01). Immunofluorescence results indicate that the HSL protein was mainly localized in the germ cells, Sertoli cells and Leydig cells from Bactrian camel testis, and strong positive signals were detected in epididymal epithelial cells, basal cells, spermatocytes and smooth muscle cells, with partially expression in hypothalamic glial cells, pituitary suspensory cells and pineal cells. According to the results of gene ontology (GO) analysis enrichment, HSL indirectly regulates the anabolism of steroid hormones through interactions with various targets. Therefore, we conclude that the HSL gene may be associated with the development and reproduction of Bactrian camels in different stages of maturity, and these results will contribute to further understanding of the regulatory mechanisms of HSL in Bactrian camel reproduction. Title: Marine fungal metabolite butyrolactone I prevents cognitive deficits by relieving inflammation and intestinal microbiota imbalance on aluminum trichloride-injured zebrafish Nie Y, Yang J, Zhou L, Yang Z, Liang J, Liu Y, Ma X, Qian Z, Hong P and Zhang Y <2 more author(s)> Nie Y, Yang J, Zhou L, Yang Z, Liang J, Liu Y, Ma X, Qian Z, Hong P, Kalueff AV, Song C, Zhang Y (- 2) Ref: J Neuroinflammation, 19:39, 2022 : PubMed ESTHER: Nie_2022_J.Neuroinflammation_19_39 PubMedSearch: Nie 2022 J.Neuroinflammation 19 39 PubMedID: 35130930 Abstract BACKGROUND: Mounting evidences indicate that oxidative stress, neuroinflammation, and dysregulation of gut microbiota are related to neurodegenerative disorders (NDs). Butyrolactone I (BTL-I), a marine fungal metabolite, was previously reported as an in vitro neuroprotectant and inflammation inhibitor. However, little is known regarding its in vivo effects, whereas zebrafish (Danio rerio) could be used as a convenient in vivo model of toxicology and central nervous system (CNS) diseases. METHODS: Here, we employed in vivo and in silico methods to investigate the anti-NDs potential of BTL-I. Specifically, we established a cognitive deficit model in zebrafish by intraperitoneal (i.p.) injection of aluminum trichloride (AlCl(3)) (21 microg) and assessed their behaviors in the T-maze test. The proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) as well as acetylcholinesterase (AChE) activity or glutathione (GSH) levels were assayed 24 h after AlCl(3) injection. The intestinal flora variation of the zebrafish was investigated by 16S rDNA high-throughput analysis. The marine fungal metabolite, butyrolactone I (BTL-I), was used to modulate zebrafish cognitive deficits evoked by AlCl(3) and evaluated about its effects on the above inflammatory, cholinergic, oxidative stress, and gut floral indicators. Furthermore, the absorption, distribution, metabolism, excretion, and toxicity (ADMET) and drug-likeness properties of BTL-I were studied by the in silico tool ADMETlab. RESULTS: BTL-I dose-dependently ameliorated AlCl(3)-induced cognitive deficits in zebrafish. While AlCl(3) treatment elevated the levels of central and peripheral proinflammatory cytokines, increased AChE activity, and lowered GSH in the brains of zebrafish, these effects, except GSH reduction, were reversed by 25-100 mg/kg BTL-I administration. Besides, 16S rDNA high-throughput sequencing of the intestinal flora of zebrafish showed that AlCl(3) decreased Gram-positive bacteria and increased proinflammatory Gram-negative bacteria, while BTL-I contributed to maintaining the predominance of beneficial Gram-positive bacteria. Moreover, the in silico analysis indicated that BTL-I exhibits acceptable drug-likeness and ADMET profiles. CONCLUSIONS: The present findings suggest that BTL-I is a potential therapeutic agent for preventing CNS deficits caused by inflammation, neurotoxicity, and gut flora imbalance. Title: Acquisition of T6SS Effector TseL Contributes to the Emerging of Novel Epidemic Strains of Pseudomonas aeruginosa Ren A, Jia M, Liu J, Zhou T, Wu L, Dong T, Cai Z, Qu J, Liu Y and Zhang Y <1 more author(s)> Ren A, Jia M, Liu J, Zhou T, Wu L, Dong T, Cai Z, Qu J, Liu Y, Yang L, Zhang Y (- 1) Ref: Microbiol Spectr, :e0330822, 2022 : PubMed ESTHER: Ren_2022_Microbiol.Spectr__e0330822 PubMedSearch: Ren 2022 Microbiol.Spectr e0330822 PubMedID: 36546869 Gene_locus related to this paper: pseae-T6SSTseL Abstract Pseudomonas aeruginosa is an opportunistic pathogen with multiple strategies to interact with other microbes and host cells, gaining fitness in complicated infection sites. The contact-dependent type VI secretion system (T6SS) is one critical secretion apparatus involved in both interbacterial competition and pathogenesis. To date, only limited numbers of T6SS-effectors have been clearly characterized in P. aeruginosa laboratory strains, and the importance of T6SS diversity in the evolution of clinical P. aeruginosa remains unclear. Recently, we characterized a P. aeruginosa clinical strain LYSZa7 from a COVID-19 patient, which adopted complex genetic adaptations toward chronic infections. Bioinformatic analysis has revealed a putative type VI secretion system (T6SS) dependent lipase effector in LYSZa7, which is a homologue of TseL in Vibrio cholerae and is widely distributed in pathogens. We experimentally validated that this TseL homologue belongs to the Tle2, a subfamily of T6SS-lipase effectors; thereby, we name this effector TseL (TseL(PA) in this work). Further, we showed the lipase-dependent bacterial toxicity of TseL(PA), which primarily targets bacterial periplasm. The toxicity of TseL(PA) can be neutralized by two immunity proteins, TsiP1 and TsiP2, which are encoded upstream of tseL. In addition, we proved this TseL(PA) contributes to bacterial pathogenesis by promoting bacterial internalization into host cells. Our study suggests that clinical bacterial strains employ a diversified group of T6SS effectors for interbacterial competition and might contribute to emerging of new epidemic clonal lineages. IMPORTANCE Pseudomonas aeruginosa is one predominant pathogen that causes hospital-acquired infections and is one of the commonest coinfecting bacteria in immunocompromised patients and chronic wounds. This bacterium harbors a diverse accessory genome with a high frequency of gene recombination, rendering its population highly heterogeneous. Numerous Pa lineages coexist in the biofilm, where successful epidemic clonal lineage or strain-specific type commonly acquires genes to increase its fitness over the other organisms. Current studies of Pa genomic diversity commonly focused on antibiotic resistant genes and novel phages, overlooking the contribution of type VI secretion system (T6SS). We characterized a Pa clinical strain LYSZa7 from a COVID-19 patient, which adopted complex genetic adaptations toward chronic infections. We report, in this study, a novel T6SS-lipase effector that is broadly distributed in Pa clinical isolates and other predominant pathogens. The study suggests that hospital transmission may raise the emergence of new epidemic clonal lineages with specified T6SS effectors. Title: Genome-wide expression analysis of carboxylesterase (CXE) gene family implies GBCXE49 functional responding to alkaline stress in cotton Rui C, Peng F, Fan Y, Zhang Y, Zhang Z, Xu N, Zhang H, Wang J, Li S and Ye W <7 more author(s)> Rui C, Peng F, Fan Y, Zhang Y, Zhang Z, Xu N, Zhang H, Wang J, Li S, Yang T, Malik WA, Lu X, Chen X, Wang D, Chen C, Gao W, Ye W (- 7) Ref: BMC Plant Biol, 22:194, 2022 : PubMed ESTHER: Rui_2022_BMC.Plant.Biol_22_194 PubMedSearch: Rui 2022 BMC.Plant.Biol 22 194 PubMedID: 35413814 Abstract BACKGROUND: Carboxylesterase (CXE) is a type of hydrolase with alpha/beta sheet hydrolase activity widely found in animals, plants and microorganisms, which plays an important role in plant growth, development and resistance to stress. RESULTS: A total of 72, 74, 39, 38 CXE genes were identified in Gossypium barbadense, Gossypium hirsutum, Gossypium raimondii and Gossypium arboreum, respectively. The gene structure and expression pattern were analyzed. The GBCXE genes were divided into 6 subgroups, and the chromosome distribution of members of the family were mapped. Analysis of promoter cis-acting elements showed that most GBCXE genes contain cis-elements related to plant hormones (GA, IAA) or abiotic stress. These 6 genes we screened out were expressed in the root, stem and leaf tissues. Combined with the heat map, GBCXE49 gene was selected for subcellular locate and confirmed that the protein was expressed in the cytoplasm. CONCLUSIONS: The collinearity analysis of the CXE genes of the four cotton species in this family indicated that tandem replication played an indispensable role in the evolution of the CXE gene family. The expression patterns of GBCXE gene under different stress treatments indicated that GBCXE gene may significantly participate in the response to salt and alkaline stress through different mechanisms. Through the virus-induced gene silencing technology (VIGS), it was speculated that GBCXE49 gene was involved in the response to alkaline stress in G. barbadense. Title: Comprehensive Detoxification Mechanism Assessment of Red Imported Fire Ant (Solenopsis invicta) against Indoxacarb Siddiqui JA, Zhang Y, Luo Y, Bamisile BS, Rehman NU, Islam W, Qasim M, Jiang Q, Xu Y Ref: Molecules, 27:, 2022 : PubMed ESTHER: Siddiqui_2022_Molecules_27_ PubMedSearch: Siddiqui 2022 Molecules 27 PubMedID: 35164134 Abstract The red imported fire ant (Solenopsis invicta) is one of the deadliest invasive ant species that threatens the world by disrupting biodiversity, important functions within a natural ecosystem, and community structure. They are responsible for huge economic losses in the infested countries every year. Synthetic insecticides, especially indoxacarb, have been broadly used to control S. invicta for many years. However, the biochemical response of S. invicta to indoxacarb remains largely undiscovered. Here, we used the sublethal doses of indoxacarb on the S. invicta collected from the eight different cities of Southern China. The alteration in the transcriptome profile of S. invicta following sublethal dosages of indoxacarb was characterized using high-throughput RNA-seq technology. We created 2 libraries, with 50.93 million and 47.44 million clean reads for indoxacarb treatment and control, respectively. A total of 2018 unigenes were regulated after insecticide treatment. Results indicated that a total of 158 differentially expressed genes (DEGs) were identified in the indoxacarb-treated group, of which 100 were significantly upregulated and 58 were downregulated, mostly belonging to the detoxification enzymes, such as AChE, CarE, and GSTs. Furthermore, results showed that most of these DEGs were found in several KEGG pathways, including steroid biosynthesis, other drug metabolizing enzymes, glycerolipid metabolism, chemical carcinogenesis, drug-metabolizing cytochrome P450, glutathione metabolism, glycerophospholipid metabolism, glycolysis/gluconeogenesis, and metabolism of xenobiotics. Together, these findings indicated that indoxacarb causes significant alteration in the transcriptome profile and signaling pathways of S. invicta, providing a foundation for further molecular inquiry. Title: Mosquitocidal efficacy of embelin and its derivatives against Aedes aegypti L. and Culex quinquefasciatus Say. (Diptera: Culicidae) and computational analysis of acetylcholinesterase 1 (AChE1) inhibition Stalin A, Daniel Reegan A, Rajiv Gandhi M, Saravanan RR, Balakrishna K, Hesham AE, Ignacimuthu S, Zhang Y Ref: Computers in Biology & Medicine, 146:105535, 2022 : PubMed ESTHER: Stalin_2022_Comput.Biol.Med_146_105535 PubMedSearch: Stalin 2022 Comput.Biol.Med 146 105535 PubMedID: 35487124 Abstract Embelin was isolated from the chloroform extract of Embelia ribes (Burm.f.) fruits; its derivative compounds 6-bromoembelin and vilangin were prepared, and they were evaluated for mosquitocidal activities against the third instar larvae and pupae of Aedes aegypti L. and Culex quinquefasciatus Say. (Diptera: Culicidae). The concentrations used were 0.5, 1.0, 1.5, and 2.0 ppm. Embelin recorded LC(50) values of 5.79 and 5.54 ppm against the larvae of Ae. aegypti and Cx. quinquefasciatus, respectively. Similarly, the LC(50) values of embelin were 10.23 and 6.93 ppm against the pupae of Ae. aegypti and Cx. quinquefasciatus, respectively. Of the two derivatives tested, vilangin showed the highest larvicidal activity with LC(50) values of 1.38 and 1.28 ppm against the larvae of Ae. aegypti and Cx. quinquefasciatus, respectively. Similarly, the LC(50) values of vilangin were 1.60 and 1.43 ppm against the pupae of Ae. aegypti and Cx. quinquefasciatus, respectively. The LC(50) values of 6-bromoembelin were 3.30 and 2.83 ppm against the larvae and 4.40 and 4.30 ppm against the pupae of Ae. aegypti and Cx. quinquefasciatus, respectively. The histopathological results displayed significant damage on cuboidal cells of the midgut (CU) in vilangin treated larvae of Ae. aegypti and Cx. quinquefasciatus at a concentration of 2.0 ppm. Similarly, peritrophic membrane (PM) was completely impaired in vilangin-treated larvae of Cx. quinquefasciatus and midgut content (MC) was very low in vilangin-treated larvae of Cx. quinquefasciatus. In addition, molecular docking and molecular dynamics studies demonstrated the efficacy of vilangin on the inhibition of acetylcholinesterase (AChE1) in Ae. aegypti and Cx. quinquefasciatus. The present results suggest that vilangin could be used to develop a natural active product against mosquito larvae. Title: The Detoxification Enzymatic Responses of Plutella xylostella (Lepidoptera: Plutellidae) to Cantharidin Sun H, Wang P, Wei C, Li Y, Zhang Y Ref: J Econ Entomol, :, 2022 : PubMed ESTHER: Sun_2022_J.Econ.Entomol__ PubMedSearch: Sun 2022 J.Econ.Entomol PubMedID: 36073195 Abstract Plutella xylostella (L.) (Lepidoptera: Plutellidae) is one of the most destructive pests of Brassicaceae vegetables. Cantharidin is an insect-derived defensive toxin, which has been reported to have toxicity to a variety of pests and especially lepidopteran pests. Although the toxicity of cantharidin on P. xylostella has been demonstrated, there is little information available on the specific detoxification response of P. xylostella against cantharidin. This study investigates the enzymatic response (including serine/threonine phosphatases [PSPs], carboxylesterases [CarEs], glutathione-S-transferases [GSTs], and cytochrome P450 monooxygenases [P450]) in P. xylostella to the sublethal and low lethal concentrations of cantharidin (LC10 and LC25). Results showed that the inhibitory activity of PSPs was increased and then decreased in vivo, while PSPs activity could be almost completely inhibited in vitro. Interestingly, the activities of detoxification enzymes (GST, CarE, and P450) in P. xylostella displayed a trend of decreasing and then increasing after exposure to the two concentrations of cantharidin. Notably, the increase in P450 enzyme activity was the most significant. The increasing trend of detoxification enzyme activity was congruent with the recovery trend of PSPs activity. This study contributes to our understanding of the detoxification mechanism of cantharidin in P. xylostella and helps in the further development of biogenic agents. Title: Comparative transcriptome analysis reveals the non-neuronal cholinergic system in the ovary of the oriental armyworm, Mythimna separata Walker (Lepidoptera: Noctuidae) Tian X, Guo J, Su X, Zhan B, Liang X, Ma A, Zhang Y, Lu S Ref: Pest Manag Sci, :, 2022 : PubMed ESTHER: Tian_2022_Pest.Manag.Sci__ PubMedSearch: Tian 2022 Pest.Manag.Sci PubMedID: 36053883 Abstract BACKGROUND: Acetylcholine (ACh), as a classical neurotransmitter, plays great roles in the nervous system. There is increasing evidence of its non-neuronal roles in regulating basic cell functions in vertebrates. However, knowledge about the non-neuronal cholinergic system in insects is scarce. RESULTS: A comparative transcriptome analysis was performed to investigate differences in the key molecular components of the cholinergic system between the head and ovary. The results showed that expression levels of most cholinergic system-related genes were higher in the head than in the ovary, and some cholinergic components were absent in the ovary. ACh contents ranged from 0.1 to 1.3 microg mg(-1) of wet weight during the development of the ovary, and weak acetylcholinesterase activity was also detected. Moreover, the ovary has a capacity for ACh synthesis. Bromoacetylcarnitine (BrACar), a specific carnitine acetyltransferase (CarAT) inhibitor, greatly inhibits ACh synthesis by 83.83% in ovary homogenates, but bromoacetylcholine (BrACh), a specific choline acetyltransferase (ChAT) inhibitor, has no effect on ACh synthesis in the ovary. These findings indicate that non-neuronal ACh in the ovary is only catalyzed by CarAT. CONCLUSION: This study reveals the existence of the non-neuronal cholinergic system in the ovary of M. separata, whose synthesis and release mechanisms are different from those of the head. These results provide novel insights into the non-neuronal cholinergic system in insects, and will be valuable in the discovery of new target genes and the future development of green pest control. 2022 Society of Chemical Industry. Title: Effect of propeptide mutations on the directed evolution of Rhizomucor miehei lipase Wang J, Bai R, Wu N, Zhang Y, Hu L Ref: Protein Pept Lett, :, 2022 : PubMed ESTHER: Wang_2022_Protein.Pept.Lett__ PubMedSearch: Wang 2022 Protein.Pept.Lett PubMedID: 35289250 Gene_locus related to this paper: rhimi-lipas Abstract BACKGROUND: A series of mutants of Rhizomucor miehei lipase (RML) screened through four rounds of directed evolution was studied as the research object. The hydrolysis activity of mutants to triglycerides was determined, and their genes were sequenced. Results showed that mutations in the propeptide can improve the activity of RML during the evolution. Two parts of propeptide (wild-type and mutant) and mature region were connected by molecular simulation technology. METHODS: The spatial structure of the most positive mutants containing the mutations in the propeptide was mainly characterized by the increase in the opening angle of the lid structure in the mature region of RML, the enhancement of the hydrophobicity of the active center, and the triad of the active center shifted outward. RESULTS: The three indexes above explain the mechanism of propeptide mutations on the activity change of the target protein. In addition, statistical analysis of all the mutants screened in directed evolution showed that: (1) most of the mutants with increased activity contained mutations of the propeptide; (2) In the later stage of directed evolution, the number of active mutants decreased gradually, and the mutations of inactivated protein mainly occurred in the mature region; and (3) In the last round of directed evolution, the mutations distributed in the propeptide improved the mutant activity further. The results show the propeptide down the evolutionary pressure of RML and delayed emergence of the evolutionary platform. CONCLUSION: These findings reveal the role of propeptide in the evolution of RML and provide strategies for the molecular transformation of other lipases. Title: Biochemical characterization of an engineered bifunctional xylanase/feruloyl esterase and its synergistic effects with cellulase on lignocellulose hydrolysis Wang H, Qi X, Gao S, Zhang Y, An Y Ref: Bioresour Technol, 355:127244, 2022 : PubMed ESTHER: Wang_2022_Bioresour.Technol_355_127244 PubMedSearch: Wang 2022 Bioresour.Technol 355 127244 PubMedID: 35489578 Abstract Herein, the xylanase and feruloyl esterase domains of the xylanase/feruloyl esterase bifunctional enzyme (Xyn-Fae) from Prevotella ruminicola 23 were identified using N- and C-terminal truncation mutagenesis. In addition, a novel and more efficient xylanase/feruloyl esterase bifunctional enzyme XynII-Fae was constructed, and its synergistic action with a commercial cellulase for lignocellulose hydrolysis was studied. When 40% cellulase was replaced by XynII-Fae, the production of reducing sugars increased by 65% than that with the cellulase alone, and the conversions of xylan and glucan were increased by 125.1% and 54.3%, respectively. When 80% cellulase was substituted by XynII-Fae, up to 43.5 microg/mL ferulic acid and 418.7 microg/mL acetic acid were obtained. The XynII-Fae could also accelerate the hydrolysis of wheat straw and sugarcane bagasse with commercial cellulase. These results indicated that the synergistic action of XynII-Fae with cellulase could dramatically improve the hydrolysis efficiency of lignocellulose, showing the great potential for industrial applications. Title: Chlorophyll Inhibits the Digestion of Soybean Oil in Simulated Human Gastrointestinal System Wang X, Li Y, Shen S, Yang Z, Zhang H, Zhang Y Ref: Nutrients, 14:, 2022 : PubMed ESTHER: Wang_2022_Nutrients_14_ PubMedSearch: Wang 2022 Nutrients 14 PubMedID: 35565719 Abstract Nowadays, much available processed and highly palatable food such as cream products and fried and convenient food, which usually showed a high energy density, had caused an increase in the intake of dietary lipids, further leading to significant growth in the prevalence of obesity. Chlorophyll, widespread in fruits and vegetables, was proven to have beneficial effects on alleviating obesity. This study investigated the effects of chlorophyll on the digestive characteristics of lipids under in vitro simulated adult and infant gastrointestinal systems. Chlorophyll decreased the release rate of free fatty acid (FFA) during in vitro adult and infant intestinal digestion by 69.2% and 60.0%, respectively. Meanwhile, after gastrointestinal digestion, chlorophyll changed the FFA composition of soybean oil emulsion and increased the particle size of oil droplets. Interestingly, with the addition of chlorophyll, the activity of pancreatic lipase was inhibited during digestion, which may be related to pheophytin (a derivative of chlorophyll after gastric digestion). Therefore, the results obtained from isothermal titration calorimetry and molecular docking further elucidated that pheophytin could bind to pancreatic lipase with a strong affinity of (4.38 +/- 0.76) x 10(7) M(-1) (K(a)), while the binding site was amino acid residue Trp253. The investigation not only explained why chlorophyll inhibited digestive enzyme activity to reduce lipids digestion but also provided exciting opportunities for developing novel chlorophyll-based healthy products for dietary application in preventing obesity. Title: Impact of AADAC gene expression on prognosis in patients with Borrmann type III advanced gastric cancer Wang Y, Fang T, Yin X, Zhang L, Zhang X, Zhang D, Zhang Y, Wang X, Wang H, Xue Y Ref: BMC Cancer, 22:635, 2022 : PubMed ESTHER: Wang_2022_BMC.Cancer_22_635 PubMedSearch: Wang 2022 BMC.Cancer 22 635 PubMedID: 35681154 Gene_locus related to this paper: human-AADAC Abstract BACKGROUND: The prognosis of Borrmann type III advanced gastric cancer (AGC) is known to vary significantly among patients. This study aimed to determine which differentially expressed genes (DEGs) are directly related to the survival time of Borrmann type III AGC patients and to construct a prognostic model. METHODS: We selected 25 patients with Borrmann type III AGC who underwent radical gastrectomy. According to the difference in overall survival (OS), the patients were divided into group A (OS<1 year, n=11) and group B (OS>3 years, n=14). DEGs related to survival time in patients with Borrmann type III AGC were determined by mRNA sequencing. The prognosis and functional differences of DEGs in different populations were determined by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) public databases. The expression of mRNA and protein in cell lines was detected by quantitative real-time reverse-transcription polymerase chain reaction (qRT-PCR) and Western blot (WB). Immunohistochemical (IHC) staining was used to detect protein expression in the paraffin-embedded tissues of 152 patients with Borrmann type III AGC who underwent radical gastrectomy. After survival analysis, nomograms were constructed to predict the prognosis of patients with Borrmann type III AGC. RESULTS: Arylacetamide deacetylase (AADAC) is a survival-related DEG in patients with Borrmann type III AGC. The higher the expression level of its mRNA and protein is, the better the prognosis of patients. Bioinformatics analysis found that AADAC showed significant differences in prognosis and function in European and American populations and Asian populations. In addition, the mRNA and protein expression levels of AADAC were high in differentiated gastric cancer (GC) cells. We also found that AADAC was an independent prognostic factor for patients with Borrmann type III AGC, and its high expression was significantly correlated with better OS and disease-free survival (DFS). Nomogram models of AADAC expression level combined with clinicopathological features can be used to predict the OS and DFS of Borrmann type III AGC. CONCLUSION: AADAC can be used as a biomarker to predict the prognosis of Borrmann type III AGC and has the potential to become a new therapeutic target for GC. Title: Soluble Epoxide Hydrolase Inhibitor t-AUCB Ameliorates Vascular Endothelial Dysfunction by Influencing the NF-kB/miR-155-5p/eNOS/NO/IkB Cycle in Hypertensive Rats Wang X, Han W, Zhang Y, Zong Y, Tan N, Li L, Liu C, Liu L Ref: Antioxidants (Basel), 11:, 2022 : PubMed ESTHER: Wang_2022_Antioxidants.(Basel)_11_ PubMedSearch: Wang 2022 Antioxidants.(Basel) 11 PubMedID: 35883863 Abstract Epoxyeicosatrienoic acids (EETs), angiogenic mediators degraded by soluble epoxide hydrolase (sEH), have been shown to exert beneficial effects on the cardiovascular system. The current study assessed the impact of increased EETs with an sEH inhibitor, t-AUCB, on two-kidney-one-clip (2K1C)-induced renovascular endothelial dysfunction, associated with hypertension, in rats. The hypertensive rats exhibited increased systolic blood pressure, reduced renal blood flow, impaired endothelium-dependent relaxation and eNOS phosphorylation in the renal arteries, elevated ROS production in the endothelium of the renal arteries, and decreased EET levels in plasma, the renal arteries, and endothelial cells; however, t-AUCB reversed all the deleterious effects. Moreover, we found that the stimulation of AMPK/UCP2 scavenged ROS and restored endothelial function in the renal arteries of hypertensive rats undergoing therapy with t-AUCB. In addition, we were the first to reveal the potential role of miR-155-5p in the occurrence and development of vascular endothelial dysfunction in hypertension. Importantly, t-AUCB recovered NO bioavailability by regulating the NF-kappaB/miR-155-5p/eNOS/NO/IkappaB cycle after the activation of AMPK/UCP2 and the subsequent inhibition of ROS in hypertensive rat renal artery endothelial cells. This study will provide evidence for this additional new mechanism, underlying the benefits of EETs and the related agents against hypertensive vasculopathy. Title: Analysis of the performance of the efficient di-(2-ethylhexyl) phthalate-degrading bacterium Rhodococcus pyridinovorans DNHP-S2 and associated catabolic pathways Wang L, Gan D, Gong L, Zhang Y, Wang J, Guan R, Zeng L, Qu J, Dong M Ref: Chemosphere, 306:135610, 2022 : PubMed ESTHER: Wang_2022_Chemosphere_306_135610 PubMedSearch: Wang 2022 Chemosphere 306 135610 PubMedID: 35810862 Abstract The widespread use of plastic has led to the global occurrence of phthalate esters (PAEs) pollution. PAEs can be effectively removed from polluted environments by microbe-mediated degradation. Di-(2-ethylhexyl) phthalate (DEHP) has the highest residual concentration in agricultural soil-contaminated areas compared to other PAEs in most of China. The Rhodococcus pyridinovorans DNHP-S2 microbial isolate identified was found to efficiently degrade DEHP. Within a 72 h period, the bacteria were able to degrade 52.47% and 99.75% of 500 mg L(-1) DEHP at 10 degreesC and 35 degreesC, respectively. Dimethyl phthalate (DMP) was first identified as an intermediate metabolite of DEHP, which is different from the previously reported DEHP catabolic pathway. Genomic sequencing of DNHP-S2 identified benzoate 1,2-dioxygenase and catechol 2,3/1,2-dioxygenase as potential mediators of DEHP degradation, consistent with the existence of two downstream metabolic pathways governing DEHP degradation. Three targets DEHP metabolism-related enzymes were found to be DEHP-inducible at the mRNA level, and DNHP-S2 was able to mediate the complete degradation of DEHP at lower temperatures, as confirmed via RT-qPCR. DNHP-S2 was also found to readily break down other PAEs including DMP, di-n-butyl phthalate (DBP), di-n-octyl phthalate (DnOP), and n-butyl benzyl phthalate (BBP). Together, these results thus highlight DNHP-S2 as a bacterial strain with great promise as a tool for the remediation of PAE pollution. In addition to providing new germplasm and genetic resources for use in the context of PAE degradation, these results also offer new insight into the potential mechanisms whereby PAEs undergo catabolic degradation, making them well-suited for use in PAE-contaminated environments. Title: Probing strigolactone perception mechanisms with rationally designed small-molecule agonists stimulating germination of root parasitic weeds Wang D, Pang Z, Yu H, Thiombiano B, Walmsley A, Yu S, Zhang Y, Wei T, Liang L and Xi Z <4 more author(s)> Wang D, Pang Z, Yu H, Thiombiano B, Walmsley A, Yu S, Zhang Y, Wei T, Liang L, Wang J, Wen X, Bouwmeester HJ, Yao R, Xi Z (- 4) Ref: Nat Commun, 13:3987, 2022 : PubMed ESTHER: Wang_2022_Nat.Commun_13_3987 PubMedSearch: Wang 2022 Nat.Commun 13 3987 PubMedID: 35810153 Abstract The development of potent strigolactone (SL) agonists as suicidal germination inducers could be a useful strategy for controlling root parasitic weeds, but uncertainty about the SL perception mechanism impedes real progress. Here we describe small-molecule agonists that efficiently stimulate Phelipanchce aegyptiaca, and Striga hermonthica, germination in concentrations as low as 10(-8) to 10(-17) M. We show that full efficiency of synthetic SL agonists in triggering signaling through the Striga SL receptor, ShHTL7, depends on the receptor-catalyzed hydrolytic reaction of the agonists. Additionally, we reveal that the stereochemistry of synthetic SL analogs affects the hydrolytic ability of ShHTL7 by influencing the probability of the privileged conformations of ShHTL7. Importantly, an alternative ShHTL7-mediated hydrolysis mechanism, proceeding via nucleophilic attack of the NE2 atom of H246 to the 2'C of the D-ring, is reported. Together, our findings provide insight into SL hydrolysis and structure-perception mechanisms, and potent suicide germination stimulants, which would contribute to the elimination of the noxious parasitic weeds. Title: Alternative splicing of a carboxyl/choline esterase gene enhances the fenpropathrin tolerance of Tetranychus cinnabarinus Wei P, Zeng X, Han H, Yang Y, Zhang Y, He L Ref: Insect Sci, :, 2022 : PubMed ESTHER: Wei_2022_Insect.Sci__ PubMedSearch: Wei 2022 Insect.Sci PubMedID: 36544383 Abstract Detoxification plays a crucial role in agricultural pests to withstand the pesticides, and cytochrome P450s, carboxyl/cholinesterases (CCEs), and glutathione-S-transferases are the main proteins responsible for their detoxification ability. The activity of CCEs can be up-regulated, down-regulated, or modified by mutation. However, few studies have examined the role of alternative splicing in altering the properties of CCEs. We identified two variants of TcCCE23 in Tetranychus cinnabarinus: a long version (CCE23-V1) and a short version that is 18 nucleotides shorter than CCE23-V1 (CCE23-V2). Whether splicing affects the activity of TcCCE23 remains unclear. Overexpression of CCE23-V2 in fenpropathrin resistant T. cinnabarinus revealed that splicing affected the detoxification of fenpropathrin by CCE23-V2. The mortality of mites was significantly higher when the expression of CCE23-V2 was knocked down (43.2% +/- 3.3%) via injection of CCE23-dsRNA compared with the control group injected with GFP-dsRNA under fenpropathrin exposure; however, the down-regulation of CCE23-V1 (61.3 +/- 6.3%) by CCE23-siRNA had no such effect, indicating CCE23-V2 plays a greater role in xenobiotic metabolism than CCE23-V1. The tolerance of flies overexpressing CCE23-V2 to fenpropathrin (LD(50) = 19.47 microg/g) was significantly higher than that of Gal4/UAS-CCE23-V1 transgenic flies (LD(50) = 13.11 microg/g). Molecular docking analysis showed that splicing opened a 'gate' that enlarge the substrate binding cavity of CCE23-V2, which might enhance the ability of CCE23-V2 to harbor fenpropathrin molecules. These findings suggest that splicing might enhance the detoxifying capability of TcCCE23. Generally, our data improve the understanding of the diversity and complexity of the mechanisms underlying the regulation of CCEs. This article is protected by copyright. All rights reserved. Title: Altereporenes A-E, five epoxy octa-hydronaphthalene polyketides produced by an endophytic fungus Alternaria sp. YUD20002 Xia DD, Duan HJ, Xie F, Xie TP, Zhang Y, Sun Y, Lu JM, Gao YH, Zhou H, Ding ZT Ref: RSC Adv, 12:22295, 2022 : PubMed ESTHER: Xia_2022_RSC.Adv_12_22295 PubMedSearch: Xia 2022 RSC.Adv 12 22295 PubMedID: 36043060 Abstract Five previously undescribed epoxy octa-hydronaphthalene polyketides, altereporenes A-E (1-5) were isolated from rice culture of the endophytic fungus Alternaria sp. YUD20002 derived from the tubers of Solanum tuberosum. Their structures were determined on the basis of comprehensive spectroscopic analyses, while the absolute configurations were elucidated by the comparison of experimental and calculated specific rotations. Meanwhile, the antimicrobial, cytotoxic, anti-inflammatory and acetylcholinesterase inhibitory activities of compounds 1-5 were also investigated. Title: Microplastics exposure as an emerging threat to ancient lineage: A contaminant of concern for abnormal bending of amphioxus via neurotoxicity Xiang K, He Z, Fu J, Wang G, Li H, Zhang Y, Zhang S, Chen L Ref: J Hazard Mater, 438:129454, 2022 : PubMed ESTHER: Xiang_2022_J.Hazard.Mater_438_129454 PubMedSearch: Xiang 2022 J.Hazard.Mater 438 129454 PubMedID: 35803186 Abstract Growing inputs of microplastics into marine sediment have increased significantly the needs for assessment of their potential risks to the marine benthos. A knowledge gap remains with regard to the effect of microplastics on benthos, such as cephalochordates. By employing amphioxus as a model benthic chordate, here we show that exposure to microplastics for 96 h at doses of 1 mg/L and 100 mg/L results in evident accumulation of the polyethylene microplastics. The accumulated microplastics are as much as 0.027% of body weight upon high-dose exposure, causing an abnormal body-bending phenotype that limits the locomotion capability of amphioxus. Mechanistic insight reveals that microplastics can bring about histological damages in gill, intestine and hepatic cecum; In-depth assay of relevant biomarkers including superoxide dismutase, catalase, glutathione, pyruvic acid and total cholesterol indicates the occurrence of oxidative damage and metabolic disorder; Further, microplastics exposure depresses the activity of acetylcholinesterase while allowing the level of acetylcholine to rise in muscle, suggesting the emergence of neurotoxicity. These consequences eventually contribute to the muscle dysfunction of amphioxus. This study rationalizes the abnormal response of the vulnerable notochord to microplastics, signifying the dilemma suffered by the ancient lineage under the emerging threat. Given the enrichment of microplastics through marine food chains, this study also raises significant concerns on the impact of microplastics to other marine organisms, and eventually human beings. Title: Effects of urea application on the reproduction of Pardosa pseudoannulata: Field and laboratory studies Yang Z, Wang Y, Wang K, Zhang Y, Yu N, Liu Z Ref: Chemosphere, 301:134697, 2022 : PubMed ESTHER: Yang_2022_Chemosphere_301_134697 PubMedSearch: Yang 2022 Chemosphere 301 134697 PubMedID: 35513078 Abstract As an important chemical fertilizer, urea can greatly increase crop yields, but it also has negative effects on beneficial arthropods in the agricultural field, such as spiders. Here, we reported that urea application reduced the reproductive performance in Pardosa pseudoannulata, a dominant species of spider in rice fields, which preys on a range of insect pests, based on both field and laboratory studies. In a field test, urea application significantly reduced the egg production of adult and subadult females collected from the urea-treated fields. A laboratory test was set up to further evaluate the impact of urea application on P. pseudoannulata reproduction. In consistent with field test results, the spiders treated by urea for 14 d and 28 d had lower reproduction ability than their control counterparts, with regard to the mating rate, egg production, and egg hatchability. The transcriptomic sequencing of individuals treated by urea for 28 d showed that urea application caused a number of differentially expressed transcripts with several downregulated unigenes related to basic enzymes and several upregulated unigenes involved in stress resistance. The knockdown of a metalloproteinase gene caused a significant decrease in egg production, and the silencing of a carboxylesterase gene significantly reduced both the egg production and egg hatchability. Taken together, the present study found that urea application reduced P. pseudoannulata reproduction ability and the negative impact partially resulted from the downregulation of certain basic enzyme genes. The study provided a fresh view of fertilizers on beneficial arthropods with great potential in the protection of P. pseudoannulata in fields. Title: Development of an esterase fluorescent probe based on naphthalimide-benzothiazole conjugation and its applications for qualitative detection of esterase in orlistat-treated biosamples Yin Y, Kong X, Li M, Wang J, Dai X, Zhang Y, Lin W Ref: Anal Chim Acta, 1190:339248, 2022 : PubMed ESTHER: Yin_2022_Anal.Chim.Acta_1190_339248 PubMedSearch: Yin 2022 Anal.Chim.Acta 1190 339248 PubMedID: 34857133 Abstract Esterase is a large hydrolysis family, and widely distributed in many kinds of cells. It is responsible for multiple physiological and pathological functions including metabolism, gene expression. While abnormality of esterase is associated with many pathological activities in obesity, Wolman's disease, and cancer. Thereby, it is essential to design an effective tool for esterase in situ detection in biological systems. Herein, a novel fluorescent probe Y-1 for monitoring esterase in living cells was rationally designed. Probe Y-1 was synthesized by the conjugation between an acetylation of 4-hydroxy naphthalimide and benzothiazole group. Benzothiazole moiety is a typical Excited-state intramolecular proton transfer (ESIPT) controller. Acetate group was selected as the responsive site and ESIPT initiator. As the acetate group could block the ESIPT effect, the probe emits no fluorescence under the excitation of 455 nm. When binding with esterase, Y-1 shows distinct fluorescence with the peak at 560 nm with short time when ESIPT is on. Y-1 displays high sensitivity (LOD is 0.216 x 10(-3) U/mL), fast response (within 5 min), high selectivity and photostability towards esterase. Furthermore, the %RSD (relative standard deviation) of within-day and day-to-day precision was no more than 13.0% and the accuracy ranged from -6.5 to -12.3%. Kinetics performance of Y-1 indicates that esterase has high affinity and hydrolysis to Y-1. For biological applications, our probe is a time-dependent visualizing esterase in living HepG2 and CoLo205 cells within 15 min. After the treatment of orlistat (1 and 5 microM) for inhibiting the activity of esterase, the bright fluorescence has also been detected using our probe. Furthermore, it has been successful in monitoring the esterase in zebrafish, the data were consistent with cellular phenomena. Therefore, all these findings indicate that the robust probe Y-1 is a useful qualitative tool for detecting esterase in biological systems. Title: Plasma-Soluble Dipeptidyl Peptidase 4 and Risk of Major Cardiovascular Events After Ischemic Stroke: Secondary Analysis of China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) You S, Miao M, Lu Z, Bao A, Du J, Che B, Xu T, Zhong C, Cao Y and He J <2 more author(s)> You S, Miao M, Lu Z, Bao A, Du J, Che B, Xu T, Zhong C, Cao Y, Liu CF, Zhang Y, He J (- 2) Ref: Neurology, :, 2022 : PubMed ESTHER: You_2022_Neurology__ PubMedSearch: You 2022 Neurology PubMedID: 35654589 Abstract BACKGROUND AND OBJECTIVES: Recent studies have suggested that plasma soluble dipeptidyl peptidase-4 (sDPP4) have important physiological effects, which may influence the prognosis of ischemic stroke. Our study aimed to examine the relationship between plasma sDDP4 levels and long-term clinical outcomes among acute ischemic stroke patients. METHODS: Secondary analysis was conducted among 3,564 participants (2,270 men and 1,294 women) from the China Antihypertensive Trial in Acute Ischemic Stroke with baseline measurement of plasma sDPP4 levels. We evaluated the associations between plasma sDPP4 levels and 2-year clinical outcomes using logistic regression and Cox regression models. We further investigated the predictive utility of sDPP4 by calculating net reclassification index (NRI) and integrated discrimination improvement (IDI). RESULTS: The highest plasma sDPP4 quartile was associated with lower risk of cardiovascular events (HR 0.62, 95% CI 0.45-0.87), recurrent stroke (HR 0.70, 95% CI 0.49-0.99), all-cause mortality (HR 0.62, 95% CI 0.44-0.87), stroke-specific mortality (HR 0.65, 95% CI 0.44-0.94) and poor functional outcomes (OR 0.66, 95% CI 0.53-0.82) at 2 years compared with the lowest sDPP4 category in multivariable models. The addition of plasma sDPP4 to conventional risk factors model significantly improved risk prediction of all outcomes. DISCUSSION: In this study, we found that higher plasma sDPP4 levels in acute ischemic stroke patients were associated with decreased risks of cardiovascular events, recurrent stroke, all-cause mortality, and poor functional outcomes after ischemic stroke. These findings suggest that plasma sDPP4 may be a potential prognostic marker for initial risk stratification in patients with acute ischemic stroke. Title: Antifeedant Mechanism of Dodonaea viscosa Saponin A Isolated from the Seeds of Dodonaea viscosa Yu P, Chen Z, Liu Y, Gu Z, Wang X, Zhang Y, Ma Y, Dong M, Tian Z and Ding X <10 more author(s)> Yu P, Chen Z, Liu Y, Gu Z, Wang X, Zhang Y, Ma Y, Dong M, Tian Z, Yu H, Li J, Wu G, Tang Q, Duan X, Liu Q, Lan M, Zhao Y, Hao X, Qin X, Ding X (- 10) Ref: Molecules, 27:, 2022 : PubMed ESTHER: Yu_2022_Molecules_27_ PubMedSearch: Yu 2022 Molecules 27 PubMedID: 35335376 35889337 Abstract Dodonaea viscosa is a medicinal plant which has been used to treat various diseases in humans. However, the anti-insect activity of extracts from D. viscosa has not been evaluated. Here, we found that the total saponins from D. viscosa (TSDV) had strong antifeedant and growth inhibition activities against 4th-instar larvae of Spodoptera litura. The median antifeeding concentration (AFC(50)) value of TSDV on larvae was 1621.81 microg/mL. TSDV affected the detoxification enzyme system of the larvae and also exerted antifeedant activity possibly through targeting the gamma-aminobutyric acid (GABA) system. The AFC(50) concentration, the carboxylesterase activity, glutathione S-transferases activity, and cytochrome P450 content increased to 258%, 205%, and 215%, respectively, and likewise the glutamate decarboxylase activity and GABA content to 195% and 230%, respectively, in larvae which fed on TSDV. However, D. viscosa saponin A (DVSA) showed better antifeedant activity and growth inhibition activity in larvae, compared to TSDV. DVSA also exerted their antifeedant activity possibly through targeting the GABA system and subsequently affected the detoxification enzyme system. Further, DVSA directly affected the medial sensillum and the lateral sensillum of the 4th-instar larvae. Stimulation of Spodoptera litura. with DVSA elicited clear, consistent, and robust excitatory responses in a single taste cell. Title: Natural products as sources of acetylcholinesterase inhibitors: Synthesis, biological activities, and molecular docking studies of osthole-based ester derivatives Yu X, Zhang Y, Zhang M, Chen Y, Yang W Ref: Front Plant Sci, 13:1054650, 2022 : PubMed ESTHER: Yu_2022_Front.Plant.Sci_13_1054650 PubMedSearch: Yu 2022 Front.Plant.Sci 13 1054650 PubMedID: 36466282 Abstract Osthole is a natural coumarin compound which isolated from Cnidium monnieri (L.) Cusson, has extensive pharmacological activities and could be used as a leading compound for drug research and development. In a continuous effort to develop new acetylcholinesterase inhibitors from natural products, eighteen osthole esters were designed, synthesized, and confirmed by (1)H NMR, (13)C NMR and HRMS. The anti-AChE activity of These derivatives was measured at a concentration of 1.0 mol/mL in vitro by Ellman's method, and the result showed that 4m and 4o had moderate inhibitory activities with 68.8% and 62.6%, respectively. Molecular docking study results further revealed AChE interacted optimally with docking poses 4m and 4o. Network pharmacology also predicted that compound 4m could be involved in Ras signaling pathway, which made it a potential therapeutic target of AD. Title: Chemical profile, anti-hepatoma activity, anti-acetylcholinesterase and antioxidant activity of aerial part of Aconitum carmichaeli Debx Yu J, Xia J, Xu J, Chen S, Zhang Y, Yin F, Fang J, Cai L, Zhang B and Liang Z <3 more author(s)> Yu J, Xia J, Xu J, Chen S, Zhang Y, Yin F, Fang J, Cai L, Zhang B, Zhan Y, Zhang X, Zeng Z, Liang Z (- 3) Ref: Nat Prod Res, :1, 2022 : PubMed ESTHER: Yu_2022_Nat.Prod.Res__1 PubMedSearch: Yu 2022 Nat.Prod.Res 1 PubMedID: 36503283 Abstract Five extracts of the aerial parts of Aconitum carmichaeli were obtained by different solvent extraction or macroporous adsorption resin purification: ethyl acetate layer extract (EAE), n-butanol layer extract (BuE), water layer extract (WE), extract eluted by 10% ethanol from macroporous resin (10%EE), extract eluted by 80% ethanol from macroporous resin (80%EE). Antioxidant activities of the five extracts were determined by ABTS, DPPH, FRAP assays, anti-AChE activities by modified Ellman's method, insvitro anti-hepatoma activities by CCK-8 assay, and chemical constituents of 80%EE were identified by UPLC-QE-Orbitrap-MS. The results demonstrated that the 80%EE showed the best insvitro anti-hepatoma activity on Huh-7 cell line with an IC(50) of 103.91 +/- 11.02 microg/mL. 10%EE and 80%EE gave the highest antioxidant activity. Furthermore, current findings demonstrated that the aerial part of Aconitum carmichaeli Debx. has high medicinal value and may be a good natural medicine. Title: Site-selective covalently immobilized alpha 1A adrenergic receptor for thermodynamic and extra-thermodynamic study of four ligands binding to the receptor by chromatographic methods Yuan X, Shayiranbieke A, Xu R, Jiang H, Yang Y, Zhang Y, Yin G, Zhao X Ref: Journal of Chromatography A, 1665:462827, 2022 : PubMed ESTHER: Yuan_2022_J.Chromatogr.A_1665_462827 PubMedSearch: Yuan 2022 J.Chromatogr.A 1665 462827 PubMedID: 35078002 Abstract Immobilized G protein-coupled receptor is a versatile tool to study ligand-receptor interactions. In this work, we synthesized the immobilized alpha 1A adrenergic receptor (alpha(1A)-AR), a GPCR subtype mediating smooth muscle contraction, through a site-selective covalent method that relies on the reaction between haloalkane dehalogenase tagged alpha(1A)-AR and macroporous silica gel coated with 6-chlorohexanoic acid. To investigate thermodynamic and extra-thermodynamic parameters for ligand binding, we utilized the covalently immobilized receptor as stationary phase to perform frontal analysis and injection-amount dependent analysis as well as compared with the random immobilization method. Terazosin gave the association constant of 1.48 x 10(5) M(-1) to alpha(1A)-AR, indicating that the oriented immobilization of alpha(1A)-AR enhances the ligand-binding activity by one order of magnitude in comparison with the random immobilization method (7.9 x 10(4) M(-1)). The binding of phentolamine and tamsulosin to the receptor was accompanied by a large absolute heat capacity (deltaC(p)) of 1.28 +/- 0.23 kJ mol(-1), demonstrating that the binding enthalpy and entropy appear to compensate for one another. These results indicated that the covalent immobilization of the receptor onto solid support has a profound impact on the ligand-binding activity of the receptor and the determination of ligand-receptor binding parameters. The receptor immobilized through the site-selective method will act as a benchmark for chromatographic determination of binding parameters in ligand-receptor interactions and can be used as an effective approach for rapid analysis of drug-protein interactions with high accuracy. Title: Methyl Jasmonate-Treated Pepper (Capsicum annuum L.) Depresses Performance and Alters Activities of Protective, Detoxification and Digestive Enzymes of Green Peach Aphid [Myzus persicae (Sulzer) (Hemiptera: Aphididae)] Zhan X, Liu Y, Liang X, Wu C, Liu X, Shui J, Zhang Y, Wang Y, Chen Q Ref: J Insect Sci, 22:, 2022 : PubMed ESTHER: Zhan_2022_J.Insect.Sci_22_ PubMedSearch: Zhan 2022 J.Insect.Sci 22 PubMedID: 36545895 Abstract Methyl jasmonate (MeJA) is a phytohormone that has been used to artificially induce plant resistance against multiple arthropod herbivores. However, it is still uncertain whether MeJA can trigger pepper plant resistance against Myzus persicae (Sulzer) (Hemiptera: Aphididae) (green peach aphid, GPA). In this study, we assessed the effects of different concentrations (0, 0.008, 0.04, 0.2, 1.0, and 5.0 mM) of MeJA-treated pepper on the development and reproduction performance of GPA to identify an appropriate concentration for vigorous resistance enhancement. MeJA dose was applied on the pepper to investigate the changes in activities of protective enzyme (superoxide dismutase, SOD; catalase, CAT; peroxidase, POD and polyphenol oxidase, PPO), detoxification enzymes (acetylcholinesterase, AchE; glutathione S-transferase, GSTs; cytocrome P450, CYP450, and carboxylesterase, CarE), and digestive enzymes (protease, PRO and amylase, AMY) in GPA. The results showed that all concentrations of MeJA-treated pepper significantly suppressed GPA performance, wherein 0.2 mM was the optimal concentration, as it presented the lowest intrinsic rate of increase (rm), finite rate of increase (lambda), and the highest population doubling time (Dt) values. Furthermore, the protective enzymes (SOD and CAT), detoxification enzymes (GSTs, CYP450, and CarE), and AMY activities increased significantly in MeJA-treated groups than the control group, while the POD and PPO activities were remarkly inhibited under 0.2 mM treatment. These findings indicate that exogenous spraying of 0.2 mM of MeJA significantly enhanced pepper resistance against GPA. The result of this study suggests MeJA application can be used as a promising strategy in integrative management of this insect pest. Title: UHPLC-QTOF/MS-based comparative metabolomics in pectoralis major of fast- and slow-growing chickens at market ages Zhang J, Cao J, Geng A, Wang H, Chu Q, Yan Z, Zhang X, Zhang Y, Liu H Ref: Food Sci Nutr, 10:487, 2022 : PubMed ESTHER: Zhang_2022_Food.Sci.Nutr_10_487 PubMedSearch: Zhang 2022 Food.Sci.Nutr 10 487 PubMedID: 35154685 Abstract The molecular regulatory mechanism underlying meat quality between different chicken genotypes remains elusive. This study aimed to identify the differences in metabolites and pathways in pectoralis major (breast muscle) between a commercial fast-growing chicken genotype (Cobb500) and a slow-growing Chinese native chicken genotype (Beijing-You chickens, BYC) at market ages respectively based on ultra-high-performance liquid chromatography-quadrupole/time of flight mass spectrometry (UHPLC-QTOF/MS). Eighteen metabolites were identified as potential biomarkers between BYC and Cobb500 at market ages. Among them, L-cysteine exhibited a higher relative intensity in BYC compared with Cobb500 and was enriched into 10 potential flavor-associated KEGG pathways. In addition, the glycerophospholipid metabolism pathway was found to be associated with chicken meat flavor and the accumulation of sn-glycerol 3-phosphate and acetylcholine was more predominant in BYC than that in Cobb500, which were catalyzed by glycerophosphocholine phosphodiesterase (GPCPD1, EC:3.1.4.2), choline O-acetyltransferase (CHAT, EC:2.3.1.6), and acetylcholinesterase (ACHE, EC:3.1.1.7). Overall, the present study provided some metabolites and pathways for further investigating the roles of the differences in meat flavor quality in breast muscle between Cobb500 and BYC at market ages. Title: Response of xenobiotic biodegradation and metabolic genes in Tribolium castaneum following eugenol exposure Zhang Y, Gao S, Zhang P, Sun H, Lu R, Yu R, Li Y, Zhang K, Li B Ref: Mol Genet Genomics, :, 2022 : PubMed ESTHER: Zhang_2022_Mol.Genet.Genomics__ PubMedSearch: Zhang 2022 Mol.Genet.Genomics PubMedID: 35419714 Abstract Eugenol, a plant-derived component possessing small side effects, has an insecticidal activity to Tribolium castaneum; however, the underlying molecular mechanisms of eugenol acting on T. castaneum are currently unclear. Here, a nerve conduction carboxylesterase and a detoxifying glutathione S-transferase were significantly inhibited after eugenol exposure, resulting in the paralysis or death of beetles. Then, RNA-sequencing of eugenol-exposed and control samples identified 362 differentially expressed genes (DEGs), containing 206 up-regulated and 156 down-regulated genes. RNA-seq data were validated further by qRT-PCR. GO analysis revealed that DEGs were associated with 1308 GO terms of which the most enriched GO terms were catalytic activity, and integral component of membrane; KEGG pathway analysis showed that these DEGs were distributed in 151 different pathways, of which some pathways associated with metabolism of xenobiotics or drug were significantly enriched, which indicated that eugenol most likely disturbed the processes of metabolism, and detoxication. Moreover, several DEGs including Hexokinase type 2, Isocitrate dehydrogenase, and Cytochrome b-related protein, might participate in the respiratory metabolism of eugenol-exposed beetles. Some DEGs encoding CYP, UGT, GST, OBP, CSP, and ABC transporter were involved in the xenobiotic or drug metabolism pathway, which suggested that these genes of T. castaneum participated in the response to eugenol exposure. Additionally, TcOBPC11/ TcGSTs7, detected by qRT-PCR and RNA-interference against these genes, significantly increased the mortality of eugenol-treated T. castaneum, providing further evidence for the involvement of OBP/GST in eugenol metabolic detoxification in T. castaneum. These results aid eugenol insecticidal mechanisms and provide the basis of insect control. Title: Acetylcholinesterase-capped mesoporous silica gated switches for selective detection of high-toxicity organophosphate compounds Zhang Y, Li T, Sun X, Liu H, Wang Y, Nie Z Ref: Anal Chim Acta, 1207:339708, 2022 : PubMed ESTHER: Zhang_2022_Anal.Chim.Acta_1207_339708 PubMedSearch: Zhang 2022 Anal.Chim.Acta 1207 339708 PubMedID: 35491047 Abstract Organophosphate (OP) compounds are widely used in agriculture, industry, and even terrorism. It is important to distinguish high-toxicity OP compounds from low-toxicity OP compounds in dealing with chemical accidents. However, there are very few portable and simple detection methods. Mesoporous silica gated switches may provide an effective solution. In this study, a gated switch based on mesoporous silica as an inorganic scaffold loaded with sulforhodamine B and capped with acetylcholinesterase (AChE) was prepared for specific detection of OP compounds. Carbamate derivatives (G1-G6) were designed and synthetized as grafting compounds in consideration of the binding ability with AChE. Through further modification and optimization, grafting compound G6 with phenylpyridine as the substituent showed the best capping capacity, and it achieved excellent blocking of mesoporous silica gated switches for loaded sulforhodamine B. In the presence of high-toxicity OP compounds, low-toxicity OP compounds, AChE substrates and reversible AChE inhibitors respectively, only high-toxicity OP compounds could make the gated switch release loaded sulforhodamine B. The limit of detection for paraoxon-ethyl was 10.6 micro. Furthermore, the preparation process of the gated switch is fast and simple, and the prepared gated switch has good stability and rapid distinguishing ability. The results of this paper provide a new idea for rapidly distinguishing high-toxicity OP compounds from low-toxicity OP compounds and other related compounds on the spot. Title: Huperzine-A Improved Animal Behavior in Cuprizone-Induced Mouse Model by Alleviating Demyelination and Neuroinflammation Zhang T, Kim MJ, Wu X, Yang HJ, Yuan H, Huang S, Yoon SM, Kim KN, Park S and Wang J <46 more author(s)> Zhang T, Kim MJ, Wu X, Yang HJ, Yuan H, Huang S, Yoon SM, Kim KN, Park S, Zhang Y, Yao J, Yin K, Liu Z, Deng C, Liu J, Hou S, Zhang H, Yu D, Zhao N, Zhao R, Chen S, Zhang ZP, Bai X, Cui WB, Chen XH, Liu X, Zhi DJ, Zhang ZX, Fei DQ, Wang DS, Zhang X, Wang Y, Zhu H, Zhong Z, Zhang CY, Tan XH, Yang HH, Jin L, Hong JR, Zhou Y, Huang XT, Zhang M, Xiang R, Glorieux C, Huang P, Young C, Morishita Y, Kim K, Kabil OO, Clarke OB, Di Jeso B, Arvan P, Wang D, Sun J, Wu S, Wang J (- 46) Ref: Int J Mol Sci, 23:, 2022 : PubMed ESTHER: Zhang_2022_Int.J.Mol.Sci_23_ PubMedSearch: Zhang 2022 Int.J.Mol.Sci 23 PubMedID: 35328781 35563299 35743309 35887300 35897843 36233022 36362390 36555825 Abstract Huperzine A (HupA) is a natural acetylcholinesterase inhibitor (AChEI) with the advantages of high efficiency, selectivity as well as reversibility and can exhibit significant therapeutic effects against certain neurodegenerative diseases. It is also beneficial in reducing the neurological impairment and neuroinflammation of experimental autoimmune encephalomyelitis (EAE), a classic model for multiple sclerosis (MS). However, whether HupA can directly regulate oligodendrocyte differentiation and maturation and promote remyelination has not been investigated previously. In this study, we have analyzed the potential protective effects of HupA on the demylination model of MS induced by cuprizone (CPZ). It was found that HupA significantly attenuated anxiety-like behavior, as well as augmented motor and cognitive functions in CPZ mice. It also decreased demyelination and axonal injury in CPZ mice. Moreover, in CPZ mice, HupA increased mRNA levels of the various anti-inflammatory cytokines (Arg1, CD206) while reducing the levels of different pro-inflammatory cytokines (iNOS, IL-1beta, IL-18, CD16, and TNF-alpha). Mecamylamine, a nicotinic acetylcholinergic receptor antagonist, could effectively reverse the effects of HupA. Therefore, we concluded that HupA primarily exerts its therapeutic effects on multiple sclerosis through alleviating demyelination and neuroinflammation. Title: Inhibition of Radix Scutellariae flavones on carboxylesterase mediated activations of prodrugs Zhang J, Xiao M, Ji X, Lai YS, Song Q, Zhang Y, Ip CM, Ng WL, Zuo Z Ref: Life Sciences, :120743, 2022 : PubMed ESTHER: Zhang_2022_Life.Sci__120743 PubMedSearch: Zhang 2022 Life.Sci 120743 PubMedID: 35780840 Abstract AIMS: Carboxylesterase (CES) plays an essential role in the hydrolysis of ester prodrugs. Our study explored the inhibitions of Radix Scutellariae flavones, including baicalein (B), baicalin (BG), wogonin (W), wogonoside (WG), oroxylin A (OXA) and oroxylin A-7-O-glucuronide (OAG), on CES-mediated hydrolysis of seven prodrugs (capecitabine, clopidogrel, mycophenolate mofetil, dabigatran etexilate, acetylsalicylic acid, prasugrel and irinotecan). MAIN METHODS: In vitro screenings were developed by incubating the flavones with prodrugs in rat plasma, intestine S9 and liver S9. Docking simulations were conducted using AMDock v1.5.2. In vivo evaluations were performed in rats co-administered with the selected flavone and prodrug via oral gavage/intravenous administration for five consecutive days. KEY FINDINGS: The in vitro investigation showed that B and OXA demonstrated strongest inhibitions on the hydrolysis of irinotecan followed by dabigatran in rat plasma, intestine S9 and liver S9. Consistent results showed in the molecular docking analyses. Additionally, in rats receiving irinotecan, B/OXA intravenous and oral pre-treatments both led to reduction trends on the active metabolite SN-38 formation in plasma. Besides, significant decreases of SN-38/irinotecan plasma concentration ratios were found in the B/OXA oral pre-treatment group with quicker and stronger inhibition potential in OXA pre-treatment than that from B pre-treatment. OXA oral pre-treatment was also found to be able to significantly inhibit intestinal CES2 activities at 0.5 h and 5 h after irinotecan administration. SIGNIFICANCE: Our current findings for the first time alert on potential CES-mediated HDIs between RS flavones and prodrugs, which provide a constructive information referring to rational drug combinations in clinical practice. Title: Toxicological and Biochemical Description of Synergism of Beauveria bassiana and Emamectin Benzoate against Megalurothrips usitatus (Bagrall) Zhang Y, Zhang X, Tian Q, Ali S, Tang L, Wu J Ref: J Fungi (Basel), 8:, 2022 : PubMed ESTHER: Zhang_2022_J.Fungi.(Basel)_8_ PubMedSearch: Zhang 2022 J.Fungi.(Basel) 8 PubMedID: 36135641 Abstract The prophylactic application of synthetic insecticides to manage Megalurothrips usitatus (Bagrall) has resulted in insecticide resistance and negative impacts upon natural ecosystems. This has driven the need for developing alternative pest control strategies. In the present study, we investigated the synergistic interaction between the entomopathogenic fungus Beauveria bassiana and the insecticide emamectin benzoate on M. usitatus. The results of our research exhibited that higher doses of emamectin benzoate inhibited the germination rate and colony growth of B. bassiana. The percentage of M. usitatus mortality following B. bassiana and emamectin benzoate treatment indicated a dose-mortality effect. All concentrations of emamectin benzoate combined with different concentrations of B. bassiana demonstrated a synergistic effect five days post-treatment. When B. bassiana and emamectin benzoate were applied alone or in combination, antioxidant enzyme activities, including acetylcholinesterase, catalase, superoxide dismutase, and peroxidase, were significantly lower in M. usiatus than in the controls at the end of the experimental period. The findings of our study confirm the synergistic effect of B. bassiana and emamectin benzoate on M. usitatus, as well as the biochemical process that might be involved in the regulation of the synergistic effect. Title: Role of epoxyeicosatrienoic acids in cardiovascular diseases and cardiotoxicity of drugs Zhang Y, Gao L, Yao B, Huang S, Liu J, Liu Z, Wang X Ref: Life Sciences, 310:121122, 2022 : PubMed ESTHER: Zhang_2022_Life.Sci_310_121122 PubMedSearch: Zhang 2022 Life.Sci 310 121122 PubMedID: 36309225 Abstract Epoxyeicosatrienoic acids (EETs) are important endogenous substances that affect heart function in human body. Animal models of cytochrome P450 (CYP) and soluble epoxide hydrolase (sEH) related cardiovascular diseases (CVD) have revealed the physiological effects of EETs, mainly including vascular function regulation, angiogenesis, myocardial fibrosis, myocardial hypertrophy, and cardiovascular inflammation. At the same time, clinical studies have found that most of the substrates and inhibitors of CYP2J2 affect the content of EETs, resulting in cardiotoxicity of drugs. Therefore, the regulation of CYP and sEH enzymes on EETs points out the direction for exploring EET-mediated cardiac protection. The metabolic pathway of EETs is not only an important target for the development of new drugs for CVD but also an important factor in preventing drug cardiotoxicity. The development and clinical application of sEH inhibitors and EETs analogues provide broad prospects for the treatment of CVD. Title: Genetic manipulation of the interconversion between diacylglycerols and triacylglycerols in Rhodosporidium toruloides Zhang Y, Zhang S, Chu Y, Zhang Q, Zhou R, Yu D, Wang S, Lyu L, Xu G, Zhao ZK Ref: Front Bioeng Biotechnol, 10:1034972, 2022 : PubMed ESTHER: Zhang_2022_Front.Bioeng.Biotechnol_10_1034972 PubMedSearch: Zhang 2022 Front.Bioeng.Biotechnol 10 1034972 PubMedID: 36394004 Abstract The basidiomycetous yeast Rhodosporidium toruloides (R. toruloides) is an excellent producer for neutral lipids, including triacylglycerols (TAG). Partially because genetic tools for this yeast were less developed, limited efforts were shown to explore its capacity for the production of higher-value lipids such as diacylglycerols (DAG). Here, four genes linked to the interconversion between DAG and TAG were manipulated to promote the production of DAG and free fatty acids (FFA). Among them, three TAG synthesis-related genes, DGA1, LRO1, and ARE1, were down-regulated successively via the RNA interference technology, and an endogenous TAG lipase encoded by TGL5 was fused with LDP1 and over-expressed to convert TAG into DAG and FFA. Results showed that those engineered R. toruloides strains grew normally under nutrient-rich conditions but notably slower than the parental strain NP11 in the lipid production stage. When cultivated in nitrogen-limited media, engineered strains were able to produce total lipids with improved contents of DAG and FFA by up to two-fold and three-fold, respectively. Further correlation analysis between lipid composition and cell density indicated that the formation of TAG correlated positively with cell growth; however, other lipids including DAG did negatively. This study offered valuable information and strains to engineer R. toruloides for advanced production of fatty acid derivatives. Title: Transcriptomic and metabolomic analyses reveal the antifungal mechanism of the compound phenazine-1-carboxamide on Rhizoctonia solani AG1IA Zhang Y, Li Q, Wang C, Liu S Ref: Front Plant Sci, 13:1041733, 2022 : PubMed ESTHER: Zhang_2022_Front.Plant.Sci_13_1041733 PubMedSearch: Zhang 2022 Front.Plant.Sci 13 1041733 PubMedID: 36483956 Abstract To explore the molecular mechanisms of the antifungal compound phenazine-1-carboxamide (PCN) inhibits Rhizoctonia solani and discover potential targets of action, we performed an integrated analysis of transcriptome and metabolome in R. solani mycelium by whether PCN treating or not. A total of 511 differentially expressed genes (DEGs) were identified between the PCN treatment and control groups. The fluorescence-based quantitative PCR (qPCR) got the accordant results of the gene expression trends for ten randomly selected DEGs. The Gene Ontology (GO) enrichment analysis revealed that fatty acid metabolic process, fatty acid oxidation, and lipid oxidation were among the most enriched in the biological process category, while integral component of membrane, plasma membrane, and extracellular region were among the most enriched in the cellular component category and oxidoreductase activity, cofactor binding, and coenzyme binding were among the most enriched in the molecular function category. KEGG enrichment analysis revealed the most prominently enriched metabolic pathways included ATP-binding cassette (ABC) transporters, nitrogen metabolism, aminobenzoate degradation. The DEGs related functions of cellular structures, cell membrane functions, cellular nutrition, vacuole-mitochondrion membrane contact site and ATPase activity, pH, anti-oxidation, were downregulated. A total of 466 differential metabolites were found between the PCN treatment and control groups after PCN treatment. KEGG enrichment found purine, arachidonic acid, and phenylpropanoid biosynthesis pathways were mainly affected. Further results proved PCN decreased the mycelial biomass and protein content of R. solani, and superoxide dismutase (SOD) activity reduced while peroxidase (POD) and cytochrome P450 activities increased. The molecule docking indicted that NADPH nitrite reductase, ATP-binding cassette transporter, alpha/beta hydrolase family domain-containing protein, and NADPH-cytochrome P450 reductase maybe the particular target of PCN. In conclusion, the mechanisms via which PCN inhibits R. solani AG1IA may be related to cell wall damage, cell membrane impairment, intracellular nutrient imbalance, disturbed antioxidant system, and altered intracellular pH, which laid foundation for the further new compound designing to improve antifungal efficacy. Title: NDRG4 Alleviates Myocardial Infarction-Induced Apoptosis through the JAK2/STAT3 Pathway Zhao C, Ren Y, Zhang Y Ref: Comput Math Methods Med, 2022:4869470, 2022 : PubMed ESTHER: Zhao_2022_Comput.Math.Methods.Med_2022_4869470 PubMedSearch: Zhao 2022 Comput.Math.Methods.Med 2022 4869470 PubMedID: 35126626 Gene_locus related to this paper: human-NDRG4 Abstract OBJECTIVE: At present, studies have confirmed that NDRG4 is specifically expressed in the heart, while its effect on the heart is still unclear. This study is to explore the effect of NDRG4 on cardiomyocyte apoptosis caused by acute myocardial infarction (AMI). METHODS: Twenty SD rats were randomly divided into Sham (left anterior descent of heart without ligation) and AMI groups. In this study, coronary artery ligation was used to establish an AMI model, and the AMI model was verified by auxiliary examination and pathological examination. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) was used to detect the expression level of Bax and Bcl-2 in heart tissues, and NDRG mRNA levels in tissues were also detected. qRT-PCR technology was used to verify the transfection efficiency of NDRG4 in H9C2 cells, and the change of apoptosis level of H9C2 cells was detected by Cell Counting Kit-8 (CCK-8) assay and TUNEL staining; besides, the expression level of apoptosis-related factors was detected by WB and qRT-PCR technology. Simultaneously with the modeling of rats, we injected adenovirus (Ad) into the heart tissue and examined the structural and functional changes of the rat heart. Then, WB technology was used to detect the expression level of the JAK2/STAT3 signaling pathway. RESULTS: The heart function and heart structure of rats in the MI group were dramatically worse, and the expression level of NDRG4 was also dramatically reduced. The overexpression of NDRG4 in H9C2 cells can effectively inhibit the ischemia/hypoxia- (I/H-) induced decrease in cell viability and increase in apoptosis rate and inhibit the increase in Bax/Bcl-2 ratio. Moreover, overexpression of NDRG4 in heart tissue can effectively improve the cardiac function and structural destruction caused by MI. In addition, NDRG4 can inhibit JAK2/STAT3 pathway activation. CONCLUSION: The expression of NDRG4 in the MI tissue of rats was suppressed, while overexpression of NDRG4 by injection of Ad can obviously protect the rat heart. Furthermore, overexpression of NDRG4 in H9C2 cells can effectively inhibit the I/H-induced decrease in cell viability and increase in apoptosis rate, and this may be related to the inhibition of the JAK2/STAT3 signaling pathway. Title: Synergistic enhancement of the emergency treatment effect of organophosphate poisoning by a supramolecular strategy Chen J, Zhang Y, Chai Y, Meng Z, Chen L, Quan D, Wang Y, Meng Q, Li C Ref: Chem Sci, 12:5202, 2021 : PubMed ESTHER: Chen_2021_Chem.Sci_12_5202 PubMedSearch: Chen 2021 Chem.Sci 12 5202 PubMedID: 34163757 Abstract Poisoning by organophosphorus agents (OPs) is a serious public health issue across the world. These compounds irreversibly inhibit acetylcholinesterase (AChE), resulting in the accumulation of acetylcholine (ACh) and overstimulation of ACh receptors. A supramolecular detoxification system (SDS) has been designed with a view to deliver pyridine-2-aldoxime methochloride (PAM) with a synergistic inhibition effect on the ACh-induced hyperstimulation through host-guest encapsulation. NMR and fluorescence titration served to confirm the complexation between carboxylatopillar[6]arene (CP6A) and PAM as well as ACh with robust affinities. Patch-clamp studies proved that CP6A could exert an inhibition effect on the ACh-induced hyperstimulation of ACh receptors. Support for the feasibility of this strategy came from fluorescence imaging results. In vivo studies revealed that complexation by CP6A serves to increase the AChE reactivation efficiency of PAM. The formation of the PAM/CP6A complex contributed to enhance in a statistically significant way the ability of PAM not only to relieve symptoms of seizures but also to improve the survival ratio in paraoxon-poisoned model rats. These favorable findings are attributed to synergistic effects that PAM reactivates AChE to hydrolyze ACh and excess ACh is encapsulated in the cavity of CP6A to relieve cholinergic crisis symptoms. Title: Development of a highly-specific (18)F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping Chen Z, Mori W, Rong J, Schafroth MA, Shao T, Van RS, Ogasawara D, Yamasaki T, Hiraishi A and Liang SH <12 more author(s)> Chen Z, Mori W, Rong J, Schafroth MA, Shao T, Van RS, Ogasawara D, Yamasaki T, Hiraishi A, Hatori A, Chen J, Zhang Y, Hu K, Fujinaga M, Sun J, Yu Q, Collier TL, Shao Y, Cravatt BF, Josephson L, Zhang MR, Liang SH (- 12) Ref: Acta Pharm Sin B, 11:1686, 2021 : PubMed ESTHER: Chen_2021_Acta.Pharm.Sin.B_11_1686 PubMedSearch: Chen 2021 Acta.Pharm.Sin.B 11 1686 PubMedID: 34221877 Gene_locus related to this paper: human-MGLL Inhibitor(s) related to this paper: PF-06795071 Abstract As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound, which was then radiolabeled with fluorine-18 via a facile S(N)Ar reaction to form 2-[(18)F]fluoropyridine scaffold. Good blood-brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [(18)F]14 (also named as [(18)F]MAGL-1902). This work may serve as a roadmap for clinical translation and further design of potent (18)F-labeled MAGL PET tracers. Title: Computational Design and Crystal Structure of a Highly Efficient Benzoylecgonine Hydrolase Chen X, Deng X, Zhang Y, Wu Y, Yang K, Li Q, Wang J, Yao W, Tong J and Yao J <2 more author(s)> Chen X, Deng X, Zhang Y, Wu Y, Yang K, Li Q, Wang J, Yao W, Tong J, Xie T, Hou S, Yao J (- 2) Ref: Angew Chem Int Ed Engl, :, 2021 : PubMed ESTHER: Chen_2021_Angew.Chem.Int.Ed.Engl__ PubMedSearch: Chen 2021 Angew.Chem.Int.Ed.Engl PubMedID: 34351032 Inhibitor(s) related to this paper: Benzoic-acid Abstract Benzoylecgonine (BZE) is the major toxic metabolite of cocaine, and is responsible for the long-term cocaine-induced toxicity due to its long residence time in humans. BZE is also the main contaminant following cocaine consumption, representing a risk to our environment and non-target organisms. Here, we identified the bacterial cocaine esterase (CocE) as a BZE-metabolizing enzyme (BZEase), which can degrade BZE into biological inactive metabolites (ecgonine and benzoic acid). CocE was redesigned by a reactant-state-based enzyme design theory. An encouraging mutant denoted as BZEase2, presented a >400-fold improved catalytic efficiency against BZE compared with wild-type (WT) CocE. In vivo , a single dose of BZEase2 (1 mg/kg, IV) could eliminate nearly all BZE within only two minutes, suggesting the enzyme have the potential for cocaine overdose treatment and BZE elimination in the environment by accelerating BZE clearance. The crystal structure of a designed BZEase was determined, providing additional insights in support of our simulation results. Title: Endophytic Fungal Community of Huperzia serrata: Diversity and Relevance to the Production of Huperzine A by the Plant Host Cui L, Noushahi HA, Zhang Y, Liu J, Cosoveanu A, Liu Y, Yan L, Zhang J, Shu S Ref: Molecules, 26:, 2021 : PubMed ESTHER: Cui_2021_Molecules_26_ PubMedSearch: Cui 2021 Molecules 26 PubMedID: 33567664 Abstract As the population ages globally, there seem to be more people with Alzheimer's disease. Unfortunately, there is currently no specific treatment for the disease. At present, Huperzine A (HupA) is one of the best drugs used for the treatment of Alzheimer's disease and has been used in clinical trials for several years in China. HupA was first separated from Huperzia serrata, a traditional medicinal herb that is used to cure fever, contusions, strains, hematuria, schizophrenia, and snakebite for several hundreds of years in China, and has been confirmed to have acetylcholinesterase inhibitory activity. With the very slow growth of H. serrata, resources are becoming too scarce to meet the need for clinical treatment. Some endophytic fungal strains that produce HupA were isolated from H. serrate in previous studies. In this article, the diversity of the endophytic fungal community within H. serrata was observed and the relevance to the production of HupA by the host plant was further analyzed. A total of 1167 strains were obtained from the leaves of H. serrata followed by the stems (1045) and roots (824). The richness as well as diversity of endophytic fungi within the leaf and stem were higher than in the root. The endophytic fungal community was similar within stems as well as in leaves at all taxonomic levels. The 11 genera (Derxomyces, Lophiostoma, Cyphellophora, Devriesia, Serendipita, Kurtzmanomyces, Mycosphaerella, Conoideocrella, Brevicellicium, Piskurozyma, and Trichomerium) were positively correlated with HupA content. The correlation index of Derxomyces with HupA contents displayed the highest value (CI = 0.92), whereas Trichomerium showed the lowest value (CI = 0.02). Through electrospray ionization mass spectrometry (ESI-MS), it was confirmed that the HS7-1 strain could produce HupA and the total alkaloid concentration was 3.7 ug/g. This study will enable us to screen and isolate the strain that can produce HupA and to figure out the correlation between endophytic fungal diversity with HupA content in different plant organs. This can provide new insights into the screening of strains that can produce HupA more effectively. Title: Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation Cui Z, Li B, Zhang Y, He J, Shi X, Wang H, Zhao Y, Yao L, Ai D and Zhu Y <1 more author(s)> Cui Z, Li B, Zhang Y, He J, Shi X, Wang H, Zhao Y, Yao L, Ai D, Zhang X, Zhu Y (- 1) Ref: Hypertension, 78:1527, 2021 : PubMed Title: Accelerated Solvent Extraction of Antioxidant Compounds from Gardeniae Fructus and Its Acetylcholinesterase Inhibitory and PC12 Cell Protective Activities Fan Y, Li X, Ding L, Zhou W, Xu G, Wang Y, Zhang Y, Ni Q Ref: Foods, 10:, 2021 : PubMed ESTHER: Fan_2021_Foods_10_ PubMedSearch: Fan 2021 Foods 10 PubMedID: 34829086 Abstract Gardeniae fructus is a common neuroprotective medicinal food in China, however the extraction efficiency and mixture activities are rarely mentioned. In this study, accelerated solvent extraction (ASE) parameters were optimized by a response surface methodology to extract antioxidants from Gardeniae fructus. Neuroprotective activity was evaluated using H(2)O(2) and amyloid-beta(25-35) peptide-treated PC12 cells. By comparing with three other extract methods (i.e., heated refluxing extraction (HRE), ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE)), it was found that the yield (35.10%), total iridoids (27.69%), total flavonoid (6.12%) content, antioxidant activities (IC(50) on DPPH, 164.46 microg/mL; FRAP value 4703.54 micromol/L), and acetylcholinesterase inhibitory ability (IC(50) 92.58 microg/mL) of ASE extract under the optimal condition (150 degreesC temperature, 10 min static time, 60% ethanol, 2 extract cycles) were significantly higher than other extract methods. The strongest ability to protect PC12 cells from damage was also present in ASE extract, as evidenced by decreasing lactate dehydrogenase and malondialdehyde levels, elevating superoxide dismutase and glutathioneperoxidase activities. Compositional analysis indicated that the extremely high crocetin level in ASE extract (1.30 microg/mg) may offer great potential. Our results indicated that ASE is a proper extraction method that could offer great potential for finding the neuroprotective ability of Gardeniae fructus for the treatment of AD. Title: Molecular Analysis of Targeted Insecticide Resistance Gene Mutations in Field-Caught Mosquitos of Medical Importance From Saudi Arabia Fang Y, Tambo E, Xue JB, Zhang Y, Zhou XN, Khater EIM Ref: Journal of Medical Entomology, :, 2021 : PubMed ESTHER: Fang_2021_J.Med.Entomol__ PubMedSearch: Fang 2021 J.Med.Entomol PubMedID: 33864372 Abstract Gene mutations on target sites can be a valuable indicator of the status of insecticide resistance. Jeddah, a global commercial and major port-of-entry city, is bearing the brunt of dengue disease burden in Saudi Arabia. In the current study, six genotypes of three codon combinations (989, 1016, and 1534) were observed on voltage-gated sodium channel (VGSC) gene in Jeddah's Aedes aegypti population, with PGF/PGC as the dominant one. Two types of introns between exon 20 and 21 on VGSC have been identified for the first time in Ae. aegypti in Saudi Arabia. Statistical and phylogenetic analyses showed that the intron type was significantly associated with the 1016 allele and may reflect the history of insecticide treatment in different continents. In addition, fixation of the L1014F allele on VGSC and G119S on acetylcholinesterase 1 gene was detected in local Culex quinquefasciatus populations, with frequencies of 95.24 and 100%, respectively. To the best of our knowledge, this is the first report of resistant-associated mutations in field-caught Cx. quinquefasciatus in Saudi Arabia. The high prevalence of insecticide resistance gene mutations in local primary mosquito vector species highlights the urgent need to carry out comprehensive insecticide resistance surveillance in Saudi Arabia. Title: The facile formation of hierarchical mesoporous silica nanocarriers for tumor-selective multimodal theranostics Guo X, Zhu M, Yuan P, Liu T, Tian R, Bai Y, Zhang Y, Chen X Ref: Biomater Sci, :, 2021 : PubMed ESTHER: Guo_2021_Biomater.Sci__ PubMedSearch: Guo 2021 Biomater.Sci PubMedID: 34223579 Abstract The combination of therapeutic and diagnostic functions in a single platform has aroused great interest due to the more optimal synergistic effects that can be obtained as compared to any single theranostic approach alone. However, current nanotheranostics are normally formed via complicated construction steps involving the pre-synthesis of each component and further conjugation via chemical bonds, which may cause low integration efficiency and limit production and applications. Herein, a tumor-targeting and tumor-responsive all-in-one nanoplatform based on mesoporous silica nanocarriers (MSNs) was fabricated via a facile approach utilizing efficient and nondestructive physical interactions for long-wavelength fluorescence imaging-guided synergistic chemo-catalytic-photothermal tumor therapy. The MSNs were endowed with these multimodal theranostics via a simple hydrothermal method after coordinating with Fe2+ and glutathione (GSH) to introduce ferroferric oxide and carbon dots in situ. The former acts as a photothermal agent and catalytic agent to generate local heat under 808 nm irradiation and also when toxic hydroxyl radicals (OH) are in contact with abundant hydrogen peroxide in cancer cells, while the latter participates in fluorescence imaging. After loading with paclitaxel (PTX), polyester and folic-acid-conjugated cyclodextrin were employed to serve as an esterase-sensitive gatekeeper controlling PTX release from the MSN pores and as a tumor-targeting agent for accurate therapy, respectively. As expected, the nanoplatform was efficiently taken up by tumor cells over healthy cells, and then, synergetic chemo-catalytic-photothermal therapy was performed, resulting in 5-fold greater apoptosis of tumor cells as compared to healthy cells under 808 nm irradiation. Moreover, in vivo data from tumor-bearing mouse models showed that tumors were significantly inhibited, and the survival rates of these mice increased to greater than 80% after 5 weeks of treatment with our nanoplatform. These therapeutic processes could be directly tracked via fluorescence imaging enabled by carbon dots and, therefore, our nanoplatform provides a promising theranostics approach for tumor treatment. Title: Bifunctional Moderator-Powered Ratiometric Electrochemiluminescence Enzymatic Biosensors for Detecting Organophosphorus Pesticides Based on Dual-Signal Combined Nanoprobes He Y, Hu F, Zhao J, Yang G, Zhang Y, Chen S, Yuan R Ref: Analytical Chemistry, :, 2021 : PubMed ESTHER: He_2021_Anal.Chem__ PubMedSearch: He 2021 Anal.Chem PubMedID: 34133127 Abstract The bifunctional moderator is urgently needed in the field of ratiometric electrochemiluminescence (ECL) sensing since it can mediate simultaneously two ECL signals to conveniently realize their opposite change trend. This work designed a novel dual-signal combined nanoprobe with carboxyl-functionalized poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-(1,4-benzo-{2,1',3}-thiadazole)] nanoparticles (c-PFBT NPs) as the anodic ECL probe and L-cysteine capped CdS quantum dots (L-CdS QDs) as the cathodic ECL probe, which performed a dual-signal output capability without any additional coreactants. More importantly, hydrogen peroxide (H(2)O(2)) produced in situ by enzyme-catalyzed reaction was developed as a bifunctional moderator for simultaneously regulating two signals. The dual-signal combined nanoprobe (c-PFBT NPs@CdS QDs) served as the matrix to immobilize acetylcholinesterase (AChE) and choline oxidase for organophosphorus (OPs) analysis. In the absence of OPs, H(2)O(2) was produced by catalyzing the substrate acetylthiocholine (ATCl) with enzymes and it quenched the anodic ECL signal from c-PFBT NPs and simultaneously promoted the cathodic ECL signal from L-CdS QDs. When OPs was present, the activity of AChE was inhibited, the anodic signal would increase, and the cathodic signal would accordingly decrease. The integration of the bifunctional moderator H(2)O(2) and dual-signal combined nanoprobe c-PFBT NPs@CdS QDs not only provides an attractive ECL platform for enzymatic sensing involving the generation or consumption of H(2)O(2) but also paves a new pathway for other ratiometric ECL systems involving enzyme catalytic amplification for detecting antigens, antibodies, DNA, RNA, etc. Title: Toxicity of gabapentin-lactam on the early developmental stage of zebrafish (Danio rerio) He Y, Jia D, Du S, Zhu R, Zhou W, Pan S, Zhang Y Ref: Environ Pollut, 287:117649, 2021 : PubMed ESTHER: He_2021_Environ.Pollut_287_117649 PubMedSearch: He 2021 Environ.Pollut 287 117649 PubMedID: 34182397 Abstract Gabapentin-lactam (GBP-L) is a transformation product (TP) of gabapentin (GBP), a widely used anti-epileptic pharmaceutical. Due to its high persistence, GBP-L has been frequently detected in the surface water. However, the effects of GBP-L on aquatic organisms have not been thoroughly investigated. In the present study, zebrafish (Danio rerio) embryos as a model organism were used to study the impacts of GBP-L in terms of embryos LC(50), spontaneous movement at 24 hpf (hours post fertilization), heartbeat rates at 48 hpf, and body length at 72 hpf, with the concentrations of GBP-L down to 0.01 microg/L, covering its environmental concentrations. Various biomarkers from nervous, antioxidant and immune systems of zebrafish larvae were analyzed, including acetylcholinesterase, acetylcholine, dopamine, gamma-aminobutyric acid, superoxide dismutase, catalase, glutathione S-transferase, C reactive protein, and lysozyme, to assess its toxicity on these systems. RT-qPCR was then used to further verify the results and explain the toxicological mechanism at the gene level. The results demonstrated that GBP-L is much more toxic than its parent compound, and could lead to adverse impacts on the aquatic organisms even at every low concentrations. Title: Hydrolase activities of cynomolgus monkey liver microsomes and recombinant CES1, CES2, and AADAC Honda S, Fukami T, Tsujiguchi T, Zhang Y, Nakano M, Nakajima M Ref: Eur J Pharm Sci, :105807, 2021 : PubMed ESTHER: Honda_2021_Eur.J.Pharm.Sci__105807 PubMedSearch: Honda 2021 Eur.J.Pharm.Sci 105807 PubMedID: 33722734 Abstract The cynomolgus monkey is a nonhuman primate that is often used for pharmacokinetic and toxicokinetic studies of new chemical entities. Species differences in drug metabolism are obstacles for the extrapolation of animal data to humans. This study aimed to characterize hydrolase activities for typical compounds by cynomolgus monkey liver microsomes and recombinant monkey carboxylesterases (CES1 and CES2) and arylacetamide deacetylase (AADAC) compared with the activities in humans. To estimate the contribution of each hydrolase, the ratios of the expression level of each hydrolase in the liver microsomes and recombinant systems were used. For almost all of the tested human CES1 substrates, hydrolase activities in cynomolgus monkey liver microsomes tended to be lower than those in human liver microsomes, and recombinant cynomolgus monkey CES1 showed catalytic activity, but not for all substrates. For human CES2 substrates, hydrolase activities in cynomolgus monkey liver were higher than those in human liver microsomes, and recombinant monkey CES2 was responsible for their hydrolysis. Among human AADAC substrates, phenacetin was mainly hydrolyzed by monkey AADAC, whereas indiplon and ketoconazole were hydrolyzed by AADAC and other unknown enzymes. Flutamide was hydrolyzed by monkey CES2, not by AADAC. Rifamycins were hardly hydrolyzed in monkey liver microsomes. In conclusion, this study characterized the hydrolase activities of cynomolgus monkeys compared with those in humans. The findings would be helpful for pharmacokinetic or toxicokinetic studies of new chemical entities whose main metabolic pathway is hydrolysis. Title: Differences in hydrolase activities in the liver and small intestine between marmosets and humans Honda S, Fukami T, Hirosawa K, Tsujiguchi T, Zhang Y, Nakano M, Uehara S, Uno Y, Yamazaki H, Nakajima M Ref: Drug Metabolism & Disposition: The Biological Fate of Chemicals, :, 2021 : PubMed ESTHER: Honda_2021_Drug.Metab.Dispos__ PubMedSearch: Honda 2021 Drug.Metab.Dispos PubMedID: 34135089 Abstract For drug development, species differences in drug-metabolism reactions present obstacles for predicting pharmacokinetics in humans. We characterized the species differences in hydrolases among humans and mice, rats, dogs, and cynomolgusmonkeys. In this study, to expand the series of such studies, we attempted to characterize marmoset hydrolases. We measured hydrolase activities for 24 compounds using marmoset liver and intestinal microsomes, as well as recombinant marmoset carboxylesterase (CES) 1, CES2, and arylacetamide deacetylase (AADAC). The contributions of CES1, CES2, and AADAC to hydrolysis in marmoset liver microsomes were estimated by correcting the activities by using the ratios of hydrolase protein levels in the liver microsomes and those in recombinant systems. For 6 out of 8 human CES1 substrates,the activities in marmoset liver microsomes were lower than those in human liver microsomes. For 2 human CES2 substrates and 3 out of 7 human AADAC substrates, the activities in marmoset liver microsomes were higher than those in human liver microsomes. Notably, among the 3 rifamycins, only rifabutin was hydrolyzed by marmoset tissue microsomes and recombinant AADAC. The activities for all substrates in marmoset intestinal microsomes tended to be lower than those in liver microsomes, which suggests that the first-pass effects of the CES and AADAC substrates are dueto hepatic hydrolysis. In most cases, the sums of the values of the contributions of CES1, CES2, and AADAC were below 100%, which indicated the involvement of other hydrolases in marmosets. In conclusion, we clarified the substrate preferences of hydrolases in marmosets. Significance Statement This study confirmed that there are large differences in hydrolase activities between humans and marmosets by characterizing marmoset hydrolase activities for compounds that are substrates of human CES1, CES2, or AADAC. The data obtained in this study may be useful for considering whether marmosets are appropriate for examining the pharmacokinetics and efficacies of new chemical entities in preclinical studies. Title: ABHD15 promotes cell viability, glycolysis, and inhibits apoptosis in cardiomyocytes under hypoxia Huang G, Guo X, Guo J, Zhang P, Liang W, Bai C, Zhang Y Ref: Nutr Metab Cardiovasc Dis, 31:681, 2021 : PubMed ESTHER: Huang_2021_Nutr.Metab.Cardiovasc.Dis_31_681 PubMedSearch: Huang 2021 Nutr.Metab.Cardiovasc.Dis 31 681 PubMedID: 33257193 Abstract BACKGROUND AND AIMS: Myocardial infarction (MI) has been an important heart disease affecting human health. The aim of this study was to investigate the regulatory effect of abhydrolase domain containing 15 (ABHD15) on hypoxic cardiomyocytes. METHODS AND RESULTS: Hypoxic cardiomyocytes are commonly used as an vitro model for the study of MI. We found that cardiomyocyte viability was decreased under hypoxia, but cell glucose uptake, insulin receptor phosphorylation level and apoptosis were increased. Interestingly, ABHD15 expression was up-regulated in hypoxia-induced cardiomyocytes. Then, we identified the function of ABHD15 in hypoxic cardiomyocytes by using ABHD15 overexpression vector or short interfering RNA (siRNA) against ABHD15. The results showed that overexpression of ABHD15 promoted hypoxic cardiomyocyte viability, glucose uptake and IR phosphorylation (p-IR), and inhibited cell apoptosis. However, knockdown of ABHD15 attenuated hypoxic cardiomyocyte viability, glucose uptake and IR phosphorylation, and promoted apoptosis. Moreover, we found that ABHD15 promoted glucose transporter 4 (GLUT4) expression, translocation and enhance rate-limiting enzyme activation of glycolysis, thereby affecting glucose uptake. Furthermore, our study suggested that ABHD15 may affect the viability and apoptosis of hypoxic cardiomyocytes through IR/Ras/Raf/ERK/MEK and IR/PI3K/AKT/Bcl2/Bad/caspase9 signaling pathways, respectively. When the phosphorylation of IR, Raf or ERK was blocked by inhibitors, the protective effect of overexpressing ABHD15 on the viability of hypoxic cardiomyocytes was eliminated. Furthermore, inhibiting the phosphorylation of IR, AKT or Bcl2 abolished the inhibitory effect of overexpressing ABHD15 on hypoxic cardiomyocyte apoptosis. CONCLUSION: ABHD15 regulated myocardial cell viability, glycolysis, and apoptosis under hypoxia, providing a novel potential therapeutic strategy for MI. Title: Degradation of epigallocatechin and epicatechin gallates by a novel tannase Tan(Hcw) from Herbaspirillum camelliae Lei J, Zhang Y, Ni X, Yu X, Wang X Ref: Microb Cell Fact, 20:197, 2021 : PubMed ESTHER: Lei_2021_Microb.Cell.Fact_20_197 PubMedSearch: Lei 2021 Microb.Cell.Fact 20 197 PubMedID: 34641872 Gene_locus related to this paper: 9burk-TanHcw Abstract BACKGROUND: Herbaspirillum camelliae is a gram-negative endophyte isolated from the tea plant. Both strains WT00C and WT00F were found to hydrolyze epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG) to release gallic acid (GA) and display tannase activity. However, no tannase gene was annotated in the genome of H. camelliae WT00C. RESULTS: The 39 kDa protein, annotated as the prolyl oligopeptidase in the NCBI database, was finally identified as a novel tannase. Its gene was cloned, and the enzyme was expressed in E. coli and purified to homogeneity. Moreover, enzymatic characterizations of this novel tannase named Tan(Hcw) were studied. Tan(Hcw) was a secretary enzyme with a Sec/SPI signal peptide of 48 amino acids at the N-terminus, and it catalyzed the degradation of tannin, methyl gallate (MG), epigallocatechin-3-gallate (EGCG) and epicatechin-3-gallate (ECG). The optimal temperature and pH of Tan(Hcw) activities were 30 degreesC, pH 6.0 for MG and 40 degreesC, pH 7.0 for both EGCG and ECG. Na(+), K(+) Mn(2+) and Triton-X100, Tween80 increased the enzyme activity of Tan(Hcw), whereas Zn(2+), Mg(2+), Hg(2+), EMSO, EDTA and beta-mercaptoethanol inhibited enzyme activity. K(m), k(cat) and k(cat) /K(m) of Tan(Hcw) were 0.30 mM, 37.84 s(-1), 130.67 mM(-1) s(-1) for EGCG, 0.33 mM, 34.59 s(-1), 105.01 mM(-1) s(-1) for ECG and 0.82 mM, 14.64 s(-1), 18.17 mM(-1) s(-1) for MG, respectively. CONCLUSION: A novel tannase Tan(Hcw) from H. camelliae has been identified and characterized. The biological properties of Tan(Hcw) suggest that it plays a crucial role in the specific colonization of H. camelliae in tea plants. Discovery of the tannase Tan(Hcw) in this study gives us a reasonable explanation for the host specificity of H. camelliae. In addition, studying the characteristics of this enzyme offers the possibility of further defining its potential in industrial application. Title: Biogenetic cantharidin is a promising leading compound to manage insecticide resistance of Mythimna separata (Lepidoptera: Noctuidae) Li Y, Sun H, Yasoob H, Tian Z, Li R, Zheng S, Liu J, Zhang Y Ref: Pestic Biochem Physiol, 172:104769, 2021 : PubMed ESTHER: Li_2021_Pestic.Biochem.Physiol_172_104769 PubMedSearch: Li 2021 Pestic.Biochem.Physiol 172 104769 PubMedID: 33518040 Abstract Cantharidin (CTD) is a natural toxin with effective toxicity to lepidopteran pests. Nevertheless, little information is available on whether pests develop resistance to CTD. After being exposed to CTD (50 mg/L to 90 mg/L) or 10 generations, the resistance ratio of laboratory selected cantharidin-resistant Mythimna separata (Cantharidin-SEL) strain was only elevated 1.95-fold. Meanwhile, the developmental time for M. separata was prolonged (delayed1.65 in males and 1.84 days in females). The reported CTD target, the serine/threonine phosphatases (PSPs), have not been shown significant activity variation during the whole process of CTD-treatment. The activity of detoxification enzymes (cytochrome monooxygenase P450, glutathione-S-transferase (GST) and carboxylesterase) were affected by CTD selection, but this change was not mathematically significant. More importantly, no obvious cross-resistance with other commonly used insecticides was observed in the M. separata population treated with CTD for 10 generations (resistance ratios were all lower 2.5). Overall, M. separata is unlikely to produce target-site insensitivity resistance, metabolic resistance to CTD. Meanwhile, cantharidin-SEL is not prone to develop cross-resistance with other insecticides. These results indicate that CTD is a promising biogenetic lead compound which can be applied in the resistance management on M. separata. Title: Inducing new bioactive metabolites production from coculture of Pestalotiopsis sp. and Penicillium bialowiezense Li F, Yan S, Huang Z, Gao W, Zhang S, Mo S, Lin S, Wang J, Hu Z, Zhang Y Ref: Bioorg Chem, 110:104826, 2021 : PubMed ESTHER: Li_2021_Bioorg.Chem_110_104826 PubMedSearch: Li 2021 Bioorg.Chem 110 104826 PubMedID: 33780746 Abstract Coculturing two or more fungi is a useful strategy to awaken the silent genes to produce structurally diverse and bioactive natural products. Through the coculture of Pestalotiopsis sp. and Penicillium bialowiezense, six new isoprenylated chromane derivatives, including two pairs of enantiomeric ones (1a/1b-2a/2b) and two optical pure ones (3-4), two new isoprenylated phenol glucoside derivatives (6-7), as well as eight known structural analogues (5 and 8-14), were obtained. The structures of these new compounds were characterized by NMR spectroscopy, single-crystal X-ray crystallography, and ECD calculation. The delta(10,11) double bond of pestaloficin D (5) was revised to E-configurated based on the extensive spectroscopic analyses. Compounds 1a/1b and 2a/2b were the first examples of enantiomeric isoprenylated chromane derivatives, which were successfully separated by chiral HPLC. Additionally, all the isolated compounds were evaluated for the in vitro beta-glucuronidase (GUS) and butyrylcholinesterase (BChE) inhibitory activities. Compounds 1a and 1b showed significant beta-glucuronidase inhibitory potency with IC(50) values of 7.6 and 10.3 microM, respectively. Compound 14 exhibited moderate BChE inhibitory activity with an IC(50) value of 21.3 microM. In addition, the structure-enzyme inhibitory activity relationship of compounds 1-14 is discussed. Title: A novel lipase from Aspergillus oryzae WZ007 catalyzed synthesis of brivaracetam intermediate and its enzymatic characterization Li Q, Zhang M, Li X, Zhang Y, Wang Z, Zheng J Ref: Chirality, 33:62, 2021 : PubMed ESTHER: Li_2021_Chirality_33_62 PubMedSearch: Li 2021 Chirality 33 62 PubMedID: 33274501 Abstract Brivaracetam is a structural derivative of the chiral drug levetiracetam and has been approved for the adjuvant treatment of partial epilepsy. As a new antiepileptic drug, it is widely used in a variety of epilepsy models. In this study, a novel lipase M16 derived from Aspergillus oryzae WZ007 was cloned, expressed, and used for chiral resolution. Lipase M16 has a high enantioselectivity to the racemic substrate (R,S)-methyl 2-propylsuccinate 4-tert-butyl ester, and the intermediate (R)-2-propylsuccinic acid 4-tert-butyl ester of brivaracetam was obtained efficiently. Under optimal conditions, the enantiomeric excess of substrate was up to 99.26%, and the e.e.(p) was 96.23%. The conversion and apparent E value were 50.63% and 342.48, respectively. This study suggests a new biocatalytic resolution via lipase M16 for preparing the brivaracetam chiral intermediate and its potential application in the pharmaceutical industry. Title: On-line coupling pressurised liquid extraction with two-dimensional counter current chromatography for isolation of natural acetylcholinesterase inhibitors from Astragalus membranaceus Li S, Liu C, Zhang Y, Tsao R Ref: Phytochem Anal, 32:640, 2021 : PubMed ESTHER: Li_2021_Phytochem.Anal_32_640 PubMedSearch: Li 2021 Phytochem.Anal 32 640 PubMedID: 33238329 Abstract INTRODUCTION: Radix Astragali, the dried root of Astragalus membranaceus (Fish.) Bge. (family Fabaceae), which is known as Huangqi in China, has been proven to be an immunostimulant, diuretic, antidiabetic, analgesic, and it has also been used as a health food supplement in some Asian populations and also serves as a lead herb in many traditional Chinese medicine formulations as well as in Chinese ethnic tonifying soups. OBJECTIVE: Screening and purification of bioactive compounds from natural products is challenging work due to their complexity. We present the first report on the use of pressurised liquid extraction and on-line two-dimensional counter current chromatography as an efficient medium for scaled-up extraction and separation of six bioactive compounds from Astragalus membranaceus. METHOD: We applied the established method with ultrafiltration-liquid chromatography to screen acetylcholinesterase inhibitors, which were then evaluated and confirmed for anti-Alzheimer activity using PC12 cell model. RESULTS: Six major compounds, namely, calycosin-7-O-beta-d-glucoside, pratensein-7-O-beta-d-glucoside, formononetin-7-O-beta-d-glucoside, calycosin, genistein, and formononetin, with acetylcholinesterase binding affinities were identified and isolated from the raw plant materials via two sets of n-hexane/ethyl acetate/0.2% acetic acid (first-stage counter current chromatography) and n-hexane/ethyl acetate/methanol/water (second-stage counter current chromatography) solvent systems: 1.87:1.0:1.33 and 5.62:1.0:2.42:5.25, v/v/v/v, which were optimised by a mathematical model. CONCLUSION: Therefore, a useful platform for the large-scale production of bioactive and nutraceutical ingredients was developed herein. With the on-line system developed here, we present a feasible, selective, and effective strategy for rapid screening and identification of enzyme inhibitors from complex mixtures. Title: Construction and characterization of CRISPR/Cas9 knockout rat model of carboxylesterase 2a gene Liu J, Shang X, Huang S, Xu Y, Lu J, Zhang Y, Liu Z, Wang X Ref: Molecular Pharmacology, :, 2021 : PubMed ESTHER: Liu_2021_Mol.Pharmacol__2 PubMedSearch: Liu 2021 Mol.Pharmacol 2 PubMedID: 34503976 Gene_locus related to this paper: ratno-LOC246252 Abstract Carboxylesterase 2 (CES2), an important metabolic enzyme, plays a critical role in drug biotransformation and lipid metabolism. Although CES2 is very important, few animal models have been generated to study its properties and functions. Rat Ces2 is similar to human CES2A-CES3A-CES4A gene cluster, with highly similar gene structure, function and substrate. In this report, CRISPR/Cas9 technology was firstly used to knock out rat Ces2a, a main subtype of Ces2 mostly distributed in liver and intestine. This model showed the absence of CES2A protein expression in liver. Further pharmacokinetic studies of diltiazem, a typical substrate of CES2A, confirmed the loss of function of CES2A both in vivo and in vitro. At the same time, the expression of CES2C and CES2J protein in liver decreased significantly. The body and liver weight of Ces2a knockout rats also increased, but the food intake did not change. Moreover, the deficiency of Ces2a led to obesity, insulin resistance and liver fat accumulation, which are consistent with the symptoms of nonalcoholic fatty liver disease (NAFLD). Therefore, this rat model is not only a powerful tool to study drug metabolism mediated by CES2, but also a good disease model to study NAFLD. Significance Statement Human CES2 plays a key role in the first-pass hydrolysis metabolism of most oral prodrugs as well as lipid metabolism. In this study, CRISPR/Cas9 technology was used to knock out Ces2a gene in rats for the first time. This model can be used not only in the study of drug metabolism and pharmacokinetics, but also as a disease model of NAFLD and other metabolic disorder. Title: A BCNO QDs-MnO(2) nanosheets based fluorescence off-on-off and colorimetric sensor with smartphone detector for the detection of organophosphorus pesticides Liu F, Lei T, Zhang Y, Wang Y, He Y Ref: Anal Chim Acta, 1184:339026, 2021 : PubMed ESTHER: Liu_2021_Anal.Chim.Acta_1184_339026 PubMedSearch: Liu 2021 Anal.Chim.Acta 1184 339026 PubMedID: 34625266 Abstract In this work, boron carbon oxynitride quantum dots (BCNO QDs) were prepared by a one-step hydrothermal process of ethanolamine and boric acid. BCNO QDs exhibited blue fluorescence with the optimal excitation/emission fluorescence peak at 335 and 420 nm, respectively. As an efficient fluorescence quencher, manganese dioxide (MnO(2)) nanosheets can effectively quench the fluorescence of BCNO QDs via the inner filter effect (IFE). Acetylcholinesterase (AChE) catalyzes the hydrolysis of acetylcholine (ATCh) to produce thiocholine (TCh). TCh can reductively degrade MnO(2) nanosheets to generate Mn(2+), thereby recovering the fluorescence of BCNO QDs. Organophosphorus pesticides (OPs) can inhibit the activity of AChE enzymes, thereby preventing the production of TCh and the decomposition of MnO(2) nanosheets, resulting in the fluorescence "turn-off". Therefore, the concentration of OPs can be detected by measuring the fluorescence intensity change of AChE-ATCh-MnO(2)-BCNO-QDs system. Under optimal experimental conditions, the dynamic detection range of paraoxon is 0.1-250 ng mL(-1), and the detection limit is 0.03 ng mL(-1). Meanwhile, the reaction system also showed concentration-dependent visual color changes from colorless to brownish. Furthermore, we prepared a portable BCNO QDs test paper. By using a smartphone to identify the RGB values of the reaction solution and the corresponding test paper, we carried out the digital image chromaticity analysis, which can shorten the detection time and reduce the detection cost, and provide an effective solution for the rapid detection of OPs on site. Title: Protection studies of an excretory-secretory protein HcABHD against Haemonchus contortus infection Lu M, Tian X, Zhang Y, Wang W, Tian AL, Aimulajiang K, Liu L, Li C, Yan R and Li X <2 more author(s)> Lu M, Tian X, Zhang Y, Wang W, Tian AL, Aimulajiang K, Liu L, Li C, Yan R, Xu L, Song X, Li X (- 2) Ref: Vet Res, 52:3, 2021 : PubMed ESTHER: Lu_2021_Vet.Res_52_3 PubMedSearch: Lu 2021 Vet.Res 52 3 PubMedID: 33407892 Gene_locus related to this paper: haeco-CDJ88804 Abstract Unlike the successful immunization of native H. contortus antigens that contributed to the realization of the first commercial vaccine Barbervax, not many studies revealed the encouraging protective efficacies of recombinant H. contortus antigens in laboratory trials or under field conditions. In our preliminary study, H. contortus alpha/beta-hydrolase domain protein (HcABHD) was demonstrated to be an immunomodulatory excretory-secretory (ES) protein that interacts with goat T cells. We herein evaluated the protective capacities of two HcABHD preparations, recombinant HcABHD (rHcABHD) antigen and anti-rHcABHD IgG, against H. contortus challenge via active and passive immunization trials, respectively. Parasitological parameter, antibody responses, hematological pathology and cytokine profiling in unchallenged and challenged goats were monitored and determined throughout both trials. Subcutaneous administration of rHcABHD with Freund adjuvants elicited protective immune responses in challenged goats, diminishing cumulative fecal egg counts (FEC) and total worm burden by 54.0% and 74.2%, respectively, whereas passive immunization with anti-rHcABHD IgG conferred substantial protection to challenged goats by generating a 51.5% reduction of cumulative FEC and a 73.8% reduction of total worm burden. Additionally, comparable changes of mucosal IgA levels, circulating IgG levels, hemoglobin levels, and serum interleukin (IL)-4 and IL-17A levels were observed in rHcABHD protein/anti-rHcABHD IgG immunized goats in both trials. Taken together, the recombinant version of HcABHD might have further application under field conditions in protecting goats against H. contortus infection, and the integrated immunological pipeline of ES antigen identification, screening and characterization may provide new clues for further development of recombinant subunit vaccines to control H. contortus. Title: Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene Luo X, Wang C, Lin L, Yuan F, Wang S, Wang Y, Wang A, Wu S, Lan X and Chen Y <9 more author(s)> Luo X, Wang C, Lin L, Yuan F, Wang S, Wang Y, Wang A, Wu S, Lan X, Xu Q, Yin R, Cheng H, Zhang Y, Xi J, Zhang J, Sun X, Yan J, Zeng F, Chen Y (- 9) Ref: Front Pediatr, 9:679342, 2021 : PubMed ESTHER: Luo_2021_Front.Pediatr_9_679342 PubMedSearch: Luo 2021 Front.Pediatr 9 679342 PubMedID: 34912755 Abstract The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14-15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14-15 deletion could cause CMS. Title: An ultrahigh-throughput screening platform based on flow cytometric droplet sorting for mining novel enzymes from metagenomic libraries Ma F, Guo T, Zhang Y, Bai X, Li C, Lu Z, Deng X, Li D, Kurabayashi K, Yang GY Ref: Environ Microbiol, 23:996, 2021 : PubMed ESTHER: Ma_2021_Environ.Microbiol_23_996 PubMedSearch: Ma 2021 Environ.Microbiol 23 996 PubMedID: 32985743 Abstract Uncultivable microbial communities provide enormous reservoirs of enzymes, but their experimental identification by functional metagenomics is challenging, mainly due to the difficulty of screening enormous metagenomic libraries. Here, we propose a reliable and convenient ultrahigh-throughput screening platform based on flow cytometric droplet sorting (FCDS). The FCDS platform employs water-in-oil-in-water double emulsion droplets serving as single-cell enzymatic micro-reactors and a commercially available flow cytometer, and it can efficiently isolate novel biocatalysts from metagenomic libraries by processing single cells as many as 10(8) per day. We demonstrated the power of this platform by screening a metagenomic library constructed from domestic running water samples. The FCDS assay screened 30 million micro-reactors in only 1h, yielding a collection of esterase genes. Among these positive hits, Est WY was identified as a novel esterase with high catalytic efficiency and distinct evolutionary origin from other lipolytic enzymes. Our study manifests that the FCDS platform is a robust tool for functional metagenomics, with the potential to significantly improve the efficiency of exploring novel enzymes from nature. Title: Protein engineering of stable IsPETase for PET plastic degradation by Premuse Meng X, Yang L, Liu H, Li Q, Xu G, Zhang Y, Guan F, Zhang W, Wu N, Tian J Ref: Int J Biol Macromol, 180:667, 2021 : PubMed ESTHER: Meng_2021_Int.J.Biol.Macromol_180_667 PubMedSearch: Meng 2021 Int.J.Biol.Macromol 180 667 PubMedID: 33753197 Gene_locus related to this paper: idesa-peth Abstract Poly(ethylene terephthalate) (PET) is used widely by human beings, but is very difficult to degrade. Up to now, the PET degradation effect of PETase from Ideonella sakaiensis 201-F6 (IsPETase) variants with low stability and activity was not ideal. In this study, a mutation design tool, Premuse, was developed to integrate the sequence alignment and quantitative selection of the preferred mutations based on natural sequence evolution. Ten single point mutants were selected from 1486 homologous sequences using Premuse, and then two mutations (W159H and F229Y) with improved stability were screened from them. The derived double point mutant, W159H/F229Y, exhibited a strikingly enhanced enzymatic performance. Its T(m) and catalytic efficiency values (k(cat)/K(m)) respectively increased by 10.4 degreesC and 2.0-fold using p-NPP as the substrate compared with wild type. The degradation activity for amorphous PET was increased by almost 40-fold in comparison with wild type at 40 degreesC in 24 h. Additionally, the variant could catalyze biodegradation of PET bottle preform at a mean rate of 23.4 mg(PET)/h/mg(enzyme). This study allowed us to design the mutation more efficiently, and provides a tool for achieving biodegradation of PET pollution under mild natural environments. Title: Adsorption mechanism of two pesticides on polyethylene and polypropylene microplastics: DFT calculations and particle size effects Mo Q, Yang X, Wang J, Xu H, Li W, Fan Q, Gao S, Yang W, Gao C and Zhang Y <2 more author(s)> Mo Q, Yang X, Wang J, Xu H, Li W, Fan Q, Gao S, Yang W, Gao C, Liao D, Li Y, Zhang Y (- 2) Ref: Environ Pollut, 291:118120, 2021 : PubMed ESTHER: Mo_2021_Environ.Pollut_291_118120 PubMedSearch: Mo 2021 Environ.Pollut 291 118120 PubMedID: 34520951 Abstract Polyethylene (PE) and polypropylene (PP) microplastics (MPs), as carriers, can bind with pesticides, which propose harmful impacts to aqueous ecosystems. Meanwhile, carbofuran and carbendazim (CBD), two widely used carbamate pesticides, are toxic to humans because of the inhibition of acetylcholinesterase activity. The interaction between two MPs and two pesticides could start in farmland and be maintained during transportation to the ocean. Herein, the adsorption behavior and mechanism of carbofuran and carbendazim (CBD) by PE and PP MPs were investigated via characterization and density functional theory (DFT) simulation. The adsorption kinetic and thermodynamic data were best described by pseudo-second-order kinetics and the Freundlich models. The adsorption behaviors of individual carbofuran/CBD on both MPs were very similar. The CBD adsorption rate and capacity of PE and PP MPs were higher than those of carbofuran. This phenomenon explained the lower negative effects of DOM (oxalic acid, glycine (Gly)) on CBD adsorption relative to those of carbofuran. The presence of oxalic acid and Gly decreased the PE adsorption by 20.40-48.02% and the PP adsorption by 19.27-42.11%, respectively. It indicated the significance of DOM in carbofuran cycling. The adsorption capacities were negatively correlated with MPs size, indicating the importance of specific surficial area. Fourier transformation infrared spectroscopy before and after adsorption suggested that the adsorption process did not produce any new covalent bond. Instead, intermolecular van der Waals forces were one of the primary adsorption mechanisms of carbofuran and CBD by MPs, as evidenced by DFT calculations. Based on the zeta potential, the electrostatic interaction explained the higher adsorption CBD by MPs than carbofuran. Title: Epigallocatechin-3-Gallate Provides Protection Against Alzheimer's Disease-Induced Learning and Memory Impairments in Rats Nan S, Wang P, Zhang Y, Fan J Ref: Drug Des Devel Ther, 15:2013, 2021 : PubMed ESTHER: Nan_2021_Drug.Des.Devel.Ther_15_2013 PubMedSearch: Nan 2021 Drug.Des.Devel.Ther 15 2013 PubMedID: 34012254 Inhibitor(s) related to this paper: Epigallocatechin-gallate Abstract PURPOSE: Recent evidence has highlighted the anti-inflammatory properties of the constituent of Green Tea Polyphenols (GTP), epigallocatechin-3-gallate (EGCG) which has been suggested to exert a neuroprotective effect on Alzheimer's disease (AD). The current study aimed to elucidate the effect of EGCG on memory function in rats with AD. METHODS: AD rat models were initially established through an injection with Abeta 25-35 solution, followed by gavage with EGCG at varying doses to determine the effect of EGCG on learning and cognitive deficits in AD. Morris water maze test was conducted to evaluate the spatial memory function of the rats. Immunohistochemistry and Western blot analysis were performed to identify Tau phosphorylation. The expression of beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1) mRNA and protein in rat hippocampus was measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. Acetylcholinesterase (AchE) activity, Abeta1-42 expression and Ach content were all detected using enzyme-linked immunosorbent assay (ELISA). RESULTS: EGCG intervention brought about a decrease in the escape latency period while increasing the time at the target quadrant among the AD rats. EGCG decreased the hyperphosphorylation of Tau in hippocampus. BACE1 expression and activity as well as the expression of Abeta1-42 were suppressed by EGCG. Moreover, EGCG promoted Ach content by diminishing the activity of AchE. CONCLUSION: The current study demonstrates that EGCG may diminish the hyperphosphorylation of the Tau protein, downregulate BACE1 and Abeta1-42 expression to improve the antioxidant system and learning and memory function of rats with AD. Title: Red ginseng has stronger anti-aging effects compared to ginseng possibly due to its regulation of oxidative stress and the gut microbiota Peng X, Hao M, Zhao Y, Cai Y, Chen X, Chen H, Zhang Y, Dong L, Liu X and Luo Y <3 more author(s)> Peng X, Hao M, Zhao Y, Cai Y, Chen X, Chen H, Zhang Y, Dong L, Liu X, Ding C, Liu W, Yang M, Luo Y (- 3) Ref: Phytomedicine, 93:153772, 2021 : PubMed ESTHER: Peng_2021_Phytomedicine_93_153772 PubMedSearch: Peng 2021 Phytomedicine 93 153772 PubMedID: 34753028 Abstract BACKGROUND: Panax ginseng (PG) and red ginseng (RG) are considered to be effective anti-aging treatments. However, evidence of their therapeutic mechanisms and difference in anti-aging effects is lacking. PURPOSE: To explore the potential therapeutic mechanisms of RG and PG in brain damage in D-Gal-induced aging mice, and evaluate the difference in anti-aging effects caused by their compositional differences. METHODS: We first tested the chemical components in PG and RG. In D-Gal aging mouse model, RG and PG (800 mg/kg) were orally administered for 9 weeks. The mice performed the Radial Arm Maze (RAM) behavior test. We collected blood, brain tissue, and fecal samples and performed biochemical analysis, histological examination, western blot, and Illumina MiSeq sequencing analysis. RESULTS: The results of component analysis showed that the total polyphenols and rare ginsenosides were present in RG in 3.2, and 2.2 fold greater concentrations, respectively, compared to PG, while the proportion of non-starch polysaccharides in the crude polysaccharides of RG was 1.94 fold greater than that of PG. In D-Gal-induced aging mice, both PG and RG could prevent the increase in acetylcholinesterase (AChE), and malondialdehyde (MDA) levels, and improved the expression of superoxide dismutase (SOD), and catalase (CAT) in the serum. Meanwhile, both PG and RG could ameliorate brain tissue architecture and behavioral trial. In addition, the D-Gal-induced translocation of nuclear factor-kappaB (NF-kappaB), as well as activation of the pro-apoptotic factors Caspase-3 and the PI3K/Akt pathways were inhibited by PG and RG. Overall, both PG and RG exerted anti-aging effects, with RG stronger than PG. Finally, although both PG and RG regulated the diversity of gut microbes, RG appeared to aggravate the increase in probiotics, such as Bifidobacterium and Akkermania, and the decrease in inflammatory bacteria to a greater extent compared to PG. CONCLUSION: Our results suggest that RG is more conducive to delay the D-Gal-induced aging process than PG, with possible mechanisms including beneficial changes in brain structure, cognitive functions, oxidative stress inhibition, and gut microbiome structure and diversity than PG, These mechanisms may rely on the presence of more total polyphenols, rare ginsenosides and non-starch polysaccharides in RG. Title: Donepezil Ameliorates Pulmonary Arterial Hypertension by Inhibiting M2-Macrophage Activation Qiu H, Zhang Y, Li Z, Jiang P, Guo S, He Y, Guo Y Ref: Front Cardiovasc Med, 8:639541, 2021 : PubMed ESTHER: Qiu_2021_Front.Cardiovasc.Med_8_639541 PubMedSearch: Qiu 2021 Front.Cardiovasc.Med 8 639541 PubMedID: 33791350 Abstract Background: The beneficial effects of parasympathetic stimulation in pulmonary arterial hypertension (PAH) have been reported. However, the specific mechanism has not been completely clarified. Donepezil, an oral cholinesterase inhibitor, enhances parasympathetic activity by inhibiting acetylcholinesterase, whose therapeutic effects in PAH and its mechanism deserve to be investigated. Methods: The PAH model was established by a single intraperitoneal injection of monocrotaline (MCT, 50 mg/kg) in adult male Sprague-Dawley rats. Donepezil was administered via intraperitoneal injection daily after 1 week of MCT administration. At the end of the study, PAH status was confirmed by echocardiography and hemodynamic measurement. Testing for acetylcholinesterase activity and cholinergic receptor expression was used to evaluate parasympathetic activity. Indicators of pulmonary arterial remodeling and right ventricular (RV) dysfunction were assayed. The proliferative and apoptotic ability of pulmonary arterial smooth muscle cells (PASMCs), inflammatory reaction, macrophage infiltration in the lung, and activation of bone marrow-derived macrophages (BMDMs) were also tested. PASMCs from the MCT-treated rats were co-cultured with the supernatant of BMDMs treated with donepezil, and then, the proliferation and apoptosis of PASMCs were evaluated. Results: Donepezil treatment effectively enhanced parasympathetic activity. Furthermore, it markedly reduced mean pulmonary arterial pressure and RV systolic pressure in the MCT-treated rats, as well as reversed pulmonary arterial remodeling and RV dysfunction. Donepezil also reduced the proliferation and promoted the apoptosis of PASMCs in the MCT-treated rats. In addition, it suppressed the inflammatory response and macrophage activation in both lung tissue and BMDMs in the model rats. More importantly, donepezil reduced the proliferation and promoted the apoptosis of PASMCs by suppressing M2-macrophage activation. Conclusion: Donepezil could prevent pulmonary vascular and RV remodeling, thereby reversing PAH progression. Moreover, enhancement of the parasympathetic activity could reduce the proliferation and promote the apoptosis of PASMCs in PAH by suppressing M2-macrophage activation. Title: Case Study Using Recommended Reference Genes Actin and 18S for Reverse-Transcription Quantitative Real-Time PCR Analysis in Myzus persicae Rahman S, Zhao Z, Umair Sial M, Zhang Y, Jiang H Ref: PLoS ONE, 16:e0258201, 2021 : PubMed ESTHER: Rahman_2021_PLoS.One_16_e0258201 PubMedSearch: Rahman 2021 PLoS.One 16 e0258201 PubMedID: 34669698 Abstract Myzus persicae is a globally important pest with the ability to adjust to a wide range of environmental situations, and many molecular technologies have been developed and applied to understand the biology and/or control this pest insect directly. Reverse-transcription quantitative real-time PCR (RT-qPCR) is a primary molecular technology that is used to quantify gene expression. Choosing a stable reference gene is significantly important for precisely clarifying the expression level of the target gene. Actin and 18S have been recommended as stable compounds for real-time RT-qPCR in M. persicae under the tested biotic and abiotic conditions. In this study, we checked the stability of Actin and 18S by analyzing the relative expression levels of the cytochrome 450 monooxygenase family member genes CYP6CY3 and CYP6-1, carboxylesterase gene E4 and vacuolar protein sorting gene VPS11 via RT-qPCR under various conditions. The expression levels of these four target genes were normalized using both Actin and 18S individually and the combination of these two genes. Our results confirmed that Actin and 18S can be used as reference genes to normalize the expression of target genes under insecticide treatment and starvation in M. persicae. However, at the developmental stages of M. persicae, the expression of the four tested target genes was normalized stably by Actin but not 18S, with the latter presenting a problematic change with the developmental stages. Thus, the stability of reference genes in response to diverse biotic and abiotic factors should be evaluated before each RT-qPCR experiment. Title: Novel Reversible-Binding PET Ligands for Imaging Monoacylglycerol Lipase Based on the Piperazinyl Azetidine Scaffold Rong J, Mori W, Xia X, Schafroth MA, Zhao C, Van RS, Yamasaki T, Chen J, Xiao Z and Liang SH <23 more author(s)> Rong J, Mori W, Xia X, Schafroth MA, Zhao C, Van RS, Yamasaki T, Chen J, Xiao Z, Haider A, Ogasawara D, Hiraishi A, Shao T, Zhang Y, Chen Z, Pang F, Hu K, Xie L, Fujinaga M, Kumata K, Gou Y, Fang Y, Gu S, Wei H, Bao L, Xu H, Collier TL, Shao Y, Carson RE, Cravatt BF, Wang L, Zhang MR, Liang SH (- 23) Ref: Journal of Medicinal Chemistry, :, 2021 : PubMed ESTHER: Rong_2021_J.Med.Chem__ PubMedSearch: Rong 2021 J.Med.Chem PubMedID: 34569803 Gene_locus related to this paper: human-MGLL Inhibitor(s) related to this paper: ZYH-deriv-F Abstract Monoacylglycerol lipase (MAGL) is a 33 kDa serine protease primarily responsible for hydrolyzing 2-arachidonoylglycerol into the proinflammatory eicosanoid precursor arachidonic acid in the central nervous system. Inhibition of MAGL constitutes an attractive therapeutic concept for treating psychiatric disorders and neurodegenerative diseases. Herein, we present the design and synthesis of multiple reversible MAGL inhibitor candidates based on a piperazinyl azetidine scaffold. Compounds 10 and 15 were identified as the best-performing reversible MAGL inhibitors by pharmacological evaluations, thus channeling their radiolabeling with fluorine-18 in high radiochemical yields and favorable molar activity. Furthermore, evaluation of [(18)F]10 and [(18)F]15 ([(18)F]MAGL-2102) by autoradiography and positron emission tomography (PET) imaging in rodents and nonhuman primates demonstrated favorable brain uptakes, heterogeneous radioactivity distribution, good specific binding, and adequate brain kinetics, and [(18)F]15 demonstrated a better performance. In conclusion, [(18)F]15 was found to be a suitable PET radioligand for the visualization of MAGL, harboring potential for the successful translation into humans. Title: The Novel Monoacylglycerol Lipase Inhibitor MJN110 Suppresses Neuroinflammation, Normalizes Synaptic Composition and Improves Behavioral Performance in the Repetitive Traumatic Brain Injury Mouse Model Selvaraj P, Tanaka M, Wen J, Zhang Y Ref: Cells, 10:, 2021 : PubMed ESTHER: Selvaraj_2021_Cells_10_3454 PubMedSearch: Selvaraj 2021 Cells 10 3454 PubMedID: 34943962 Inhibitor(s) related to this paper: MJN110 Abstract Modulation of the endocannabinoid system has emerged as an effective approach for the treatment of many neurodegenerative and neuropsychological diseases. However, the underlying mechanisms are still uncertain. Using a repetitive mild traumatic brain injury (mTBI) mouse model, we found that there was an impairment in locomotor function and working memory within two weeks post-injury, and that treatment with MJN110, a novel inhibitor of the principal 2-arachidononyl glycerol (2-AG) hydrolytic enzyme monoacylglycerol lipase dose-dependently ameliorated those behavioral changes. Spatial learning and memory deficits examined by Morris water maze between three and four weeks post-TBI were also reversed in the drug treated animals. Administration of MJN110 selectively elevated the levels of 2-AG and reduced the production of arachidonic acid (AA) and prostaglandin E(2) (PGE(2)) in the TBI mouse brain. The increased production of proinflammatory cytokines, accumulation of astrocytes and microglia in the TBI mouse ipsilateral cerebral cortex and hippocampus were significantly reduced by MJN110 treatment. Neuronal cell death was also attenuated in the drug treated animals. MJN110 treatment normalized the expression of the NMDA receptor subunits NR2A and NR2B, the AMPA receptor subunits GluR1 and GluR2, and the GABA(A) receptor subunits alpha1, beta2,3 and gamma2, which were all reduced at 1, 2 and 4 weeks post-injury. The reduced inflammatory response and restored glutamate and GABA receptor expression likely contribute to the improved motor function, learning and memory in the MJN110 treated animals. The therapeutic effects of MJN110 were partially mediated by activation of CB1 and CB2 cannabinoid receptors and were eliminated when it was co-administered with DO34, a novel inhibitor of the 2-AG biosynthetic enzymes. Our results suggest that augmentation of the endogenous levels of 2-AG can be therapeutically useful in the treatment of TBI by suppressing neuroinflammation and maintaining the balance between excitatory and inhibitory neurotransmission. Title: Repeated low-dose exposures to sarin disrupted the homeostasis of phospholipid and sphingolipid metabolism in guinea pig hippocampus Shi M, Deng S, Cui Y, Chen X, Shi T, Song L, Zhang R, Zhang Y, Xu J and Li L <2 more author(s)> Shi M, Deng S, Cui Y, Chen X, Shi T, Song L, Zhang R, Zhang Y, Xu J, Shi J, Wang C, Li L (- 2) Ref: Toxicol Lett, 338:32, 2021 : PubMed ESTHER: Shi_2021_Toxicol.Lett_338_32 PubMedSearch: Shi 2021 Toxicol.Lett 338 32 PubMedID: 33253782 Abstract Repeated low-level exposure to sarin results to hippocampus dysfunction. Metabonomics involves a holistic analysis of a set of metabolites in an organism in the search for a relationship between these metabolites and physiological or pathological changes. The objective of the present study was to evaluate the effects of repeated exposure to low-level sarin on the metabonomics in hippocampus of a guinea pig model. Guinea pigs were divided randomly into control and sarin treated groups (n = 14). Guinea pigs in the control group received saline; while the sarin-treated group received 0.4xLD(50) (16.8 microg/kg) sarin. Daily injections (a total of 14 days) were administered sc between the shoulder blades in a volume of 1.0 ml/kg body weight. At the end of the final injection, 6 animals in each group were chosen for Morris water maze test. The rest guinea pigs (n = 8 for each group) were sacrificed by decapitation, and hippocampus were dissected for analysis. Compared with the control-group, the escape latency in sarin-group was significantly (p < 0.05) longer while the crossing times were significantly decreased in the Morris water task (p < 0.05). Sarin inhibited activities of acetylcholinesterase (AChE) and neuropathy target esterase (NTE) in hippocampus. The AChE activity of hippocampus from sarin-treated groups is equivalent to 59.9 +/- 6.4 %, and the NTE activity of hippocampus from sarin-groups is equivalent to 78.1 +/- 8.3 % of that from control-group. Metabolites were identified and validated. A total of 14 variables were selected as potential biomarkers. Phospholipids [phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), phosphatidylglycerol (PG), phosphatidylinositol (PI), Lysophosphatidylethanolamine (LysoPE or LPE)] and sphingolipids (SPs) [sphinganine (SA), phytosphingosine (PSO) and sphinganine-1-phosphate (SA1P)] were clearly modified. In conclusion, repeated low-dose exposures to sarin disrupted the homeostasis of phospholipid and sphingolipid metabolism in guinea pig hippocampus and may lead to a neuronal-specific function disorders. Identified metabolites such as SA1P need to be studied more deeply on their biological function that against sarin lesions. In future research, we should pay more attention to characterize the physiological roles of lipid metabolism enzymes as well as their involvement in pathologies induced by repeated low-level sarin exposure. Title: Molecular cloning and characterization of an atypical butyrylcholinesterase-like protein in zebrafish Tan KS, Zhang Y, Liu L, Li S, Zou X, Zeng W, Cheng G, Wang D, Tan W Ref: Comparative Biochemistry & Physiology B Biochem Mol Biol, :110590, 2021 : PubMed ESTHER: Tan_2021_Comp.Biochem.Physiol.B.Biochem.Mol.Biol__110590 PubMedSearch: Tan 2021 Comp.Biochem.Physiol.B.Biochem.Mol.Biol 110590 PubMedID: 33662568 Gene_locus related to this paper: danre-a0a0r4iu19.1 Abstract Cholinesterases act as bio scavengers to clear organophosphorus (OP) compounds and prodrugs. The butyrylcholinesterase (BChE) gene has been found in several types of teleost fish but this gene has yet to be identified in cyprinid fish. Indeed, BChE homologs have not been found in the zebrafish (Danio rerio) genomic database. Here, we demonstrate that BChE activity is present in zebrafish, in line with other groups' findings. Using in-gel native-PAGE enzymatic activity staining and LC-MS/MS technique, an atypical BChE-like protein was identified in zebrafish. The si:ch211-93f2.1 gene was cloned, and His-tagged recombinant protein was expressed using the Pichia yeast system. The purified protein (molecular weight ~ 180 kDa) showed BChE activity, and degraded acetylcholinesterase (ACh) at a higher rate than BCh. However, phylogram analysis shows that this novel cholinesterase shared an evolutionary origin with carboxylic esterase rather than BChE. The zebrafish BChE-like protein shares structural characteristics with cholinesterase and carboxylesterase. The 2-arachidonoylglycerol (2-AG), nicosulfuron, and triacetin exhibited a higher binding affinity to the zebrafish BChE-like protein than BCh and ACh. With the identification of BChE-like protein in zebrafish, this study could shed light on the origin of BChE and may contribute towards the development of a BChE knockout zebrafish model for sensitive drug or toxin screening. Title: Late-Stage Modification of Medicine: Pd-Catalyzed Direct Synthesis and Biological Evaluation of N-Aryltacrine Derivatives Wan LX, Zhen YQ, He ZX, Zhang Y, Zhang L, Li X, Gao F, Zhou XL Ref: ACS Omega, 6:9960, 2021 : PubMed ESTHER: Wan_2021_ACS.Omega_6_9960 PubMedSearch: Wan 2021 ACS.Omega 6 9960 PubMedID: 33869976 Abstract A new series of N-aryltacrine derivatives were designed and synthesized as cholinesterase inhibitors by the late-stage modification of tacrine, using the palladium-catalyzed Buchwald-Hartwig cross-coupling reaction. In vitro inhibition assay against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) demonstrated that most of the synthesized compounds had potent AChE inhibitory activity with negative inhibition of BuChE. Among them, N-(4-(trifluoromethyl)phenyl)-tacrine (3g) and N-(4-methoxypyridin-2-yl)-tacrine (3o) showed the most potent activity against AChE (IC(50) values of 1.77 and 1.48 microM, respectively). The anti-AChE activity of 3g and 3o was 3.5 times more than that of tacrine (IC(50) value of 5.16 microM). Compound 3o also displayed anti-BuChE activity with an IC(50) value of 19.00 microM. Cell-based assays against HepG2 and SH-SY5Y cell lines revealed that 3o had significantly lower hepatotoxicity compared to tacrine, with additional neuroprotective activity against H(2)O(2)-induced damage in SH-SY5Y cells. The advantages including synthetic accessibility, high potency, low toxicity, and adjunctive neuroprotective activity make compound 3o a new promising multifunctional candidate for the treatment of Alzheimer's disease. Title: Dammarane Sapogenins Improving Simulated Weightlessness-Induced Depressive-Like Behaviors and Cognitive Dysfunction in Rats Wang Q, Dong L, Wang M, Chen S, Li S, Chen Y, He W, Zhang H, Zhang Y and Liu X <2 more author(s)> Wang Q, Dong L, Wang M, Chen S, Li S, Chen Y, He W, Zhang H, Zhang Y, Pires Dias AC, Yang S, Liu X (- 2) Ref: Front Psychiatry, 12:638328, 2021 : PubMed ESTHER: Wang_2021_Front.Psychiatry_12_638328 PubMedSearch: Wang 2021 Front.Psychiatry 12 638328 PubMedID: 33841208 Abstract Background: Our studies demonstrated that the space environment has an impact on the brain function of astronauts. Numerous ground-based microgravity and social isolation showed that the space environment can induce brain function damages in humans and animals. Dammarane sapogenins (DS), an active fraction from oriental ginseng, possesses neuropsychic protective effects and has been shown to improve depression and memory. This study aimed to explore the effects and mechanisms of DS in attenuating depressive-like behaviors and cognitive deficiency induced by simulated weightlessness and isolation [hindlimb suspension and isolation (HLSI)] in rats. Methods: Male rats were orally administered with two different doses of DS (37.5, 75 mg/kg) for 14 days, and huperzine-A (1 mg/kg) served as positive control. Rats were subjected to HLSI for 14 days except the control group during drug administration. The depressive-like behaviors were then evaluated by the open-field test, the novel object recognition test, and the forced swimming test. The spatial memory and working memory were evaluated by the Morris water maze (MWM) test, and the related mechanism was further explored by analyzing the activity of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), and superoxide dismutase (SOD) in the hippocampus of rats. Results: The results showed that DS treatment significantly reversed the HLSI-induced depressive-like behaviors in the open-field test, the novel object recognition test, and the forced swimming test and improved the HLSI-induced cognitive impairment in the MWM test. Furthermore, after DS treatment, the ChAT and SOD activities of HLSI rats were increased while AChE activity was significantly suppressed. Conclusions: These findings clearly demonstrated that DS might exert a significant neuropsychic protective effect induced by spaceflight environment, driven in part by the modulation of cholinergic system and anti-oxidation in the hippocampus. Title: Discovery of 7-O-1, 2, 3-triazole hesperetin derivatives as multi-target-directed ligands against Alzheimer's disease Wang M, Fang L, Liu T, Chen X, Zheng Y, Zhang Y, Chen S, Li Z Ref: Chemico-Biological Interactions, :109489, 2021 : PubMed ESTHER: Wang_2021_Chem.Biol.Interact__109489 PubMedSearch: Wang 2021 Chem.Biol.Interact 109489 PubMedID: 33905740 Abstract The development of multi-target-directed ligands (MTDLs) may improve complex central nervous system diseases such as Alzheimer's disease (AD). Here, a series of 7-O-1, 2, 3-triazole hesperetin derivatives was evaluated for their inhibition of cholinesterase, anti-neuroinflammatory, and neuroprotective activity. Among the hesperetin derivatives, compound a8 (7-O-((1-(3-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)hesperetin) possessed excellent anti-butyrylcholinesterase activity (IC(50) = 3.08 +/- 0.29 microM) and exhibited good anti-neuroinflammatory activity (IC(50) = 2.91 +/- 0.47 microM) against NO production through remarkably blocking the NF-kappaB signaling pathway and inhibiting the phosphorylation of P65. In addition, a8 showed a remarkable neuroprotective effect and lacked neurotoxicity up to 50 microM concentration. Furthermore, possessing significant self-mediated Abeta(1-42) aggregation inhibitory activity, chelated biometals and reduced ROS production were found in compound a8. In the bi-directional transport assay, a8 exhibited a blood-brain barrier penetrating ability. In this study, the Morris water maze task showed that compound a8 significantly improved the learning and memory impairment of the scopolamine-induced AD mice model. Results highlighted the potential of compound a8 to be a potential MTDL for the development of anti-AD agents. Title: Two novel Mutations of the LPL Gene in two Chinese family cases with Familial Chylomicronemia Syndrome Wang M, Zhou Y, He X, Deng C, Liu X, Li J, Zhou L, Li Y, Zhang Y and Li L <1 more author(s)> Wang M, Zhou Y, He X, Deng C, Liu X, Li J, Zhou L, Li Y, Zhang Y, Liu H, Li L (- 1) Ref: Clinica Chimica Acta, :, 2021 : PubMed ESTHER: Wang_2021_Clin.Chim.Acta__ PubMedSearch: Wang 2021 Clin.Chim.Acta PubMedID: 34324844 Abstract The aim of this study was to investigate the clinical features and genetic causes of two family cases with familial chylomicronemia syndrome (FCS). Clinical manifestations of proband 1 and her families, and also proband 2 showed severe hypertriglyceridemia, especially the triglycerides levels of two probands were extremely high. Gene sequencing results showed that the LPL genes in each of the two probands had a new mutation site. For the proband 1, a compound heterozygous mutation at c.429 (c.429+1G>T) was detected in the LPL gene, which was splicing mutation and inherited from her mother. Homozygous mutation was detected in the LPL gene of proband 2, the nucleotide mutation at c.802 (c.802C > T) exhibited missense mutation, his parents and brother had a heterozygous mutation at the same site. It was confirmed that the conservative lipoprotein lipase superfamily domain changed an amino acid from histidine to tyrosine at p. 268 (p. His268Tyr). Flow cytometry confirmed the deficient expression of LPL protein in two families. These results indicated that the mutation in LPL gene might be the cause of familial chylomicronemia syndrome. Title: An Evolving Technology That Integrates Classical Methods with Continuous Technological Developments: Thin-Layer Chromatography Bioautography Wang M, Zhang Y, Wang R, Wang Z, Yang B, Kuang H Ref: Molecules, 26:, 2021 : PubMed ESTHER: Wang_2021_Molecules_26_ PubMedSearch: Wang 2021 Molecules 26 PubMedID: 34361800 Abstract Thin-layer chromatography (TLC) bioautography is an evolving technology that integrates the separation and analysis technology of TLC with biological activity detection technology, which has shown a steep rise in popularity over the past few decades. It connects TLC with convenient, economic and intuitive features and bioautography with high levels of sensitivity and specificity. In this study, we discuss the research progress of TLC bioautography and then establish a definite timeline to introduce it. This review summarizes known TLC bioautography types and practical applications for determining antibacterial, antifungal, antitumor and antioxidant compounds and for inhibiting glucosidase, pancreatic lipase, tyrosinase and cholinesterase activity constitutes. Nowadays, especially during the COVID-19 pandemic, it is important to identify original, natural products with anti-COVID potential compounds from Chinese traditional medicine and natural medicinal plants. We also give an account of detection techniques, including in situ and ex situ techniques; even in situ ion sources represent a major reform. Considering the current technical innovations, we propose that the technology will make more progress in TLC plates with higher separation and detection technology with a more portable and extensive scope of application. We believe this technology will be diffusely applied in medicine, biology, agriculture, animal husbandry, garden forestry, environmental management and other fields in the future. Title: Antibodies to Full-Length Agrin Protein in Chinese Patients With Myasthenia Gravis Wang S, Yang H, Guo R, Wang L, Zhang Y, Lv J, Zhao X, Zhang J, Fang H and Gao F <5 more author(s)> Wang S, Yang H, Guo R, Wang L, Zhang Y, Lv J, Zhao X, Zhang J, Fang H, Zhang Q, Yang J, Cui X, Gao P, Chang T, Gao F (- 5) Ref: Front Immunol, 12:753247, 2021 : PubMed ESTHER: Wang_2021_Front.Immunol_12_753247 PubMedSearch: Wang 2021 Front.Immunol 12 753247 PubMedID: 34956185 Abstract This study aimed to establish a cell-based assay (CBA) for the detection of agrin antibodies (Agrin-Ab) to explore the clinical features of agrin antibody-positive Chinese patients with myasthenia gravis (Agrin-MG). We developed a CBA based on the human full-length agrin protein expressed in HEK293T cells for the reliable and efficient detection of Agrin-Ab. Clinical data and serum samples were collected from 1948 MG patients in 26 provinces in China. The demographic and clinical features of Agrin-MG patients were compared with those of other MG patient subsets. Eighteen Agrin-MG cases were identified from 1948 MG patients. Nine patients were Agrin-Ab positive, and nine were AChR-Ab and Agrin-Ab double-positive (Agrin/AChR-MG). Eleven (61.11%) patients were males older than 40 years of age. The initial symptom in 13 (81.25%) cases was ocular weakness. Occasionally, the initial symptom was limb-girdle weakness (two cases) or bulbar muscle weakness (one case). Agrin-MG patients demonstrated slight improvement following treatment with either acetylcholinesterase inhibitor or prednisone; however, the combination of the two drugs could effectively relieve MG symptoms. In China, Agrin-MG demonstrated seropositivity rates of 0.92%. These patients were commonly middle-aged or elderly men. The patients usually presented weakness in the ocular, bulbar, and limb muscles, which may be combined with thymoma. These patients have more severe diseases, although the combination of pyridostigmine and prednisone was usually effective in relieving symptoms. Title: Single-Nucleotide Polymorphisms Promote Dysregulation Activation by Essential Gene Mediated Bio-Molecular Interaction in Breast Cancer Wang X, Zhao Z, Han X, Zhang Y, Li F, Li H Ref: Front Oncol, 11:791943, 2021 : PubMed ESTHER: Wang_2021_Front.Oncol_11_791943 PubMedSearch: Wang 2021 Front.Oncol 11 791943 PubMedID: 34926308 Gene_locus related to this paper: human-ABHD11 Abstract BACKGROUND: Breast cancer (BRCA) is a malignant tumor with a high mortality rate and poor prognosis in patients. However, understanding the molecular mechanism of breast cancer is still a challenge. MATERIALS AND METHODS: In this study, we constructed co-expression networks by weighted gene co-expression network analysis (WGCNA). Gene-expression profiles and clinical data were integrated to detect breast cancer survival modules and the leading genes related to prognostic risk. Finally, we introduced machine learning algorithms to build a predictive model aiming to discover potential key biomarkers. RESULTS: A total of 42 prognostic modules for breast cancer were identified. The nomogram analysis showed that 42 modules had good risk assessment performance. Compared to clinical characteristics, the risk values carried by genes in these modules could be used to classify the high-risk and low-risk groups of patients. Further, we found that 16 genes with significant differential expressions and obvious bridging effects might be considered biological markers related to breast cancer. Single-nucleotide polymorphisms on the CYP24A1 transcript induced RNA structural heterogeneity, which affects the molecular regulation of BRCA. In addition, we found for the first time that ABHD11-AS1 was significantly highly expressed in breast cancer. CONCLUSION: We integrated clinical prognosis information, RNA sequencing data, and drug targets to construct a breast cancer-related risk module. Through bridging effect measurement and machine learning modeling, we evaluated the risk values of the genes in the modules and identified potential biomarkers for breast cancer. The protocol provides new insight into deciphering the molecular mechanism and theoretical basis of BRCA. Title: Binding mechanism and functional evaluation of quercetin 3-rhamnoside on lipase Wu D, Duan R, Tang L, Hu X, Geng F, Sun Q, Zhang Y, Li H Ref: Food Chem, 359:129960, 2021 : PubMed ESTHER: Wu_2021_Food.Chem_359_129960 PubMedSearch: Wu 2021 Food.Chem 359 129960 PubMedID: 33945987 Abstract The interaction between lipase and quercetin 3-rhamnoside was studied by fluorescence spectroscopy, enzyme kinetics, and molecular dynamics simulation. The results showed that quercetin 3-rhamnoside had a strong quenching effect on the intrinsic fluorescence of lipase. The binding constant decreased with increasing temperature, and the number of binding sites approached 1. Thermodynamic parameters indicated that hydrogen bonding and van der Waals forces are the dominant forces when the interaction occurs. Circular dichroism spectroscopy and infrared spectroscopy proved that the ligand perturbed the structure of lipase. Enzyme kinetics results showed that quercetin 3-rhamnoside inhibited lipase, and the inhibitory effect was dose-dependent. Molecular dynamics simulation further explained the interaction mechanism and inhibitory effect. This study confirmed the inhibitory effect of quercetin 3-rhamnoside on lipase explained their binding mechanism, which will contribute to guiding the development of fat-reducing functional foods. Title: TIR signal promotes interactions between lipase-like proteins and ADR1-L1 receptor and ADR1-L1 oligomerization Wu Z, Tian L, Liu X, Zhang Y, Li X Ref: Plant Physiol, 187:681, 2021 : PubMed ESTHER: Wu_2021_Plant.Physiol_187_681 PubMedSearch: Wu 2021 Plant.Physiol 187 681 PubMedID: 34608964 Abstract TIR signaling promotes the interactions between lipase-like proteins EDS1/PAD4 and ADR1-L1 immune receptor, and oligomerization of ADR1-L1. Title: Peroxidase-mimicking Activity of PCN-222(Fe) for Colorimetric Sensing of Acetylcholinesterase Activity and Inhibition Xia M, Liu T, Zhang Y Ref: Anal Sci, 37:1023, 2021 : PubMed ESTHER: Xia_2021_Anal.Sci_37_1023 PubMedSearch: Xia 2021 Anal.Sci 37 1023 PubMedID: 33071263 Abstract A colorimetric method for detection of acetylcholinesterase (AChE) activity and inhibition was developed using metal organic frameworks (i.e., PCN-222(Fe)) with peroxidase-like activity. The blue tetramethylbenzidine oxidized by PCN-222(Fe) fades due to the reduction by acetylthiocholine chloride produced from AChE catalysis. The detection method shows a linear range of 0.05 - 10 mU mL(-1) and a detection limit of 0.03 mU mL(-1) AChE. Average recoveries in serum samples varied from 93 to 115% and relative standard deviation (RSD) was lower than 4.9%. Title: Neuroprotective effects of minocycline and KML29, a potent inhibitor of monoacylglycerol lipase, in an experimental stroke model: a small-animal positron emission tomography study Yamasaki T, Hatori A, Zhang Y, Mori W, Kurihara Y, Ogawa M, Wakizaka H, Rong J, Wang L and Zhang MR <1 more author(s)> Yamasaki T, Hatori A, Zhang Y, Mori W, Kurihara Y, Ogawa M, Wakizaka H, Rong J, Wang L, Liang S, Zhang MR (- 1) Ref: Theranostics, 11:9492, 2021 : PubMed ESTHER: Yamasaki_2021_Theranostics_11_9492 PubMedSearch: Yamasaki 2021 Theranostics 11 9492 PubMedID: 34646382 Inhibitor(s) related to this paper: KML29 Abstract Hypoxia caused by ischemia induces acidosis and neuroexcitotoxicity, resulting in neuronal death in the central nervous system (CNS). Monoacylglycerol lipase (MAGL) is a modulator of 2-arachidonoylglycerol (2-AG), which is involved in retrograde inhibition of glutamate release in the endocannabinoid system. In the present study, we used positron emission tomography (PET) to monitor MAGL-positive neurons and neuroinflammation in the brains of ischemic rats. Additionally, we performed PET imaging to evaluate the neuroprotective effects of an MAGL inhibitor in an ischemic injury model. Methods: Ischemic-injury rat models were induced by intraluminal right middle cerebral artery occlusion (MCAO). PET studies of the brains of the ischemic rats were performed at several experimental time points (pre-occlusion, days 2, 4, and 7 after the MCAO surgery) using [(11)C]SAR127303 for MAGL and [(18)F]FEBMP for 18 kDa translocator protein (TSPO, a hall-mark of neuroinflammation). Medication using minocycline (a well-known neuroprotective agent) or KML29 (a potent MAGL inhibitor) was given immediately after the MCAO surgery and then daily over the subsequent three days. Results: PET imaging of the ischemic rats using [(11)C]SAR127303 showed an acute decline of radioactive accumulation in the ipsilateral side at two days after MCAO surgery (ratio of the area under the curve between the ipsilateral and contralateral sides: 0.49 +/- 0.04 in the cortex and 0.73 +/- 0.02 in the striatum). PET imaging with [(18)F]FEBMP, however, showed a moderate increase in accumulation of radioactivity in the ipsilateral hemisphere on day 2 (1.36 +/- 0.11), and further increases on day 4 (1.72 +/- 0.15) and day 7 (1.99 +/- 0.06). Treatment with minocycline or KML29 eased the decline in radioactive accumulation of [(11)C]SAR127303 for MAGL (minocycline-treated group: 0.82 +/- 0.06 in the cortex and 0.81 +/- 0.05 in the striatum; KML29-treated group: 0.72 +/- 0.07 in the cortex and 0.88 +/- 0.04 in the striatum) and increased uptake of [(18)F]FEBMP for TSPO (minocycline-treated group: 1.52 +/- 0.21 in the cortex and 1.56 +/- 0.11 in the striatum; KML29-treated group: 1.63 +/- 0.09 in the cortex and 1.50 +/- 0.17 in the striatum). In MCAO rats, minocycline treatment showed a neuroprotective effect in the sensorimotor cortex suffering from severe hypoxic injury, whereas KML29 treatment saved neurons in the striatum, including bundles of myelinated axons. Conclusions: PET imaging allowed visualization of the different neuroprotective effects of minocycline and KML29, and indicated that combination pharmacotherapy using these drugs may be an effective therapy in acute ischemia. Title: Identification and characterization of a novel carboxylesterase EstQ7 from a soil metagenomic library Yan Z, Ding L, Zou D, Wang L, Tan Y, Guo S, Zhang Y, Xin Z Ref: Arch Microbiol, :, 2021 : PubMed ESTHER: Yan_2021_Arch.Microbiol__ PubMedSearch: Yan 2021 Arch.Microbiol PubMedID: 34057548 Gene_locus related to this paper: 9bact-MW804671 Abstract A novel lipolytic gene, estq7, was identified from a fosmid metagenomic library. The recombinant enzyme EstQ7 consists of 370 amino acids with an anticipated molecular mass of 42 kDa. Multiple sequence alignments showed that EstQ7 contained a pentapeptide motif GHSMG, and a putative catalytic triad Ser174-Asp306-His344. Interestingly, EstQ7 was found to have very little similarity to the characterized lipolytic enzymes. Phylogenetic analysis revealed that EstQ7 may be a member of a novel family of lipolytic enzymes. Biochemical characterization of the recombinant enzyme revealed that it constitutes a slightly alkalophilic, moderate thermophilic and highly active carboxylesterase against short-chain fatty acid esters with optimum temperature 50 degC and pH 8.2. The Km and kcat values toward p-nitrophenyl acetate were determined to be 0.17 mM and 1910s(-1), respectively. Moreover, EstQ7 was demonstrated to have acyltransferase activity by GC-MS analysis. Structural modeling of the three-dimensional structure of this new enzyme showed that it exhibits a typical alpha/beta hydrolase fold, and the catalytic triad residues are spatially close. Molecular docking revealed the interactions between the enzyme and the ligand. The high levels of lipolytic activity of EstQ7, combined with its moderate thermophilic property and acyltransferase activity, render this novel enzyme a promising candidate biocatalyst for food, pharmaceutical and biotechnological applications. Title: Dipeptidyl peptidase IV is required for endometrial carcinoma cell proliferation and tumorigenesis via the IL-6/STAT3 pathway Yang X, Zhu Y, Shi Q, Zhao X, Huang Y, Yao F, Zhang Y, Wang Z Ref: J Obstet Gynaecol Res, :, 2021 : PubMed ESTHER: Yang_2021_J.Obstet.Gynaecol.Res__ PubMedSearch: Yang 2021 J.Obstet.Gynaecol.Res PubMedID: 33969570 Abstract AIM: To study the functions and signaling pathways controlled by dipeptidyl peptidase IV (DPPIV) in endometrial carcinoma (EC). METHODS: DPPIV expression in EC cells was detected by flow cytometry, reverse transcription-polymerase chain reaction analysis and Western blot. Interleukin-6 (IL-6) expression in the supernatant was measured by enzyme-linked immunosorbent assay. The protein levels of signal transducers and activators of transcription-3 (STAT3), phosphorylate STAT3, cellular Myc, and vascular endothelial growth factor in EC cells were measured by Western blot. Colony formation assays were used to assess the clonogenicity of EC cells. Ki67 immunostaining and cell counting were used to test the proliferative ability of EC cells. Nude mouse tumorigenicity assay was used to confirm DPPIV promotes the tumorigenicity of EC cells. A cell counting kit-8 assay was used to determine the half-maximal inhibitory concentration of sitagliptin. RESULTS: Overexpression of DPPIV in EC cells with low DPPIV expression promoted cell proliferation in vitro (p < 0.01) and enhanced tumorigenicity in vivo (p < 0.05). Conversely, knocking down DPPIV expression in EC cells with high DPPIV expression inhibited cell proliferation (p < 0.01) and in vivo tumorigenicity (p < 0.01). DPPIV promoted EC cell proliferation via activation of IL-6/STAT3 signaling pathway, and that IL-6 could trigger a positive feedback loop that increased DPPIV expression (p < 0.01). Furthermore, the DPPIV inhibitor reduced STAT3 expression (p < 0.01) and inhibited growth of EC cells (p < 0.001). CONCLUSION: DPPIV enhances the properties that allow tumorigenesis in EC via IL-6 and STAT3 signaling. Title: Identification of NDRG Family Member 4 (NDRG4) and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) as Key Prognostic Genes in Adrenocortical Carcinoma by Transcriptomic Analysis Yang Z, Cheng H, Zhang Y, Zhou Y Ref: Med Sci Monit, 27:e928523, 2021 : PubMed ESTHER: Yang_2021_Med.Sci.Monit_27_e928523 PubMedSearch: Yang 2021 Med.Sci.Monit 27 e928523 PubMedID: 33667214 Gene_locus related to this paper: human-NDRG4 Abstract BACKGROUND Adrenocortical carcinoma (ACC) is an aggressive cancer with heterogeneous outcomes. In this study, we aimed to investigate genomic and prognostic features of ACC. MATERIAL AND METHODS Clinical, pathologic, and transcriptomic data from 2 independent datasets derived from ACC samples (TCGA-ACC dataset, GEO-GSE76021 dataset) were collected. Weighted gene co-expression network analysis (WGCNA) and survival analyses were performed to identify prognostic genes. Pathway analysis was performed for mechanistic analysis. xCell deconvolution was performed for tumor microenvironment analysis. RESULTS In the TCGA-ACC cohort, WGCNA identified a prognostic module of 5408 genes. Differential expression analysis identified 1969 genes that differed in expression level between long-term and short-term survivors. Univariate Cox regression model analysis identified 8393 genes with prognostic value. The intersection of these gene sets included 820 prognostic genes. Similar protocols were performed for the GSE76021 dataset, and 5 candidate genes were identified. Further intersection of these genes finally identified NDRG4 and CKS2 as key prognostic genes. Multivariate Cox regression model analysis validated the prognostic value of NDRG4 (HR=0.61, 95% CI 0.46-0.80) and CKS2 (HR=2.52, 95% CI 1.38-4.60). Moreover, NDRG4 and CKS2 expression predicted survival in patients treated with mitotane (P<0.001). Further mechanism exploration found an association between CKS2 and DNA mismatch repair pathways. Moreover, NDRG4 positively correlated with CD8 T cell infiltration, while CKS2 negatively correlated with it. CONCLUSIONS We identified NDRG4 and CKS2 expression as key prognostic genes in ACC, which may help in risk stratification of ACC. Moreover, a close relationship was found between CKS2 and mismatch repair pathways. Moreover, immune cell infiltration differed according to NDRG4 and CKS2 expression. Title: The overexpression and variant of a P450 gene CYP6G4 associated with propoxur resistance in the housefly, Musca domestica L You C, Shan C, Ma Z, Zhang Y, Zhao R, Gao X Ref: Pest Manag Sci, :, 2021 : PubMed ESTHER: You_2021_Pest.Manag.Sci__ PubMedSearch: You 2021 Pest.Manag.Sci PubMedID: 33942965 Abstract BACKGROUND: The control of housefly, Musca domestica, heavily relies on the application of insecticides. Propoxur, a carbamate, was widely used for vector control. The housefly populations with high propoxur resistance displayed the point mutations and overexpression of the acetylcholinesterase. However, the roles of cytochrome P450 monoxygenases (P450s), as a kind of the important detoxification enzymes, remain poorly understand in the housefly resistant to propoxur. RESULTS: P450s were implied to contribute to propoxur resistance based on the synergism of PBO and the increase of P450 enzyme activity in the propoxur resistance near-isogenic line (N-PRS). Five P450 (CYP6G4, CYP6A25, CYP304A1, CYP6D3, and CYP6A1) genes by RNA-seq comparison were significantly up-regulated in the N-PRS strain with >1035-fold resistance to propoxur. A total of thirteen nonsynonymous mutations of three P450 genes (CYP6G4, CYP6D3, and CYP6D8) were found in the N-PRS strain. The amino acid substitutions of CYP6D3 and CYP6D8 were probably not resistance-associated single nucleotide polymorphisms (SNPs) because they were also found in the aabys susceptible strain. However, CYP6G4 variant in the N-PRS strain was not found in the aabys strain. The conjoint analysis of mutations and a series of genetic crosses exhibited that the housefly propoxur resistance was strongly associated with the mutations of CYP6G4 gene. CONCLUSION: Our results suggested that a combination of upregulated transcript levels and mutations of CYP6G4 contributed to propoxur resistance in the housefly. This article is protected by copyright. All rights reserved. Title: Thirteen cyathane diterpenoids with acetylcholinesterase inhibitory effects from the fungus Cyathus africanus Yu M, Kang X, Li Q, Liang Y, Zhang M, Gong Y, Chen C, Zhu H, Zhang Y Ref: Phytochemistry, 193:112982, 2021 : PubMed ESTHER: Yu_2021_Phytochemistry_193_112982 PubMedSearch: Yu 2021 Phytochemistry 193 112982 PubMedID: 34700067 Abstract Eight undescribed cyathane diterpenoids, representative specialised metabolites of the genus Cyathus, named cyathins Q-X, along with five known congeners, were isolated from the liquid fermentation of Cyathus africanus. Their structures and absolute configurations were elucidated by integrating NMR spectroscopic analyses, electronic circular dichroism (ECD) calculations, and X-ray diffraction. Reasonable correction to the C-12 configuration of cyathin I was corroborated by the crystal data. The structural identification in this research expanded the number of candidates to allow for more bioactivity-screening options. Among them, (12S)-11alpha,14alpha-epoxy-13alpha,14beta,15-trihydroxycyath-3-ene displayed significant acetylcholinesterase (AChE) inhibitory effect with an IC(50) value of 4.60 +/- 0.85 microM. Molecular docking studies were also performed to unravel the underlying modes of interactions with the active sites of AChE for active compounds. Title: Rapid screening of lipase inhibitors in licorice extract by using porcine pancreatic lipase immobilized on Fe(3)O(4) magnetic nanoparticles Zeng F, Wu W, Zhang Y, Pan X, Duan J Ref: Food Funct, :, 2021 : PubMed ESTHER: Zeng_2021_Food.Funct__ PubMedSearch: Zeng 2021 Food.Funct PubMedID: 34018495 Abstract Chalcones, a class of natural lipase inhibitors, have received substantial attention from researchers in recent years. Although many kinds of chalcones are typically distributed in G. inflata, there is little literature about the anti-lipase activity of G. inflata extracts (GIEs). In the present study, a ligand fishing strategy for fast screening of lipase inhibitors from GIEs was thus proposed. Porcine pancreatic lipase (PPL) was firstly immobilized on carboxyl modified Fe3O4 magnetic nanoparticles (MNPs) to obtain PPL functionalized MNPs (PPL@MNPs), and then the PPL@MNPs were incubated with a bioactive fraction to fish out the ligands. Eight ligands were obtained and identified as one flavone together with seven chalcones. Licochalcone A, licochalcone D and licochalcone E inhibited pancreatic lipase (PL) with IC50 of 4.9, 3.2 and 5.8 microM, respectively. Meanwhile, investigation of the structure-activity relationship also revealed that isopentenyl and hydroxyl substituents at ring A were essential for the noncovalent inhibitory potency of the chalcones. Title: Substrate Engineering in Lipase-Catalyzed Selective Polymerization of d-/l-Aspartates and Diols to Prepare Helical Chiral Polyester Zhang Y, Xia B, Li Y, Lin X, Wu Q Ref: Biomacromolecules, :, 2021 : PubMed ESTHER: Zhang_2021_Biomacromolecules__ PubMedSearch: Zhang 2021 Biomacromolecules PubMedID: 33427463 Abstract The synthesis of optically pure polymers is one of the most challenging tasks in polymer chemistry. Herein, Novozym 435 (Lipase B from Candida antarctica, immobilized on Lewatit VP OC 1600)-catalyzed polycondensation between d-/l-aspartic acid (Asp) diester and diols for the preparation of helical chiral polyesters was reported. Compared with d-Asp diesters, the fast-reacting l-Asp diesters easily reacted with diols to provide a series of chiral polyesters containing N-substitutional l-Asp repeating units. Besides amino acid configuration, N-substituent side chains and the chain length of diols were also investigated and optimized. It was found that bulky acyl N-substitutional groups like N-Boc and N-Cbz were more favorable for this polymerization than small ones probably due to competitively binding of these small acyl groups into the active site of Novozym 435. The highest molecular weight can reach up to 39.5 x 10(3) g/mol (M(w,) D = 1.64). Moreover, the slow-reacting d-Asp diesters were also successfully polymerized by modifying the substrate structure to create a "nonchiral" condensation environment artificially. These enantiocomplementary chiral polyesters are thermally stable and have specific helical structures, which was confirmed by circular dichroism (CD) spectra, scanning electron microscope (SEM), and molecular calculation. Title: A bi-enzymatic cascade pathway towards optically pure FAHFAs Zhang Y, Eser BE, Guo Z Ref: Chembiochem, :, 2021 : PubMed ESTHER: Zhang_2021_Chembiochem__ PubMedSearch: Zhang 2021 Chembiochem PubMedID: 33792147 Abstract Recently discovered endogenous mammalian lipids fatty acid esters of hydroxy fatty acids (FAHFAs), proved to have anti-inflammatory and anti-diabetic effects. Due to their extremely low abundancies in vivo , forging a feasible scenario for FAHFA synthesis is critical for their use in uncovering biological mechanism or clinical trials. Here, we showcase a fully enzymatic approach, a novel in vitro bi-enzymatic cascade system, enabling an effective conversion of nature-abundant fatty acids into FAHFAs. Two hydratases from L. acidophilus were used for converting unsaturated fatty acids to various enantiomeric hydroxy fatty acids, followed by esterification with another fatty acid catalyzed by C. antarctica lipase A (CALA). Various FAHFAs were synthesized in a semi-preparative scale using this bi-enzymatic approach in a one-pot two-step operation mode. In all, we demonstrate that hydratase-CALA system offers a promising route for synthesis of optically pure structure-diverse FAHFAs. Title: Profibrotic mechanisms of DPP8 and DPP9 highly expressed in the proximal renal tubule epithelial cells Zhang Y, Li K, Li Y, Zhao W, Wang L, Chen Z, Ma X, Yao T, Wang J and Fu R <3 more author(s)> Zhang Y, Li K, Li Y, Zhao W, Wang L, Chen Z, Ma X, Yao T, Wang J, Dong W, Li X, Tian X, Fu R (- 3) Ref: Pharmacol Res, 169:105630, 2021 : PubMed ESTHER: Zhang_2021_Pharmacol.Res_169_105630 PubMedSearch: Zhang 2021 Pharmacol.Res 169 105630 PubMedID: 33932609 Gene_locus related to this paper: human-DPP8, human-DPP9 Abstract BACKGROUND: DPP8 and DPP9 have been demonstrated to play important roles in multiple diseases. Evidence for increased gene expression of DPP8 and DPP9 in tubulointerstitium was found to be associated with the decline of kidney function in chronic kidney disease (CKD) patients, which was observed in the Nephroseq human database. To examine the role of DPP8 and DPP9 in the tubulointerstitial injury, we determined the efficacy of DPP8 and DPP9 on epithelial-to-mesenchymal transition (EMT) and tubulointerstitial fibrosis (TIF) as well as the underlying mechanisms. METHODS: We conducted the immunofluorescence of DPP8 and DPP9 in kidney biopsy specimens of CKD patients, established unilateral ureteral obstruction (UUO) animal model, treated with TC-E5007 (a specific inhibitor of both DPP8 and DPP9) or Saxagliptin (positive control) or saline, and HK-2 cells model. RESULTS: We observed the significantly increased expression of DPP8 and DPP9 in the renal proximal tubule epithelial cells of CKD patients compared to the healthy control subjects. DPP8/DPP9 inhibitor TC-E5007 could significantly attenuate the EMT and extracellular matrix (ECM) synthesis in UUO mice, all these effects were mediated via interfering with the TGF-beta1/Smad signaling. TC-E5007 treatment also presented reduced renal inflammation and improved renal function in the UUO mice compared to the placebo-treated UUO group. Furthermore, the siRNA for DPP8 and DPP9, and TC-E5007 treatment decreased EMT- and ECM-related proteins in TGF-beta1-treated HK-2 cells respectively, which could be reversed significantly by transduction with lentivirus-DPP8 and lentivirus-DPP9. CONCLUSION: These data obtained provide evidence that the DPP8 and DPP9 could be potential therapeutic targets against TIF. Title: Active site architecture of an acetyl xylan esterase indicates a novel cold adaptation strategy Zhang Y, Ding HT, Jiang WX, Zhang X, Cao HY, Wang JP, Li CY, Huang F, Zhang XY and Li PY <2 more author(s)> Zhang Y, Ding HT, Jiang WX, Zhang X, Cao HY, Wang JP, Li CY, Huang F, Zhang XY, Chen XL, Zhang YZ, Li PY (- 2) Ref: Journal of Biological Chemistry, :100841, 2021 : PubMed ESTHER: Zhang_2021_J.Biol.Chem__100841 PubMedSearch: Zhang 2021 J.Biol.Chem 100841 PubMedID: 34058201 Abstract SGNH-type acetyl xylan esterases (AcXEs) play important roles in marine and terrestrial xylan degradation, which are necessary for removing acetyl side groups from xylan. However, only a few cold-adapted AcXEs have been reported, and the underlying mechanisms for their cold adaptation are still unknown due to the lack of structural information. Here, a cold-adapted AcXE, AlAXEase, from the Arctic marine bacterium Arcticibacterium luteifluviistationis SM1504(T) was characterized. AlAXEase could deacetylate xylooligosaccharides and xylan, which, together with its homologs, indicates a novel SGNH-type carbohydrate esterase family. AlAXEase showed the highest activity at 30 degreesC and retained over 70% activity at 0 degreesC, but had unusual thermostability with a T(m) value of 56 degreesC. To explain the cold adaption mechanism of AlAXEase, we next solved its crystal structure. AlAXEase has similar noncovalent stabilizing interactions to its mesophilic counterpart at the monomer level and forms stable tetramers in solution, which may explain its high thermostability. However, a long loop containing the catalytic residues Asp200 and His203 in AlAXEase was found to be flexible due to the reduced stabilizing hydrophobic interactions and increased destabilizing asparagine and lysine residues, leading to a highly flexible active site. Structural and enzyme kinetic analyses combined with molecular dynamics simulations at different temperatures revealed that the flexible catalytic loop contributes to the cold adaptation of AlAXEase by modulating the distance between the catalytic His203 in this loop and the nucleophilic Ser32. This study reveals a new cold adaption strategy adopted by the thermostable AlAXEase, shedding light on the cold adaption mechanisms of AcXEs. Title: Identification and Characterization of a Novel Carboxylesterase Belonging to Family VIII with Promiscuous Acyltransferase Activity Toward Cyanidin-3-O-Glucoside from a Soil Metagenomic Library Zhang Y, Ding L, Yan Z, Zhou D, Jiang J, Qiu J, Xin Z Ref: Appl Biochem Biotechnol, :, 2021 : PubMed ESTHER: Zhang_2021_Appl.Biochem.Biotechnol__ PubMedSearch: Zhang 2021 Appl.Biochem.Biotechnol PubMedID: 34255285 Abstract An alkaline esterase, designated as EstXT1, was identified through functional screening from a metagenomic library. Sequence analysis revealed that EstXT1 belonged to the family VIII carboxylesterases and contained a characteristic conserved S-x-x-K motif and a deduced catalytic triad Ser56-Lys59-Tyr165. EstXT1 exhibited the strongest activity toward methyl ferulate at pH 8.0 and temperature 55 degreesC and retained over 80% of its original activity after incubation in the pH range of 7.0-10.6 buffers. Biochemical characterization of the recombinant enzyme showed that it was activated by Zn(2+) and Co(2+) metal ion, while inhibited by Cu(2+) and CTAB. EstXT1 exhibited significant promiscuous acyltransferase activity preferred to the acylation of benzyl alcohol acceptor using short-chain pNP-esters (C2-C8) as acyl-donors. A structure-function analysis indicated that a WAG motif is essential to acyltransferase activity. This is the first report example that WAG motif plays a pivotal role in acyltransferase activity in family VIII carboxylesterases beside WGG motif. Further experiment indicated that EstXT1 successfully acylated cyanidin-3-O-glucoside in aqueous solution. The results from the current investigation provided new insights for the family VIII carboxylesterase and lay a foundation for the potential applications of EstXT1 in food and biotechnology fields. Title: Astilbin ameliorates oxidative stress and apoptosis in D-galactose-induced senescence by regulating the PI3K/Akt/m-TOR signaling pathway in the brains of mice Zhang Y, Ding C, Cai Y, Chen X, Zhao Y, Liu X, Zhang J, Sun S, Liu W Ref: Int Immunopharmacol, 99:108035, 2021 : PubMed ESTHER: Zhang_2021_Int.Immunopharmacol_99_108035 PubMedSearch: Zhang 2021 Int.Immunopharmacol 99 108035 PubMedID: 34435579 Abstract An increasing amount of evidence has shown that injection of D-galactose (D-gal) can mimic natural aging that typically is associated with brain injury. Oxidative stress and apoptosis has been shown to play an essential role in aging process. The purpose of this study was to investigate the protective effectsof astilbin (ASB) on D-Gal-induced agingin miceand to further explore the underlying mechanisms. We randomly divided 50 mice into 5 groups.To establish this model of aging, 40micewere intraperitoneally administered D-Gal (500 mg/kg). The mice in the treatmentgroupswere intragastricaly administratedASB at doses of 40 and 80 mg/kg. H&E and TUNEL staining were used to determine the effect of ASB on the number of apoptotic cells in the brain. Furthermore, biochemical indices of serum, oxidative stress factors, and apoptosis factors were determined to clarify the underlying mechanism using reagent test kits and western blotting. The results showed that varying doses of ASB could improve D-Gal-induced histopathological damageand significantly alleviatedthe aging induced by D-Galin mice. ASB remarkably decreased the activities of malondialdehyde (MDA)(p < 0.01)and Acetyl cholinesterase (AChE)(p < 0.05) and markedlyincreased the content of catalase (CAT)(p < 0.01)and superoxide dismutase (SOD)(p < 0.01), respectively. In addition, Western blotting revealed thatASB treatment (40 mg/kg)attenuated the D-gal-induced Bax and Caspase 3 protein expression(p < 0.01) and reversed the increase in Bcl-2protein expressionin brain. Moreover, ASB treatment significantly upregulated the protein expression ofp-PI3K/PI3K and altered the p-Akt/Akt ratio (p < 0.05), while inhibiting the expression of p-m-TOR relative to m-TOR(p < 0.05). Moreover, the expression of P53 tended to decreasein the low ASB treatmentgroup (40 mg/kg), whereas no change was observed in the high ASB treatmentgroup (80 mg/kg). In the intestinal flora, the richness of the normal group and the ASB group was higher than that of the D-Gal group. Heat map analysis also showed that ASB promoted Lactobacillus and other probiotics and also confirmed the advantages of ASB. The observed changes in intestinal flora further verified the efficacy of ASB. Title: Development and validation of genomic and epigenomic signatures associated with tumor immune microenvironment in hepatoblastoma Zhang Y, Zhang T, Yin Q, Luo H Ref: BMC Cancer, 21:1156, 2021 : PubMed ESTHER: Zhang_2021_BMC.Cancer_21_1156 PubMedSearch: Zhang 2021 BMC.Cancer 21 1156 PubMedID: 34711185 Abstract BACKGROUND: This study aimed to probe and verify aberrantly methylated and expressed genes in hepatoblastoma and to analyze their interactions with tumor immune microenvironment. METHODS: Aberrantly methylated and expressed genes were obtained by comprehensively analyzing gene expression and DNA methylation profiles from GSE81928, GSE75271 and GSE78732 datasets. Their biological functions were predicted by the STRING and Metascape databases. CIBERSORT was utilized for inferring the compositions of tumor-infiltrating immune cells (TIICs) in each sample. Correlation between hub genes and immune cells was then analyzed. Hub genes were validated in hepatoblastoma tissues via western blot or immunohistochemistry. After transfection with sh-NOTUM, migration and invasion of HuH-6 and HepG2 cells were investigated. The nude mouse tumorigenesis model was constructed. RESULTS: Totally, 83 aberrantly methylated and expressed genes were determined in hepatoblastoma, which were mainly involved in metabolic and cancer-related pathways. Moreover, their expression was liver-specific. 13 hub genes were screened, which were closely related to immune cells in hepatoblastoma tissues. Among them, it was confirmed that AXIN2, LAMB1 and NOTUM were up-regulated and SERPINC1 was down-regulated in hepatoblastoma than normal tissues. NOTUM knockdown distinctly weakened migration and invasion of HuH-6 and HepG2 cells and tumor growth in vivo. CONCLUSIONS: This study identified aberrantly methylated and expressed signatures that were in relation to immune microenvironment in hepatoblastoma. Targeting NOTUM hub gene could suppress migration and invasion of hepatoblastoma cells. Thus, these aberrantly methylated and expressed genes might act as therapeutic agents in hepatoblastoma therapy. Title: Brain-targeted delivery of obidoxime, using aptamer-modified liposomes, for detoxification of organophosphorus compounds Zhang Y, He J, Shen L, Wang T, Yang J, Li Y, Wang Y, Quan D Ref: J Control Release, 329:1117, 2021 : PubMed ESTHER: Zhang_2021_J.Control.Release_329_1117 PubMedSearch: Zhang 2021 J.Control.Release 329 1117 PubMedID: 33096123 Abstract Effective intracerebral delivery acetylcholinesterase (AChE) reactivator is key for the acute organophosphorus (OPs) poison treatment. However, the blood-brain barrier (BBB) restricts the transport of these drugs from blood into the brain. Herein, we developed transferrin receptor (TfR) aptamer-functionalized liposomes (Apt-LP) that could deliver AChE reactivator (obidoxime) across the BBB to act against paraoxon (POX) poisoning. The aptamer had strong affinity for TfR and was modified with 3'-inverted deoxythymidine (dT) to improve serum stability. The uptake of Apt-LP by bEnd.3 cells was significantly higher than that of non-targeting liposomes. The ability of Apt-LP to penetrate intact BBB was confirmed in in vitro BBB mice model and in vivo biodistribution studies. Treatment of POX-poisoned mice with Apt-LP-LuH-6 reactivated 18% of the brain AChE activity and prevented brain damage to some extent. Taken together, these results showed that Apt-LP may be used as a promising brain-targeted drug delivery system against OPs toxicity. Title: Mycobacterium tuberculosis puromycin hydrolase displays a prolyl oligopeptidase fold and an acyl aminopeptidase activity Zhao Y, Feng Q, Zhou X, Zhang Y, Lukman M, Jiang J, Ruiz-Carrillo D Ref: Proteins, :, 2021 : PubMed ESTHER: Zhao_2021_Proteins__ PubMedSearch: Zhao 2021 Proteins PubMedID: 33426726 Gene_locus related to this paper: myctu-CNE19725 Abstract Puromycin-hydrolizing peptidases have been described as members of the prolyl oligopeptidase peptidase family. These enzymes are present across all domains of life but still little is known of the homologs found in the pathogenic bacterium Mycobacterium tuberculosis. The crystal structure of a M. tuberculosis puromycin hydrolase peptidase has been determined at 3 Angstrom resolution, revealing a conserved prolyl oligopeptidase fold, defined by alpha/beta-hydrolase and beta-propeller domains with two distinctive loops that occlude access of large substrates to the active site. The enzyme displayed amino peptidase activity with a substrate specificity preference for hydrophobic residues in the decreasing order of phenylalanine, leucine, alanine and proline. The enzyme's active site is lined by residues Glu564 for the coordination of the substrates amino terminal moiety and His561, Val608, Tyr78, Trp306, Phe563 and Ty567 for the accommodation of hydrophobic substrates. The availability of a crystal structure for puromycin hydrolase of M. tuberculosis shall facilitate the development of inhibitors with therapeutic applications. This article is protected by copyright. All rights reserved. Title: Synthesis and Structure-Activity Relationships of 3-Arylisoquinolone Analogues as Highly Specific hCES2A Inhibitors Zhao Y, Xiong Y, Dong S, Guan X, Song Y, Yang Y, Zou K, Li Z, Zhang Y and Ge G <5 more author(s)> Zhao Y, Xiong Y, Dong S, Guan X, Song Y, Yang Y, Zou K, Li Z, Zhang Y, Fang S, Li B, Zhu W, Chen K, Jia Q, Ge G (- 5) Ref: ChemMedChem, 16:388, 2021 : PubMed ESTHER: Zhao_2021_ChemMedChem_16_388 PubMedSearch: Zhao 2021 ChemMedChem 16 388 PubMedID: 32935462 Abstract Mammalian carboxylesterases (CES) are key enzymes that participate in the hydrolytic metabolism of various endogenous and exogenous substrates. Human carboxylesterase 2A (hCES2A), mainly distributed in the small intestine and colon, plays a significant role in the hydrolysis of many drugs. In this study, 3-arylisoquinolones 3h [3-(4-(benzyloxy)-3-methoxyphenyl)-7,8-dimethoxyisoquinolin-1(2H)-one] and 4a [3-(4-(benzyloxy)-3-methoxyphenyl)-4-bromo-7,8-dimethoxyisoquinolin-1(2H)-one] were found to have potent inhibitory effects on hCES2A (IC(50) =0.68microM, K(i) =0.36microM) and excellent specificity (more than 147.05-fold over hCES1A). Moreover, 4a exhibited threefold improved inhibition on intracellular hCES2A in living HepG2 cells relative to 3h, with an IC(50) value of 0.41microM. Results of inhibition kinetics studies and molecular docking simulations demonstrate that both 3h and 4a can bind to multiple sites on hCES2A, functioning as mixed inhibitors. Structure-activity relationship analysis revealed that the lactam moiety on the B ring is crucial for specificity towards hCES2A, while a benzyloxy group is optimal for hCES2A inhibitory potency; the introduction of a bromine atom may enhance cell permeability, thereby increasing the intracellular hCES2A inhibitory activity. Title: Metabolic degradation of lentinan in liver mediated by CYP450 enzymes and epoxide hydrolase Zheng Z, Zhang Y, Liu Y, Wang J, Cui Z, Pan X, Tang W, Wang K Ref: Carbohydr Polym, 253:117255, 2021 : PubMed ESTHER: Zheng_2021_Carbohydr.Polym_253_117255 PubMedSearch: Zheng 2021 Carbohydr.Polym 253 117255 PubMedID: 33279005 Abstract Lentinan (LNT), a typical triple helix beta-glucan, has been widely used as drug and biomaterial. However, its pharmacokinetics in vivo is rarely reported, which severely limits its further development and application. The aim of this study is to establish a sensitive method for detecting LNT in biosamples and to evaluate the plasma level, tissue distribution and metabolic degradation of LNT in rats. 5-([4,6-Dichlorotriazin-2-yl] amino) fluorescein (DTAF) was labelled to LNT. After purification and identification, FLNT was intravenously administered to rats at dose of 32 mg/kg. LNT was predominantly incorporated into the liver and liver microsomes were used to study the degradation mechanism of LNT in the liver. The results showed that two cytochrome P450 (CYP450) enzymes subtypes (CYP2D6 and CYP2C9), as well as epoxide hydrolase, were involved in the metabolic degradation of LNT. These findings provide a pharmacokinetic reference for further study and application of LNT and other beta-glucans. Title: Poria cocos polysaccharide attenuates damage of nervus in Alzheimer's disease rat model induced by D-galactose and aluminum trichloride Zhou X, Zhang Y, Jiang Y, Zhou C, Ling Y Ref: Neuroreport, 32:727, 2021 : PubMed ESTHER: Zhou_2021_Neuroreport_32_727 PubMedSearch: Zhou 2021 Neuroreport 32 727 PubMedID: 33913927 Abstract Poria cocos polysaccharide (PCP) is a compound from Poria cocos, and which is used as a classical tonic agent. This article aims to investigate the effects of PCP on neuronal damage of hippocampus and cognitive function in a rat model of Alzheimer's disease induced by D-galactose and aluminum trichloride. Oxiracetam (ORC) was used as a positive drug in this experiment. The rats were treated with PCP at doses of 100, 200 and 300 mg/kg/day for 30 days and ORC at dose of 346 mg/kg/day after modeling. The results of behavioral test showed that PCP could prevent cognitive decline in Alzheimer's disease rats as assessed by Y-maze test and Morris water maze test. Results of hippocampus slices showed that neurons were integrated and regularly arranged in the groups, which were administered along with PCP. Moreover, PCP could reduce neuronal apoptosis in hippocampus of Alzheimer's disease rats. Furthermore, the activities of superoxide dismutase in the hippocampus were elevated by PCP administration, while acetyl cholinesterase, reactive oxygen, malondialdehyde and inflammatory factors levels were reduced. In addition, we found PCP could attenuate MAPK/NF-kappaB signal pathway in the hippocampus. All results illustrated that PCP could exert neuroprotective effects at least partly through alleviating oxidative stress, apoptosis, inflammation and inhibiting the MAPK/NF-kappaB pathway in Alzheimer's disease rats induced by D-galactose and aluminum trichloride. Title: Alterations of the endocannabinoid system and its therapeutic potential in autism spectrum disorder Zou M, Liu Y, Xie S, Wang L, Li D, Li L, Wang F, Zhang Y, Xia W and Wu L <1 more author(s)> Zou M, Liu Y, Xie S, Wang L, Li D, Li L, Wang F, Zhang Y, Xia W, Sun C, Wu L (- 1) Ref: Open Biol, 11:200306, 2021 : PubMed ESTHER: Zou_2021_Open.Biol_11_200306 PubMedSearch: Zou 2021 Open.Biol 11 200306 PubMedID: 33529552 Abstract Autism spectrum disorder (ASD) is a group of developmental disabilities, the aetiology of which remains elusive. The endocannabinoid (eCB) system modulates neurotransmission and neuronal plasticity. Evidence points to the involvement of this neuromodulatory system in the pathophysiology of ASD. We investigated whether there is a disruption to the eCB system in ASD and whether pharmacological modulation of the eCB system might offer therapeutic potential. We examined three major components of the eCB system-endogenous cannabinoids, their receptors and associated enzymes-in ASD children as well as in the valproic acid (VPA) induced animal model in autism. Furthermore, we specifically increased 2-arachidonoylglycerol (2-AG) levels by administering JZL184, a selective inhibitor of monoacylglycerol lipase which is the hydrolytic enzyme for 2-AG, to examine ASD-like behaviours in VPA-induced rats. Results showed that autistic children and VPA-induced rats exhibited reduced eCB content, increased degradation of enzymes and upregulation of CBRs. We found that repetitive and stereotypical behaviours, hyperactivity, sociability, social preference and cognitive functioning improved after acute and chronic JZL184 treatment. The major efficacy of JZL184 was observed after administration of a dosage regimen of 3 mg kg(-1), which affected both the eCB system and ASD-like behaviours. In conclusion, a reduced eCB signalling was observed in autistic children and in the ASD animal model, and boosting 2-AG could ameliorate ASD-like phenotypes in animals. Collectively, the results suggested a novel approach to ASD treatment. Title: Use of data-independent acquisition mass spectrometry for comparative proteomics analyses of sera from pregnant women with intrahepatic cholestasis of pregnancy Zou S, Dong R, Wang J, Liang B, Zhu T, Zhao S, Zhang Y, Wang T, Zou P and Luo L <5 more author(s)> Zou S, Dong R, Wang J, Liang B, Zhu T, Zhao S, Zhang Y, Wang T, Zou P, Li N, Wang Y, Chen M, Zhou C, Zhang T, Luo L (- 5) Ref: J Proteomics, :104124, 2021 : PubMed ESTHER: Zou_2021_J.Proteomics__104124 PubMedSearch: Zou 2021 J.Proteomics 104124 PubMedID: 33545297 Abstract We used data-independent acquisition (DIA) proteomics technology followed by ELISAs and automated biochemical analyses to identify and validate protein expression levels in Intrahepatic Cholestasis of Pregnancy (ICP) and healthy pregnant controls. We employed bioinformatics to identify metabolic processes associated with differentially expressed proteins.The expression levels of two proteins (S100-A9 and the L-lactate dehydrogenase A chain) were significantly higher in ICP patients than in controls; the areas under the receiver operating characteristic (ROC) curves (AUCs) were 0.774 and 0.828, respectively. The expression levels of two other proteins (apolipoprotein A-I and cholinesterase) were significantly lower in patients, with values of 0.900 and 0.842, respectively. Multiple logistic regression showed that a combination of the levels of the four proteins optimized the AUC (0.962), thus more reliably diagnosing ICP. The levels of all four proteins were positively associated with that of total bile acids. Bioinformatics analyses indicated that the four proteins principally affected neutrophil activation involved in the immune response, cell adhesion, lipoprotein metabolism, and the PPAR signaling pathway. SIGNIFICANCE: This preliminary work improves our understanding of changes in serum levels of protein in pregnant women with ICP. The four proteins may serve as novel noninvasive biomarkers for ICP. Title: Development of potent inhibitors of the human microsomal epoxide hydrolase Barnych B, Singh N, Negrel S, Zhang Y, Magis D, Roux C, Hua X, Ding Z, Morisseau C and Hammock BD <2 more author(s)> Barnych B, Singh N, Negrel S, Zhang Y, Magis D, Roux C, Hua X, Ding Z, Morisseau C, Tantillo DJ, Siegel JB, Hammock BD (- 2) Ref: Eur Journal of Medicinal Chemistry, 193:112206, 2020 : PubMed ESTHER: Barnych_2020_Eur.J.Med.Chem_193_112206 PubMedSearch: Barnych 2020 Eur.J.Med.Chem 193 112206 PubMedID: 32203787 Gene_locus related to this paper: human-EPHX1, mouse-EPHX1 Inhibitor(s) related to this paper: 62-mEH Abstract Microsomal epoxide hydrolase (mEH) hydrolyzes a wide range of epoxide containing molecules. Although involved in the metabolism of xenobiotics, recent studies associate mEH with the onset and development of certain disease conditions. This phenomenon is partially attributed to the significant role mEH plays in hydrolyzing endogenous lipid mediators, suggesting more complex and extensive physiological functions. In order to obtain pharmacological tools to further study the biology and therapeutic potential of this enzyme target, we describe the development of highly potent 2-alkylthio acetamide inhibitors of the human mEH with IC50 values in the low nanomolar range. These are around 2 orders of magnitude more potent than previously obtained primary amine, amide and urea-based mEH inhibitors. Experimental assay results and rationalization of binding through docking calculations of inhibitors to a mEH homology model indicate that an amide connected to an alkyl side chain and a benzyl-thio function as key pharmacophore units. Title: Genome sequencing of the Australian wild diploid species Gossypium australe highlights disease resistance and delayed gland morphogenesis Cai Y, Cai X, Wang Q, Wang P, Zhang Y, Cai C, Xu Y, Wang K, Zhou Z and Liu F <25 more author(s)> Cai Y, Cai X, Wang Q, Wang P, Zhang Y, Cai C, Xu Y, Wang K, Zhou Z, Wang C, Geng S, Li B, Dong Q, Hou Y, Wang H, Ai P, Liu Z, Yi F, Sun M, An G, Cheng J, Shi Q, Xie Y, Shi X, Chang Y, Huang F, Chen Y, Hong S, Mi L, Sun Q, Zhang L, Zhou B, Peng R, Zhang X, Liu F (- 25) Ref: Plant Biotechnol J, 18:814, 2020 : PubMed ESTHER: Cai_2020_Plant.Biotechnol.J_18_814 PubMedSearch: Cai 2020 Plant.Biotechnol.J 18 814 PubMedID: 31479566 Gene_locus related to this paper: gosra-a0a0d2pzd7 Abstract The diploid wild cotton species Gossypium australe possesses excellent traits including resistance to disease and delayed gland morphogenesis, and has been successfully used for distant breeding programmes to incorporate disease resistance traits into domesticated cotton. Here, we sequenced the G. australe genome by integrating PacBio, Illumina short read, BioNano (DLS) and Hi-C technologies, and acquired a high-quality reference genome with a contig N50 of 1.83 Mb and a scaffold N50 of 143.60 Mb. We found that 73.5% of the G. australe genome is composed of various repeat sequences, differing from those of G. arboreum (85.39%), G. hirsutum (69.86%) and G. barbadense (69.83%). The G. australe genome showed closer collinear relationships with the genome of G. arboreum than G. raimondii and has undergone less extensive genome reorganization than the G. arboreum genome. Selection signature and transcriptomics analyses implicated multiple genes in disease resistance responses, including GauCCD7 and GauCBP1, and experiments revealed induction of both genes by Verticillium dahliae and by the plant hormones strigolactone (GR24), salicylic acid (SA) and methyl jasmonate (MeJA). Experiments using a Verticillium-resistant domesticated G. barbadense cultivar confirmed that knockdown of the homologues of these genes caused a significant reduction in resistance against Verticillium dahliae. Moreover, knockdown of a newly identified gland-associated gene GauGRAS1 caused a glandless phenotype in partial tissues using G. australe. The G. australe genome represents a valuable resource for cotton research and distant relative breeding as well as for understanding the evolutionary history of crop genomes. Title: A Hydrolase-Catalyzed Cyclization Forms the Fused Bicyclic beta-Lactone in Vibralactone Feng KN, Yang YL, Xu YX, Zhang Y, Feng T, Huang SX, Liu JK, Zeng Y Ref: Angew Chem Int Ed Engl, 59:7209, 2020 : PubMed ESTHER: Feng_2020_Angew.Chem.Int.Ed.Engl_59_7209 PubMedSearch: Feng 2020 Angew.Chem.Int.Ed.Engl 59 7209 PubMedID: 32050043 Gene_locus related to this paper: 9agam-VibC, stehr-Sh.112560 Inhibitor(s) related to this paper: Vibralactone Abstract Vibralactone is isolated from the basidiomycete fungus Boreostereum vibrans as one of the strongest lipase inhibitors. Its unusual beta-lactone-fused bicycle is derived from an aryl ring moiety via an oxidative ring-expansion prior to an intramolecular cyclization. Here, we report the discovery of the cyclase VibC which belongs to the alpha/beta-hydrolase superfamily and is involved in the vibralactone biosynthesis. Biochemical and crystal studies suggest that VibC may catalyze an aldol or an electrocyclic reaction initiated by the catalytic Ser-His-Asp triad. For the aldol and pericyclic chemistry in living cells, VibC is a unique hydrolase performing the carbocycle formation of an oxepinone to a fused bicyclic b-lactone. This presents a naturally occurring new enzyme reaction in both aldol and hydrolase (bio)chemistry that will guide future exploitation of these enzymes in synthetic biology for chemical diversity expansion of natural products. Title: Insecticidal Activity of Artemisia vulgaris Essential Oil and Transcriptome Analysis of Tribolium castaneum in Response to Oil Exposure Gao S, Zhang K, Wei L, Wei G, Xiong W, Lu Y, Zhang Y, Gao A, Li B Ref: Front Genet, 11:589, 2020 : PubMed ESTHER: Gao_2020_Front.Genet_11_589 PubMedSearch: Gao 2020 Front.Genet 11 589 PubMedID: 32670352 Abstract Red flour beetle (Tribolium castaneum) is one of the most destructive pests of stored cereals worldwide. The essential oil (EO) of Artemisia vulgaris (mugwort) is known to be a strong toxicant that inhibits the growth, development, and reproduction of T. castaneum. However, the molecular mechanisms underlying the toxic effects of A. vulgaris EO on T. castaneum remain unclear. Here, two detoxifying enzymes, carboxylesterase (CarEs) and cytochrome oxidase P450 (CYPs), were dramatically increased in red flour beetle larvae when they were exposed to A. vulgaris EO. Further, 758 genes were differentially expressed between EO treated and control samples. Based on Gene Ontology (GO) analysis, numerous differentially expressed genes (DEGs) were enriched for terms related to the regulation of biological processes, response to stimulus, and antigen processing and presentation. Our results indicated that A. vulgaris EO disturbed the antioxidant activity in larvae and partially inhibited serine protease (SP), cathepsin (CAT), and lipase signaling pathways, thus disrupting larval development and reproduction as well as down-regulating the stress response. Moreover, these DEGs showed that A. vulgaris indirectly affected the development and reproduction of beetles by inducing the expression of genes encoding copper-zinc-superoxide dismutase (CuZnSOD), heme peroxidase (HPX), antioxidant enzymes, and transcription factors. Moreover, the majority of DEGs were mapped to the drug metabolism pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Notably, the following genes were detected: 6 odorant binding proteins (OBPs), 5 chemosensory proteins (CSPs), 14 CYPs, 3 esterases (ESTs), 5 glutathione S-transferases (GSTs), 6 UDP-glucuronosyltransferases (UGTs), and 2 multidrug resistance proteins (MRPs), of which 8 CYPs, 2 ESTs, 2 GSTs, and 3 UGTs were up-regulated dramatically after exposure to A. vulgaris EO. The residual DEGs were significantly down-regulated in EO exposed larvae, implying that partial compensation of metabolism detoxification existed in treated beetles. Furthermore, A. vulgaris EO induced overexpression of OBP/CYP, and RNAi against these genes significantly increased mortality of larvae exposed to EO, providing further evidence for the involvement of OBP/CYP in EO metabolic detoxification in T. castaneum. Our results provide an overview of the transcriptomic changes in T. castaneum in response to A. vulgaris EO. Title: Susceptibility of Four Species of Aphids in Wheat to Seven Insecticides and Its Relationship to Detoxifying Enzymes Gong P, Chen D, Wang C, Li M, Li X, Zhang Y, Zhu X Ref: Front Physiol, 11:623612, 2020 : PubMed ESTHER: Gong_2020_Front.Physiol_11_623612 PubMedSearch: Gong 2020 Front.Physiol 11 623612 PubMedID: 33536942 Abstract Sitobion avenae (Fabricius), Rhopalosiphum padi (Linnaeus), Schizaphis graminum (Rondani), and Metopolophium dirhodum (Walker) (Hemiptera: Aphididae) are important pests of wheat and other cereals worldwide. In this study, the susceptibilities of four wheat aphid species to seven insecticides were assessed. Furthermore, the activities of carboxylesterase (CarE), glutathione S-transferase (GSTs), and cytochrome P450 monooxygenase (P450s) were determined in imidacloprid treated and untreated aphids. The results showed that the susceptibilities of four wheat aphid species to tested insecticides are different and M. dirhodum has shown higher tolerance to most insecticides. Relatively higher CarE and GST activities were observed in M. dirhodum, and P450s activities increased significantly in response to imidacloprid treatment. Moreover, susceptibility to imidacloprid were increased by the oxidase inhibitor piperonyl butoxide in M. dirhodum (20-fold). The results we have obtained imply that P450s may play an important role in imidacloprid metabolic process in M. dirhodum. We suggest that a highly species-specific approach is essential for managing M. dirhodum. Title: Tunicyclin L, a cyclic peptide from Psammosilene tunicoides: Isolation, characterization, conformational studies and biological activity Hou Y, Wang M, Sun C, Peng C, Zhang Y, Li X Ref: Fitoterapia, :104628, 2020 : PubMed ESTHER: Hou_2020_Fitoterapia__104628 PubMedSearch: Hou 2020 Fitoterapia 104628 PubMedID: 32433930 Abstract Tunicyclin L (1), cyclo (L-Pro(1)-Gly-L-Phe(1)-L-Ile-L-Pro(2)-L-Phe -L-Thr-L-Val), and 11 known compounds, including one cyclic peptide (2), eight carboline alkaloids (3-10), one lignan (11) and one flavone (12) were isolated from the roots of Psammosilene tunicoides. Their structures were elucidated on the basis of extensive UV, IR, MS, NMR spectroscopic data and comparison with literature. Single-crystal X-ray diffraction results revealed the stereochemistry of the 24-membered ring cyclic peptide (1). Among these known compounds, compound 6 was found to be a new natural product, and compounds 3, 4, and 11 were isolated from this plant for the first time. Five compounds (1, 3, 4, 7, and 9) showed moderate anti-acetylcholinesterase (AChE) activity. Title: Antioxidant and pancreatic lipase inhibitory effects of flavonoids from different citrus peel extracts: An in vitro study Huang R, Zhang Y, Shen S, Zhi Z, Cheng H, Chen S, Ye X Ref: Food Chem, 326:126785, 2020 : PubMed ESTHER: Huang_2020_Food.Chem_326_126785 PubMedSearch: Huang 2020 Food.Chem 326 126785 PubMedID: 32438224 Abstract Obesity and oxidative damage are two important risk factors associated closely with metabolic syndrome. Utilization of functional food ingredients is considered as a feasible way to tackle these challenges. In the present study, eight representative species of citrus peel extracts (CPEs) were evaluated and compared for their flavonoid profiles, antioxidant activities, and pancreatic lipase (PL) inhibitory capacities and mechanisms. Results indicated that hesperidin, naringin, neohesperidin, narirutin and eriocitrin were the five major flavonoids in CPEs, among which hesperidin was the main active PL inhibitor. Moreover, hesperidin could interact with PL by hydrogen bonds and van der Waals forces, and the interaction would not obviously change the secondary structure of PL. Overall, ponkan peel extract, having the strongest overall antioxidant activity, the highest content of hesperidin and total phenolic compounds among all tested CPEs, is a promising natural ingredient to scavenge free radicals and manage obesity. Title: Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach Huang F, Hu H, Wang K, Peng C, Xu W, Zhang Y, Gao J, Liu Y, Zhou H and Xu Y <3 more author(s)> Huang F, Hu H, Wang K, Peng C, Xu W, Zhang Y, Gao J, Liu Y, Zhou H, Huang R, Li M, Shen J, Xu Y (- 3) Ref: Journal of Medicinal Chemistry, 63:7052, 2020 : PubMed ESTHER: Huang_2020_J.Med.Chem_63_7052 PubMedSearch: Huang 2020 J.Med.Chem 63 7052 PubMedID: 32459096 Inhibitor(s) related to this paper: 6M08-BWL, 6M07-BWO, 6M06-BWF Abstract Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases. Title: Single and combined effects of carbamazepine and copper on nervous and antioxidant systems of zebrafish (Danio rerio) Jia D, Li X, Du S, Xu N, Zhang W, Yang R, Zhang Y, He Y Ref: Environ Toxicol, :, 2020 : PubMed ESTHER: Jia_2020_Environ.Toxicol__ PubMedSearch: Jia 2020 Environ.Toxicol PubMedID: 32485069 Abstract Various pollutants co-exist in the aquatic environment such as carbamazepine (CBZ) and copper (Cu), which can cause complex effects on inhabiting organisms. The toxic impacts of the single substance have been studied extensively. However, the studies about their combined adverse impacts are not enough. In the present study, zebrafish were exposed to environmental relevant concentrations of CBZ (1, 10, and 100 mug/L), Cu (0.5, 5, and 10 mug/L) and the mixtures (1 mug/L CBZ + 0.5 mug/L Cu, 10 mug/L CBZ + 5 mug/L Cu, 100 mug/L CBZ + 10 mug/L Cu) for 45 days, the effects on nervous and antioxidant systems of zebrafish were investigated. The results demonstrated that, in comparison with single exposure group, the combined presence of CBZ and Cu exacerbated the effect of antioxidant system (the ability of inhibition of hydroxyl radicals (IHR), superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST)) but not nervous system (Acetylcholinesterase [AChE]). The qPCR results supported the changes of corresponding enzymes activities. Hepatic histopathological analysis verified the results of biomarkers. Our work illustrated that the toxicity of mixed pollutants is very complicated, which cannot simply be inferred from the toxicity of single pollutant, and calls for more co-exposure experiments to better understanding of the co-effects of pollutants on aquatic organisms. Title: Monobutyl phthalate (MBP) can dysregulate the antioxidant system and induce apoptosis of zebrafish liver Jiao Y, Tao Y, Yang Y, Diogene T, Yu H, He Z, Han W, Chen Z, Wu P, Zhang Y Ref: Environ Pollut, 257:113517, 2020 : PubMed ESTHER: Jiao_2020_Environ.Pollut_257_113517 PubMedSearch: Jiao 2020 Environ.Pollut 257 113517 PubMedID: 31761585 Abstract In this paper, the acute toxicity of monobutyl phthalate (MBP), the main hydrolysis product of dibutyl phthalate, on adult zebrafish liver antioxidant system was studied. Compared the toxicity effect of MBP and DBP by histopathology and apoptosis experiments, we speculated that the toxic effects of DBP on animals may be caused by its metabolite MBP. The results indicated that the antioxidant Nrf2-Keap1 pathway was insufficient to resist MBP-induced hepatotoxicity and led to an imbalance of membrane ion homeostasis and liver damage. Decreased cell viability, significant tissue lesions and early hepatocyte apoptosis were observed in the zebrafish liver in MBP exposure at high concentration (10 mg/L). The activities of antioxidant enzymes and ATPases in zebrafish liver were inhibited with increased malondialdehyde (MDA) content and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities. Integrated biomarker response (IBR) calculation results indicated that MBP mainly inhibited catalase (CAT) activity. Simultaneously, the expression of antioxidant-related genes (SOD, CAT, GPx, Nrf2, HO-1) was down-regulated, while apoptosis-related genes (p53, bax, cas3) were significantly up-regulated. Title: Downregulation of Keap1 Confers Features of a Fasted Metabolic State Knatko EV, Tatham MH, Zhang Y, Castro C, Higgins M, Dayalan Naidu S, Leonardi C, de la Vega L, Honda T and Dinkova-Kostova AT <2 more author(s)> Knatko EV, Tatham MH, Zhang Y, Castro C, Higgins M, Dayalan Naidu S, Leonardi C, de la Vega L, Honda T, Griffin JL, Hay RT, Dinkova-Kostova AT (- 2) Ref: iScience, 23:101638, 2020 : PubMed ESTHER: Knatko_2020_iScience_23_101638 PubMedSearch: Knatko 2020 iScience 23 101638 PubMedID: 33103077 Abstract Transcription factor nuclear factor erythroid 2 p45-related factor 2 (Nrf2) and its main negative regulator, Kelch-like ECH-associated protein 1 (Keap1), are at the interface between redox and intermediary metabolism, allowing adaptation and survival under conditions of oxidative, inflammatory, and metabolic stress. Nrf2 is the principal determinant of redox homeostasis, and contributes to mitochondrial function and integrity and cellular bioenergetics. Using proteomics and lipidomics, we show that genetic downregulation of Keap1 in mice, and the consequent Nrf2 activation to pharmacologically relevant levels, leads to upregulation of carboxylesterase 1 (Ces1) and acyl-CoA oxidase 2 (Acox2), decreases triglyceride levels, and alters the lipidome. This is accompanied by downregulation of hepatic ATP-citrate lyase (Acly) and decreased levels of acetyl-CoA, a trigger for autophagy. These findings suggest that downregulation of Keap1 confers features of a fasted metabolic state, which is an important consideration in the drug development of Keap1-targeting pharmacologic Nrf2 activators. Title: Silencing of soluble epoxide hydrolase 2 gene reduces H2O2-induced oxidative damage in rat intestinal epithelial IEC-6 cells via activating PI3K/Akt/GSK3beta signaling pathway Li J, Luo J, Zhang Y, Tang C, Wang J, Chen C Ref: Cytotechnology, :, 2020 : PubMed ESTHER: Li_2020_Cytotech__ PubMedSearch: Li 2020 Cytotech PubMedID: 31907700 Abstract Oxidative stress plays a vital role in the occurrence and development of intestinal injury. Soluble epoxide hydrolase 2 gene (EPHX2) is a class of hydrolytic enzymes. We aim to explore the effects and molecular mechanism of siEPHX2 on H2O2-induced oxidative damage in rat intestinal epithelial IEC-6 cells. IEC-6 cells were transfected with EPHX2-siRNA and control si RNA plasmids by lipofectamine 2000 transfection reagent. The transfected samples were treated with H2O2 (50, 100, 200, 300, 400, and 500 micromol/L) for 12, 24, and 48 h, respectively. Cell viability was determined by cell counting kit-8 (CCK-8). Lactate dehydrogenase (LDH), malondialdehyde (MDA), and superoxide dismutase (SOD) were assessed by respective detection kits. Mitochondrial membrane potential (MMP), cell apoptosis and reactive oxygen species (ROS) and the levels of factors were determined by flow cytometer, quantitative real-time PCR (qRT-PCR) and western blot assays, respectively. We found that the IC50 of H2O2 was 200 micromol/L at 24 h, and the transfection of siEHPX2 in H2O2-induced IEC-6 cells significantly promoted the cell viability, SOD activity and MMP rate, and reduced the rates of ROS and apoptosis as well as LDH and MDA contents. siEHPX2 up-regulated the B-cell lymphoma-2 (Bcl-2) level and down-regulated the levels of fibroblast-associated (Fas), Fas ligand (Fasl), Bcl-2 associated X protein (Bax), and Caspase-3. Moreover, the phosphorylation levels of phosphoinositide 3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase3beta (GSK3beta) were up-regulated. We proved that siEPHX2 had a protective effect on H2O2-induced oxidative damage in IEC-6 cells through activating PI3K/Akt/GSK3beta signaling pathway. Title: Study on a Novel Cold-Active and Halotolerant Monoacylglycerol Lipase Widespread in Marine Bacteria Reveals a New Group of Bacterial Monoacylglycerol Lipases Containing Unusual C(A/S)HSMG Catalytic Motifs Li PY, Zhang YQ, Zhang Y, Jiang WX, Wang YJ, Zhang YS, Sun ZZ, Li CY, Zhang YZ and Chen XL <3 more author(s)> Li PY, Zhang YQ, Zhang Y, Jiang WX, Wang YJ, Zhang YS, Sun ZZ, Li CY, Zhang YZ, Shi M, Song XY, Zhao LS, Chen XL (- 3) Ref: Front Microbiol, 11:9, 2020 : PubMed ESTHER: Li_2020_Front.Microbiol_11_9 PubMedSearch: Li 2020 Front.Microbiol 11 9 PubMedID: 32038595 Gene_locus related to this paper: glanf-g4qji4 Abstract Monoacylglycerol lipases (MGLs) are present in all domains of life. However, reports on bacterial MGLs are still limited. Until now, reported bacterial MGLs are all thermophilic/mesophilic enzymes from warm terrestrial environments or deep-sea hydrothermal vent, and none of them originates from marine environments vastly subject to low temperature, high salts, and oligotrophy. Here, we characterized a novel MGL, GnMgl, from the marine cold-adapted and halophilic bacterium Glaciecola nitratireducens FR1064(T). GnMgl shares quite low sequence similarities with characterized MGLs (lower than 31%). GnMgl and most of its bacterial homologs harbor a catalytic Ser residue located in the conserved C(A/S)HSMG motif rather than in the typical GxSxG motif reported on other MGLs, suggesting that GnMgl-like enzymes might be different from reported MGLs in catalysis. Phylogenetic analysis suggested that GnMgl and its bacterial homologs are clustered as a separate group in the monoglyceridelipase_lysophospholipase family of the Hydrolase_4 superfamily. Recombinant GnMgl has no lysophospholipase activity but could hydrolyze saturated (C12:0-C16:0) and unsaturated (C18:1 and C18:2) MGs and short-chain triacylglycerols, displaying distinct substrate selectivity from those of reported bacterial MGLs. The substrate preference of GnMgl, predicted to be a membrane protein, correlates to the most abundant fatty acids within the strain FR1064(T), suggesting the role of GnMgl in the lipid catabolism in this marine bacterium. In addition, different from known bacterial MGLs that are all thermostable enzymes, GnMgl is a cold-adapted enzyme, with the maximum activity at 30 degrees C and retaining 30% activity at 0 degrees C. GnMgl is also a halotolerant enzyme with full activity in 3.5M NaCl. The cold-adapted and salt-tolerant characteristics of GnMgl may help its source strain FR1064(T) adapt to the cold and saline marine environment. Moreover, homologs to GnMgl are found to be abundant in various marine bacteria, implying their important physiological role in these marine bacteria. Our results on GnMgl shed light on marine MGLs. Title: Admission serum cholinesterase concentration for prediction of in-hospital mortality in very elderly patients with acute ischemic stroke: a retrospective study Li M, Chen Y, Zhang Y, Liu X, Xie T, Yin J, Wang L, Gang S, Chen J and Geng T <2 more author(s)> Li M, Chen Y, Zhang Y, Liu X, Xie T, Yin J, Wang L, Gang S, Chen J, Liu L, Yang F, Geng T (- 2) Ref: Aging Clin Exp Res, :, 2020 : PubMed ESTHER: Li_2020_Aging.Clin.Exp.Res__ PubMedSearch: Li 2020 Aging.Clin.Exp.Res PubMedID: 32067216 Abstract BACKGROUND: Cholinesterase as a sensitive biomarker for prognosis in a variety of conditions but it is rare in stroke studies. The very elderly (>/= 80 years of age) represent the most susceptible group of ischemic stroke. We aimed to determine whether admission serum cholinesterase concentration had any effect on clinical outcome in very elderly patients (individuals aged >/= 80 years) with acute ischemic stroke. METHODS: A retrospective record review was conducted in two tertiary university hospitals. Elderly patients aged >/= 80 years admitted with a diagnosis of acute ischemic stroke from January 1, 2014 to November 30, 2019, who had a cholinesterase concentration drawn, were included. The patients were grouped based on the inflection points of the locally weighted regression and smoothing scatterplot (LOESS) curve between cholinesterase levels and in-hospital mortality (study outcome) with lower concentration as reference group. RESULTS: A total of 612 patients were admitted with a diagnosis of acute ischemic stroke, and 569 met the inclusion criteria. A threshold effect was identified using regression smoothing scatterplot (LOESS), with one cutoff point of 4.0 KU/L. There was a significant difference in-hospital mortality was observed (P < 0.001). After adjusted demographic and clinical features, the OR of cholinesterase for mortality was 0.43 (95% CI 0.34-0.54, P < 0.001), suggesting that lower admission cholinesterase level was an independent risk factors for all-cause mortality among patients with AIS. CONCLUSIONS: We have demonstrated a significant association between admission cholinesterase concentration and in-hospital mortality in very elderly patients with AIS. Title: Evaluation of toxicological responses and promising biomarkers of topmouth gudgeon (Pseudorasbora parva) exposed to fipronil at environmentally relevant levels Li H, Zhang R, Sun F, Zhang Y Ref: Environ Sci Pollut Res Int, :, 2020 : PubMed ESTHER: Li_2020_Environ.Sci.Pollut.Res.Int__ PubMedSearch: Li 2020 Environ.Sci.Pollut.Res.Int PubMedID: 32304060 Abstract Fipronil is an insecticide commonly used in agriculture. We report here on the sublethal and sub-chronic effects of fipronil on non-target topmouth gudgeon (Pseudorasbora parva) at environmentally relevant levels. The results showed that fipronil did not cause significant changes in brain acetylcholinesterase activities, glutathione S-transferase (GST) activities in the intestine, and GST, glutamic pyruvic transaminase (GPT), and glutamic oxaloacetic transaminase (GOT) activities in the liver tissues at environmentally relevant levels for 96-h exposure. In the further test for a 12-day exposure, dose-dependent responses of the serum GPT and GOT activities were observed in all treated groups with sublethal concentrations of fipronil. Furthermore, fipronil could reduce the liver mitochondrial membrane fluidity of P. parva, especially with high concentration of fipronil at high temperature. The results suggest that serum GPT and GOT in P. parva might be useful biomarkers for effects of fipronil exposure at environmentally relevant level, and reducing fluidity of liver mitochondrial membrane may be one toxic mechanism of fipronil. Title: Positive correlation between human exposure to organophosphate esters and gastrointestinal cancer in patients from Wuhan, China Li Y, Fu Y, Hu K, Zhang Y, Chen J, Zhang S, Zhang B, Liu Y Ref: Ecotoxicology & Environmental Safety, 196:110548, 2020 : PubMed ESTHER: Li_2020_Ecotoxicol.Environ.Saf_196_110548 PubMedSearch: Li 2020 Ecotoxicol.Environ.Saf 196 110548 PubMedID: 32278140 Abstract As kinds of endocrine disruptors, organophosphate esters (OPEs) pollution in the environment had received increasing attention recently. Food and water intake were two important exposure pathways for OPEs. However, the studies about the potential association between OPEs and gastrointestinal cancer were limited. This study investigated the possible association between OPEs and gastrointestinal cancer. All cancer patients were diagnosed with gastrointestinal cancer from a Grade 3 A hospital in Wuhan, China, while the control group was non-cancer healthy persons. The results showed that 6 OPEs were found in the control samples, while 8 in the samples from patients with gastrointestinal cancer. The detection frequencies of OPEs in gastrointestinal cancer patients were significantly higher than those in the control group (p < 0.05 or p < 0.01), except for triethyl phosphate (TEP) and tris (methylphenyl) phosphate (TMPP) in the gastric cancer group. The concentrations of OPEs in the control group were significantly lower than those in the gastric cancer group and colorectal cancer group (p < 0.01). In the control group and gastrointestinal cancer group, TEP was the dominant pollutant. Correlation analysis found that concentrations of TEP, tris(2-chloroisopropyl) phosphate (TCIPP), triphenyl phosphate (TPHP), TMPP, tris(2-ethylhexyl) phosphate (TEHP), and 2-ethylhexyl diphenyl phosphate (EHDPP) were associated with gastric cancer (p < 0.01), and concentrations of TEP, TCIPP, TPHP, TMPP and TEHP were associated with colorectal cancer (p < 0.01). A cluster analysis divided the 34 patients with gastric cancer and 40 patients with colorectal cancer in four groups. The results showed that the elderly male patients with gastric cancer were more sensitive to the exposure of EHDPP, while the TEP exposure was more sensitive to the relatively young gastrointestinal cancer patients. These findings indicated that OPEs might play a role in developing gastrointestinal cancer. Title: An efficient LSPR method to quantitatively detect dimethoate: Development, characterization and evaluation Li D, Zhang Y, Guo Q, Sun X, Zhang H, Wang S, Birech Z, Hu J Ref: PLoS ONE, 15:e0239632, 2020 : PubMed ESTHER: Li_2020_PLoS.One_15_e0239632 PubMedSearch: Li 2020 PLoS.One 15 e0239632 PubMedID: 32970749 Abstract In recent years, there has been growing concern among consumers about pesticide contamination in fruits. Therefore, rapid, reliable, and consistent detection methods for OPPs, especially dimethoate, are crucially needed. The existing quantitative methods for detecting dimethoate are not suitable for rapid measuring system such as the dimethoate samples from two channels. Hence this paper examines the utilization of a dual-channel system for utilize the absorption variations of the Localized Surface Plasmon Resonance (LSPR) bands of gold nanoparticles (AuNPs) were investigate for detection of dimethoate. Under optimized conditions, the relationship between concentrations of dimethoate and absorbance ratios (A(520)/A(640)) was linearly found in the concentration range of 10-100 nM. Result from the experiment shows that both channels exhibit a linear correlation coefficient as high as 0.97 and a limit of detection (LOD) as low as 5.5 nM. This LSPR detection system was characterized by testing the dimethoate in apple samples and the recovery rates were found to be in the range of 85.90% to 107.37%. The proposed dual-channel LSPR system for detecting dimethoate creating a new approach for detecting organophosphate insecticide in agricultural fields. It could lay the foundation for designing a high-throughput analysis of the insecticides using a wavelength division multiplexing switch (WDMS). Title: GALNT2 regulates ANGPTL3 cleavage in cells and in vivo of mice Li X, Zhang Y, Zhang M, Wang Y Ref: Sci Rep, 10:16168, 2020 : PubMed ESTHER: Li_2020_Sci.Rep_10_16168 PubMedSearch: Li 2020 Sci.Rep 10 16168 PubMedID: 32999434 Abstract Angiopoietin-like protein 3 (ANGPTL3) is an important inhibitor of lipoprotein lipase and endothelial lipase that plays critical roles in lipoprotein metabolism. It specifically expresses in the liver and undergoes proprotein convertase-mediated cleavage during secretion, which generates an N-terminal coiled-coil domain and C-terminal fibrinogen-like domain that has been considered as the activation step for its function. Previous studies have reported that the polypeptide GalNAc-transferase GALNT2 mediates the O-glycosylation of the ANGPTL3 near the cleavage site, which inhibits the proprotein convertase (PC)-mediated cleavage in vitro and in cultured cells. However, loss-of-function mutation for GALNT2 has no effect on ANGPTL3 cleavage in human. Thus whether GALNT2 regulates the cleavage of ANGPTL3 in vivo is unclear. In present study, we systematically characterized the cleavage of Angptl3 in cultured cells and in vivo of mice. We found that endogenous Angptl3 is cleaved in primary hepatocytes and in vivo of mice, and this cleavage can be blocked by Galnt2 overexpression or PC inhibition. Moreover, suppressing galnt2 expression increases the cleavage of Angptl3 in mice dramatically. Thus, our results support the conclusion that Galnt2 is a key endogenous regulator for Angptl3 cleavage both in vitro and in vivo. Title: Reduced insecticide sensitivity of the wheat aphid Sitobion miscanthi after infection by the secondary bacterial symbiont Hamiltonella defensa Li Q, Sun J, Qin Y, Fan J, Zhang Y, Tan X, Hou M, Chen J Ref: Pest Manag Sci, 77:1936, 2020 : PubMed ESTHER: Li_2020_Pest.Manag.Sci_77_1936 PubMedSearch: Li 2020 Pest.Manag.Sci 77 1936 PubMedID: 33300163 Abstract BACKGROUND: Bacterial symbionts in insects, especially aphids, have a major influence on host adaptation. The authors previously showed that infection with the secondary symbiont Hamiltonella defensa increases the fitness of the wheat aphid Sitobion miscanthi, yielding increases in fitness parameters such as adult weight and offspring number. However, whether H. defensa affects the sensitivity of host aphids to insecticides remains unknown. RESULTS: We tested the effects of H. defensa on host aphid susceptibility to the insecticides chlorpyrifos methyl, imidacloprid, cyantraniliprole and acetamiprid. Our results showed that compared with Hamiltonella-free aphid clones, Hamiltonella-infected aphid clones exhibited lower sensitivity to most of the tested insecticides at low concentrations. Quantitative PCR showed that the density of H. defensa in the infected clones was slightly decreased at 24 h but then sharply increased until the late stage after treatment with the different insecticides. H. defensa in the host aphids was detected by fluorescence in situ hybridization and was localized to the aphid hindgut. The levels of the detoxification enzymes acetylcholinesterase (AChE), glutathione transferase (GST) and carboxylesterase (CarE) were significantly higher in the Hamiltonella-infected clones than in the Hamiltonella-free clones. CONCLUSIONS: The findings indicated that infection with H. defensa reduced aphid sensitivity to the investigated insecticides at low concentrations, potentially by increasing detoxification enzyme activity in the host. Therefore, symbiont-mediated insecticide resistance should be taken into account when performing resistance-monitoring studies. Studies of symbiont-mediated insecticide resistance may enhance our understanding of the emergence of insecticide resistance in agricultural systems. This article is protected by copyright. All rights reserved. Title: Identification of key residues of carboxylesterase PxEst-6 involved in pyrethroid metabolism in Plutella xylostella (L.) Li Y, Sun H, Tian Z, Ye X, Li R, Li X, Zheng S, Liu J, Zhang Y Ref: J Hazard Mater, 407:124612, 2020 : PubMed ESTHER: Li_2020_J.Hazard.Mater_407_124612 PubMedSearch: Li 2020 J.Hazard.Mater 407 124612 PubMedID: 33338816 Gene_locus related to this paper: pluxy-f1c4b8 Abstract The long-term and excessive use of insecticides has led to severe environmental problems and the evolution of insecticide resistance in insects. Carboxylesterases (CarEs) are important detoxification enzymes conferring insecticide resistance on insects. Herein, the detoxification process of Plutella xylostella (L.) carboxylesterase 6 (PxEst-6), one representative P. xylostella carboxylesterase, is investigated with cypermethrin, bifenthrin, cyfluthrin and lambda-cyhalothrin. RT-qPCR shows that PxEst-6 is highly expressed in the midgut and cuticles of the third instar larvae. Exposure to pyrethroid insecticides resulted in PxEst-6 up-regulation in a short time. Metabolic assays indicate that PxEst-6 has the capacity to metabolize these pyrethroid insecticides. The combination of molecular docking, binding mode analyses and alanine mutations demonstrated that His451, Lys458 and Gln431 were key residues of PxEst-6 for metabolizing pyrethroids and the acetate groups derived from pyrethroids were key sites for being metabolized by PxEst-6. H451- and K458-derived hydrogen bond (H-bond) interactions with the pyrethroid acetate groups and the polar interactions with the pyrethroid acetate group provided by the Q431 sidechain were crucial to the pyrethroids' metabolism by PxEst-6. Our study contributes to revealing the reasons for pyrethroid resistance in P. xylostella, and provides a fundamental basis for the development of novel pyrethroid insecticides. Title: Application of accelerated solvent extraction coupled with online two-dimensional countercurrent chromatography for continuous extraction and separation of bioactive compounds from Citrus limon peel Li S, Liu C, Zhang Y, Shi D, Tsao R Ref: J Sep Sci, 43:3793, 2020 : PubMed ESTHER: Li_2020_J.Sep.Sci_43_3793 PubMedSearch: Li 2020 J.Sep.Sci 43 3793 PubMedID: 32745365 Abstract Drug discovery from complex mixtures, like Chinese herbs, is challenging and extensive false positives make it difficult to obtain compounds with anti-Alzheimer's activity. In this study, a continuous method comprised of accelerated solvent extraction coupled with online two-dimensional countercurrent chromatography was developed for the efficient, scaled-up extraction and separation of six bioactive compounds from Citrus limon peels: neoeriocitrin, isonaringin, naringin, hesperidin, neohesperidin, and limonin. These active compounds were isolated and purified from the raw plant materials by two-dimensional countercurrent chromatography separation via two sets of an n-hexane/n-butanol/methanol/water solvent system: 0.23:1.00:0.25:1.13 and 0.47:1.00:0.38:1.46, v/v/v/v. The compounds were collected in yields of 0.22, 0.25, 0.10, 0.31, 0.29, and 0.28 mg/g, respectively, with purities of 95.79, 96.47, 97.69, 97.22, 98.11, and 98.82%, respectively. Subsequently, a simple and efficient in vitro method was developed for rapidly evaluating the acetylcholinesterase inhibitory activities of six bioactive components. Furthermore, the PC12 cell model and the in vitro metabolism of cytochromes P450 were employed to verify the monomers obtained from the continuous method. The results demonstrated that these six bioactive extracts from the C. limon peels were strong acetylcholinesterase inhibitors. Title: The Chromosome-Based Rubber Tree Genome Provides New Insights into Spurge Genome Evolution and Rubber Biosynthesis Liu J, Shi C, Shi CC, Li W, Zhang QJ, Zhang Y, Li K, Lu HF, Zhu ST and Gao LZ <27 more author(s)> Liu J, Shi C, Shi CC, Li W, Zhang QJ, Zhang Y, Li K, Lu HF, Zhu ST, Xiao ZY, Nan H, Yue Y, Zhu XG, Wu Y, Hong XN, Fan GY, Tong Y, Zhang D, Mao CL, Liu YL, Hao SJ, Liu WQ, Lv MQ, Zhang HB, Liu Y, Hu-Tang GR, Wang JP, Wang JH, Sun YH, Ni SB, Chen WB, Zhang XC, Jiao YN, Eichler EE, Li GH, Liu X, Gao LZ (- 27) Ref: Mol Plant, 13:336, 2020 : PubMed ESTHER: Liu_2020_Mol.Plant_13_336 PubMedSearch: Liu 2020 Mol.Plant 13 336 PubMedID: 31838037 Gene_locus related to this paper: hevbr-a0a6a6mdr9 Abstract The rubber tree, Hevea brasiliensis, produces natural rubber that serves as an essential industrial raw material. Here, we present a high-quality reference genome for a rubber tree cultivar GT1 using single-molecule real-time sequencing (SMRT) and Hi-C technologies to anchor the -1.47-Gb genome assembly into 18 pseudochromosomes. The chromosome-based genome analysis enabled us to establish a model of spurge chromosome evolution, since the common paleopolyploid event occurred before the split of Hevea and Manihot. We show recent and rapid bursts of the three Hevea-specific LTR-retrotransposon families during the last 10 million years, leading to the massive expansion by -65.88% (-970 Mbp) of the whole rubber tree genome since the divergence from Manihot. We identify large-scale expansion of genes associated with whole rubber biosynthesis processes, such as basal metabolic processes, ethylene biosynthesis, and the activation of polysaccharide and glycoprotein lectin, which are important properties for latex production. A map of genomic variation between the cultivated and wild rubber trees was obtained, which contains -15.7 million high-quality single-nucleotide polymorphisms. We identified hundreds of candidate domestication genes with drastically lowered genomic diversity in the cultivated but not wild rubber trees despite a relatively short domestication history of rubber tree, some of which are involved in rubber biosynthesis. This genome assembly represents key resources for future rubber tree research and breeding, providing novel targets for improving plant biotic and abiotic tolerance and rubber production. Title: Recent advances in multitarget-directed ligands targeting G-protein-coupled receptors Ma H, Huang B, Zhang Y Ref: Drug Discov Today, 25:1682, 2020 : PubMed ESTHER: Ma_2020_Drug.Discov.Today_25_1682 PubMedSearch: Ma 2020 Drug.Discov.Today 25 1682 PubMedID: 32652312 Abstract Mounting evidence indicates that single-target drugs might be inadequate to achieve satisfactory therapeutic effects on complex diseases. Recently, increasing attention has been paid to developing drugs that can manipulate multiple targets to generate beneficial effects through potential synergy. G-protein-coupled receptors (GPCRs) become desirable targets for developing multitarget-directed ligands (MTDLs) because of their crucial roles in the pathophysiology of various human diseases and the accessibility of druggable sites at the cell surface. Herein, we review the most recent advances in the development of GPCR-targeted MTDLs in treating complex diseases, and discuss their potential therapeutic strategies to reveal current trends and shed insights into the utility of GPCR-targeted MTDLs for future drug design and development. Title: In silico exploration of bioactive phytochemicals against neurodegenerative diseases via inhibition of cholinesterases Mahomoodally F, Abdallah HH, Suroowan S, Zhang Y, Hu X, Jugreet S Ref: Curr Pharm Des, :, 2020 : PubMed ESTHER: Mahomoodally_2020_Curr.Pharm.Des__ PubMedSearch: Mahomoodally 2020 Curr.Pharm.Des PubMedID: 32178608 Abstract Neurodegenerative disorders are estimated to become the second leading cause of death worldwide by 2040. Despite the usage of several allopathic drugs, these brain associated disorders can only be partially addressed and long termed treatment is often linked with dependency and other unwanted side effects. Nature, believed to be an arsenal of remedies for any illness, presents an interesting avenue for the development of novel neuroprotective agents. Interestingly, inhibition of cholinesterases, involved in the breakdown of acetylcholine in the synaptic cleft, has been proposed to be neuroprotective. This study therefore aims to provide additional insight via docking studies of previously studied compounds that have shown potent activity against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in vitro. Indeed, the determination of potent plant-based ligands for this purpose through in silico methods enables the elimination of lengthy and costly traditional methods of drug discovery. Herein, a literature search was conducted to identify active phytochemicals cholinesterase inhibitors. Following which in silico docking methods were applied to obtain docking scores. Compounds structures' were extracted from online ZINC database and optimized using AM1 implemented in gaussian09 software. (+)-thalictricavine, (+)-canadine, Catecholamine-O-methyltransferase inhibitors from common herbal products such as Ginkgo biloba L., Curcuma longa L. and ayurvedic formulations, as well as plant-derived 19, 20-dihydroervahanine A and 8-C-lavandurylkaempferol have been revealed as potent cholinesterase inhibitors. Thus, ligand optimization between such phytochemicals and cholinesterases together with in vitro, in vivo studies and randomized clinical trials can lead to the development of novel drugs against neurodegenerative disorders. Title: Embryonic development and oxidative stress effects in the larvae and adult fish livers of zebrafish (Danio rerio) exposed to the strobilurin fungicides, kresoxim-methyl and pyraclostrobin Mao L, Jia W, Zhang L, Zhang Y, Zhu L, Sial MU, Jiang H Ref: Sci Total Environ, 729:139031, 2020 : PubMed ESTHER: Mao_2020_Sci.Total.Environ_729_139031 PubMedSearch: Mao 2020 Sci.Total.Environ 729 139031 PubMedID: 32387777 Abstract Two important strobilurin fungicides, kresoxim-methyl and pyraclostrobin, are widely used globally. Their effects on embryonic development and oxidative stress effects in the larvae and adult fish livers of zebrafish (Danio rerio) were assessed in our study. The hatching, mortality, and teratogenic rates were determined when the eggs of fish were exposed to kresoxim-methyl and pyraclostrobin for 24-144 h postfertilization (hpf). For further study, the effects of kresoxim-methyl and pyraclostrobin on antioxidant enzymes [catalase (CAT), superoxide dismutase (SOD) and peroxidase (POD)], detoxification enzymes [carboxylesterase (CarE) and glutathione S-transferase (GST)] and the malondialdehyde (MDA) content of larval zebrafish (96 h) and male or female adult zebrafish livers (up to 28 d) were evaluated for potential toxicity mechanisms. The study of embryonic development revealed that both kresoxim-methyl and pyraclostrobin caused developmental toxicity (hatching inhibition, mortality, and teratogenic rates) increase with significant concentration- and time-dependent responses, and the 144-h median lethal values (LC50) of kresoxim-methyl and pyraclostrobin were 195.0 and 81.3 mug L(-1), respectively. In the larval zebrafish study, both kresoxim-methyl and pyraclostrobin at the highest concentrations (100 mug L(-1) and 15 mug L(-1), respectively) significantly increased the CAT, POD and CarE activities and MDA content compared with those of the control group (P < 0.05). We further found that oxidative stress effects in adult zebrafish livers caused by long-term kresoxim-methyl and pyraclostrobin exposure differed with time and sex. Regarding the residues in natural waters, the potential adverse effects of kresoxim-methyl and pyraclostrobin would be relatively low for adult zebrafish but must not be overlooked for zebrafish embryos/larvae (hatching impairment). Our results from the detoxification enzyme study also initially indicated that adult zebrafish had a greater detoxification ability than larvae and that males had a greater detoxification ability than females. Title: The toxicity assessment of extract of Peganum harmala L. seeds in Caenorhabditis elegans Miao X, Zhang X, Yuan Y, Zhang Y, Gao J, Kang N, Liu X, Wu J, Liu Y, Tan P Ref: BMC Complement Med Ther, 20:256, 2020 : PubMed ESTHER: Miao_2020_BMC.Complement.Med.Ther_20_256 PubMedSearch: Miao 2020 BMC.Complement.Med.Ther 20 256 PubMedID: 32807143 Abstract BACKGROUND: Peganum harmala L. is a medicinal herb extensively used in traditional Chinese medicine (TCM). So far, relevant reports on the toxicity of Peganum harmala L. seeds (PHS) are hardly available. Especially, we still know little about the in vivo mechanism for PHS toxicity. This study aims to evaluate the toxicity effects of PHS in Caenorhabditis elegans (C. elegans), investigate the possible mechanism of the toxicity effects of PHS, and provide reference for the pharmacological research of PHS. METHODS: In the present study, the C. elegans was exposed to 0.25, 0.50, 1.00 mg/mL of PHS in nematode growth medium (NGM) at 22 degC in the presence of food. Lethality, lifespan, growth, reproduction, and locomotion behavior assays were performed to evaluate the toxicity effects of PHS in C. elegans. We then determined the mechanism of the toxicity effect of PHS by quantitative real-time polymerase chain reaction (qRT-PCR), acetylcholinesterase (AChE) activity assay, and oxidative stress resistance assays. The main components of PHS were detected by high performance liquid chromatography (HPLC). RESULTS: Compared with the control group, the lethality of C. elegans was significantly increased when they were exposed to the ethanol extract of PHS at 0.25, 0.50 and 1.00 mg/mL (P < 0.01), and the mean lifespan was significantly decreased (P < 0.01). We also observed that PHS exposure could induce the toxicity on body length, brood size, and locomotion behavior. CONCLUSION: Our study shows that the ethanol extract of PHS exerts obvious toxic effects on C. elegans, which would provide new ideas and methods for the biological evaluation of the toxicity of Chinese medicinal materials. Title: Alternative splicing at neuroligin site A regulates glycan interaction and synaptogenic activity Oku S, Feng H, Connor S, Toledo A, Zhang P, Zhang Y, Thoumine O, Zhang C, Craig AM Ref: Elife, 9:, 2020 : PubMed ESTHER: Oku_2020_Elife_9_ PubMedSearch: Oku 2020 Elife 9 PubMedID: 32915137 Abstract Post-transcriptional mechanisms regulating cell surface synaptic organizing complexes that control the properties of connections in brain circuits are poorly understood. Alternative splicing regulates the prototypical synaptic organizing complex, neuroligin-neurexin. In contrast to the well-studied neuroligin splice site B, little is known about splice site A. We discovered that inclusion of the positively charged A1 insert in mouse neuroligin-1 increases its binding to heparan sulphate, a modification on neurexin. The A1 insert increases neurexin recruitment, presynaptic differentiation, and synaptic transmission mediated by neuroligin-1. We propose that the A1 insert could be a target for alleviating the consequences of deleterious NLGN1/3 mutations, supported by assays with the autism-linked neuroligin-1-P89L mutant. An enrichment of neuroligin-1 A1 in GABAergic neuron types suggests a role in synchrony of cortical circuits. Altogether, these data reveal an unusual mode by which neuroligin splicing controls synapse development through protein-glycan interaction and identify it as a potential therapeutic target. Title: Identification and characterization of a novel phthalate-degrading hydrolase from a soil metagenomic library Qiu J, Zhang Y, Shi Y, Jiang J, Wu S, Li L, Shao Y, Xin Z Ref: Ecotoxicology & Environmental Safety, 190:110148, 2020 : PubMed ESTHER: Qiu_2020_Ecotoxicol.Environ.Saf_190_110148 PubMedSearch: Qiu 2020 Ecotoxicol.Environ.Saf 190 110148 PubMedID: 31911388 Gene_locus related to this paper: 9zzzz-EstJ6 Abstract Phthalate esters have raised public concerns owing to their effects on the environment and human health. We identified a novel phthalate-degrading hydrolase, EstJ6, from a metagenomic library using function-driven screening. Phylogenetic analysis indicated that EstJ6 is a member of family IV esterases. EstJ6 hydrolyzed various dialkyl and monoalkyl phthalate esters, and exhibited high hydrolytic activity (128 U/mg) toward dibutyl phthalate at 40 degrees C and pH 7.5. EstJ6 hydrolyzed not only common phthalate esters with simple side chains but also diethylhexyl phthalate and monoethylhexyl phthalate, which have complex and long side chains. Site-directed mutagenesis indicated that the catalytic triad residues of EstJ6 consists of Ser146, Glu240, and His270. EstJ6 is therefore a promising biodegradation enzyme, and our study illustrates the advantages of a metagenomic approach in identifying enzyme-coding genes for agricultural, food, and biotechnological applications. Title: The genome sequence of the grape phylloxera provides insights into the evolution, adaptation, and invasion routes of an iconic pest Rispe C, Legeai F, Nabity PD, Fernandez R, Arora AK, Baa-Puyoulet P, Banfill CR, Bao L, Barbera M and Tagu D <64 more author(s)> Rispe C, Legeai F, Nabity PD, Fernandez R, Arora AK, Baa-Puyoulet P, Banfill CR, Bao L, Barbera M, Bouallegue M, Bretaudeau A, Brisson JA, Calevro F, Capy P, Catrice O, Chertemps T, Couture C, Deliere L, Douglas AE, Dufault-Thompson K, Escuer P, Feng H, Forneck A, Gabaldon T, Guigo R, Hilliou F, Hinojosa-Alvarez S, Hsiao YM, Hudaverdian S, Jacquin-Joly E, James EB, Johnston S, Joubard B, Le Goff G, Le Trionnaire G, Librado P, Liu S, Lombaert E, Lu HL, Maibeche M, Makni M, Marcet-Houben M, Martinez-Torres D, Meslin C, Montagne N, Moran NA, Papura D, Parisot N, Rahbe Y, Lopes MR, Ripoll-Cladellas A, Robin S, Roques C, Roux P, Rozas J, Sanchez-Gracia A, Sanchez-Herrero JF, Santesmasses D, Scatoni I, Serre RF, Tang M, Tian W, Umina PA, van Munster M, Vincent-Monegat C, Wemmer J, Wilson ACC, Zhang Y, Zhao C, Zhao J, Zhao S, Zhou X, Delmotte F, Tagu D (- 64) Ref: BMC Biol, 18:90, 2020 : PubMed ESTHER: Rispe_2020_BMC.Biol_18_90 PubMedSearch: Rispe 2020 BMC.Biol 18 90 PubMedID: 32698880 Abstract BACKGROUND: Although native to North America, the invasion of the aphid-like grape phylloxera Daktulosphaira vitifoliae across the globe altered the course of grape cultivation. For the past 150 years, viticulture relied on grafting-resistant North American Vitis species as rootstocks, thereby limiting genetic stocks tolerant to other stressors such as pathogens and climate change. Limited understanding of the insect genetics resulted in successive outbreaks across the globe when rootstocks failed. Here we report the 294-Mb genome of D. vitifoliae as a basic tool to understand host plant manipulation, nutritional endosymbiosis, and enhance global viticulture. RESULTS: Using a combination of genome, RNA, and population resequencing, we found grape phylloxera showed high duplication rates since its common ancestor with aphids, but similarity in most metabolic genes, despite lacking obligate nutritional symbioses and feeding from parenchyma. Similarly, no enrichment occurred in development genes in relation to viviparity. However, phylloxera evolved > 2700 unique genes that resemble putative effectors and are active during feeding. Population sequencing revealed the global invasion began from the upper Mississippi River in North America, spread to Europe and from there to the rest of the world. CONCLUSIONS: The grape phylloxera genome reveals genetic architecture relative to the evolution of nutritional endosymbiosis, viviparity, and herbivory. The extraordinary expansion in effector genes also suggests novel adaptations to plant feeding and how insects induce complex plant phenotypes, for instance galls. Finally, our understanding of the origin of this invasive species and its genome provide genetics resources to alleviate rootstock bottlenecks restricting the advancement of viticulture. Title: An Epoxide Intermediate in Glycosidase Catalysis Sobala LF, Speciale G, Zhu S, Raich L, Sannikova N, Thompson AJ, Hakki Z, Lu D, Shamsi Kazem Abadi S and Williams SJ <10 more author(s)> Sobala LF, Speciale G, Zhu S, Raich L, Sannikova N, Thompson AJ, Hakki Z, Lu D, Shamsi Kazem Abadi S, Lewis AR, Rojas-Cervellera V, Bernardo-Seisdedos G, Zhang Y, Millet O, Jimenez-Barbero J, Bennet AJ, Sollogoub M, Rovira C, Davies GJ, Williams SJ (- 10) Ref: ACS Cent Sci, 6:760, 2020 : PubMed ESTHER: Sobala_2020_ACS.Cent.Sci_6_760 PubMedSearch: Sobala 2020 ACS.Cent.Sci 6 760 PubMedID: 32490192 Abstract Retaining glycoside hydrolases cleave their substrates through stereochemical retention at the anomeric position. Typically, this involves two-step mechanisms using either an enzymatic nucleophile via a covalent glycosyl enzyme intermediate or neighboring-group participation by a substrate-borne 2-acetamido neighboring group via an oxazoline intermediate; no enzymatic mechanism with participation of the sugar 2-hydroxyl has been reported. Here, we detail structural, computational, and kinetic evidence for neighboring-group participation by a mannose 2-hydroxyl in glycoside hydrolase family 99 endo-alpha-1,2-mannanases. We present a series of crystallographic snapshots of key species along the reaction coordinate: a Michaelis complex with a tetrasaccharide substrate; complexes with intermediate mimics, a sugar-shaped cyclitol beta-1,2-aziridine and beta-1,2-epoxide; and a product complex. The 1,2-epoxide intermediate mimic displayed hydrolytic and transfer reactivity analogous to that expected for the 1,2-anhydro sugar intermediate supporting its catalytic equivalence. Quantum mechanics/molecular mechanics modeling of the reaction coordinate predicted a reaction pathway through a 1,2-anhydro sugar via a transition state in an unusual flattened, envelope (E 3) conformation. Kinetic isotope effects (k cat/K M) for anomeric-(2)H and anomeric-(13)C support an oxocarbenium ion-like transition state, and that for C2-(18)O (1.052 +/- 0.006) directly implicates nucleophilic participation by the C2-hydroxyl. Collectively, these data substantiate this unprecedented and long-imagined enzymatic mechanism. Title: Proteomic Analysis Reveals that EPHX1 Contributes to 5-Fluorouracil Resistance in a Human Hepatocellular Carcinoma Cell Line Sun R, Dong C, Li R, Chu H, Liu J, Hao D, Zhang L, Zhao B, Wang L, Zhang Y Ref: Proteomics Clin Appl, 14:e1900080, 2020 : PubMed ESTHER: Sun_2020_Proteomics.Clin.Appl_14_e1900080 PubMedSearch: Sun 2020 Proteomics.Clin.Appl 14 e1900080 PubMedID: 32067389 Gene_locus related to this paper: human-EPHX1 Abstract PURPOSE: The extensive drug resistance of hepatocellular carcinoma (HCC) has become a major cause of chemotherapy failure. A deeper understanding of the drug resistance mechanism of tumor cells is very significant for improving the clinical prognosis of patients with HCC. EXPERIMENTAL DESIGN: In this study, proteomic studies on the composition of 5-fluorouracil (5-Fu) resistant Bel/5Fu cell line and its parent Bel7402 cell line by using an ionic liquid assisted proteins extraction method with the advantage of extracting plasma membrane proteins to a wider extent are performed. Then the expression level and function of differentially expressed plasma membrane proteins are verified. RESULTS: In total, 25 plasma membrane proteins are shown differentially expressed in Bel/5Fu compared with Bel7402. Western blot analysis results further confirmed that the EPHX1 PLIN2 RAB27B SLC4A2 are upregulated in Bel/5Fu cells in accordance with the proteomics data. Moreover, cell viability assay and clonogenic survival assay results demonstrated that EPHX1 is closely related to the chemoresistance of Bel/5Fu to 5-Fu. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma membrane protein EPHX1 is closely related to the chemotherapy resistance of Bel/5Fu cells and can be used as a new drug target to improve the clinical prognosis of patients with HCC. Title: Developing a Library of Mannose-Based Mono- and Disaccharides: A General Chemoenzymatic Approach to Monohydroxylated Building Blocks Tanzi L, Robescu MS, Marzatico S, Recca T, Zhang Y, Terreni M, Bavaro T Ref: Molecules, 25:, 2020 : PubMed ESTHER: Tanzi_2020_Molecules_25_ PubMedSearch: Tanzi 2020 Molecules 25 PubMedID: 33297422 Abstract Regioselective deprotection of acetylated mannose-based mono- and disaccharides differently functionalized in anomeric position was achieved by enzymatic hydrolysis. Candida rugosa lipase (CRL) and Bacillus pumilus acetyl xylan esterase (AXE) were immobilized on octyl-Sepharose and glyoxyl-agarose, respectively. The regioselectivity of the biocatalysts was affected by the sugar structure and functionalization in anomeric position. Generally, CRL was able to catalyze regioselective deprotection of acetylated monosaccharides in C6 position. When acetylated disaccharides were used as substrates, AXE exhibited a marked preference for the C2, or C6 position when C2 was involved in the glycosidic bond. By selecting the best enzyme for each substrate in terms of activity and regioselectivity, we prepared a small library of differently monohydroxylated building blocks that could be used as intermediates for the synthesis of mannosylated glycoconjugate vaccines targeting mannose receptors of antigen presenting cells. Title: Genome of Tripterygium wilfordii and identification of cytochrome P450 involved in triptolide biosynthesis Tu L, Su P, Zhang Z, Gao L, Wang J, Hu T, Zhou J, Zhang Y, Zhao Y and Gao W <9 more author(s)> Tu L, Su P, Zhang Z, Gao L, Wang J, Hu T, Zhou J, Zhang Y, Zhao Y, Liu Y, Song Y, Tong Y, Lu Y, Yang J, Xu C, Jia M, Peters RJ, Huang L, Gao W (- 9) Ref: Nat Commun, 11:971, 2020 : PubMed ESTHER: Tu_2020_Nat.Commun_11_971 PubMedSearch: Tu 2020 Nat.Commun 11 971 PubMedID: 32080175 Gene_locus related to this paper: triwf-a0a7j7c8l4 Abstract Triptolide is a trace natural product of Tripterygium wilfordii. It has antitumor activities, particularly against pancreatic cancer cells. Identification of genes and elucidation of the biosynthetic pathway leading to triptolide are the prerequisite for heterologous bioproduction. Here, we report a reference-grade genome of T. wilfordii with a contig N50 of 4.36 Mb. We show that copy numbers of triptolide biosynthetic pathway genes are impacted by a recent whole-genome triplication event. We further integrate genomic, transcriptomic, and metabolomic data to map a gene-to-metabolite network. This leads to the identification of a cytochrome P450 (CYP728B70) that can catalyze oxidation of a methyl to the acid moiety of dehydroabietic acid in triptolide biosynthesis. We think the genomic resource and the candidate genes reported here set the foundation to fully reveal triptolide biosynthetic pathway and consequently the heterologous bioproduction. Title: Enhancing secretion of polyethylene terephthalate hydrolase PETase in Bacillus subtilis WB600 mediated by the SP(amy) signal peptide Wang N, Guan F, Lv X, Han D, Zhang Y, Wu N, Xia X, Tian J Ref: Lett Appl Microbiol, :, 2020 : PubMed ESTHER: Wang_2020_Lett.Appl.Microbiol__ PubMedSearch: Wang 2020 Lett.Appl.Microbiol PubMedID: 32394501 Abstract The polyethylene terephthalate hydrolase (PETase) has been proved to have a high activity to degrade polyethylene terephthalate (PET), but few studies have been carried on its secretion in Bacillus subtilis. In this study, the coding gene of PETase, which was isolated from the Ideonella sakaiensis, was synthesized and expressed in B. subtilis. Then, we evaluated the ability of five Bacillus signal peptides to enhance PETase secretion by B. subtilis. The results indicated that the SP(amy) -induced secretion of PETase was the highest, and its activity against p-Nitrophenyl palmitate was about fourfold that of the natural signal peptide SP(PETase) . The weak promoter P43 provided sufficient time for translation and folding of PETase, resulting in increased extracellular expression. Use of P43 and SP(amy) in combination yielded the greatest bis-(2-hydroxyethyl) terephthalate degradation and PET-film etching activity due to maximized secretion of PETase by B. subtilis. Our findings will facilitate biodegradation of PET plastic. Title: Efficacy and safety of DBPR108 monotherapy in patients with type 2 diabetes: a 12-week, randomized, double-blind, placebo-controlled, phase II clinical trial Wang W, Yao J, Guo X, Guo Y, Yan C, Liu K, Zhang Y, Wang X, Li H and Yuan J <22 more author(s)> Wang W, Yao J, Guo X, Guo Y, Yan C, Liu K, Zhang Y, Wang X, Li H, Wen Z, Li S, Xiao X, Liu W, Li Z, Zhang L, Shao S, Ye S, Qin G, Li Y, Li F, Zhang X, Li X, Peng Y, Deng H, Xu X, Zhou L, Huang Y, Cao M, Xia X, Shi M, Dou J, Yuan J (- 22) Ref: Curr Med Res Opin, 36:1107, 2020 : PubMed ESTHER: Wang_2020_Curr.Med.Res.Opin_36_1107 PubMedSearch: Wang 2020 Curr.Med.Res.Opin 36 1107 PubMedID: 32338063 Inhibitor(s) related to this paper: Prusogliptin Abstract Objective: DBPR108, a novel dipeptidyl-peptidase-4 inhibitor, has shown great antihyperglycemic effect in animal models. This study was to evaluate the efficacy and safety of DBPR108 monotherapy in type 2 diabetes mellitus (T2DM).Methods: This was a 12-week, double-blind, placebo-controlled phase II clinical trial. The newly diagnosed or inadequately controlled untreated T2DM patients were randomized to receive 50, 100, 200 mg DBPR108 or placebo in a ratio of 1:1:1:1. The primary efficacy outcome was HbA1c change from baseline to week 12. Relevant secondary efficacy parameters and safety were assessed. The clinical trial registration is NCT04124484.Results: Overall, 271 of the 276 randomized patients, who received 50 mg (n = 68), 100 mg (n = 67), 200 mg (n = 69) DBPR108 or placebo (n = 67), were included in full analysis set. At week 12, HbA1c change from baseline was -0.04 +/- 0.77 in placebo group, -0.51 +/- 0.71, -0.75 +/- 0.73, and -0.57 +/- 0.78 (%, p < .001 vs. placebo) in 50, 100, and 200 mg DBPR108 groups, respectively. Since week 4, DBPR108 monotherapy resulted in significant improvements in secondary efficacy parameters. At end of 12-week treatment, the goal of HbA1c >=7% was achieved in 29.85, 58.82, 55.22, and 47.83% of the patients in placebo, 50, 100, and 200 mg DBPR108 groups, respectively. The incidence of adverse events did not show significant difference between DBPR108 and placebo except mild hypoglycemia in DBPR108 200 mg group.Conclusions: The study results support DBPR108 100 mg once daily as the primary dosing regimen for T2DM patients in phase III development program. Title: Biological evaluation of 7-O-amide hesperetin derivatives as multitarget-directed ligands for the treatment of Alzheimer's disease Wu M, Zhu X, Zhang Y, Wang M, Liu T, Han J, Li J, Li Z Ref: Chemico-Biological Interactions, 334:109350, 2020 : PubMed ESTHER: Wu_2020_Chem.Biol.Interact_334_109350 PubMedSearch: Wu 2020 Chem.Biol.Interact 334 109350 PubMedID: 33307048 Abstract A series of 7-O-amide hesperetin derivatives were subjected to multi-target biological evaluation of anti-Alzheimer's disease. Most of the compounds showed good in vitro inhibitory activity against cholinesterase, of which compound 7c (7-O-(4-(morpholinoethyl)-acetamide) hesperetin) was the most effective anti-eqBuChE derivative (IC(50) = 0.28 +/- 0.05 M) and exerted neuroprotective effects. Further biological evaluation found that compounds 4d, 4e and 7c showed strong antioxidant, anti-Abeta self-aggregation and anti-neuroinflammatory activities. Compound 7c could inhibit the expression of iNOS and COX-2 proteins and prevent LPS-induced inflammatory response in BV2 cells. In addition, compound 7c could chelate biometal ions such as Cu(2+) and Zn(2+). In the vivo study, the MWM test confirmed that compound 7c could improve the cognitive impairment caused by scopolamine. In summary, the above studies have shown that the optimized compound 7c has great development potential as MTDL for the treatment of AD. Title: Hepatocyte-Specific Expression of Human Carboxylesterase 1 Attenuates Diet-Induced Steatohepatitis and Hyperlipidemia in Mice Xu Y, Zhu Y, Bawa FC, Hu S, Pan X, Yin L, Zhang Y Ref: Hepatol Commun, 4:527, 2020 : PubMed ESTHER: Xu_2020_Hepatol.Commun_4_527 PubMedSearch: Xu 2020 Hepatol.Commun 4 527 PubMedID: 32258948 Abstract Rodents have at least five carboxylesterase 1 (Ces1) genes, whereas there is only one CES1 gene in humans, raising the question as to whether human CES1 and mouse Ces1 genes share the same functions. In this study, we investigate the role of human CES1 in the development of steatohepatitis or dyslipidemia in C57BL/6 mice. Hepatocyte-specific expression of human CES1 prevented Western diet or alcohol-induced steatohepatitis and hyperlipidemia. Mechanistically, human CES1 induced lipolysis and fatty acid oxidation, leading to a reduction in hepatic triglyceride and free fatty acid levels. Human CES1 also reduced hepatic-free cholesterol levels and induced low-density lipoprotein receptor. In addition, human CES1 induced hepatic lipoprotein lipase and apolipoprotein C-II expression. Conclusion: Hepatocyte-specific overexpression of human CES1 attenuates diet-induced steatohepatitis and hyperlipidemia. Title: Development of a multivalent acetylcholinesterase inhibitor via dynamic combinatorial chemistry Xu J, Zhao S, Zhang S, Pei J, Li Y, Zhang Y, He X, Hu L Ref: Int J Biol Macromol, 150:1184, 2020 : PubMed ESTHER: Xu_2020_Int.J.Biol.Macromol_150_1184 PubMedSearch: Xu 2020 Int.J.Biol.Macromol 150 1184 PubMedID: 31758986 Abstract In this study, we report the generation of a polymer based dynamic combinatorial library (DCL) using aldehyde-functionalized linear poly(glycidol) and hydrazide derivatives as initial building blocks. In combination with tetrameric acetylcholinesterase (AChE), a certain type of amplified acylhydrazone side chain is identified and further used for the synthesis of a multivalent AChE inhibitor. The cytotoxicity and inhibition properties of the multivalent inhibitor are evaluated, and the results indicate superior bioactivity compared to the commercial reference Edrophonium chloride. Title: Evaluation of the effect of feruloyl esterase-producing Lactobacillus plantarum and cellulase pretreatments on lignocellulosic degradation and cellulose conversion of co-ensiled corn stalk and potato pulp Xu D, Ding Z, Bai J, Ke W, Zhang Y, Li F, Guo X Ref: Bioresour Technol, 310:123476, 2020 : PubMed ESTHER: Xu_2020_Bioresour.Technol_310_123476 PubMedSearch: Xu 2020 Bioresour.Technol 310 123476 PubMedID: 32402987 Abstract The effects of feruloyl esterase-producing Lactobacillus plantarum A1, cellulase, or their combination on the fermentation characteristics, carbohydrate composition, and enzymatic hydrolysis of mixed corn stalk and potato pulp silage were investigated. Two mixture ratios were used: a weight ratio of rehydrated corn stalk to potato pulp of 35:1 (HD) and a weight ratio of dry corn stalk to potato pulp of 5:11 (LD). No advantage was observed with the addition of strain A1 alone for lignocellulosic degradation and cellulose conversion, while its combination with cellulase enhanced the lignocellulosic degradation and preserved more fermentable carbohydrates in co-ensiled corn stalk and potato pulp. The enzymatic hydrolysis results indicated a potential benefit of pretreatment for biogas production, as the co-ensiled HD ratio mixture without additive treatment showed high glucose yield after enzymatic hydrolysis following 60 d of fermentation. Title: Hepatocyte-specific Expression of Human Carboxylesterase 2 Attenuates Non-alcoholic Steatohepatitis in Mice Xu Y, Pan X, Hu S, Zhu Y, Cassim Bawa F, Li Y, Yin L, Zhang Y Ref: American Journal of Physiology Gastrointest Liver Physiol, :, 2020 : PubMed ESTHER: Xu_2020_Am.J.Physiol.Gastrointest.Liver.Physiol__ PubMedSearch: Xu 2020 Am.J.Physiol.Gastrointest.Liver.Physiol PubMedID: 33325808 Abstract Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were i.v. injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced non-alcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/db mice. Human CES2 also improved glucose tolerance and insulin sensitivity. Mechanistically, human CES2 reduced hepatic triglyceride and free fatty acid levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis via suppression of sterol regulatory element-binding protein 1. Furthermore, human CES2 overexpression improved mitochondrial respiration and glycolytic function, and inhibited gluconeogenesis, lipid peroxidation, apoptosis and inflammation. Our data suggest that hepatocyte-specific expression of human CES2 prevents and reverses steatohepatitis. Targeting hepatic CES2 may be an attractive strategy for treatment of NAFLD. Title: Toxicity comparison of nano-sized and micron-sized microplastics to Goldfish Carassius auratus Larvae Yang H, Xiong H, Mi K, Xue W, Wei W, Zhang Y Ref: J Hazard Mater, 388:122058, 2020 : PubMed ESTHER: Yang_2020_J.Hazard.Mater_388_122058 PubMedSearch: Yang 2020 J.Hazard.Mater 388 122058 PubMedID: 31951993 Abstract Plastic pollution is one of the most serious environmental issues worldwide. The negative influence of plastics on aquatic organisms has increasingly concerned, especially the influence of microplastic (MPs). In the present study, the toxicology of nano-sized MPs (nMPs) and micron-sized MPs (mMPs) were comparatively studied. Goldfish larvae were exposed to 10, 100 and 1000 mug/L nMPs and mMPs for 1, 3 and 7 days. The enrichment of MPs, body length, heart rate, motor ability, microscopic and ultrastructure of intestine, liver, gill and muscle tissue, as well as the oxidative stress were analyzed. Results showed that both 70 nm and 50 mum MPs were accumulated in the digestive tract of larvae. MPs at high concentrations could induce oxidative stress, destroy intestine, liver and gill tissues, increase heart rate, and inhibit growth and swimming speed of the larvae. The most important finding was that nMPs could enter into the muscle tissue through the epidermis of the larvae. It could cause damage to muscle tissue, destroy nerve fibers, inhibit acetylcholinase (AchE) activity, and show great adverse effects on larval movement than mMPs. In conclusion, both nMPs and mMPs at higher concentrations can cause damage to fish larvae and nMPs are potentially more hazardous. Title: Chemical Composition and Anti-Alzheimer's Disease-related Activities of a Functional Oil from the Edible Seaweed Hizikia fusiforme Yang WC, Zhang YY, Li YJ, Nie YY, Liang JY, Liu YY, Liu JS, Zhang Y, Song C, Qian ZJ Ref: Chem Biodivers, 17:e2000055, 2020 : PubMed ESTHER: Yang_2020_Chem.Biodivers_17_e2000055 PubMedSearch: Yang 2020 Chem.Biodivers 17 e2000055 PubMedID: 32419273 Abstract Cholinergic disorder, oxidative stress, and neuroinflammation play important roles in the pathology of Alzheimer's disease. To explore the healthy potential of the edible seaweed Hizikia fusiforme on this aspect, a functional oil (HFFO) was extracted from this alga and investigated on its constituents by gas chromatography-mass spectrometry (GC-MS) in this study. Its anti-Alzheimer's related bioactivities including acetylcholinesterase (AChE) inhibition, antioxidation, and anti-neuroinflammation were evaluated, traced, and simulated by in vitro and in silico methods. GC-MS analysis indicated that HFFO mainly contained arachidonic acid (ARA), 11,14,17-eicosatrienoic acid (ETrA), palmitic acid, phytol, etc. HFFO showed moderate AChE inhibition and antioxidant activity. Bioactivity tracing using commercial standards verified that AChE inhibition of HFFO mainly originated from ARA and ETrA, whereas antioxidant activity mainly from ARA. Lineweaver-Burk plots showed that both ARA and ETrA are noncompetitive AChE inhibitors. A molecular docking study demonstrated low CDOCKER interaction energy of -26.33 kcal/mol for ARA and -50.36 kcal/mol for ETrA when interacting with AChE and multiple interactions in the ARA (or ETrA)-AChE complex. In the anti-neuroinflammatory evaluation, HFFO showed no toxicity toward BV-2 cells at 20 mug/mL and effectively inhibited the production of nitroxide and reduced the level of reactive oxygen species in liposaccharide-induced BV-2 cells. The results indicated that HFFO could be used in functional foods for its anti-Alzheimer's disease-related activities. Title: An anti-inflammatory isoflavone from soybean inoculated with a marine fungus Aspergillus terreus C23-3 Yang JM, Liu YY, Yang WC, Ma XX, Nie YY, Glukhov E, Gerwick L, Gerwick WH, Lei XL, Zhang Y Ref: Biosci Biotechnol Biochem, :1, 2020 : PubMed ESTHER: Yang_2020_Biosci.Biotechnol.Biochem__1 PubMedSearch: Yang 2020 Biosci.Biotechnol.Biochem 1 PubMedID: 32434451 Abstract A new isoflavone derivative compound 1 (psoralenone) was isolated from soybean inoculated with a marine fungus Aspergillus terreus C23-3, together with seven known compounds including isoflavones 2-6, butyrolactone I (7) and blumenol A (8). Their structures were elucidated by MS, NMR, and ECD. Psoralenone displayed moderate in vitro anti-inflammatory activity in the LPS-induced RAW264.7 cell model. Compound 2 (genistein) showed moderate acetylcholinesterase (AChE) inhibitory activity whereas compounds 2, 5 (biochanin A), 6 (psoralenol), and 7 exhibited potent larvicidal activity against brine shrimp. Compounds 3 (daidzein), 4 (4'-hydroxy-6,7-dimethoxyisoflavone), and 5-7 showed broad-spectrum anti-microbial activity, and compound 7 also showed moderate 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging activity. Title: A Novel Targeted and High-Efficiency Nanosystem for Combinational Therapy for Alzheimer's Disease Yang H, Mu W, Wei D, Zhang Y, Duan Y, Gao JX, Gong XQ, Wang HJ, Wu XL and Chang J <1 more author(s)> Yang H, Mu W, Wei D, Zhang Y, Duan Y, Gao JX, Gong XQ, Wang HJ, Wu XL, Tao H, Chang J (- 1) Ref: Adv Sci (Weinh), 7:1902906, 2020 : PubMed ESTHER: Yang_2020_Adv.Sci.(Weinh)_7_1902906 PubMedSearch: Yang 2020 Adv.Sci.(Weinh) 7 1902906 PubMedID: 33042734 Abstract Alzheimer's disease (AD) remains the most prevalent neurodegenerative disease, and no effective treatment is available yet. Metal-ion-triggered aggregates of amyloid-beta (Abeta) peptide and acetylcholine imbalance are reported to be possible factors in AD pathogenesis. Thus, a combination therapy that can not only inhibit and reduce Abeta aggregation but also simultaneously regulate acetylcholine imbalance that can serve as a potential treatment for AD is needed. Here, clioquinol (metal-ion chelating agent) and donepezil (acetylcholinesterase (AChE) inhibitor) co-encapsulated human serum albumin (HSA) nanoparticles (dcHGT NPs) are designed, which are modified with transcriptional activator protein (TAT) and monosialotetrahexosylganglioside (GM1). The GM1 lipid and TAT peptide endow this drug delivery nanosystem with high brain entry efficiency and long-term retention capabilities through intranasal administration. It is found that dcHGT NPs can significantly inhibit and eliminate Abeta aggregation, relieve acetylcholine-related inflammation in microglial cells, and protect primary neurons from Abeta oligomer-induced neurotoxicity in vitro. The alleviation of Abeta-related inflammation and AChE-inhibited effect further synergistically adjust acetylcholine imbalance. It is further demonstrated that dcHGT NPs reduce Abeta deposition, ameliorate neuron morphological changes, rescue memory deficits, and greatly improve acetylcholine regulation ability in vivo. This multifunctional synergetic nanosystem can be a new candidate to achieve highly efficient combination therapy for AD. Title: Neuroprotective Effects of Higenamine Against the Alzheimer's Disease Via Amelioration of Cognitive Impairment, Abeta Burden, Apoptosis and Regulation of Akt/GSK3beta Signaling Pathway Yang X, Du W, Zhang Y, Wang H, He M Ref: Dose Response, 18:1559325820972205, 2020 : PubMed ESTHER: Yang_2020_Dose.Response_18_1559325820972205 PubMedSearch: Yang 2020 Dose.Response 18 1559325820972205 PubMedID: 33354171 Abstract The present investigation was envisaged to elucidate the neuroprotective effect of Higenamine (HGN) against aluminum chloride (AlCl(3)) triggered experimental Alzheimer's disease (AD) rat model. Thirty-six male albino Wister rats were randomized and divided in 6 groups and subjected to experimentation for 6 weeks. Control group, AlCl(3) (100 mg/kg orally), HGN (50 mg/kg orally), HGN25, HGN50, HGN75 (HGN 25, 50 and 75 mg/kg respectively and AlCl(3) 100 mg/kg orally). After completion of 42 days protocol, the animals were subjected to passive avoidance test. The animals were then anesthetized by intramuscularly injecting ketamine hydrochloride (24 mg/kg body weight) and euthanized by cervical amputation. Cortical and hippocampal tissues were carefully removed and were employed for quantification of aluminum and acetylcholinesterase. The tissues were quantified using Western blotting and detection kits for APP, Abeta(1-42), beta and gamma secretases, Bax, Bad, caspases-9, cyto-c, pAkt and pGSK-3beta, and oxidative markers. HGN significantly protected AlCl(3) induced memory and learning impairments, Al overload, AChE hyperactivity, amyloid beta (Abeta) burden and apoptosis in brain tissues via activating Akt/GSK3beta pathway. HGN attenuated oxidative damage induced by Al by modulation of oxidative markers. Our findings advocate the neuroprotective effect of HGN in AlCl(3) induced AD rat model. Title: Propoxur resistance associated with insensitivity of acetylcholinesterase (AChE) in the housefly, Musca domestica (Diptera: Muscidae) You C, Shan C, Xin J, Li J, Ma Z, Zhang Y, Zeng X, Gao X Ref: Sci Rep, 10:8400, 2020 : PubMed ESTHER: You_2020_Sci.Rep_10_8400 PubMedSearch: You 2020 Sci.Rep 10 8400 PubMedID: 32439946 Abstract Two unique housefly strains, PSS and N-PRS (near-isogenic line with the PSS), were used to clarify the mechanisms associated with propoxur resistance in the housefly, Musca domestica. The propoxur-selected resistant (N-PRS) strain exhibited >1035-fold resistance to propoxur and 1.70-, 12.06-, 4.28-, 57.76-, and 57.54-fold cross-resistance to beta-cypermethrin, deltamethrin, bifenthrin, phoxim, and azamethiphos, respectively, compared to the susceptible (PSS) strain. We purified acetylcholinesterase (AChE) from the N-PRS and PSS strains using a procainamide affinity column and characterized the AChE. The sensitivity of AChE to propoxur based on the bimolecular rate constant (Ki) was approximately 100-fold higher in the PSS strain compared to the N-PRS strain. The cDNA encoding Mdace from both the N-PRS strain and the PSS strain were cloned and sequenced using RT-PCR. The cDNA was 2073 nucleotides long and encoded a protein of 691 amino acids. A total of four single nucleotide polymorphisms (SNPs), I162M, V260L, G342A, and F407Y, were present in the region of the active site of AChE from the N-PRS strain. The transcription level and DNA copy number of Mdace were significantly higher in the resistant strain than in the susceptible strain. These results indicated that mutations combined with the up-regulation of Mdace might be essential in the housefly resistance to propoxur. Title: Complete metabolic study by dibutyl phthalate degrading Pseudomonas sp. DNB-S1 Yu H, Wang L, Lin Y, Liu W, Tuyiringire D, Jiao Y, Zhang L, Meng Q, Zhang Y Ref: Ecotoxicology & Environmental Safety, 194:110378, 2020 : PubMed ESTHER: Yu_2020_Ecotoxicol.Environ.Saf_194_110378 PubMedSearch: Yu 2020 Ecotoxicol.Environ.Saf 194 110378 PubMedID: 32146194 Abstract The primary purpose of this study was to systematically explore the complete metabolic pathway and tolerance mechanism of strain DNB-S1 to dibutyl phthalate (DBP), and the effect of DBP on energy metabolism of DNB-S1. Here, DNB-S1, a strain of Pseudomonas sp. that was highly effective in degrading DBP, was identified, and differentially expressed metabolites and metabolic networks of DBP were studied. The results showed that the differentially expressed metabolites were mainly aromatic compounds and lipid compounds, with only a few toxic intermediate metabolites. It speculated that phthalic acid, salicylic acid, 3-hydroxybenzoate acid, 3-Carboxy-cis, cis-muconate, fumarypyravate were intermediate metabolites of DBP. Their up-regulation indicated that there were two metabolic pathways in the degradation of DBP (protocatechuate pathway and gentisate pathway), which had been verified by peak changes at 290 nm, 320 nm, 330 nm, and 375 nm in the enzymatic method. Also, aspartate, GSH, and other metabolites were up-regulation, indicating that DNB-S1 had a high tolerance to DBP and maintained cell homeostasis, which was also one of the essential reasons to ensure the efficient degradation of DBP. Altogether, this study firstly proposed two pathways to degrade DBP and comprehensively explored the effect of DBP on the metabolic function of DNB-S1, which enriched the study of microbial metabolism of organic pollutants, and which provided a basis for the application of metabolomics. Title: Peraksine derivatives with potential anti-inflammatory activities from the stems of Rauvolfia vomitoria Zhan G, Miao R, Zhang F, Hao Y, Zhang Y, Khurm M, Zhang X, Guo Z Ref: Fitoterapia, :104704, 2020 : PubMed ESTHER: Zhan_2020_Fitoterapia__104704 PubMedSearch: Zhan 2020 Fitoterapia 104704 PubMedID: 32827693 Abstract Five new peraksine derivatives rauvomine C-G (1-5) along with four known analogues (6-9) were isolated from the stems of Rauvolfia vomitoria Afzel. (Apocynaceae). Structural determinations of the new monoterpene indole alkaloids were elucidated via comprehensive spectroscopic analyses and ECD calculations. Rauvomine C (1) with an unprecedented framework type represents the first example of C(18) peraksine-type nor-monoterpene indole alkaloid featuring a chlorine atom at C-16 and its plausible biosynthetic pathway was also proposed. All the isolates were evaluated for their anti-inflammatory, cytotoxic, and acetylcholinesterase inhibitory activities. Among them, the new framework alkaloid rauvomine C (1) showed significant anti-inflammatory activities on NO production in LPS-induced RAW264.7 mouse macrophages with IC(50) value of 10.76 muM. Additionally, peraksine-type alkaloids featuring pyran ring (5, 8, and 9) exhibited potential anti-inflammatory activities with IC(50) values ranging from 17.52 to 20.99 muM. Title: Chemical composition, antioxidant, antibacterial and cholinesterase inhibitory activities of three Juniperus species Zhang Y, Wu D, Kuang S, Qing M, Ma Y, Yang T, Wang T, Li D Ref: Nat Prod Res, 34:3531, 2020 : PubMed ESTHER: Zhang_2020_Nat.Prod.Res_34_3531 PubMedSearch: Zhang 2020 Nat.Prod.Res 34 3531 PubMedID: 30822132 Abstract The chemical composition, antioxidant, antibacterial and cholinesterase inhibitory activities of three Juniperus species were studied. The contents of total phenolic and 10 phenolic compounds were highest in Juniperus rigida Sieb.et Zucc., of which catechin and cumaric acid were the predominant phenolic compounds, but were lowest in Juniperus sibirica Burgsd. GC-MS analysis showed the highest contents of essential oils were in J. rigida (92.61%), followed by Juniperus formosana Hayata (87.30%) and J. sibirica (84.89%). The a-pinene was the most dominant compound in J. rigida (23.99%) and J. formosana (9.71%), however, it has not been detected in J. sibirica. Ethanol extracts showed the higher radical scavenging capacity in ABTS, FRAP and DPPH assays than essential oils. The essential oils and ethanol extracts of J.sibirica showed the strong antibacterial activity against Salmonella typhimurium and Escherichia coli. Three Juniperus species showed certain acetylcholinesterase and butyrylcholinesterase inhibitions and J. formosana showed better cholinesterase inhibitory. Title: Self-assembly of lipase hybrid nanoflowers with bifunctional Ca(2+) for improved activity and stability Zhang Y, Sun W, Elfeky NM, Wang Y, Zhao D, Zhou H, Wang J, Bao Y Ref: Enzyme Microb Technol, 132:109408, 2020 : PubMed ESTHER: Zhang_2020_Enzyme.Microb.Technol_132_109408 PubMedSearch: Zhang 2020 Enzyme.Microb.Technol 132 109408 PubMedID: 31731973 Gene_locus related to this paper: 9gamm-a0a1b1ijp3 Abstract Lipase ZC12, a cold-adapted lipase derived from Psychrobacter sp. ZY124, can be effectively activated by Ca(2+). Inspired by this significant property, we developed a novel immobilized lipase ZC12/Ca3(PO4)2 hybrid nanoflowers (LHNs). The LHNs have been characterized as a regular hierarchical flowerlike structure nanoflowers by scanning electron microscopy (SEM). Compared with free lipase ZC12, the LHNs exerted enhanced enzymatic activity of 206% and 2.31-fold in kcat/Km value, especially high specific activity at low temperature. After 7 successive cycles, the LHNs could still maintain its initial activity, demonstrating superior durability than the free lipase ZC12. Meanwhile, its stability basically kept unchanged in a wide range of temperature and pH. Finally, fructose laurate was transformed by the LHNs with 57.39% conversion rate which is twice as much as the free lipase. To sum up, these results validated that LHNs could emerge as an efficient immobilized lipase and possess the promising potential for practical applications. Title: Esterase-mediated spinosad resistance in house flies Musca domestica (Diptera: Muscidae) Zhang Y, Guo M, Ma Z, You C, Gao X, Shi X Ref: Ecotoxicology, 29:35, 2020 : PubMed ESTHER: Zhang_2020_Ecotoxicology_29_35 PubMedSearch: Zhang 2020 Ecotoxicology 29 35 PubMedID: 31749037 Gene_locus related to this paper: musdo-EST23aes07 Abstract Although esterase-mediated spinosad resistance has been proposed for several insects, the associated molecular mechanism remains poorly understood. In this study, we investigated the mechanism of esterase-based spinosad resistance in house flies using a susceptible strain (SSS) and a spinosad-resistant, near-isogenic line (N-SRS). Combined with the synergistic effect of DEF on spinosad in the N-SRS strain, decreased ali-esterase activity in the spinosad-resistant strain has implicated the involvement of mutant esterase in spinosad resistance in house flies. Examination of the carboxylesterase gene MdalphaE7 in the two strains revealed that four non-synonymous mutations (Trp(251)-Leu, Asp(273)-Glu, Ala(365)-Val, and Ile(396)-Val) may be associated with spinosad resistance in house flies. Single nucleotide polymorphism analysis further indicated a strong relationship between these four mutations and spinosad resistance. Moreover, quantitative real-time PCR revealed a female-linked MdalphaE7 expression pattern in the N-SRS strain, which may contribute to sex-differential spinosad resistance in house flies. Title: Overexpressed CES2 has prognostic value in CRC and knockdown CES2 reverses L-OHP-resistance in CRC cells by inhibition of the PI3K signaling pathway Zhang Y, Sun L, Sun Y, Chen Y, Wang X, Xu M, Chi P, Xu Z, Lu X Ref: Experimental Cell Research, :111856, 2020 : PubMed ESTHER: Zhang_2020_Exp.Cell.Res__111856 PubMedSearch: Zhang 2020 Exp.Cell.Res 111856 PubMedID: 31981591 Gene_locus related to this paper: human-CES2 Abstract CES-2 (carboxylesterase-2) belongs to the carboxylesterase gene family, which plays crucial roles in lipid mobilization and chemosensitivity to irinotecan. However, its role in chemosensitivity to oxaliplatin (L-OHP) remains unclear. Herein, L-OHP-resistant cells (HCT-116L and RKOL) were established by increasing the concentration of L-OHP. The results showed that CES2 expression was upregulated in L-OHP-resistant tissues and cells lines (P<0.01). Low expression of CES2 correlated with a better survival, and the results were further confirmed in the R2 platform: a biologist friendly web-based genomics analysis and visualization application. Downregulation of CES2 suppressed cell proliferation, induced apoptosis and reversed L-OHP resistance by medicating the PI3K signaling pathway in L-OHP-resistant cells. However, both PI3K inhibitor (LY294002) and activator (IGF-1) could not medicate CES2 expression. These findings indicated that CES2 may be utilized as a novel biomarker and therapeutic target for L-OHP resistance in CRC treatment. Title: Acupotomy Alleviates Energy Crisis at Rat Myofascial Trigger Points Zhang Y, Du NY, Chen C, Wang T, Wang LJ, Shi XL, Li SM, Guo CQ Ref: Evid Based Complement Alternat Med, 2020:5129562, 2020 : PubMed ESTHER: Zhang_2020_Evid.Based.Complement.Alternat.Med_2020_5129562 PubMedSearch: Zhang 2020 Evid.Based.Complement.Alternat.Med 2020 5129562 PubMedID: 32190087 Abstract The aim of this study was to determine the effects of acupotomy on energy crises in rat trigger points (TrPs) by measuring mechanical pain thresholds (MPTs) and levels of acetylcholinesterase (AChE), free sarcoplasmic calcium (Ca(2+)), adenosine 5'-triphosphate (ATP), adenosine 5'-monophosphate (AMP), substance P (SP), and calcitonin gene-related peptide (CGRP) in rat muscle TrP tissue. Male Sprague Dawley rats (n = 32) were randomly divided into four groups: control, TrP, acupotomy, and lidocaine injection. Enzyme-linked immunosorbent assays were used to measure AChE, and free sarcoplasmic Ca(2+) concentrations were determined by fluorescent staining with Fura-2 AM; high-performance liquid chromatography was used to measure ATP and AMP, and SP and CGRP were evaluated by immunohistochemistry. Compared with the control group, free sarcoplasmic Ca(2+), AMP, SP, and CGRP were higher in the model group, while MPT, AChE, and ATP were lower. Treatment with acupotomy or lidocaine injection reduced free sarcoplasmic Ca(2+), SP, and CGRP and increased MPTs and AChE levels compared with the model group. However, only acupotomy also led to decreased AMP and increased ATP levels relative to the model group. We conclude that acupotomy can alleviate energy crises at TrPs. Title: Constructing Cross-linked Nanofibrous Scaffold via Dual-Enzyme-Instructed Hierarchical Assembly Zhang S, Cortes W, Zhang Y Ref: Langmuir, :, 2020 : PubMed ESTHER: Zhang_2020_Langmuir__ PubMedSearch: Zhang 2020 Langmuir PubMedID: 32418429 Abstract To explore the potential of step-by-step assembly in the fabrication of biological materials, we designed and synthesized two peptide-based molecules for enzyme-instructed hierarchical assembly (EIHA). Upon the treatment of alkaline phosphatase (ALP), one molecule undergoes enzyme-instructed self-assembly (EISA) forming uniformed nanofibers. The other one that can self-assemble into vesicles undergoes enzyme-induced transformation of self-assembly (EITSA) converting vesicles into irregular aggregates upon the treatment of carboxylesterase (CES). Co-administration of two enzymes to a mixture of these two molecules in a stage-by-stage fashion leads to a physically knotted nanofibrous scaffold that is applicable as a nanostructured matrix for cell culture. Title: Total flavonoids of Selaginella pulvinata alleviates cognitive impairment in mice Zhang L, Zhang Y, Hou Y, Li H, Li C, Xin J, Zhou N, Li Q, Song Y, Zhang Z Ref: Biomed Rep, 13:8, 2020 : PubMed ESTHER: Zhang_2020_Biomed.Rep_13_8 PubMedSearch: Zhang 2020 Biomed.Rep 13 8 PubMedID: 32607237 Abstract Cognitive impairment (CI) refers to dysfunctional cognition, which encompasses a spectrum of disorders, ranging from mild cognitive impairment to dementia. Any factor that results in cortical damage may cause CI. Total flavonoids of Selaginella pulvinata (TFSP), have shown promising antioxidant and protective effects in animal models. In the present study, mice were intraperitoneally treated with scopolamine, sodium nitrite or 45% ethanol to induce memory impairment, and the effects were assessed using a step-down test. After performing the behavioural test, hippocampal sections were collected for anatomical analysis, and the brain and serum levels of memory-related molecules were evaluated. The results showed that TFSP improved memory in a mouse model of CI significantly. Serum data were consistent with the behavioural results: TFSP increased blood acetylcholine levels through modulation of the acetylcholinesterase and choline acetyltransferase levels. It also ameliorated oxidative stress in neurons, increasing superoxide dismutase, glutathione peroxidase and inhibiting nitric oxide synthase levels in the brain. These results suggest that TFSP may exhibit potential as a clinical treatment for neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and senile dementia. Title: Rapid bioluminescence assay for monitoring rat CES1 activity and its alteration by traditional Chinese medicines Zhang J, Wang D, Zou L, Xiao M, Zhang Y, Li Z, Yang L, Ge G, Zuo Z Ref: J Pharm Anal, 10:253, 2020 : PubMed ESTHER: Zhang_2020_J.Pharm.Anal_10_253 PubMedSearch: Zhang 2020 J.Pharm.Anal 10 253 PubMedID: 32612872 Abstract In traditional Chinese medicine herbs (TCM), including Radix Salviae Miltiorrhizae (Danshen), Radix Puerariae Lobatae (Gegen), Radix Angelicae Sinensis (Danggui), and Rhizoma Chuanxiong (Chuanxiong) are widely used for the prevention and treatment of cardiovascular diseases and also often co-administered with Western drugs as a part of integrative medicine practice. Carboxylesterase 1 (CES1) plays a pivotal role in the metabolisms of pro-drugs. Since (S)-2-(2-(6-dimethylamino)-benzothiazole)-4,5-dihydro-thiazole-4-carboxylate (NLMe) has recently been identified by us as a selective CES1 bioluminescent sensor, we developed a rapid method using this substrate for the direct measurement of CES1 activity in rats. This bioluminescence assay was applied to determine CES1 activity in rat tissues after a two-week oral administration of each of the four herbs noted above. The results demonstrated the presence of CES1 enzyme in rat blood and all tested tissues with much higher enzyme activity in the blood, liver, kidney and heart than that in the small intestine, spleen, lung, pancreas, brain and stomach. In addition, the four herbs showed tissue-specific effects on rat CES1 expression. Based on the CES1 biodistribution and its changes after treatment in rats, the possibility that Danshen, Gegen and Danggui might alter CES1 activities in human blood and kidney should be considered. In summary, a selective and sensitive bioluminescence assay was developed to rapidly evaluate CES1 activity and the effects of orally administered TCMs in rats. Title: Optimization of chemoenzymatic Baeyer-Villiger oxidation of cyclohexanone to sigma-caprolactone using response surface methodology Zhang Y, Jiang W, Lv K, Sun Y, Gao X, Zhao Q, Ren W, Wang F, Liu J Ref: Biotechnol Prog, 36:e2901, 2020 : PubMed ESTHER: Zhang_2020_Biotechnol.Prog_36_e2901 PubMedSearch: Zhang 2020 Biotechnol.Prog 36 e2901 PubMedID: 31465150 Abstract sigma-Caprolactone (sigma-CL) has attracted a great deal of attention and a high product concentration is of great significance for reducing production cost. The optimization of sigma-CL synthesis through chemoenzymatic Baeyer-Villiger oxidation mediated by immobilized Trichosporon laibacchii lipase was studied using response surface methodology (RSM). The yield of sigma-CL was 98.06% with about 1.2 M sigma-CL concentration that has a substantial increase mainly due to both better stability of the cross-linked immobilized lipase used and the optimum reaction conditions in which the concentration of cyclohexanone was 1.22 M, the molar ratio of cyclohexanone:urea hydrogen peroxide (UHP) was 1:1.3, and the reaction temperature was 56.5 degreesC. Based on our experimental results, it can be safely concluded that there are three reactions in this reaction system, not just two reactions, in which the third reaction is that the acetic acid formed reacts with UHP to form peracetic acid in situ catalyzed by the immobilized lipase. A quadratic polynomial model based on RSM experimental results was developed and the R(2) value of the equation is 0.9988, indicating that model can predict the experimental results with high precision. The experimental results also show that the molar ratio of cyclohexanone to UHP has very significant impact on the yield of sigma-CL (p < .0006). Title: Crystal structure and biochemical characterization of Striga hermonthica HYPO-SENSITIVE TO LIGHT 8 (ShHTL8) in strigolactone signaling pathway Zhang Y, Wang D, Shen Y, Xi Z Ref: Biochemical & Biophysical Research Communications, 523:1040, 2020 : PubMed ESTHER: Zhang_2020_Biochem.Biophys.Res.Commun_523_1040 PubMedSearch: Zhang 2020 Biochem.Biophys.Res.Commun 523 1040 PubMedID: 31973817 Gene_locus related to this paper: strhe-ShHTL8 Abstract Striga is a parasitic weed that disperses easily, and its seeds can persist in the soil for many years, presenting long-term threats to food security. If SLs stimulate the seed germination of root parasitic weeds before planting, weeds will wither due to no host. Therefore, it is necessary to determine the mechanism of strigolactone (SL) signaling in Striga to reduce the impacts of this parasitic weed. Striga has eleven different kinds of HYPO-SENSITIVE to LIGHT (ShHTL) hydrolases. Different ShHTL hydrolases exhibit distinct responses to SLs, despite these ShHTLs exhibiting more than 60% sequence identity. Currently, structural information is available for only five ShHTL proteins, and more structural information is needed to design Striga germination stimulants or inhibitors. In this paper, we report the crystal structure of ShHTL8, which is determined at a resolution of 1.4 A. Scanning fluorimetry and HPLC assays indicate that L125, M147, M154 and I194 are important binding sites, and of which L125 may act as a key holder involved in the catalytic reaction. Additionally, the corresponding residue, Y124 of ShHTL1 and F135 of ShHTL2 also play a significant role in the substrate recognition. Title: Directed evolution of Aspergillus oryzae lipase for the efficient resolution of (R,S)-ethyl-2-(4-hydroxyphenoxy) propanoate Zhang M, Li Q, Lan X, Li X, Zhang Y, Wang Z, Zheng J Ref: Bioprocess Biosyst Eng, 43:2131, 2020 : PubMed ESTHER: Zhang_2020_Bioprocess.Biosyst.Eng_43_2131 PubMedSearch: Zhang 2020 Bioprocess.Biosyst.Eng 43 2131 PubMedID: 32959146 Gene_locus related to this paper: aspor-TGLA Abstract Aspergillus oryzae lipase (AOL) is a potential biocatalyst for industrial application. In this study, a mutant lipase AOL-3(F38N/V230R) was screened through two rounds of directed evolution, resulting in a fourfold increase in lipase activity, and threefold in catalytic efficiency (k(cat)/K(m)), while maintaining its excellent stereoselectivity. AOL-3(F38N/V230R) enzyme activity was maximum at pH 7.5 and also at 40 degreesC. And compared with wild-type AOL-3, AOL-3(F38N/V230R) preferentially hydrolyzed the fatty acid ethyl ester carbon chain length from C4 to C6-C10. In the same catalytic reaction conditions, the conversion of (R,S)-ethyl-2-(4-hydroxyphenoxy) propanoate ((R,S)-EHPP) by AOL-3(F38N/V230R) can be increased 169.7% compared to the original enzyme. The e.e.(s) of (R,S)-EHPP achieved 99.4% and conversion about 50.2% with E value being 829.0. Therefore, AOL-3(F38N/V230R) was a potential biocatalyst for obtaining key chiral compounds for aryloxyphenoxy propionate (APP) herbicides. Title: Structures and esterolytic reactivity of novel binuclear copper(ii) complexes with reduced l-serine Schiff bases as mimic carboxylesterases Zhang Q, Shu J, Zhang Y, Xu Z, Yue J, Liu X, Xu B, Chen Z, Jiang W Ref: Dalton Trans, 49:10261, 2020 : PubMed ESTHER: Zhang_2020_Dalton.Trans_49_10261 PubMedSearch: Zhang 2020 Dalton.Trans 49 10261 PubMedID: 32672259 Abstract Three novel binuclear copper(ii) complexes with reduced l-serine Schiff bases were synthesized and their structures were analyzed with single-crystal X-ray diffraction and DFT calculations. The crystal data revealed that all of these binuclear complexes are chiral. Both 5-halogenated (bromo- and chloro-) binuclear complexes exhibit right-handed helix structural character. Interestingly, the 5-methyl-containing analogue has a two-dimensional pore structure. In this paper, the esterolysis reactivity of the as-prepared complexes shows that in the hydrolysis of p-nitrophenyl acetate (PNPA) these three complexes provide 26, 18, 40-fold rate acceleration as compared to the spontaneous hydrolysis of PNPA at pH 7.0, respectively. Under selected conditions, in excess buffered aqueous solution a rate enhancement by three orders of magnitude was observed for the catalytic hydrolysis of another carboxylic ester, p-nitrophenyl picolinate (PNPP). These complexes efficiently promoted PNPP hydrolysis in a micellar solution of cetyltrimethylammonium bromide (CTAB), giving rise to a rate enhancement in excess of four orders of magnitude, which is approximately 2.0-3.2 times higher than that in the buffer. Title: Genome assembly of wild tea tree DASZ reveals pedigree and selection history of tea varieties Zhang W, Zhang Y, Qiu H, Guo Y, Wan H, Zhang X, Scossa F, Alseekh S, Zhang Q and Wen W <11 more author(s)> Zhang W, Zhang Y, Qiu H, Guo Y, Wan H, Zhang X, Scossa F, Alseekh S, Zhang Q, Wang P, Xu L, Schmidt MH, Jia X, Li D, Zhu A, Guo F, Chen W, Ni D, Usadel B, Fernie AR, Wen W (- 11) Ref: Nat Commun, 11:3719, 2020 : PubMed ESTHER: Zhang_2020_Nat.Commun_11_3719 PubMedSearch: Zhang 2020 Nat.Commun 11 3719 PubMedID: 32709943 Gene_locus related to this paper: camsi-a0a7j7g2i2 Abstract Wild teas are valuable genetic resources for studying domestication and breeding. Here we report the assembly of a high-quality chromosome-scale reference genome for an ancient tea tree. The further RNA sequencing of 217 diverse tea accessions clarifies the pedigree of tea cultivars and reveals key contributors in the breeding of Chinese tea. Candidate genes associated with flavonoid biosynthesis are identified by genome-wide association study. Specifically, diverse allelic function of CsANR, CsF3'5'H and CsMYB5 is verified by transient overexpression and enzymatic assays, providing comprehensive insights into the biosynthesis of catechins, the most important bioactive compounds in tea plants. The inconspicuous differentiation between ancient trees and cultivars at both genetic and metabolic levels implies that tea may not have undergone long-term artificial directional selection in terms of flavor-related metabolites. These genomic resources provide evolutionary insight into tea plants and lay the foundation for better understanding the biosynthesis of beneficial natural compounds. Title: Voacafrines A-N, aspidosperma-type monoterpenoid indole alkaloids from Voacanga africana with AChE inhibitory activity Zhao Q, Zhu WT, Ding X, Huo ZQ, Donkor PO, Adelakun TA, Hao XJ, Zhang Y Ref: Phytochemistry, 181:112566, 2020 : PubMed ESTHER: Zhao_2020_Phytochemistry_181_112566 PubMedSearch: Zhao 2020 Phytochemistry 181 112566 PubMedID: 33197743 Abstract Fourteen undescribed monoterpenoid indole alkaloids, voacafrines A-N, along with 7 known monoterpenoid indole alkaloids were isolated from the seeds of Voacanga africana Stapf. Among them, voacafrines A-G were aspidosperma-aspidosperma type bisindole alkaloids, while voacafrines H-N were aspidosperma-type monomers. Their structures and absolute configurations were elucidated by a combination of NMR, MS, and ECD analyses. Voacafrines A-C were characterized by an acetonyl moiety at C-5', while voacafrine H possessed a methoxymethyl moiety at C-14 within aspidosperma-type alkaloids. The acetylcholinesterase (AChE) inhibitory activity and cytotoxicity of voacafrines A-N were evaluated. Voacafrines A-C and E-G were bisindole alkaloids that exhibited AChE inhibitory activity with IC(50) values of 4.97-33.28 M, while voacafrines I and J were monomers that showed cytotoxicity against several human cancer cell lines with IC(50) values of 4.45-7.49 M. Title: Immobilization of Lipozyme TL 100L for methyl esterification of soybean oil deodorizer distillate Zheng J, Wei W, Wang S, Li X, Zhang Y, Wang Z Ref: 3 Biotech, 10:51, 2020 : PubMed ESTHER: Zheng_2020_3.Biotech_10_51 PubMedSearch: Zheng 2020 3.Biotech 10 51 PubMedID: 32002342 Gene_locus related to this paper: humla-1lipa Abstract An immobilization method for binding cross-linked enzyme aggregates of Lipozyme TL 100L on macroporous resin NKA (CLEA-TLL@NKA) was developed in this study. The esterification activity of CLEA-TLL@NKA reached 6.4 U/mg. The surface structure of immobilized lipase was characterized by scanning electron microscopy. Methyl esterification reaction of soybean oil deodorizer distillate (SODD) was catalyzed by CLEA-TLL@NKA, which the conversion rate reached 98% and its activity retained over 90% after 20 batches of reaction. Compared with the commercial enzyme Lipozyme TLIM, half-life (t 1/2) of CLEA-TLL@NKA increased by 25 times and the catalytic activity increased by approximate 10 times. Thus, CLEA-TLL@NKA had high catalytic activity, good operational stability, and potential industrial application in the field of oil processing. Title: Dp44mT, an iron chelator, suppresses growth and induces apoptosis via RORA-mediated NDRG2-IL6/JAK2/STAT3 signaling in glioma Zhou J, Jiang Y, Zhao J, Zhang H, Fu J, Luo P, Ma Y, Zou D, Gao H and Jing Z <2 more author(s)> Zhou J, Jiang Y, Zhao J, Zhang H, Fu J, Luo P, Ma Y, Zou D, Gao H, Hu J, Zhang Y, Jing Z (- 2) Ref: Cell Oncol (Dordr), 43:461, 2020 : PubMed ESTHER: Zhou_2020_Cell.Oncol.(Dordr)_43_461 PubMedSearch: Zhou 2020 Cell.Oncol.(Dordr) 43 461 PubMedID: 32207044 Gene_locus related to this paper: human-NDRG2 Abstract PURPOSE: The iron-chelating agent di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) has been found to inhibit cell growth and to induce apoptosis in several human cancers. However, its effects and mechanism of action in glioma are unknown. METHODS: Human glioma cell line LN229 and patient-derived glioma stem cells GSC-42 were applied for both in vitro and in vivo xenograft nude mouse experiments. The anti-tumor effects of Dp44mT were assessed using MTS, EdU, TUNEL, Western blotting, qRT-PCR, luciferase reporter, chromatin immunoprecipitation and immunohistochemical assays. RESULTS: We found that Dp44mT can upregulate the expression of the anti-oncogene N-myc downstream-regulated gene (NDRG)2 by directly binding to and activating the RAR-related orphan receptor (ROR)A. In addition, we found that NDRG2 overexpression suppressed inflammation via activation of interleukin (IL)-6/Janus kinase (JAK)2/signal transducer and activator of transcription (STAT)3 signaling. CONCLUSIONS: Our data indicate that Dp44mT may serve as an effective drug for the treatment of glioma by targeting RORA and enhancing NDRG2-mediated IL-6/JAK2/STAT3 signaling. Title: Preventive Effects of Different Fermentation Times of Shuidouchi on Diphenoxylate-Induced Constipation in Mice Chen L, Zhang J, Suo H, Wang W, Wang H, Zhang Y, Hu Q, Zhao X, Li J Ref: Foods, 8:, 2019 : PubMed ESTHER: Chen_2019_Foods_8_ PubMedSearch: Chen 2019 Foods 8 PubMedID: 30832248 Abstract This study compares the prevention effects of Shuidouchi with different fermentation times on constipation in mice. Shuidouchi is a short-time fermented soybean product. By improving its processing technology, it can incur better biological activity and become a health food. The Shuidouchi-treated mice were evaluated using constipation-related kits, quantitative polymerase chain reaction (qPCR), and Western blot assays. After the mice were fed 72-h-fermented Shuidouchi (72-SDC) for 9 d, the defecation time to excrete the first black stool was lower than that of the control and 24-SDC and 48-SDC groups, but was much higher than that of the normal group. The gastrointestinal (GI) transit of the small intestine of the 72-SDC group was higher than that of the control and the 24-SDC and 48-SDC groups, but lower that of the normal group. Meanwhile, 72-SDC could significantly increase the levels of ghrelin, endothelin-1 (ET-1), vasoactive intestinal peptide (VIP), and acetylcholinesterase (AchE) in the serum of constipated mice compared to the levels in mice in the control group. Moreover, 72-SDC could raise c-Kit, stem cell factor (SCF), glial cell-derived neurotrophic factor (GNDF), neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) and protein expression levels, and reduce transient receptor potential cation channel subfamily V member 1 (TRPV1) and inducible nitric oxide synthase (iNOS) expression levels in small-intestinal tissue compared to the levels in the control group. Meanwhile, 72-SDC also raised ghrelin mRNA expression in gastric tissue and transient receptor potential ankyrin 1 (TRPA1) mRNA expression in colon tissue compared to the control group mice; these effects were stronger than those of 24-SDC and 48-SDC. Shuidouchi has good preventative effects on constipation and performs best when fermented for at least 72 h. Title: Cell-Membrane-Cloaked Oil Nanosponges Enable Dual-Modal Detoxification Chen Y, Zhang Y, Zhuang J, Lee JH, Wang L, Fang RH, Gao W, Zhang L Ref: ACS Nano, 13:7209, 2019 : PubMed ESTHER: Chen_2019_ACS.Nano_13_7209 PubMedSearch: Chen 2019 ACS.Nano 13 7209 PubMedID: 31117372 Abstract The lack of pharmaceutical antidotes for deadly toxicants has motivated tremendous research interests in seeking synthetic nanoscavengers to absorb and neutralize harmful biological or chemical agents. Herein, we report a cell-membrane-cloaked oil nanosponge formulation capable of dual-modal detoxification. The biomimetic oil nanosponge consists of an olive oil nanodroplet wrapped by a red blood cell membrane. In such a construct, the oil core can nonspecifically soak up toxicants through physical partition and the cell membrane shell can specifically absorb and neutralize toxicants through biological binding. The dual-modal detoxification capability of the oil nanosponges was validated using three distinct organophosphates (OPs), including paraoxon, diisopropyl fluorophosphate, and dichlorvos. By inhibiting acetylcholinesterase, OPs cause the accumulation of acetylcholine, which leads to neuromuscular disorders and even death. In mouse models of OP poisoning, the oil nanosponges reduced clinical signs of OP intoxication, lowered OP concentration in tissues, and greatly enhanced mouse survival in both the therapeutic regimen and the prophylactic regimen. Overall, oil nanosponges combine the merits of both cell membrane and oil nanodroplets for safe and effective detoxification, which also serve as a prototype of multimodal detoxification platforms. Title: Design, Synthesis, and Evaluation of Reversible and Irreversible Monoacylglycerol Lipase Positron Emission Tomography (PET) Tracers Using a Tail Switching Strategy on a Piperazinyl Azetidine Skeleton Chen Z, Mori W, Deng X, Cheng R, Ogasawara D, Zhang G, Schafroth MA, Dahl K, Fu H and Liang SH <24 more author(s)> Chen Z, Mori W, Deng X, Cheng R, Ogasawara D, Zhang G, Schafroth MA, Dahl K, Fu H, Hatori A, Shao T, Zhang Y, Yamasaki T, Zhang X, Rong J, Yu Q, Hu K, Fujinaga M, Xie L, Kumata K, Gou Y, Chen J, Gu S, Bao L, Wang L, Collier TL, Vasdev N, Shao Y, Ma JA, Cravatt BF, Fowler C, Josephson L, Zhang MR, Liang SH (- 24) Ref: Journal of Medicinal Chemistry, 62:3336, 2019 : PubMed ESTHER: Chen_2019_J.Med.Chem_62_3336 PubMedSearch: Chen 2019 J.Med.Chem 62 3336 PubMedID: 30829483 Gene_locus related to this paper: human-MGLL Abstract Monoacylglycerol lipase (MAGL) is a serine hydrolase that degrades 2-arachidonoylglycerol (2-AG) in the endocannabinoid system (eCB). Selective inhibition of MAGL has emerged as a potential therapeutic approach for the treatment of diverse pathological conditions, including chronic pain, inflammation, cancer, and neurodegeneration. Herein, we disclose a novel array of reversible and irreversible MAGL inhibitors by means of "tail switching" on a piperazinyl azetidine scaffold. We developed a lead irreversible-binding MAGL inhibitor 8 and reversible-binding compounds 17 and 37, which are amenable for radiolabeling with (11)C or (18)F. [(11)C]8 ([(11)C]MAGL-2-11) exhibited high brain uptake and excellent binding specificity in the brain toward MAGL. Reversible radioligands [(11)C]17 ([(11)C]PAD) and [(18)F]37 ([(18)F]MAGL-4-11) also demonstrated excellent in vivo binding specificity toward MAGL in peripheral organs. This work may pave the way for the development of MAGL-targeted positron emission tomography tracers with tunability in reversible and irreversible binding mechanisms. Title: Design, Synthesis, and Evaluation of (18)F-Labeled Monoacylglycerol Lipase Inhibitors as Novel Positron Emission Tomography Probes Chen Z, Mori W, Fu H, Schafroth MA, Hatori A, Shao T, Zhang G, Van RS, Zhang Y and Liang SH <17 more author(s)> Chen Z, Mori W, Fu H, Schafroth MA, Hatori A, Shao T, Zhang G, Van RS, Zhang Y, Hu K, Fujinaga M, Wang L, Belov V, Ogasawara D, Giffenig P, Deng X, Rong J, Yu Q, Zhang X, Papisov MI, Shao Y, Collier TL, Ma JA, Cravatt BF, Josephson L, Zhang MR, Liang SH (- 17) Ref: Journal of Medicinal Chemistry, 62:8866, 2019 : PubMed ESTHER: Chen_2019_J.Med.Chem_62_8866 PubMedSearch: Chen 2019 J.Med.Chem 62 8866 PubMedID: 31518130 Inhibitor(s) related to this paper: PF-06795071 Abstract Dysfunction of monoacylglycerol lipase (MAGL) is associated with several psychopathological disorders, including drug addiction and neurodegenerative diseases. Herein we design, synthesize, and evaluate several irreversible fluorine-containing MAGL inhibitors for positron emission tomography (PET) ligand development. Compound 6 (identified from a therapeutic agent) was advanced for (18)F-labeling via a novel spirocyclic iodonium ylide (SCIDY) strategy, which demonstrated high brain permeability and excellent specific binding. This work supports further development of novel (18)F-labeled MAGL PET probes. Title: The effect of anti-dementia drugs on Alzheimer disease-induced cognitive impairment: A network meta-analysis Cui CC, Sun Y, Wang XY, Zhang Y, Xing Y Ref: Medicine (Baltimore), 98:e16091, 2019 : PubMed ESTHER: Cui_2019_Medicine.(Baltimore)_98_e16091 PubMedSearch: Cui 2019 Medicine.(Baltimore) 98 e16091 PubMedID: 31277107 Abstract BACKGROUND: Cognitive impairment is a principal manifestation of Alzheimer disease (AD). To provide a clinical reference for the treatment of AD, a network meta-analysis (NMA) was performed to evaluate the effects of different anti-dementia drugs on the cognitive impairment exhibited by patients with AD. METHODS: Relevant randomized controlled trials are found through the Pubmed database, Web of Science, Clinical Trials, Embase, Cohranne library, Chinese National Knowledge Infrastructure database, CBM databases, and Wanfang among others. A total of 33 articles were collected, with the earliest document collected having been published in February 2017. The included reports were screened for quality of papers by using strict inclusion and exclusion criteria. All analyses were based on previously published studies reporting de-identified data; thus, no ethical approval or patient consent were required. The Mini-Mental State Examination scores informed the classification of the 33 articles into a mild subgroup, which featured 11 articles, and 12 drugs (besides a placebo); a moderate subgroup, which featured 17 articles and 15 drugs (besides a placebo); and a severe subgroup, which featured 5 articles and 3 drugs (besides a placebo). RESULTS: While donepezil, galanthamine, and huperzine demonstrated the highest efficacy in the mild cognitive dysfunction subgroup (mean difference = 5.2, 2.5, and 2.4, respectively). Donepezil, huperzine A, and rivastigmine achieved the most significant effects in the moderate cognitive dysfunction subgroup (MD = 3.8, 2.9, and 3.0 respectively). In the severe subgroup, donepezil was demonstrably superior to memantine. Donepezil was thus found to effectively address cognitive impairment in patients with AD regardless of the degrees of cognitive decline. CONCLUSIONS: Evaluation of the clinically common anti-dementia drugs using NMA affirmed the utility of cholinesterase inhibitors, especially donepezil, in alleviating cognitive dysfunction of patients with AD. This study may therefore help to inform the clinical selection of pharmacotherapeutic interventions addressing cognitive dysfunction in patients with AD. Title: In vivo and in vitro metabolism and pharmacokinetics of cholinesterase inhibitor deoxyvasicine from aerial parts of Peganum harmala Linn in rats via UPLC-ESI-QTOF-MS and UPLC-ESI-MS/MS Deng G, Liu W, Ma C, Rong X, Zhang Y, Wang Y, Wu C, Cao N, Ding W and Wang C <2 more author(s)> Deng G, Liu W, Ma C, Rong X, Zhang Y, Wang Y, Wu C, Cao N, Ding W, Guan H, Cheng X, Wang C (- 2) Ref: J Ethnopharmacol, 236:288, 2019 : PubMed ESTHER: Deng_2019_J.Ethnopharmacol_236_288 PubMedSearch: Deng 2019 J.Ethnopharmacol 236 288 PubMedID: 30872168 Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Aerial parts of Peganum harmala Linn are a Uighur traditional medicinal herb in China used to treat amnesia, bronchial asthma, and cough. Deoxyvasicine (DVAS), a potent cholinesterase inhibitor exhibiting anti-senile dementia activity, is one of the chief active ingredients in aerial parts of P. harmala and plays a key role in mediating the pharmacological effects of P. harmala. However, the metabolic profiling and in vivo pharmacokinetic characteristics of DVAS still remain unknown. AIM OF THE STUDY: The aim of this present study was to investigate the metabolism and pharmacokinetic properties of DVAS in rats by using ultra-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC-ESI-QTOF-MS) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-ESI-MS/MS) method. MATERIALS AND METHODS: The metabolic profiling of DVAS was evaluated in vitro and in vivo by rat liver microsomes (RLMs) incubation and by rat bio-specimens, such as urine, feces, plasma, and bile, after the oral administration of 45mg/kg DVAS. An efficient and sensitive UPLC-ESI-MS/MS method was developed and validated to simultaneously determine DVAS and its major four metabolites, namely, vasicine, deoxyvasicinone, vasicinone, and 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazolin-3-beta-D-glucuronide in rat plasma. For pharmacokinetic studies, 32 Sprague-Dawley rats were randomly divided into four groups, namely, intravenous dosage group (2mg/kg DVAS) and three oral dosage groups (5, 15, and 45mg/kg DVAS). In addition, the activity of the components in plasma after intravenous administration of DVAS was evaluated by in vitro anti-butyrylcholinesterase (BChE) assays. RESULTS: A total of 23 metabolites were found in RLMs, plasma, urine, feces, and bile by UPLC-ESI-QTOF-MS. The metabolic pathway of DVAS in vivo and in vitro mainly involved hydroxylation, dehydrogenation, acetylation, methylation, glucuronidation, and O-sulphate conjugation, and the C-3 and C-9 sites were the main metabolic soft spots. All 23 metabolites were detected in the urine sample, and 13, 8, 22, and 6 metabolites were identified from rat feces, plasma, bile, and RLMs, respectively. The standard curves of DVAS and four metabolites in rat plasma showed good linearity in the concentration range of 0.82-524.00ng/mL with acceptable selectivity, precision, accuracy, recovery, and stability. DVAS exhibited linear dose-proportional pharmacokinetics at doses of 5, 15, and 45mg/kg after oral administration, and the average oral absolute bioavailability of DVAS was 47.46%. The in vitro anti-BChE assays implied that the inhibitive activities were mainly due to the different concentrations of prototype DVAS. CONCLUSIONS: DVAS can be rapidly absorbed and excreted by blood, and it is also extensively metabolized in vivo, and the anti-BChE activity in blood is mainly attributed to DVAS. These findings can lay a foundation for new drug development for DVAS. Title: Resistance to pyrethroid and organophosphate insecticides, and the geographical distribution and polymorphisms of target-site mutations in voltage-gated sodium channel and acetylcholinesterase 1 genes in Anopheles sinensis populations in Shanghai, China Fang Y, Shi WQ, Wu JT, Li YY, Xue JB, Zhang Y Ref: Parasit Vectors, 12:396, 2019 : PubMed ESTHER: Fang_2019_Parasit.Vectors_12_396 PubMedSearch: Fang 2019 Parasit.Vectors 12 396 PubMedID: 31399130 Abstract BACKGROUND: In the final phase of China's national programme to eliminate malaria by 2020, it is vitally important to monitor the resistance of malaria vectors for developing effective vector control strategies. In 2017 Shanghai declared that it had eliminated malaria; however, the insecticide resistance status of the primary malaria vector Anopheles sinensis remains unknown. METHODS: We examined the pyrethroid and organophosphate resistance of An. sinensis via a bioassay of two populations from the Chongming District of Shanghai. The voltage-gated sodium channel (VGSC) and acetylcholinesterase 1 (ace-1) genes were partially sequenced to examine the association between resistance phenotype and target site genotype. In addition, the geographical distribution, polymorphism and genotype frequencies of insecticide resistance genes were examined using samples collected during routine mosquito surveillance in 2016 and 2017 from Chongming, Songjiang, Jiading and Qingpu Districts. RESULTS: In Chongming District, the An. sinensis population near Dongtan National Nature Reserve showed resistance to pyrethroids, sensitivity to organophosphate, no knockdown resistance (kdr) mutations in the VGSC gene, and a low frequency (1.71%) of the ace-1 119S allele. An An. sinensis population near the Chongming central area (CM-Xinhe population) showed high resistance to pyrethroids and organophosphates and high frequencies of kdr 1014F and 1014C (80.73%) and ace-1 119S (85.98%) alleles. A significant association was detected between the homozygous kdr mutation 1014F/1014F and pyrethroid resistance in the CM-Xinhe population, indicating that the kdr mutation is probably recessive. Eight kdr genotypes with 1014F and 1014C substitutions were detected in the four surveyed districts of Shanghai. TTT and GGC/AGC were the dominant kdr allele and ace-1 genotype, respectively, and were prevalent in most Shanghai An. sinensis populations. CONCLUSIONS: On the basis of our assessment of insecticide resistance gene mutations in Shanghai, we identified a kdr mutation-free population in Chongming Dongtan. However, high frequencies of target-site mutations of insecticide resistance genes were observed in most areas of Shanghai. Bioassays of An. sinensis populations in the central Chongming District indicated the high insecticide resistance status of An. sinensis populations in Shanghai. We accordingly recommend a restriction on insecticide usage and development of effective integrated pest/vector management interventions to support disease control efforts. Title: Study on the Multitarget Synergistic Effects of Kai-Xin-San against Alzheimer's Disease Based on Systems Biology Guo S, Wang J, Wang Y, Zhang Y, Bi K, Zhang Z, Li Q Ref: Oxid Med Cell Longev, 2019:1707218, 2019 : PubMed ESTHER: Guo_2019_Oxid.Med.Cell.Longev_2019_1707218 PubMedSearch: Guo 2019 Oxid.Med.Cell.Longev 2019 1707218 PubMedID: 31976026 Abstract Kai-Xin-San (KXS), a classical Chinese traditional prescription, was widely applied in the treatment of Alzheimer's disease (AD), while its functional mechanisms still remain unclear. By using systems biology approaches at animal, cellular, and molecular levels, the improvement of KXS on cognitive impairment was achieved by inhibiting abnormal acetylcholinesterase. The function on the nerve skeleton was performed by regulating the Tau phosphorylation pathway. Its antioxidant, anti-inflammatory, and antiapoptotic effects by modulating the aberrant upregulation of ROS, proinflammatory factors, and apoptosis-related proteins in the brain were studied to reveal the synergistic therapeutic efficacy of KXS. Then, formula dismantling in vitro indicated that ginseng was the principal herb, whereas three other herbs served adjuvant roles to achieve the best effect. After that, the in vivo analysis of components into plasma and brain of AD rats showed that 8 of 23 components in blood and 4 of 10 components in brain were from ginseng, respectively, further verifying the principal status of ginseng and the synergistic effects of the formula. Thus, the anti-AD effects of KXS were achieved by multitargets and multichannels. The systems biology approaches presented here provide a novel way in traditional herbal medicine research. Title: A transcriptomics-based analysis of the toxicity mechanisms of gabapentin to zebrafish embryos at realistic environmental concentrations He Y, Li X, Jia D, Zhang W, Zhang T, Yu Y, Xu Y, Zhang Y Ref: Environ Pollut, 251:746, 2019 : PubMed ESTHER: He_2019_Environ.Pollut_251_746 PubMedSearch: He 2019 Environ.Pollut 251 746 PubMedID: 31121539 Abstract Gabapentin (GPT) has become an emerging contaminant in aquatic environments due to its wide application in medical treatment all over the world. In this study, embryos of zebrafish were exposed to gabapentin at realistically environmental concentrations, 0.1mug/L and 10mug/L, so as to evaluate the ecotoxicity of this emergent contaminant. The transcriptomics profiling of deep sequencing was employed to illustrate the mechanisms. The zebrafish (Danio rerio) embryo were exposed to GPT from 12 hpf to 96 hpf resulting in 136 and 750 genes differentially expressed, respectively. The results of gene ontology (GO) analysis and the Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis illustrated that a large amount of differentially expressed genes (DEGs) were involved in the antioxidant system, the immune system and the nervous system. RT-qPCR was applied to validate the results of RNA-seq, which provided direct evidence that the selected genes involved in those systems mentioned above were all down-regulated. Acetylcholinesterase (AChE), lysozyme (LZM) and the content of C-reactive protein (CRP) were decreased at the end of exposure, which is consistent with the transcriptomics results. The overall results of this study demonstrate that GPT simultaneously affects various vital functionalities of zebrafish at early developmental stage, even at environmentally relevant concentrations. Title: Alkaloids from the Branches and Leaves of Elaeocarpus angustifolius Hong W, Zhang Y, Yang J, Xia MY, Luo JF, Li XN, Wang YH, Wang JS Ref: Journal of Natural Products, 82:3221, 2019 : PubMed ESTHER: Hong_2019_J.Nat.Prod_82_3221 PubMedSearch: Hong 2019 J.Nat.Prod 82 3221 PubMedID: 31736307 Abstract Nine new alkaloids, (+)-1, (-)-1, 2, (+)-3, (-)-3, and 4-7, along with five known compounds (8-12), were obtained from the branches and leaves of Elaeocarpus angustifolius. The alkaloids were structurally characterized by NMR and MS data. The absolute configurations of (+)-1, (-)-1, (+)-3, and (-)-3 were determined by comparing their experimental and computed electronic circular dichroism spectra. (+/-)-8,9-Dehydroelaeocarpine (5), (+/-)-9-epielaeocarpine cis-N-oxide trifluoroacetate (6), and (+/-)-elaeocarpine trifluoroacetate (9) exerted weak inhibitory activities against butyrylcholinesterase with IC50 values of 39, 29, and 35 muM, respectively, while that of tacrine, the positive control, was 0.07 +/- 0.01 muM. This is the first report of the cholinesterase inhibitory activities of Elaeocarpus alkaloids. Title: Evaluation of the cholinesterase activity of a potential therapeutic cocaine esterase for cocaine overdose Hou S, Zhang Y, Zhu Y, Zhang C, Kong Y, Chen X, Chen R, Yin X, Xie T Ref: Drug Alcohol Depend, 202:168, 2019 : PubMed ESTHER: Hou_2019_Drug.Alcohol.Depend_202_168 PubMedSearch: Hou 2019 Drug.Alcohol.Depend 202 168 PubMedID: 31352306 Abstract BACKGROUND: Cocaine is a commonly abused drug and there is no approved medication specifically to treat its addiction or overdose. Bacterial cocaine esterase (CocE)-derived RBP-8000 is currently under clinical development for cocaine overdose treatment. It is proven to be effective for human use to accelerate cocaine metabolism into physiologically inactive products. Besides cocaine, RBP-8000 may hydrolyze the neurotransmitter acetylcholine (ACh), however, no study has reported its cholinesterase activity. The present study aims to examine RBP-8000's cholinesterase activity and substrate selectivity to address the potential concern that this enzyme therapy might produce cholinergic side-effects. METHODS: Both computational modeling and experimental kinetic analysis were carried out to characterize the potential cholinesterase activity of RBP-8000. Substrates interacting with RBP-8000 were modeled for their enzyme-substrate binding complexes. In vitro enzymatic kinetic parameters were measured using Ellman's colorimetric assay and analyzed by Michaelis-Menten kinetics. RESULTS: It is the first demonstration that RBP-8000 catalyzes the hydrolysis of acetylthiocholine (ATC). However, its catalytic efficiency (kcat/KM) against ATC is 1000-fold and 5000-fold lower than it against cocaine at 25 degrees C and 37 degrees C, respectively, suggesting RBP-8000 has the desired substrate selectivity for cocaine over ACh. CONCLUSION: Given the fact that clinically relevant dose of RBP-8000 displays insignificant cholinesterase activity relative to endogenous cholinesterases in human, administration of RBP-8000 is unlikely to produce any significant cholinergic side-effects. This study provides supplemental evidences in support of further development of RBP-8000 towards a clinically used pharmacotherapy for cocaine overdose. Title: Synthesis and biological evaluation of 3-(4-aminophenyl)-coumarin derivatives as potential anti-Alzheimer's disease agents Hu YH, Yang J, Zhang Y, Liu KC, Liu T, Sun J, Wang XJ Ref: J Enzyme Inhib Med Chem, 34:1083, 2019 : PubMed ESTHER: Hu_2019_J.Enzyme.Inhib.Med.Chem_34_1083 PubMedSearch: Hu 2019 J.Enzyme.Inhib.Med.Chem 34 1083 PubMedID: 31117844 Abstract The work is focused on the design of drugs that prevent and treat Alzheimer's disease (AD) and its complications. A series of 3-(4-aminophenyl)-coumarin derivatives designed, synthesised, fully characterised and evaluated in vitro/vivo. The biological assay experiments showed that some compounds displayed a clearly selective inhibition for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Among all compounds, compound 4m exhibited the highest AChE inhibition with an IC50 value of 0.091 +/- 0.011 microM and compound 4k exhibited the highest BuChE inhibition with an IC50 value of 0.559 +/- 0.017 microM. A zebrafish behaviour analyser (Zebrobox) was used to determine the behavioural effects of the active compound on the movement distance of the aluminium chloride-induced zebrafish. Compound 4m offered a potential drug design concept for the development of therapeutic or preventive agents for AD and its complications. Title: Design, synthesis, and evaluation of genipin derivatives for the treatment of Alzheimer's Disease Huang W, Wang Y, Li J, Zhang Y, Ma X, Zhu P Ref: Chemical Biology Drug Des, 93:110, 2019 : PubMed ESTHER: Huang_2019_Chem.Biol.Drug.Des_93_110 PubMedSearch: Huang 2019 Chem.Biol.Drug.Des 93 110 PubMedID: 29543387 Abstract Twenty-two novel genipin derivatives have been designed, synthesized, and evaluated for their inhibitory activity against acetylcholinesterase (AChE). As a result, compound 13a bearing ligustrazine moiety displayed the most potent AChE inhibitory activity in this series with IC50 value of 218 nm. Besides, MTT assay was performed to investigate the neuroprotection of these compounds against PC12 cells injured by Amyloid beta-protein 1-42 (Abeta1-42 ). Among them, 8a showed higher inhibition rate (%Inhibition = 22.29) than the positive reference Donepezil (%Inhibition = 17.65). Title: One-Step Facile Synthesis of Nitrogen-Doped Carbon Dots: A Ratiometric Fluorescent Probe for Evaluation of Acetylcholinesterase Activity and Detection of Organophosphorus Pesticides in Tap Water and Food Huang S, Yao J, Chu X, Liu Y, Xiao Q, Zhang Y Ref: Journal of Agricultural and Food Chemistry, 67:11244, 2019 : PubMed ESTHER: Huang_2019_J.Agric.Food.Chem_67_11244 PubMedSearch: Huang 2019 J.Agric.Food.Chem 67 11244 PubMedID: 31532667 Abstract Evaluation of acetylcholinesterase (AChE) activity and determination of organophosphorus pesticides (OPs) are of great importance for the clinical diagnosis of several serious diseases correlated with their variations in human blood serum. In this study, a highly selective and sensitive ratiometric fluorescent probe was innovatively fabricated for the evaluation of AChE activity and the determination of OPs in tap water and food on the basis of the inner filter effect (IFE) between nitrogen-doped carbon dots (N-CDs) and 2,3-diaminophenazine (DAP). N-CDs were synthesized via a one-pot hydrothermal method by using pancreatin and 1,2-ethanediamine as precursors. N-CDs showed excellent fluorescence properties and negligible cytotoxicity on human cervical carcinoma HeLa cells and human embryonic kidney 293T cells, suggesting their further biological applications. Upon the addition of AChE and choline oxidase, acetylcholine was catalyzed to produce choline that was further oxidized to produce H2O2. In the presence of horseradish peroxidase, o-phenylenediamine reacted with H2O2 to produce fluorescent DAP. Therefore, a ratiometric fluorescent probing platform existed via IFE between N-CDs with a fluorescence signal at 450 nm and DAP with a fluorescence signal at 574 nm. OPs irreversibly impeded the catalytic activity of AChE, finally leading to the decrease of DAP amount and the variation of ratiometric fluorescent signal. Under optimal conditions, such a fluorescent probe showed relatively low detection limits of 0.38 U/L for AChE, 3.2 ppb for dichlorvos, and 13 ppb for methyl-parathion. Practical application of this ratiometric fluorescent probe to detect OPs was further verified in tap water and food samples with satisfying results that were highly consisted with the results obtained by GC-MS. Title: Integration of lipidomic and transcriptomic profiles reveals novel genes and regulatory mechanisms of Schizochytrium sp. in response to salt stress Jiang JY, Zhu S, Zhang Y, Sun X, Hu X, Huang H, Ren LJ Ref: Bioresour Technol, 294:122231, 2019 : PubMed ESTHER: Jiang_2019_Bioresour.Technol_294_122231 PubMedSearch: Jiang 2019 Bioresour.Technol 294 122231 PubMedID: 31606596 Abstract In this study, the effects of salt stress on the physiological, lipidomic and transcriptomic profiles of halophilic microalga Schizochytrium sp. were investigated. In general, Schizochytrium sp. could survive under high osmotic fermentation medium containing 30g/L NaCl, and showed a significant increase in C14:0 percentage in total fatty acids. In lipidomic analysis, C14:0 was specifically enriched in phosphatidylcholine (PC), and membrane phospholipids participated in the salt stress response mostly. Specially, one novel signal lipid N-acylphosphatidylethanolamine (NAPE) (18:0/20:3/14:0) was upregulated significantly. Transcriptomic analysis revealed glycerol-3-phosphate acyltransferase (GPAT) and phospholipase ABHD3 (PLABDH3) were involved in C14:0 metabolism and NAPE biosynthesis. Signalling pathways they mediated were activated as evident by high expression level of Myristoyl-CoA: protein N-myristoyltransferase (NMT) and NAPE-hydrolyzing PLD (NAPE-PLD). This study gives us an insight in specific responses to salt stress in Schizochytrium sp. and provides a considerable proportion of novel genes that could commendably be used for engineering modification. Title: Role of esterase mediated hydrolysis of simvastatin in human and rat blood and its impact on pharmacokinetic profiles of simvastatin and its active metabolite in rat Li Z, Zhang J, Zhang Y, Zuo Z Ref: J Pharm Biomed Anal, 168:13, 2019 : PubMed ESTHER: Li_2019_J.Pharm.Biomed.Anal_168_13 PubMedSearch: Li 2019 J.Pharm.Biomed.Anal 168 13 PubMedID: 30776567 Abstract Simvastatin is known as a pro-drug, which could be hydrolyzed by esterases to its active form, simvastatin acid. Although pharmacokinetics of simvastatin and simvastatin acid have been widely studied, hydrolysis of simvastatin to simvastatin acid during blood sampling and plasma preparation has been overlooked in the previous studies, leading to underestimation of simvastatin concentration and overestimation of simvastatin acid concentration in plasma. Since both efficacy and adverse drug reaction of simvastatin are highly dependent on simvastatin and simvastatin acid concentrations in vivo, accurate assessment of the two compounds are critical in their pharmacokinetic and pharmacodynamic studies. The current study was proposed aiming to investigate the esterase mediated hydrolysis of simvastatin in human and rat blood and its impact on the pharmacokinetic study of simvastatin and simvastatin acid. Using various esterase inhibitors including potassium florid (KF), bis(4-nitrophenyl) phosphate (BNPP), and ethylenediaminetetraacetic acid (EDTA), carboxylesterase was found to be the major esterase that hydrolyzed simvastatin in rat blood, while carboxylesterase and paraoxonase were the major esterases mediating the hydrolysis of simvastatin in human blood. Further studies using human recombinant enzymes identified simvastatin as substrates of PON1, CES1b, PON3 and CES1c with Clint of 8.75, 5.77, 3.93, and 2.45 muL/min/mg protein. Therefore, inhibition treatments with 20 mM BNPP and 50 mM KF/ 10 mM EDTA were developed to efficiently prevent the hydrolysis of simvastatin during blood sampling and plasma preparation in rat/human. The subsequent pharmacokinetics of orally administered simvastatin at 8.66 mg/kg in rats found that the Cmax and AUC0-infinity of simvastatin in absence of such esterase inhibitors in the blood sampling process were only 17.04 +/- 6.60% and 15.30 +/- 6.76% of those in presence of the inhibitors, whereas the Cmax and AUC0-infinity of simvastatin acid were 1.60 +/- 0.30 and 1.80 +/- 0.22 times of that obtained in presence of the inhibitors. Nevertheless, T1/2 of simvastatin and simvastatin acid remained the same regardless of the blood sampling method. Our current study for the first time demonstrated the importance for assessment of simvastatin stability during the blood sampling and plasma preparation process, which may be applicable to therapeutic drug monitoring of not only simvastatin but also other pro-drugs/compounds sharing similar metabolic properties. Title: Notum attenuates HBV-related liver fibrosis through inhibiting Wnt 5a mediated non-canonical pathways Li W, Yu X, Zhu C, Wang Z, Zhao Z, Li Y, Zhang Y Ref: Biol Res, 52:10, 2019 : PubMed ESTHER: Li_2019_Biol.Res_52_10 PubMedSearch: Li 2019 Biol.Res 52 10 PubMedID: 30871618 Gene_locus related to this paper: human-NOTUM Abstract BACKGROUND: Non-canonical Wnt pathways play important roles in liver fibrosis. Notum is a newly discovered inhibitor to Wnt proteins. This study was to investigate anti-fibrotic effects of Notum. METHODS: 53 patients with hepatitis B virus (HBV) infection as well as a cell co-culture system of LX-2 and Hep AD38 cells were engaged in this study. Clinical, biological and virological data of each patient were analyzed. Cell viability was detected at different time points. mRNA and protein levels of NFATc1 (Nuclear factor of activated T-cells), Jnk, alpha-SMA, Col1A1 and TIMP-1 were detected both in LX-2 and liver tissue. Protein levels of NFATc1 and Jnk in liver tissue and their correlations with fibrosis score were analyzed. RESULTS: Hepatitis B virus replication up-regulated Wnt5a induced NFATc1 and Jnk activity in Hep AD38. Notum suppressed NFATc1, Jnk and fibrosis genes expression, reduced cell viability in co-cultured LX-2 cells induced by HBV. Interestingly, Patients with HBV DNA > 5log copies/ml had higher mRNA levels of NFATc1 and fibrosis genes than patients with HBV DNA < 5log copies/ml. Most importantly, protein expressions of NFATc1 and pJnk have positive correlations with liver fibrosis scores in HBV-infected patients. CONCLUSIONS: Our data showed that Notum inhibited HBV-induced liver fibrosis through down-regulating Wnt 5a mediated non-canonical pathways. This study shed light on anti-fibrotic treatment. Title: Identification and Analysis of Chemical Constituents and Rat Serum Metabolites in Lycopodium clavatum Using UPLC-Q-TOF/MS Combined with Multiple Data-Processing Approaches Li X, Kang M, Ma N, Pang T, Zhang Y, Jin H, Yang Z, Song L Ref: Evid Based Complement Alternat Med, 2019:5165029, 2019 : PubMed ESTHER: Li_2019_Evid.Based.Complement.Alternat.Med_2019_5165029 PubMedSearch: Li 2019 Evid.Based.Complement.Alternat.Med 2019 5165029 PubMedID: 31354854 Abstract Lycopodium clavatum is a dry whole grass of Lycopodium japonicum Thunb.; it has been extensively used to anti-inflammatory, antioxidant, and antimicrobial actions and inhibits acetylcholinesterase activity. However, it lacks further compounds research of Lycopodium clavatum in vivo and in vitro. In this work, a rapid method was established using the ultra high performance liquid chromatography with quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS) combined with multiple data-processing approaches for compounds analysis of Lycopodium clavatum in vitro and in vivo. Finally, 30 peaks were characterized in 75% ethanol extract of Lycopodium clavatum and 17 peaks were characterized in rat plasma that including 12 prototype compounds and 5 metabolites. Methylation and demethylation are the main transformation reactions of Lycopodium clavatum in rat serum. This work could be helpful for understanding the complex compounds of Lycopodium clavatum and further analyzing the pharmacological studies of active compounds. Title: Clinical analysis of Chinese anti-low-density-lipoprotein-receptor-associated protein 4 antibodies in patients with myasthenia gravis Li M, Han J, Zhang Y, Lv J, Zhang J, Zhao X, Ren L, Fang H, Yang J and Gao F <4 more author(s)> Li M, Han J, Zhang Y, Lv J, Zhang J, Zhao X, Ren L, Fang H, Yang J, Cui X, Zhang Q, Li Q, Du Y, Gao F (- 4) Ref: Eur Journal of Neurology, 26:1296, 2019 : PubMed ESTHER: Li_2019_Eur.J.Neurol_26_1296 PubMedSearch: Li 2019 Eur.J.Neurol 26 1296 PubMedID: 31050101 Abstract BACKGROUND AND PURPOSE: Low-density-lipoprotein-receptor-associated protein 4 (LRP4) autoantibodies have recently been detected in myasthenia gravis (MG), but little is known about the clinical characteristics associated with this serological type. In this study, the clinical features of Chinese patients with anti-LRP4 antibody-positive MG were characterized. METHODS: A total of 2172 MG serum samples were collected from patients in various parts of China. An enzyme-linked immunosorbent assay was used to detect acetylcholine receptor (AChR) antibody and titin antibody, and cell-based assays were used to detect muscle-specific kinase antibody and LRP4 antibody. Clinical data for patients with MG were collected from different provinces in China. RESULTS: In total, 16 (0.8%) patients with LRP4-MG were found amongst 2172 total patients, including three patients with AChR/LRP4-MG. Additionally, 13 (2.9%) patients with LRP4-MG were found amongst 455 patients with double seronegative MG. The ratio of males to females for these 13 patients was 1:1.6, and 53.8% patients were children. A total of 91.7% of cases exhibited initial ocular involvement, and 58.3% of cases exhibited simple eye muscle involvement. Responses to acetylcholinesterase inhibitors and prednisone were observed. CONCLUSION: The expanded sample confirmed that the positive rate of LRP4 antibodies in China is lower than that in western countries. Our results highlighted the differences between LRP4-MG and other antibody groups. Children and female patients with LRP4-MG have a higher prevalence, often involving the ocular muscles and limb muscles. The clinical symptoms are mild, and satisfactory responses to treatment are often achieved. Title: Morning and Evening Circadian Pacemakers Independently Drive Premotor Centers via a Specific Dopamine Relay Liang X, Ho MCW, Zhang Y, Li Y, Wu MN, Holy TE, Taghert PH Ref: Neuron, 102:843, 2019 : PubMed ESTHER: Liang_2019_Neuron_102_843 PubMedSearch: Liang 2019 Neuron 102 843 PubMedID: 30981533 Abstract Many animals exhibit morning and evening peaks of locomotor behavior. In Drosophila, two corresponding circadian neural oscillators-M (morning) cells and E (evening) cells-exhibit a corresponding morning or evening neural activity peak. Yet we know little of the neural circuitry by which distinct circadian oscillators produce specific outputs to precisely control behavioral episodes. Here, we show that ring neurons of the ellipsoid body (EB-RNs) display spontaneous morning and evening neural activity peaks in vivo: these peaks coincide with the bouts of locomotor activity and result from independent activation by M and E pacemakers. Further, M and E cells regulate EB-RNs via identified PPM3 dopaminergic neurons, which project to the EB and are normally co-active with EB-RNs. These in vivo findings establish the fundamental elements of a circadian neuronal output pathway: distinct circadian oscillators independently drive a common pre-motor center through the agency of specific dopaminergic interneurons. Title: Specific quorum sensing molecules of ammonia oxidizers and their role during ammonium metabolism in Zhalong wetland, China Liu F, Zhang Y, Liang H, Gao D Ref: Sci Total Environ, 666:1106, 2019 : PubMed ESTHER: Liu_2019_Sci.Total.Environ_666_1106 PubMedSearch: Liu 2019 Sci.Total.Environ 666 1106 PubMedID: 30970476 Abstract The primary challenge of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) surviving in wetlands are the rapid and unpredictable environmental changes. To adapt to a fluctuant environment, ammonia oxidizers have to communicate with each other via acyl-homoserine lactones (AHLs). In this study, AOA and AOB in the soil samples taken from Zhalong wetland were incubated. Dynamics of AHLs during the incubation of ammonia oxidizers were measured. Then, the specific AHLs of AOA and AOB were identified, respectively. The results showed that AOA secreted N-butyryl-dl-homoserine lactone (C4-HSL) and N-octanoyl-l-homoserine lactone (C8-HSL) to cope with nitrite accumulation, while they secreted N-(3-oxododecanoyl)-dl-homoserine lactone (OXOC12-HSL) to regulate their ammonium metabolism activity. AOB secreted N-hexanoyl-dl-homoserine lactone (C6-HSL), N-dodecanoyl-l-homoserine lactone (C12-HSL), N-tetradecanoyl-dl-homoserine lactone (C14-HSL) and N-(3-oxododecanoyl)-tetradecanoyl-dl-homoserine lactone (OXOC14-HSL) only to enhance the metabolism activity. The dominant AOA belonged to the Nitrososphaera lineage, while the dominant AOB grouped into the Nitrosomonas lineage. The AHLs receptor homologs were identified in both AOA and AOB, which confirmed that AOA and AOB had the QS system. The present work was the first study that elucidated the QS system of AOA and AOB in multidimensional, and confirmed the role of QS system in ammonia oxidizers' metabolism. Title: An enhanced staining method K-B-2R staining for three-dimensional nerve reconstruction Luo P, Dong J, Qi J, Zhang Y, Liu X, Zhong Y, Xian CJ, Wang L Ref: BMC Neurosci, 20:32, 2019 : PubMed ESTHER: Luo_2019_BMC.Neurosci_20_32 PubMedSearch: Luo 2019 BMC.Neurosci 20 32 PubMedID: 31286881 Abstract BACKGROUND: Three-dimensional (3D) reconstruction of human peripheral nerves, as a useful tool to understand the nerve internal information and functional basis, has become an important area of research in the peripheral nerve field. METHODS: In this study, we proposed a two-dimensional (2D) Karnovsky-Roots toluidine blue ponceau 2R (K-B-2R) staining method based upon conventional Karnovsky-Roots staining. It significantly improved the ability to display nerve fascicles, motor and sensory nerve fiber textures. In this method, Karnovsky-Roots staining was carried out, followed by toluidine blue counterstain and ponceau 2R counterstain. RESULTS: Comparisons were conducted between the three methods in staining of median nerve sections, which showed similar distribution characters in acetylcholinesterase-positive sites. The additional counterstaining did not change the basis of Karnovsky-Roots staining. However, the resulting images from this new method significantly facilitated the subsequent 3D nerve reconstruction and 3D printing. CONCLUSIONS: These results show that the new staining method significantly enhanced the display qualities of nerve fascicle edges and fiber textures of motor and sensory nerves and facilitated 3D nerve reconstruction. Title: A Novel VIII Carboxylesterase with High Hydrolytic Activity Against Ampicillin from a Soil Metagenomic Library Nan F, Jiang J, Wu S, Zhang Y, Qiu J, Qiao B, Li S, Xin Z Ref: Mol Biotechnol, 61:892, 2019 : PubMed ESTHER: Nan_2019_Mol.Biotechnol_61_892 PubMedSearch: Nan 2019 Mol.Biotechnol 61 892 PubMedID: 31664703 Abstract A novel carboxylesterase gene, named dlfae4, was discovered and sequenced from a soil metagenomic library. The dlfae4 gene was composed of 1017 base pairs encoding 338 amino acid residues with a predicted molecular mass of 37.2 kDa. DLFae4 exhibited strong hydrolytic activity towards methyl ferulate under optimum pH and temperature conditions (pH 8.6, 50 degrees C) and displayed remarkable thermostability, with residual activity as high as 50% after incubation for 3 h at 60 degrees C. A family VIII esterase DLFae4 was found to contain a typical serine residue within the S-X-X-K motif, which serves as a catalytic nucleophile in class C beta-lactamases and family VIII esterases. As a consequence of its high sequence similarity with beta-lactamases, DLFae4 exhibited significant hydrolytic activity towards ampicillin. In addition, DLFae4 was found to be the first known member of family VIII carboxylesterases with phthalate-degrading ability. Site-directed mutagenesis studies revealed that Ser11, Lys14, and Tyr121 residues play an essential catalytic role in DLFae4. These new findings, which are of great importance for further in-depth research and engineering development of carboxylesterases, should advance the implementation of biotechnological applications. Title: ABHD5 blunts the sensitivity of colorectal cancer to fluorouracil via promoting autophagic uracil yield Ou J, Peng Y, Yang W, Zhang Y, Hao J, Li F, Chen Y, Zhao Y, Xie X and Liang H <8 more author(s)> Ou J, Peng Y, Yang W, Zhang Y, Hao J, Li F, Chen Y, Zhao Y, Xie X, Wu S, Zha L, Luo X, Xie G, Wang L, Sun W, Zhou Q, Li J, Liang H (- 8) Ref: Nat Commun, 10:1078, 2019 : PubMed ESTHER: Ou_2019_Nat.Commun_10_1078 PubMedSearch: Ou 2019 Nat.Commun 10 1078 PubMedID: 30842415 Gene_locus related to this paper: human-ABHD5 Abstract The efficacy of Fluorouracil (FU) in the treatment of colorectal cancer (CRC) is greatly limited by drug resistance. Autophagy has been implicated in chemoresistance, but the role of selective autophagic degradation in regulating chemoresistance remains unknown. In this study, we revealed a critical role of ABHD5 in charging CRC sensitivity to FU via regulating autophagic uracil yield. We demonstrated that ABHD5 localizes to lysosome and interacts with PDIA5 to prevent PDIA5 from interacting with RNASET2 and inactivating RNASET2. ABHD5 deficiency releases PDIA5 to directly interact with RNASET2 and leave RNASET2 in an inactivate state, which impairs RNASET2-mediated autophagic uracil yield and promotes CRC cells to uptake FU as an exogenous uracil, thus increasing their sensitivity to FU. Our findings for the first time reveal a novel role of ABHD5 in regulating lysosome function, highlighting the significance of ABHD5 as a compelling biomarker predicting the sensitivity of CRCs to FU-based chemotherapy. Title: Association of Antidementia Therapies With Time to Skilled Nursing Facility Admission and Cardiovascular Events Among Elderly Adults With Alzheimer Disease San-Juan-Rodriguez A, Zhang Y, He M, Hernandez I Ref: JAMA Netw Open, 2:e190213, 2019 : PubMed ESTHER: San-Juan-Rodriguez_2019_JAMA.Netw.Open_2_e190213 PubMedSearch: San-Juan-Rodriguez 2019 JAMA.Netw.Open 2 e190213 PubMedID: 30821828 Abstract Importance: To date, no study has compared time to skilled nursing facility (SNF) admission and cardiovascular events across medications available to treat Alzheimer disease. Objective: To compare time to SNF admission and cardiovascular events between acetylcholinesterase inhibitor (AChEI) monotherapy, memantine hydrochloride monotherapy, and combination therapy with an AChEI and memantine in treating elderly adults with Alzheimer disease. Design, Setting, and Participants: This retrospective cohort study uses January 1, 2006, to December 31, 2014, claims data from a 5% random sample of Medicare beneficiaries who had received a new diagnosis of Alzheimer disease between January 1, 2007, and December 31, 2013, and who initiated AChEI monotherapy, memantine monotherapy, or combination therapy with an AChEI and memantine (N = 73475). Patients were followed up until discontinuation of treatment, switch of treatment, death, or the end of the study period. Statistical analysis was conducted from February 15, 2018, to June 15, 2018. Exposures: Acetylcholinesterase inhibitor monotherapy (n = 44424), memantine monotherapy (n = 11809), and combination therapy with an AChEI and memantine (n = 17242). Main Outcomes and Measures: Primary outcomes were time to SNF admission and the composite of the following cardiovascular events: acute myocardial infarction, bradycardia, syncope, atrioventricular block, QT interval prolongation, and ventricular tachycardia. Cox proportional hazards regression models were constructed to compare outcomes between each pair of treatment groups, controlling for a comprehensive list of patient characteristics. Results: The study population included 73475 participants (53068 women and 20407 men; mean [SD] age, 81.8 [8.3] years); 25.5% of the participants initiating AChEI monotherapy, 25.6% of participants initiating memantine monotherapy, and 29.7% of participants initiating combination therapy with an AChEI and memantine were admitted to an SNF. Similarly, 22.2% of the participants initiating AChEI monotherapy, 20.0% of those initiating memantine monotherapy, and 24.5% of those initiating combination therapy experienced at least 1 cardiovascular event. No difference in time to SNF admission was found across the 3 treatment groups. The risk of the composite measure of any cardiovascular event did not differ between the combination therapy and AChEI monotherapy groups (adjusted hazard ratio [aHR], 0.99; 95% CI, 0.96-1.03); however, it was higher for both AChEI monotherapy (aHR, 1.07; 95% CI, 1.02-1.12) and combination therapy (aHR, 1.07; 95% CI, 1.01-1.12), relative to memantine monotherapy. This result was mainly driven by the lower risk of bradycardia and syncope observed for the memantine monotherapy group relative to both AChEI monotherapy (bradycardia: aHR, 0.88; 95% CI, 0.82-0.95; and syncope: aHR, 0.92; 95% CI, 0.86-0.97) and combination therapy (bradycardia: aHR, 0.89; 95% CI, 0.82-0.97; and syncope: aHR, 0.87; 95% CI, 0.83-0.94). Conclusions and Relevance: Time to SNF admission did not differ across treatment groups, but memantine monotherapy was associated with a lower risk of cardiovascular events compared with both AChEI monotherapy and combination therapy with an AChEI and memantine. Title: A systemic study of indoxacarb resistance in Spodoptera litura revealed complex expression profiles and regulatory mechanism Shi L, Shi Y, Zhang Y, Liao X Ref: Sci Rep, 9:14997, 2019 : PubMed ESTHER: Shi_2019_Sci.Rep_9_14997 PubMedSearch: Shi 2019 Sci.Rep 9 14997 PubMedID: 31628365 Abstract The tobacco cutworm, Spodoptera litura, is an important pest of crop and vegetable plants worldwide, and its resistance to insecticides have quickly developed. However, the resistance mechanisms of this pest are still unclear. In this study, the change in mRNA and miRNA profiles in the susceptible, indoxacarb-resistant and field indoxacarb-resistant strains of S. litura were characterized. Nine hundred and ten co-up-regulated and 737 co-down-regulated genes were identified in the resistant strains. Further analysis showed that 126 co-differentially expressed genes (co-DEGs) (cytochrome P450, carboxy/cholinesterase, glutathione S-transferase, ATP-binding cassette transporter, UDP-glucuronosyl transferase, aminopeptidase N, sialin, serine protease and cuticle protein) may play important roles in indoxacarb resistance in S. litura. In addition, a total of 91 known and 52 novel miRNAs were identified, and 10 miRNAs were co-differentially expressed in the resistant strains of S. litura. Furthermore, 10 co-differentially expressed miRNAs (co-DEmiRNAs) had predicted co-DEGs according to the expected miRNA-mRNA negative regulation pattern and 37 indoxacarb resistance-related co-DEGs were predicted to be the target genes. These results not only broadened our understanding of molecular mechanisms of insecticide resistance by revealing complicated profiles, but also provide important clues for further study on the mechanisms of miRNAs involved in indoxacarb resistance in S. litura. Title: CA10 and CA11 negatively regulate neuronal activity-dependent growth of gliomas Tao B, Ling Y, Zhang Y, Li S, Zhou P, Wang X, Li B, Jun Z, Zhang W and Wang L <2 more author(s)> Tao B, Ling Y, Zhang Y, Li S, Zhou P, Wang X, Li B, Jun Z, Zhang W, Xu C, Shi J, Wang L (- 2) Ref: Mol Oncol, 13:1018, 2019 : PubMed ESTHER: Tao_2019_Mol.Oncol_13_1018 PubMedSearch: Tao 2019 Mol.Oncol 13 1018 PubMedID: 30636076 Abstract Recent studies have revealed that neurons can promote glioma growth through activity-dependent secretion of neurotrophins, especially neuroligin-3. It has therefore been suggested that blocking neuron-derived neurotrophins may serve as a therapeutic intervention for gliomas. Carbonic anhydrase-related proteins 11 and 10 (CA11 and CA10) are secreted synaptic proteins which function as neurexin ligands, and the gene-encoding CA11 is part of a gene signature associated with radiotherapy and prognosis in gliomas. We therefore hypothesized that CA11/CA10 might participate in the neuronal activity-dependent regulation of glioma growth. In this study, we report that CA11 secreted by depolarized cultured neurons within conditioned medium (CM) inhibited the growth of glioma cell lines. CM from depolarized neurons inhibited CA11 expression in glioma cell lines via the Akt signaling pathway. Consistently, CA11 expression was also reduced in clinical glioma samples and negatively associated with high histological grade. Low CA11 expression of gliomas was associated with short survival in four independent datasets [repository of brain neoplasia data (REMBRANDT), The Cancer Genome Atlas (TCGA) lower grade glioma (LGG), GSE4271, and GSE42669]. CA11 knockdown promoted cell growth, clone formation, and migration; inhibited apoptosis; and increased tumor size in xenografted nude mice. Similarly, CA10 and CA10 secreted by depolarized cultured neurons also inhibited the growth of glioma cell lines. Low CA10 expression was associated with short survival in REMBRANDT, TCGA LGG, and GEO GSE4271 datasets. Our results suggest that CA11 and CA10 negatively regulate neuronal activity-dependent glioma growth and inhibit glioma aggression. Thus, CA11/CA10 may represent a potential therapeutic target for the treatment of gliomas. Title: Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells Wan L, Xia T, Du Y, Liu J, Xie Y, Zhang Y, Guan F, Wu J, Wang X, Shi C Ref: FASEB Journal, :fj201802675R, 2019 : PubMed ESTHER: Wan_2019_FASEB.J__fj201802675R PubMedSearch: Wan 2019 FASEB.J fj201802675R PubMedID: 30970216 Abstract The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia-inducible factor 1 (Hif-1) regulated HSC activation, and, therefore, we investigated in current work whether Hif-1 regulates exosome secretion and the metabolic switch of HSCs, thus affecting the metabolism of liver nonparenchymal cells. In this study, the characteristics of exosomes from HSCs were assessed via electron microscopy, Western blot analysis, and acetylcholinesterase activity. Confocal microscopy was used to measure the uptake of exosomes by quiescent HSCs, Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). Hif-1alpha was inhibited via 2-ME or specific small interfering RNAs to investigate its role in exosomes derived from HSCs. It was determined that glucose transporter 1 and pyruvate kinase M2 were increasingly expressed in fibrotic liver samples, cell lysates, and exosomes derived from activated HSCs. Exosomes released from HSCs were associated with activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, KCs, and LSECs. Disruption of Hif-1 expression suppressed the glycolysis effect delivered by exosomes. Conclusively, our results demonstrated that exosomes secreted by activated HSCs affect the metabolic switch of liver nonparenchymal cells via delivery of glycolysis-related proteins. These findings represent a novel mechanism that contributes to liver fibrosis and has significant implications for new diagnosis and treatment of liver diseases.-Wan, L., Xia, T., Du, Y., Liu, J., Xie, Y., Zhang, Y., Guan, F., Wu, J., Wang, X., Shi, C. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exomes in metabolic switch of liver nonparenchymal cells. Title: Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of beta-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer's Disease Wang Y, Xia J, Shen M, Zhou Y, Wu Z, Shi Y, Xu J, Hou L, Zhang R and Wang H <4 more author(s)> Wang Y, Xia J, Shen M, Zhou Y, Wu Z, Shi Y, Xu J, Hou L, Zhang R, Qiu Z, Xie Q, Chen H, Zhang Y, Wang H (- 4) Ref: Front Aging Neurosci, 11:3, 2019 : PubMed ESTHER: Wang_2019_Front.Aging.Neurosci_11_3 PubMedSearch: Wang 2019 Front.Aging.Neurosci 11 3 PubMedID: 30723404 Inhibitor(s) related to this paper: bis9-(-)-nor-meptazinol Abstract Alzheimer's disease (AD) is the main type of dementia and is characterized by progressive memory loss and a notable decrease in cholinergic neuron activity. As classic drugs currently used in the clinic, acetylcholinesterase inhibitors (AChEIs) restore acetylcholine levels and relieve the symptoms of AD, but are insufficient at delaying the onset of AD. Based on the multi-target-directed ligand (MTDL) strategy, bis-(-)-nor-meptazinol (BIS-MEP) was developed as a multi-target AChEI that mainly targets AChE catalysis and the beta-amyloid (Abeta) aggregation process. In this study, we bilaterally injected Abeta oligomers and ibotenic acid (IBO) into the hippocampus of ICR mice and then subcutaneously injected mice with BIS-MEP to investigate its therapeutic effects and underlying mechanisms. According to the results from the Morris water maze test, BIS-MEP significantly improved the spatial learning and memory impairments in AD model mice. Compared with the vehicle control, the BIS-MEP treatment obviously inhibited the AChE activity in the mouse brain, consistent with the findings from the behavioral tests. The BIS-MEP treatment also significantly reduced the Abeta plaque area in both the hippocampus and cortex, suggesting that BIS-MEP represents a direct intervention for AD pathology. Additionally, the immunohistochemistry and ELISA results revealed that microglia (ionized calcium-binding adapter molecule 1, IBA1) and astrocyte (Glial fibrillary acidic protein, GFAP) activation and the secretion of relevant inflammatory factors (TNFalpha and IL-6) induced by Abeta were decreased by the BIS-MEP treatment. Furthermore, BIS-MEP showed more advantages than donepezil (an approved AChEI) as an Abeta intervention. Based on our findings, BIS-MEP improved spatial learning and memory deficits in AD mice by regulating acetylcholinesterase activity, Abeta deposition and the inflammatory response in the brain. Title: Carotid baroreceptor stimulation suppresses ventricular fibrillation in canines with chronic heart failure Wang J, Dai M, Cao Q, Yu Q, Luo Q, Shu L, Zhang Y, Bao M Ref: Basic Res Cardiol, 114:41, 2019 : PubMed ESTHER: Wang_2019_Basic.Res.Cardiol_114_41 PubMedSearch: Wang 2019 Basic.Res.Cardiol 114 41 PubMedID: 31502080 Abstract Carotid baroreceptor stimulation (CBS) has been shown to improve cardiac dysfunction and pathological structure remodelling. This study aimed to investigate the effects of CBS on the ventricular electrophysiological properties in canines with chronic heart failure (CHF). Thirty-eight beagles were randomized into control (CON), CHF, low-level CBS (LL-CBS), and moderate-level CBS (ML-CBS) groups. The CHF model was established with 6 weeks of rapid right ventricular pacing (RVP), and concomitant LL-CBS and ML-CBS were applied in the LL-CBS and ML-CBS groups, respectively. After 6 weeks of RVP, ventricular electrophysiological parameters and left stellate ganglion (LSG) neural activity and function were measured. Autonomic neural remodelling in the LSG and left ventricle (LV) and ionic remodelling in the LV were detected. Compared with the CHF group, both LL-CBS and ML-CBS decreased spatial dispersion of action potential duration (APD), suppressed APD alternans, reduced ventricular fibrillation (VF) inducibility, and inhibited enhanced LSG neural discharge and function. Only ML-CBS significantly inhibited ventricular repolarization prolongation and increased the VF threshold. Moreover, ML-CBS inhibited the increase in growth-associated protein-43 and tyrosine hydroxylase-positive nerve fibre densities in LV, increased acetylcholinesterase protein expression in LSG, and decreased nerve growth factor protein expression in LSG and LV. Chronic RVP resulted in a remarkable reduction in protein expression encoding both potassium and L-type calcium currents; these changes were partly amended by ML-CBS and LL-CBS. In conclusion, CBS suppresses VF in CHF canines, potentially by modulating autonomic nerve and ion channels. In addition, the effects of ML-CBS on ventricular electrophysiological properties, autonomic remodelling, and ionic remodelling were superior to those of LL-CBS. Title: Molecular characterization of ABHD5 gene promoter in intramuscular preadipocytes of Qinchuan cattle: Roles of Evi1 and C/EBPalpha Wang X, Khan R, Raza SHA, Li A, Zhang Y, Liang C, Yang W, Wu S, Zan L Ref: Gene, 690:38, 2019 : PubMed ESTHER: Wang_2019_Gene_690_38 PubMedSearch: Wang 2019 Gene 690 38 PubMedID: 30583026 Gene_locus related to this paper: bovin-q0vcc8 Abstract The genetic regulation of lipolytic enzyme is closely related to carcass quality traits through deposition of intramuscular fat (marbling) in beef cattle breeds. The alpha/beta hydrolase domain containing 5 (ABHD5) is an accelerating factor of adipose triglyceride lipase (ATGL), which plays a key role in triglyceride metabolism. In this study, we determined that bovine ABHD5 gene was highly expressed in adult bovine adipose tissue. To elucidate the molecular mechanisms involved in bovine ABHD5 regulation, we cloned and characterized the promoter region of ABHD5. Applying 5'-rapid amplification of cDNA end analysis (RACE), we identified transcriptional start site (TSS) found in the predicted CpG island within promoter region of ABHD5 gene. Using the recombinant dual fluorescent reporter vectors, the fragment of -109/+307 was identified as proximal minimum core promoter region of ABHD5 in bovine intramuscular adipocytes. Site directed mutagenesis and electrophoretic mobility shift assay (EMSA) confirmed the role of two transcription factors, namely Ectopic viral integration site-1 (Evi1) and CCAAT/enhancer binding protein alpha (C/EBPalpha), in the regulation of ABHD5 gene. Taken together these findings we can conclude that ABHD5 gene regulated by Evi1 and C/EBPalpha could be used as potential marker in marker assisted selection for the improvement of Qinchuan cattle breed for carcass quality traits. Title: Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD Wang N, Rosen O, Wang L, Turner HL, Stevens LJ, Corbett KS, Bowman CA, Pallesen J, Shi W and McLellan JS <8 more author(s)> Wang N, Rosen O, Wang L, Turner HL, Stevens LJ, Corbett KS, Bowman CA, Pallesen J, Shi W, Zhang Y, Leung K, Kirchdoerfer RN, Becker MM, Denison MR, Chappell JD, Ward AB, Graham BS, McLellan JS (- 8) Ref: Cell Rep, 28:3395, 2019 : PubMed ESTHER: Wang_2019_Cell.Rep_28_3395 PubMedSearch: Wang 2019 Cell.Rep 28 3395 PubMedID: 31553909 Abstract Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the receptor-binding domain (RBD) on MERS-CoV spike (S) protein have been characterized, but much less is known about antibodies targeting non-RBD epitopes. Here, we report the structural and functional characterization of G2, a neutralizing antibody targeting the MERS-CoV S1 N-terminal domain (S1-NTD). Structures of G2 alone and in complex with the MERS-CoV S1-NTD define a site of vulnerability comprising two loops, each of which contain a residue mutated in G2-escape variants. Cell-surface binding studies and in vitro competition experiments demonstrate that G2 strongly disrupts the attachment of MERS-CoV S to its receptor, dipeptidyl peptidase-4 (DPP4), with the inhibition requiring the native trimeric S conformation. These results advance our understanding of antibody-mediated neutralization of coronaviruses and should facilitate the development of immunotherapeutics and vaccines against MERS-CoV. Title: Characterization of one novel microbial esterase WDEst9 and its use to make l-methyl lactate Wang Y, Xu S, Li R, Sun A, Zhang Y, Sai K, Hu Y Ref: Biocatalysis and Biotransformation, 37:190, 2019 : PubMed ESTHER: Wang_2019_Biocatal.Biotransformation_37_190 PubMedSearch: Wang 2019 Biocatal.Biotransformation 37 190 Gene_locus related to this paper: 9actn-a0a2d1pk72 Abstract Chiral lactic acids and their ester derivatives are crucial building blocks and intermediates for the synthesis of a great variety of valuable functional materials and pharmaceuticals. Before our study, the reports about the enantioselective preparation of pure L-lactic acid and its ester derivatives through direct hydrolysis of racemic substrate were quite rare. Herein, we heterologously expressed and functionally characterized one novel microbial esterase WDEst9 from Dactylosporangium aurantiacum, which exhibited high resistance to diverse metal ions, organic solvents, surfactants, NaCl and KCl. We further utilized WDEst9 as a green biocatalyst in the kinetic resolution of (+/-)-methyl lactate through direct hydrolysis and generated L-methyl lactate with high enantiomeric excess (e.e. >99%) and high yield (>86%) after process optimization. Notably, the enantioselectivity of WDEst9 was opposite than that of two previously reported esterases PHE14 and BSE01701 that can generate D-methyl lactate though kinetic resolution of (+/-)-methyl lactate. Microbial esterase WDEst9 is a promising green biocatalyst in the preparation of valuable chiral chemicals and opens the door for the identification of useful industrial enzymes and biocatalysts from the genus Dactylosporangium. Title: Functional analysis of four upregulated carboxylesterase genes associated with fenpropathrin resistance in Tetranychus cinnabarinus (Boisduval) Wei P, Li J, Liu X, Nan C, Shi L, Zhang Y, Li C, He L Ref: Pest Manag Sci, 75:252, 2019 : PubMed ESTHER: Wei_2019_Pest.Manag.Sci_75_252 PubMedSearch: Wei 2019 Pest.Manag.Sci 75 252 PubMedID: 29877064 Gene_locus related to this paper: tetur-t1k786 Abstract BACKGROUND: Carboxylesterases (CarEs) are important in pesticide resistance. Four overexpressed CarE genes with inducible character were screened out in fenpropathrin-resistant Tetranychus cinnabarinus, but their functional roles remained to be further analyzed by RNAi and protein expression. RESULTS: Feeding a single double-stranded (ds)RNA of each of four genes led to gene-specific downregulation of mRNA, decreased esterase activity and diminished resistance in T. cinnabarinus. More interestingly, feeding four dsRNAs simultaneously led to a more significant decrease in enzymatic activity and fold resistance than feeding a single dsRNA individually, suggesting that these CarE genes were involved in fenpropathrin-resistance and had cooperative roles. The gene CarE6 was regarded as the primary and representative candidate to be functionally expressed, because silencing of CarE6 led to the most significant decrease in resistance level. The activity of CarE6 protein was competitively inhibited by fenpropathrin. It could effectively decompose 41.7 +/- 0.09% of fenpropathrin within 3 h, proving that CarE6 protein was capable of metabolizing fenpropathrin effectively in T. cinnabarinus. CONCLUSION: The results confirm that four CarE genes are cooperatively involved in fenpropathrin resistance and the metabolic enzymes encoded by these overexpressed genes do indeed metabolize acaricide in resistant T. cinnabarinus in the evolution of acaricide resistance. (c) 2018 Society of Chemical Industry. Title: STAT3-induced upregulation of lncRNA ABHD11-AS1 promotes tumour progression in papillary thyroid carcinoma by regulating miR-1301-3p/STAT3 axis and PI3K/AKT signalling pathway Wen J, Wang H, Dong T, Gan P, Fang H, Wu S, Li J, Zhang Y, Du R, Zhu Q Ref: Cell Prolif, 52:e12569, 2019 : PubMed ESTHER: Wen_2019_Cell.Prolif_52_e12569 PubMedSearch: Wen 2019 Cell.Prolif 52 e12569 PubMedID: 30657221 Gene_locus related to this paper: human-ABHD11 Abstract OBJECTIVES: Emerging evidences indicated the importance of long non-coding RNAs (lncRNAs) in the tumorigenesis and deterioration of malignant tumours. To our knowledge, the study about lncRNAs in papillary thyroid carcinoma (PTC) is still inadequate. ABHD11-AS1 was highly expressed in the PTC samples of The Cancer Genome Atlas database. This study focused on the biological function and mechanism of lncRNA ABHD11-AS1 in PTC. MATERIALS AND METHODS: qRT-PCR analysis was used to examine the expression of ABHD11-AS1 in PTC tissues and cell lines. The prognostic significance of ABHD11-AS1 for the patients with PTC was analysed with Kaplan-Meier analysis. The effects of ABHD11-AS1 knockdown on the cell proliferation and metastasis were evaluated by in vitro functional assays and in vivo experiments. The molecular mechanism which contributed to the oncogenic role of ABHD11-AS1 in PTC was explored by conducting mechanism experiments. Rescue assays were carried out for final demonstration. RESULTS: High expression of ABHD11-AS1 predicted poor prognosis for patients with PTC and promoted cell proliferation and metastasis in vitro and in vivo. ABHD11-AS1 was activated by the transcription factor STAT3. ABHD11-AS1 positively regulated PI3K/AKT signalling pathway. ABHD11-AS1 acted as a competitive endogenous (ce) RNA to upregulate STAT3 by sponging miR-1301-3p. CONCLUSIONS: STAT3-induced lncRNA ABHD11-AS1 promoted PTC progression by regulating PI3K/AKT signalling pathway and miR-1301-3p/STAT3 axis. Title: Rhodopseudomonas palustris wastewater treatment: Cyhalofop-butyl removal, biochemicals production and mathematical model establishment Wu P, Chen Z, Zhang Y, Wang Y, Zhu F, Cao B, Wu Y, Li N Ref: Bioresour Technol, 282:390, 2019 : PubMed ESTHER: Wu_2019_Bioresour.Technol_282_390 PubMedSearch: Wu 2019 Bioresour.Technol 282 390 PubMedID: 30884459 Abstract Simultaneous (SPW and cyhalofop-butyl) wastewater treatment and the production of biochemicals by Rhodopseudomonas palustris (R. palustris) was investigated with supplementation of soybean processing wastewater (SPW). Compared to control group, cyhalofop-butyl was removed and single cell protein, carotenoid, bacteriochlorophyll productions were enhanced with the supplementation of SPW. Cyhalofop-butyl removal reached 100% after 5days under 4000mg/L COD group. Cyhalofop-butyl induced chbH gene expression to synthesize cyhalofop-butyl-hydrolyzing carboxylesterase through activating MAPKKKs, MAPKKs, MAPKs genes in MAPK signal transduction pathway. The induction process took one day for R. palustris. However, lack of organics in original wastewater did not maintain R. palustris growth for over one day. The supplementation of SPW provided sufficient carbon source. This new method resulted in the mixed wastewater treatment and improvement of biochemicals simultaneously, as well as the realization of reutilization of R. palustris. High-order non-linear mathematical model of the relationship between Rchb, Xc, and Xt was established. Title: The removal of cyhalofop-butyl in soil by surplus Rhodopseudanonas palustris in wastewater purification Wu P, Mo W, Chen Z, Wang Y, Cui Y, Zhang Y, Song Y, Jin L, Hou Y and Li N <2 more author(s)> Wu P, Mo W, Chen Z, Wang Y, Cui Y, Zhang Y, Song Y, Jin L, Hou Y, Zhu F, Cao B, Li N (- 2) Ref: J Environ Manage, 245:168, 2019 : PubMed ESTHER: Wu_2019_J.Environ.Manage_245_168 PubMedSearch: Wu 2019 J.Environ.Manage 245 168 PubMedID: 31152960 Abstract The biorestoration of cyhalofop-butyl and fertility in soil using Rhodopseudanonas palustris (R. palustris) in the treated wastewater were investigated in this research. Cyhalofop-butyl was not degraded under control group. The treated wastewater containing R. palustris degraded cyhalofop-butyl and remediated fertility. Interestingly, the cyhalofop-butyl-hydrolyzing carboxylesterase gene was expressed after inoculation 24h. Subsequently, the cyhalofop-butyl-hydrolyzing carboxylesterase were synthesized to degrade cyhalofop-butyl. The cyhalofop-butyl started to be degraded after inoculation 24h. The cyhalofop-butyl as stimulus signal induced cyhalofop-butyl-hydrolyzing carboxylesterase gene expression through signal transduction pathway. This process took 24h for R. palustris as they were ancient bacteria. The residual organics in the wastewater provided sufficient carbon sources and energy for R. palustris under three dosage groups. The new method completed the remediation of cyhalofop-butyl pollution, the improvement of soil fertility and soybean processing wastewater treatment simultaneously, and realized the resource reutilization of wastewater and R. palustris as sludge. Title: Molecular cloning, expression and characterization of a novel feruloyl esterase from a soil metagenomic library with phthalate-degrading activity Wu S, Nan F, Jiang J, Qiu J, Zhang Y, Qiao B, Li S, Xin Z Ref: Biotechnol Lett, 41:995, 2019 : PubMed ESTHER: Wu_2019_Biotechnol.Lett_41_995 PubMedSearch: Wu 2019 Biotechnol.Lett 41 995 PubMedID: 31102076 Gene_locus related to this paper: pseai-a0a222d555 Abstract OBJECTIVES: To discover novel feruloyl esterases (FAEs) by the function-driven screening procedure from soil metagenome. RESULTS: A novel FAE gene bds4 was isolated from a soil metagenomic library and over-expressed in Escherichia coli. The recombinant enzyme BDS4 was purified to homogeneity with a predicted molecular weight of 38.8 kDa. BDS4 exhibited strong activity (57.05 U/mg) toward methyl ferulate under the optimum pH and temperature of 8.0 and 37 degrees C. Based on its amino acid sequence and model substrates specificity, BDS4 was classified as a type-C FAE. The quantity of the releasing ferulic acid can be enhanced significantly in the presence of xylanase compared with BDS4 alone from de-starched wheat bran. In addition, BDS4 can also hydrolyze several phthalates such as diethyl phthalate, dimethyl phthalate and dibutyl phthalate. CONCLUSION: The current investigation discovered a novel FAE with phthalate-degrading activity and highlighted the usefulness of metagenomic approaches as a powerful tool for discovery of novel FAEs. Title: Impact of the Chinese herbal medicines on dual antiplatelet therapy with clopidogrel and aspirin: Pharmacokinetics and pharmacodynamics outcomes and related mechanisms in rats Xiao M, Qian C, Luo X, Yang M, Zhang Y, Wu C, Mok C, Lee P, Zuo Z Ref: J Ethnopharmacol, 235:100, 2019 : PubMed ESTHER: Xiao_2019_J.Ethnopharmacol_235_100 PubMedSearch: Xiao 2019 J.Ethnopharmacol 235 100 PubMedID: 30710735 Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Dual antiplatelet therapy (DAPT) with aspirin (ASA) and clopidogrel (CLP) has been consistently shown clinical effectiveness in patients with coronary artery disease. According to the literature, four traditional Chinese medicine (TCM) herbs effective for prevention cardiovascular diseases, namely Radix Salvia Miltiorrhiza (Red sage root, Danshen), Radix Pueraria Lobata (Kudzu root, Gegen), Radix Angelica Sinensis (Angelica root, Danggui), and Rhizoma Ligusticum chuanxiong (Szehuan lovage rhizome, Chuanxiong), are of high potential to be co-administered during DAPT. Since all these herbs are blood vitalizing medicines and can promote blood circulation and eliminate blood stasis, it was hypothesized that they may potentially alter the clinical outcomes of DAPT with clopidogrel and aspirin. AIM OF STUDY: The current study is proposed aiming to preliminarily evaluate the impact of these four commonly used Chinese medicinal herbs on the pharmacokinetics and pharmacodynamics of the combination therapy with clopidogrel and aspirin and its relevant outcomes and mechanisms. MATERIALS AND METHODS: In order to mimic the standard dosing regimen for DAPT in human, various Sprague-Dawley rats treatment groups were received a bolus oral dose of DAPT on day 1 followed by DAPT for consecutive 13 days in absence and presence of orally co-administered four TCM herbs (Danshen, Gegen, Danggui and Chuanxiong) at their low and high doses. On day 14, serial blood samples were collected after dosing to obtain the plasma concentrations of ASA, CLP and their corresponding metabolites by LC/MS/MS. At the end of last blood sampling point of each rat, about 4.5ml of whole blood were collected to estimate the prothrombin time from each treatment groups. After all the blood sampling, the rats were sacrificed followed by collecting their livers for evaluations of enzyme activities and expressions in the related liver microsome preparations and stomach tissues for evaluations of their potential ulcer index. In addition, gene expression and protein levels of related biomarkers (COX-1, COX-2, P2Y12) in rat livers were measured by RT-PCR and Western blot, respectively, and compared among different treatment groups. RESULTS: Co-administration of Gegen and Danggui significantly altered the pharmacokinetics of ASA and CLP in DAPT with increased systemic exposure of ASA and CLP respectively. Although minimal impact on aspirin esterase activity for all co-administered herbs, significant inhibition on rCyp2c11 and carboxylesterase activities were observed for DAPT with Danshen, Gegen and Danggui co-treatment. In addition, significantly longer PT were found in all DAPT treatment groups. However, a trend of decrease in PT of DAPT in presence of Gegen, Danggui and Chuanxiong was noticed. Nevertheless, all the treatments did not cause detectable changes in COX and P2Y12 mRNA and protein expressions. CONCLUSION: Among the four studied TCMs, it was demonstrated that co-administration of Gegen and Danggui could lead to altered pharmacokinetics of DAPT with significant inhibition on rCyp2c11 and carboxylesterase activities. Although Gegen, Danggui and Chuanxiong might potentially offset the anticoagulant activity of DAPT, the overall pharmacodynamics outcome was not considered to be harmful due to lack of risk in bleeding, which warrant further verification for its clinical impact. Title: Genome-wide association studies reveal genetic loci associated with plasma cholinesterase activity in ducks Xu Y, Liu H, Jiang Y, Fan W, Hu J, Zhang Y, Guo Z, Xie M, Huang W and Hou S <2 more author(s)> Xu Y, Liu H, Jiang Y, Fan W, Hu J, Zhang Y, Guo Z, Xie M, Huang W, Liu X, Zhou Z, Hou S (- 2) Ref: Anim Genet, 50:287, 2019 : PubMed ESTHER: Xu_2019_Anim.Genet_50_287 PubMedSearch: Xu 2019 Anim.Genet 50 287 PubMedID: 30994195 Gene_locus related to this paper: anapl-BCHE Abstract Plasma cholinesterase (PCHE) activity is an important auxiliary test in human clinical medicine. It can distinguish liver diseases from non-liver diseases and help detect organophosphorus poisoning. Animal experiments have confirmed that PCHE activity is associated with obesity and hypertension and changes with physiological changes in an animal's body. The objective of this study was to locate the genetic loci responsible for PCHE activity variation in ducks. PCHE activity of Pekin duck x mallard F2 ducks at 3 and 8 weeks of age were analyzed, and genome-wide association studies were conducted. A region of about 1.5 Mb (21.8-23.3 Mb) on duck chromosome 9 was found to be associated with PCHE activity at both 3 and 8 weeks of age. The top SNP, g.22643979C>T in the butyrylcholinesterase (BCHE) gene, was most highly associated with PCHE activity at 3 weeks (-logP = 21.45) and 8 weeks (-logP = 27.60) of age. For the top SNP, the strong associations of CC and CT genotypes with low PCHE activity and the TT genotype with high PCHE activity indicates the dominant inheritance of low PCHE activity. Problems with block inheritance or linkage exist in this region. This study supports that BCHE is a functional gene for determining PCHE levels in ducks and that the genetic variations around this gene can cause phenotypic variations of PCHE activity. Title: Fluevirines E and F, two new alkaloids from Flueggea virosa Yang X, Liu J, Huo Z, Yuwen H, Li Y, Zhang Y Ref: Nat Prod Res, :1, 2019 : PubMed ESTHER: Yang_2019_Nat.Prod.Res__1 PubMedSearch: Yang 2019 Nat.Prod.Res 1 PubMedID: 30721084 Abstract Two new alkaloids, fluevirines E (1) and F (2), along with six known Securinega alkaloids, were isolated from the methanol extract of the twigs and leaves of Flueggea virosa. The structures and absolute configurations of the new compounds were elucidated by means of MS, NMR, and ECD analyses. Compound 1 is a new dimeric indole alkaloid while 2 is a new securinega-type alkaloid. The in vitro cytotoxic activities of the isolated alkaloids against several human cancer cell lines and their acetylcholinesterase inhibitory activity were also evaluated. Title: Biomarker Effects in Carassius auratus Exposure to Ofloxacin, Sulfamethoxazole and Ibuprofen Yang X, Xu X, Wei X, Wan J, Zhang Y Ref: Int J Environ Research Public Health, 16:, 2019 : PubMed ESTHER: Yang_2019_Int.J.Environ.Res.Public.Health_16_ PubMedSearch: Yang 2019 Int.J.Environ.Res.Public.Health 16 PubMedID: 31075982 Abstract Ofloxacin, sulfamethoxazole and ibuprofen are three commonly used drugs which can be detected in aquatic environments. To assess their ecotoxicity, the effects of these three pharmaceuticals and their mixture on AChE (acetylcholinesterase) activity in the brain, and EROD (7-ethoxyresorufin-O-deethylase) and SOD (superoxide dismutase) activities in the liver of the freshwater crucian carp Carassius auratus were tested after exposure for 1, 2, 4 and 7 days. The results showed that treatments with 0.002(-)0.01 mg/L ofloxacin and 0.0008(-)0.004 mg/L sulfamethoxazole did not significantly change AChE, EROD and SOD activities. AChE activity was significantly inhibited in response to treatment with 0.05mg/L ofloxacin and 0.02mg/L sulfamethoxazole. All three biomarkers were induced significantly in treatments with ibuprofen and the mixture of the three pharmaceuticals at all the tested concentrations. The combined effects of ofloxacin, sulfamethoxazole and ibuprofen were compared with their isolated effects on the three biomarkers, and the results indicated that exposure to ibuprofen and the mixture at environmentally relevant concentrations could trigger adverse impacts on Carassius auratus. The hazard quotient (HQ) index also demonstrated a high risk for ibuprofen. Moreover, the present study showed that the effects of ofloxacin, sulfamethoxazole and ibuprofen might be additive on the physiological indices of Carassius auratus. Title: Carboxylesterase, a de-esterification enzyme, catalyzes the degradation of chlorimuron-ethyl in Rhodococcus erythropolis D310-1 Zang H, Wang H, Miao L, Cheng Y, Zhang Y, Liu Y, Sun S, Wang Y, Li C Ref: J Hazard Mater, :121684, 2019 : PubMed ESTHER: Zang_2019_J.Hazard.Mater__121684 PubMedSearch: Zang 2019 J.Hazard.Mater 121684 PubMedID: 31784128 Gene_locus related to this paper: rhoe4-c1a280 Abstract Microbial degradation is considered to be the most acceptable method for degradation of chlorimuron-ethyl, a typical long-term residual sulfonylurea herbicide, but the underlying mechanism at the genetic and biochemical levels is unclear. In this work, the genome sequence of the chlorimuron-ethyl-degrading bacterium Rhodococcus erythropolis D310-1 was completed, and the gene clusters responsible for the degradation of chlorimuron-ethyl in D310-1 were predicted. A carboxylesterase gene, carE, suggested to be responsible for carboxylesterase de-esterification, was cloned from D310-1. CarE was expressed in Escherichia coli BL21 and purified to homogeneity. The active site of the chlorimuron-ethyl-degrading enzyme CarE and the biochemical activities of CarE were elucidated. The results demonstrated that CarE is involved in catalyzing the de-esterification of chlorimuron-ethyl. A carE deletion mutant strain, D310-1DeltacarE, was constructed, and the chlorimuron-ethyl degradation rate in the presence of 100mgL(-1) chlorimuron-ethyl within 120h decreased from 86.5 % (wild-type strain D310-1) to 58.2 % (mutant strain D310-1DeltacarE). Introduction of the plasmid pNit-carE restored the ability of the mutant strain to utilize chlorimuron-ethyl. This study is the first to demonstrate that carboxylesterase can catalyze the de-esterification reaction of chlorimuron-ethyl and provides new insights into the mechanism underlying the degradation of sulfonylurea herbicides and a theoretical basis for the utilization of enzyme resources. Title: Synergistic effect of acetyl xylan esterase from Talaromyces leycettanus JCM12802 and xylanase from Neocallimastix patriciarum achieved by introducing carbohydrate-binding module-1 Zhang Y, Yang H, Yu X, Kong H, Chen J, Luo H, Bai Y, Yao B Ref: AMB Express, 9:13, 2019 : PubMed ESTHER: Zhang_2019_AMB.Express_9_13 PubMedSearch: Zhang 2019 AMB.Express 9 13 PubMedID: 30694400 Gene_locus related to this paper: 9euro-a0a411dz87 Abstract Wheat bran is an effective raw material for preparation xylooligosaccharides; however, current research mainly focuses on alkali extraction and enzymatic hydrolysis methods. Since ester bonds are destroyed during the alkali extraction process, xylanase and arabinofuranosidase are mainly used to hydrolyze xylooligosaccharides. However, alkali extraction costs are very high, and the method also causes pollution. Therefore, this study focuses on elucidating a method to efficiently and directly degrade destarched wheat bran. First, an acidic acetyl xylan esterase (AXE) containing a carbohydrate-binding module-1 (CBM1) domain was cloned from Talaromyces leycettanus JCM12802 and successfully expressed in Pichia pastoris. Characterization showed that the full-length acetyl xylan esterase AXE + CBM1 was similar toe uncovered AXE with an optimum temperature and pH of 55 degrees C and 6.5, respectively. Testing the acetyl xylan esterase and xylanase derived from Neocallimastix patriciarum in a starch-free wheat bran cooperative experiment revealed that AXE + CBM1 and AXE produced 29% and 16% reducing sugars respectively, compared to when only NPXYN11 was used. In addition, introduced the CBM1 domain into NPXYN11, and the results indicated that the CBM1 domain showed little effect on NPXYN11 properties. Finally, the systematically synergistic effects between acetyl xylan esterase and xylanase with/without the CBM1 domain demonstrated that the combined ratio of AXE + CBM1 coming in first and NPXYN11 + CBM1 s increased reducing sugars by almost 35% with AXE and NPXYN11. Furthermore, each component's proportion remained the same with respect to xylooligosaccharides, with the largest proportion (86%) containing of 49% xylobiose and 37% xylotriose. Title: Potential Pharmacokinetic Drug(-)Drug Interaction Between Harmine, a Cholinesterase Inhibitor, and Memantine, a Non-Competitive N-Methyl-d-Aspartate Receptor Antagonist Zhang Y, Li S, Wang Y, Deng G, Cao N, Wu C, Ding W, Cheng X, Wang C Ref: Molecules, 24:, 2019 : PubMed ESTHER: Zhang_2019_Molecules_24_ PubMedSearch: Zhang 2019 Molecules 24 PubMedID: 30978991 Inhibitor(s) related to this paper: Harmine Abstract Harmine (HAR) is a beta-carboline alkaloid widely distributed in nature. It exhibits psychopharmacological effects of improving learning and memory. However, excessive dose of HAR can cause central tremor toxicity, which may be related to the glutamate system. Memantine (MEM) is a non-competitive N-methyl-d-aspartate receptor antagonist. It can be used for the treatment of Alzheimer's disease and also can block the neurotoxicity caused by glutamate. Therefore, combination of HAR and MEM would be meaningful and the pharmacokinetics investigation of HAR and MEM in combination is necessary. A ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established and validated for the simultaneous quantitative determination of MEM, HAR and harmol (HOL), a main metabolite of HAR, in rat plasma after oral administration of HAR and MEM in combination (5.0 mg/kg of MEM combined with 20.0, 40.0, 80.0 mg/kg of HAR). The contents of HAR and HOL were determined after oral administration of HAR (20.0, 40.0 and 80.0 mg/kg), and the content of MEM was determined after oral administration of MEM (5.0 mg/kg). Blood samples were collected from each rat at 0 (pre-dose), 0.08, 0.17, 0.25, 0.33, 0.50, 0.75, 1.0, 2.0, 4.0, 8.0, 12.0 and 24.0 h after administration. The maximum peak concentration (Cmax) of MEM was obviously decreased, and the area under the plasma concentration versus time curve from zero to time t (AUC(0-t)) and mean residence time (MRT) were significantly increased after combination with HAR. The Cmax and AUC(0-t) of HAR and its metabolite HOL were increased after combination with MEM. These findings suggested that co-administration of HAR and MEM could extend their residence time in rats, and then might increase the efficacy for treatment of Alzheimer's disease. Therefore, this study will provide a basis for the rational combined application of HAR and MEM. Title: Rational design of a Yarrowia lipolytica derived lipase for improved thermostability Zhang H, Sang J, Zhang Y, Sun T, Liu H, Yue R, Zhang J, Wang H, Dai Y and Liu F <1 more author(s)> Zhang H, S |
