Author Report for: Zhang CNo contact information in database for Zhang C
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, 95:8340, 2023 : PubMed ESTHER: Dong_2023_Anal.Chem_95_8340 PubMedSearch: Dong 2023 Anal.Chem 95 8340 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: IL-33 Downregulates Hepatic Carboxylesterase 1 in Acute Liver Injury via Macrophage-derived Exosomal miR-27b-3p Gao P, Li M, Lu J, Xiang D, Wang X, Xu Y, Zu Y, Guan X, Li G, Zhang C Ref: J Clin Transl Hepatol, 11:1130, 2023 : PubMed ESTHER: Gao_2023_J.Clin.Transl.Hepatol_11_1130 PubMedSearch: Gao 2023 J.Clin.Transl.Hepatol 11 1130 PubMedID: 37577217 Abstract BACKGROUND AND AIMS: We previously reported that carboxylesterase 1 (CES1) expression was suppressed following liver injury. The study aimed to explore the role of interleukin (IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1. METHODS: IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide (LPS)-, acetaminophen (APAP)-treated mice. We constructed IL-33 and ST2 knockout (KO) mice. ST2-enriched immune cells in livers were screened to identify the responsible cells. Macrophage-derived exosome (MDE) activity was tested by adding exosome inhibitors. Micro-RNAs (miRs) were extracted from control and IL-33-stimulated MDEs (IL-33-MDEs) and subjected miR sequencing (miR-Seq). Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays. Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p. RESULTS: Patient liver IL-33 and CES1 expression levels were inversely correlated. CES1 downregulation in liver injury was rescued in both IL-33-deficient and ST2 KO mice. Macrophages were shown to be responsible for IL-33 effects. IL-33-MDEs reduced CES1 levels in hepatocytes. Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs; miR-27b-3p was implicated in Nrf2 targeting. IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent. CONCLUSIONS: IL-33-ST2-GATA3 pathway signaling increases miR-27b-3p content in MDEs, which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2. The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury. Title: MAGL inhibition relieves synovial inflammation and pain via regulating NOX4-Nrf2 redox balance in osteoarthritis Li X, Tao H, Zhou J, Zhang L, Shi Y, Zhang C, Sun W, Chu M, Chen K and Hao Y <3 more author(s)> Li X, Tao H, Zhou J, Zhang L, Shi Y, Zhang C, Sun W, Chu M, Chen K, Gu C, Yang X, Geng D, Hao Y (- 3) Ref: Free Radic Biol Med, 208:13, 2023 : PubMed ESTHER: Li_2023_Free.Radic.Biol.Med_208_13 PubMedSearch: Li 2023 Free.Radic.Biol.Med 208 13 PubMedID: 37516370 Gene_locus related to this paper: human-MGLL Inhibitor(s) related to this paper: MJN110 Abstract Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage injury, hyperplasia of bone and inflammatory lesions of synovium. Monoacylglycerol lipase (MAGL), a member of the alpha/beta hydrolase superfamily, is involved in regulation of injury protection and immune-inflammation response. Autoinflammatory response of the synovium and the release of inflammatory mediators play critical roles in occurrence of early-stage OA. Fibroblast-like synoviocytes (FLSs) are resident mesenchymal cells of the synovial tissue. Considering that MAGL inhibition regulates the inflammatory signaling cascade, it is crucial to ascertain the biological effects and specific mechanisms of MAGL in alleviating inflammatory infiltration of OA FLSs. The aim of this study was to investigate the effect of MAGL on biological function in OA FLSs. Results from in vitro experiments showed that MAGL blockade not only effectively inhibited proliferation, invasion and migration of FLSs, but also downregulated expression of inflammatory-associated proteins. Sequencing results indicated that MAGL inhibition significantly suppressed NOX4-mediated oxidative stress, thus promoting Nrf2 nuclear accumulation and inhibiting generation of intracellular reactive oxygen species (ROS). Attenuation of NOX4 further alleviated redox dysplasia and ultimately improved tumor-like phenotypes, such as abnormal proliferation, migration and migration of FLSs. In vivo results corroborated this finding, with MAGL inhibition found to modulate pain and disease progression in an OA rat model. Collectively, these results indicate that MAGL administration is an ideal therapy treating OA. Title: An ultra-sensitive photoelectrochemical sensor for chlorpyrifos detection based on a novel BiOI/TiO(2) n-n heterojunction Lyu R, Lei Y, Zhang C, Li G, Han R, Zou L Ref: Anal Chim Acta, 1275:341579, 2023 : PubMed ESTHER: Lyu_2023_Anal.Chim.Acta_1275_341579 PubMedSearch: Lyu 2023 Anal.Chim.Acta 1275 341579 PubMedID: 37524465 Abstract Due to widespread application of chlorpyrifos for controlling pests in agriculture, the continuous accumulation of chlorpyrifos residue has caused serious environmental pollution.The detection of chlorpyrifos is of great significance for humans and environment because it can arise a series of diseases by inhibiting acetylcholinesterase (AChE) activity. Photoelectrochemical sensing, as an emerging sensing technology, has great potential in the detection of chlorpyrifos. It is urgent that find a suitable photoelectric sensing strategy to effectively monitor chlorpyrifos. Herein, an n-n heterojunction was constructed by uniformly immobilizing n-type 3DBiOI, which had loose porous structure composed of numerous small and thin nanosheets, on the surface of TiO(2) with anatase/rutile (AR-TiO(2)) heterophase junction. Under light irradiation, the proposed BiOI/AR-TiO(2) n-n heterojunction exhibited excellent optical absorption characteristics and photoelectrochemical activity. Additionally, the photoelectrochemical sensing platform demonstrated excellent analytical performance in monitoring chlorpyrifos. Under optimized conditions, it showed a wide detection range of 1 pg mL(-1)- 200 ng mL(-1) and a detection limit (S/N = 3) as low as 0.24 pg mL(-1), with superior selectivity and stability. The ultra-sensitivity and great specificity for detection of chlorpyrifos can be ascribed to chelation between Bi () and C=N and P=S bonds in chlorpyrifos, which had been confirmed in this work. Meanwhile, the PEC sensor also had potential application value for monitoring chlorpyrifos in water samples, lettuce and pitaya, which the recoveries of samples ranged from 96.9% to 104.7% with a relative standard deviation (RSD) of 1.11%-5.93%. This sensor provided a novel idea for constructing heterojunctions with high photoelectric conversion efficiency and had a high application prospect for the detection of chlorpyrifos and other structural analogues. Title: Molecular Modeling Insights into Metal-Organic Frameworks (MOFs) as a Potential Matrix for Immobilization of Lipase: An In Silico Study Patil PJ, Kamble SA, Dhanavade MJ, Liang X, Zhang C, Li X Ref: Biology (Basel), 12:, 2023 : PubMed ESTHER: Patil_2023_Biology.(Basel)_12_ PubMedSearch: Patil 2023 Biology.(Basel) 12 PubMedID: 37626937 Abstract CRL is a highly versatile enzyme that finds extensive utility in numerous industries, which is attributed to its selectivity and catalytic efficiency, which have been impeded by the impracticality of its implementation, leading to a loss of native catalytic activity and non-reusability. Enzyme immobilization is a necessary step for enabling its reuse, and it provides methods for regulating the biocatalyst's functional efficacy in a synthetic setting. MOFs represent a novel category of porous materials possessing distinct superlative features that make MOFs an optimal host matrix for developing enzyme-MOF composites. In this study, we employed molecular modeling approaches, for instance, molecular docking and MD simulation, to explore the interactions between CRL and a specific MOF, ZIF-8. The present study involved conducting secondary structural analysis and homology modeling of CRL, followed by docking ZIF-8 with CRL. The results of the molecular docking analysis indicate that ZIF-8 was situated within the active site pocket of CRL, where it formed hydrogen bonds with Val-81, Phe-87, Ser-91, Asp-231, Thr-132, Lue-297, Phe-296, Phe-344, Thr-347, and Ser-450. The MD simulation analysis revealed that the CRL and ZIF-8 docked complex exhibited stability over the entire simulation period, and all interactions presented in the initial docked complex were maintained throughout the simulation. The findings derived from this investigation could promote comprehension of the molecular mechanisms underlying the interaction between CRL and ZIF-8 as well as the development of immobilized CRL for diverse industrial purposes. Title: A cell-type-specific alternative splicing regulator shapes synapse properties in a trans-synaptic manner Traunmuller L, Schulz J, Ortiz R, Feng H, Furlanis E, Gomez AM, Schreiner D, Bischofberger J, Zhang C, Scheiffele P Ref: Cell Rep, 42:112173, 2023 : PubMed ESTHER: Traunmuller_2023_Cell.Rep_42_112173 PubMedSearch: Traunmuller 2023 Cell.Rep 42 112173 PubMedID: 36862556 Abstract The specification of synaptic properties is fundamental for the function of neuronal circuits. "Terminal selector" transcription factors coordinate terminal gene batteries that specify cell-type-specific properties. Moreover, pan-neuronal splicing regulators have been implicated in directing neuronal differentiation. However, the cellular logic of how splicing regulators instruct specific synaptic properties remains poorly understood. Here, we combine genome-wide mapping of mRNA targets and cell-type-specific loss-of-function studies to uncover the contribution of the RNA-binding protein SLM2 to hippocampal synapse specification. Focusing on pyramidal cells and somatostatin (SST)-positive GABAergic interneurons, we find that SLM2 preferentially binds and regulates alternative splicing of transcripts encoding synaptic proteins. In the absence of SLM2, neuronal populations exhibit normal intrinsic properties, but there are non-cell-autonomous synaptic phenotypes and associated defects in a hippocampus-dependent memory task. Thus, alternative splicing provides a critical layer of gene regulation that instructs specification of neuronal connectivity in a trans-synaptic manner. Title: Exploration of the SIRT1-mediated BDNF-TrkB signaling pathway in the mechanism of brain damage and learning and memory effects of fluorosis Wang F, Li Y, Tang D, Yang B, Tian T, Tian M, Meng N, Xie W, Zhang C and Liu Y <3 more author(s)> Wang F, Li Y, Tang D, Yang B, Tian T, Tian M, Meng N, Xie W, Zhang C, He Z, Zhu X, Ming D, Liu Y (- 3) Ref: Front Public Health, 11:1247294, 2023 : PubMed ESTHER: Wang_2023_Front.Public.Health_11_1247294 PubMedSearch: Wang 2023 Front.Public.Health 11 1247294 PubMedID: 37711250 Abstract INTRODUCTION: Fluoride is considered an environmental pollutant that seriously affects organisms and ecosystems, and its harmfulness is a perpetual public health concern. The toxic effects of fluoride include organelle damage, oxidative stress, cell cycle destruction, inflammatory factor secretion, apoptosis induction, and synaptic nerve transmission destruction. To reveal the mechanism of fluorosis-induced brain damage, we analyzed the molecular mechanism and learning and memory function of the SIRT1-mediated BDNF-TrkB signaling pathway cascade reaction in fluorosis-induced brain damage through in vivo experiments. METHODS: This study constructed rat models of drinking water fluorosis using 50 mg/L, 100 mg/L, and 150 mg/L fluoride, and observed the occurrence of dental fluorosis in the rats. Subsequently, we measured the fluoride content in rat blood, urine, and bones, and measured the rat learning and memory abilities. Furthermore, oxidative stress products, inflammatory factor levels, and acetylcholinesterase (AchE) and choline acetyltransferase (ChAT) activity were detected. The pathological structural changes to the rat bones and brain tissue were observed. The SIRT1, BDNF, TrkB, and apoptotic protein levels were determined using western blotting. RESULTS: All rats in the fluoride exposure groups exhibited dental fluorosis; decreased learning and memory abilities; and higher urinary fluoride, bone fluoride, blood fluoride, oxidative stress product, and inflammatory factor levels compared to the control group. The fluoride-exposed rat brain tissue had abnormal AchE and ChAT activity, sparsely arranged hippocampal neurons, blurred cell boundaries, significantly fewer astrocytes, and swollen cells. Furthermore, the nucleoli were absent from the fluoride-exposed rat brain tissue, which also contained folded neuron membranes, deformed mitochondria, absent cristae, vacuole formation, and pyknotic and hyperchromatic chromatin. The fluoride exposure groups had lower SIRT1, BDNF, and TrkB protein levels and higher apoptotic protein levels than the control group, which were closely related to the fluoride dose. The findings demonstrated that excessive fluoride caused brain damage and affected learning and memory abilities. DISCUSSION: Currently, there is no effective treatment method for the tissue damage caused by fluorosis. Therefore, the effective method for preventing and treating fluorosis damage is to control fluoride intake. 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: Flavin-enabled reductive and oxidative epoxide ring opening reactions De BC, Zhang W, Yang C, Mandi A, Huang C, Zhang L, Liu W, Ruszczycky MW, Zhu Y and Zhang C <4 more author(s)> De BC, Zhang W, Yang C, Mandi A, Huang C, Zhang L, Liu W, Ruszczycky MW, Zhu Y, Ma M, Bashiri G, Kurtan T, Liu Hw, Zhang C (- 4) Ref: Nat Commun, 13:4896, 2022 : PubMed ESTHER: De BC#Zhang_2022_Nat.Commun_13_4896 PubMedSearch: De BC#Zhang 2022 Nat.Commun 13 4896 PubMedID: 35986005 Abstract Epoxide ring opening reactions are common and important in both biological processes and synthetic applications and can be catalyzed in a non-redox manner by epoxide hydrolases or reductively by oxidoreductases. Here we report that fluostatins (FSTs), a family of atypical angucyclines with a benzofluorene core, can undergo nonenzyme-catalyzed epoxide ring opening reactions in the presence of flavin adenine dinucleotide (FAD) and nicotinamide adenine dinucleotide (NADH). The 2,3-epoxide ring in FST C is shown to open reductively via a putative enol intermediate, or oxidatively via a peroxylated intermediate with molecular oxygen as the oxidant. These reactions lead to multiple products with different redox states that possess a single hydroxyl group at C-2, a 2,3-vicinal diol, a contracted five-membered A-ring, or an expanded seven-membered A-ring. Similar reactions also take place in both natural products and other organic compounds harboring an epoxide adjacent to a carbonyl group that is conjugated to an aromatic moiety. Our findings extend the repertoire of known flavin chemistry that may provide new and useful tools for organic synthesis. Title: FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis Du Q, Liu P, Zhang C, Liu T, Wang W, Shang C, Wu J, Liao Y, Chen Y and Yao S <5 more author(s)> Du Q, Liu P, Zhang C, Liu T, Wang W, Shang C, Wu J, Liao Y, Chen Y, Huang J, Tan H, Zhao Y, Xia M, Liu J, Yao S (- 5) Ref: Cell Death Dis, 13:488, 2022 : PubMed ESTHER: Du_2022_Cell.Death.Dis_13_488 PubMedSearch: Du 2022 Cell.Death.Dis 13 488 PubMedID: 35597782 Abstract Cervical cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. Clarification of the detailed mechanisms underlying LNM may provide potential clinical therapeutic targets for CC patients with LNM. However, the molecular mechanism of LNM in CC is unclear. In the present study, we demonstrated that fatty acid synthase (FASN), one of the key enzymes in lipid metabolism, had upregulated expression in the CC samples and was correlated with LNM. Moreover, multivariate Cox proportional hazards analysis identified FASN as an independent prognostic factor of CC patients. Furthermore, gain-of-function and loss-of-function approaches showed that FASN promoted CC cell migration, invasion, and lymphangiogenesis. Mechanistically, on the one hand, FASN could regulate cholesterol reprogramming and then activate the lipid raft-related c-Src/AKT/FAK signaling pathway, leading to enhanced cell migration and invasion. On the other hand, FASN induced lymphangiogenesis by secreting PDGF-AA/IGFBP3. More importantly, knockdown of FASN with FASN shRNA or the inhibitors C75 and Cerulenin dramatically diminished LNM in vivo, suggesting that FASN plays an essential role in LNM of CC and the clinical application potential of FASN inhibitors. Taken together, our findings uncover a novel molecular mechanism in LNM of CC and identify FASN as a novel prognostic factor and potential therapeutic target for LNM in CC. Title: Fuzzy supertertiary interactions within PSD-95 enable ligand binding Hamilton GL, Saikia N, Basak S, Welcome FS, Wu F, Kubiak J, Zhang C, Hao Y, Seidel CAM and Bowen ME <2 more author(s)> Hamilton GL, Saikia N, Basak S, Welcome FS, Wu F, Kubiak J, Zhang C, Hao Y, Seidel CAM, Ding F, Sanabria H, Bowen ME (- 2) Ref: Elife, 11:, 2022 : PubMed ESTHER: Hamilton_2022_Elife_11_ PubMedSearch: Hamilton 2022 Elife 11 PubMedID: 36069777 Abstract The scaffold protein PSD-95 links postsynaptic receptors to sites of presynaptic neurotransmitter release. Flexible linkers between folded domains in PSD-95 enable a dynamic supertertiary structure. Interdomain interactions within the PSG supramodule, formed by PDZ3, SH3 and Guanylate Kinase domains, regulate PSD-95 activity. Here we combined Discrete Molecular Dynamics and single molecule FRET to characterize the PSG supramodule, with time resolution spanning picoseconds to seconds. We used a FRET network to measure distances in full-length PSD-95 and model the conformational ensemble. We found that PDZ3 samples two conformational basins, which we confirmed with disulfide mapping. To understand effects on activity, we measured binding of the synaptic adhesion protein neuroligin. We found that PSD-95 bound neuroligin well at physiological pH while truncated PDZ3 bound poorly. Our hybrid structural models reveal how the supertertiary context of PDZ3 enables recognition of this critical synaptic ligand. Title: Evaluation on the Metabolic Activity of Two Carboxylesterase Isozymes in Mouse Liver Microsomes by a LC-MS/MS Method Lan L, Li M, Xu Y, Ren X, Zhang C Ref: Journal of Chromatography Sci, :, 2022 : PubMed ESTHER: Lan_2022_J.Chromatogr.Sci__ PubMedSearch: Lan 2022 J.Chromatogr.Sci PubMedID: 36585777 Abstract An applicable method for the precise measurement of major carboxylesterase (CESs) activity in liver still limited. Clopidogrel and irinotecan are specific substrates for CES1 and CES2, respectively. Clopidogrel is metabolized to the inactive metabolite clopidogrel carboxylate (CCAM) by CES1. Irinotecan is metabolized to the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by CES2. In the present study, the LC-MS/MS method for the determination of CCAM and SN-38 were separately developed to characterize the metabolic activities of CES1 and CES2 in mouse liver microsomal. CCAM was separated on a Ecosil ODS column with an isocratic mobile phase consisted of 5smmol/L ammonium formate and 0.1% formic acid in water and acetonitrile (15:85, V:V) at a flow rate of 0.4mL/min. SN-38 was separated on a Waters symmetry C18 column with an gradient mobile phase consisted of 5smmol/L ammonium formate and 0.1% formic acid in water and acetonitrile at a flow rate of 0.3smL/min. Calibration curves were linear within the concentration range of 100-20,000sng/mL for CCAM and 1-200sng/mL for SN-38. The results of method showed excellent accuracy and precision. The recovery rate, matrix effect and stability inspection results were within the acceptance criteria. The optimized incubation conditions were as follows: protein concentration of microsomes were all 0.1smg/mL, incubation time was 60smin for clopidogrel and 30smin for irinotecan, respectively. This method was sensitive and applicable for the determination of the activity of CESs in the mouse liver microsomes. Title: Simultaneous measurement of six biomarkers of dichlorvos in blood by ultra performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry Li P, Zhang C, Guo Z, Wei Z, Yun K, Liu Y Ref: Journal of Chromatography B Analyt Technol Biomed Life Sciences, 1208:123381, 2022 : PubMed ESTHER: Li_2022_J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci_1208_123381 PubMedSearch: Li 2022 J.Chromatogr.B.Analyt.Technol.Biomed.Life.Sci 1208 123381 PubMedID: 35932694 Abstract A protocol was developed, via a data-dependent high-resolution tandem mass spectrometry (ddHRMS/MS), to detect six biomarkers of dichlorvos in its metabolites and blood adducts of butyrylcholinesterase and albumin without using standard synthetic peptides. Firstly, the adducts of dimethoxy phosphonate (DMP-BChE) and the aged adducts of methoxy phosphonate (MxP-BChE) were isoloated by immunomagnetic separation (IMS), and then digested to DMP-nonapeptide and MxP-nonapeptide by pepsin. The dichlorvos and its metabolites (Trimethyl phosphate, Dimethyl phosphate) were analyzed in the supernatant of IMS treatment after protein precipitation. The precipitate was digested by pronase to phosphorylated tyrosine (DMP-Tyr), which were quantified by ultra performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry (UPLC-MS). The linearity of detector response of all biomarkers was studied in their respective ranges, and the correlation coefficients (R(2)) were all greater than 0.9981. The limits of detection (LOD) and limits of quantification (LOQ) were 0.2-10 ng/mL and 0.5-20 ng/mL, respectively. The recoveries of the six biomarkers were 78.6-110.0 %, matrix effect were 64.1-106.8 %. Inter- and intra-assay precision had coefficients of variation of >=13.2 % and >=9.7 %, respectively. In addition, MxP- BChE, DMP-Tyr, TMP, DMP and DDVP were detected in the blood of three cases who died from DDVP poisoning, but DMP- BChE was not detected in all of them, which may be caused by the instability of DMP- BChE and its easy aging to form MxP-BCHE. Title: Protective effects of isofraxidin against scopolamine-induced cognitive and memory impairments in mice involve modulation of the BDNF-CREB-ERK signaling pathway Lian B, Gu J, Zhang C, Zou Z, Yu M, Li F, Wu X, Zhao AZ Ref: Metabolic Brain Disease, :, 2022 : PubMed ESTHER: Lian_2022_Metab.Brain.Dis__ PubMedSearch: Lian 2022 Metab.Brain.Dis PubMedID: 35921056 Abstract BACKGROUND: Isofraxidin is a coumarin compound mainly isolated from several traditional and functional edible plants beneficial for neurodegenerative diseases, including Sarcandra glabra and Apium graveolens, and Siberian Ginseng. OBJECTIVE: This study aimed to assess effects of isofraxidin against memory impairments and cognition deficits in a scopolamine-induced mouse model. MATERIALS & METHODS: Animals were randomly divided into 6 groups, control, vehicle, donepezil (10 mg/kg, p.o.), and isofraxidin (3, 10, and 30 mg/kg, p.o.). Isofraxidin or donepezil was administered for 44 days, once per day. The scopolamine insults (1 mg/kg, i.p.) was given from the 21st day, once per day. Morris water maze test and Y-maze test were used for the behavioral test. After that, brain samples were collected for analysis. RESULTS: Firstly, isofraxidin significantly improved scopolamine-induced behavioral impairments and cognition deficits in Morris water maze and Y-maze test. Then, isofraxidin facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, isofraxidin decreased lipid peroxidation level but enhanced levels of glutathione, glutathione peroxidase, and superoxide dismutase. Moreover, isofraxidin suppressed the expression of inflammatory mediators and cytokines. Further investigations showed that isofraxidin up-regulated expression of brain-derived neurotrophic factor (BDNF), and promoted phosphorylation of tropomyosin-related kinase B (TrkB), cyclic AMP-response element-binding protein (CREB), and extracellular signal-regulated kinase (ERK). DISCUSSION & CONCLUSIONS: These results suggested that isofraxidin ameliorated scopolamine-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress and inflammatory response, and modulating BDNF-CREB-ERK pathways. Title: Inhibition of Dipeptidyl Peptidase-4 by Flavonoids: Structure-Activity Relationship, Kinetics and Interaction Mechanism Pan J, Zhang Q, Zhang C, Yang W, Liu H, Lv Z, Liu J, Jiao Z Ref: Front Nutr, 9:892426, 2022 : PubMed ESTHER: Pan_2022_Front.Nutr_9_892426 PubMedSearch: Pan 2022 Front.Nutr 9 892426 PubMedID: 35634373 Abstract With the aim to establish a structure-inhibitory activity relationship of flavonoids against dipeptidyl peptidase-4 (DPP-4) and elucidate the interaction mechanisms between them, a pannel of 70 structurally diverse flavonoids was used to evaluate their inhibitory activities against DPP-4, among which myricetin, hyperoside, narcissoside, cyanidin 3-O-glucoside, and isoliquiritigenin showed higher inhibitory activities in a concentration-dependent manner. Structure-activity relationship analysis revealed that introducing hydroxyl groups to C3', C4', and C6 of the flavonoid structure was beneficial to improving the inhibitory efficacy against DPP-4, whereas the hydroxylation at position 3 of ring C in the flavonoid structure was unfavorable for the inhibition. Besides, the methylation of the hydroxyl groups at C3', C4', and C7 of the flavonoid structure tended to lower the inhibitory activity against DPP-4, and the 2,3-double bond and 4-carbonyl group on ring C of the flavonoid structure was essential for the inhibition. Glycosylation affected the inhibitory activity diversely, depending on the structure of flavonoid aglycone, type of glycoside, as well as the position of substitution. Inhibition kinetic analysis suggested that myricetin reversibly inhibited DPP-4 in a non-competitive mode, whereas hyperoside, narcissoside, cyanidin 3-O-glucoside, and isoliquiritigenin all reversibly inhibited DPP-4 in a mixed type. Moreover, the fluorescence quenching analysis indicated that all the five flavonoid compounds could effectively quench the intrinsic fluorescence of DPP-4 by spontaneously binding with it to form an unstable complex. Hydrogen bonds and van der Waals were the predominant forces to maintain the complex of myricetin with DPP-4, and electrostatic forces might play an important role in stabilizing the complexes of the remaining four flavonoids with DPP-4. The binding of the tested flavonoids to DPP-4 could also induce the conformation change of DPP-4 and thus led to inhibition on the enzyme. Molecular docking simulation further ascertained the binding interactions between DPP-4 and the selected five flavonoids, among which hyperoside, narcissoside, cyaniding 3-O-glucoside, and isoliquiritigenin inserted into the active site cavity of DPP-4 and interacted with the key amino acid residues of the active site, whereas the binding site of myricetin was located in a minor cavity close to the active pockets of DPP-4. Title: Identification of closely associated SNPs and candidate genes with seed size and shape via deep re-sequencing GWAS in soybean Shao Z, Shao J, Huo X, Li W, Kong Y, Du H, Li X, Zhang C Ref: Theor Appl Genet, :, 2022 : PubMed ESTHER: Shao_2022_Theor.Appl.Genet__ PubMedSearch: Shao 2022 Theor.Appl.Genet PubMedID: 35588015 Abstract A soybean natural population was genotyped by deep re-sequencing and phenotyped for six seed size- and shape-related traits under six environments to identify closely associated SNPs and candidate genes. Seed size and shape are important determining factors for soybean yield formation, while their genetic basis and molecular mechanism are still largely unknown, which seriously constrains the increasing of soybean yield at present. In view of this, a natural population was genotyped via the deep re-sequencing technique (~ 20 x) and phenotyped for six related traits under six environments. In total, 154 SNPs were closely associated with seed length across diverse environments, and 323, 483, 565, 394 and 2038 SNPs were closely associated with seed width, seed diameter, seed circumference, seed area and ratio of length to width under multiple environments. Moreover, 98.70%, 96.28%, 48.24%, 85.13%, 97.21% and 98.58% of them were further demonstrated by the BLUP and mean values of the related traits. Furthermore, 218 genes flanking the associated SNPs on chromosomes 6 and 10 were analyzed for DNA mutations and RNA expressions through SNP alleles and transcriptome data, simultaneously. The candidate genes, Glyma.10G035200 (Sn1-specific diacylglycerol lipase), Glyma.10G035400 (transcription factor) and Glyma.10G058200 (phenylalanine ammonia-lyase), were discovered to relate with the seed size and shape for their different DNA sequences or differential RNA expressions among soybean varieties at five seed developmental stages. Thus, these closely associated SNPs and related genes provide novel insights and useful information for the seed size and shape genetic basis dissection and breeding improvement in soybean. Title: A symbiotic gut bacterium enhances Aedes albopictus resistance to insecticide Wang H, Liu H, Peng H, Wang Y, Zhang C, Guo X, Liu L, Lv W, Cheng P, Gong M Ref: PLoS Negl Trop Dis, 16:e0010208, 2022 : PubMed ESTHER: Wang_2022_PLoS.Negl.Trop.Dis_16_e0010208 PubMedSearch: Wang 2022 PLoS.Negl.Trop.Dis 16 e0010208 PubMedID: 35245311 Abstract BACKGROUND: The increasing insecticide resistance of Aedes albopictus puts many countries in Asia and Africa, including China, at great risk of a mosquito-borne virus epidemic. To date, a growing number of researches have focused on the relationship between intestinal symbiotic bacteria and their hosts' resistance to insecticides. This provides a novel aspect to the study of resistant mechanisms. METHODS/FINDINGS: This study reveals significant composition and dynamic changes in the intestinal symbiotic bacteria of Ae. albopictus between the resistant and susceptible strains based on full-length sequencing technology. The relative abundance of Serratia oryzae was significantly higher in the resistance strain than in the susceptible strains; also, the relative abundance of S. oryzae was significantly higher in deltamethrin-induced Ae. albopictus than in their counterpart. These suggested that S. oryzae may be involved in the development of insecticide resistance in Ae. albopictus. To explore the insecticide resistance mechanism, adult mosquitoes were fed with GFP-tagged S. oryzae, which resulted in stable bacterial enrichment in the mosquito gut without affecting the normal physiology, longevity, oviposition, and hatching rates of the host. The resistance measurements were made based on bioassays as per the WHO guidelines. The results showed that the survival rate of S. oryzae-enriched Ae. albopictus was significantly higher than the untreated mosquitoes, indicating the enhanced resistance of S. oryzae-enriched Ae. albopictus. Also, the activities of three metabolic detoxification enzymes in S. oryzae-enriched mosquitoes were increased to varying degrees. Meanwhile, the activity of extracellular enzymes released by S. oryzae was measured, but only carboxylesterase activity was detected. HPLC and UHPLC were respectively used to measure deltamethrin residue concentration and metabolite qualitative analysis, showing that the deltamethrin degradation efficiency of S. oryzae was positively correlated with time and bacterial amount. Deltamethrin was broken down into 1-Oleoyl-2-hydroxy-sn-glycero-3-PE and 2',2'-Dibromo-2'-deoxyguanosine. Transcriptome analysis revealed that 9 cytochrome P450s, 8 GSTs and 7 CarEs genes were significantly upregulated. CONCLUSIONS: S. oryzae can be accumulated into adult Ae. albopictus by artificial feeding, which enhances deltamethrin resistance by inducing the metabolic detoxification genes and autocrine metabolic enzymes. S. oryzae is vertically transmitted in Ae. albopictus population. Importantly, S. oryzae can degrade deltamethrin in vitro, and use deltamethrin as the sole carbon source for their growths. Therefore, in the future, S. oryzae may also be commercially used to break down the residual insecticides in the farmland and lakes to protect the environment. Title: Peroxidase-like activity of Ru-N-C nanozymes in colorimetric assay of acetylcholinesterase activity Yan B, Wang F, He S, Liu W, Zhang C, Chen C, Lu Y Ref: Anal Chim Acta, 1191:339362, 2022 : PubMed ESTHER: Yan_2022_Anal.Chim.Acta_1191_339362 PubMedSearch: Yan 2022 Anal.Chim.Acta 1191 339362 PubMedID: 35033267 Abstract Herein, the Ru-N-C nanozymes with abundant active Ru-N(x) sites have been successfully prepared by pyrolyzing Ru(acac)(3) trapped zeolitic-imidazolate-frameworks (Ru(acac)(3)@ZIF-8). Taking advantages of the remarkable peroxidase-mimicking activity, outstanding stability and reusability of Ru-N-C nanozymes, a novel biosensing system with explicit mechanism is strategically fabricated for sensitively determining acetylcholinesterase (AChE) and tacrine. The limit of detection for AChE activity can achieve as low as 0.0433 mU mL(-1), and the IC(50) value of tacrine for AChE is about 0.190 micromol L(-1). The robust analytical performance in serums test verifies the great application potential of this assay in real matrix. Furthermore, "INH" and "IMPLICATION-AND" logic gates are rationally constructed based on the proposed colorimetric sensor. This work not only provides one sustainable and effective avenue to fabricate Ru-N-C-based peroxidase mimic with high catalytic performance, and also gives new impetuses for developing novel biosensors by applying Ru-N-C-based enzyme mimics as substitutes for the natural enzyme. Title: Acute thiamethoxam exposure induces hepatotoxicity and neurotoxicity in juvenile Chinese mitten crab (Eriocheir sinensis) Yang Y, Yu Q, Zhang C, Wang X, He L, Huang Y, Li E, Qin J, Chen L Ref: Ecotoxicology & Environmental Safety, 249:114399, 2022 : PubMed ESTHER: Yang_2022_Ecotoxicol.Environ.Saf_249_114399 PubMedSearch: Yang 2022 Ecotoxicol.Environ.Saf 249 114399 PubMedID: 36508784 Abstract The similar nervous system structure between crustaceans and insects and the high-water solubility of thiamethoxam can lead to the more severe toxicity of thiamethoxam to crustaceans. However, the effects of thiamethoxam on crustaceans are unclear. Therefore, a 96-h acute toxicity test was performed to explore the hepatotoxicity and neurotoxicity effects of thiamethoxam on Chinese mitten crab (Eriocheir sinensis) at concentrations 0 microg/L, 150 microg/L and 300 microg/L. The antioxidant and detoxification systems (including phases I and II) were significantly activated after exposure of juvenile crabs to thiamethoxam for 24sh in 300 microg/L group, whereas the toxic activation effect in 150 microg/L group was delayed. Moreover, a similar pattern was observed for the transcription levels of immune-related genes. Further analysis of inflammatory signaling pathway-related genes showed that thiamethoxam exposure with 300 microg/L for 24sh may induce a pro-inflammatory response through the NF-kappaB pathway. In contrast, the gene expression levels in 150 microg/L group were significantly upregulated compared with 0 microg/L group after 96sh. In addition, although the acute exposure of 150 microg/L thiamethoxam did not seem to induce significant neurotoxicity, the acetylcholinesterase activity was significantly decreased in 300 microg/L group after thiamethoxam exposure for 96sh. Correspondingly, thiamethoxam exposure with 300 microg/L for 24sh resulted in significantly downregulated transcriptional levels of synaptic transmission-related genes (e.g. dopamine-, gamma-aminobutyric acid- and serotonin-related receptors). Therefore, thiamethoxam may be harmful and cause potential toxic threats such as neurotoxicity and metabolic damage to crustaceans. Title: Activated autophagy-lysosomal pathway in dairy cows with hyperketonemia is associated with lipolysis of adipose tissues Yu H, Fan M, Chen X, Jiang X, Loor JJ, Aboragah A, Zhang C, Bai H, Fang Z and Du X <5 more author(s)> Yu H, Fan M, Chen X, Jiang X, Loor JJ, Aboragah A, Zhang C, Bai H, Fang Z, Shen T, Wang Z, Song Y, Li X, Liu G, Du X (- 5) Ref: J Dairy Sci, :, 2022 : PubMed ESTHER: Yu_2022_J.Dairy.Sci__ PubMedSearch: Yu 2022 J.Dairy.Sci PubMedID: 35688731 Abstract Activated autophagy-lysosomal pathway (ALP) can degrade virtually all kinds of cellular components, including intracellular lipid droplets, especially during catabolic conditions. Sustained lipolysis and increased plasma fatty acids concentrations are characteristic of dairy cows with hyperketonemia. However, the status of ALP in adipose tissue during this physiological condition is not well known. The present study aimed to ascertain whether lipolysis is associated with activation of ALP in adipose tissues of dairy cows with hyperketonemia and in calf adipocytes. In vivo, blood and subcutaneous adipose tissue (SAT) biopsies were collected from nonhyperketonemic (nonHYK) cows [blood beta-hydroxybutyrate (BHB) concentration <1.2 mM, n = 10] and hyperketonemic (HYK) cows (blood BHB concentration 1.2-3.0 mM, n = 10) with similar days in milk (range: 3-9) and parity (range: 2-4). In vitro, calf adipocytes isolated from 5 healthy Holstein calves (1 d old, female, 30-40 kg) were differentiated and used for (1) treatment with lipolysis inducer isoproterenol (ISO, 10 microM, 3 h) or mammalian target of rapamycin inhibitor Torin1 (250 nM, 3 h), and (2) pretreatment with or without the ALP inhibitor leupeptin (10 microg/mL, 4 h) followed by ISO (10 microM, 3 h) treatment. Compared with nonHYK cows, serum concentration of free fatty acids was greater and serum glucose concentration, DMI, and milk yield were lower in HYK cows. In SAT of HYK cows, ratio of phosphorylated hormone-sensitive lipase to hormone-sensitive lipase, and protein abundance of adipose triacylglycerol lipase were greater, but protein abundance of perilipin 1 (PLIN1) and cell death-inducing DNA fragmentation factor-alpha-like effector c (CIDEC) was lower. In addition, mRNA abundance of autophagy-related 5 (ATG5), autophagy-related 7 (ATG7), and microtubule-associated protein 1 light chain 3 beta (MAP1LC3B), protein abundance of lysosome-associated membrane protein 1, and cathepsin D, and activity of beta-N-acetylglucosaminidase were greater, whereas protein abundance of sequestosome-1 (p62) was lower in SAT of HYK cows. In calf adipocytes, treatment with ISO or Torin1 decreased protein abundance of PLIN1, and CIDEC, and triacylglycerol content in calf adipocytes, but increased glycerol content in the supernatant of calf adipocytes. Moreover, the mRNA abundance of ATG5, ATG7, and MAP1LC3B was upregulated, the protein abundance of lysosome-associated membrane protein 1, cathepsin D, and activity of beta-N-acetylglucosaminidase were increased, whereas the protein abundance of p62 was decreased in calf adipocytes treated with ISO or Torin1 compared with control group. Compared with treatment with ISO alone, the protein abundance of p62, PLIN1, and CIDEC, and triacylglycerol content in calf adipocytes were higher, but the glycerol content in the supernatant of calf adipocytes was lower in ISO and leupeptin co-treated group. Overall, these data indicated that activated ALP is associated with increased lipolysis in adipose tissues of dairy cows with hyperketonemia and in calf adipocytes. Title: Reduced serum cholinesterase is an independent risk factor for all-cause mortality in the pediatric intensive care unit Yue C, Zhang C, Ying C, Jiang H Ref: Front Nutr, 9:809449, 2022 : PubMed ESTHER: Yue_2022_Front.Nutr_9_809449 PubMedSearch: Yue 2022 Front.Nutr 9 809449 PubMedID: 36505241 Abstract OBJECTIVE: Our aim was to assess the relationship between serum cholinesterase levels at intensive care unit admission and all-cause mortality in the pediatric intensive care unit. METHODS: We used the pediatric intensive care unit database (a large pediatric intensive care database in China from 2010 to 2018) to conduct a retrospective analysis to evaluate the serum cholinesterase levels at intensive care unit admission of 11,751 critically ill children enrolled to the intensive care unit. We analyzed the association between serum cholinesterase and all-cause mortality. Adjusted smoothing spline plots, subgroup analysis and segmented multivariate logistic regression analysis were conducted to estimate the relative risk between proportional risk between serum cholinesterase and death. RESULTS: Of the 11,751 children, 703 (5.98%) died in hospital. After adjusting for confounders, there was a negative association between serum cholinesterase and the risk of death in pediatric intensive care unit. For every 1,000 U/L increase in serum cholinesterase, the risk of death was reduced by 16% (adjusted OR = 0.84, 95% CI: 0.79, 0.89). The results of sensitivity analysis showed that in different stratified analyses (age, intensive care unit category, albumin, alanine aminotransferase, creatinine, neutrophils), the effect of serum cholinesterase on all-cause mortality remained stable. CONCLUSION: After adjusting for inflammation, nutrition, and liver function factors, cholinesterase reduction is still an independent risk factor for pediatric intensive care unit all-cause mortality. Title: Water-soluble non-conjugated polymer dots with strong green fluorescence for sensitive detection of organophosphate pesticides Zhang C, Li S, Duan Z, Li Q, Zhao M, Chen Y, Zhai X, Mao G, Wang H Ref: Anal Chim Acta, 1206:339792, 2022 : PubMed ESTHER: Zhang_2022_Anal.Chim.Acta_1206_339792 PubMedSearch: Zhang 2022 Anal.Chim.Acta 1206 339792 PubMedID: 35473871 Abstract Water-soluble non-conjugated polymer dots (PDs) have been synthesized using hyperbranched polyethyleneimine (PEI) and dihydroxybenzaldehyde (DHB) for the first time via the Schiff base reaction at room temperature. The yielded non-conjugated PDs of PEI-DHB could display the well-defined spheric structure and good water solubility. In contrast to the common PDs otherwise showing blue emission, the PEI-DHB PDs could give out strong green fluorescence in aqueous media. Especially, the fluorescence of the PEI-DHB PDs could be specifically quenched by MnO(2) nanosheets through the inner filter effects and further restored by the thiocholine that could reduce MnO(2) nanosheets into Mn(2+). Herein, thiocholine could be produced in hydrolysis reaction of acetylthiocholine catalyzed by the acetylcholinesterase (AChE), of which the catalytic activity could be irreversibly inhibitted by the introduction of organophosphates. A highly selective fluorimetric method was thereby been developed for the detection of organophosphorus pesticides using dimethyl-dichloro-vinyl phosphate as a model. The linear concentrations ranges from 0.050 to 2.5 microM. Importantly, the non-conjugated PDs probes with strong green fluorescence and high water solubility may promise the extensive applications in the environmental, food, and clinical analysis fields. Title: Novel aerosol treatment of airway hyper-reactivity and inflammation in a murine model of asthma with a soluble epoxide hydrolase inhibitor Zhang C, Li W, Li X, Wan D, Mack S, Zhang J, Wagner K, Wang C, Tan B and Yang J <7 more author(s)> Zhang C, Li W, Li X, Wan D, Mack S, Zhang J, Wagner K, Wang C, Tan B, Chen J, Wu CW, Tsuji K, Takeuchi M, Chen Z, Hammock BD, Pinkerton KE, Yang J (- 7) Ref: PLoS ONE, 17:e0266608, 2022 : PubMed ESTHER: Zhang_2022_PLoS.One_17_e0266608 PubMedSearch: Zhang 2022 PLoS.One 17 e0266608 PubMedID: 35443010 Inhibitor(s) related to this paper: TPPU Abstract Asthma currently affects more than 339 million people worldwide. In the present preliminary study, we examined the efficacy of a new, inhalable soluble epoxide hydrolase inhibitor (sEHI), 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), to attenuate airway inflammation, mucin secretion, and hyper-responsiveness (AHR) in an ovalbumin (OVA)-sensitized murine model. Male BALB/c mice were divided into phosphate-buffered saline (PBS), OVA, and OVA+TPPU (2- or 6-h) exposure groups. On days 0 and 14, the mice were administered PBS or sensitized to OVA in PBS. From days 26-38, seven challenge exposures were performed with 30 min inhalation of filtered air or OVA alone. In the OVA+TPPU groups, a 2- or 6-h TPPU inhalation preceded each 30-min OVA exposure. On day 39, pulmonary function tests (PFTs) were performed, and biological samples were collected. Lung tissues were used to semi-quantitatively evaluate the severity of inflammation and airway constriction and the volume of stored intracellular mucosubstances. Bronchoalveolar lavage (BAL) and blood samples were used to analyze regulatory lipid mediator profiles. Significantly (p < 0.05) attenuated alveolar, bronchiolar, and pleural inflammation; airway resistance and constriction; mucosubstance volume; and inflammatory lipid mediator levels were observed with OVA+TPPU relative to OVA alone. Cumulative findings indicated TPPU inhalation effectively inhibited inflammation, suppressed AHR, and prevented mucosubstance accumulation in the murine asthmatic model. Future studies should determine the pharmacokinetics (i.e., absorption, distribution, metabolism, and excretion) and pharmacodynamics (i.e., concentration/dose responses) of inhaled TPPU to explore its potential as an asthma-preventative or -rescue treatment. Title: Genome-Wide Detection of Copy Number Variations and Evaluation of Candidate Copy Number Polymorphism Genes Associated With Complex Traits of Pigs Zhang C, Zhao J, Guo Y, Xu Q, Liu M, Cheng M, Chao X, Schinckel AP, Zhou B Ref: Front Vet Sci, 9:909039, 2022 : PubMed ESTHER: Zhang_2022_Front.Vet.Sci_9_909039 PubMedSearch: Zhang 2022 Front.Vet.Sci 9 909039 PubMedID: 35847642 Abstract Copy number variation (CNV) has been considered to be an important source of genetic variation for important phenotypic traits of livestock. In this study, we performed whole-genome CNV detection on Suhuai (SH) (n = 23), Chinese Min Zhu (MZ) (n = 11), and Large White (LW) (n = 12) pigs based on next-generation sequencing data. The copy number variation regions (CNVRs) were annotated and analyzed, and 10,885, 10,836, and 10,917 CNVRs were detected in LW, MZ, and SH pigs, respectively. Some CNVRs have been randomly selected for verification of the variation type by real-time PCR. We found that SH and LW pigs are closely related, while MZ pigs are distantly related to the SH and LW pigs by CNVR-based genetic structure, PCA, V(ST), and QTL analyses. A total of 14 known genes annotated in CNVRs were unique for LW pigs. Among them, the cyclin T2 (CCNT2) is involved in cell proliferation and the cell cycle. The FA Complementation Group M (FANCM) is involved in defective DNA repair and reproductive cell development. Ten known genes annotated in 47 CNVRs were unique for MZ pigs. The genes included glycerol-3-phosphate acyltransferase 3 (GPAT3) is involved in fat synthesis and is essential to forming the glycerol triphosphate. Glutathione S-transferase mu 4 (GSTM4) gene plays an important role in detoxification. Eleven known genes annotated in 23 CNVRs were unique for SH pigs. Neuroligin 4 X-linked (NLGN4X) and Neuroligin 4 Y-linked (NLGN4Y) are involved with nerve disorders and nerve signal transmission. IgLON family member 5 (IGLON5) is related to autoimmunity and neural activities. The unique characteristics of LW, MZ, and SH pigs are related to these genes with CNV polymorphisms. These findings provide important information for the identification of candidate genes in the molecular breeding of pigs. Title: Administration of Huperzine A microspheres ameliorates myocardial ischemic injury via alpha7nAChR-dependent JAK2/STAT3 signaling pathway Zhang C, Li M, Xie W, You C, Wang T, Fu F Ref: European Journal of Pharmacology, 940:175478, 2022 : PubMed ESTHER: Zhang_2022_Eur.J.Pharmacol_940_175478 PubMedSearch: Zhang 2022 Eur.J.Pharmacol 940 175478 PubMedID: 36563953 Abstract Acetylcholinesterase (AChE) inhibitor (AChEI) is well established as rst-line agents for relieving the symptoms of Alzheimer's disease (AD). Injectable sustained-release formulation of AChEI may be suitable for treating AD patients. However, it needs to know whether continuous inhibition of AChE could deteriorate or attenuate myocardial damage if myocardial ischemia (MI) occurs. Huperzine A microspheres (HAM) are a sustained-release formulation releasing sustainably huperzine A (an AChEI) for more than 7 days after a single dose of HAM. This study aimed to investigate the myocardial damage in an isoprenaline (ISO)-induced MI mice model during HAM treatment. The heart injury was evaluated by assaying serum CK-MB, Tn-I and observing histopathological changes. The levels of proinflammatory cytokines in serum were detected. The level of p-P65 and the expression of proteins in the JAK2/STAT3 signaling pathway were assayed with Western blot. Administration with a single dose of HAM resulted in inhibiting the MI-induced increases of CK-MB and Tn-I, alleviating the damage of heart tissue, and decreasing the levels of TNF-alpha and IL-6. In addition, HAM decreased the levels of p-P65, p-JAK2, and p-STAT3 in heart tissue. The effects of HAM could be weakened or abolished by the specific alpha7nAChR antagonist. These findings suggest that continuous AChE inhibition could protect the heart from ischemic damage during administration of sustained-release formulation of AChEI, which is associated with the anti-inflammatory effect of HAM by regulating alpha7nAChR-dependent JAK2/STAT3 signaling pathway. Title: Molecular mechanism of LIP05 derived from Monascus purpureus YJX-8 for synthesizing fatty acid ethyl esters under aqueous phase Zhao J, Xu Y, Lu H, Zhao D, Zheng J, Lin M, Liang X, Ding Z, Dong W and Li X <4 more author(s)> Zhao J, Xu Y, Lu H, Zhao D, Zheng J, Lin M, Liang X, Ding Z, Dong W, Yang M, Li W, Zhang C, Sun B, Li X (- 4) Ref: Front Microbiol, 13:1107104, 2022 : PubMed ESTHER: Zhao_2022_Front.Microbiol_13_1107104 PubMedSearch: Zhao 2022 Front.Microbiol 13 1107104 PubMedID: 36713181 Abstract Fatty acid ethyl esters are important flavor chemicals in strong-flavor Baijiu. Monascus purpureus YJX-8 is recognized as an important microorganism for ester synthesis in the fermentation process. Enzyme LIP05 from YJX-8 can efficiently catalyze the synthesis of fatty acid ethyl esters under aqueous phase, but the key catalytic sites affecting esterification were unclear. The present work combined homology modeling, molecular dynamics simulation, molecular docking and site-directed mutation to analyze the catalytic mechanism of LIP05. Protein structure modeling indicated LIP05 belonged to alpha/beta fold hydrolase, contained a lid domain and a core catalytic pocket with conserved catalytic triad Ser150-His215-Asp202, and the oxyanion hole composed of Gly73 and Thr74. Ile30 and Leu37 of the lid domain were found to affect substrate specificity. The Pi-bond stacking between Tyr116 and Tyr149 played an important role in stabilizing the catalytic active center of LIP05. Tyr116 and Ile204 determined the substrate spectrum by composing the substrate-entrance channel. Residues Leu83, Ile204, Ile211 and Leu216 were involved in forming the hydrophobic substrate-binding pocket through steric hindrance and hydrophobic interaction. The catalytic mechanism for esterification in aqueous phase of LIP05 was proposed and provided a reference for clarifying the synthesis of fatty acid ethyl esters during the fermentation process of strong-flavor Baijiu. Title: Biodegradation of lambda-cyhalothrin through cell surface display of bacterial carboxylesterase Ding J, Liu Y, Gao Y, Zhang C, Wang Y, Xu B, Yang Y, Wu Q, Huang Z Ref: Chemosphere, 289:133130, 2021 : PubMed ESTHER: Ding_2021_Chemosphere_289_133130 PubMedSearch: Ding 2021 Chemosphere 289 133130 PubMedID: 34863720 Gene_locus related to this paper: 9baci-MW588803 Abstract Pyrethroids are the third widespread used insecticides globally which have been extensively applied in agricultural or household environments. Due to continuous applications, pyrethroids have been detected both in living cells and environments. The permanent exposure to pyrethroids have caused substantial health risks and ecosystem concerns. In this work, a lambda-cyhalothrin (one kind of pyrethroid insecticides) degrading bacterium Bacillus velezensis sd was isolated and a carboxylesterase gene, CarCB2 was characterized. A whole cell biocatalyst was developed for lambda-cyhalothrin biodegradation by displaying CarCB2 on the surface of Escherichia coli cells. CarCB2 was successfully displayed and functionally expressed on E. coli cells with optimal pH and temperature of 7.5 and 30 degreesC, using p-NPC(4) as substrate, respectively. The whole cell biocatalyst exhibited better stability than the purified CarCB2, and approximately 120%, 60% or 50% of its original activity at 4 degreesC, 30 degreesC or 37 degreesC over a period of 35 d was retained, respectively. No enzymatic activity was detected when incubated the purified CarCB2 at 30 degreesC for 120 h, or 37 degreesC for 72 h, respectively. Additionally, 30 mg/L of lambda-cyhalothrin was degraded in citrate-phosphate buffer by 10 U of the whole cell biocatalyst in 150 min. This work reveals that the whole cell biocatalyst affords a promising approach for efficient biodegradation of lambda-cyhalothrin, and might have the potential to be applied in further environmental bioremediation of other different kinds of pyrethroid insecticides. Title: A Neuroligin Isoform Translated by circNlgn Contributes to Cardiac Remodeling Du WW, Xu J, Yang W, Wu N, Li F, Zhou L, Wang S, Li X, He AT and Yang BB <7 more author(s)> Du WW, Xu J, Yang W, Wu N, Li F, Zhou L, Wang S, Li X, He AT, Du KY, Zeng K, Ma J, Lyu J, Zhang C, Zhou C, Maksimovic K, Yang BB (- 7) Ref: Circulation Research, :, 2021 : PubMed ESTHER: Du_2021_Circ.Res__ PubMedSearch: Du 2021 Circ.Res PubMedID: 34261347 Abstract Rationale: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrythmia and progressive heart failure. The underlying mechanisms remain unclear.Objective: We performed high-throughput RNA sequencing to analyze circular RNA (circRNA) profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA-derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 and C8orf44-SGK3 promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared to wild type mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload-induced remodeling. This mechanism may hold therapeutic implications for cardiac disease. Title: The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics and pharmacodynamics in patients with atrial fibrillation Ji Q, Zhang C, Xu Q, Wang Z, Li X, Lv Q Ref: British Journal of Clinical Pharmacology, 87:2247, 2021 : PubMed ESTHER: Ji_2021_Br.J.Clin.Pharmacol_87_2247 PubMedSearch: Ji 2021 Br.J.Clin.Pharmacol 87 2247 PubMedID: 33179295 Abstract AIMS: Our study aimed to determine the impact of genetic polymorphisms of ABCB1 and CES1 on the pharmacokinetics (PK) and pharmacodynamics (PD) of dabigatran in patients with nonvalvular atrial fibrillation (NVAF). METHODS: We conducted a prospective study and enrolled NVAF patients treated with dabigatran. Blood samples were obtained from each patient and used for genotyping and determination of plasma dabigatran concentration (PDC) and coagulation parameters including activated partial thromboplastin time (APTT) and thrombin time. Patients' demographics and clinical outcomes from scheduled follow-up visits were all recorded. Statistical analysis was performed to identify the impact of genetic polymorphisms on the PK/PD and bleeding risk of dabigatran. RESULTS: A total of 198 patients were included in analysis. For the ABCB1 polymorphisms rs4148738 and rs1045642, no significant association was found with dabigatran PK/PD. For the CES1 polymorphism rs8192935, the minor allele(C) was associated with increased trough PDCs (ANOVA: P < .001; CC vs. TT genotype, P < .001; CT vs. TT genotype, P = .014) and with APTT values at trough level (P = .015). For the CES1 polymorphism rs2244613, the minor allele(A) carriers had higher levels of trough PDC than noncarriers (ANOVA: P < .001; AA vs. CC genotype, P < .001; CA vs. CC genotype, P = .004) and increased risk for minor bleeding (P = .034; odds ratio = 2.71, 95% confidence interval 1.05-7.00). CONCLUSION: Our study indicated that the minor allele(C) on the CES1 SNP rs8192935 was associated with PDCs and APTT values at trough level. The minor allele(A) on the CES1 SNP rs2244613 was associated with increased trough PDCs and higher risk for minor bleeding in NVAF patients treated with dabigatran. Title: Strigolactone mimic 2-nitrodebranone is highly active in Arabidopsis growth and development Li S, Li Y, Chen L, Zhang C, Wang F, Li H, Wang M, Wang Y, Nan F and Yan J <1 more author(s)> Li S, Li Y, Chen L, Zhang C, Wang F, Li H, Wang M, Wang Y, Nan F, Xie D, Yan J (- 1) Ref: Plant J, :, 2021 : PubMed ESTHER: Li_2021_Plant.J__ PubMedSearch: Li 2021 Plant.J PubMedID: 33860570 Abstract Strigolactones play crucial roles in regulating plant architecture and development, as endogenous hormones, and orchestrating symbiotic interactions with fungi and parasitic plants, as components of root exudates. rac-GR24 is currently the most widely used strigolactone analog and serves as a reference compound in investigating the action of strigolactones. In this study, we evaluated a suite of debranones and found that 2-nitrodebranone (2NOD) exhibited higher biological activity than rac-GR24 in various aspects of plant growth and development in Arabidopsis, including hypocotyl elongation inhibition, root hair promotion and senescence acceleration. The enhanced activity of 2NOD in promoting AtD14-SMXL7 and AtD14-MAX2 interactions indicates that the molecular structure of 2NOD is a better match for the ligand perception site pocket of D14. Moreover, 2NOD showed lower activity than rac-GR24 in promoting Orobanche cumana seed germination, suggesting its higher ability to control plant architecture than parasitic interactions. In combination with the improved stability of 2NOD, these results demonstrate that 2NOD is a strigolactone analog that can specifically mimic the activity of strigolactones and that 2NOD exhibits strong potential as a tool for studying the strigolactone signaling pathway in plants. Title: IL-6 downregulates hepatic carboxylesterases via NF-kappaB activation in dextran sulfate sodium-induced colitis Li M, Lan L, Zhang S, Xu Y, He W, Xiang D, Liu D, Ren X, Zhang C Ref: Int Immunopharmacol, 99:107920, 2021 : PubMed ESTHER: Li_2021_Int.Immunopharmacol_99_107920 PubMedSearch: Li 2021 Int.Immunopharmacol 99 107920 PubMedID: 34217990 Abstract Ulcerative colitis (UC) is associated with increased levels of inflammatory factors, which is attributed to the abnormal expression and activity of enzymes and transporters in the liver, affecting drug disposition in vivo. This study aimed to examine the impact of intestinal inflammation on the expression of hepatic carboxylesterases (CESs) in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Two major CESs isoforms, CES1 and CES2, were down-regulated, accompanied by decreases in hepatic microsomal metabolism of clopidogrel and irinotecan. Meanwhile, IL-6 levels significantly increased compared with other inflammatory factors in the livers of UC mice. In contrast, using IL-6 antibody simultaneously reversed the down-regulation of CES1, CES2, pregnane X receptor (PXR), and constitutive androstane receptor (CAR), as well as the nuclear translocation of NF-kappaB in the liver. We further confirmed that treatment with NF-kappaB inhibitor abolished IL-6-induced down-regulation of CES1, CES2, PXR, and CAR in vitro. Thus, it was concluded that IL-6 represses hepatic CESs via the NF-kappaB pathway in DSS-induced colitis. These findings indicate that caution should be exercised concerning the proper and safe use of therapeutic drugs in patients with UC. Title: Biological detoxification of fumonisin by a novel carboxylesterase from Sphingomonadales bacterium and its biochemical characterization Li Z, Wang Y, Liu Z, Jin S, Pan K, Liu H, Liu T, Li X, Zhang C and Zhang T <3 more author(s)> Li Z, Wang Y, Liu Z, Jin S, Pan K, Liu H, Liu T, Li X, Zhang C, Luo X, Song Y, Zhao J, Zhang T (- 3) Ref: Int J Biol Macromol, 169:18, 2021 : PubMed ESTHER: Li_2021_Int.J.Biol.Macromol_169_18 PubMedSearch: Li 2021 Int.J.Biol.Macromol 169 18 PubMedID: 33309671 Gene_locus related to this paper: 9sphn-a0a101vlk1 Abstract Fumonisins have posed hazardous threat to human and animal health worldwide. Enzymatic degradation is a desirable detoxification approach but is severely hindered by serious shortage of detoxification enzymes. After mining enzymes by bioinformatics analysis, a novel carboxylesterase FumDSB from Sphingomonadales bacterium was expressed in Escherichia coli, and confirmed to catalyze fumonisin B1 to produce hydrolyzed fumonisin B1 by liquid chromatography mass spectrometry for the first time. FumDSB showed high sequence novelty, sharing only ~34% sequence identity with three reported fumonisin detoxification carboxylesterases. Besides, FumDSB displayed its high degrading activity at 30-40 degreesC within a broad pH range from 6.0 to 9.0, which is perfectly suitable to be used in animal physiological condition. It also exhibited excellent pH stability and moderate thermostability. This study provides a FB1 detoxification carboxylesterase which could be further used as a potential food and feed additive. Title: Excitatory Impact of Dental Occlusion on Dorsal Motor Nucleus of Vagus Liu X, Shi M, Ren H, Xie M, Zhang C, Wang D, Li J, Wang M Ref: Front Neural Circuits, 15:638000, 2021 : PubMed ESTHER: Liu_2021_Front.Neural.Circuits_15_638000 PubMedSearch: Liu 2021 Front.Neural.Circuits 15 638000 PubMedID: 33776655 Abstract Neurons in the trigeminal mesencephalic nucleus (Vme) have axons that branch peripherally to innervate the orofacial region and project centrally to several motor nuclei in brainstem. The dorsal motor nucleus of vagus nerve (DMV) resides in the brainstem and takes a role in visceral motor function such as pancreatic exocrine secretion. The present study aimed to demonstrate the presence of Vme-DMV circuit, activation of which would elicit a trigeminal neuroendocrine response. A masticatory dysfunctional animal model termed unilateral anterior crossbite (UAC) model created by disturbing the dental occlusion was used. Cholera toxin B subunit (CTb) was injected into the inferior alveolar nerve of rats to help identify the central axon terminals of Vme neurons around the choline acetyltransferase (ChAT) positive motor neurons in the DMV. The level of vesicular glutamate transporter 1 (VGLUT1) expressed in DMV, the level of acetylcholinesterase (AChE) expressed in pancreas, the level of glucagon and insulin expression in islets and serum, and the blood glucose level were detected and compared between UAC and the age matched sham-operation control mice. Data indicated that compared with the controls, there were more CTb/VGLUT1 double labeled axon endings around the ChAT positive neurons in the DMV of UAC groups. Mice in UAC group expressed a higher VGLUT1 protein level in DMV, AChE protein level in pancreas, glucagon and insulin level in islet and serum, and higher postprandial blood glucose level, but lower fasting blood glucose level. All these were reversed at 15-weeks when UAC cessation was performed from 11-weeks (all, P < 0.05). Our findings demonstrated Vme-DMV circuit via which the aberrant occlusion elicited a trigeminal neuroendocrine response such as alteration in the postprandial blood glucose level. Dental occlusion is proposed as a potential therapeutic target for reversing the increased postprandial glucose level. Title: Remarkable improvement in the regiocomplementarity of a Glycine max epoxide hydrolase by reshaping its substrate-binding pocket for the enantioconvergent preparation of (R)-hexane-1,2-diol Liu Y-Y, Wu M-D, Zhu X-X, Zhang X-D, Zhang C, Xu Y-H, Wu M-C Ref: Molecular Catalysis, 514:111851, 2021 : PubMed ESTHER: Liu_2021_Mol.Catal_514_111851 PubMedSearch: Liu 2021 Mol.Catal 514 111851 Gene_locus related to this paper: soybn-c6t8y6 Abstract E. coli/gmeh3, an E. coli transformant expressing GmEH3, had the best regiocomplementarity (alphaS = 72.4% and betaR = 97.6%) for (S)- and (R)-1,2-epoxyhexanes among five tested aliphatic chain rac-1,2-epoxides (1a-5a). To prepare (R)-hexane-1,2-diol (1b) with high eep via enantioconvergent hydrolysis of rac-1a, the regioselectivity coefficient alphaS of GmEH3 for (S)-1a was improved by reshaping its substrate-binding pocket (SBP). Based on the semi-rational design, Trp102, Ile105, Ile178, Pro187 and Leu189 lining GmEH3's SBP were identified, each of which was substituted with four residues, respectively. From 17 transformants harboring single-site variants of gmeh3, E. coli/gmeh3W102L, /gmeh3W102I, /gmeh3W102V and /gmeh3P187F were selected, catalyzing the conversion of rac-1a into (R)-1b with obviously enhanced eep values of 59.3-78.3%. Then, three transformants containing double-site variants were constructed by combinatorial mutagenesis of gmeh3P187F separately with gmeh3W102L, gmeh3W102I and gmeh3W102V. Among the three transformants, E. coli/gmeh3W102V/P187F displayed the largest alphaS of 89.7% with betaR of 96.2%. The enantioconvergent hydrolysis of 500 mM rac-1a was conducted using 200 mg/mL wet cells of E. coli/gmeh3W102V/P187F at 25 degreesC for 12 h, affording (R)-1b with 83.1% eep and 91.5% yield. The molecular docking simulation analysis demonstrated that GmEH3W102V/P187F more regiopreferentially attacks Calpha in the oxirane ring of (S)-1a than GmEH3. Title: The Effects of Benoxacor on the Liver and Gut Microbiome of C57BL/6 Mice Simonsen D, Cady N, Zhang C, Shrode RL, McCormick ML, Spitz DR, Chimenti MS, Wang K, Mangalam A, Lehmler HJ Ref: Toxicol Sci, :, 2021 : PubMed ESTHER: Simonsen_2021_Toxicol.Sci__ PubMedSearch: Simonsen 2021 Toxicol.Sci PubMedID: 34850242 Abstract The toxicity of many "inert" ingredients of pesticide formulations, such as safeners, is poorly characterized, despite evidence that humans may be exposed to these chemicals. Analysis of ToxCast data for dichloroacetamide safeners with the ToxPi tool identified benoxacor as the safener with the highest potential for toxicity, especially liver toxicity. Benoxacor was subsequently administered to mice via oral gavage for three days at concentrations of 0, 0.5, 5, and 50 mg/kg bodyweight (b.w.). Bodyweight-adjusted liver and testes weights were significantly increased in the 50 mg/kg b.w. group. There were no overt pathologies in either the liver or the intestine. 16S rRNA analysis of the cecal microbiome revealed no effects of benoxacor on alpha- or beta-diversity; however, changes were observed in the abundance of certain bacteria. RNAseq analysis identified 163 hepatic genes affected by benoxacor exposure. Benoxacor exposure expressed a gene regulation profile similar to dichloroacetic acid and the fungicide sedaxane. Metabolomic analysis identified nine serum and fifteen liver metabolites that were affected by benoxacor exposure, changes that were not significant after correcting for multiple comparisons. The activity of antioxidant enzymes was not altered by benoxacor exposure. In vitro metabolism studies with liver microsomes and cytosol from male mice demonstrated that benoxacor is enantioselectively metabolized by cytochrome P450 enzymes (CYPs), carboxylesterases (CESs), and glutathione S-transferases (GSTs). These findings suggest that the minor toxic effects of benoxacor may be due to its rapid metabolism to toxic metabolites, such as dichloroacetic acid. This result challenges the assumption that inert ingredients of pesticide formulations are safe. Title: Inhibitory Effect of Lactococcus lactis subsp. lactis HFY14 on Diphenoxylate-Induced Constipation in Mice by Regulating the VIP-cAMP-PKA-AQP3 Signaling Pathway Tan Q, Hu J, Zhou Y, Wan Y, Zhang C, Liu X, Long X, Tan F, Zhao X Ref: Drug Des Devel Ther, 15:1971, 2021 : PubMed ESTHER: Tan_2021_Drug.Des.Devel.Ther_15_1971 PubMedSearch: Tan 2021 Drug.Des.Devel.Ther 15 1971 PubMedID: 34007157 Abstract AIM: The naturally fermented yak yogurt of pastoralists in the Tibetan Plateau, China, because of its unique geographical environment and the unique lifestyle of Tibetan pastoralists, is very different from other kinds of sour milk, and the microorganisms it contains are special. Lactococcus lactis subsp. lactis HFY14 (LLSL-HFY14) is a new lactic acid bacterium isolated from naturally fermented yak yogurt. The purpose of this study was to study the inhibitory effect of the bacterium on constipation. METHODS: Constipation was induced in ICR mice with diphenoxylate, and the constipated mice were treated with LLSL-HFY14. The weight and feces of the mice were visually detected. Colonic tissues were observed on hematoxylin and eosin-stained sections. Serum indices were detected with kits. mRNA expression in the colon was determined by quantitative polymerase chain reaction assay. RESULTS: Constipation caused weight loss, the number of defecation granules, defecation weight, fecal water content decreased, and the first black stool excretion time increased. LLSL-HFY14 alleviated these symptoms, and the effects were similar to those of lactulose (drug). The pathological examination revealed that constipation caused pathological changes in the colon, and LLSL-HFY14 effectively alleviated the disease. LLSL-HFY14 increased serum levels of motilin, gastrin, endothelin, substance P, acetylcholinesterase, and vasoactive intestinal peptide (VIP) and decreased serum levels of somatostatin in constipated mice. In addition, LLSL-HFY14 upregulated VIP, cAMP, protein kinase A, and aquaporin 3 expression in colonic tissues of constipated mice in a dose-dependent manner. CONCLUSION: LLSL-HFY14 inhibited constipation, similar to lactulose, and has the potential to become a biological agent. Title: Colorimetric detection of acetylcholinesterase and its inhibitor based on thiol-regulated oxidase-like activity of 2D palladium square nanoplates on reduced graphene oxide Yan B, Liu W, Duan G, Ni P, Jiang Y, Zhang C, Wang B, Lu Y, Chen C Ref: Mikrochim Acta, 188:162, 2021 : PubMed ESTHER: Yan_2021_Mikrochim.Acta_188_162 PubMedSearch: Yan 2021 Mikrochim.Acta 188 162 PubMedID: 33839958 Abstract A convenient and sensitive colorimetric assay for acetylcholinesterase (AChE) and its inhibitor has been designed based on the oxidase-like activity of {100}-faceted Pd square nanoplates which are grown in situ on reduced graphene oxide (PdSP@rGO). PdSP@rGO can effectively catalyze the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) without the assistance of H(2)O(2) to generate blue oxidized TMB (oxTMB) with a characteristic absorption peak at 652 nm. In the presence of AChE, acetylthiocholine (ATCh), a typical AChE substrate, is hydrolyzed to thiocholine (TCh). The generated TCh can effectively inhibit the PdSP@rGO-triggered chromogenic reaction of TMB via cheating with Pd, resulting in color fading and decrease in absorbance. Thus, a sensitive probe for AChE activity is constructed with a working range of 0.25-5 mU mL(-1) and a limit of detection (LOD) of 0.0625 mU mL(-1). Furthermore, because of the inhibition effect of tacrine on AChE, tacrine is also detected through the colorimetric AChE assay system within the concentrations range 0.025-0.4 microM with a LOD of 0.00229 microM. Hence, a rapid and facile colorimetric procedure to sensitively detect AChE and its inhibitor can be anticipated through modulating the oxidase-like activity of PdSP@rGO. Colorimetric method for detection of AChE and its inhibitor is established by modulating the oxidase mimetic activity of {100}-faceted Pd square nanoplates on reduced graphene oxide (PdSP@rGO). Title: Toxic effects of subacute exposure to acrylamide on motor endplates of the gastrocnemius in rats Yanxian B, Gu Z, Zhang T, Luo Y, Zhang C, Luo L, Ma Y, Liu J Ref: Toxicology, :152934, 2021 : PubMed ESTHER: Yanxian_2021_Toxicology__152934 PubMedSearch: Yanxian 2021 Toxicology 152934 PubMedID: 34509579 Abstract Acrylamide (ACR) is a recognized toxin that is known to induce neurotoxicity in humans and experimental animals. This study aimed to investigate the toxic effects of subacute exposure of the motor endplate (MEP) of the gastrocnemius in rats to ACR. All rats were randomly divided into control, 9, 18, and 36 mg/kg ACR groups, and ACR was administered by gastric gavage for 21 days. The behavioral tests were performed weekly. On the 22(nd) day, the wet weight of the gastrocnemius was measured. The changes in muscle fiber structure, nerve endings, and MEP in the gastrocnemius were examined by hematoxylin-eosin (HE) and gold chloride staining. Acetylcholinesterase (AChE) content in the gastrocnemius was detected by AChE staining. The expression of AChE and calcitonin gene-related peptide was detected by immunohistochemistry and western blot. Rats exposed to ACR showed a significant increase in gait scores and hind limb splay distance compared with the control group, and the wet weight of the gastrocnemius was reduced, HE staining showed that the muscle fiber structure of the gastrocnemius became thin and the arrangement was dense with nuclear aggregation, gold chloride staining showed that nerve branches decreased and became thin, nerve fibers became short and light, the number of MEPs was decreased, the staining became light, and the structure was not clear. AChE staining showed that the number of MEPs was significantly reduced after exposure to ACR, the shape became small, and the AChE content decreased in a dose-dependent manner. Immunohistochemistry and western blot analysis results of the expression levels of AchE and CGRP showed a decreasing trend as compared to the control group with increasing ACR exposure dose. The reduction in protein levels may be the mechanism by which ACR has a toxic effect on the MEP in the gastrocnemius of rats. Title: A stable biosensor based on chitosan-modified graphene for detecting organophosphorus pesticides Zhang J, Hu H, Wang P, Zhang C, Wuma J, Yang L Ref: Biotechnol Appl Biochem, :, 2021 : PubMed ESTHER: Zhang_2021_Biotechnol.Appl.Biochem__ PubMedSearch: Zhang 2021 Biotechnol.Appl.Biochem PubMedID: 33660328 Abstract An acetylcholinesterase (AChE) biosensor was successfully fabricated with a stable structure and high detection accuracy. Graphene (Gra) nano-fragments modified with chitosan and acetylcholinesterase were successively drip-coated on the surface of a glassy carbon electrode via a layer-by-layer assembly method. The concentration range of the sensor to detect dichlorvos was 0.1 nM to 100000 nM, and the limit of detection was 54 pM. Chitosan (CS) was used to modify graphene for the first time, which enhanced the mechanical flexibility of these graphene nanostructures, significantly improving the stability and detection accuracy of this sensor. This article is protected by copyright. All rights reserved. Title: COX-2/sEH Dual Inhibitor PTUPB Alleviates CCl (4) -Induced Liver Fibrosis and Portal Hypertension Zhao Z, Zhang C, Lin J, Zheng L, Li H, Qi X, Huo H, Lou X, Hammock BD and Luo M <2 more author(s)> Zhao Z, Zhang C, Lin J, Zheng L, Li H, Qi X, Huo H, Lou X, Hammock BD, Hwang SH, Bao Y, Luo M (- 2) Ref: Front Med (Lausanne), 8:761517, 2021 : PubMed ESTHER: Zhao_2021_Front.Med.(Lausanne)_8_761517 PubMedSearch: Zhao 2021 Front.Med.(Lausanne) 8 761517 PubMedID: 35004731 Inhibitor(s) related to this paper: PTUPB Abstract Background: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl) -benzenesulfonamide (PTUPB), a dual cyclooxygenase-2 (COX-2)/soluble epoxide hydrolase (sEH) inhibitor, was found to alleviate renal, pulmonary fibrosis and liver injury. However, few is known about the effect of PTUPB on liver cirrhosis. In this study, we aimed to explore the role of PTUPB in liver cirrhosis and portal hypertension (PHT). Method: Rat liver cirrhosis model was established via subcutaneous injection of carbon tetrachloride (CCl(4)) for 16 weeks. The experimental group received oral administration of PTUPB (10 mg/kg) for 4 weeks. We subsequently analyzed portal pressure (PP), liver fibrosis, inflammation, angiogenesis, and intra- or extrahepatic vascular remodeling. Additionally, network pharmacology was used to investigate the possible mechanisms of PTUPB in live fibrosis. Results: CCl(4) exposure induced liver fibrosis, inflammation, angiogenesis, vascular remodeling and PHT, and PTUPB alleviated these changes. PTUPB decreased PP from 17.50 +/- 4.65 to 6.37 +/- 1.40 mmHg, reduced collagen deposition and profibrotic factor. PTUPB alleviated the inflammation and bile duct proliferation, as indicated by decrease in serum interleukin-6 (IL-6), liver cytokeratin 19 (CK-19), transaminase, and macrophage infiltration. PTUPB also restored vessel wall thickness of superior mesenteric arteries (SMA) and inhibited intra- or extrahepatic angiogenesis and vascular remodeling via vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), etc. Moreover, PTUPB induced sinusoidal vasodilation by upregulating endothelial nitric oxide synthase (eNOS) and GTP-cyclohydrolase 1 (GCH1). In enrichment analysis, PTUPB engaged in multiple biological functions related to cirrhosis, including blood pressure, tissue remodeling, immunological inflammation, macrophage activation, and fibroblast proliferation. Additionally, PTUPB suppressed hepatic expression of sEH, COX-2, and transforming growth factor-beta (TGF-beta). Conclusion: 4-(5-phenyl-3-{3-[3-(4-trifluoromethylphenyl)-ureido]-propyl}-pyrazol-1-yl)- benzenesulfonamide ameliorated liver fibrosis and PHT by inhibiting fibrotic deposition, inflammation, angiogenesis, sinusoidal, and SMA remodeling. The molecular mechanism may be mediated via the downregulation of the sEH/COX-2/TGF-beta. Title: Melatonin inhibits lipid accumulation to repress prostate cancer progression by mediating the epigenetic modification of CES1 Zhou L, Zhang C, Yang X, Liu L, Hu J, Hou Y, Tao H, Sugimura H, Chen Z and Chen K <1 more author(s)> Zhou L, Zhang C, Yang X, Liu L, Hu J, Hou Y, Tao H, Sugimura H, Chen Z, Wang L, Chen K (- 1) Ref: Clin Transl Med, 11:e449, 2021 : PubMed ESTHER: Zhou_2021_Clin.Transl.Med_11_e449 PubMedSearch: Zhou 2021 Clin.Transl.Med 11 e449 PubMedID: 34185414 Gene_locus related to this paper: human-CES1 Abstract BACKGROUND: Androgen deprivation therapy (ADT) is the main clinical treatment for patients with advanced prostate cancer (PCa). However, PCa eventually progresses to castration-resistant prostate cancer (CRPC), largely because of androgen receptor variation and increased intratumoral androgen synthesis. Several studies have reported that one abnormal lipid accumulation is significantly related to the development of PCa. Melatonin (MLT) is a functionally pleiotropic indoleamine molecule and a key regulator of energy metabolism. The aim of our study is finding the links between CRPC and MLT and providing the basis for MLT treatment for CRPC. METHODS: We used animal CRPC models with a circadian rhythm disorder, and PCa cell lines to assess the role of melatonin in PCa. RESULTS: We demonstrated that MLT treatment inhibited tumor growth and reversed enzalutamide resistance in animal CRPC models with a circadian rhythm disorder. A systematic review and meta-analysis demonstrated that MLT is positively associated with an increased risk of developing advanced PCa. Restoration of carboxylesterase 1 (CES1) expression by MLT treatment significantly reduced lipid droplet (LD) accumulation, thereby inducing apoptosis by increasing endoplasmic reticulum stress, reducing de novo intratumoral androgen synthesis, repressing CRPC progression and reversing the resistance to new endocrine therapy. Mechanistic investigations demonstrated that MLT regulates the epigenetic modification of CES1. Ces1-knockout (Ces(-/-) ) mice verified the important role of endogenous Ces1 in PCa. CONCLUSIONS: Our findings provide novel preclinical and clinical information about the role of melatonin in advanced PCa and characterize the importance of enzalutamide combined with MLT administration as a therapy for advanced PCa. Title: Improved production of recombinant Rhizomucor miehei lipase by coexpressing protein folding chaperones in Pichia pastoris, which triggered ER stress Huang J, Zhao Q, Chen L, Zhang C, Bu W, Zhang X, Zhang K, Yang Z Ref: Bioengineered, 11:375, 2020 : PubMed ESTHER: Huang_2020_Bioengineered_11_375 PubMedSearch: Huang 2020 Bioengineered 11 375 PubMedID: 32175802 Gene_locus related to this paper: rhimi-lipas Abstract Rhizomucor miehei lipase (RML) is a biocatalyst that widely used in laboratory and industrial. Previously, RML with a 70-amino acid propeptide (pRML) was cloned and expressed in P. pastoris. Recombinant strains with (strain containing 4-copy prml) and without ER stress (strain containing 2-copy prml) were obtained. However, the effective expression of pRML in P. pastoris by coexpressing ER-related elements in pRML-produced strain with or without ER stress has not been reported to date. In this study, an efficient way to produce functional pRML was explored in P. pastoris. The coexpression of protein folding chaperones, including PDI and ERO1, in different strains with or without ER stress, was investigated. PDI overexpression only increased pRML production in 4-copy strain from 705 U/mL to 1430 U/mL because it alleviated the protein folded stress, increased the protein concentration from 0.56 mg/mL to 0.65 mg/mL, and improved enzyme-specific activity from 1238 U/mg to 2186 U/mg. However, PDI coexpression could not improve pRML production in the 2-copy strain because it increased protein folded stress, while ERO1 coexpression in the two strains all had a negative effect on pRML expression. We also investigated the effect of the propeptide on the substrate specificity and the condition for pRML enzyme powder preparation. Results showed that the relative activity exceeded 80% when the substrates C8-C10 were detected at 35 degrees C and pH 6, and C8-C12 at 45 degrees C and pH 8. The optimal enzyme powder preparation pH was 7, and the maximum recovery rate for pRML was 73.19%. Title: Synthesis, Biological Activity, Molecular Docking Studies of a Novel Series of 3-Aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one Derivatives as the Acetylcholinesterase Inhibitors Jin Z, Zhang C, Liu M, Jiao S, Zhao J, Liu X, Lin H, Wan DC, Hu C Ref: J Biomol Struct Dyn, :1, 2020 : PubMed ESTHER: Jin_2020_J.Biomol.Struct.Dyn__1 PubMedSearch: Jin 2020 J.Biomol.Struct.Dyn 1 PubMedID: 32266865 Abstract The acetylcholinesterase inhibitors play a critical role in the drug therapy for Alzheimer's disease. In this study, twenty-nine novel 3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives were synthesized and assayed for their human acetylcholinesterase (hAChE) inhibitory activities. Inhibitory ratio values of seventeen compounds were above 55% with 4c having the highest value as 77.19%. The compounds with the halogen atoms in the aromatic ring, and N,N-diethylamino or N,N-dimethylamino groups in the side chains at C-3 positions exhibited good inhibitory activity. SAR study was carried out by means of molecular docking technique. According to molecular docking results, the common interacting site for all compounds were found to be peripheral anionic site whereas highly active compounds were interacting with the catalytic active site too. Title: Ultrasensitive detection of butyrylcholinesterase activity based on the inner filter effect of MnO(2) nanosheets on sulfur nanodots Li T, Gao Y, Li H, Zhang C, Xing Y, Jiao M, Shi YE, Li W, Zhai Y, Wang Z Ref: Analyst, 145:5206, 2020 : PubMed ESTHER: Li_2020_Analyst_145_5206 PubMedSearch: Li 2020 Analyst 145 5206 PubMedID: 32578586 Abstract Butyrylcholinesterase (BChE) activity is an important index for a variety of diseases. In this work, a "turn-on" assay is proposed based on controlling the inner filter effect (IFE) of MnO(2) nanosheets (NSs) on sulfur nanodots (S-dots). The fluorescence of S-dots is effectively quenched by the MnO(2) NSs, due to the wide overlap of the emission spectrum of S-dots and absorption spectrum of MnO(2) NSs, together with the superior light absorption capability of MnO(2) NSs. BChE can catalyze acetylthiocholine and produce thiocholine, which effectively decomposes the MnO(2) NSs into Mn(2+), resulting in the disappearance of the IFE and recovery of fluorescence of S-dots. Two-stage linear relationships between the ratio of fluorescence intensity and concentration of BChE are observed from 0.05 to 10 and from 10 to 500 U L(-1). A limit of detection of 0.035 U L(-1) is achieved, which is the best performance so far. The as-proposed assay is robust enough for practical detection in human serum, and it can avoid interference from its sister enzyme (acetylcholinesterase) and glutathione at the micromolar level. The presented results provide a clue for the functionalization of S-dots, and offer a powerful tool as an analytic technique for nanomedicine and environmental science. Title: Neuroprotective Effects of D-(-)-Quinic Acid on Aluminum Chloride-Induced Dementia in Rats Liu L, Liu Y, Zhao J, Xing X, Zhang C, Meng H Ref: Evid Based Complement Alternat Med, 2020:5602597, 2020 : PubMed ESTHER: Liu_2020_Evid.Based.Complement.Alternat.Med_2020_5602597 PubMedSearch: Liu 2020 Evid.Based.Complement.Alternat.Med 2020 5602597 PubMedID: 32454864 Abstract Objective: The present study was designed to evaluate the neuroprotective effects of D-(-)-quinic acid on aluminum chloride- (AlCl3-) induced neurobehavioral and biochemical changes in rats. This study showed the behavioral and biochemical effects of D-(-)-quinic acid on rats with particular emphasis on the hippocampus and frontal cortex which are associated with memory. Materials and Methods: Chronic administration of aluminum chloride at a dose of 175 mg/kg, p.o. for a period of 25 days markedly increased the level of acetylcholinesterase (AChE) activity and reduced the levels of antioxidant enzymes in the brain. Two doses of D-(-)-quinic acid (200 mg/kg and 400 mg/kg) were selected based on previous safety/toxicity studies and administered orally from the 26th day to the 36th day of the trial. Behavioral parameters were assessed using the Morris water maze test and an actophotometer in rats. Biochemical parameter content and histology of brain tissue were assessed on the final day of the experiment. Results: D-(-)-Quinic acid (200 mg/kg and 400 mg/kg) orally administered alongside AlCl3 rescued AChE activity and the behavioral impairments caused by aluminum. There was significant inhibition of MAO-B in D-(-)-quinic acid-treated rats. Histopathological studies in the hippocampus and cortex of the rat brain also supported that D-(-)-quinic acid markedly reduced the toxicity of AlCl3 and preserved the normal histoarchitecture pattern of the hippocampus and cortex. These results indicate that D-(-)-quinic acid can reverse memory loss caused by aluminum intoxication by attenuating AChE activity and rescuing the deleterious effect of AlCl3. Title: MS1, a direct target of MS188, regulates the expression of key sporophytic pollen coat protein genes in Arabidopsis Lu JY, Xiong SX, Yin W, Teng XD, Lou Y, Zhu J, Zhang C, Gu JN, Wilson ZA, Yang ZN Ref: J Exp Bot, :, 2020 : PubMed ESTHER: Lu_2020_J.Exp.Bot__ PubMedSearch: Lu 2020 J.Exp.Bot PubMedID: 32374882 Abstract Sporophytic pollen coat proteins (sPCPs) derived from the anther tapetum are deposited into pollen wall cavities and function in pollen-stigma interactions, pollen hydration and environmental protection. In Arabidopsis, 13 highly-abundant proteins have been identified in pollen coat, including 7 major Glycine-Rich Proteins GRP14, 16, 17, 18, 19, 20 and GRP-Oleosin; two Caleosin-related family proteins (AT1G23240, AT1G23250); three lipase proteins EXL4, EXL5, EXL6 and ATA27/BGLU20. Here, we show that GRP14, 17, 18, 19, and EXL4 and EXL6 fused with GFP are translated in the tapetum and then accumulate in the anther locule following tapetum degeneration. The expression of these sPCPs is dependent on two essential tapetum transcription factors, MALE STERILE188 (MS188) and MALE STERILITY 1 (MS1). The majority of sPCP genes are up-regulated within 30h after MS1 induction and could be restored by MS1 expression driven by the MS188 promoter in ms188, indicating that MS1 is sufficient to activate their expression, however additional MS1-downstream factors appear to be required for high-level sPCP expression. Our ChIP, in vivo transactivation assays and EMSA data indicate that MS188 directly activates MS1. Together, these results reveal a regulatory cascade that outer pollen wall formation is regulated by MS188 followed by sPCPs synthesis controlled by MS1. 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: Functional Characterization of an alpha-Esterase Gene Associated with Malathion Detoxification in Bradysia odoriphaga Tang B, Dai W, Qi L, Du S, Zhang C Ref: Journal of Agricultural and Food Chemistry, :, 2020 : PubMed ESTHER: Tang_2020_J.Agric.Food.Chem__ PubMedSearch: Tang 2020 J.Agric.Food.Chem PubMedID: 32401500 Abstract Carboxylesterases (CarEs) are a multigene superfamily of metabolic enzymes involved in metabolic detoxification of xenobiotics. In this study, an alpha-esterase gene (BoalphaE1) was identified from Bradysia odoriphaga. Phylogenetic analysis classified BoalphaE1 into the alpha-esterase clade. Developmental expression analysis indicated that BoalphaE1 was significantly expressed in the second to fourth larval stages. Tissue-specific expression analysis indicated that BoalphaE1 was highly expressed in the larval midgut. After exposure to LC30 of malathion, the CarE activity of B. odoriphaga was induced and the transcriptional level of BoalphaE1 was significantly up-regulated. Silencing of BoalphaE1 significantly increased the susceptibility of B. odoriphaga larvae to malathion. Inhibition assays in vitro indicated that malathion significantly inhibited BoalphaE1 activity. GC-MS assay showed that BoalphaE1 possesses hydrolase activity toward malathion and participates in the detoxification of malathion. These results strongly suggest that BoalphaE1 plays a crucial role in detoxification of malathion in B. odoriphaga. Title: Donepezil down-regulates propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation in the brain of bilateral common carotid artery occlusion-induced vascular dementia rats Wang H, Lu J, Gao WC, Ma X, Li N, Ding Z, Wu C, Zhu M, Qiao G and Zheng CB <5 more author(s)> Wang H, Lu J, Gao WC, Ma X, Li N, Ding Z, Wu C, Zhu M, Qiao G, Xiao C, Zhang C, Chen C, Weng Z, Yang W, Zheng CB (- 5) Ref: Clinical & Experimental Pharmacology & Physiology, :, 2020 : PubMed ESTHER: Wang_2020_Clin.Exp.Pharmacol.Physiol__ PubMedSearch: Wang 2020 Clin.Exp.Pharmacol.Physiol PubMedID: 32424975 Abstract Vascular dementia (VaD), caused by stroke or small vessel disease, is the second-most common type of dementia after Alzheimer's disease (AD). Donepezil is an acetylcholinesterase inhibitor that is currently used in patients with mild to moderate AD, and has recently been shown to improve cognitive performance in patients with VaD. In this study, we evaluated the effects of donepezil on VaD, and investigated the underlying molecular mechanisms of action. VaD was established by ligation of the bilateral common carotid artery occlusion (BCCAO). Executive function was tested by the Morris Water Maze (MWM) test and the attentional set shifting task (ASST). Our results showed that donepezil improved executive dysfunction and cognitive flexibility in BCCAO rats. In addition, we showed that donepezil treatment decreased the level of Abeta1-42 in BCCAO rats by enzyme-linked immunosorbent assay. Posttranslational modifications (PTMs) are known to be critical mechanisms in the regulation of various cellular processes. Furthermore, PTMs have been linked to the central nervous system, which highlightes the importance of PTMs in neurodegenerative diseases. In this study, we used Western blot analysis to identify several novel PTMs in the hippocampus of BCCAO rats that were treated with or without donepezil. The data revealed that lysine propionylation, 2-hydroxyisobutyrylation, butyrylation, succinylation, and crotonylation were elevated in the hippocampus of BCCAO rats when compared to sham rats. This increase was abolished by donepezil treatment. Taken together, we speculate that donepezil treatment improves cognitive function in our animal model of VaD, possibly by reducing aberrant acyl-PTMs. Title: Biological Impact and Enzyme Activities of Spodoptera litura (Lepidoptera: Noctuidae) in Response to Synergistic Action of Matrine and Beauveria brongniartii Wu J, Li J, Zhang C, Yu X, Cuthbertson AGS, Ali S Ref: Front Physiol, 11:584405, 2020 : PubMed ESTHER: Wu_2020_Front.Physiol_11_584405 PubMedSearch: Wu 2020 Front.Physiol 11 584405 PubMedID: 33224038 Abstract Matrine, a naturally occurring heterocyclic compound, has been shown to enhance the pathogenicity of the entomopathogenic fungus Beauveria brongniartii against Spodoptera litura. In the current study, the biological impacts and synergism activities of these two agents on nutritional efficiency and antioxidant enzymes in S. litura were explored. Our results showed a high antifeedant activity of B. brongniartii and matrine on S. litura. The S. litura larvae were unable to pupate and emerge when treated with combinations of matrine and B. brongniartii. Following on, we measured the activities of five important antioxidant enzymes [superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), acetylcholinesterase (AChE), and glutathione-S-transferase (GST)] when treated with B. brongniartii SB010 (1 x 10(9) spores/ml), matrine (0.5 mg/ml), and B. brongniartii SB010 (1 x 10(9) spores/ml) + matrine (0.5 mg/ml). The results indicated the detoxification activity of the five enzymes in the fat body and hemolymph of S. litura when facing a combined B. brongniartii and matrine challenge. The activities of the enzymes were significantly lower than that of the control group 7 days post-treatment, indicating the inhibitory effect of the two xenobiotics. Matrine had better inhibition effects than B. brongniartii in a majority of the trials. The improved detoxification activity of the five enzymes may be the internal mechanism of synergism of matrine on B. brongniartii. Title: Discovery and development of a novel short-chain fatty acid ester synthetic biocatalyst under aqueous phase from Monascus purpureus isolated from Baijiu Xu Y, Wang X, Liu X, Li X, Zhang C, Li W, Sun X, Wang W, Sun B Ref: Food Chem, 338:128025, 2020 : PubMed ESTHER: Xu_2020_Food.Chem_338_128025 PubMedSearch: Xu 2020 Food.Chem 338 128025 PubMedID: 32927200 Gene_locus related to this paper: monpu-a0a507qkl5 Abstract Short-chain fatty acid esters are important flavor chemicals in Chinese traditional fermented Baijiu. Monascus purpureus was recognized as an important microorganism contributing to ester synthesis. However, the molecular basis for ester synthesis was still lacking. The present work combined genome sequencing, transcriptome sequencing, gene library construction, and enzyme engineering to discover a novel catalyst from M. purpureus (isolated from Baijiu fermentation starter). Enzyme LIP05, belonging to the alpha/beta hydrolase family, was identified to synthesize short-chain fatty acid esters under aqueous phase. After deleting the lid domain of LIP05, the synthesis of ethyl pentanoate, ethyl hexanoate, ethyl octanoate, or ethyl decanoate was achieved. Ethyl octanoate with the highest conversion ratio of 93.7% was obtained with the assistance of ultrasound. The study reveals the molecular basis for synthesizing short-chain fatty acid esters by M. purpureus and will promote the application of the species or the enzyme in food industry. Title: Biodegradation of phthalate esters by Paracoccus kondratievae BJQ0001 isolated from Jiuqu (Baijiu fermentation starter) and identification of the ester bond hydrolysis enzyme Xu Y, Minhazul K, Wang X, Liu X, Li X, Meng Q, Li H, Zhang C, Sun X, Sun B Ref: Environ Pollut, 263:114506, 2020 : PubMed ESTHER: Xu_2020_Environ.Pollut_263_114506 PubMedSearch: Xu 2020 Environ.Pollut 263 114506 PubMedID: 32268225 Gene_locus related to this paper: 9rhob-a0a5p8jcg2, 9rhob-a0a5p8jaa4 Abstract Phthalate ester (PAE) pollution is an increasing problem globally. Paracoccus kondratievae BJQ0001 was isolated from the fermentation starter of Baijiu and showed an efficient degradation capability toward PAEs. To our poor knowledge, this is the first report of a P. kondratievae strain capable of degrading PAEs. The first complete genome sequence of P. kondratievae was presented without gaps, and composed of two circular chromosomes and one plasmid. The species simultaneously degraded di-methyl phthalate (DMP), di-ethyl phthalate (DEP), di-butyl phthalate (DBP), di-isobutyl phthalate (DIBP) and di-(2-ethylhexyl) phthalate (DEHP), with DMP and DEP as the preferred substrates. The half-life (t(1/2)) of DMP was only 6.34 h with an initial concentration of 200 mg/L. Combined with gene annotation and metabolic intermediate analysis, a metabolic pathway was proposed for the species. Benzoic acid, the intermediate of anaerobic PAE metabolism, was identified in the aerobic degradation process. Two key enzymes for alkyl ester bond hydrolysis were obtained, and belonged to families IV and VI of hydrolases, respectively. These results will promote the investigation of PAE degradation by P. kondratievae, and provide useful information for improving the quality control of food and environmental PAE treatment. Title: Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J and Vellas B <14 more author(s)> Yu JT, Xu W, Tan CC, Andrieu S, Suckling J, Evangelou E, Pan A, Zhang C, Jia J, Feng L, Kua EH, Wang YJ, Wang HF, Tan MS, Li JQ, Hou XH, Wan Y, Tan L, Mok V, Dong Q, Touchon J, Gauthier S, Aisen PS, Vellas B (- 14) Ref: Journal of Neurology Neurosurg Psychiatry, 91:1201, 2020 : PubMed ESTHER: Yu_2020_J.Neurol.Neurosurg.Psychiatry_91_1201 PubMedSearch: Yu 2020 J.Neurol.Neurosurg.Psychiatry 91 1201 PubMedID: 32690803 Abstract BACKGROUND: Evidence on preventing Alzheimer's disease (AD) is challenging to interpret due to varying study designs with heterogeneous endpoints and credibility. We completed a systematic review and meta-analysis of current evidence with prospective designs to propose evidence-based suggestions on AD prevention. METHODS: Electronic databases and relevant websites were searched from inception to 1 March 2019. Both observational prospective studies (OPSs) and randomised controlled trials (RCTs) were included. The multivariable-adjusted effect estimates were pooled by random-effects models, with credibility assessment according to its risk of bias, inconsistency and imprecision. Levels of evidence and classes of suggestions were summarised. RESULTS: A total of 44676 reports were identified, and 243 OPSs and 153 RCTs were eligible for analysis after exclusion based on pre-decided criteria, from which 104 modifiable factors and 11 interventions were included in the meta-analyses. Twenty-one suggestions are proposed based on the consolidated evidence, with Class I suggestions targeting 19 factors: 10 with Level A strong evidence (education, cognitive activity, high body mass index in latelife, hyperhomocysteinaemia, depression, stress, diabetes, head trauma, hypertension in midlife and orthostatic hypotension) and 9 with Level B weaker evidence (obesity in midlife, weight loss in late life, physical exercise, smoking, sleep, cerebrovascular disease, frailty, atrial fibrillation and vitamin C). In contrast, two interventions are not recommended: oestrogen replacement therapy (Level A2) and acetylcholinesterase inhibitors (Level B). INTERPRETATION: Evidence-based suggestions are proposed, offering clinicians and stakeholders current guidance for the prevention of AD. Title: Significant improvement in catalytic activity and enantioselectivity of a Phaseolus vulgaris epoxide hydrolase, PvEH3, towards ortho-cresyl glycidyl ether based on the semi-rational design Zhang C, Liu Y, Li C, Xu Y, Su Y, Li J, Zhao J, Wu M Ref: Sci Rep, 10:1680, 2020 : PubMed ESTHER: Zhang_2020_Sci.Rep_10_1680 PubMedSearch: Zhang 2020 Sci.Rep 10 1680 PubMedID: 32015448 Gene_locus related to this paper: phavu-PvEH3 Abstract The investigation of substrate spectrum towards five racemic (rac-) aryl glycidyl ethers (1a-5a) indicated that E. coli/pveh3, an E. coli BL21(DE3) transformant harboring a PvEH3-encoding gene pveh3, showed the highest EH activity and enantiomeric ratio (E) towards rac-3a. For efficiently catalyzing the kinetic resolution of rac-3a, the activity and E value of PvEH3 were further improved by site-directed mutagenesis of selected residues. Based on the semi-rational design of an NC-loop in PvEH3, four single-site variants of pveh3 were amplified by PCR, and intracellularly expressed in E. coli BL21(DE3), respectively. E. coli/pveh3(E134K) and /pveh3(T137P) had the enhanced EH activities of 15.3 +/- 0.4 and 16.1 +/- 0.5 U/g wet cell as well as E values of 21.7 +/- 1.0 and 21.2 +/- 1.1 towards rac-3a. Subsequently, E. coli/pveh3(E134K/T137P) harboring a double-site variant gene was also constructed, having the highest EH activity of 22.4 +/- 0.6 U/g wet cell and E value of 24.1 +/- 1.2. The specific activity of the purified PvEH3(E134K/T137P) (14.5 +/- 0.5 U/mg protein) towards rac-3a and its catalytic efficiency (k(cat)/K(m) of 5.67 mM(-1) s(-1)) for (S)-3a were 1.7- and 3.54-fold those (8.4 +/- 0.3 U/mg and 1.60 mM(-1) s(-1)) of PvEH3. The gram-scale kinetic resolution of rac-3a using whole wet cells of E. coli/pveh3(E134K/T137P) was performed at 20 degC for 7.0 h, producing (R)-3a with 99.4% ee(s) and 38.5 +/- 1.2% yield. Additionally, the mechanism of PvEH3(E134K/T137P) with remarkably improved E value was analyzed by molecular docking simulation. Title: Circumdatin D Exerts Neuroprotective Effects by Attenuating LPS-Induced Pro-Inflammatory Responses and Downregulating Acetylcholinesterase Activity In Vitro and In Vivo Zhang C, Hu L, Liu D, Huang J, Lin W Ref: Front Pharmacol, 11:760, 2020 : PubMed ESTHER: Zhang_2020_Front.Pharmacol_11_760 PubMedSearch: Zhang 2020 Front.Pharmacol 11 760 PubMedID: 32523534 Abstract Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with multifactorial causes, of which systemic inflammation may play a key role to promote neurodegeneration, and acetylcholinesterase (AChE) is a target protein to induce cholinergic transmission. Inhibitors toward inflammation and targeting AChE are regarded to promote cholinergic signaling of the central nervous system in AD therapy. During the search for neuroprotection agents from marine-derived compounds, seven circumdatin-type alkaloids from a coral-associated fungus Aspergillus ochraceus LZDX-32-15 showed potent inhibition against lipopolysaccharide (LPS)-induced nitric oxide (NO) production and activation of NF-kappaB report gene along with anti-AChE activities. Among the tested compounds, circumdatin D showed the most potent inhibitory effect against AChE activity and NO production. In vivo experiments using AD-like nematode models demonstrated that circumdatin D effectively delayed paralysis of CL4176 worms upon temperature up-shift via suppression of AChE activity and inflammatory-related gene expression. Moreover, circumdatin D interfered with inflammatory response by inhibiting the secretion of pro-inflammatory cytokines in LPS-induced BV-2 and primary microglia cells. Mechanistically, circumdatin D modulated Toll-like receptor 4 (TLR4)-mediated NF-kappaB, MAPKs and JAK/STAT inflammatory pathways in LPS-stimulated BV-2 cells, and protected primary neurons cells from LPS-induced neurotoxicity. Thus, circumdatin D is a potential agent for neuroprotective effects by the multi-target strategy. Title: Mutation of an atypical oxirane oxyanion hole improves regioselectivity of the alpha/beta-fold epoxide hydrolase Alp1U Zhang L, De BC, Zhang W, Mandi A, Fang Z, Yang C, Zhu Y, Kurtan T, Zhang C Ref: Journal of Biological Chemistry, 295:16987, 2020 : PubMed ESTHER: Zhang_2020_J.Biol.Chem_295_16987 PubMedSearch: Zhang 2020 J.Biol.Chem 295 16987 PubMedID: 33004437 Gene_locus related to this paper: stram-q1rqu8 Abstract Epoxide hydrolases (EHs) have been characterized and engineered as biocatalysts that convert epoxides to valuable chiral vicinal diol precursors of drugs and bioactive compounds. Nonetheless, the regioselectivity control of the epoxide ring opening by EHs remains challenging. Alp1U is an alpha/beta-fold EH that exhibits poor regioselectivity in the epoxide hydrolysis of fluostatin C (1), and produces a pair of stereoisomers. Herein, we established the absolute configuration of the two stereoisomeric products and determined the crystal structure of Alp1U. A W186/W187/Y247 oxirane oxygen hole was identified in Alp1U that replaced the canonical Tyr/Tyr pair in alpha/beta-EHs. Mutation of residues in the atypical oxirane oxygen hole of Alp1U improved the regioselectivity for epoxide hydrolysis on 1. The single site Y247F mutation led to highly regioselective (98%) attack at C-3 of 1, while the double mutation W187F/Y247F resulted in regioselective (94%) nucleophilic attack at C-2. Furthermore, single crystal X-ray structures of the two regioselective Alp1U variants in complex with 1 were determined. These findings allowed insights into the reaction details of Alp1U, and provided a new approach for engineering regioselective epoxide hydrolases. Title: Highly regio- and enantio-selective hydrolysis of two racemic epoxides by GmEH3, a novel epoxide hydrolase from Glycine max Zhang C, Li C, Zhu XX, Liu YY, Zhao J, Wu MC Ref: Int J Biol Macromol, 164:2795, 2020 : PubMed ESTHER: Zhang_2020_Int.J.Biol.Macromol_164_2795 PubMedSearch: Zhang 2020 Int.J.Biol.Macromol 164 2795 PubMedID: 32763395 Gene_locus related to this paper: soybn-GmEH3 Abstract A novel epoxide hydrolase from Glycine max, designated GmEH3, was excavated based on the computer-aided analysis. Then, gmeh3, a GmEH3-encoding gene, was cloned and successfully expressed in E. coli Rosetta(DE3). Among the ten investigated rac-epoxides, GmEH3 possessed the highest and best complementary regioselectivities (regioselectivity coefficients, alpha(S) = 93.7% and beta(R) = 97.2%) in the asymmetric hydrolysis of rac-m-chlorostyrene oxide (5a), and the highest enantioselectivity (enantiomeric ratio, E = 55.6) towards rac-phenyl glycidyl ether (7a). The catalytic efficiency (k(cat)(S)/K(m)(S) = 2.50 mM(-1) s(-1)) of purified GmEH3 for (S)-5a was slightly higher than that (k(cat)(R)/K(m)(R) = 1.52 mM(-1) s(-1)) for (R)-5a, whereas the k(cat)/K(m) (5.16 mM(-1) s(-1)) for (S)-7a was much higher than that (0.09 mM(-1) s(-1)) for (R)-7a. Using 200 mg/mL wet cells of E. coli/gmeh3 as the biocatalyst, the scale-up enantioconvergent hydrolysis of 150 mM rac-5a at 25 degreesC for 1.5 h afforded (R)-5b with 90.2% ee(p) and 95.4% yield(p), while the kinetic resolution of 500 mM rac-7a for 2.5 h retained (R)-7a with over 99% ee(s) and 43.2% yield(s). Furthermore, the sources of high regiocomplementarity of GmEH3 for (S)- and (R)-5a as well as high enantioselectivity towards rac-7a were analyzed via molecular docking (MD) simulation. Title: LIPG-promoted lipid storage mediates adaptation to oxidative stress in breast cancer Cadenas C, Vosbeck S, Edlund K, Grgas K, Madjar K, Hellwig B, Adawy A, Glotzbach A, Stewart JD and Hengstler JG <17 more author(s)> Cadenas C, Vosbeck S, Edlund K, Grgas K, Madjar K, Hellwig B, Adawy A, Glotzbach A, Stewart JD, Lesjak MS, Franckenstein D, Claus M, Hayen H, Schriewer A, Gianmoena K, Thaler S, Schmidt M, Micke P, Ponten F, Mardinoglu A, Zhang C, Kafferlein HU, Watzl C, Frank S, Rahnenfuhrer J, Marchan R, Hengstler JG (- 17) Ref: International Journal of Cancer, 145:901, 2019 : PubMed ESTHER: Cadenas_2019_Int.J.Cancer_145_901 PubMedSearch: Cadenas 2019 Int.J.Cancer 145 901 PubMedID: 30653260 Abstract Endothelial lipase (LIPG) is a cell surface associated lipase that displays phospholipase A1 activity towards phosphatidylcholine present in high-density lipoproteins (HDL). LIPG was recently reported to be expressed in breast cancer and to support proliferation, tumourigenicity and metastasis. Here we show that severe oxidative stress leading to AMPK activation triggers LIPG upregulation, resulting in intracellular lipid droplet accumulation in breast cancer cells, which supports survival. Neutralizing oxidative stress abrogated LIPG upregulation and the concomitant lipid storage. In human breast cancer, high LIPG expression was observed in a limited subset of tumours and was significantly associated with shorter metastasis-free survival in node-negative, untreated patients. Moreover, expression of PLIN2 and TXNRD1 in these tumours indicated a link to lipid storage and oxidative stress. Altogether, our findings reveal a previously unrecognized role for LIPG in enabling oxidative stress-induced lipid droplet accumulation in tumour cells that protects against oxidative stress, and thus supports tumour progression. Title: Ambient light sensor based colorimetric dipstick reader for rapid monitoring organophosphate pesticides on a smart phone Fu Q, Zhang C, Xie J, Li Z, Qu L, Cai X, Ouyang H, Song Y, Du D and Tang Y <1 more author(s)> Fu Q, Zhang C, Xie J, Li Z, Qu L, Cai X, Ouyang H, Song Y, Du D, Lin Y, Tang Y (- 1) Ref: Anal Chim Acta, 1092:126, 2019 : PubMed ESTHER: Fu_2019_Anal.Chim.Acta_1092_126 PubMedSearch: Fu 2019 Anal.Chim.Acta 1092 126 PubMedID: 31708025 Abstract Organophosphate pesticides (OPs) are widely used around the world to control pests in agricultural, residential, and commercial settings. Ingestion of high-dose OPs could lead to acute toxicity, and persistent influence on health could result from acute poisoning or long-term exposure to low dose OPs. An easy to operate, low cost and home available OPs testing platform is urgently needed. Ambient light sensor (ALS) based smart phone colorimetric reader has the advantages of easy to operate, low cost, high accuracy and versatility. In this work, a novel ALS based smart phone colorimetric dipsticks (CDs) reader was reported for rapid monitoring OPs. In this method, acetylcholinesterase (ACHE) CDs was used to test OPs and results were analyzed using an ALS based reader according to the absorbance of ACHE CDs. The results obtained using the ALS based CDs reader were comparable to those obtained using gas chromatography-mass spectrometry (GC-MS) and Ellman assay. The ALS based CDs reader has the advantages of portable, low cost, and high accuracy, and therefore could act an effective platform for OPs monitoring. Title: Vitamin E Ameliorates Lipid Metabolism in Mice with Nonalcoholic Fatty Liver Disease via Nrf2/CES1 Signaling Pathway He W, Xu Y, Ren X, Xiang D, Lei K, Zhang C, Liu D Ref: Digestive Diseases & Sciences, 64:3182, 2019 : PubMed ESTHER: He_2019_Dig.Dis.Sci_64_3182 PubMedSearch: He 2019 Dig.Dis.Sci 64 3182 PubMedID: 31076985 Abstract BACKGROUND: Vitamin E has been reported to have a beneficial effect on nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism of action has not yet been clearly defined. AIM: We aimed to evaluate the effects and mechanisms of vitamin E on lipid and glucose homeostasis both in vivo and in vitro. METHODS: An NAFLD model was established in C57BL/6 mice fed a 30% fructose solution for 8 weeks. Subsequently, NAFLD mice were given vitamin E (70 mg/kg) for 2 weeks. In addition, L02 cells were treated with 5 mM fructose and 100 nM vitamin E to explore the potential mechanisms of action. RESULTS: Vitamin E reversed the impaired glucose tolerance of fructose-treated mice. Histopathological examination showed that liver steatosis was significantly relieved in vitamin E-treated mice. These effects may be attributed to the upregulation of nuclear factor erythroid-2-related factor 2 (Nrf2), carboxylesterase 1 (CES1), and downregulated proteins involved in lipid synthesis by vitamin E treatment. In vivo, vitamin E also significantly reduced lipid accumulation in fructose-treated L02 cells, and the Nrf2 inhibitor ML385 reversed the protective effects of vitamin E. CONCLUSION: These data indicated that the therapeutic effects of vitamin E on lipid and glucose homeostasis may be associated with activation of the Nrf2/CES1 signaling pathway. 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: Development of the hidden multifunctional agents for Alzheimer's disease Huang W, Liang M, Li Q, Zheng X, Zhang C, Wang Q, Tang L, Zhang Z, Wang B, Shen Z Ref: Eur Journal of Medicinal Chemistry, 177:247, 2019 : PubMed ESTHER: Huang_2019_Eur.J.Med.Chem_177_247 PubMedSearch: Huang 2019 Eur.J.Med.Chem 177 247 PubMedID: 31158742 Abstract Alzheimer's disease (AD) is a chronic, fatal and complex neurodegenerative disorder, which is characterized by cholinergic system dysregulation, metal dyshomeostasis, amyloid-beta (Abeta) aggregation, etc. Therefore in most cases, single-target or single-functional agents are insufficient to achieve the desirable effect against AD. Multi-Target-Directed Ligand (MTDL), which is rationally designed to simultaneously hit multiple targets to improve the pharmacological profiles, has been developed as a promising approach for drug discovery against AD. To identify the multifunctional agents for AD, we developed an innovative method to successfully conceal the metal chelator into acetylcholinesterase (AChE) inhibitor. Briefly, the "hidden" agents first cross the Blood Brain Barrier (BBB) to inhibit the function of AChE, and the metal chelator will then be released via the enzymatic hydrolysis by AChE. Therefore, the AChE inhibitor, in this case, is not only a single-target agent against AD, but also a carrier of the metal chelator. In this study a total of 14 quinoline derivatives were synthesized and biologically evaluated. Both in vitro and in vivo results demonstrated that compound 9b could cross the BBB efficiently, then release 8a, the metabolite of 9b, into brain. In vitro, 9b had a potent AChE inhibitory activity, while 8a displayed a significant metal ion chelating function, therefore in combination, both 9b and 8a exhibited a considerable inhibition of Abeta aggregation, one of the observations that plays important roles in the pathogenesis of AD. The efficacy of 9b against AD was further investigated in both a zebrafish model and two different mice models. Title: Single intranasal immunization with chimpanzee adenovirus-based vaccine induces sustained and protective immunity against MERS-CoV infection Jia W, Channappanavar R, Zhang C, Li M, Zhou H, Zhang S, Zhou P, Xu J, Shan S and Zhang L <5 more author(s)> Jia W, Channappanavar R, Zhang C, Li M, Zhou H, Zhang S, Zhou P, Xu J, Shan S, Shi X, Wang X, Zhao J, Zhou D, Perlman S, Zhang L (- 5) Ref: Emerg Microbes Infect, 8:760, 2019 : PubMed ESTHER: Jia_2019_Emerg.Microbes.Infect_8_760 PubMedSearch: Jia 2019 Emerg.Microbes.Infect 8 760 PubMedID: 31130102 Abstract The recently identified Middle East Respiratory Syndrome Coronavirus (MERS-CoV) causes severe and fatal acute respiratory illness in humans. However, no approved prophylactic and therapeutic interventions are currently available. The MERS-CoV envelope spike protein serves as a crucial target for neutralizing antibodies and vaccine development, as it plays a critical role in mediating viral entry through interactions with the cellular receptor, dipeptidyl peptidase 4 (DPP4). Here, we constructed a recombinant rare serotype of the chimpanzee adenovirus 68 (AdC68) that expresses full-length MERS-CoV S protein (AdC68-S). Single intranasal immunization with AdC68-S induced robust and sustained neutralizing antibody and T cell responses in BALB/c mice. In a human DPP4 knock-in (hDPP4-KI) mouse model, it completely protected against lethal challenge with a mouse-adapted MERS-CoV (MERS-CoV-MA). Passive transfer of immune sera to naive hDPP4-KI mice also provided survival advantages from lethal MERS-CoV-MA challenge. Analysis of sera absorption and isolated monoclonal antibodies from immunized mice demonstrated that the potent and broad neutralizing activity was largely attributed to antibodies targeting the receptor binding domain (RBD) of the S protein. These results show that AdC68-S can induce protective immune responses in mice and represent a promising candidate for further development against MERS-CoV infection in both dromedaries and humans. Title: Detection techniques of carboxylesterase activity: An update review Lan L, Ren X, Yang J, Liu D, Zhang C Ref: Bioorg Chem, :103388, 2019 : PubMed ESTHER: Lan_2019_Bioorg.Chem__103388 PubMedSearch: Lan 2019 Bioorg.Chem 103388 PubMedID: 31676115 Abstract Mammalian carboxylesterases (CESs) are essential members of serine esterase hydrolase superfamily, which are widely distributed in many tissues including liver, intestine, lung and kidney. CESs play an important role in the metabolism of various xenobiotics including ester drugs and environmental toxicants, and also participate in lipid homeostasis, so the development of CESs activity detection techniques are of great significance for drug discovery and biomedical research. With the rapid development of separated and detection technologies such as chromatography, capillary electrophoresis, fluorescent probe-based detection technology, bioluminescent sensor and colorimetric sensor in recent decade, the research of physiological functions of CESs have make huge breakthrough. This review summarizes the development and application of CESs activity detection techniques, as well as comparatively analyzes the characteristics of various detection techniques. The information and knowledge represented here will help the researchers carry out various biochemical studies for understanding activation mechanism and role of CESs in drug metabolism. Title: Metal coordination polymer induced perylene probe excimer fluorescence and its application in acetylcholinesterase sensing and alpha-fetoprotein immunoassay Li Y, Yin S, Hou J, Meng L, Gao M, Sun Y, Zhang C, Bai S, Ren J, Yu C Ref: Analyst, 144:2034, 2019 : PubMed ESTHER: Li_2019_Analyst_144_2034 PubMedSearch: Li 2019 Analyst 144 2034 PubMedID: 30702092 Abstract A novel sensing strategy for acetylcholinesterase (AChE) and alpha-fetoprotein (AFP) is developed, based on the perylene probe monomer to excimer fluorescence transformation induced by the in situ generation of a metal coordination polymer. In the presence of AChE, acetylthiocholine chloride was hydrolyzed to thiocholine. Ag(+) and the produced thiocholine formed a positively charged metal coordination polymer, which induced the aggregation of a negatively charged perylene probe and the formation of probe excimer emission. The intensity ratio of excimer to monomer emission was proportional to the AChE concentration. A sensing method for AChE was thus established with a detection limit of 0.02 mU mL(-1). The excimer emission with a large Stokes shift could avoid the interference of background fluorescence from complex biological samples, and thus achieved selective and sensitive detection of AChE. In addition, a fluorescence immunoassay strategy for AFP was then developed. Gold nanoparticles (AuNPs) co-immobilized with acetylcholinesterase and the AFP antibody as the capture and amplification probe were first prepared. In the presence of AFP, the sandwich structure was formed by immunological recognition. The hydrolysis of acetylthiocholine was catalyzed by AChE on the AuNPs, and the metal coordination polymer was then formed which resulted in the aggregation of the perylene probe and the formation of the excimer emission. The proposed sensing method offers a new strategy for the detection of other biomarkers. Title: Improving the activity and enantioselectivity of PvEH1, a Phaseolus vulgaris epoxide hydrolase, for o-methylphenyl glycidyl ether by multiple site-directed mutagenesis on the basis of rational design Li C, Kan T-T, Hu D, Wang T-T, Su Y-J, Zhang C, Cheng J-Q, Wu M-C Ref: Molecular Catalysis, 476:110517, 2019 : PubMed ESTHER: Li_2019_Mol.Catal_476_110517 PubMedSearch: Li 2019 Mol.Catal 476 110517 Gene_locus related to this paper: phavu-PvEH1 Abstract Substrate spectrum assay exhibited that PvEH1, which is an epoxide hydrolase from P. vulgaris, had the highest specific activity and enantiomeric ratio (E) for racemic o-methylphenyl glycidyl ether (rac-1) among tested aryl glycidyl ethers (1-5). To produce (R)-1 via kinetic resolution of rac-1 efficiently, the catalytic properties of PvEH1 were further improved on the basis of rational design. Firstly, the seven single-site variants of PvEH1-encoding gene (pveh1) were PCR-amplified as designed, and expressed in E. coli BL21(DE3). Among all expressed single-site mutants, PvEH1L105I and PvEH1V106I had the highest specific activities of 17.6 and 16.4 U/mg protein, respectively, while PvEH1L196D had an enhanced E value of 9.2. Secondly, to combine their respective merits, one triple-site variant, pveh1L105I/V106I/L196D, was also amplified, and expressed. The specific activity, E value, and catalytic efficiency of PvEH1L105I/V106I/L196D were 23.1 U/mg, 10.9, and 6.65 mM1 s1, respectively, which were 2.0-, 1.8- and 2.4-fold higher than those of wild-type PvEH1. The source of PvEH1L105I/V106I/L196D with enhanced E value for rac-1 was preliminarily analyzed by molecular docking simulation. Finally, the scale-up kinetic resolution of 100 mM rac-1 was conducted using 5 mg wet cells/mL E. coli/pveh1L105I/V106I/L196D at 25 degreesC for 1.5 h, producing (R)-1 with 95.0% ees, 32.1% yield and 3.52 g/L/h space-time yield. Title: Inhibition of cell proliferation and migration in nonsmall cell lung cancer cells through the suppression of LYPLA1 Mohammed A, Zhang C, Zhang S, Shen Q, Li J, Tang Z, Liu H Ref: Oncol Rep, 41:973, 2019 : PubMed ESTHER: Mohammed_2019_Oncol.Rep_41_973 PubMedSearch: Mohammed 2019 Oncol.Rep 41 973 PubMedID: 30431103 Gene_locus related to this paper: human-LYPLA1 Abstract Lysophospholipase1 (LYPLA1) also known as acylprotein thioesterase1 (APT1) belongs to the superfamily of alpha/beta hydrolase. It has been found to have the properties of a homodimer by manifesting depalmitoylation as well as lysophospholipase activity. LYPLAs are under the control of both microRNAs, miR138 and miR424. They were observed to be significantly overexpressed in chronic lymphocytic leukemia cells. To date, LYPLAs are the sole enzymes recognized to activate depalmitoylation. In this study, we provide the expression pattern of LYPLA1 in nonsmall cell lung cancer (NSCLC) using four different NSCLC cell lines. Western blot analysis and RTPCR were performed to detect the protein expression and mRNA expression of LYPLA1 in NSCLC cell lines. We detected the highest LYPLA1 protein expression level in SPCA1 cells followed by A549 cells, and the highest LYPLA1 mRNA expression level was detected in the SPCA1 cells followed by the H1299 cell line. We found that suppression of LYPLA1 expression using smallinterfering RNA significantly inhibited proliferation, migration and invasion of the LYPLA1transfected NSCLC cells. Furthermore, we explored the involvement of LYPLA1 in the regulation of epithelialmesenchymal transition (EMT). The epithelial marker Ecadherin was significantly increased, while mesenchymal markers Ncadherin, vimentin and SNAIL were markedly decreased in the LYPLA1silenced cells. Collectively the results of the present study suggest that the LYPLA1 gene plays a tumorpromotor role in NSCLC cells in vitro. Title: Catalytic Hydrolysis Mechanism of Cocaine by Human Carboxylesterase 1: An Orthoester Intermediate Slows Down the Reaction Yan M, Zhang Z, Liu Z, Zhang C, Zhang J, Fan S, Yang Z Ref: Molecules, 24:, 2019 : PubMed ESTHER: Yan_2019_Molecules_24_ PubMedSearch: Yan 2019 Molecules 24 PubMedID: 31717501 Gene_locus related to this paper: human-CES1 Abstract Human carboxylesterase 1 (hCES1) is a major carboxylesterase in the human body and plays important roles in the metabolism of a wide variety of substances, including lipids and drugs, and therefore is attracting more and more attention from areas including lipid metabolism, pharmacokinetics, drug-drug interactions, and prodrug activation. In this work, we studied the catalytic hydrolysis mechanism of hCES1 by the quantum mechanics computation method, using cocaine as a model substrate. Our results support the four-step theory of the esterase catalytic hydrolysis mechanism, in which both the acylation stage and the deacylation stage include two transition states and a tetrahedral intermediate. The roles and cooperation of the catalytic triad, S221, H468, and E354, were also analyzed in this study. Moreover, orthoester intermediates were found in hCES1-catalyzed cocaine hydrolysis reaction, which significantly elevate the free energy barrier and slow down the reaction. Based on this finding, we propose that hCES1 substrates with beta-aminocarboxylester structure might form orthoester intermediates in hCES1-catalyzed hydrolysis, and therefore prolong their in vivo half-life. Thus, this study helps to clarify the catalytic mechanism of hCES1 and elucidates important details of its catalytic process, and furthermore, provides important insights into the metabolism of hCES1 substrates and drug designing. Title: Augmentation of peripheral lymphocyte-derived cholinergic activity in patients with acute ischemic stroke Yuan M, Han B, Xia Y, Liu Y, Wang C, Zhang C Ref: BMC Neurol, 19:236, 2019 : PubMed ESTHER: Yuan_2019_BMC.Neurol_19_236 PubMedSearch: Yuan 2019 BMC.Neurol 19 236 PubMedID: 31615442 Abstract BACKGROUND: Brain ischemia activates the parasympathetic cholinergic pathway in animal models of human disease. However, it remains unknown whether activation of the cholinergic pathway impacts immune defenses and disease outcomes in patients with ischemic stroke. This study investigated a possible association between peripheral cholinergic activity, post-stroke infection, and mortality. METHODS: In this study, we enrolled 458 patients with acute ischemic stroke (< 24 h after onset), 320 patients with ischemic stroke on day 10, and 216 healthy subjects. Peripheral cholinergic activity, reflected by intracellular acetylcholine (ACh) content in human peripheral blood mononuclear cells (PBMCs), was determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Expression of acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) was measured by quantitative real-time PCR and western blot. Regression analyses were used to assess associations between peripheral cholinergic function and clinical outcomes. RESULTS: Within 24 h after the onset of acute ischemic stroke, there was a rapid increase in peripheral cholinergic activity that correlated with brain infarction volume (r = 0.67, P < 0.01). Specifically, lymphocyte-derived ACh levels were significantly higher in stroke patients with pneumonia (0.21 +/- 0.02 ng/10(6) PBMC versus 0.15 +/- 0.01 ng/10(6) PBMC, P = 0.03). Of note, lymphocytic AChE catalytic activity was significantly lower in these patients. One-year mortality was significantly greater in patients with higher intracellular ACh levels within the first 24 h after acute stroke. CONCLUSIONS: Lymphocytes produced increased amounts of ACh in patients with acute stroke, and pneumonia was a likely result. The association between this enhanced cholinergic activity and increased risk of pneumonia/mortality suggests that increased cholinergic activity may contribute to fatal post-stroke infection. Title: Cholinesterase inhibitory isoquinoline alkaloids from Corydalis mucronifera Zhang J, Zhang C, Xu FC, Quesheng, Zhang QY, Tu PF, Liang H Ref: Phytochemistry, 159:199, 2019 : PubMed ESTHER: Zhang_2019_Phytochemistry_159_199 PubMedSearch: Zhang 2019 Phytochemistry 159 199 PubMedID: 30634082 Abstract Eight previously undescribed isoquinoline alkaloids, mucroniferanines H-M, together with 16 known isoquinoline alkaloids, were isolated from Corydalis mucronifera Maxim.. The structures of the previously undescribed compounds were elucidated by interpretation of 1D and 2D NMR spectroscopic and HRMS data, and their absolute configurations were established by computational electronic circular dichroism (ECD) calculations and X-ray diffraction data. Mucroniferanine L is reported as the first natural amide bond linked isoquinoline alkaloid dimer. The isolated compounds were evaluated for AChE and BuChE inhibitory activities and mucroniferanine H showed significant activities with IC50 values of 2.31muM and 36.71muM, respectively. Title: Transcriptomic analysis of Chlorimuron-ethyl degrading bacterial strain Klebsiella jilinsis 2N3 Zhang C, Hao Q, Zhang S, Zhang Z, Zhang X, Sun P, Pan H, Zhang H, Sun F Ref: Ecotoxicology & Environmental Safety, 183:109581, 2019 : PubMed ESTHER: Zhang_2019_Ecotoxicol.Environ.Saf_183_109581 PubMedSearch: Zhang 2019 Ecotoxicol.Environ.Saf 183 109581 PubMedID: 31446172 Abstract Chlorimuron-ethyl is a sulfonylurea herbicide with a long residual period in the field and is toxic to rotational crops. Klebsiella jilinsis 2N3 is a gram-negative bacterium that can rapidly degrade Chlorimuron-ethyl. In this study, the gene expression changes in strain 2N3 during degradation of Chlorimuron-ethyl was analyzed by RNA-Seq. Results showed that 386 genes were up-regulated and 453 genes were down-regulated. KEGG pathway enrichment analysis revealed the highest enrichment ratio in the pathway of sulfur metabolism. On the basis of the functional annotation and gene expression, we predicted that carboxylesterase, monooxygenase, glycosyltransferase, and cytochrome P450 were involved in the metabolism of Chlorimuron-ethyl biodegradation. Results of qRT-PCR showed that the relative mRNA expression levels of these genes were higher in treatment group than those in control group. The cytochrome P450 encoded by Kj-CysJ and the alkanesulfonate monooxygenase encoded by Kj-SsuD were predicted and further experimentally confirmed by gene knockout as the key enzymes in the biodegradation process. Cultured in basal medium containing Chlorimuron-ethyl (5mgL(-1)) in 36h, the strains of DeltaKj-CysJ, DeltaKj-SsuD, and WT reached the highest OD600 values of 0.308, 0.873, and 1.085, and the highest degradation rates of Chlorimuron-ethyl of 11.83%, 96.21%, and 95.62%, respectively. Title: An ultrasensitive signal-on electrochemiluminescence biosensor based on Au nanoclusters for detecting acetylthiocholine Zhang C, Fan Y, Zhang H, Chen S, Yuan R Ref: Anal Bioanal Chem, 411:905, 2019 : PubMed ESTHER: Zhang_2019_Anal.Bioanal.Chem_411_905 PubMedSearch: Zhang 2019 Anal.Bioanal.Chem 411 905 PubMedID: 30565170 Abstract For improving the sensitivity of the electrochemiluminescent (ECL) detection and extending the applications of luminophore, the development of coreactant accelerator is one of the important ways. In this work, Au nanoclusters (Au NCs) were chosen as the luminescent material, and thiocholine, which was in situ generated by enzymatic reaction, was found to serve as a coreactant accelerator for Au NC-S2O8(2-) ECL system. Based on this discovery, a highly sensitive detection of acetylthiocholine (ATCl) was achieved using the acetylcholinesterase (AChE) biosensor. CeO2 nanowires (CeO2 NWs) were used to improve the stability of Au NCs on the glassy carbon electrode (GCE) due to the large specific surface area and good film-forming properties of CeO2 NWs. ATCl was catalyzed by acetylcholinesterase (AChE) to produce thiocholine, which served as the coreactant accelerator to improve the ECL signal of Au NC-S2O8(2-) system. The biosensor obtained a low detection limit of 0.17 nM. The integration of thiocholine and Au NCs would provide a new ECL platform for bioanalysis. Graphical abstract . Title: Whole Genome Sequencing and Analysis of Chlorimuron-Ethyl Degrading Bacteria Klebsiella pneumoniae 2N3 Zhang C, Hao Q, Zhang Z, Zhang X, Pan H, Zhang J, Zhang H, Sun F Ref: Int J Mol Sci, 20:, 2019 : PubMed ESTHER: Zhang_2019_Int.J.Mol.Sci_20_ PubMedSearch: Zhang 2019 Int.J.Mol.Sci 20 PubMedID: 31234527 Gene_locus related to this paper: klep7-a6tb98, klep7-mhpc Abstract Klebsiella pneumoniae 2N3 is a strain of gram-negative bacteria that can degrade chlorimuron-ethyl and grow with chlorimuron-ethyl as the sole nitrogen source. The complete genome of Klebsiella pneumoniae 2N3 was sequenced using third generation high-throughput DNA sequencing technology. The genomic size of strain 2N3 was 5.32 Mb with a GC content of 57.33% and a total of 5156 coding genes and 112 non-coding RNAs predicted. Two hydrolases expressed by open reading frames (ORFs) 0934 and 0492 were predicted and experimentally confirmed by gene knockout to be involved in the degradation of chlorimuron-ethyl. Strains of DeltaORF 0934, DeltaORF 0492, and wild type (WT) reached their highest growth rates after 8-10 hours in incubation. The degradation rates of chlorimuron-ethyl by both DeltaORF 0934 and DeltaORF 0492 decreased in comparison to the WT during the first 8 hours in culture by 25.60% and 24.74%, respectively, while strains DeltaORF 0934, DeltaORF 0492, and the WT reached the highest degradation rates of chlorimuron-ethyl in 36 hours of 74.56%, 90.53%, and 95.06%, respectively. This study provides scientific evidence to support the application of Klebsiella pneumoniae 2N3 in bioremediation to control environmental pollution. Title: Inhibiting Abeta toxicity in Alzheimer's disease by a pyridine amine derivative Zhu Z, Yang T, Zhang L, Liu L, Yin E, Zhang C, Guo Z, Xu C, Wang X Ref: Eur Journal of Medicinal Chemistry, 168:330, 2019 : PubMed ESTHER: Zhu_2019_Eur.J.Med.Chem_168_330 PubMedSearch: Zhu 2019 Eur.J.Med.Chem 168 330 PubMedID: 30826509 Abstract Alzheimer's disease (AD) is a neurodegenerative disorder with no radical therapy. Aggregation of amyloid beta-peptide (Abeta) induced by various factors is associated with pathogenesis of AD. A pyridine amine derivative, 3-bis(pyridin-2-ylmethyl)aminomethyl-5-hydroxybenzyltriphenylphosphonium bromide (PAT), is synthesized. The inhibition of self- and metal-induced Abeta aggregation by PAT is confirmed by thioflavine T fluorescence, circular dichroism spectroscopy, and TEM. Western blot, RT-PCR and fluorescence imaging indicate that PAT can alleviate the Abeta-induced paralysis, reduce the production of ROS, and protect the mitochondrial function in transgenic C. elegans. Genetic analyses indicate that heat shock protein is involved in the alleviation of Abeta toxicity. PAT also inhibits the activity of acetylcholinesterase in C. elegans. Morris water maze test shows that the memory and cognitive ability of APP/PS1 AD model mice are significantly improved by PAT. Both in vitro and in vivo studies demonstrate that PAT is effective in counteracting Abeta toxicity and ameliorating cognitive functions in AD mice, and therefore a potential lead compound of anti-AD drugs. Title: CXCL5, the upregulated chemokine in patients with uterine cervix cancer, in vivo and in vitro contributes to oncogenic potential of Hela uterine cervix cancer cells Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P and Wang W <7 more author(s)> Feng X, Zhang D, Li X, Ma S, Zhang C, Wang J, Li Y, Liang L, Zhang P, Qu Y, Zhang Z, Yang Z, Xiang Y, Zhang W, Wang S, Shao W, Wang W (- 7) Ref: Biomed Pharmacother, 107:1496, 2018 : PubMed ESTHER: Feng_2018_Biomed.Pharmacother_107_1496 PubMedSearch: Feng 2018 Biomed.Pharmacother 107 1496 PubMedID: 30257367 Abstract CXCL5 is showed a surprisingly elevated profile and implicated in tumorigenesis in several tumors. However, the expression and function of CXCL5 in uterine cervix cancer (UCC) remain largely unknown. The current study aimed to elucidate the expression pattern of CXCL5 in human UCC tissues and Hela cervix cancer cell, as well as its functions in Hela cells. Our data showed that CXCL5 and its receptor CXCR2 were expressed by Hela uterine cervix cancer cells. CXCL5 was upregulated in UCC tissues, and its overexpression was positively correlated with age, but did not correlate with clinical stages and tumor infiltration. Exogenous administration of CXCL5 and CXCL5 overexpression contributed to proliferation and migration activities of Hela cells in vitro, consistent with this, CXCL5 overexpression also promoted growth of Hela cells in a nude mouse xenograft model. At the gene level, CXCL5 overexpression regulated the expression of tumor-related genes including ERK, p-ERK, AKT, p-AKT, DIABOL, NUMB, NDRG3 and CXCR2. Taken together, CXCL5 may contribute to a dominant role in UCC progression and sever as a potential molecular therapeutic target for UCC. Title: Genome Sequencing of Streptomyces atratus SCSIOZH16 and Activation Production of Nocardamine via Metabolic Engineering Li Y, Zhang C, Liu C, Ju J, Ma J Ref: Front Microbiol, 9:1269, 2018 : PubMed ESTHER: Li_2018_Front.Microbiol_9_1269 PubMedSearch: Li 2018 Front.Microbiol 9 1269 PubMedID: 29963027 Gene_locus related to this paper: strar-a0a2z5jcs5 Abstract The Actinomycetes are metabolically flexible microorganisms capable of producing a wide range of interesting compounds, including but by no means limited to, siderophores which have high affinity for ferric iron. In this study, we report the complete genome sequence of marine-derived Streptomyces atratus ZH16 and the activation of an embedded siderophore gene cluster via the application of metabolic engineering methods. The S. atratus ZH16 genome reveals that this strain has the potential to produce 26 categories of natural products (NPs) barring the ilamycins. Our activation studies revealed S. atratus SCSIO ZH16 to be a promising source of the production of nocardamine-type (desferrioxamine) compounds which are important in treating acute iron intoxication and performing ecological remediation. We conclude that metabolic engineering provides a highly effective strategy by which to discover drug-like compounds and new NPs in the genomic era. Title: Dental malocclusion stimulates neuromuscular circuits associated with temporomandibular disorders Liu X, Zhang C, Liu Q, Zhou K, Yin N, Zhang H, Shi M, Wang M Ref: Eur J Oral Sci, 126:466, 2018 : PubMed ESTHER: Liu_2018_Eur.J.Oral.Sci_126_466 PubMedSearch: Liu 2018 Eur.J.Oral.Sci 126 466 PubMedID: 30341927 Abstract Unilateral anterior crossbite (UAC) has been demonstrated to cause masseter hyperactivity via the periodontal trigeminal mesencephalic nucleus (Vme)-trigeminal motor nucleus circuit. Here, we studied activation of motor neurons of the facial nucleus (VII), hypoglossal nucleus (XII), nucleus ambiguus (Amb), and spinal nucleus of the accessory nerve (SNA) in rats with UAC via their similar connections with Vme. An anterograde tracer, biotinylated dextran amine (BDA), was injected into the Vme to identify the central axon terminals around the motor neurons of VII, XII, Amb, and SNA. The expression of vesicular glutamate transporter 1 (VGLUT1) in neurons of VII, XII, Amb, and SNA, and the expression of acetylcholinesterase (AChE) were measured in the stapedius, lingualis, palatopharyngeal, and sternocleidomastoid muscles. In BDA-treated rats, many BDA-labeled cell bodies in the Vme and terminals in VII, XII, Amb, and SNA were identified. Compared with control rats, rats with UAC showed higher expression of VGLUT1 in these nuclei, and statistically significantly higher expression of AChE in the stapedius, lingualis, and sternocleidomastoid muscles, but not in the palatopharyngeal muscle. These findings suggest that UAC activates orofacial, head, and cervical multimotor behaviors via connections between the Vme and the corresponding motor nuclei. Title: Efficient resolution of (R,S)-1-(1-naphthyl)ethylamine by Candida antarctica lipase B in ionic liquids Wang B, Zhang C, He Q, Qin H, Liang G, Liu W Ref: Molecular Catalysis, 448:116, 2018 : PubMed ESTHER: Wang_2018_Mol.Catal_448_116 PubMedSearch: Wang 2018 Mol.Catal 448 116 Abstract The resolution of (R,S)-1-(1-naphthyl)ethylamine ((R,S)-NEA) by Candida antarctica lipase B (CALB) in ionic liquids (ILs) containing 1-alkyl-3-methylimidazolium cations ([Cnmim]+) and [Tf2N]-, [BF4]-, and [PF6]- anions was investigated. When the alkyl chain on the cation contained less than six carbons, the lipase activity corresponded with the hydrophobicity of the ILs, but further increase in the chain length suppressed the enzyme activity. The enzyme activity decreased depending on the anion, where [Tf2N]- > [PF6]- > [BF4]-. The effects of acyl donors, pH, temperature, water activity, and substrate concentration on the resolution were determined. Under the optimal conditions, the conversion of (R,S)-NEA and enantiomer excess of (R)-n-octyl acyl-NEA was 49.3% and 99.2%, respectively. The resolution kinetics of (R,S)-NEA by CALB in [C6mim][Tf2N] were studied and a ping-pong mechanism with a two substrate inhibition model was selected. The kinetic parameters of the fitting results were as follows: Michaelis constant of (R,S)-NEA Kma, 461.8 mmol/L; Michaelis constant of vinyl n-octanoateKmb, 262.1 mmol/L; inhibition constant of (R,S)-NEA Kia, 8737.2 mmol/L; inhibition constant of vinyl n-octanoateKib, 62336.8 mmol/L; maximum reaction rate rmax, 0.352 mmol/(mg min). Moreover, circular dichroism revealed that incubation of CALB in [C6mim][Tf2N] resulted in increased beta-sheet content; its secondary structure was stable. Title: Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer's Disease Wu W, Liang X, Xie G, Chen L, Liu W, Luo G, Zhang P, Yu L, Zheng X and Yi W <2 more author(s)> Wu W, Liang X, Xie G, Chen L, Liu W, Luo G, Zhang P, Yu L, Zheng X, Ji H, Zhang C, Yi W (- 2) Ref: Molecules, 23:, 2018 : PubMed ESTHER: Wu_2018_Molecules_23_ PubMedSearch: Wu 2018 Molecules 23 PubMedID: 30301153 Abstract A series of novel ligustrazine derivatives 8a(-)r were designed, synthesized, and evaluated as multi-targeted inhibitors for anti-Alzheimer's disease (AD) drug discovery. The results showed that most of them exhibited a potent ability to inhibit both ChEs, with a high selectivity towards AChE. In particular, compounds 8q and 8r had the greatest inhibitory abilities for AChE, with IC50 values of 1.39 and 0.25 nM, respectively, and the highest selectivity towards AChE (for 8q, IC50 BuChE/IC50 AChE = 2.91 x 10(6); for 8r, IC50 BuChE/IC50 AChE = 1.32 x 10(7)). Of note, 8q and 8r also presented potent inhibitory activities against Abeta aggregation, with IC50 values of 17.36 microM and 49.14 microM, respectively. Further cellular experiments demonstrated that the potent compounds 8q and 8r had no obvious cytotoxicity in either HepG2 cells or SH-SY5Y cells, even at a high concentration of 500 muM. Besides, a combined Lineweaver-Burk plot and molecular docking study revealed that these compounds might act as mixed-type inhibitors to exhibit such effects via selectively targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChEs. Taken together, these results suggested that further development of these compounds should be of great interest. Title: Evolving artificial metalloenzymes via random mutagenesis Yang H, Swartz AM, Park HJ, Srivastava P, Ellis-Guardiola K, Upp DM, Lee G, Belsare K, Gu Y and Lewis JC <2 more author(s)> Yang H, Swartz AM, Park HJ, Srivastava P, Ellis-Guardiola K, Upp DM, Lee G, Belsare K, Gu Y, Zhang C, Moellering RE, Lewis JC (- 2) Ref: Nat Chem, 10:318, 2018 : PubMed ESTHER: Yang_2018_Nat.Chem_10_318 PubMedSearch: Yang 2018 Nat.Chem 10 318 PubMedID: 29461523 Inhibitor(s) related to this paper: ArM-dirhodium-cofactor Abstract Random mutagenesis has the potential to optimize the efficiency and selectivity of protein catalysts without requiring detailed knowledge of protein structure; however, introducing synthetic metal cofactors complicates the expression and screening of enzyme libraries, and activity arising from free cofactor must be eliminated. Here we report an efficient platform to create and screen libraries of artificial metalloenzymes (ArMs) via random mutagenesis, which we use to evolve highly selective dirhodium cyclopropanases. Error-prone PCR and combinatorial codon mutagenesis enabled multiplexed analysis of random mutations, including at sites distal to the putative ArM active site that are difficult to identify using targeted mutagenesis approaches. Variants that exhibited significantly improved selectivity for each of the cyclopropane product enantiomers were identified, and higher activity than previously reported ArM cyclopropanases obtained via targeted mutagenesis was also observed. This improved selectivity carried over to other dirhodium-catalysed transformations, including N-H, S-H and Si-H insertion, demonstrating that ArMs evolved for one reaction can serve as starting points to evolve catalysts for others. Title: Prolonged neuromuscular block associated with cholinesterase deficiency Zhang C, Cao H, Wan ZG, Wang J Ref: Medicine (Baltimore), 97:e13714, 2018 : PubMed ESTHER: Zhang_2018_Medicine.(Baltimore)_97_e13714 PubMedSearch: Zhang 2018 Medicine.(Baltimore) 97 e13714 PubMedID: 30593143 Abstract RATIONALE: Hereditary genetic mutations may cause congenital cholinesterase deficiency. When succinylcholine and mivacurium are applied on cholinesterase-deficient patients during general anesthesia, prolonged postoperative asphyxia occurs, which is an uncommon but very serious complication. PATIENT CONCERNS: A previously healthy 30-year-old female presented prolonged spontaneous breathing recovery after general anesthesia. DIAGNOSES: After the patient's postoperative spontaneous breathing recovery delayed, the plasma cholinesterase was found to be 27 U/L, which was far below the normal level (4000 U/L to 13500 U/L). This patient had no disease that can cause plasma cholinesterase deficiency and was therefore diagnosed as congenital cholinesterase deficiency. INTERVENTIONS AND OUTCOMES: The patient was sent to the intensive care unit (ICU) intubated for mechanical ventilator support, and on the next day the tracheal tube was removed without any complications when her spontaneous respiration resumed. LESSONS: Cholinesterase is an enzyme secreted by the liver involved in many physiological processes in human body. Plasma cholinesterase commonly contains acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). When succinylcholine and mivacurium are applied on patients with cholinesterase-deficiency during general anesthesia, prolonged postoperative asphyxia occurs, which is an uncommon but very serious complication. Lately, new evidences have suggested that hereditary genetic mutations may be responsible for congenital cholinesterase deficiency. Title: Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis Deng W, Zhu Y, Lin J, Zheng L, Zhang C, Luo M Ref: Prostaglandins Other Lipid Mediat, 131:67, 2017 : PubMed ESTHER: Deng_2017_Prostaglandins.Other.Lipid.Mediat_131_67 PubMedSearch: Deng 2017 Prostaglandins.Other.Lipid.Mediat 131 67 PubMedID: 28822809 Inhibitor(s) related to this paper: t-TUCB Abstract Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (alpha-SMA) expression and liver fibrosis, which was associated with a decrease in NF-kappaB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis. Title: Non-neuronal cholinergic activity is potentiated in myasthenia gravis Han B, Zhang C, Liu S, Xia Y, Sun H, Gong Z, Simard AR, Liu Q, Hao J Ref: BMC Neurol, 17:28, 2017 : PubMed ESTHER: Han_2017_BMC.Neurol_17_28 PubMedSearch: Han 2017 BMC.Neurol 17 28 PubMedID: 28178923 Abstract BACKGROUND: Non-neuronal acetylcholine (ACh) restricts autoimmune responses and attenuates inflammation by cholinergic anti-inflammation pathway. To date, the implication of ACh in myasthenia gravis (MG) remained unexplored. This study aimed to investigate the possible relationship between ACh levels, anti-muscle-specific tyrosine kinase (MuSK) antibody titers, main clinical features and outcomes of MG patients. METHODS: We successfully measured ACh levels in human peripheral blood mononuclear cells (PBMCs) from 125 MG patients and 50 matched healthy controls by using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We assessed the quantitative MG (QMG) scores for each patient and titered anti-MuSK antibody. RESULTS: We found that PBMC-derived ACh level was significantly higher in MG patients, especially in patients of class III, IV-V, compared with that in controls (0.142 +/- 0.108 vs. 0.075 +/- 0.014 ng/million cells, p = 0.0003) according to the Myasthenia Gravis Foundation of America clinical classification. Importantly, we also found that ACh levels were positively correlated with QMG scores (r = 0.83, p < 0.0001) and anti-MuSK Ab levels (r = 0.85, p < 0.0001). CONCLUSIONS: Our demonstration of elevated ACh levels in PBMCs of MG patients foreshadows potential new avenues for MG research and treatment. Title: Proprioceptive mechanisms in occlusion-stimulated masseter hypercontraction Liu X, Zhang C, Wang D, Zhang H, Li J, Wang M Ref: Eur J Oral Sci, 125:127, 2017 : PubMed ESTHER: Liu_2017_Eur.J.Oral.Sci_125_127 PubMedSearch: Liu 2017 Eur.J.Oral.Sci 125 127 PubMedID: 28145597 Abstract Neurons in the trigeminal mesencephalic nucleus (Vme) have an axon that branches peripherally to innervate the orofacial region and projects centrally to the trigeminal motor nucleus (Vmo). They function as the primary neurons conveying proprioceptive messages. The present study aimed to demonstrate the presence of a periodontal-Vme-Vmo circuit and to provide evidence for its involvement in an experimental unilateral anterior crossbite (UAC) model, which can induce osteoarthritis in the temporomandibular joint. Cholera toxin B subunit (CTb) was injected into the inferior alveolar nerve of rats to help identify the central axon terminals of Vme neurons in the Vmo. The levels of vesicular glutamate transporter 1 (VGLUT1) expressed in the periodontal region, Vme, Vmo, and masseter, and the level of acetylcholinesterase (AChE) expressed in the masseter, were assessed in UAC rats and controls. In CTb-treated rats, many CTb-labeled cell bodies and endings were identified in the Vme and in the Vmo, respectively. In UAC rats, VGLUT1 was expressed at a statistically significantly higher level in the periodontal ligament, Vme, Vmo, and masseter than it was in control rats. The level of AChE protein was 1.97 times higher in UAC rat masseter compared with control rat masseter. These findings reveal a trigeminal mechanism underlying masseter hyperactivity induced by an altered occlusion. Title: Mimicking Neuroligin-2 Functions in beta-Cells by Functionalized Nanoparticles as a Novel Approach for Antidiabetic Therapy Munder A, Israel LL, Kahremany S, Ben-Shabat-Binyamini R, Zhang C, Kolitz-Domb M, Viskind O, Levine A, Senderowitz H and Gruzman A <2 more author(s)> Munder A, Israel LL, Kahremany S, Ben-Shabat-Binyamini R, Zhang C, Kolitz-Domb M, Viskind O, Levine A, Senderowitz H, Chessler S, Lellouche JP, Gruzman A (- 2) Ref: ACS Appl Mater Interfaces, 9:1189, 2017 : PubMed ESTHER: Munder_2017_ACS.Appl.Mater.Interfaces_9_1189 PubMedSearch: Munder 2017 ACS.Appl.Mater.Interfaces 9 1189 PubMedID: 28045486 Abstract Both pancreatic beta-cell membranes and presynaptic active zones of neurons include in their structures similar protein complexes, which are responsible for mediating the secretion of bioactive molecules. In addition, these membrane-anchored proteins regulate interactions between neurons and guide the formation and maturation of synapses. These proteins include the neuroligins (e.g., NL-2) and their binding partners, the neurexins. The insulin secretion and maturation of beta-cells is known to depend on their 3-dimensional (3D) arrangement. It was also reported that both insulin secretion and the proliferation rates of beta-cells increase when cells are cocultured with clusters of NL-2. Use of full-length NL-2 or even its exocellular domain as potential beta-cell functional enhancers is limited by the biostability and bioavailability issues common to all protein-based therapeutics. Thus, based on molecular modeling approaches, a short peptide with the potential ability to bind neurexins was derived from the NL-2 sequence. Here, we show that the NL-2-derived peptide conjugates onto innovative functional maghemite (gamma-Fe2O3)-based nanoscale composite particles enhance beta-cell functions in terms of glucose-stimulated insulin secretion and protect them under stress conditions. Recruiting the beta-cells' "neuron-like" secretory machinery as a target for diabetes treatment use has never been reported before. Such nanoscale composites might therefore provide a unique starting point for designing a novel class of antidiabetic therapeutic agents that possess a unique mechanism of action. Title: Cell-sized lipid vesicles for cell-cell synaptic therapies Vallejo D, Lee SH, Lee D, Zhang C, Rapier C, Chessler SD, Lee AP Ref: Technology (Singap World Sci), 5:201, 2017 : PubMed ESTHER: Vallejo_2017_Technology.(Singap.World.Sci)_5_201 PubMedSearch: Vallejo 2017 Technology.(Singap.World.Sci) 5 201 PubMedID: 29744376 Abstract Cell-sized lipid vesicles (CLVs) have shown great promise for therapeutic and artificial cell applications, but their fragility and short shelf life has hindered widespread adoption and commercial viability. We present a method to circumvent the storage limitations of CLVs such as giant unilamellar vesicles (GUVs) and single-compartment multisomes (SCMs) by storing them in a double emulsion precursor form. The double emulsions can be stored for at least 8 months and readily converted into either GUVs or SCMs at any time. In this study, we investigate the interfacial parameters responsible for this morphological change, and we also demonstrate the therapeutic potential of CLVs by utilizing them to present a transmembrane protein, neuroligin-2, to pancreatic beta-cells, forming cell-cell synapses that stimulate insulin secretion and cellular growth. Title: Hepatotoxicity induced by radix Sophorae tonkinensis in mice and increased serum cholinesterase as a potential supplemental biomarker for liver injury Wang L, Lu J, Sun W, Gu Y, Zhang C, Jin R, Li L, Zhang Z, Tian X Ref: Exp Toxicol Pathol, 69:193, 2017 : PubMed ESTHER: Wang_2017_Exp.Toxicol.Pathol_69_193 PubMedSearch: Wang 2017 Exp.Toxicol.Pathol 69 193 PubMedID: 28126209 Abstract Radix Sophorae tonkinensis (S. tonkinensis) is used in Chinese folk medicine to treat sore throats, viral hepatitis, and jaundice. However, little is known about the hepatotoxicity induced by it. This study is to investigate hepatotoxicity induced by radix S. tonkinensis and a potential supplemental biomarker for liver injury through acute toxicity, accumulative toxicity, tolerance test, and sub-chronic toxicity. The contents of cytisine (CYT), matrine (MT), and oxymatrine (OMT) in radix S. tonkinensis extracts were determined simultaneously by the method we developed. In the acute toxicity study, mice were scheduled for single oral gavage at doses of 0, 2.4, 3.2, 4.2, 5.6, 7.5g/kg of radix S. tonkinensis extracts respectively. Another three groups of mice received radix S. tonkinensis extracts orally in single doses of 0, 4.3, 5.6g/kg, while the two groups of the hepatic injury model were induced by intraperitoneal injection with 0.1% and 0.2% carbon tetrachloride (CCl4). Mortality rate, analysis of serum biochemistry, and histopathological examination were used to assess the acute toxicity. In the accumulative toxicity study, mice were treated radix S. tonkinensis extracts orally by the method of dose escalation for 20days respectively. Accumulative toxicity was assessed by mortality rate. In the tolerance test, half of the mice of test group in the accumulative toxicity were administered the dose of 4.3g/kg radix S. tonkinensis extracts, and the rest of the mice in the test group were assigned to receive the dose of 5.6g/kg radix S. tonkinensis extracts. In the sub-chronic toxicity study, mice were treated with daily doses of 0, 0.25, 1.0, 2.5g/kg radix S. tonkinensis extracts for 90days. Assessments of body weights, serum biochemical analysis, and histopathological examination were performed. An enzyme-inhibition assay for butyrylcholinesterase (BuChE) and acetylcholinesterase (AChE) of CYT, MT, and OMT was also carried out. The contents of CYT, MT, and OMT in radix S. tonkinensis extracts were 5.63mg/g, 27.63mg/g, and 16.20mg/g respectively. In the acute toxicity study, LD50 of radix S. tonkinensis extracts was 4.3g/kg. No mice were found dead in the accumulative toxicity study. In the acute toxicity and tolerance test, increased ALT, AST, and CHE levels were observed in a dose-response manner, while the severity of histological changes in liver was shown in a dose-dependent mode. In the sub-chronic toxicity, though there was a decline trend of ALT and AST levels found in 0.25g/kg, 1.0g/kg, and 2.5g/kg radix S. tonkinensis extracts as compared to control, which might be related to weight loss, the severity of histopathological changes in the liver and the increased serum CHE level was shown in a dose-response manner. MT, OMT, and CYT showed inhibitory effects on BuChE and AChE in the enzyme-inhibition assay. The results of this study indicate that radix S. tonkinensis should have hepatotoxicity, and increased serum CHE is a potential supplemental biomarker for liver injury. Title: Screening of a natural compound library identifies emodin, a natural compound from Rheum palmatum Linn that inhibits DPP4 Wang Z, Yang L, Fan H, Wu P, Zhang F, Zhang C, Liu W, Li M Ref: PeerJ, 5:e3283, 2017 : PubMed ESTHER: Wang_2017_PeerJ_5_e3283 PubMedSearch: Wang 2017 PeerJ 5 e3283 PubMedID: 28507818 Abstract Historically, Chinese herbal medicines have been widely used in the treatment of hyperglycemia, but the mechanisms underlying their effectiveness remain largely unknown. Here, we screened a compound library primarily comprised of natural compounds extracted from herbs and marine organisms. The results showed that emodin, a natural compound from Rheum palmatum Linn, inhibited DPP4 activity with an in vitro IC50 of 5.76 microM without inhibiting either DPP8 or DPP9. A docking model revealed that emodin binds to DPP4 protein through Glu205 and Glu206, although with low affinity. Moreover, emodin treatment (3, 10 and 30 mg/kg, P.O.) in mice decreased plasma DPP4 activity in a dose-dependent manner. Our study suggests that emodin inhibits DPP4 activity and may represent a novel therapeutic for the treatment of type 2 diabetes. Title: The Inhibitory Effect of alpha/beta-Hydrolase Domain-Containing 6 (ABHD6) on the Surface Targeting of GluA2- and GluA3-Containing AMPA Receptors Wei M, Jia M, Zhang J, Yu L, Zhao Y, Chen Y, Ma Y, Zhang W, Shi YS, Zhang C Ref: Front Mol Neurosci, 10:55, 2017 : PubMed ESTHER: Wei_2017_Front.Mol.Neurosci_10_55 PubMedSearch: Wei 2017 Front.Mol.Neurosci 10 55 PubMedID: 28303090 Abstract The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) are major excitatory receptors that mediate fast neurotransmission in the mammalian brain. The surface expression of functional AMPARs is crucial for synaptic transmission and plasticity. AMPAR auxiliary subunits control the biosynthesis, membrane trafficking, and synaptic targeting of AMPARs. Our previous report showed that alpha/beta-hydrolase domain-containing 6 (ABHD6), an auxiliary subunit for AMPARs, suppresses the membrane delivery and function of GluA1-containing receptors in both heterologous cells and neurons. However, it remained unclear whether ABHD6 affects the membrane trafficking of glutamate receptor subunits, GluA2 and GluA3. Here, we examine the effects of ABHD6 overexpression in HEK293T cells expressing GluA1, GluA2, GluA3, and stargazin, either alone or in combination. The results show that ABHD6 suppresses the glutamate-induced currents and the membrane expression of AMPARs when expressing GluA2 or GluA3 in the HEK293T cells. We generated a series of GluA2 and GluA3 C-terminal deletion constructs and confirm that the C-terminus of GluAs is required for ABHD6's inhibitory effects on glutamate-induced currents and surface expression of GluAs. Meanwhile, our pull-down experiments reveal that ABHD6 binds to GluA1-3, and deletion of the C-terminal domain of GluAs abolishes this binding. These findings demonstrate that ABHD6 inhibits the AMPAR-mediated currents and its surface expression, independent of the type of AMPAR subunits, and this inhibitor's effects are mediated through the binding with the GluAs C-terminal regions. Title: Discovery of Novel Pyrazolopyrimidinone Derivatives as Phosphodiesterase 9A Inhibitors Capable of Inhibiting Butyrylcholinesterase for Treatment of Alzheimer's Disease Yu YF, Huang YD, Zhang C, Wu XN, Zhou Q, Wu D, Wu Y, Luo HB Ref: ACS Chem Neurosci, 8:2522, 2017 : PubMed ESTHER: Yu_2017_ACS.Chem.Neurosci_8_2522 PubMedSearch: Yu 2017 ACS.Chem.Neurosci 8 2522 PubMedID: 28783948 Abstract Discovery of multitarget-directed ligands (MTDLs), targeting different factors simultaneously to control the complicated pathogenesis of Alzheimer's disease (AD), has become an important research area in recent years. Both phosphodiesterase 9A (PDE9A) and butyrylcholinesterase (BuChE) inhibitors could participate in different processes of AD to attenuate neuronal injuries and improve cognitive impairments. However, research on MTDLs combining the inhibition of PDE9A and BuChE simultaneously has not been reported yet. In this study, a series of novel pyrazolopyrimidinone-rivastigmine hybrids were designed, synthesized, and evaluated in vitro. Most compounds exhibited remarkable inhibitory activities against both PDE9A and BuChE. Compounds 6c and 6f showed the best IC(50) values against PDE9A (6c, 14 nM; 6f, 17 nM) together with the considerable inhibition against BuChE (IC(50), 6c, 3.3 microM; 6f, 0.97 microM). Their inhibitory potencies against BuChE were even higher than the anti-AD drug rivastigmine. It is worthy mentioning that both showed moderate selectivity for BuChE over acetylcholinesterase (AChE). Molecular docking studies revealed their binding patterns and explained the influence of configuration and substitutions on the inhibition of PDE9A and BuChE. Furthermore, compounds 6c and 6f exhibited negligible toxicity, which made them suitable for the further study of AD in vivo. Title: Degradation of methomyl by the combination of Aminobacter sp. MDW-2 and Afipia sp. MDW-3 Zhang C, Yang Z, Jin W, Wang X, Zhang Y, Zhu S, Yu X, Hu G, Hong Q Ref: Lett Appl Microbiol, 64:289, 2017 : PubMed ESTHER: Zhang_2017_Lett.Appl.Microbiol_64_289 PubMedSearch: Zhang 2017 Lett.Appl.Microbiol 64 289 PubMedID: 28083911 Abstract Methomyl (S-methyl N-(methylcarbamoyloxy) thioacetimidate) is a kind of oxime carbamate insecticide. It is considered to be extremely toxic to nontarget organism. To date, no pure culture or consortium has been reported to have the ability to degrade methomyl completely. In this study, a methomyl-degrading enrichment E1 was obtained by using the sludge from the wastewater-treating system of a pesticide manufacturer as the original inoculant. Two bacterial strains named MDW-2 and MDW-3 were isolated from this enrichment, and they were preliminarily identified as Aminobacter sp. and Afipia sp. respectively. Strains MDW-2 and MDW-3 could coexist and degrade 50smgsl(-1) methomyl completely within 3sdays by the cooperative metabolism. Methomyl was first converted to methomyl oxime and methylcarbamic acid by strain MDW-2, and the latter could be used as the carbon source for the growth of strain MDW-2. But methomyl oxime could not be sequentially degraded by strain MDW-2. However, it could be degraded and used as the carbon source by strain MDW-3. SIGNIFICANCE AND IMPACT OF THE STUDY: This study presents a bacterial combination of Aminobacter sp. MDW-2 and Afipia sp. MDW-3, which could degrade methomyl completely by biochemical cooperation. This study also proposes the biodegradation pathway of methomyl for the first time and highlights the application potential of a bacterial combination in the remediation of methomyl-contaminated environments. Title: Comparative Genomics Analysis of Streptomyces Species Reveals Their Adaptation to the Marine Environment and Their Diversity at the Genomic Level Tian X, Zhang Z, Yang T, Chen M, Li J, Chen F, Yang J, Li W, Zhang B and Xiao J <3 more author(s)> Tian X, Zhang Z, Yang T, Chen M, Li J, Chen F, Yang J, Li W, Zhang B, Wu J, Zhang C, Long L, Xiao J (- 3) Ref: Front Microbiol, 7:998, 2016 : PubMed ESTHER: Tian_2016_Front.Microbiol_7_998 PubMedSearch: Tian 2016 Front.Microbiol 7 998 PubMedID: 27446038 Gene_locus related to this paper: 9actn-a0a1e7k9d4, 9actn-a0a1e7l883, 9actn-a0a1e7kw84, 9actn-a0a1e7kkk9, 9actn-a0a1e7jip1, 9actn-a0a1e7jjj1, 9actn-a0a1e7k159, 9actn-a0a1e7kfw2, 9actn-a0a1e7l1n0, 9actn-a0a1e7jf99 Abstract Over 200 genomes of streptomycete strains that were isolated from various environments are available from the NCBI. However, little is known about the characteristics that are linked to marine adaptation in marine-derived streptomycetes. The particularity and complexity of the marine environment suggest that marine streptomycetes are genetically diverse. Here, we sequenced nine strains from the Streptomyces genus that were isolated from different longitudes, latitudes, and depths of the South China Sea. Then we compared these strains to 22 NCBI downloaded streptomycete strains. Thirty-one streptomycete strains are clearly grouped into a marine-derived subgroup and multiple source subgroup-based phylogenetic tree. The phylogenetic analyses have revealed the dynamic process underlying streptomycete genome evolution, and lateral gene transfer is an important driving force during the process. Pan-genomics analyses have revealed that streptomycetes have an open pan-genome, which reflects the diversity of these streptomycetes and guarantees the species a quick and economical response to diverse environments. Functional and comparative genomics analyses indicate that the marine-derived streptomycetes subgroup possesses some common characteristics of marine adaptation. Our findings have expanded our knowledge of how ocean isolates of streptomycete strains adapt to marine environments. The availability of streptomycete genomes from the South China Sea will be beneficial for further analysis on marine streptomycetes and will enrich the South China Sea's genetic data sources. Title: alpha/beta-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors Wei M, Zhang J, Jia M, Yang C, Pan Y, Li S, Luo Y, Zheng J, Ji J and Zhang C <4 more author(s)> Wei M, Zhang J, Jia M, Yang C, Pan Y, Li S, Luo Y, Zheng J, Ji J, Chen J, Hu X, Xiong J, Shi Y, Zhang C (- 4) Ref: Proc Natl Acad Sci U S A, 113:E2695, 2016 : PubMed ESTHER: Wei_2016_Proc.Natl.Acad.Sci.U.S.A_113_E2695 PubMedSearch: Wei 2016 Proc.Natl.Acad.Sci.U.S.A 113 E2695 PubMedID: 27114538 Gene_locus related to this paper: human-ABHD6 Abstract In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. alpha/beta-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6. Title: Regulations of Xenobiotics and Endobiotics on Carboxylesterases: A Comprehensive Review Xu Y, Zhang C, He W, Liu D Ref: Eur J Drug Metab Pharmacokinet, 41:321, 2016 : PubMed ESTHER: Xu_2016_Eur.J.Drug.Metab.Pharmacokinet_41_321 PubMedSearch: Xu 2016 Eur.J.Drug.Metab.Pharmacokinet 41 321 PubMedID: 26914100 Abstract Carboxylesterases (CESs) play major roles in catalyzing the hydrolysis of a wide range of ester- and amide-containing compounds. CESs dominate both the biotransformation of numerous therapeutic drugs and the detoxification of environmental toxicants, and the activity alteration of CESs may be a determinant reason for modification of the resultant pharmacokinetic/pharmacodynamic profile when two or more drugs are concurrently used. Herein, we provide a comprehensive review of the current literature involving of induction and inhibition on CESs by both exogenous and endogenous compounds. In particular, the inhibition constant and inhibition pattern of inhibitors on CESs in studies using animal microsomes or human recombinant CESs are summarized. Further studies are needed to clarify the underlying regulation mechanism, and alterations in CESs activity should be taken into consideration for safe clinical therapy. Title: Design, synthesis and evaluation of novel tacrine-multialkoxybenzene hybrids as multi-targeted compounds against Alzheimer's disease Zhang C, Du QY, Chen LD, Wu WH, Liao SY, Yu LH, Liang XT Ref: Eur Journal of Medicinal Chemistry, 116:200, 2016 : PubMed ESTHER: Zhang_2016_Eur.J.Med.Chem_116_200 PubMedSearch: Zhang 2016 Eur.J.Med.Chem 116 200 PubMedID: 27061983 Abstract A series of benzoates (or phenylacetates or cinnamates) - tacrine hybrids (7a-o) were designed, synthesized and evaluated as multi-potent anti-Alzheimer drug candidates. The screening results showed that most of them exhibited a significant ability to inhibit ChEs, certain selectivity for AChE over BuChE and strong potency inhibitory of self-induced beta-amyloid (Abeta) aggregation. All IC50 values of biological activity were at the nanomolar range. Especially, compound 7c displayed the greatest ability to inhibit AChE with an IC50 value of 5.63 nM and the highest selectivity with ratio of BuChE/AChE value of 64.6. Moreover, it also exhibited a potent inhibitory of Abeta aggregation with an IC50 value of 51.81 nM. A Lineweaver-Burk plot and molecular modeling study showed that compound 7c targeted both the CAS and PAS of ChEs. A structure-activity relationship analysis suggested that the electron density of aromatic ring which was linked with tacrine through acetyl group played a significant role in determining the inhibitory activity. Title: Extracellular CADM1 Interactions Influence Insulin Secretion by Rat and Human Islet Beta-Cells and Promote Clustering of Syntaxin-1 Zhang C, Caldwell TA, Mirbolooki MR, Duong D, Park EJ, Chi NW, Chessler SD Ref: American Journal of Physiology Endocrinol Metab, 310:e874, 2016 : PubMed ESTHER: Zhang_2016_Am.J.Physiol.Endocrinol.Metab_310_e874 PubMedSearch: Zhang 2016 Am.J.Physiol.Endocrinol.Metab 310 e874 PubMedID: 27072493 Abstract Contact between beta-cells is necessary for their normal function. Identification of the proteins mediating the effects of beta-cell-to-beta-cell contact is a necessary step towards gaining a full understanding of the determinants of beta-cell function and insulin secretion. The secretory machinery of the beta-cells is nearly identical to that of central nervous system (CNS) synapses, and we hypothesize that the trans-cellular protein interactions that drive maturation of the two secretory machineries upon contact of one cell (or neural process) with another are also highly similar. Two such trans-cellular interactions, important for both synaptic and beta-cell function, have been identified: EphA/ephrin-A and neuroligin/neurexin. Here we test the role of another synaptic-cleft protein, CADM1, in insulinoma cells and in rat and human islet beta-cells. We find that CADM1 is a predominant CADM isoform in beta-cells. In INS-1 cells and primary beta-cells, CADM1 constrains insulin secretion, and its expression decreases after prolonged glucose stimulation. Using a coculture model, we find that CADM1 also influences insulin secretion in a trans-cellular manner. We ask whether extracellular CADM1 interactions exert their influence via the same mechanisms by which they influence neurotransmitter exocytosis. Our results suggest that, as in the CNS, CADM1 interactions drive exocytic site assembly and promote actin network formation. These results support the broader hypothesis that the effects of cell-cell contact on beta-cell maturation and function are mediated by the same extracellular protein interactions that drive the formation of the presynaptic exocytic machinery. These interactions may be therapeutic targets for reversing beta-cell dysfunction in diabetes. Title: Single point mutations enhance activity of cis-epoxysuccinate hydrolase Zhang C, Pan H, Yao L, Bao W, Wang J, Xie Z, Zhang J Ref: Biotechnol Lett, 38:1301, 2016 : PubMed ESTHER: Zhang_2016_Biotechnol.Lett_38_1301 PubMedSearch: Zhang 2016 Biotechnol.Lett 38 1301 PubMedID: 27259723 Abstract OBJECTIVES: To enhance activity of cis-epoxysuccinate hydrolase from Klebsiella sp. BK-58 for converting cis-epoxysuccinate to tartrate. Title: Genome sequence of the Asian Tiger mosquito, Aedes albopictus, reveals insights into its biology, genetics, and evolution Chen XG, Jiang X, Gu J, Xu M, Wu Y, Deng Y, Zhang C, Bonizzoni M, Dermauw W and James AA <21 more author(s)> Chen XG, Jiang X, Gu J, Xu M, Wu Y, Deng Y, Zhang C, Bonizzoni M, Dermauw W, Vontas J, Armbruster P, Huang X, Yang Y, Zhang H, He W, Peng H, Liu Y, Wu K, Chen J, Lirakis M, Topalis P, Van Leeuwen T, Hall AB, Thorpe C, Mueller RL, Sun C, Waterhouse RM, Yan G, Tu ZJ, Fang X, James AA (- 21) Ref: Proc Natl Acad Sci U S A, 112:E5907, 2015 : PubMed ESTHER: Chen_2015_Proc.Natl.Acad.Sci.U.S.A_112_E5907 PubMedSearch: Chen 2015 Proc.Natl.Acad.Sci.U.S.A 112 E5907 PubMedID: 26483478 Gene_locus related to this paper: aedae-q177c7, aedal-a0a182gwe3, aedal-a0a182gwt8, aedal-a0a023eq67 Abstract The Asian tiger mosquito, Aedes albopictus, is a highly successful invasive species that transmits a number of human viral diseases, including dengue and Chikungunya fevers. This species has a large genome with significant population-based size variation. The complete genome sequence was determined for the Foshan strain, an established laboratory colony derived from wild mosquitoes from southeastern China, a region within the historical range of the origin of the species. The genome comprises 1,967 Mb, the largest mosquito genome sequenced to date, and its size results principally from an abundance of repetitive DNA classes. In addition, expansions of the numbers of members in gene families involved in insecticide-resistance mechanisms, diapause, sex determination, immunity, and olfaction also contribute to the larger size. Portions of integrated flavivirus-like genomes support a shared evolutionary history of association of these viruses with their vector. The large genome repertory may contribute to the adaptability and success of Ae. albopictus as an invasive species. Title: Donepezil improves learning and memory deficits in APP/PS1 mice by inhibition of microglial activation Guo HB, Cheng YF, Wu JG, Wang CM, Wang HT, Zhang C, Qiu ZK, Xu JP Ref: Neuroscience, 290C:530, 2015 : PubMed ESTHER: Guo_2015_Neurosci_290C_530 PubMedSearch: Guo 2015 Neurosci 290C 530 PubMedID: 25662507 Abstract Donepezil, a cholinesterase inhibitor, is a representative symptomatic therapy for Alzheimer's disease (AD). Recent studies have reported the anti-inflammatory effects of donepezil. However, limited studies that investigate its anti-inflammatory effect in AD have been reported. Considering the role of proinflammatory molecules and microglial activation in the pathogenesis of AD, the current study aimed to elucidate the effects of donepezil on microglial activation induced by amyloid deposition in transgenic mice. Our results showed that chronic treatment with donepezil significantly improved the cognitive function in the novel object recognition test and Morris water maze test in amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice. We further demonstrated that these cognitive enhancements were related to the anti-inflammatory effect of donepezil. We found that donepezil could inhibit the expression of CD68, a specific marker of microglial activation, and reduce the release of proinflammatory cytokines including tumor necrosis factor-alpha and interleukin-1beta. Immunohistochemistry and Congo red co-staining revealed that congophilic amyloid and activated microglia around plaques were also reduced by donepezil treatment. Enzyme-linked immunosorbent assay (ELISA) analysis showed that donepezil decreased insoluble Abeta40/Abeta42 and soluble Abeta40 levels. Moreover, donepezil reversed the impaired expression of insulin-degrading enzyme in the hippocampus of APP/PS1 mice. Our findings indicated that donepezil improves cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of microglial activation and release of proinflammatory cytokines. Title: The Synergistic Effects of Heat Shock Protein 70 and Ginsenoside Rg1 against Tert-Butyl Hydroperoxide Damage Model In Vitro Lu D, Xu A, Mai H, Zhao J, Zhang C, Qi R, Wang H, Zhu L Ref: Oxid Med Cell Longev, 2015:437127, 2015 : PubMed ESTHER: Lu_2015_Oxid.Med.Cell.Longev_2015_437127 PubMedSearch: Lu 2015 Oxid.Med.Cell.Longev 2015 437127 PubMedID: 25685255 Abstract Neural stem cells (NSCs) transplanted is one of the hottest research to treat Alzheimer's disease (AD), but cholinergic neurons from stem cells were also susceptible to cell death which Heat shock protein 70 (HSP70) was affirmed to reverse. Related to cognitive impairment, cholinergic nervous cells should be investigated and ginsenoside Rg1 (G-Rg1) was considered to increase them. We chose tert-butyl hydroperoxide (t-BHP) damage model to study in vitro. Functional properties of our recombination plasmid pEGFP-C2-HSP70 were affirmed by SH-SY5Y cells. To opposite the transitory appearance of HSP70, NSCs used as the vectors of HSP70 gene overexpressed HSP70 for at least 7 days in vitro. After transfection for 3 days, G-Rg1 pretreatment for 4 hours, and coculture for 3 days, the expression of acetylcholinesterase (ChAT), synaptophysin, and the ratio of NeuN and GFAP were assessed by western blot; Morphological properties were detected by 3D reconstruction and immunofluorescence. ChAT was markedly improved in the groups contained G-Rg1. In coculture system, the ratio of neurons/astrocytes and the filaments of neurons were increased; apoptosis cells were decreased, compared to monotherapy (P < 0.05). In conclusion, we demonstrated that, as a safe cotreatment affirmed in vitro, overexpression of HSP70 in NSCs plus G-Rg1 promoted nervous cells regeneration from chronic oxidative damage. Title: Expression and Characterization of a Novel Thermo-Alkalistable Lipase from Hyperthermophilic Bacterium Thermotoga maritima Tian R, Chen H, Ni Z, Zhang Q, Zhang Z, Zhang T, Zhang C, Yang S Ref: Appl Biochem Biotechnol, 176:1482, 2015 : PubMed ESTHER: Tian_2015_Appl.Biochem.Biotechnol_176_1482 PubMedSearch: Tian 2015 Appl.Biochem.Biotechnol 176 1482 PubMedID: 25957275 Abstract A gene coding for lipase (Tm1350) from the hyperthermophilic bacterium Thermotoga maritima MSB8 was cloned and overexpressed by Escherichia coli. The enzyme can degrade substrates with both short and long acyl chain lengths. The apparent Km and Vmax values for p-nitrophenyl butyrate were 8 mM and 333 U/mg, respectively. The enzyme displayed optimal activity at pH 7.5 and 70 degrees C, maintained 66 % of the original activity after 8 h of incubation, and its half-lives at pHs 9 and 10 were 8 and 1 h. The activity of Tm1350 was stimulated up to 131 or 151 % of the original activity by incubating with 4 M urea or 20 % (v/v) methanol, and 90.1 or 70.2 % of the activity was maintained after 8 h incubation of the enzyme in 20 or 75 % (v/v) of the methanol, showing potential for biodiesel production. The activity of the enzyme without cysteine residue was stimulated up to 618 and 550 % of the original activity by incubating with dithiothreitol (DTT) and reduced glutathione (GSH) at a concentration of 1 mM. However, the circular dichroism spectra of the enzyme have no obvious change after DTT treatment. It is speculated that DTT interacts with potential residues in some key active sites without influence of structure. Title: Comparative Analysis of Amaryllidaceae Alkaloids from Three Lycoris Species Tian Y, Zhang C, Guo M Ref: Molecules, 20:21854, 2015 : PubMed ESTHER: Tian_2015_Molecules_20_21854 PubMedSearch: Tian 2015 Molecules 20 21854 PubMedID: 26690108 Abstract The major active constituents from Amaryllidaceae family were reported to be Amaryllidaceae alkaloids (AAs), which exhibited a wide spectrum of biological activities, such as anti-tumor, anti-viral, and acetyl-cholinesterase-inhibitory activities. In order to better understand their potential as a source of bioactive AAs and the phytochemical variations among three different species of Lycoris herbs, the HPLC fingerprint profiles of Lycoris aurea (L. aurea), L. radiata, and L. guangxiensis were firstly determined and compared using LC-UV and LC-MS/MS. As a result, 39 peaks were resolved and identified as AAs, of which nine peaks were found in common for all these three species, while the other 30 peaks could be revealed as characteristic AAs for L. aurea, L. radiata and L. guangxiensis, respectively. Thus, these AAs can be used as chemical markers for the identification and quality control of these plant species. To further reveal correlations between chemical components and their pharmaceutical activities of these species at the molecular level, the bioactivities of the total AAs from the three plant species were also tested against HepG2 cells with the inhibitory rate at 78.02%, 84.91% and 66.81% for L. aurea, L. radiata and L. guangxiensis, respectively. This study firstly revealed that the three species under investigation were different not only in the types of AAs, but also in their contents, and both contributed to their pharmacological distinctions. To the best of our knowledge, the current research provides the most detailed phytochemical profiles of AAs in these species, and offers valuable information for future valuation and exploitation of these medicinal plants. Title: An upp-based markerless gene replacement method for genome reduction and metabolic pathway engineering in Pseudomonas mendocina NK-01 and Pseudomonas putida KT2440 Wang Y, Zhang C, Gong T, Zuo Z, Zhao F, Fan X, Yang C, Song C Ref: J Microbiol Methods, 113:27, 2015 : PubMed ESTHER: Wang_2015_J.Microbiol.Methods_113_27 PubMedSearch: Wang 2015 J.Microbiol.Methods 113 27 PubMedID: 25828098 Abstract A markerless gene replacement method was adapted by combining a suicide plasmid, pEX18Tc, with a counterselectable marker, the upp gene encoding uracil phosphoribosyltransferase (UPRTase), for the medium-chain length polyhydroxyalkanoates (PHAMCL)-producing strain Pseudomonas mendocina NK-01. An NK-01 5-fluorouracil (5-FU) resistant background strain was first constructed by deleting the chromosomal upp gene. The suicide plasmid pEX18Tc, carrying a functional allele of the upp gene of P. mendocina NK-01, was used to construct the vectors to delete the algA (encoding mannose-1-phosphate guanylyltransferase) and phaZ (encoding PHAMCL depolymerase) genes, and a 30kb chromosomal fragment in the 5-FU resistant background host. The genes were removed efficiently from the genome of P. mendocina NK-01 and left a markerless chromosomal mutant. In addition, two exogenous genes were inserted into the phaC1 (PHAMCL polymerase) loci of Pseudomonas putida KT-UPP simultaneously. Thus, we constructed a genetically stable and marker-free P. putida KT2440 mutant with integrated mpd (encoding methyl parathion hydrolase (MPH)) and pytH (encoding a pyrethroid-hydrolyzing carboxylesterase (PytH)) gene on the chromosome. The upp-based counterselection system could be further adapted for P. mendocina NK-01 and P. putida KT2440 and used for genome reduction and metabolic pathway engineering. Title: Upregulation of Acetylcholinesterase Mediated by p53 Contributes to Cisplatin-Induced Apoptosis in Human Breast Cancer Cell Ye X, Zhang C, Chen Y, Zhou T Ref: J Cancer, 6:48, 2015 : PubMed ESTHER: Ye_2015_J.Cancer_6_48 PubMedSearch: Ye 2015 J.Cancer 6 48 PubMedID: 25553088 Abstract BACKGROUND: The expression of acetylcholinesterase (AChE) could be induced during apoptosis in various cell types. And reduced AChE expression either by siRNA could prevent apoptosis. However, the detailed mechanisms underlying the AChE regulation are largely unknown in human breast cancer cell. MATERIAL AND Title: Differential expression of lipid metabolism-related genes and myosin heavy chain isoform genes in pig muscle tissue leading to different meat quality Zhang C, Luo JQ, Zheng P, Yu B, Huang ZQ, Mao XB, He J, Yu J, Chen JL, Chen DW Ref: Animal, 9:1073, 2015 : PubMed ESTHER: Zhang_2015_Animal_9_1073 PubMedSearch: Zhang 2015 Animal 9 1073 PubMedID: 25716066 Abstract The aim of this study was to investigate the variations in meat quality, lipid metabolism-related genes, myosin heavy chain (MyHC) isoform genes and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) gene mRNA expressions in longissimus dorsi muscle (LM) of two different pig breeds. Six Rongchang and six Landrace barrows were slaughtered at 161 days of age. Subsequently, meat quality traits and gene expression levels in LM were observed. Results showed that Rongchang pigs not only exhibited greater pH, CIE a*24 h and intramuscular fat content but also exhibited lower body weight, carcass weight, dressing percentage, LM area and CIE b*24 h compared with Landrace pigs (P<0.05). Meanwhile, the mRNA expression levels of the lipogenesis (peroxisome proliferator-activated receptor gamma, acetyl-CoA carboxylase and fatty acid synthase) and fatty acid uptake (lipoprotein lipase)-related genes were greater in the Rongchang (P<0.05), whereas the lipolysis (adipose triglyceride lipase and hormone sensitive lipase) and fatty acid oxidation (carnitine palmitoyltransferase-1B)-related genes were better expressed in the Landrace. Moreover, compared with the Landrace, the mRNA expression levels of MyHCI, MyHCIIa and MyHCIIx were greater, whereas the mRNA expression levels of MyHCIIb were lower in the Rongchang pigs (P<0.05). In addition, the mRNA expression levels of PGC-1alpha were greater in Rongchang pigs than in the Landrace (P<0.05), which can partly explain the differences in MyHC isoform gene expressions between Rongchang and Landrace pigs. Although the small number of samples does not allow to obtain a definitive conclusion, we can suggest that Rongchang pigs possess better meat quality, and the underlying molecular mechanisms responsible for the better meat quality in fatty pigs may be partly due to the higher mRNA expression levels of lipogenesis and fatty acid uptake-related genes, as well as the oxidative and intermediate muscle fibers, and due to the lower mRNA expression levels of lipolysis and fatty acid oxidation-related genes, as well as the glycolytic muscle fibers. Title: Down-regulation of carboxylesterases 1 and 2 plays an important role in prodrug metabolism in immunological liver injury rats Zhang C, Xu Y, Gao P, Lu J, Li X, Liu D Ref: Int Immunopharmacol, 24:153, 2015 : PubMed ESTHER: Zhang_2015_Int.Immunopharmacol_24_153 PubMedSearch: Zhang 2015 Int.Immunopharmacol 24 153 PubMedID: 25499727 Abstract Liver plays a central role in xenobiotics metabolism, thus affecting the in vivo disposition and therapeutic effects of drugs. Carboxylesterases (CESs), with the main isoforms CES1 and CES2, are important in the metabolism of ester-type prodrugs. However, influences of immunological liver injury on the activity of CES remain undefined. In the present study, we demonstrated treatment with lipopolysaccharide (LPS) suppressed the activities of CES1 and CES2. The decreased activities of CES1 and CES2 were preliminarily assessed by the hydrolysis assay for their common substrate p-nitrophenyl acetate (PNPA) with rat hepatic microsomal enzyme. Subsequently, RT-PCR results showed that the levels of CES1 mRNA and mRNA of CES2 (AB010635) and CES2 (AY034877) in the model group were significantly lower than those of the normal control group (P<0.05). Western blot results showed that the expressions of CES1 and CES2 proteins were decreased (P<0.05). To further clarify the effects of LPS on the metabolic activities of CESs, pharmacokinetic studies were performed in rats by utilizing imidapril and irinotecan (CPT-11) as the specific substrates for CES1 and CES2, respectively. After treatment with LPS, AUC0-inf and Cmax of imidaprilat were decreased from 2084.86+/-340.66ng.h(-1).mL(-1) and 234.66+/-68.85ng.mL(-1) to 983.87+/-315.34ng.h(-1).mL(-1) and 113.1+/-19.69ng.mL(-1) (P<0.05), respectively. Moreover, AUC0-inf and Cmax of SN-38 were decreased from 8100+/-918.6ng.h(-1).mL(-1) and 144.67+/-20.28ng.mL(-1) to 3270+/-500.5ng.h(-1).mL(-1) and 56.19+/-10.38ng.mL(-1) (P<0.05), respectively. In summary, immunological liver injury remarkably attenuated the expressions and metabolic activities of CES1 and CES2, which may be associated with the regulatory effects of cytokines under inflammation. Title: [Effects of methomyl on acetylcholinesterase in erythrocyte membrane and various brain areas] Zhao F, Li T, Zhang C, Xu Y, Xu H, Shi N Ref: Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi, 33:417, 2015 : PubMed ESTHER: Zhao_2015_Zhonghua.Lao.Dong.Wei.Sheng.Zhi.Ye.Bing.Za.Zhi_33_417 PubMedSearch: Zhao 2015 Zhonghua.Lao.Dong.Wei.Sheng.Zhi.Ye.Bing.Za.Zhi 33 417 PubMedID: 26653373 Abstract OBJECTIVE: To study the toxicity of methomyl to acetylcholinesterase (AChE) in different regions. Title: Intranasal H102 Peptide-Loaded Liposomes for Brain Delivery to Treat Alzheimer's Disease Zheng X, Shao X, Zhang C, Tan Y, Liu Q, Wan X, Zhang Q, Xu S, Jiang X Ref: Pharm Res, 32:3837, 2015 : PubMed ESTHER: Zheng_2015_Pharm.Res_32_3837 PubMedSearch: Zheng 2015 Pharm.Res 32 3837 PubMedID: 26113236 Abstract PURPOSE: H102, a novel beta-sheet breaker peptide, was encapsulated into liposomes to reduce its degradation and increase its brain penetration through intranasal administration for the treatment of Alzheimer's disease (AD). Title: Effects of maternal undernutrition during late pregnancy on the development and function of ovine fetal liver Gao F, Liu Y, Li L, Li M, Zhang C, Ao C, Hou X Ref: Anim Reprod Sci, 147:99, 2014 : PubMed ESTHER: Gao_2014_Anim.Reprod.Sci_147_99 PubMedSearch: Gao 2014 Anim.Reprod.Sci 147 99 PubMedID: 24852270 Abstract This study investigated the effects of maternal undernutrition during late pregnancy on the development and function of ovine fetal liver. Eighteen ewes with singleton fetuses were allocated to three groups at d 90 of pregnancy: Restricted Group 1 (RG1, 0.175MJMEkgBW(-0.75)d(-1), n=6), Restricted Group 2 (RG2, 0.33MJMEkgBW(-0.75)d(-1), n=6) and a Control Group (CG, ad libitum, 0.67MJMEkgBW(-0.75)d(-1), n=6). Fetuses were recovered at slaughter on d 140. Fetuses in the RG1 group exhibited decreased (P<0.05) liver weight, total antioxidant capacity (T-AOC), superoxide dismutase activity (SOD), cholinesterase (CHE), total protein (TP), globulin (GLB), and alanine transaminase (ALT). In addition, intermediate changes were found in the RG2 fetuses, including decreased liver weight, T-AOC and CHE (P<0.05). In contrast, increases in fetal hepatic collagen fibers and reticular fibers, glutathione peroxidase (GSH-Px), malondialdehyde (MDA), nitric oxide (NO), nitric oxide synthase (NOs), monoamine oxidase (MAO), albumin (ALB)/GLB, aspartate transaminase (AST), and AST/ALT were found in the RG1 fetuses (P<0.05). The RG2 fetuses had increased fetal hepatic collagen fibers, NOs and MAO (P<0.05) relative to the control fetuses. These results indicate that impaired fetal hepatic growth, fibrosis, antioxidant imbalance and dysfunction were associated with maternal undernutrition. Title: Genome Sequence of the epsilon-Poly-l-Lysine-Producing Strain Streptomyces albulus NK660, Isolated from Soil in Gutian, Fujian Province, China Gu Y, Yang C, Wang X, Geng W, Sun Y, Feng J, Wang Y, Quan Y, Che Y and Wang S <6 more author(s)> Gu Y, Yang C, Wang X, Geng W, Sun Y, Feng J, Wang Y, Quan Y, Che Y, Zhang C, Gong T, Zhang W, Gao W, Zuo Z, Song C, Wang S (- 6) Ref: Genome Announc, 2:e00532, 2014 : PubMed ESTHER: Gu_2014_Genome.Announc_2_e00532 PubMedSearch: Gu 2014 Genome.Announc 2 e00532 PubMedID: 24926050 Gene_locus related to this paper: stra9-a0a059w351 Abstract We determined the complete genome sequence of a soil bacterium, Streptomyces albulus NK660. It can produce epsilon-poly-l-lysine, which has antimicrobial activity against a spectrum of microorganisms. The genome of S. albulus NK660 contains a 9,360,281-bp linear chromosome and a 12,120-bp linear plasmid. Title: Eucommia ulmoides Oliv.: Ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine He X, Wang J, Li M, Hao D, Yang Y, Zhang C, He R, Tao R Ref: J Ethnopharmacol, 151:78, 2014 : PubMed ESTHER: He_2014_J.Ethnopharmacol_151_78 PubMedSearch: He 2014 J.Ethnopharmacol 151 78 PubMedID: 24296089 Abstract ETHNOPHARMACOLOGICAL RELEVANCE: Eucommia ulmoides Oliv. (Family Eucommiaceae), also known as Du-zhong (Chinese: ), Tuchong (in Japanese), is the sole species of the genus Eucommia. The leaf, stem, and bark as well as staminate flower of Eucommia ulmoides have been traditionally used to cure many diseases in China, Japan, Korea, among others. The aim of this review is to comprehensively outline the botanical description, ethnopharmacology, phytochemistry, biological activities, and toxicology of Eucommia ulmoides and to discuss possible trends for further study of Eucommia ulmoides. MATERIALS AND Title: M1 muscarinic acetylcholine receptor in Alzheimer's disease Jiang S, Li Y, Zhang C, Zhao Y, Bu G, Xu H, Zhang YW Ref: Neurosci Bull, 30:295, 2014 : PubMed ESTHER: Jiang_2014_Neurosci.Bull_30_295 PubMedSearch: Jiang 2014 Neurosci.Bull 30 295 PubMedID: 24590577 Abstract The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer's disease (AD). Muscarinic acetylcholine receptors (mAChRs) mediate acetylcholine-induced neurotransmission and five mAChR subtypes (M1-M5) have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists for AD treatment. Title: Chrysin attenuates experimental autoimmune neuritis by suppressing immuno-inflammatory responses Xiao J, Zhai H, Yao Y, Wang C, Jiang W, Zhang C, Simard AR, Zhang R, Hao J Ref: Neuroscience, 262:156, 2014 : PubMed ESTHER: Xiao_2014_Neurosci_262_156 PubMedSearch: Xiao 2014 Neurosci 262 156 PubMedID: 24412705 Abstract Guillain-Barre syndrome (GBS) is an acute, post-infectious, immune-mediated, demyelinating disease of peripheral nerves and nerve roots. Experimental autoimmune neuritis (EAN) is an animal model of GBS. Chrysin, which is a naturally occurring flavonoid, exhibits various biological activities. This study was designed to investigate the anti-inflammatory and neuroprotective properties of preventative and therapeutic chrysin treatment in EAN rats. For preventative treatment, chrysin was administered orally from day 1 to day 16 (50mg/kg once daily) while, for therapeutic treatment, rats received chrysin from day 7 to day 16 at the same dose once daily. Control animals received the same volume of the vehicle (phosphate-buffered saline/2% dimethylsulfoxide). Regardless of the treatment regimen, chrysin attenuated the severity and duration of the clinical course of EAN and reduced inflammatory cell infiltration and demyelination of sciatic nerves. In the sciatic nerves, the expression of inducible nitric oxide synthase, cyclooxygenase-2 and nuclear factor kappa B was reduced. Furthermore, chrysin inhibited the splenic mononuclear cell secretion of interleukin-1beta, interleukin-2, interleukin-6, inteleukin-12, interferon gamma and tumor necrosis factor alpha, and elevated the level of inteleukin-4. In summary, our data demonstrate that chrysin is a potentially useful agent for the treatment of EAN with its anti-inflammatory and neuroprotective effects. Title: In Vitro Evaluation of the Inhibitory Potential of Pharmaceutical Excipients on Human Carboxylesterase 1A and 2 Zhang C, Xu Y, Zhong Q, Li X, Gao P, Feng C, Chu Q, Chen Y, Liu D Ref: PLoS ONE, 9:e93819, 2014 : PubMed ESTHER: Zhang_2014_PLoS.One_9_e93819 PubMedSearch: Zhang 2014 PLoS.One 9 e93819 PubMedID: 24699684 Abstract Two major forms of human carboxylesterase (CES), CES1A and CES2, dominate the pharmacokinetics of most prodrugs such as imidapril and irinotecan (CPT-11). Excipients, largely used as insert vehicles in formulation, have been recently reported to affect drug enzyme activity. The influence of excipients on the activity of CES remains undefined. In this study, the inhibitory effects of 25 excipients on the activities of CES1A1 and CES2 were evaluated. Imidapril and CPT-11 were used as substrates and cultured with liver microsomes in vitro. Imidapril hydrolase activities of recombinant CES1A1 and human liver microsomes (HLM) were strongly inhibited by sodium lauryl sulphate (SLS) and polyoxyl 40 hydrogenated castor oil (RH40) [Inhibition constant (Ki) = 0.04+/-0.01 mug/ml and 0.20+/-0.09 mug/ml for CES1A1, and 0.12+/-0.03 mug/ml and 0.76+/-0.33 mug/ml, respectively, for HLM]. The enzyme hydrolase activity of recombinant CES2 was substantially inhibited by Tween 20 and polyoxyl 35 castor oil (EL35) (Ki = 0.93+/-0.36 mug/ml and 4.4+/-1.24 mug/ml, respectively). Thus, these results demonstrate that surfactants such as SLS, RH40, Tween 20 and EL35 may attenuate the CES activity; such inhibition should be taken into consideration during drug administration. Title: Marsupellins A-F, ent-longipinane-type sesquiterpenoids from the Chinese liverwort Marsupella alpine with acetylcholinesterase inhibitory activity Zhang J, Fan P, Zhu R, Li R, Lin Z, Sun B, Zhang C, Zhou J, Lou H Ref: Journal of Natural Products, 77:1031, 2014 : PubMed ESTHER: Zhang_2014_J.Nat.Prod_77_1031 PubMedSearch: Zhang 2014 J.Nat.Prod 77 1031 PubMedID: 24673187 Abstract Acetylcholinesterase (AChE) inhibitory activity-guided fractionation of the Chinese liverwort Marsupella alpine afforded six new [marsupellins A-F (1-6)] and three known (7-9) ent-longipinane-type sesquiterpenoids. The structures were determined from MS and NMR spectroscopic data, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1-9 exhibited moderate to weak AChE inhibitory activity. Title: Global analysis of gene expression profiles in physic nut (Jatropha curcas L.) seedlings exposed to salt stress Zhang L, Zhang C, Wu P, Chen Y, Li M, Jiang H, Wu G Ref: PLoS ONE, 9:e97878, 2014 : PubMed ESTHER: Zhang_2014_PLoS.ONE_9_E97878 PubMedSearch: Zhang 2014 PLoS.ONE 9 E97878 PubMedID: 24837971 Gene_locus related to this paper: jatcu-a0a067k7w6, jatcu-a0a067juw0, jatcu-a0a067jz21, jatcu-a0a067jeh8, jatcu-a0a067jvs1, jatcu-a0a067jvz5, jatcu-a0a067jc69, jatcu-a0a067jpe1, jatcu-a0a067jf51, jatcu-a0a067kvu1, jatcu-a0a067kfw0, jatcu-a0a067l7t8, jatcu-a0a067kfv9, jatcu-a0a067kbk6, jatcu-a0a067kqg8, jatcu-a0a067k9z6, jatcu-a0a067k9m8, jatcu-a0a067kc24, jatcu-a0a067jzr6, jatcu-a0a067kjc7, jatcu-a0a067kq44, jatcu-a0a067kwm1, jatcu-a0a067kws6, jatcu-a0a067l048, jatcu-a0a067l054, jatcu-a0a067l7y4, jatcu-a0a067l929, jatcu-a0a067k816 Abstract BACKGROUND: Salt stress interferes with plant growth and production. Plants have evolved a series of molecular and morphological adaptations to cope with this abiotic stress, and overexpression of salt response genes reportedly enhances the productivity of various crops. However, little is known about the salt responsive genes in the energy plant physic nut (Jatropha curcas L.). Thus, excavate salt responsive genes in this plant are informative in uncovering the molecular mechanisms for the salt response in physic nut. METHODOLOGY/PRINCIPAL FINDINGS: We applied next-generation Illumina sequencing technology to analyze global gene expression profiles of physic nut plants (roots and leaves) 2 hours, 2 days and 7 days after the onset of salt stress. A total of 1,504 and 1,115 genes were significantly up and down-regulated in roots and leaves, respectively, under salt stress condition. Gene ontology (GO) analysis of physiological process revealed that, in the physic nut, many "biological processes" were affected by salt stress, particular those categories belong to "metabolic process", such as "primary metabolism process", "cellular metabolism process" and "macromolecule metabolism process". The gene expression profiles indicated that the associated genes were responsible for ABA and ethylene signaling, osmotic regulation, the reactive oxygen species scavenging system and the cell structure in physic nut. CONCLUSIONS/SIGNIFICANCE: The major regulated genes detected in this transcriptomic data were related to trehalose synthesis and cell wall structure modification in roots, while related to raffinose synthesis and reactive oxygen scavenger in leaves. The current study shows a comprehensive gene expression profile of physic nut under salt stress. The differential expression genes detected in this study allows the underling the salt responsive mechanism in physic nut with the aim of improving its salt resistance in the future. Title: Influence of butyl benzyl phthalate (BBP) exposure on nervous system and antioxidant system in zebrafish Zhang C, Yang X, He Z, Zhong Q, Guo J, Hu XJ, Xiong L, Liu D Ref: Ecotoxicology, 23:1854, 2014 : PubMed ESTHER: Zhang_2014_Ecotoxicology_23_1854 PubMedSearch: Zhang 2014 Ecotoxicology 23 1854 PubMedID: 25239577 Abstract In order to observe the toxic effects of butyl benzyl phthalate (BBP) on zebrafish, the AChE and SOD activity of zebrafish exposed to different concentrations of BBP (0, 0.332, 0.665, 1.33 mg L(-1)) in a short-term (7d) test were determined. Semi-quantitative PCR was used to determine the mRNA transcript levels of the AChE and SOD gene in zebrafish brain and muscle. The results showed: AChE activity decreased with increased exposure concentration, and was significantly inhibited (p < 0.01) compared with the control group at 0.665 mg L(-1) concentration. Low BBP concentrations stimulated and high concentrations inhibited SOD activity with a concentration of 0.332 mg L(-1) resulting in a significant induction (p < 0.05) compared with the control, and 0.665 and 1.33 mg L(-1) concentrations resulting in significant inhibition (p < 0.05, p < 0.01) relative to the control group. The RT-PCR data showed a decrease in brain and muscle mRNA transcription of AChE gene with an increase in exposure concentration. The mRNA transcription of SOD in the brain was not different between the exposed groups and control group; in muscle, the mRNA transcription inhibition decreased and then increased: all differences from the control were statistically significant. Title: Whole-genome sequencing of the snub-nosed monkey provides insights into folivory and evolutionary history Zhou X, Wang B, Pan Q, Zhang J, Kumar S, Sun X, Liu Z, Pan H, Lin Y and Li R <24 more author(s)> Zhou X, Wang B, Pan Q, Zhang J, Kumar S, Sun X, Liu Z, Pan H, Lin Y, Liu G, Zhan W, Li M, Ren B, Ma X, Ruan H, Cheng C, Wang D, Shi F, Hui Y, Tao Y, Zhang C, Zhu P, Xiang Z, Jiang W, Chang J, Wang H, Cao Z, Jiang Z, Li B, Yang G, Roos C, Garber PA, Bruford MW, Li R (- 24) Ref: Nat Genet, 46:1303, 2014 : PubMed ESTHER: Zhou_2014_Nat.Genet_46_1303 PubMedSearch: Zhou 2014 Nat.Genet 46 1303 PubMedID: 25362486 Gene_locus related to this paper: rhibe-a0a2k6jtl7, rhibe-ACHE, rhibe-a0a2k6k3y7, rhibe-a0a2k6k493, rhibe-a0a2k6lev4, rhibe-a0a2k6lfa5, rhibe-a0a2k6m6k8, rhiro-a0a2k6p1u8, rhiro-a0a2k6q1t8, rhiro-a0a2k6q1w3, rhibe-a0a2k6n5t9, rhibe-a0a2k6ju46, rhibe-a0a2k6kt48, rhibe-a0a2k6llm5, rhibe-a0a2k6lnt5, rhiro-a0a2k6qzp6, rhiro-a0a2k6q4a6, rhibe-a0a2k6kn93, rhibe-a0a2k6lm22, rhibe-a0a2k6jwp8, rhiro-a0a2k6qun2, rhiro-a0a2k6nj56, rhiro-a0a2k6n885, rhiro-a0a2k6nnj4, rhiro-a0a2k6n7n5, rhibe-a0a2k6jvz4, rhiro-a0a2k6nfk9, rhiro-a0a2k6qjv0, rhibe-a0a2k6jn19, rhibe-a0a2k6k333, rhibe-a0a2k6mff5 Abstract Colobines are a unique group of Old World monkeys that principally eat leaves and seeds rather than fruits and insects. We report the sequencing at 146x coverage, de novo assembly and analyses of the genome of a male golden snub-nosed monkey (Rhinopithecus roxellana) and resequencing at 30x coverage of three related species (Rhinopithecus bieti, Rhinopithecus brelichi and Rhinopithecus strykeri). Comparative analyses showed that Asian colobines have an enhanced ability to derive energy from fatty acids and to degrade xenobiotics. We found evidence for functional evolution in the colobine RNASE1 gene, encoding a key secretory RNase that digests the high concentrations of bacterial RNA derived from symbiotic microflora. Demographic reconstructions indicated that the profile of ancient effective population sizes for R. roxellana more closely resembles that of giant panda rather than its congeners. These findings offer new insights into the dietary adaptations and evolutionary history of colobine primates. Title: The interaction between OsMADS57 and OsTB1 modulates rice tillering via DWARF14 Guo S, Xu Y, Liu H, Mao Z, Zhang C, Ma Y, Zhang Q, Meng Z, Chong K Ref: Nat Commun, 4:1566, 2013 : PubMed ESTHER: Guo_2013_Nat.Commun_4_1566 PubMedSearch: Guo 2013 Nat.Commun 4 1566 PubMedID: 23463009 Abstract Rice tillering is a multigenic trait that influences grain yield, but its regulation molecular module is poorly understood. Here we report that OsMADS57 interacts with OsTB1 (TEOSINTE BRANCHED1) and targets D14 (Dwarf14) to control the outgrowth of axillary buds in rice. An activation-tagged mutant osmads57-1 and OsMADS57-overexpression lines showed increased tillers, whereas OsMADS57 antisense lines had fewer tillers. OsMIR444a-overexpressing lines exhibited suppressed OsMADS57 expression and tillering. Furthermore, osmads57-1 was insensitive to strigolactone treatment to inhibit axillary bud outgrowth, and OsMADS57's function in tillering was dependent on D14. D14 expression was downregulated in osmads57-1, but upregulated in antisense and OsMIR444a-overexpressing lines. OsMADS57 bound to the CArG motif [C(A/T)TTAAAAAG] in the promoter and directly suppressed D14 expression. Interaction of OsMADS57 with OsTB1 reduced OsMADS57 inhibition of D14 transcription. Therefore, OsMIR444a-regulated OsMADS57, together with OsTB1, target D14 to control tillering. This regulation mechanism could have important application in rice molecular breeding programs focused on high grain yield. Title: Draft genome of the wheat A-genome progenitor Triticum urartu Ling HQ, Zhao S, Liu D, Wang J, Sun H, Zhang C, Fan H, Li D, Dong L and Zhang A <39 more author(s)> Ling HQ, Zhao S, Liu D, Wang J, Sun H, Zhang C, Fan H, Li D, Dong L, Tao Y, Gao C, Wu H, Li Y, Cui Y, Guo X, Zheng S, Wang B, Yu K, Liang Q, Yang W, Lou X, Chen J, Feng M, Jian J, Zhang X, Luo G, Jiang Y, Liu J, Wang Z, Sha Y, Zhang B, Tang D, Shen Q, Xue P, Zou S, Wang X, Liu X, Wang F, Yang Y, An X, Dong Z, Zhang K, Luo MC, Dvorak J, Tong Y, Yang H, Li Z, Wang D, Zhang A (- 39) Ref: Nature, 496:87, 2013 : PubMed ESTHER: Ling_2013_Nature_496_87 PubMedSearch: Ling 2013 Nature 496 87 PubMedID: 23535596 Gene_locus related to this paper: triua-m8a764, triua-m8ag96, triua-m7zp69, wheat-w5d1z6, wheat-w5d232, wheat-w5bnf5, triua-t1nm05, wheat-w5cae4, triua-m7ytf7, wheat-w5f1j8, triua-m8ad49, wheat-a0a077s1q2, wheat-a0a3b6c2m6, triua-m7zi26, wheat-a0a3b6at77 Abstract Bread wheat (Triticum aestivum, AABBDD) is one of the most widely cultivated and consumed food crops in the world. However, the complex polyploid nature of its genome makes genetic and functional analyses extremely challenging. The A genome, as a basic genome of bread wheat and other polyploid wheats, for example, T. turgidum (AABB), T. timopheevii (AAGG) and T. zhukovskyi (AAGGA(m)A(m)), is central to wheat evolution, domestication and genetic improvement. The progenitor species of the A genome is the diploid wild einkorn wheat T. urartu, which resembles cultivated wheat more extensively than do Aegilops speltoides (the ancestor of the B genome) and Ae. tauschii (the donor of the D genome), especially in the morphology and development of spike and seed. Here we present the generation, assembly and analysis of a whole-genome shotgun draft sequence of the T. urartu genome. We identified protein-coding gene models, performed genome structure analyses and assessed its utility for analysing agronomically important genes and for developing molecular markers. Our T. urartu genome assembly provides a diploid reference for analysis of polyploid wheat genomes and is a valuable resource for the genetic improvement of wheat. Title: Altered pancreatic islet function and morphology in mice lacking the Beta-cell surface protein neuroligin-2 Zhang C, Suckow AT, Chessler SD Ref: PLoS ONE, 8:e65711, 2013 : PubMed ESTHER: Zhang_2013_PLoS.One_8_e65711 PubMedSearch: Zhang 2013 PLoS.One 8 e65711 PubMedID: 23776533 Abstract Neuroligin-2 is a transmembrane, cell-surface protein originally identified as an inhibitory synapse-associated protein in the central nervous system. Neuroligin-2 is also present on the pancreatic beta-cell surface, and there it engages in transcellular interactions that drive functional maturation of the insulin secretory machinery; these are necessary for normal insulin secretion. The effects of neuroligin-2 deficiency on brain and neuronal function and morphology and on behavior and coordination have been extensively characterized using neuroligin-2 knockout mice. The effects of absent neuroligin-2 expression on islet development and function, however, are unknown. Here, to help test whether neuroligin-2 is necessary for normal islet development, we characterized islet morphology in mice lacking neuroligin-2. To test whether-as predicted by our earlier co-culture studies-absence of neuroligin-2 impairs beta cell function, we compared glucose-stimulated insulin secretion by islets from mutant and wild-type mice. Our results show that while islets from neuroligin-2-deficient mice do not to appear to differ architecturally from wild-type islets, they are smaller, fewer in number, and contain beta cells with lower insulin content. Evaluation of transcript levels suggests that upregulation of neuroligin-1 helps compensate for loss of neuroligin-2. Surprisingly, under both basal and stimulating glucose levels, isolated islets from the knockout mice secreted more of their intracellular insulin content. Rat islets with shRNA-mediated neuroligin-2 knockdown also exhibited increased insulin secretion. Neurexin transcript levels were lower in the knockout mice and, consistent with our prior finding that neurexin is a key constituent of the insulin granule docking machinery, insulin granule docking was reduced. These results indicate that neuroligin-2 is not necessary for the formation of pancreatic islets but that neuroligin-2 influences islet size and number. Neuroligin-2-perhaps through its effects on the expression and/or activity of its binding partner neurexin-promotes insulin granule docking, a known constraint on insulin secretion. Title: Crystal structures of two phytohormone signal-transducing alpha/beta hydrolases: karrikin-signaling KAI2 and strigolactonesignaling DWARF14 Zhao LH, Zhou XE, Wu ZS, Yi W, Xu Y, Li S, Xu TH, Liu Y, Chen RZ and Xu HE <11 more author(s)> Zhao LH, Zhou XE, Wu ZS, Yi W, Xu Y, Li S, Xu TH, Liu Y, Chen RZ, Kovach A, Kang Y, Hou L, He Y, Xie C, Song W, Zhong D, Wang Y, Li J, Zhang C, Melcher K, Xu HE (- 11) Ref: Cell Res, 23:436, 2013 : PubMed ESTHER: Zhao_2013_Cell.Res_23_436 PubMedSearch: Zhao 2013 Cell.Res 23 436 PubMedID: 23381136 Gene_locus related to this paper: orysj-Q10QA5 Title: 6-acetyl-5H-thiazolo[3,2-a]pyrimidine derivatives as the novel acetylcholinesterase inhibitors: design, synthesis, and biological activity Zhi H, Zhang C, Cheng Z, Jin Z, Huang E, Li S, Lin H, Wan DC, Hu C Ref: Med Chem, 9:703, 2013 : PubMed ESTHER: Zhi_2013_Med.Chem_9_703 PubMedSearch: Zhi 2013 Med.Chem 9 703 PubMedID: 23270368 Abstract Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer's drugs. A series of 6-acetyl- 5H-thiazolo[3,2-a]pyrimidine derivatives as the novel acetylcholinesterase inhibitors were designed based on virtual screening methods. The target compounds which are not reported in the literature were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, 1H-NMR and 13C-NMR. The biological evaluation against human acetylcholinesterase in vitro showed most of the target compounds exhibited varying inhibition at 10 microM using the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer's disease, and a foundation in search for improved acetylcholinesterase inhibitors with the novel scaffolds. The preliminary structure-activity relationships were the 2-hydroxyethoxy group at the phenyl ring at C4 position of the parent nucleus played significant roles in the AChE inhibitory activity of the target compounds. Title: Enhancement of nose-to-brain delivery of basic fibroblast growth factor for improving rat memory impairments induced by co-injection of beta-amyloid and ibotenic acid into the bilateral hippocampus Feng C, Zhang C, Shao X, Liu Q, Qian Y, Feng L, Chen J, Zha Y, Zhang Q, Jiang X Ref: Int J Pharm, 423:226, 2012 : PubMed ESTHER: Feng_2012_Int.J.Pharm_423_226 PubMedSearch: Feng 2012 Int.J.Pharm 423 226 PubMedID: 22193058 Abstract Basic fibroblast growth factor (bFGF) delivery to the brain of animals appears to be an emerging potential therapeutic approach to neurodegenerative diseases, such as Alzheimer's disease (AD). The intranasal route of administration could provide an alternative to intracerebroventricular infusion. A nasal spray of bFGF had been developed previously and the objective of the present study was to investigate whether bFGF nasal spray could enhance brain uptake of bFGF and ameliorate memory impairment induced by co-injection of beta-amyloid(25-35) and ibotenic acid into bilateral hippocampus of rats. The results of brain uptake study showed that the AUC(0-12h) of bFGF nasal spray in olfactory bulb, cerebrum, cerebellum and hippocampus was respectively 2.47, 2.38, 2.56 and 2.19 times that of intravenous bFGF solution, and 1.11, 1.95, 1.40 and 1.93 times that of intranasal bFGF solution, indicating that intranasal administration of bFGF nasal spray was an effective means of delivering bFGF to the brain, especially to cerebrum and hippocampus. In Morris water maze tasks, intravenous administration of bFGF solution at high dose (40 mug/kg) showed little improvement on spatial memory impairment. In contrast, bFGF solution of the same dose following intranasal administration could significantly ameliorate spatial memory impairment. bFGF nasal spray obviously improved spatial memory impairment even at a dose half (20 mug/kg) of bFGF solution, recovered their acetylcholinesterase and choline acetyltransferase activity to the sham control level, and alleviated neuronal degeneration in rat hippocampus, indicating neuroprotective effects on the central nerve system. In a word, bFGF nasal spray may be a new formulation of great potential for treating AD. Title: Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK and Kobayashi T <1 more author(s)> Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T, Kobayashi T (- 1) Ref: Nature, 482:547, 2012 : PubMed ESTHER: Haga_2012_Nature_482_547 PubMedSearch: Haga 2012 Nature 482 547 PubMedID: 22278061 Abstract The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation. Title: Transcellular neuroligin-2 interactions enhance insulin secretion and are integral to pancreatic beta cell function Suckow AT, Zhang C, Egodage S, Comoletti D, Taylor P, Miller MT, Sweet IR, Chessler SD Ref: Journal of Biological Chemistry, 287:19816, 2012 : PubMed ESTHER: Suckow_2012_J.Biol.Chem_287_19816 PubMedSearch: Suckow 2012 J.Biol.Chem 287 19816 PubMedID: 22528485 Abstract Normal glucose-stimulated insulin secretion is dependent on interactions between neighboring beta cells. Elucidation of the reasons why this cell-to-cell contact is essential will probably yield critical insights into beta cell maturation and function. In the central nervous system, transcellular protein interactions (i.e. interactions between proteins on the surfaces of different cells) involving neuroligins are key mediators of synaptic functional development. We previously demonstrated that beta cells express neuroligin-2 and that insulin secretion is affected by changes in neuroligin-2 expression. Here we show that the effect of neuroligin-2 on insulin secretion is mediated by transcellular interactions. Neuroligin-2 binds with nanomolar affinity to a partner on the beta cell surface and contributes to the increased insulin secretion brought about by beta cell-to-beta cell contact. It does so in a manner seemingly independent of interactions with neurexin, a known binding partner. As in the synapse, transcellular neuroligin-2 interactions enhance the functioning of the submembrane exocytic machinery. Also, as in the synapse, neuroligin-2 clustering is important. Neuroligin-2 in soluble form, rather than presented on a cell surface, decreases insulin secretion by rat islets and MIN-6 cells, most likely by interfering with endogenous neuroligin interactions. Prolonged contact with neuroligin-2-expressing cells increases INS-1 beta cell proliferation and insulin content. These results extend the known parallels between the synaptic and beta cell secretory machineries to extracellular interactions. Neuroligin-2 interactions are one of the few transcellular protein interactions thus far identified that directly enhance insulin secretion. Together, these results indicate a significant role for transcellular neuroligin-2 interactions in the establishment of beta cell function. Title: Dexamethasone regulates differential expression of carboxylesterase 1 and carboxylesterase 2 through activation of nuclear receptors Zhang C, Gao P, Yin W, Xu Y, Xiang D, Liu D Ref: J Huazhong Univ Sci Technolog Med Sci, 32:798, 2012 : PubMed ESTHER: Zhang_2012_J.Huazhong.Univ.Sci.Technolog.Med.Sci_32_798 PubMedSearch: Zhang 2012 J.Huazhong.Univ.Sci.Technolog.Med.Sci 32 798 PubMedID: 23271276 Abstract Carboxylesterases (CESs) play important roles in the metabolism of endogenous and foreign compounds in physiological and pharmacological responses. The aim of this study was to investigate the effect of dexamethasone at different doses on the expression of CES1 and CES2. Imidapril and irinotecan hydrochloride (CPT-11) were used as special substrates for CES1 and CES2, respectively. Rat hepatocytes were cultured and treated with different concentrations of dexamethasone. The hydrolytic activity of CES1 and CES2 was tested by incubation experiment and their expression was quantitated by real-time PCR. A pharmacokinetic study was conducted in SD rats to further evaluate the effect of dexamethasone on CESs activity in vivo. Western blotting was performed to investigate the regulatory mechanism related to pregnane X receptor (PXR) and glucocorticoid receptor (GR). The results showed that exposure of cultured rat hepatocytes to nanomolar dexamethasone inhibited the imidapril hydrolase activity, which was slightly elevated by micromolar dexamethasone. For CES2, CPT-11 hydrolase activity was induced only when dexamethasone reached micromolar levels. The real-time PCR demonstrated that CES1 mRNA was markedly decreased by nanomolar dexamethasone and increased by micromolar dexamethasone, whereas CES2 mRNA was significantly increased by micromolar dexamethasone. The results of a complementary animal study showed that the concurrent administration of dexamethasone significantly increased the plasma concentration of the metabolite of imidapril while the ratio of CPT-11 to its metabolite SN-38 was significantly decreased. PXR protein was gradually increased by serial concentrations of dexamethasone. However, only nanomolar dexamethasone elevated the level of GR protein. The different concentrations of dexamethasone required suggested that suppression of CES1 may be mediated by GR whereas the induction of CES2 may result from the role of PXR. It was concluded that dexamethasone at different concentrations can differentially regulate CES1 and CES2. Title: Identification of carboxylesterases expressed in rat intestine and effects of their hydrolyzing activity in predicting first-pass metabolism of ester prodrugs Liu D, Gao J, Zhang C, Ren X, Liu Y, Xu Y Ref: Pharmazie, 66:888, 2011 : PubMed ESTHER: Liu_2011_Pharmazie_66_888 PubMedSearch: Liu 2011 Pharmazie 66 888 PubMedID: 22204136 Abstract Carboxylesterases (CESs) located in the intestine play an unique role in the absorption of many drugs especially ester prodrugs. In order to determine the expression and hydrolyzing activity of CESs isozymes (CES1 and CES2) located in rat intestine, the activities of CES1 and CES2 were evaluated by the intestinal S9 incubation with imidapril and irinotecan (CPT-11), the substrates of CES1 and CES2, respectively. The distribution characteristics of CES1, CES2, Pregnane X Receptor (PXR) and Constitutive Androstane Receptor were analyzed by real-time polymerase chain reaction (RT-PCR) or Western blot. Imidaprilat metabolized from imidapril by CES1 was too low to be detected in rat intestinal S9 fractions, while there was little and even no expression of CES1 mRNA in intestinal segments. In contrast, Vmax values for CPT-11 diminished gradually from proximal to distal segments within the rat intestine which was consistent with the mRNA expression level of CES2. These results indicated that CES2 represents the major CESs isoform in the rat complete intestine and decreased from duodenum to colon, whereas the expression of CES1 was too low to influence the metabolism of ester prodrugs. The expression of PXR and CAR decreased slightly along the entire intestine on both mRNA and protein levels which indicated that PXR and CAR may be one of the major factors which contribute to the expression of CES1 and CES2. Thus, the knowledge about the characteristic and site-specific expression of CES1 and CES2 in rat intestine will help to predict the oral bioavailability of ester prodrugs. Title: Cloning and characterization of the biosynthetic gene cluster of the bacterial RNA polymerase inhibitor tirandamycin from marine-derived Streptomyces sp. SCSIO1666 Mo X, Wang Z, Wang B, Ma J, Huang H, Tian X, Zhang S, Zhang C, Ju J Ref: Biochemical & Biophysical Research Communications, 406:341, 2011 : PubMed ESTHER: Mo_2011_Biochem.Biophys.Res.Commun_406_341 PubMedSearch: Mo 2011 Biochem.Biophys.Res.Commun 406 341 PubMedID: 21329667 Gene_locus related to this paper: 9actn-f1di35 Abstract Tirandamycins are bacterial RNA polymerase inhibitors holding great potential for antibacterial agent design. To elucidate the biosynthetic machinery and generate new derivatives, the tirandamycin biosynthetic gene cluster was cloned and sequenced from marine-derived Streptomyces sp. SCSIO1666. The biosynthetic gene cluster of tirandamycin spans a DNA region of ~56kb and consists of 15 open reading frames (ORFs) which encode three type I polyketide synthases (TrdAI, AII, AIII), one non-ribosomal peptide synthetase (TrdD), one phosphopantetheinyl transferase (TrdM), one Type II thioesterase (TrdB), one FAD-dependent oxidoreductase (TrdL), one cytochrome P450 monooxygenase (TrdI), three proteins related to resistance and regulations (TrdHJK), and four proteins with unknown function (TrdCEFG). To investigate the roles of the genes played in the biosynthetic machinery, seven genes (trdAI and trdBDFHIK) were inactivated via in frame replacement with an apramycin gene cassette using -RED recombination technology. The trdAI and trdD mutants targeting the ketosynthase and adenylation domain of TrdAI and TrdD, respectively, abolished the production of tirandamycins, confirming their involvement in the tirandamycin biosynthesis. TrdH showed high homology to LuxR family transcriptional regulatory proteins, disruption of which abolished the production of tirandamycins, indicating that TrdH is a positive regulator for tirandamycin biosynthesis. On the other hand, TrdK showed high homology to TetR-family transcriptional regulatory proteins, disruption of which significantly increased the yields of tirandamycins almost one-fold, implicating that TrdK is a negative regulator for tirandamycin biosynthesis. Disruption of the gene trdI resulted in the accumulation of the intermediate tirandamycin C (3) and a trace amount of new product tirandamycin C2 (5). A model of tirandamycin biosynthesis was proposed based on bioinformatics analyses, gene inactivation experiments and intermediates isolated from the mutants. These findings set the stage for further study of the tirandamycin biosynthetic mechanism and rationally engineer new tirandamycin analogues. Title: Comparative evaluation of the protective potentials of human paraoxonase 1 and 3 against CCl4-induced liver injury Peng W, Zhang C, Lv H, Zhu J, Zang Y, Pang X, Zhang J, Qin J Ref: Toxicol Lett, 193:159, 2010 : PubMed ESTHER: Peng_2010_Toxicol.Lett_193_159 PubMedSearch: Peng 2010 Toxicol.Lett 193 159 PubMedID: 20079818 Abstract We previously reported that electroporation mediated hPON1 or hPON3 gene delivery could protect against CCl(4)-induced liver injury. However, substantial evidence supported that the in vivo physiological functions of hPON1 and hPON3 were distinct. To compare the protective efficacies of hPON1 and hPON3 against liver injury, recombinant adenovirus AdPON1 and AdPON3, which were capable of expressing hPON1 and hPON3 respectively, were intravenously injected into mice before they were given CCl(4). Adenovirus mediated expression of hPON1 and hPON3 were demonstrated by elevated serum esterase activity, hepatic lactonase activity, and hPON1/hPON3 mRNA expression in liver. Serum transaminase assay, histological observation and TUNEL analysis revealed that the extent of liver injury and hepatocyte apoptosis in AdPON1 or AdPON3 treated mice was significantly ameliorated in comparison with control. Meanwhile, overexpression of hPON1 and hPON3 reduced the hepatic oxidative stress and strengthen the total antioxidant capabilities in liver through affecting the hepatic malondialdehyde (MDA), glutathione (GSH) and total antioxidant capability (T-AOC) levels, regardless of the exposure to CCl(4) or corn oil. Administration of AdPON1 or AdPON3 also suppressed inflammatory response by decreasing TNF-alpha and IL-1beta levels in CCl(4) mice. In this study, hPON1 exhibited a slightly higher efficacy than hPON3 in alleviating liver injury, but the difference between them were not significant. Title: Studies on protective effects of human paraoxonases 1 and 3 on atherosclerosis in apolipoprotein E knockout mice Zhang C, Peng W, Wang M, Zhu J, Zang Y, Shi W, Zhang J, Qin J Ref: Gene Therapy, 17:626, 2010 : PubMed ESTHER: Zhang_2010_Gene.Ther_17_626 PubMedSearch: Zhang 2010 Gene.Ther 17 626 PubMedID: 20182519 Abstract Paraoxonase (PON) possesses antiatherogenic potentials, but the distinct functions of PON members in alleviating atherosclerosis are not yet clear. This study aimed to evaluate the protective effects of hPON1 and hPON3 against atherosclerosis, and thereby exploring their synergistic mechanism in atherosclerosis development. We generated the recombinant adenovirus AdPON1 and AdPON3, which were capable of expressing hPON1 and hPON3. After AdPON1 and AdPON3 were injected intravenously into 5-week-old apolipoprotein E knockout mice, abundant hPON1 and hPON3 mRNA expression levels were detected. However, increase in serum lactonase activity was detected only in AdPON1-treated mice. Serum antioxidation and anti-inflammation capabilities in AdPON1-treated mice, reflected by malondialdehyde, total antioxidant capability and tumor necrosis factor-alpha levels, were greatly enhanced, whereas those in AdPON3-treated mice were not significantly affected. Nevertheless, histological analysis revealed that adenovirus-mediated expression of hPON1, hPON3 or both of them reduced atherosclerotic plaque area to a similar extent. Although no synergistic mechanism was detected in reducing arterial lesion size, hPON1 and hPON3 showed synergistic effects on promoting macrophage cholesterol efflux. In conclusion, hPON1 and hPON3 exhibited similar potentials in reducing arterial lesion size, but they exerted antiatherogenic effects in distinct ways. Title: Neurexins physically and functionally interact with GABA(A) receptors Zhang C, Atasoy D, Arac D, Yang X, Fucillo MV, Robison AJ, Ko J, Brunger AT, Sudhof TC Ref: Neuron, 66:403, 2010 : PubMed ESTHER: Zhang_2010_Neuron_66_403 PubMedSearch: Zhang 2010 Neuron 66 403 PubMedID: 20471353 Abstract Neurexins are presynaptic cell-adhesion molecules that form trans-synaptic complexes with postsynaptic neuroligins. When overexpressed in nonneuronal cells, neurexins induce formation of postsynaptic specializations in cocultured neurons, suggesting that neurexins are synaptogenic. However, we find that when overexpressed in neurons, neurexins do not increase synapse density, but instead selectively suppressed GABAergic synaptic transmission without decreasing GABAergic synapse numbers. This suppression was mediated by all subtypes of neurexins tested, in a cell-autonomous and neuroligin-independent manner. Strikingly, addition of recombinant neurexin to cultured neurons at submicromolar concentrations induced the same suppression of GABAergic synaptic transmission as neurexin overexpression. Moreover, experiments with native brain proteins and purified recombinant proteins revealed that neurexins directly and stoichiometrically bind to GABA(A) receptors, suggesting that they decrease GABAergic synaptic responses by interacting with GABA(A) receptors. Our findings suggest that besides their other well-documented interactions, presynaptic neurexins directly act on postsynaptic GABA(A) receptors, which may contribute to regulate the excitatory/inhibitory balance in brain. Title: Neuroligin-1 performs neurexin-dependent and neurexin-independent functions in synapse validation Ko J, Zhang C, Arac D, Boucard AA, Brunger AT, Sudhof TC Ref: EMBO Journal, 28:3244, 2009 : PubMed ESTHER: Ko_2009_Embo.J_28_3244 PubMedSearch: Ko 2009 Embo.J 28 3244 PubMedID: 19730411 Gene_locus related to this paper: ratno-1neur Abstract Postsynaptic neuroligins are thought to perform essential functions in synapse validation and synaptic transmission by binding to, and dimerizing, presynaptic alpha- and beta-neurexins. To test this hypothesis, we examined the functional effects of neuroligin-1 mutations that impair only alpha-neurexin binding, block both alpha- and beta-neurexin binding, or abolish neuroligin-1 dimerization. Abolishing alpha-neurexin binding abrogated neuroligin-induced generation of neuronal synapses onto transfected non-neuronal cells in the so-called artificial synapse-formation assay, even though beta-neurexin binding was retained. Thus, in this assay, neuroligin-1 induces apparent synapse formation by binding to presynaptic alpha-neurexins. In transfected neurons, however, neither alpha- nor beta-neurexin binding was essential for the ability of postsynaptic neuroligin-1 to dramatically increase synapse density, suggesting a neurexin-independent mechanism of synapse formation. Moreover, neuroligin-1 dimerization was not required for either the non-neuronal or the neuronal synapse-formation assay. Nevertheless, both alpha-neurexin binding and neuroligin-1 dimerization were essential for the increase in apparent synapse size that is induced by neuroligin-1 in transfected neurons. Thus, neuroligin-1 performs diverse synaptic functions by mechanisms that include as essential components of alpha-neurexin binding and neuroligin dimerization, but extend beyond these activities. Title: Analysis of complete genome sequence of Neorickettsia risticii: causative agent of Potomac horse fever Lin M, Zhang C, Gibson K, Rikihisa Y Ref: Nucleic Acids Research, 37:6076, 2009 : PubMed ESTHER: Lin_2009_Nucleic.Acids.Res_37_6076 PubMedSearch: Lin 2009 Nucleic.Acids.Res 37 6076 PubMedID: 19661282 Gene_locus related to this paper: neori-c6v4w3, neori-c6v608 Abstract Neorickettsia risticii is an obligate intracellular bacterium of the trematodes and mammals. Horses develop Potomac horse fever (PHF) when they ingest aquatic insects containing encysted N. risticii-infected trematodes. The complete genome sequence of N. risticii Illinois consists of a single circular chromosome of 879 977 bp and encodes 38 RNA species and 898 proteins. Although N. risticii has limited ability to synthesize amino acids and lacks many metabolic pathways, it is capable of making major vitamins, cofactors and nucleotides. Comparison with its closely related human pathogen N. sennetsu showed that 758 (88.2%) of protein-coding genes are conserved between N. risticii and N. sennetsu. Four-way comparison of genes among N. risticii and other Anaplasmataceae showed that most genes are either shared among Anaplasmataceae (525 orthologs that generally associated with housekeeping functions), or specific to each genome (>200 genes that are mostly hypothetical proteins). Genes potentially involved in the pathogenesis of N. risticii were identified, including those encoding putative outer membrane proteins, two-component systems and a type IV secretion system (T4SS). The bipolar localization of T4SS pilus protein VirB2 on the bacterial surface was demonstrated for the first time in obligate intracellular bacteria. These data provide insights toward genomic potential of N. risticii and intracellular parasitism, and facilitate our understanding of PHF pathogenesis. Title: Synthesis, biological evaluation and molecular modeling of oxoisoaporphine and oxoaporphine derivatives as new dual inhibitors of acetylcholinesterase/butyrylcholinesterase Tang H, Wei YB, Zhang C, Ning FX, Qiao W, Huang SL, Ma L, Huang ZS, Gu LQ Ref: Eur Journal of Medicinal Chemistry, 44:2523, 2009 : PubMed ESTHER: Tang_2009_Eur.J.Med.Chem_44_2523 PubMedSearch: Tang 2009 Eur.J.Med.Chem 44 2523 PubMedID: 19243862 Abstract Aporphine alkaloids, isolated from Chinese medicinal herb, are important natural products. We recently reported that synthetic derivatives of oxoisoaporphine alkaloids exhibited high acetylcholinesterase inhibitory activity and high selectivity for AChE over BuChE (Bioorg. Med. Chem. Lett. 2007, 17, 3765-3768). In this paper, further research results were presented. A series of novel derivatives of oxoaporphine alkaloids (5a-j, 4-carboxylic amide-7-oxo-7H-dibenzo[de,g]quinoline, Ar-CONH(CH(2))(n)NR) and their quaternary methiodide salts (6a-h, Ar-CONH(CH(2))(n)N(+)(CH(3))RI(-)) were designed and synthesized as acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE) inhibitors. The AChE inhibition potency of synthetic oxoaporphine derivatives was decreased about 2-3 orders of magnitude as compared with that of oxoisoaporphine derivatives. Non-competitive binding mode was found for both kinds of derivatives. Molecular docking simulations on the oxoisoaporphine derivatives 7 series and oxoaporphine derivatives 6 series with AChE from Torpedo californica have demonstrated that the ligands bound to the dual-site of the enzyme. Title: Hypertriglyceridemia in Watanabe heritable hyperlipidemic rabbits was associated with increased production and reduced catabolism of very-low-density lipoproteins Zhang C, Jin Y, Liu T, Liu F, Ito T Ref: Pathobiology, 76:315, 2009 : PubMed ESTHER: Zhang_2009_Pathobiology_76_315 PubMedSearch: Zhang 2009 Pathobiology 76 315 PubMedID: 19955843 Abstract Watanabe heritable hyperlipidemic (WHHL) rabbit is an animal model for human familial hypercholesterolemia. Recently, we segregated a new mutant of WHHL rabbits with plasma levels of triglycerides (TG) >500 mg/dl (designated as TGH-WHHL). To investigate the underlying mechanisms for hypertriglyceridemia, we compared TGH-WHHL with WHHL rabbits with lower plasma TG levels (<250 mg/dl, designated as TGL-WHHL). A Triton WR-1339 injection experiment revealed that TGH-WHHL rabbits had increased secretion and decreased clearance of TG-rich lipoproteins. Furthermore, TGH-WHHL rabbits had lower a post-heparin activity of lipoprotein lipase and a higher cholesterol ester transfer protein activity than TGL-WHHL rabbits. Cultured hepatocytes isolated from TGH-WHHL rabbits showed a higher secretion rate of TG and cholesterol than those of TGL-WHHL rabbits. In addition, TGH-WHHL rabbits exhibited marked insulin resistance. These data suggest that hypertriglyceridemia exhibited by WHHL rabbits is caused by both increased production and impaired catabolism of TG-rich lipoproteins and associated with insulin resistance. Title: A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export Zhang C, Milunsky JM, Newton S, Ko J, Zhao G, Maher TA, Tager-Flusberg H, Bolliger MF, Carter AS and Sudhof TC <2 more author(s)> Zhang C, Milunsky JM, Newton S, Ko J, Zhao G, Maher TA, Tager-Flusberg H, Bolliger MF, Carter AS, Boucard AA, Powell CM, Sudhof TC (- 2) Ref: Journal of Neuroscience, 29:10843, 2009 : PubMed ESTHER: Zhang_2009_J.Neurosci_29_10843 PubMedSearch: Zhang 2009 J.Neurosci 29 10843 PubMedID: 19726642 Abstract Neuroligins (NLs) are postsynaptic cell-adhesion molecules essential for normal synapse function. Mutations in neuroligin-4 (NL4) (gene symbol: NLGN4) have been reported in some patients with autism spectrum disorder (ASD) and other neurodevelopmental impairments. However, the low frequency of NL4 mutations and the limited information about the affected patients and the functional consequences of their mutations cast doubt on the causal role of NL4 mutations in these disorders. Here, we describe two brothers with classical ASD who carry a single amino-acid substitution in NL4 (R87W). This substitution was absent from the brothers' asymptomatic parents, suggesting that it arose in the maternal germ line. R87 is conserved in all NL isoforms, and the R87W substitution is not observed in control individuals. At the protein level, the R87W substitution impaired glycosylation processing of NL4 expressed in HEK293 and COS cells, destabilized NL4, caused NL4 retention in the endoplasmic reticulum in non-neuronal cells and neurons, and blocked NL4 transport to the cell surface. As a result, the R87W substitution inactivated the synapse-formation activity of NL4 and abolished the functional effect of NL4 on synapse strength. Viewed together, these observations suggest that a point mutation in NL4 can cause ASD by a loss-of-function mechanism. Title: Variations in DNA elucidate molecular networks that cause disease Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang C, Lamb J, Edwards S and Schadt EE <12 more author(s)> Chen Y, Zhu J, Lum PY, Yang X, Pinto S, MacNeil DJ, Zhang C, Lamb J, Edwards S, Sieberts SK, Leonardson A, Castellini LW, Wang S, Champy MF, Zhang B, Emilsson V, Doss S, Ghazalpour A, Horvath S, Drake TA, Lusis AJ, Schadt EE (- 12) Ref: Nature, 452:429, 2008 : PubMed ESTHER: Chen_2008_Nature_452_429 PubMedSearch: Chen 2008 Nature 452 429 PubMedID: 18344982 Abstract Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors. Title: Comparative genomics of emerging human ehrlichiosis agents Dunning Hotopp JC, Lin M, Madupu R, Crabtree J, Angiuoli SV, Eisen JA, Seshadri R, Ren Q, Wu M and Tettelin H <30 more author(s)> Dunning Hotopp JC, Lin M, Madupu R, Crabtree J, Angiuoli SV, Eisen JA, Seshadri R, Ren Q, Wu M, Utterback TR, Smith S, Lewis M, Khouri H, Zhang C, Niu H, Lin Q, Ohashi N, Zhi N, Nelson W, Brinkac LM, Dodson RJ, Rosovitz MJ, Sundaram J, Daugherty SC, Davidsen T, Durkin AS, Gwinn M, Haft DH, Selengut JD, Sullivan SA, Zafar N, Zhou L, Benahmed F, Forberger H, Halpin R, Mulligan S, Robinson J, White O, Rikihisa Y, Tettelin H (- 30) Ref: PLoS Genet, 2:e21, 2006 : PubMed ESTHER: Dunning Hotopp_2006_PLoS.Genet_2_e21 PubMedSearch: Dunning Hotopp 2006 PLoS.Genet 2 e21 PubMedID: 16482227 Gene_locus related to this paper: anapz-q2gj80, anapz-q2gle9, anapz-q2glf0, anapz-q2gln7, ehrch-q40iu0, ehrch-q40jj7, ehrcr-q2gfq9, neosm-q2gcq8, neosm-q2gdf2, neosm-q2gcn8, anapz-q2gk48, ehrcr-q2ggj6 Abstract Anaplasma (formerly Ehrlichia) phagocytophilum, Ehrlichia chaffeensis, and Neorickettsia (formerly Ehrlichia) sennetsu are intracellular vector-borne pathogens that cause human ehrlichiosis, an emerging infectious disease. We present the complete genome sequences of these organisms along with comparisons to other organisms in the Rickettsiales order. Ehrlichia spp. and Anaplasma spp. display a unique large expansion of immunodominant outer membrane proteins facilitating antigenic variation. All Rickettsiales have a diminished ability to synthesize amino acids compared to their closest free-living relatives. Unlike members of the Rickettsiaceae family, these pathogenic Anaplasmataceae are capable of making all major vitamins, cofactors, and nucleotides, which could confer a beneficial role in the invertebrate vector or the vertebrate host. Further analysis identified proteins potentially involved in vacuole confinement of the Anaplasmataceae, a life cycle involving a hematophagous vector, vertebrate pathogenesis, human pathogenesis, and lack of transovarial transmission. These discoveries provide significant insights into the biology of these obligate intracellular pathogens. Title: Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling Wang Y, Du D, Fang L, Yang G, Zhang C, Zeng R, Ullrich A, Lottspeich F, Chen Z Ref: EMBO Journal, 25:5058, 2006 : PubMed ESTHER: Wang_2006_EMBO.J_25_5058 PubMedSearch: Wang 2006 EMBO.J 25 5058 PubMedID: 17053785 Abstract The conserved polarity complex, comprising the partitioning-defective (Par) proteins Par3 and Par6, and the atypical protein kinase C, functions in various cell-polarization events and asymmetric cell divisions. However, little is known about whether and how external stimuli-induced signals may regulate Par3 function in epithelial cell polarity. Here, we found that Par3 was tyrosine phosphorylated through phosphoproteomic profiling of pervanadate-induced phosphotyrosine proteins. We also demonstrated that the tyrosine phosphorylation event induced by multiple growth factors including epidermal growth factor (EGF) was dependent on activation of Src family kinase (SFK) members c-Src and c-Yes. The tyrosine residue 1127 (Y1127) of Par3 was identified as the major EGF-induced phosphorylation site. Moreover, we found that Y1127 phosphorylation reduced the association of Par3 with LIM kinase 2 (LIMK2), thus enabling LIMK2 to regulate cofilin phosphorylation dynamics. Substitution of Y1127 for phenylalanine impaired the EGF-induced Par3 and LIMK2 dissociation and delayed epithelial tight junction (TJ) assembly considerably. Collectively, these data suggest a novel, phosphotyrosine-dependent fine-tuning mechanism of Par3 in epithelial TJ assembly controlled by the EGF receptor-SFK signaling pathway. Title: Functional variants of the lipoprotein lipase gene and the risk of preeclampsia among non-Hispanic Caucasian women Zhang C, Austin MA, Edwards KL, Farin FM, Li N, Hsu L, Srinouanprachanh SL, Williams MA Ref: Clin Genet, 69:33, 2006 : PubMed ESTHER: Zhang_2006_Clin.Genet_69_33 PubMedSearch: Zhang 2006 Clin.Genet 69 33 PubMedID: 16451134 Abstract Hypertriglyceridemia is an important pathophysiologic feature of preeclampsia, a common vascular disorder of pregnancy. Three well-documented functional variants (N291S, S447X, and D9N) of the lipoprotein lipase gene were related to hypertriglyceridemia. Results from the only two studies concerning the relationship between these variants and preeclampsia risk have been inconsistent. We investigated this relationship in a case-control study including 144 preeclamptic and 290 normotensive pregnant women (all non-Hispanic Caucasians). We estimated odds ratios (OR) and 95% confidence intervals (CI) adjusted for maternal age, pre-pregnancy body mass index, and parity. After adjusting for covariates, women with the 291 N/S or S/S genotype had significantly increased risk of preeclampsia (OR 6.9, 95% CI 1.9-25.4) compared with women with the common 291N/N genotype. The 447 S/X or X/X genotype was not significantly associated with preeclampsia risk. The frequency of the 9N variant allele was 1.8% in controls, while this allele was not observed among cases. Haplotype 9D/291S/447S was strongly associated with higher risk of preeclampsia as compared with the most common haplotype 9D/291N/447S (adjusted OR 6.6, 95% CI 1.7-25.0). Results from our study support the thesis that abnormal lipid metabolism is important in the pathogenesis of preeclampsia. Title: Interactions between the -514C->T polymorphism of the hepatic lipase gene and lifestyle factors in relation to HDL concentrations among US diabetic men Zhang C, Lopez-Ridaura R, Rimm EB, Rifai N, Hunter DJ, Hu FB Ref: Am J Clin Nutr, 81:1429, 2005 : PubMed ESTHER: Zhang_2005_Am.J.Clin.Nutr_81_1429 PubMedSearch: Zhang 2005 Am.J.Clin.Nutr 81 1429 PubMedID: 15941898 Abstract BACKGROUND: Low plasma HDL-cholesterol concentrations are a hallmark of diabetic dyslipidemia. A common polymorphism (-514C-->T) of the hepatic lipase gene (LIPC), which accounts for up to 30% of the variation in hepatic lipase activity, has been associated with low hepatic lipase activity and high HDL-cholesterol concentrations. OBJECTIVE: We examined the association between this polymorphism and plasma HDL-cholesterol concentrations and evaluated whether this association was modified by adiposity and dietary fat intake. DESIGN: We followed men aged 40-75 y who participated in the Health Professionals Follow-Up Study in 1986. Among 18 159 men who returned blood samples by 1994, 780 had confirmed type 2 diabetes at blood drawing or during follow-up to 1998 and were free of cardiovascular disease at blood drawing. Title: Increased paraoxon detection by acetylcholinesterase inactivation with ionic liquid additives Zhang C, Malhotra SV Ref: Talanta, 67:560, 2005 : PubMed ESTHER: Zhang_2005_Talanta_67_560 PubMedSearch: Zhang 2005 Talanta 67 560 PubMedID: 18970206 Abstract This is the first study using ionic liquids (ILs) as additive in the aqueous solvent medium for detection of paraoxon by acetylcholinesterase inhibition method. A systematic comparison of various ILs with organic solvents has been made. The aqueous buffer solution containing ionic liquid ethylpyridinium hexafluorophosphate [EtPy](+)[PF(6)](-) has been found to give the best results. The inhibition kinetic follows the first order model. Ionic liquids modified aqueous solutions show the potential to provide a promising and effective medium in detection of paraoxon with acetylcholinesterase. Title: Crystallization and preliminary X-ray studies of methyl parathion hydrolase from Pseudomonas sp. WBC-3 Sun L, Dong Y, Zhou Y, Yang M, Zhang C, Rao Z, Zhang XE Ref: Acta Crystallographica D Biol Crystallogr, 60:954, 2004 : PubMed ESTHER: Sun_2004_Acta.Crystallogr.D.Biol.Crystallogr_60_954 PubMedSearch: Sun 2004 Acta.Crystallogr.D.Biol.Crystallogr 60 954 PubMedID: 15103151 Abstract Methyl parathion hydrolase (MPH) from Pseudomonas sp. WBC-3, an enzyme that catalyzes the degradation of methyl parathion (O,O-dimethyl O-p-nitrophenyl phosphorothioate; MP), has been purified and crystallized by the hanging-drop vapour-diffusion method. The crystals were grown at 291 K using a precipitant solution consisting of 30% PEG 400, 0.1 M sodium acetate pH 4.6, 0.1 M CdCl(2). MPH is a zinc-containing enzyme judged by inductively coupled plasma mass-spectrometric (ICP-MS) analysis. Multiple-wavelength anomalous dispersive X-ray data were collected at 2.5 A resolution from a single crystal on beamline 41XU at SPring-8. The crystal belongs to space group P4(3)2(1)2, with unit-cell parameters a = 84.94, b = 84.94, c = 200.38 A, alpha = beta = gamma = 90 degrees. The asymmetric unit contains two molecules and has a solvent content of approximately 52%. Crystal structure determination is in progress. Title: Protective effect of tetramethylpyrazine on learning and memory function in D-galactose-lesioned mice Zhang C, Wang SZ, Zuo PP, Cui X, Cai J Ref: Chin Med Sci J, 19:180, 2004 : PubMed ESTHER: Zhang_2004_Chin.Med.Sci.J_19_180 PubMedSearch: Zhang 2004 Chin.Med.Sci.J 19 180 PubMedID: 15506643 Abstract OBJECTIVE: To explore the protective effect of tetramethylpyrazine (TMP) on the learning and memory function in D-galactose (D-gal)-lesioned mice. Title: [Effect of tetramethylpyrazine on learning, memory and cholinergic system in D-galactose-lesioned mice] Zhang C, Wang SZ, Zuo PP, Cui X, Cai J Ref: Zhongguo Yi Xue Ke Xue Yuan Xue Bao, 25:553, 2003 : PubMed ESTHER: Zhang_2003_Zhongguo.Yi.Xue.Ke.Xue.Yuan.Xue.Bao_25_553 PubMedSearch: Zhang 2003 Zhongguo.Yi.Xue.Ke.Xue.Yuan.Xue.Bao 25 553 PubMedID: 14650157 Abstract OBJECTIVE: To explore the effect of tetramethylpyrazine on learning, memory, and cholinergic system in D-galactose-lesioned mice. Title: The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins Dehal P, Satou Y, Campbell RK, Chapman J, Degnan B, De Tomaso A, Davidson B, Di Gregorio A, Gelpke M and Rokhsar DS <77 more author(s)> Dehal P, Satou Y, Campbell RK, Chapman J, Degnan B, De Tomaso A, Davidson B, Di Gregorio A, Gelpke M, Goodstein DM, Harafuji N, Hastings KE, Ho I, Hotta K, Huang W, Kawashima T, Lemaire P, Martinez D, Meinertzhagen IA, Necula S, Nonaka M, Putnam N, Rash S, Saiga H, Satake M, Terry A, Yamada L, Wang HG, Awazu S, Azumi K, Boore J, Branno M, Chin-Bow S, DeSantis R, Doyle S, Francino P, Keys DN, Haga S, Hayashi H, Hino K, Imai KS, Inaba K, Kano S, Kobayashi K, Kobayashi M, Lee BI, Makabe KW, Manohar C, Matassi G, Medina M, Mochizuki Y, Mount S, Morishita T, Miura S, Nakayama A, Nishizaka S, Nomoto H, Ohta F, Oishi K, Rigoutsos I, Sano M, Sasaki A, Sasakura Y, Shoguchi E, Shin-I T, Spagnuolo A, Stainier D, Suzuki MM, Tassy O, Takatori N, Tokuoka M, Yagi K, Yoshizaki F, Wada S, Zhang C, Hyatt PD, Larimer F, Detter C, Doggett N, Glavina T, Hawkins T, Richardson P, Lucas S, Kohara Y, Levine M, Satoh N, Rokhsar DS (- 77) Ref: Science, 298:2157, 2002 : PubMed ESTHER: Dehal_2002_Science_298_2157 PubMedSearch: Dehal 2002 Science 298 2157 PubMedID: 12481130 Gene_locus related to this paper: cioin-141645, cioin-147959, cioin-150181, cioin-154370, cioin-ACHE1, cioin-ACHE2, cioin-cxest, cioin-f6qcp0, cioin-f6r8z1, cioin-f6u176, cioin-f6vac9, cioin-f6x584, cioin-f6xa69, cioin-f6y403, cioin-h2xqb4, cioin-H2XTI0, cioin-F6T1M3, cioin-H2XUP7, cioin-CIN.7233, cioin-F6V269, cioin-Cin16330, cioin-h2xua2, cioin-f6vaa5, cioin-f6v9x6, cioin-f6swc9, cioin-f7amz2, cioin-f6s021, cioin-h2xxq9, cioin-h2xne6, cioin-f6ynr2 Abstract The first chordates appear in the fossil record at the time of the Cambrian explosion, nearly 550 million years ago. The modern ascidian tadpole represents a plausible approximation to these ancestral chordates. To illuminate the origins of chordate and vertebrates, we generated a draft of the protein-coding portion of the genome of the most studied ascidian, Ciona intestinalis. The Ciona genome contains approximately 16,000 protein-coding genes, similar to the number in other invertebrates, but only half that found in vertebrates. Vertebrate gene families are typically found in simplified form in Ciona, suggesting that ascidians contain the basic ancestral complement of genes involved in cell signaling and development. The ascidian genome has also acquired a number of lineage-specific innovations, including a group of genes engaged in cellulose metabolism that are related to those in bacteria and fungi. Title: Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F Ref: Molecular & Cellular Biochemistry, 229:35, 2002 : PubMed ESTHER: Qu_2002_Mol.Cell.Biochem_229_35 PubMedSearch: Qu 2002 Mol.Cell.Biochem 229 35 PubMedID: 11936845 Gene_locus related to this paper: human-NDRG1, human-NDRG2, human-NDRG3, human-NDRG4 Abstract NDRG1 (N-Myc downstream regulated) is upregulated during cell differentiation, repressed by N-myc and c-myc in embryonic cells, and suppressed in several tumor cells. A nonsense mutation in the NDRG1 gene has been reported to be causative for hereditary motor and sensory neuropathy-Lom (HMSNL), indicating that NDRG1 functions in the peripheral nervous system necessary for axonal survival. Here, we cloned three human cDNAs encoding NDRG2 (371aa), NDRG3 (375aa) and NDRG4 (339aa), which are homologous to NDRG1. These three genes, together with NDRG1, constitute the NDRG gene family. The phylogenetic analysis of the family demonstrated that human NDRG1 and NDRG3 belong to a subfamily, and NDRG2 and NDRG4 to another. At amino acid (aa) level, the four members share 53-65% identity. Each of the four proteins contains an alpha/beta hydrolase fold as in human lysosomal acid lipase. Expression of the fusion proteins NDRG2/GFP, NDRG3/GFP and NDRG4/GFP in COS-7 cells showed that all of them are cytosolic proteins. Based on UniGene cluster analysis, the genes NDRG2, NDRG3 and NDRG4 are located at chromosome 14q11.1-11.2, 20q12-11.23 and 16q21-22.1, respectively. Northern and dot blot analysis shows that all of the three genes are highly expressed in adult brain and almost not detected in the eight human cancer lines. In addition, in contrast to the relatively ubiquitous expression of NDRG1, NDRG2 is highly expressed in adult skeletal muscle and brain, NDRG3 highly expressed in brain and testis, and NDRG4 specifically expressed in brain and heart, suggesting that they might display different specific functions in distinct tissues. Title: A new subdivision, marginal division, in the neostriatum of the monkey brain Shu SY, Bao XM, Zhang C, Li SX, Chan WY, Yew D Ref: Neurochem Res, 25:231, 2000 : PubMed ESTHER: Shu_2000_Neurochem.Res_25_231 PubMedSearch: Shu 2000 Neurochem.Res 25 231 PubMedID: 10786707 Abstract A new subdivision, the "marginal division" (MrD), was discovered at the caudal border of the striatum and surrounds the rostral edge of the globus pallidus in the rat brain in our previous studies. The neuronal somata of the MrD are mostly fusiform in shape with their long axes lining dorsoventrally. The MrD is more densely filled with substance P (SP)-, Leucine-enkephalin (L-Enk)-, dynorphin B-, neurotensin-, somatostatin- and cholecystokinin (CCK)-immunoreactive fibers and terminal-like structures than the rest of the striatum. The MrD was confirmed in the cat neostriatum as well. The present study intended to explore whether the MrD exists in the monkey neostriatum (putamen) with Nissl, histochemical and immunohistochemical methods. A band of fusiform neurons were obviously identified at the caudomedial edge of the putamen. These neurons lie outside the lateral medullary lamina and indirectly surround the rostrolateral border of the globus pallidus. The abundance of SP-, L-Enk-, neuropeptide Y-, CCK-, dopamine- and serotonin-positive fibers and terminal-like structures with a few positive fusiform neurons accumulating at the caudomedial border of the putamen obviously distinguishes this zone from the rest of neostriatum and globus pallidus. The acetylcholinesterase (AChE) positive and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) containing fusiform neurons are distinctly visualized in the same zone. The morphological figure and the location of these neurons, and the histochemical and immunohistochemical characteristics of this area coincide well with those of the MrD in the rat and cat striatum. This study thus convincingly identifies the existence of the MrD in the monkey neostriatum. It is fairly asserted that the MrD is a universal structure in the mammalian brain. Title: Sphingosine kinase-mediated Ca2+ signalling by G-protein-coupled receptors Meyer zu Heringdorf D, Lass H, Alemany R, Laser KT, Neumann E, Zhang C, Schmidt M, Rauen U, Jakobs KH, van Koppen CJ Ref: EMBO Journal, 17:2830, 1998 : PubMed ESTHER: Meyer_1998_EMBO.J_17_2830 PubMedSearch: Meyer 1998 EMBO.J 17 2830 PubMedID: 9582276 Abstract Formation of inositol 1,4,5-trisphosphate (IP3) by phospholipase C (PLC) with subsequent release of Ca2+ from intracellular stores, is one of the major Ca2+ signalling pathways triggered by G-protein-coupled receptors (GPCRs). However, in a large number of cellular systems, Ca2+ mobilization by GPCRs apparently occurs independently of the PLC-IP3 pathway, mediated by an as yet unknown mechanism. The present study investigated whether sphingosine kinase activation, leading to production of sphingosine-1-phosphate (SPP), is involved in GPCR-mediated Ca2+ signalling as proposed for platelet-derived growth factor and FcepsilonRI antigen receptors. Inhibition of sphingosine kinase by DL-threo-dihydrosphingosine and N,N-dimethylsphingosine markedly inhibited [Ca2+]i increases elicited by m2 and m3 muscarinic acetylcholine receptors (mAChRs) expressed in HEK-293 cells without affecting mAChR-induced PLC stimulation. Activation of mAChRs rapidly and transiently stimulated production of SPP in HEK-293 cells. Finally, intracellular injection of SPP induced a rapid and transient Ca2+ mobilization in HEK-293 cells which was not antagonized by heparin. We conclude that mAChRs utilize the sphingosine kinase-SPP pathway in addition to PLC-IP3 to mediate Ca2+ mobilization. As Ca2+ signalling by various, but not all, GPCRs in different cell types was likewise attenuated by the sphingosine kinase inhibitors, we suggest a general role for sphingosine kinase, besides PLC, in mediation of GPCR-induced Ca2+ signalling. Title: A role for Rho in receptor- and G protein-stimulated phospholipase C. Reduction in phosphatidylinositol 4,5-bisphosphate by Clostridium difficile toxin B Schmidt M, Bienek C, Rumenapp U, Zhang C, Lummen G, Jakobs KH, Just I, Aktories K, Moos M, von Eichel-Streiber C Ref: Naunyn Schmiedebergs Arch Pharmacol, 354:87, 1996 : PubMed ESTHER: Schmidt_1996_Naunyn.Schmiedebergs.Arch.Pharmacol_354_87 PubMedSearch: Schmidt 1996 Naunyn.Schmiedebergs.Arch.Pharmacol 354 87 PubMedID: 8857584 Abstract Receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins) activate phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)-hydrolyzing phospholipase C (PLC) enzymes by activated alpha of free beta gamma subunits of the relevant G proteins. To study whether low molecular weight G proteins of the Rho family are involved in receptor signaling to PLC, we examined the effect of Clostridium difficile toxin B, which glucosylates and thereby inactivates Rho proteins, on the regulation of PLC activity in human embryonic kidney (HEK) cells stably expressing the m3 muscarinic acetylcholine receptor (mAChR) subtype. Toxin B treatment of HEK cells did not affect basal PLC activity, but potently and efficiently inhibited mAChR-stimulated inositol phosphate formation. PLC activation by the endogenously expressed thrombin receptor and by the direct G protein activators, A1F-4 and guanosine 5'-[gamma-thio]triphosphate (GTP gamma S), studied in intact and permeabilized cells, respectively, were also inhibited by toxin B treatment. C3 exoenzyme, which ADP-ribosylates Rho proteins, mimicked the inhibitory effect of toxin B on GTP gamma S-stimulated PLC activity. Finally both toxin B and C3 exoenzyme significantly reduced, by 40 to 50%, the total level of PtdIns(4,5)P2 in HEK cells, without affecting the levels of phosphatidylinositol and phosphatidylinositol 4-phosphate. Accordingly, When PLC activity was measured with exogenous PtdIns(4,5)P2 as enzyme substrate, Ca(2+)- as well as GTP gamma S- or A1F-4-stimulated PLC activities were not altered by prior toxin B treatment. In conclusion, evidence is provided that toxin B and C3 exoenzyme, apparently by inactivating Rho proteins, inhibit G protein-coupled receptor signalling to PLC, most likely by reducing the cellular substrate supply. Title: Muscarinic acetylcholine receptor trafficking in streptolysin O-permeabilized MDCK cells Vogt S, Vogler O, Zhang C, Weller U, Jakobs KH, van Koppen CJ Ref: Naunyn Schmiedebergs Arch Pharmacol, 354:128, 1996 : PubMed ESTHER: Vogt_1996_Naunyn.Schmiedebergs.Arch.Pharmacol_354_128 PubMedSearch: Vogt 1996 Naunyn.Schmiedebergs.Arch.Pharmacol 354 128 PubMedID: 8857589 Abstract We investigated the validity of streptolysin O (SLO)-permeabilized Madin-Darbin canine kidney (MDCK) cells which express muscarinic acetylcholine receptors (mAChRs) coupled to pertussis toxin-sensitive guanine nucleotide-binding proteins (G proteins) for the study of the molecular machinery that regulated mAChR internalization and recycling. Exposure of SLO-permeabilized cells to carbachol-reduced cell surface receptor number by up to 40% without changing total receptor number. The kinetics and maximal extent of receptor internalization as well as the potency of carbachol to induce receptor internalization were almost identical in SLO-permeabilized and non-permeabilized cells. Using this semi-intact cell system, we studied the effect of various agents affecting components potentially involved in receptor trafficking. Internalization was prevented by treatment of the SLO-permeabilized MDCK cells with (i) the stable ATP analogues, adenosine 5'-O-(3-thiotriphosphate) and adenylylimidodiphosphate, to block ATP-dependent processes, and (ii) heparin to block G protein-coupled receptor kinases. Inclusion of the stable GTP analogue, guanosine 5'-O-(3-thiotriphosphate), increased the rate but not the extent of receptor internalization. None of the membrane-impermeant agents affected receptor internalization in intact MDCK cells. This model system also allowed recycling of internalized receptors back to the plasma membrane. After removal of the agonist, cell surface receptor number in SLO-permeabilized cells returned to control values within 90 min with the same kinetics as seen in intact cells. Inclusion of guanosine 5'O-(3-thiotriphosphate) shortened the recovery time. These data suggest that both ATP-dependent kinases including G protein-coupled receptor kinases and G proteins participate in receptor internalization and recycling. In summary, the SLO-permeabilized MDCK cell is a feasible model system for the study of mAChR internalization and recycling and allows manipulation of the intracellular milieu with membrane-impermeable macromolecules. Title: Activation of a high affinity Gi protein-coupled plasma membrane receptor by sphingosine-1-phosphate van Koppen CJ, Meyer zu Heringdorf M, Laser KT, Zhang C, Jakobs KH, Bunemann M, Pott L Ref: Journal of Biological Chemistry, 271:2082, 1996 : PubMed ESTHER: van Koppen_1996_J.Biol.Chem_271_2082 PubMedSearch: van Koppen 1996 J.Biol.Chem 271 2082 PubMedID: 8567663 Abstract Sphingosine-1-phosphate (SPP) has attracted much attention as a possible second messenger controlling cell proliferation and motility and as an intracellular Ca(2+)-releasing agent. Here, we present evidence that SPP activates a G protein-coupled receptor in the plasma membrane of various cells, leading to increase in cytoplasmic Ca2+ concentration ([Ca2+]i), inhibition of adenylyl cyclase, and opening of G protein-regulated potassium channels. In human enbryonic kidney (HEK) cells, SPP potently (EC50, 2 nM) and rapidly increased [Ca2+]i in a pertussis toxin-sensitive manner. Pertussis toxin-sensitive increase in [Ca2+]i was also observed with sphingosylphosphorylcholine (EC50, 460 nM), whereas other sphingolipids, including ceramide-1-phosphate, N-palmitoyl-sphingosine, psychosine, and D-erythro-sphingosine at micromolar concentrations did not or only marginally increased [Ca2+]i. Furthermore, SPP inhibited forskolin-stimulated cAMP accumulation in HEK cells and increased binding of guanosine 5'3-O-(thio) triphosphate to HEK cell membranes. Rapid [Ca2+]i responses were also observed in human transitional bladder carcinoma (J82) cells, monkey COS-1 cells, mouse NIH 3T3 cells, Chinese hamster ovary (CHO-K1) cells, and rat C6 glioma cells, whereas human HL-60 leukemia cells and human erythroleukemia cells failed to respond to SPP. In guinea pig atrial myocytes, SPP activated Gi protein-regulated inwardly rectifying potassium channels. Activation of these channels occurred strictly when SPP was applied at the extracellular face of atrial myocyte plasma membrane as measured in cell-attached and inside-out patch clamp current recordings. We conclude that SPP, in addition to its proposed direct action on intracellular Ca2+ stores, interacts with a high affinity Gi protein-coupled receptor in the plasma membrane of apparently many different cell types. Title: The role of membrane proximal threonine residues conserved among guanine-nucleotide-binding-protein-coupled receptors in internalization of the m4 muscarinic acetylcholine receptor van Koppen CJ, Lenz W, Nunes JP, Zhang C, Schmidt M, Jakobs KH Ref: European Journal of Biochemistry, 234:536, 1995 : PubMed ESTHER: Van Koppen_1995_Eur.J.Biochem_234_536 PubMedSearch: Van Koppen 1995 Eur.J.Biochem 234 536 PubMedID: 8536700 Abstract Many guanine-nucleotide-binding-protein-coupled receptors contain consensus sequences for phosphorylation by cAMP-dependent protein kinase (PKA), often located in the membrane proximal regions critically important for receptor signalling. In the present study, we have evaluated by site-directed mutagenesis the role of the putative PKA phosphorylation sites in the m4 muscarinic acetylcholine receptor (mAChR), i.e. Thr145 in the second cytoplasmic loop and Thr399 in the third cytoplasmic loop, and the influence of PKA on m4 mAChR function and internalization. Antagonist binding was unaltered by any of the mutations studied, while the agonist-binding affinity was either not affected (Thr145 alanine), increased (Thr399 alanine) or decreased (Thr399 serine or aspartic acid). m4 mAChR-mediated inhibition of adenylyl cyclase was unaltered by the mutations, except for an approximately tenfold reduced agonist potency of the Thr399 aspartic acid mutated receptor. Agonist-induced receptor internalization was unaltered with Thr399 serine or aspartic acid mutations of the receptors, but was strongly decreased in its rate and extent upon replacement of Thr399, Thr145 or both of these residues with alanine. These mutational effects could not be reproduced by treatment of wild-type receptor-expressing cells with the PKA inhibitor H-8. Furthermore, maximal stimulation of cellular PKA neither affected receptor internalization nor signalling measured as receptor-mediated Ca2+ mobilization. We conclude that the membrane proximal threonine residues of the m4 mAChR are not required for receptor signalling, but replacement by alanine residues can significantly affect receptor internalization, independently of PKA phosphorylation. Sequence comparisons suggest that threonine residues at corresponding positions may be relevant to internalization of other guanine-nucleotide-binding-protein-coupled receptors. Title: [Effects of arsenic on the offspring development in mice]. [Chinese] Ma L, Zhang C, Liu WJ Ref: Chinese Journal of Preventive Medicine, 28:20, 1994 : PubMed ESTHER: Ma_1994_Zhonghua.Yu.Fang.Yi.Xue.Za.Zhi_28_20 PubMedSearch: Ma 1994 Zhonghua.Yu.Fang.Yi.Xue.Za.Zhi 28 20 PubMedID: 8082454 Abstract Effects of arsenic exposure on offspring development were studied in pregnant mice. The results showed arsenic contents of the body and brain tissue increased and the structure of neural cells in cerebral cortex became abnormal after exposure. The offspring neurobehavioral development appeared retardant and the proportion of their peripheral lymphocytes with alpha-naphthalene acetate enzyme (ANAE) declined in a mice group with exposure to 0.75 mg/kg arsenic, and the offspring body weight gain slowed after weaning, blood cholinesterase activity and serum level of haemolysin declined significantly in a group with 4.50 mg/kg. It indicated arsenic could affect embryonic and offspring development in mice through pregnant exposure. | |||||||
|
