Chen L


Full name : Chen Lin

First name : Lin

Mail : Molecular and Computational Biology, Departments of Biological Sciences and Chemistry, University of Southern California, Los Angeles, California

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Country : USA

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References (208)

Title : Combination of retagliptin and henagliflozin as add-on therapy to metformin in patients with type 2 diabetes inadequately controlled with metformin: A multicentre, randomized, double-blind, active-controlled, phase 3 trial - Wang_2024_Diabetes.Obes.Metab__
Author(s) : Wang W , Guo X , Zhang C , Ning T , Ma G , Huang Y , Jia R , Zhou D , Cao M , Zhang T , Yao L , Yuan J , Chen L , Wang Y , Jiang C , Dong X , Chen M , Gu Q , Zhang L , Fu Y , Pan T , Bi Y , Song W , Xu J , Lu W , Sun X , Ye Z , Zhang D , Peng L , Lin X , Dai W , Wang Q , Yang W
Ref : Diabetes Obes Metab , : , 2024
Abstract : AIM: This study assessed the efficacy and safety of co-administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. METHODS: This multicentre, phase 3 trial consisted of a 24-week, randomized, double-blind, active-controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once-daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co-administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. RESULTS: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (-1.51%) and R100/H10 (-1.54%) groups compared with those receiving the corresponding doses of individual agents (-0.98% for R100, -0.86% for H5 and -0.95% for H10, respectively; p < .0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2-h postprandial glucose were also more pronounced in the co-administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. CONCLUSIONS: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co-administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses.
ESTHER : Wang_2024_Diabetes.Obes.Metab__
PubMedSearch : Wang_2024_Diabetes.Obes.Metab__
PubMedID: 38221859 || 38618970

Title : Pharmacokinetics, Pharmacodynamics, and Safety of Single Dose HSK7653 Tablets in Chinese Subjects with Normal or Impaired Renal Function - Shi_2024_Clin.Pharmacokinet__
Author(s) : Shi D , Chen L , Li G , Wu N , Zhang F , Wang X , Mu N , Chen X , Yang X , Lu J , Lu Y , Wang M , Zhang D
Ref : Clinical Pharmacokinetics , : , 2024
Abstract : OBJECTIVE: HSK7653 is a novel, ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, promising for type 2 diabetes mellitus with a dosing regimen of once every 2 weeks. This trial investigates the pharmacokinetics (PKs), pharmacodynamics (PDs),and safety of HSK7653 in outpatients with normal or impaired renal function. METHODS: This is a multicenter, open-label, nonrandomized, parallel-controlled phase I clinical study that investigates the pharmacokinetic profiles of HSK7653 after a single oral administration in 42 subjects with mild (n = 8), moderate (n = 10), severe renal impairment (n = 10), and end-stage renal disease (without dialysis, n = 5) compared with matched control subjects with normal renal function (n = 9). Safety was evaluated throughout the study, and the pharmacodynamic effects were assessed on the basis of a DPP-4 inhibition rate. RESULTS: HSK7653 exposure levels including the maximum plasma concentration (C(max)), area under the plasma concentration-time curve from zero to last time of quantifiable concentration (AUC(0-t)), and area under the plasma concentration-time curve from zero to infinity (AUC(0-inf)) showed no significant differences related to the severity of renal impairment. Renal clearance (CL(R)) showed a certain downtrend along with the severity of renal impairment. The CL(R) of the group with severe renal impairment and the group with end-stage renal disease were basically similar. The DPP-4 inhibition rate-time curve graph was similar among the renal function groups. All groups had favorable safety, and no serious adverse events occurred. CONCLUSIONS: HSK7653 is a potent oral DPP-4 inhibitor with a long plasma half-life, supporting a dosing regimen of once every 2 weeks. Impaired renal function does not appear to impact the pharmacokinetic and pharmacodynamic properties of HSK7653 after a single administration in Chinese subjects. HSK7653 is also well tolerated without an increase in adverse events with increasing renal impairment. These results indicate that dose adjustment of HSK7653 may not be required in patients with renal impairment. TRIAL REGISTRATION: Identifier: NCT05497297.
ESTHER : Shi_2024_Clin.Pharmacokinet__
PubMedSearch : Shi_2024_Clin.Pharmacokinet__
PubMedID: 38184489

Title : Combinatorial preparation and structural characterization of anthocyanins and aglycones from Purple-heart Radish for evaluation of physicochemical stability and pancreatic lipase inhibitory activity - Yuan_2024_Food.Chem_446_138832
Author(s) : Yuan T , Wang L , Chen L , Zhong J , Lin Y , Wang Y , Lin C , Fan H
Ref : Food Chem , 446 :138832 , 2024
Abstract : In this study, an efficient approach to preparation of different anthocyanins from Purple-heart Radish was developed by combining microwave-assisted extraction (MAE), macroporous resin purification (MRP) and ultrasound-assisted acid hydrolysis (UAAH) for evaluation of physicochemical stability and pancreatic lipase (PL) inhibitory activity. By optimization of MAE, MRP and UAAH processes, the anthocyanins reached the yield of 6.081 +/- 0.106 mg/g, the purity of 78.54 +/- 0.62 % (w/w) and the content of 76.29 +/- 1.31 % (w/w), respectively. With high-resolution UHPLC-Q-Orbitrap/MS, 15 anthocyanins were identified as pelargonins with diverse glucosides and confirmed by pelargonidin standard. By glycosylation, pelargonins exhibited higher stability in different pH, temperature, light, metal ions environments than that of pelargonidin. However, PL inhibitory assay, kinetic analysis and molecular docking demonstrated that pelargonidin had higher PL inhibitory activity than pelargonins even though with similar binding sites and a dose-effect relationship. The above results revealed that the effect of glycosylation and deglycosylation on PL inhibitory activity and physicochemical stability.
ESTHER : Yuan_2024_Food.Chem_446_138832
PubMedSearch : Yuan_2024_Food.Chem_446_138832
PubMedID: 38412808

Title : New Near-Infrared Fluorescence Imaging Platform with Large Stokes Shift for Carboxylesterase 2 Detection in Thyroid Cancer and Inflammatory Diseases Diagnosis - Wang_2024_Anal.Chem__
Author(s) : Wang X , Gao J , Fan C , Gao Y , Yang X , Chen L
Ref : Analytical Chemistry , : , 2024
Abstract : Development of new near-infrared fluorophores is one of the eternal themes in the field of biosensing and biological imaging. In this work, we constructed a novel fluorophore platform MOR by replacing methylindole of hemicyanine fluorophore (CyR) with benzoxazole to acquire better fluorescence characteristics. Based on the platform, a near infrared (NIR) fluorescent probe MOR-CES2 was synthesized for the specific "off-on" response to carboxylesterase 2 (CES2). The probe exhibited excellent properties including near-infrared emission (735 nm), large Stokes shift (105 nm), high sensitivity (LOD, 0.3 ng/mL), and rapid response (15 min). The successful application of MOR-CES2 in biological imaging of CES2 in mice with thyroid cancer and inflammatory bowel disease demonstrated that the probe could identify cancer cells and tissues and sensitively respond to inflammation. The results proved the potency of MOR-CES2 as an efficient imaging tool to assist in the surgical resection of CES2-related tumors.
ESTHER : Wang_2024_Anal.Chem__
PubMedSearch : Wang_2024_Anal.Chem__
PubMedID: 38372636

Title : Biochemical and molecular-level effects of co-exposure to chlorpyrifos and lambda-cyhalothrin on the earthworm (Eisenia fetida) - Wang_2024_Ecotoxicol.Environ.Saf_277_116374
Author(s) : Wang D , Chen L , Yang G , Xu Z , Lv L , Tang T , Wang Y
Ref : Ecotoxicology & Environmental Safety , 277 :116374 , 2024
Abstract : Farmland soil organisms frequently encounter pesticide mixtures presented in their living environment. However, the underlying toxic mechanisms employed by soil animals to cope with such combined pollution have yet to be explored. This investigation aimed to reveal the changes in cellular and mRNA levels under chlorpyrifos (CPF) and lambda-cyhalothrin (LCT) co-exposures in earthworms (Eisenia fetida). Results exhibited that the combination of CPF and LCT triggered an acute synergistic influence on the animals. Most exposures resulted in significant alterations in the activities of total superoxide dismutase (T-SOD), copper/zinc superoxide dismutase (Cu/Zn-SOD), caspase 3, and carboxylesterase (CarE) compared to the basal level. Moreover, when exposed to chemical mixtures, the transcription levels of four genes [heat shock protein 70 (hsp70), gst, sod, and calreticulin (crt)] also displayed more pronounced changes compared with their individual exposures. These changes in determined parameters indicated the occurrence of oxidative stress, cell death, detoxification dysfunction, and endoplasmic reticulum damage after co-exposure to CPF and LCT in E. fetida. The comprehensive examination of mixture toxicities of CPF and LCT at different endpoints would help to understand the overall toxicity they cause to soil invertebrates. The augmented deleterious effect of these pesticides in a mixture suggested that mixture toxicity assessment was necessary for the safety evaluation and application of pesticide mixtures.
ESTHER : Wang_2024_Ecotoxicol.Environ.Saf_277_116374
PubMedSearch : Wang_2024_Ecotoxicol.Environ.Saf_277_116374
PubMedID: 38677072

Title : Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity - Zhang_2024_Sci.Immunol_9_eadh2334
Author(s) : Zhang T , Yu W , Cheng X , Yeung J , Ahumada V , Norris PC , Pearson MJ , Yang X , van Deursen W , Halcovich C , Nassar A , Vesely MD , Zhang Y , Zhang J , Ji L , Flies DB , Liu L , Langermann S , LaRochelle WJ , Humphrey R , Zhao D , Zhang Q , Gu R , Schalper KA , Sanmamed MF , Chen L
Ref : Sci Immunol , 9 :eadh2334 , 2024
Abstract : T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues. PLA2G10 overexpression in immunogenic mouse tumors excluded T cells from infiltration, resulting in resistance to anti-PD-1 immunotherapy. PLA2G10 can hydrolyze phospholipids into small lipid metabolites, thus inhibiting chemokine-mediated T cell mobility. Ablation of PLA2G10's enzymatic activity enhanced T cell infiltration and sensitized PLA2G10-overexpressing tumors to immunotherapies. Our study implicates a role for PLA2G10 in T cell exclusion from tumors and suggests a potential target for cancer immunotherapy.
ESTHER : Zhang_2024_Sci.Immunol_9_eadh2334
PubMedSearch : Zhang_2024_Sci.Immunol_9_eadh2334
PubMedID: 38669316

Title : Tabersonine Induces the Apoptosis of Human Hepatocellular Carcinoma In vitro and In vivo - Li_2024_Anticancer.Agents.Med.Chem__
Author(s) : Li X , Chen L , Deng Y , Zheng Z , Ming Y
Ref : Anticancer Agents Med Chem , : , 2024
Abstract : BACKGROUND: Tabersonine, a natural indole alkaloid derived from Apocynaceae plants, exhibits antiinflammatory and acetylcholinesterase inhibitory activities, among other pharmacological effects. However, its anti-tumor properties and the underlying molecular mechanisms remain underexplored. OBJECTIVE: The present study aims to investigate the anti-tumor effects of tabersonine and its mechanisms in inducing apoptosis in hepatocellular carcinoma. METHODS: The inhibitory effects of tabersonine on the viability and proliferation of liver cancer cells were evaluated using MTT assay and colony formation assay. AO/EB, Hoechst, and Annexin V-FITC/ PI staining techniques were employed to observe cell damage and apoptosis. JC-1 staining was used to detect changes in mitochondrial membrane potential. Western blot analysis was conducted to study the anti-tumor mechanism of tabersonine on liver cancer cells. Additionally, a xenograft model using mice hepatoma HepG2 cells was established to assess the anti-tumor potency of tabersonine in vivo. RESULTS AND DISCUSSION: Our findings revealed that tabersonine significantly inhibited cell viability and proliferation, inducing apoptosis in liver cancer cells. Treatment with tabersonine inhibited Akt phosphorylation, reduced mitochondrial membrane potential, promoted cytochrome c release from mitochondria to the cytoplasm, and increased the ratio of Bax to Bcl-2. These findings suggested that tabersonine induces apoptosis in liver cancer cells through the mitochondrial pathway. Furthermore, tabersonine treatment activated the death receptor pathway of apoptosis. In vivo studies demonstrated that tabersonine significantly inhibited xenograft tumor growth. CONCLUSION: Our study is the first to demonstrate that tabersonine induces apoptosis in HepG2 cells through both mitochondrial and death receptor apoptotic pathways, suggesting its potential as a therapeutic agent candidate for hepatic cancer.
ESTHER : Li_2024_Anticancer.Agents.Med.Chem__
PubMedSearch : Li_2024_Anticancer.Agents.Med.Chem__
PubMedID: 38465429

Title : Design and Synthesis of Dual-Targeting Inhibitors of sEH and HDAC6 for the Treatment of Neuropathic Pain and Lipopolysaccharide-Induced Mortality - Chen_2024_J.Med.Chem__
Author(s) : Chen Y , Sun J , Tong H , Wang J , Cao R , Xu H , Chen L , Morisseau C , Zhang M , Shi Y , Han C , Zhuang J , Jing Y , Liu Z , Hammock BD , Chen G
Ref : Journal of Medicinal Chemistry , : , 2024
Abstract : Epoxyeicosatrienoic acids with anti-inflammatory effects are inactivated by soluble epoxide hydrolase (sEH). Both sEH and histone deacetylase 6 (HDAC6) inhibitors are being developed as neuropathic pain relieving agents. Based on the structural similarity, we designed a new group of compounds with inhibition of both HDAC6 and sEH and obtained compound M9. M9 exhibits selective inhibition of HDAC6 over class I HDACs in cells. M9 shows good microsomal stability, moderate plasma protein binding rate, and oral bioavailability. M9 exhibited a strong analgesic effect in vivo, and its analgesic tolerance was better than gabapentin. M9 improved the survival time of mice treated with lipopolysaccharide (LPS) and reversed the levels of inflammatory factors induced by LPS in mouse plasma. M9 represents the first sEH/HDAC6 dual inhibitors with in vivo antineuropathic pain and anti-inflammation.
ESTHER : Chen_2024_J.Med.Chem__
PubMedSearch : Chen_2024_J.Med.Chem__
PubMedID: 38236416

Title : Evolution-Based Discovery of Polyketide Acylated Valine from a Cytochalasin-Like Gene Cluster in Simplicillium lamelliciola HDN13430 - Wu_2024_J.Nat.Prod__
Author(s) : Wu Z , Wang W , Li J , Ma C , Chen L , Che Q , Zhang G , Zhu T , Li D
Ref : Journal of Natural Products , : , 2024
Abstract : Utilizing a gene evolution-oriented approach for gene cluster mining, a cryptic cytochalasin-like gene cluster (sla) in Antarctic-derived Simplicillium lamelliciola HDN13430 was identified. Compared with the canonical cytochalasin biosynthetic gene clusters (BGCs), the sla gene cluster lacks the key alpha,beta-hydrolase gene. Heterologous expression of the sla gene cluster led to the discovery of a new compound, slamysin (1), characterized by an N-acylated amino acid structure and demonstrating weak anti-Bacillus cereus activity. These findings underscore the potential of genetic evolution in uncovering novel compounds and indicating specific adaptive evolution within specialized habitats.
ESTHER : Wu_2024_J.Nat.Prod__
PubMedSearch : Wu_2024_J.Nat.Prod__
PubMedID: 38447096

Title : Design, Synthesis, and Biological Activity of Donepezil: Aromatic Amine Hybrids as Anti-Alzheimerss Drugs - Wan_2023_ACS.Omega_8_21802
Author(s) : Wan D , Wang FQ , Xie J , Chen L , Zhou XL
Ref : ACS Omega , 8 :21802 , 2023
Abstract : In this study, benzylpiperidine, the active group of donepezil (DNP), was connected with the neurotransmitter phenylethylamine by square amide, in which the fat chain of phenylethylamine was reduced and the benzene rings were substituted. A series of multifunctional hybrid compounds, including DNP-aniline hybrids (1-8), DNP-benzylamine hybrids (9-14), and DNP-phenylethylamine hybrids (15-21) were obtained and their cholinesterase inhibitory activity and neuroprotection of the SH-SY5Y cell line were determined. Results showed that compound 3 exhibited excellent acetylcholinesterase inhibitory activity with an IC(50) value of 4.4 microM, higher than that of positive control DNP and significant neuroprotective effects against H(2)O(2)-induced oxidative damage in SH-SY5Y cells with 80.11% viability rate at 12.5 microM, much higher than that of the model group (viability rate = 53.1%). The mechanism of action of compound 3 was elucidated by molecular docking, reactive oxygen species (ROS), and immunofluorescence analysis. The results suggest that compound 3 could be further explored as a lead compound for the treatment of Alzheimer's disease. In addition, molecular docking research indicated that the square amide group formed strong interactions with the target protein. Based on the above analysis, we believe that square amide could be an interesting construction unit in anti-AD agents.
ESTHER : Wan_2023_ACS.Omega_8_21802
PubMedSearch : Wan_2023_ACS.Omega_8_21802
PubMedID: 37360465

Title : Atomistic insight into the binding mode and self-regulation mechanism of IsPETase towards PET substrates with different polymerization degrees - Chen_2023_Phys.Chem.Chem.Phys_25_18332
Author(s) : Chen L , Fan F , Yang M , Wang L , Bai Y , Qiu S , Lyu C , Huang J
Ref : Phys Chem Chem Phys , 25 :18332 , 2023
Abstract : Poly(ethylene terephthalate) (PET) is one of the most widely used synthetic polyesters, however, its extensive use creates a long-term environmental burden. Unlike traditional recycling methods, biodegradation is a sustainable strategy. The emergence of PETase from Ideonella sakaiensis 201-F6 (IsPETase) has brought great potential for the industrialization of degradable PET. In this work, models of enzyme-substrate complexes with different degrees of polymerization were established to study the binding mode using molecular dynamics simulation. We found that the whole binding site can be further subdivided into three parts, including head, middle and tail binding regions. Most importantly, the presence of the middle region formed by both ends of Ser93 and Ser236 provides a potential possibility for the binding of substrates with different chain lengths, and exerts the self-regulation ability of enzymes to accommodate substrates. Meanwhile, the 'pocket bottom' Arg280 in the tail region echoes the 'pocket mouth' Trp185 in the head region, defining the substrate binding region. This work reveals the self-regulation of IsPETase, as well as the key residues for the substrate binding. The solution to these problems enables us to better understand the function of enzymes and design high-performance degradation enzymes, which is of great significance for industrial application research.
ESTHER : Chen_2023_Phys.Chem.Chem.Phys_25_18332
PubMedSearch : Chen_2023_Phys.Chem.Chem.Phys_25_18332
PubMedID: 37401198

Title : Nanoplasmonic biosensors for multicolor visual analysis of acetylcholinesterase activity and drug inhibitor screening in point-of-care testing - Li_2023_Biosens.Bioelectron_247_115912
Author(s) : Li Y , Chen L , Li CY , Zhang J , Zhao Y , Yang YH , Yang T
Ref : Biosensors & Bioelectronics , 247 :115912 , 2023
Abstract : The monitoring of acetylcholinesterase (AChE) activity and the screening of its inhibitors are significance of the diagnosis and drug therapy of nervous diseases. A metal ions-mediated signal amplification strategy was developed for the highly sensitive and multicolor assay of AChE activity and visually screening its drug inhibitors. After the specific reaction between AChE and acetylthiocholine (ATCh), the hydrolysis product thiocholine (TCh) can directly and decompose the alpha-FeOOH nanorods (NRs) to release amounts of Fe(2+), which was regarded as Fenton reagent to efficiently catalyze H(2)O(2) to produce .OH. Then, the as-formed .OH can further largely shorten the gold nanobipyramids (Au NBPs), generating a series of palpable color variations. The linear range for AChE activity was 0.01-500.0 U/L with the limit of detection as low as 0.0074 U/L. The vivid visual effects could be easily distinguished for the multicolor assay of AChE activity by naked eye in visible light. To achieve the point-of-care testing, Au NBPs were further assembled on polymeric electrospun nanofibrous films (ENFs) surface as test strips for the easy-to-use test of AChE activity by RGB values with a smartphone. Fascinatingly, this proposed strategy can be used for the visual screening AChE inhibitors or non-inhibitors. Comparing with the clinical drugs (rivastigmine tartrate, and donepezil), some natural alkaloids such as evodiamine, caffeine, camptothecin, and berberine hydrochloride were selected as inhibitor modes to confirm the drug screening capability of this method. This proposed strategy may have great potential in the other disease-related enzymatic biomarkers assay and the rapid screening of drug therapy.
ESTHER : Li_2023_Biosens.Bioelectron_247_115912
PubMedSearch : Li_2023_Biosens.Bioelectron_247_115912
PubMedID: 38096721

Title : Response Surface Optimization of Extraction Conditions for the Active Components with High Acetylcholinesterase Inhibitory Activity and Identification of Key Metabolites from Acer truncatum Seed Oil Residue - Meng_2023_Foods_12_
Author(s) : Meng R , Ou K , Chen L , Jiao Y , Jiang F , Gu R
Ref : Foods , 12 : , 2023
Abstract : The State Council of China has called for the comprehensive development and utilization of Acer truncatum resources. However, research on one of its by-products, namely seed oil residue (ASR), from seed oil extraction is seriously insufficient, resulting in a waste of these precious resources. We aimed to optimize the conditions of ultrasound-assisted extraction (UAE) using a response surface methodology to obtain high acetylcholinesterase (AChE) inhibitory components from ASR and to tentatively identify the active metabolites in ASR using non-targeted metabolomics. Based on the results of the independent variables test, the interaction effects of three key extracting variables, including methanol concentration, ultrasonic time, and material-to-liquid ratio, were further investigated using the Box-Behnken design (BBD) to obtain prior active components with high AChE inhibitory activity. UPLC-QTOF-MS combined with a multivariate method was used to analyze the metabolites in ASR and investigate the causes of activity differences. Based on the current study, the optimal conditions for UAE were as follows: methanol concentration of 85.06%, ultrasonic time of 39.1 min, and material-to-liquid ratio of 1.06:10 (g/mL). Under these optimal conditions, the obtained extracts show strong inhibitions against AChE with half maximal inhibitory concentration (IC(50)) values ranging from 0.375 to 0.459 microg/mL according to an Ellman's method evaluation. Furthermore, 55 metabolites were identified from the ASR extracted using methanol in different concentrations, and 9 biomarkers were subsequently identified as potential compounds responsible for the observed AChE inhibition. The active extracts have potential to be used for the development of functional foods with positive effects on Alzheimer's disease owing to their high AChE inhibition activity. Altogether, this study provides insights into promoting the comprehensive utilization of A. truncatum resources.
ESTHER : Meng_2023_Foods_12_
PubMedSearch : Meng_2023_Foods_12_
PubMedID: 37174291

Title : Soluble polysaccharides decrease inhibitory activity of banana condensed tannins against porcine pancreatic lipase - Pu_2023_Food.Chem_418_136013
Author(s) : Pu Y , Chen L , He X , Cao J , Jiang W
Ref : Food Chem , 418 :136013 , 2023
Abstract : The inhibition of soluble polysaccharides (SPs) (arabic gum, dextran and pectin from citrus) on the binding between banana condensed tannins (BCTs) and pancreatic lipase (PL) was studied from variant aspects. Molecular docking simulations predicted that BCTs strongly bound SPs and PL through non-covalent interactions. The experimental results showed that SPs reduced the inhibition of BCTs on PL, and the IC(50) value increased. However, the addition of SPs did not change the inhibitory type of BCTs on PL, which all were non-competitive inhibition. BCTs quenched PL fluorescence through static quenching mechanism and changed the secondary structure of PL. The addition of SPs alleviated the trending. The effect of SPs on the binding of BCTs-PL was mainly due to the strong non-covalent interaction between SPs and BCTs. This study emphasized that attention should be paid to the counteracting effects of polysaccharides and polyphenols in dietary intake to maximize their respective roles.
ESTHER : Pu_2023_Food.Chem_418_136013
PubMedSearch : Pu_2023_Food.Chem_418_136013
PubMedID: 36989646

Title : Polygoni Multiflori Radix Praeparata and Acori Tatarinowii Rhizoma ameliorate scopolamine-induced cognitive impairment by regulating the cholinergic and synaptic associated proteins - Xie_2023_J.Ethnopharmacol_311_116400
Author(s) : Xie Y , Liu L , Zheng J , Shi K , Ai W , Zhang X , Wang P , Lan Z , Chen L
Ref : J Ethnopharmacol , 311 :116400 , 2023
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: The combination of Polygoni Multiflori Radix Praeparata (PMRP) and Acori Tatarinowii Rhizoma (ATR) is often used in traditional Chinese medicine to prevent and treat Alzheimer's disease (AD). However, it is not clear whether the effects and mechanisms of the decoction prepared by traditional decocting method (PA) is different from that prepared by modern decocting method (P + A). AIM OF THE STUDY: The present study aimed to investigate the differences in the protective effects of PA and P + A on scopolamine induced cognitive impairment, and to explore its potential mechanism. MATERIALS AND METHODS: To assess the protective effect of PA and P + A on cognitive dysfunction, the mice were orally administrated with PA (1.56, 6.24 g kg(-1)day(-1)) and P + A (1.56, 6.24 g kg(-1)day(-1)) for 26 days before co-treatment with scopolamine (4 mg kg(-1)day(-1), i.p.). The learning and memory abilities of mice were examined by Morris water maze test, and the expressions of proteins related to cholinergic system and synaptic function were detected by the methods of ELISA, real-time PCR and Western blotting. Then, molecular docking technique was used to verify the effect of active compounds in plasma after PA administration on Acetylcholinesterase (AChE) protein. Finally, the Ellman method was used to evaluate the effects of different concentrations of PA, P + A (1 microg/mL-100 mg/mL) and the compounds (1-100 microM) on AChE activity in vitro. RESULTS: On one hand, in the scopolamine-induced cognitive impairment mouse model, both of PA and P + A could improve the cognitive impairment, while the effect of PA on cognitive amelioration was better than that of P + A. Moreover, PA regulated the cholinergic and synaptic functions by enhancing the concentration of acetylcholine (ACh), the mRNA levels of CHT1, Syn, GAP-43 and PSD-95, and the related proteins (CHT1, VACHT, Syn, GAP-43 and PSD-95), and significantly inhibiting the expression of AChE protein. Meanwhile, P + A only up-regulated the mRNA levels of GAP-43 and PSD-95, increased the expressions of CHT1, VACHT, Syn, GAP-43 and PSD-95 proteins, and inhibited the expression of AChE protein. On the other hand, the in vitro study showed that some compounds including emodin-8-o-beta-d-Glucopyranoside, THSG and alpha-Asarone inhibited AChE protein activity with the IC(50) values 3.65 microM, 5.42 microM and 9.43 microM, respectively. CONCLUSIONS: These findings demonstrate that both of PA and P + A can ameliorate the cognitive deficits by enhancing cholinergic and synaptic related proteins, while PA has the stronger improvement effect on the cholinergic function, which may be attributed to the compounds including THSG, emodin, emodin-8-O-beta-D-glucopyranoside and alpha-asarone. The present study indicated that PA has more therapeutic potential in the treatment of neurodegenerative diseases such as AD. The results provide the experimental basis for the clinical use of PA.
ESTHER : Xie_2023_J.Ethnopharmacol_311_116400
PubMedSearch : Xie_2023_J.Ethnopharmacol_311_116400
PubMedID: 37003402

Title : Rutin hydrate relieves neuroinflammation in zebrafish models: Involvement of NF-kB pathway as a central network - Hu_2023_Fish.Shellfish.Immunol_141_109062
Author(s) : Hu Y , Jia K , Zhou Y , Chen L , Wang F , Yi X , Huang Y , Ge Y , Chen X , Liao D , Peng Y , Meng Y , Liu Y , Luo Q , Cheng B , Zhao Y , Lu H , Yuan W
Ref : Fish Shellfish Immunol , 141 :109062 , 2023
Abstract : Neuroinflammation is prevalent in multiple brain diseases and may also lead to dementia, cognitive impairment, and impaired spatial memory function associated with neurodegenerative diseases. A neuroprotective and antioxidant flavonoid, rutin hydrate (RH), was evaluated for the anti-neuroinflammatory activity mediated by copper sulfate (CuSO(4)) solution and lipopolysaccharide (LPS) in zebrafish. The results showed that 100 mg/L RH significantly reduced the ratio of neutrophil mobility in caudal hematopoietic tissue (CHT) region caused by CuSO(4) and the number of neutrophils co-localized with facial peripheral nerves. In the LPS model, RH co-injection significantly diminished neutrophil and macrophage migration. Therefore, RH exhibited a significant rescue effect on both models. In addition, RH treatment remarkably reduced the effects of neuroinflammation on the locomotor ability, expression levels of genes associated with behavioral disorders, and acetylcholinesterase (AChE) activity. Furthermore, network pharmacology techniques were employed to investigate the potential mechanisms, and the associated genes and enzyme activities were validated in order to elucidate the underlying mechanisms. Network pharmacological analysis and zebrafish model indicated that RH regulated the expressions of NF-kappaB pathway-related targets (Toll-like receptor 9 (tlr9), nuclear factor kappa B subunit 1 (nfkb1), RELA proto-oncogene (RelA), nitric oxide synthase 2a, inducible (nos2a), tumour necrosis factor alpha-like (tnfalpha), interleukin 6 (il6), interleukin 1beta (il1beta), chemokine 8 (cxcl8), and macrophage migration inhibitory factor (mif)) as well as six key factors (arachidonic acid 4 alpha-lipoxygenase (alox4a), arachidonate 5-lipoxygenase a (alox5), prion protein a (prnpa), integrin, beta 2 (itgb2), catalase (CAT), and alkaline phosphatase (ALP) enzymes). Through this study, a thorough understanding of the mechanism underlying the therapeutic effects of RH in neuroinflammation has been achieved, thereby establishing a solid foundation for further research on the potential therapeutic applications of RH in neuroinflammatory disorders.
ESTHER : Hu_2023_Fish.Shellfish.Immunol_141_109062
PubMedSearch : Hu_2023_Fish.Shellfish.Immunol_141_109062
PubMedID: 37678480

Title : Clinical and genetic characteristics of CEL-MODY (MODY8): a literature review and screening in Chinese individuals diagnosed with early-onset type 2 diabetes - Sun_2023_Endocrine__
Author(s) : Sun S , Gong S , Li M , Wang X , Wang F , Cai X , Liu W , Luo Y , Zhang S , Zhang R , Zhou L , Zhu Y , Ma Y , Ren Q , Zhang X , Chen J , Chen L , Wu J , Gao L , Zhou X , Li Y , Zhong L , Han X , Ji L
Ref : Endocrine , : , 2023
Abstract : OBJECTIVE: CEL-related maturity-onset diabetes of the young (CEL-MODY, MODY8) is a special type of monogenetic diabetes caused by mutations in the carboxyl-ester lipase (CEL) gene. This study aimed to summarize the genetic and clinical characteristics of CEL-MODY patients and to determine the prevalence of the disease among Chinese patients with early-onset type 2 diabetes (EOD). METHODS: We systematically reviewed the literature associated with CEL-MODY in PubMed, Embase, Web of Science, China National Knowledge Infrastructure and Wanfang Data to analyze the features of patients with CEL-MODY. We screened and evaluated rare variants of the CEL gene in a cohort of 679 Chinese patients with EOD to estimate the prevalence of CEL-MODY in China. RESULTS: In total, 21 individuals reported in previous studies were diagnosed with CEL-MODY based on the combination of diabetes and pancreatic exocrine dysfunction as well as frameshift mutations in exon 11 of the CEL gene. CEL-MODY patients were nonobese and presented with exocrine pancreatic affection (e.g., chronic pancreatitis, low fecal elastase levels, pancreas atrophy and lipomatosis) followed by insulin-dependent diabetes. No carriers of CEL missense mutations were reported with exocrine pancreatic dysfunction. Sequencing of CEL in Chinese EOD patients led to the identification of the variant p.Val736Cysfs*22 in two patients. However, these patients could not be diagnosed with CEL-MODY because there were no signs that the exocrine pancreas was afflicted. CONCLUSION: CEL-MODY is a very rare disease caused by frameshift mutations affecting the proximal VNTR segments of the CEL gene. Signs of exocrine pancreatic dysfunction provide diagnostic clues for CEL-MODY, and genetic testing is vital for proper diagnosis. Further research in larger cohorts is needed to investigate the characteristics and prevalence of CEL-MODY in the Chinese population.
ESTHER : Sun_2023_Endocrine__
PubMedSearch : Sun_2023_Endocrine__
PubMedID: 37726640

Title : Degradation of poly(butylene adipate-co-terephthalate) films by Thermobifida fusca FXJ-1 isolated from compost - Jia_2023_J.Hazard.Mater_441_129958
Author(s) : Jia X , Zhao K , Zhao J , Lin C , Zhang H , Chen L , Chen J , Fang Y
Ref : J Hazard Mater , 441 :129958 , 2023
Abstract : In recent years, Poly(butylene adipate-co-terephthalate) (PBAT) films were wildly used due to its biodegradable properties. However, there are few reports of strains that can high efficiently degrade PBAT. Thermobifida fusca FXJ-1, a thermophilic actinomycete, was screened and identified from compost. FXJ-1 can efficiently degrade PBAT at 55C in MSM medium. The degradation rates of the pure PBAT film (PF), PBAT film used for mulching on agricultural fields (PAF), and PBAT-PLA-ST film (PPSF) were 82.871.01%, 87.832.00% and 52.530.54%, respectively, after nine days of incubation in MSM medium. Cracking areas were monitored uniformly distributed on the surfaces of three kinds of PBAT-based films after treatment with FXJ-1 using scanning electron microscopy. The LC-MS results showed that PBAT might be degraded into adipic acid, terephthalic acid, butylene adipate, butylene terephthalate and butylene adipate-co-terephthalate, and these products are involved in the cleavage of ester bonds. We also found that amylase produced by FXJ-1 played an important role in the degradation of PPSF. FXJ-1 also showed an efficient PBAT-based films degradation ability in simulating compost environment, which implied its potential application in PBAT and starch-based film degradation by industrial composting.
ESTHER : Jia_2023_J.Hazard.Mater_441_129958
PubMedSearch : Jia_2023_J.Hazard.Mater_441_129958
PubMedID: 36122523

Title : Extracellular Macrophage Migration Inhibitory Factor (MIF) Downregulates Adipose Hormone-Sensitive Lipase (HSL) and Contributes to Obesity - Chen_2023_Mol.Metab__101834
Author(s) : Chen L , Li L , Cui D , Huang Y , Tong H , Zabihi H , Wang S , Qi Y , Lakowski T , Leng L , Liu S , Wu H , Young LH , Bucala R , Qi D
Ref : Mol Metab , :101834 , 2023
Abstract : Attenuation of adipose hormone sensitive lipase (HSL) may impair lipolysis and exacerbate obesity. We investigate the role of cytokine, macrophage migration inhibitory factor (MIF) in regulating adipose HSL and adipocyte hypertrophy. Extracellular MIF released from adipocytes downregulates HSL in an autocrine fashion, by activating the AMPK/JNK signaling pathway upon binding to its membrane receptor, CD74. WT mice fed high fat diet (HFD), as well as mice overexpressing MIF, both had high circulating MIF levels and showed suppression of HSL during the development of obesity. Blocking the extracellular action of MIF by a neutralizing MIF antibody significantly reduced obesity in HFD mice. Interestingly, intracellular MIF binds with Csn5 and JNK, which leads to an opposing effect to inhibit JNK phosphorylation. With global MIF deletion, adipocyte JNK phosphorylation increased, resulting in decreased HSL expression, suggesting that the loss of MIF's intracellular inhibitory action on JNK was dominant in Mif(-/-) mice. Adipose tissue from Mif(-/-) mice also exhibited higher Akt and lower PKA phosphorylation following HFD feeding compared with WT, which may contribute to the downregulation of HSL activation during more severe obesity. Both intracellular and extracellular MIF have opposing effects to regulate HSL, but extracellular actions predominate to downregulate HSL and exacerbate the development of obesity during HFD.
ESTHER : Chen_2023_Mol.Metab__101834
PubMedSearch : Chen_2023_Mol.Metab__101834
PubMedID: 37935315

Title : Design, synthesis, and biological evaluation studies of novel carboxylesterase 2 inhibitors for the treatment of irinotecan-induced delayed diarrhea - Yang_2023_Bioorg.Chem_138_106625
Author(s) : Yang Z , Cao Z , Wang W , Chen Y , Huang W , Jiao S , Chen S , Chen L , Liu Y , Mao J , Zhang L , Li Z
Ref : Bioorg Chem , 138 :106625 , 2023
Abstract : Human carboxylesterase 2 (hCES2A), one of the most important serine hydrolases distributed in the small intestine and colon, plays a crucial role in the hydrolysis of various prodrugs and esters. Accumulating evidence has demonstrated that the inhibition of hCES2A effectively alleviate the side effects induced by some hCES2A-substrate drugs, including delayed diarrhea caused by the anticancer drug irinotecan. Nonetheless, there is a scarcity of selective and effective inhibitors that are suitable for irinotecan-induced delayed diarrhea. Following screening of the in-house library, the lead compound 01 was identified with potent inhibition on hCES2A, which was further optimized to obtain LK-44 with potent inhibitory activity (IC(50) = 5.02 +/- 0.67 microM) and high selectivity on hCES2A. Molecular docking and molecular dynamics simulations indicated that LK-44 can formed stable hydrogen bonds with amino acids surrounding the active cavity of hCES2A. The results of inhibition kinetics studies unveiled that LK-44 inhibited hCES2A-mediated FD hydrolysis in a mixed inhibition manner, with a K(i) value of 5.28 microM. Notably, LK-44 exhibited low toxicity towards HepG2 cells according to the MTT assay. Importantly, in vivo studies showed that LK-44 significantly reduced the side effects of irinotecan-induced diarrhea. These findings suggested that LK-44 is a potent inhibitor of hCES2A with high selectivity against hCES1A, which has potential as a lead compound for the development of more effective hCES2A inhibitors to mitigate irinotecan-induced delayed diarrhea.
ESTHER : Yang_2023_Bioorg.Chem_138_106625
PubMedSearch : Yang_2023_Bioorg.Chem_138_106625
PubMedID: 37300962
Gene_locus related to this paper: human-CES2

Title : Screening of Acetylcholinesterase Inhibitors by Capillary Electrophoresis with Oriented-Immobilized Enzyme Microreactors Based on Gold Nanoparticles - Zhang_2023_Molecules_29_
Author(s) : Zhang J , Li Y , Chen L , Zheng Z , Liu C
Ref : Molecules , 29 : , 2023
Abstract : A facial and efficient method for the screening of acetylcholinesterase (AChE) inhibitors by capillary electrophoresis was developed. Based on the specific affinity of concanavalin A (Con A) for binding to the glycosyl group of AChE, enzyme molecules were oriented-immobilized on the surface of gold nanoparticles (AuNPs@Con A@AChE). Then, these modified nanoparticles were bounded to the capillary inlet (about 1.0 cm) by electrostatic self-assembly to obtain the oriented-immobilized enzyme microreactor (OIMER). Compared to an IMER with a free enzyme, the peak area of the product obtained by the OIMER increased by 52.6%. The Michaelis-Menten constant (K(m)) was as low as (0.061 +/- 0.003) mmol/L. The method exhibits good repeatability with a relative standard deviation (RSD) of 1.3% for 100 consecutive runs. The system was successfully applied to detect the IC(50) values of donepezil and four components from Chinese medicinal plants. This work demonstrates the potential of this method as a low cost, simple, and accurate screening method for other enzyme inhibitors.
ESTHER : Zhang_2023_Molecules_29_
PubMedSearch : Zhang_2023_Molecules_29_
PubMedID: 38202701

Title : Structure-Directed Discovery of Potent Soluble Epoxide Hydrolase Inhibitors for the Treatment of Inflammatory Diseases - Chen_2023_J.Med.Chem__
Author(s) : Chen Y , Chen L , Xu H , Cao R , Morisseau C , Zhang M , Shi Y , Hammock BD , Wang J , Zhuang J , Liu Z , Chen G
Ref : Journal of Medicinal Chemistry , : , 2023
Abstract : Soluble epoxide hydrolase (sEH) has been identified as an attractive target for anti-inflammatory drug design in recent years. Picomolar level compound G1 against sEH was obtained by introducing the hydrophilic group homopiperazine and hydrophobic fragment propionyl onto the structure of lead compound A. G1 showed good microsomal stability, a moderate plasma protein binding rate, and good oral bioavailability and was well tolerated in rats. G1 has significant analgesic effects on CFA-induced AIA mice, ameliorated the pancreatic injury in acute pancreatitis induced by l-arginine, reversed pancreatic injury, edema, and neutrophil infiltration, and increased the survival time of C57BL/6 mice in a lipopolysaccharide (LPS)-induced sepsis model. Moreover the expression levels of sEH, COX-2, NOS-2, vascular cell adhesion molecule (VCAM), IL-6, MCP-5, and tumor necrosis factor alpha (TNF-alpha) were measured by Western blot or enzyme-linked immunosorbent assay (ELISA), with varying degrees of decrease. These results suggested that G1 is a drug candidate worthy of further evaluation for the treatment of inflammation-induced diseases such as arthritis, acute pancreatitis, and sepsis.
ESTHER : Chen_2023_J.Med.Chem__
PubMedSearch : Chen_2023_J.Med.Chem__
PubMedID: 36689364

Title : Identification of the first selective bioluminescent probe for real-time monitoring of carboxylesterase 2 in vitro and in vivo - Chen_2023_Analyst__
Author(s) : Chen Z , Yu J , Sun K , Song J , Chen L , Jiang Y , Wang Z , Chen Y , Zhao T , Miao Z , Huang T , Chen M , Zhao Y , Hai A , Qi Q , Feng P , Li M , Ke B
Ref : Analyst , : , 2023
Abstract : Carboxylesterase (CES), a main hydrolysis enzyme family in the human body, plays a crucial role in drug metabolism. Among them, CES1 and CES2 are the primary subtypes, and each exhibits distinct distribution and functions. However, convenient and non-invasive methods for distinguishing them and the real-time monitoring of CES2 are relatively rare, hindering the further understanding of physiological functions and underlying mechanisms. In this study, we have designed, synthesized, and evaluated the first selective bioluminescent probe (CBP 1) for CES2 with high sensitivity, high specificity and rapid reactivity. This probe offers a promising approach for the real-time detection of CES2 and its dynamic fluctuations both in vitro and in vivo.
ESTHER : Chen_2023_Analyst__
PubMedSearch : Chen_2023_Analyst__
PubMedID: 36661088 || 38078792

Title : Screening and identification of lipase inhibitors extracted from Dioscorea nipponica Makino by UV-vis and HPLC coupled to UPLC-Q-TOF-MS\/MS - Jin_2023_Int.J.Biol.Macromol__123427
Author(s) : Jin P , Chen L , Zhong J , Yuan T , Gan L , Huang J , Wang L , Fan H , Lin C
Ref : Int J Biol Macromol , :123427 , 2023
Abstract : Dioscoreae nipponica Makino (D. nipponica) as the rhizome of dioscoreaceae rich in steroidal saponins, have been reported to have the hypolipidemic effects etc. However, it is still unclear which exact active components are primary responsible for the beneficial effects. This study was conducted to fish out the lipase inhibitors from D. nipponica, and evaluate the inhibitory activity on porcine pancreatic lipase (PPL) through in vitro kinetic assay using p-nitrophenyl palmitate as substrate. Accordingly, the ethanolic extract was subjected to D101 macroporous resin purification for spectrophotometric screening, high performance liquid chromatography (HPLC) separation and structural characterization by ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Through orlistat validation, the PPL inhibitory activity and IC(50) value of the extract were respectively 68.34 +/- 1.47 % and 107.05 microg/mL under the optimized inhibition conditions. From 6 steroidal saponins identified, the inhibitory components named the protodioscin, protogracillin, dioscin and gracillin were fished out by grouping separation and HPLC analysis. Furthermore, dioscin and gracillin with the parent structure of diogenin were confirmed as the major inhibitors by virtue of stability tests based on transformation of protodioscin and protogracillin. Finally, the inhibitory mechanism of the major inhibitors toward PPL was further clarified by kinetic analysis and molecular docking analysis. The proposed method not only revealed the PPL inhibitory components in D. nipponica, but also provided an effective approach to hierarchical screening of PPL inhibitors from natural plants.
ESTHER : Jin_2023_Int.J.Biol.Macromol__123427
PubMedSearch : Jin_2023_Int.J.Biol.Macromol__123427
PubMedID: 36706882

Title : TPPU inhibits inflammation-induced excessive autophagy to restore the osteogenic differentiation potential of stem cells and improves alveolar ridge preservation - Dang_2023_Sci.Rep_13_1574
Author(s) : Dang H , Chen W , Chen L , Huo X , Wang F
Ref : Sci Rep , 13 :1574 , 2023
Abstract : Inflammation-induced autophagy is a double-edged sword. Dysfunction of autophagy impairs the differentiation capacity of mesenchymal stem cells and enhances inflammation-induced bone loss. Tooth extraction with periodontal and/or endodontic lesions exacerbates horizontal and vertical resorption of alveolar bone during the healing period. Alveolar socket preservation (ASP) procedure following tooth extraction has important clinical implications for future prosthodontic treatments. Studies have shown that epoxyeicosatrienoic acids (EETs) have significant anti-inflammatory effects and participate in autophagy. However, whether EETs can minimize alveolar bone resorption and contribute to ASP by regulating autophagy levels under inflammatory conditions remain elusive. Here, we figured out that LPS-induced inflammatory conditions increased the inflammatory cytokine and inhibited osteogenic differentiation of human dental pulp stem cells (hDPSCs), and led to excessive autophagy of hDPSCs. Moreover, we identified that increased EETs levels using TPPU, a soluble epoxide hydrolase inhibitor, reversed these negative outcomes. We further demonstrated the potential of TPPU to promote early healing of extraction sockets and ASP, and speculated that it was related to autophagy. Taken together, these results suggest that targeting inhibition of soluble epoxide hydrolase using TPPU plays a protective role in the differentiation and autophagy of mesenchymal stem cells and provides potential feasibility for applying TPPU for ASP, especially under inflammatory conditions.
ESTHER : Dang_2023_Sci.Rep_13_1574
PubMedSearch : Dang_2023_Sci.Rep_13_1574
PubMedID: 36709403

Title : Discovery of novel carboxylesterase 2 inhibitors for the treatment of delayed diarrhea and ulcerative colitis - Cao_2023_Biochem.Pharmacol__115742
Author(s) : Cao Z , Liu Y , Chen S , Wang W , Yang Z , Chen Y , Jiao S , Huang W , Chen L , Sun L , Li Z , Zhang L
Ref : Biochemical Pharmacology , :115742 , 2023
Abstract : Human carboxylesterase 2 (hCES2) is an enzyme that metabolizes irinotecan to SN-38, a toxic metabolite considered a significant source of side effects (lethal delayed diarrhea). The hCES2 inhibitors could block the hydrolysis of irinotecan in the intestine and thus reduce the exposure of intestinal SN-38, which may alleviate irinotecan-associated diarrhea. However, existing hCES2 inhibitors (except loperamide) are not used in clinical applications due to lack of validity or acceptable safety. Therefore, developing more effective and safer drugs for treating delayed diarrhea is urgently needed. This study identified a lead compound 1 with a novel scaffold by high-throughput screening in our in-house library. After a comprehensive structure-activity relationship study, the optimal compound 24 was discovered as an efficient and highly selective hCES2 inhibitor (hCES2: IC(50) = 6.72 microM; hCES1: IC(50) > 100 microM). Further enzyme kinetics study indicated that compound 24 is a reversible inhibitor of hCES2 with competitive inhibition mode (Ki = 6.28 microM). The cell experiments showed that compound 24 could reduce the level of hCES2 in living cells (IC(50) = 6.54 microM). The modeling study suggested that compound 24 fitted very well with the binding pocket of hCES2 by forming multiple interactions. Notably, compound 24 can effectively treat irinotecan-induced delayed diarrhea and DSS-induced ulcerative colitis, and its safety has also been verified in subtoxic studies. Based on the overall pharmacological and preliminary safety profiles, compound 24 is worthy of further evaluation as a novel agent for irinotecan-induced delayed diarrhea.
ESTHER : Cao_2023_Biochem.Pharmacol__115742
PubMedSearch : Cao_2023_Biochem.Pharmacol__115742
PubMedID: 37567318

Title : Effects of Methyl Jasmonate Fumigation on the Growth and Detoxification Ability of Spodoptera litura to Xanthotoxin - Chen_2023_Insects_14_
Author(s) : Chen L , Song J , Wang J , Ye M , Deng Q , Wu X , Ren B
Ref : Insects , 14 : , 2023
Abstract : Methyl jasmonate (MeJA) is a volatile substance derived from jasmonic acid (JA), and it responds to interbiotic and abiotic stresses by participating in interplant communication. Despite its function in interplant communication, the specific role of MeJA in insect defense responses is poorly understood. In this study, we found that carboxylesterase (CarE) activities, glutathione-S-transferase (GSTs) activities, and cytochrome mono-oxygenases (P450s) content increased more after the feeding of diets containing xanthotoxin, while larvae exposed to MeJA fumigation also showed higher enzyme activity in a dose-dependent manner: lower and medium concentrations of MeJA induced higher detoxification enzyme activities than higher concentrations of MeJA. Moreover, MeJA improved the growth of larvae fed on the control diet without toxins and diets with lower concentrations of xanthotoxin (0.05%); however, MeJA could not protect the larvae against higher concentrations of xanthotoxin (0.1%, 0.2%). In summary, we demonstrated that MeJA is effective at inducing S. litura defense response, but the enhanced detoxifying ability could not overcome the strong toxins.
ESTHER : Chen_2023_Insects_14_
PubMedSearch : Chen_2023_Insects_14_
PubMedID: 36835714

Title : Detecting the combined toxicity of 18 binary and 24 ternary pesticide combinations to carboxylesterase based on fluorescence probe technology - Zhu_2022_J.Environ.Sci.Health.B__1
Author(s) : Zhu X , Chen L , Liu T , He S , Zhao X , Tian Y , Fang Y , Cui J
Ref : J Environ Sci Health B , :1 , 2022
Abstract : A rapid test method for the determination of pesticide toxicity was established by using carboxylesterase (CES) and fluorescence probe ACE-NH based on the principle of enzyme inhibition, and this method was applied to detect the combined toxicity of 18 binary and 24 ternary pesticide combinations commonly used for fruits and vegetables to CES. The results show that chlorpyrifos + carbendazim, carbofuran + carbendazim, imidacloprid + carbendazim, imidacloprid + dimethomorph, dimethoate + dimethomorph, prochloraz + carbendazim and imidacloprid + acetamiprid + carbendazim had synergistic effects under three concentration gradients, it indicated that most binary combinations containing carbendazim or imidacloprid had synergistic effects. Based on structure-activity relationship between pesticides and CES, pesticides with phosphate ester bonds had great toxicity to CES, or though they have no toxicity to CES alone, they showed a strong synergistic effect when mixed with other pesticides. Pesticides with amide or ester bond had medium toxicity and little synergistic effect. Pesticides with urea, carbamate or nitrite nitrogen group had little or no toxicity, while there was a strong synergistic effect after mixing with other pesticides. The test method and results in this study can provide scientific basis for risk assessment of cumulative exposure to mixed pesticide residues.
ESTHER : Zhu_2022_J.Environ.Sci.Health.B__1
PubMedSearch : Zhu_2022_J.Environ.Sci.Health.B__1
PubMedID: 35287560

Title : Nanoporous ZIF-8 Microparticles as Acetylcholinesterase and Alkaline Phosphatase Mimics for the Selective and Sensitive Detection of Ascorbic Acid Oxidase and Copper Ions - Chen_2022_Biosensors.(Basel)_12_
Author(s) : Chen GY , Yin SJ , Chen L , Zhou X , Yang FQ
Ref : Biosensors (Basel) , 12 : , 2022
Abstract : In this study, the alkaline phosphatase (ALP)-like activity of zeolitic-imidazolate framework-8 (ZIF-8) is reported for the first time. Then, colorimetric sensors for the ascorbic acid oxidase (AAO) and copper ion (Cu(2+)) detection were developed based on the acetylcholinesterase (AChE)- and ALP-like activities of ZIF-8. The ZIF-8 has good mimetic enzyme activity and exhibits high affinity to the substrates. Its AChE- and ALP-like activities also have good reusability and storage stability. Good linear dependences are obtained in the range of 1.3-250.0 microM (AChE-like activity-based) and 4.5-454.5 microM (ALP-like activity based) for Cu(2+) detection. Furthermore, good linear dependence is also obtained based on the ALP-like activity of ZIF-8 for AAO detection in the range of 2.3-454.5 U/L. Their limits of detection (LODs) are calculated to be 0.7 microM, 2.8 microM, and 1.8 U/L, respectively. Finally, the sample spiked recoveries of Cu(2+) in tap water, Cu(2+), and AAO in human serum and rabbit plasma were measured, and the results are in the range of 80.0-119.3%. In short, the preparation of ZIF-8 is simple, environmentally friendly, and harmless, and can realize highly selective detection of AAO and Cu(2+) in an efficient and fast process.
ESTHER : Chen_2022_Biosensors.(Basel)_12_
PubMedSearch : Chen_2022_Biosensors.(Basel)_12_
PubMedID: 36421167

Title : Tanshinone IIA regulates glycogen synthase kinase-3beta-related signaling pathway and ameliorates memory impairment in APP\/PS1 transgenic mice - Peng_2022_Eur.J.Pharmacol__174772
Author(s) : Peng X , Chen L , Wang Z , He Y , Ruganzu JB , Guo H , Zhang X , Ji S , Zheng L , Yang W
Ref : European Journal of Pharmacology , :174772 , 2022
Abstract : Our previous findings indicated that tanshinone IIA (tan IIA), a natural component extracted from the root and rhizome of danshen, significantly attenuated beta-amyloid accumulation, neuroinflammation, and endoplasmic reticulum stress, as well as improved learning and memory deficits in APP/PS1 transgenic mouse model of Alzheimer's disease (AD). However, whether tan IIA can ameliorate tau pathology and the underlying mechanism in APP/PS1 mice remains unclear. In the current study, tan IIA (15 mg/kg and 30 mg/kg) or saline was intraperitoneally administered to the 5-month-old APP/PS1 mice once daily for 4 weeks. The open-field test, novel object recognition test, Y-maze test, and Morris water maze test were performed to assess the cognitive function. Nissl staining, immunohistochemistry, TUNEL, and western blotting were conducted to explore tau hyperphosphorylation, neuronal injury, and phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt)/glycogen synthase kinase-3beta (GSK-3beta) signaling pathway. The activity of GSK-3beta, acetylcholinesterase (AChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px), and the level of malondialdehyde (MDA) were measured using commercial kits. Our results revealed that tan IIA treatment significantly ameliorated behavioral deficits and improved spatial learning and memory ability of APP/PS1 mice. Additionally, tan IIA markedly attenuated tau hyperphosphorylation and prevented neuronal loss and apoptosis in the parietal cortex and hippocampus. Simultaneously, tan IIA reversed cholinergic dysfunction and reduced oxidative stress. Furthermore, tan IIA activated the PI3K/Akt signaling pathway and suppressed GSK-3beta. Taken together, the above findings suggested that tan IIA improves cognitive decline and tau pathology may through modulation of PI3K/Akt/GSK-3beta signaling pathway.
ESTHER : Peng_2022_Eur.J.Pharmacol__174772
PubMedSearch : Peng_2022_Eur.J.Pharmacol__174772
PubMedID: 35090935

Title : SARM1 deletion in parvalbumin neurons is associated with autism-like behaviors in mice - Xiang_2022_Cell.Death.Dis_13_638
Author(s) : Xiang L , Wu Q , Sun H , Miao X , Lv Z , Liu H , Chen L , Gu Y , Chen J , Zhou S , Jiang H , Du S , Zhou Y , Dong H , Fan Y , Miao S , Lu Q , Chang L , Wang H , Lu Y , Xu X , Wang W , Huang Z
Ref : Cell Death Dis , 13 :638 , 2022
Abstract : Autism spectrum disorder (ASD), a group of neurodevelopmental disorder diseases, is characterized by social deficits, communication difficulties, and repetitive behaviors. Sterile alpha and TIR motif-containing 1 protein (SARM1) is known as an autism-associated protein and is enriched in brain tissue. Moreover, SARM1 knockdown mice exhibit autism-like behaviors. However, its specific mechanism in ASD pathogenesis remains unclear. Here we generated parvalbumin-positive interneurons (PVI)-specific conditional SARM1 knockout (SARM1(PV)-CKO) mice. SARM1(PV)-CKO male mice showed autism-like behaviors, such as mild social interaction deficits and repetitive behaviors. Moreover, we found that the expression level of parvalbumin was reduced in SARM1(PV)-CKO male mice, together with upregulated apoptosis-related proteins and more cleaved-caspase-3-positive PVIs, suggesting that knocking out SARM1 may cause a reduction in the number of PVIs due to apoptosis. Furthermore, the expression of c-fos was shown to increase in SARM1(PV)-CKO male mice, in combination with upregulation of excitatory postsynaptic proteins such as PSD-95 or neuroligin-1, indicating enhanced excitatory synaptic input in mutant mice. This notion was further supported by the partial rescue of autism-like behavior deficits by the administration of GABA receptor agonists in SARM1(PV)-CKO male mice. In conclusion, our findings suggest that SARM1 deficiency in PVIs may be involved in the pathogenesis of ASD.
ESTHER : Xiang_2022_Cell.Death.Dis_13_638
PubMedSearch : Xiang_2022_Cell.Death.Dis_13_638
PubMedID: 35869039

Title : Association Lp-PLA2 Gene Polymorphisms with Coronary Heart Disease - Ma_2022_Dis.Markers_2022_9775699
Author(s) : Ma S , Ding L , Cai M , Chen L , Yan B , Yang J
Ref : Dis Markers , 2022 :9775699 , 2022
Abstract : OBJECTIVES: The study evaluated the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) gene polymorphisms and coronary heart disease (CHD), in order to explore the molecular genetics of CHD. METHODS: Groups of CHD patients (n = 283) and healthy controls (n = 261) were involved in this study. R92H, V279F, and A379V polymorphisms of LP-PLA2 gene were confirmed using polymerase chain reaction (PCR) and direct DNA sequencing. These polymorphisms and their interaction were also analyzed as potential risk factors of CHD. RESULTS: In this study population, the genotypes of R92H (GG, GA, and AA), V279F (CC, AC, and AA) and A379V (GG, GA, and AA) were studied. There was a significantly difference in frequencies of R92H between CHD patients and controls (P < 0.05). In contrast, no significant difference in frequencies of V279F and A379V existed between CHD patients and controls. Furthermore, R92H and A379V were in strong linkage disequilibrium. CONCLUSIONS: These results suggested that R92H polymorphism might contribute to increased risk of CHD.
ESTHER : Ma_2022_Dis.Markers_2022_9775699
PubMedSearch : Ma_2022_Dis.Markers_2022_9775699
PubMedID: 35818585
Gene_locus related to this paper: human-PLA2G7

Title : Assessment of parental benzo[a]pyrene exposure-induced cross-generational neurotoxicity and changes in offspring sperm DNA methylome in medaka fish - Wan_2022_Environ.Epigenet_8_dvac013
Author(s) : Wan T , Au DW , Mo J , Chen L , Cheung KM , Kong RY , Seemann F
Ref : Environ Epigenet , 8 :dvac013 , 2022
Abstract : Previous studies have revealed that DNA methylation changes could serve as potential genomic markers for environmental benzo[a]pyrene (BaP) exposure and intergenerational inheritance of various physiological impairments (e.g. obesity and reproductive pathologies). As a typical aromatic hydrocarbon pollutant, direct BaP exposure has been shown to induce neurotoxicity. To unravel the inheritance mechanisms of the BaP-induced bone phenotype in freshwater medaka, we conducted whole-genome bisulfite sequencing of F1 sperm and identified 776 differentially methylated genes (DMGs). Ingenuity pathway analysis revealed that DMGs were significantly enriched in pathways associated with neuronal development and function. Therefore, it was hypothesized that parental BaP exposure (1 microg/l, 21 days) causes offspring neurotoxicity. Furthermore, the possibility for sperm methylation as an indicator for a neurotoxic phenotype was investigated. The F0 adult brains and F1 larvae were analyzed for BaP-induced direct and inherited toxicity. Acetylcholinesterase activity was significantly reduced in the larvae, together with decreased swimming velocity. Molecular analysis revealed that the marker genes associated with neuron development and growth (alpha1-tubulin, mbp, syn2a, shh, and gap43) as well as brain development (dlx2, otx2, and krox-20) were universally downregulated in the F1 larvae (3 days post-hatching). While parental BaP exposure at an environmentally relevant concentration could induce neurotoxicity in the developing larvae, the brain function of the exposed F0 adults was unaffected. This indicates that developmental neurotoxicity in larvae may result from impaired neuronal development and differentiation, causing delayed brain growth. The present study demonstrates that the possible adverse health effects of BaP in the environment are more extensive than currently understood. Thus, the possibility of multigenerational BaP toxicity should be included in environmental risk assessments.
ESTHER : Wan_2022_Environ.Epigenet_8_dvac013
PubMedSearch : Wan_2022_Environ.Epigenet_8_dvac013
PubMedID: 35769199

Title : Development and Validation of a Non-invasive Model to Predict Liver Histological Lesions in Chronic Hepatitis B Patients With Persistently Normal Alanine Aminotransferase and Detectable Viremia - Hu_2022_Front.Med.(Lausanne)_9_944547
Author(s) : Hu Q , Wang Q , Xu W , Huang C , Tao S , Qi X , Zhang Y , Li X , Jiang X , Song J , Li Q , Chen L , Huang Y
Ref : Front Med (Lausanne) , 9 :944547 , 2022
Abstract : BACKGROUND: A critical and controversial issue is whether antiviral therapy should be recommended in chronic hepatitis B virus (HBV) infection patients with persistently normal alanine aminotransferase (PNALT) and detectable HBV DNA. The study aimed to develop a non-invasive model for predicting significant liver histological changes (SLHC), which is the histological indication for antiviral therapy in chronic hepatitis B (CHB) patients with PNALT and detectable HBV DNA. METHODS: 398 chronic HBV infection patients with PNALT and detectable HBV DNA who underwent liver biopsy were divided into the estimation set (n = 256) and validation set (n = 142). A multivariate logistic regression model was developed to predict SLHC in the estimation set, and the diagnostic performance was further validated in the validation set. RESULTS: 132 patients (33.2%) with PNALT and detectable HBV DNA had SLHC. Aspartate aminotransferase (AST), cholinesterase (ChE), and liver stiffness measurement (LSM) were identified as the independent predictors of SLHC. The AUROC of the SLHC index, which combined AST, ChE, and LSM, was 0.824 and 0.816 in the estimation and validation set, respectively, for the prediction of SLHC. Applying the SLHC index >= 0.15, the presence of SLHC could be excluded with high negative predictive value in the estimation set (93.2%) and in the validation set (90.2%). Applying the SLHC index <= 0.55, the presence of SLHC could be considered with high positive predictive value in the estimation set (79.2%) and in the validation set (76.5%). CONCLUSION: The SLHC index provides a high accuracy in predicting liver histological indication for antiviral therapy in CHB patients with PNALT and detectable HBV DNA.
ESTHER : Hu_2022_Front.Med.(Lausanne)_9_944547
PubMedSearch : Hu_2022_Front.Med.(Lausanne)_9_944547
PubMedID: 35911415

Title : Immobilization of Candida Rugosa lipase on Ca\/Kit-6 used as bifunctional biocatalysts for the transesterification of coconut oil to biodiesel - Mendez_2022_Mol.Catal_533_112793
Author(s) : Mendez JC , Arellano U , Solis S , Wang JA , Chen L
Ref : Molecular Catalysis , 533 :112793 , 2022
Abstract : Immobilization of Candida Rugosa lipase (CRL) on Ca doped Kit-6 solid was investigated via the adsorption method. Effects of the experimental parameters, such as pH value, temperature, time, and Ca content on the adsorption of CRL on Ca/Kit-6 were studied. In the Ca doped Ca/Kit-6 materials, Ca2+ coexisted in two environments: Ca2+ in CaO nanoparticles and in Ca-O-Si in the framework of Kit-6. There existed three kind of oxygen species: (1) lattice oxygen in CaO and SiO2; (2) Oxygen in structural defects; and (3) non-stoichiometric surface oxygen in OH form. The 0.5Ca/Kit-6 showed the most CRL immobilization capacity and stability under the optimal adsorption condition, which was correlated with its greater amount of basicity resulting from its more non-stoichiometric surface oxygen and oxygen in structural defects as well as more Ca2+ incorporation in the Kit-6 framework. In the production of biodiesel via transesterification of coconut oil, the catalysts showed better catalytic performance under weak basic than acidic condition. Under the optimal reaction conditions (40 degreesC, pH 7.5, 200 rpm, oil to methanol ratio 1:3 with stepwise addition of methanol, and 0.1 g of CRL/0.5Ca/Kit-6), the coconut oil conversion and biodiesel yield catalyzed with CRL/0.5Ca/Kit-6 was 95 and 98%, respectively. 10wt% water in the reaction mixture promoted the coconut oil transesterification to biodiesel. The CRL/0.5Ca/Kit-6 catalyst possessed bifunctional roles of the enzymatic catalysis role from immobilized CRL and the basic catalysis role from CaO doping. The CRL adsorption modes, water influence and the reaction mechanism of coconut oil transesterification were discussed.
ESTHER : Mendez_2022_Mol.Catal_533_112793
PubMedSearch : Mendez_2022_Mol.Catal_533_112793

Title : Characterization of the synergistic inhibitory effect of cyanidin-3-O-glucoside and catechin on pancreatic lipase - Wang_2022_Food.Chem_404_134672
Author(s) : Wang Y , Chen L , Liu H , Xie J , Yin W , Xu Z , Ma H , Wu W , Zheng M , Liu M , Liu J
Ref : Food Chem , 404 :134672 , 2022
Abstract : This study aimed to identify novel pancreatic lipase (PL) inhibitors using affinity ultrafiltration combined with spectroscopy and molecular docking. Cyanidin-3-O-glucoside (C3G; IC(50): 0.268 mg/mL) and catechin (IC(50): 0.280 mg/mL) were shown to be potent PL inhibitors extracted from black rice and adzuki bean coat extracts. Isobologram analysis revealed that the combined use of C3G and catechin at a ratio of 2:3 had a remarkable synergistic effect (IC(50) of the mixture: 0.201 mg/mL). The inhibitory mechanism of C3G-catechin mixture was of mixed type. The C3G-catechin mixture had a great impact on PL secondary structures. Molecular docking analysis further demonstrated that these polyphenols formed hydrophobic interactions and hydrogen bonds with amino acid residues in the binding pocket of PL. Collectively, C3G and catechin were shown to inhibit PL in a synergistic manner and can be potentially used for the development of food supplements for obesity prevention.
ESTHER : Wang_2022_Food.Chem_404_134672
PubMedSearch : Wang_2022_Food.Chem_404_134672
PubMedID: 36323025

Title : Invasive Plants Have Higher Resistance to Native Generalist Herbivores Than Exotic Noninvasive Congeners - Wu_2022_Environ.Entomol__
Author(s) : Wu S , Chen L , Zhou Y , Xiao F , Liu D , Wang Y
Ref : Environ Entomol , : , 2022
Abstract : Research on the invasive plant Phytolacca americana (L.) mostly focuses on its medicinal value and enrichment of heavy metals. However, little is known regarding its impact on native herbivorous insects. In this study, we explored the effects of P. americana and the exotic noninvasive Phytolacca icosandra (L.) on the Spodoptera litura (Fabricius) (native tobacco cutworm) via bioassay, oviposition preference, detoxifying enzyme activity analysis, and phytochemical determination. We found that the oviposition preference index (OPI) of S. litura feeding on P. icosandra was higher than that of P. americana. The developmental duration of S. litura feeding on P. icosandra was shorter than that of P. americana. Additionally, the Acetylcholinesterase (AchE) and Glutathione-S-transferase (GST) activities of S. litura feeding on P. americana were higher than that of S. litura feeding on artificial diets or P. icosandra. The content of lignin and flavonoids in P. americana was relatively high, whereas starch content was relatively low. These findings suggest invasive plants have higher resistance to herbivores, thereby suffering less damage than exotic noninvasive plants.
ESTHER : Wu_2022_Environ.Entomol__
PubMedSearch : Wu_2022_Environ.Entomol__
PubMedID: 36545824

Title : Structure-guided rational design of the Geobacillus thermoglucosidasius feruloyl esterase GthFAE to improve its thermostability - Yang_2022_Biochem.Biophys.Res.Commun_600_117
Author(s) : Yang W , Sun L , Dong P , Chen Y , Zhang H , Huang X , Wu L , Chen L , Jing D , Wu Y
Ref : Biochemical & Biophysical Research Communications , 600 :117 , 2022
Abstract : Feruloyl esterases are indispensable biocatalysts catalyzing the cleavage of ester bonds between polysaccharides and their hydroxycinnamoyl cross-links. GthFAE from Geobacillus thermoglucosidasius was identified as a thermophilic alkaline feruloyl esterase with potential applications in paper manufacturing. To improve the enzymatic properties rationally and efficiently, the structure of GthFAE was solved at 1.9 A, revealing a core domain of classical alpha/beta hydrolase fold and an inserted alpha/beta cap domain. In silico analysis based on it helped us to investigate whether the residues at the active center have positive effects on the stability, and how. Several site-directed mutations were conducted, of which substitutions at residues T41 and T150 apparently improved the thermostability. The combination mutant T41N/T150R exhibited an optimal temperature of 65 degreesC, a 6.4 degreesC higher T(m) compared to wild type by 80 degreesC, and a 35-fold longer in half-life (201 min) at 70 degreesC. Molecular dynamics simulations further illustrated that the structure of T41N/T150R was more stable than the wild type and T150R stabilized the cap domain by introducing salt bridges to the region with E154 and D164. This study not only highlighted residues within the active center on their thermostability improving effects, but also contributed to the prospective industrial application of GthFAE.
ESTHER : Yang_2022_Biochem.Biophys.Res.Commun_600_117
PubMedSearch : Yang_2022_Biochem.Biophys.Res.Commun_600_117
PubMedID: 35219099
Gene_locus related to this paper: partm-GthFAE

Title : Microplastics exposure as an emerging threat to ancient lineage: A contaminant of concern for abnormal bending of amphioxus via neurotoxicity - Xiang_2022_J.Hazard.Mater_438_129454
Author(s) : Xiang K , He Z , Fu J , Wang G , Li H , Zhang Y , Zhang S , Chen L
Ref : J Hazard Mater , 438 :129454 , 2022
Abstract : Growing inputs of microplastics into marine sediment have increased significantly the needs for assessment of their potential risks to the marine benthos. A knowledge gap remains with regard to the effect of microplastics on benthos, such as cephalochordates. By employing amphioxus as a model benthic chordate, here we show that exposure to microplastics for 96 h at doses of 1 mg/L and 100 mg/L results in evident accumulation of the polyethylene microplastics. The accumulated microplastics are as much as 0.027% of body weight upon high-dose exposure, causing an abnormal body-bending phenotype that limits the locomotion capability of amphioxus. Mechanistic insight reveals that microplastics can bring about histological damages in gill, intestine and hepatic cecum; In-depth assay of relevant biomarkers including superoxide dismutase, catalase, glutathione, pyruvic acid and total cholesterol indicates the occurrence of oxidative damage and metabolic disorder; Further, microplastics exposure depresses the activity of acetylcholinesterase while allowing the level of acetylcholine to rise in muscle, suggesting the emergence of neurotoxicity. These consequences eventually contribute to the muscle dysfunction of amphioxus. This study rationalizes the abnormal response of the vulnerable notochord to microplastics, signifying the dilemma suffered by the ancient lineage under the emerging threat. Given the enrichment of microplastics through marine food chains, this study also raises significant concerns on the impact of microplastics to other marine organisms, and eventually human beings.
ESTHER : Xiang_2022_J.Hazard.Mater_438_129454
PubMedSearch : Xiang_2022_J.Hazard.Mater_438_129454
PubMedID: 35803186

Title : An artificial self-assembling peptide with carboxylesterase activity and substrate specificity restricted to short-chain acid p-nitrophenyl esters - Liu_2022_Front.Chem_10_996641
Author(s) : Liu Y , Gan L , Feng P , Huang L , Chen L , Li S , Chen H
Ref : Front Chem , 10 :996641 , 2022
Abstract : Natural enzymes possess remarkable catalytic activity and high substrate specificity. Many efforts have been dedicated to construct artificial enzymes with high catalytic activity. However, how to mimic the exquisite substrate specificity of a natural enzyme remains challenging because of the complexity of the enzyme structure. Here, we report artificial carboxylesterases that are specific for short chain fatty acids and were constructed via peptide self-assembly. These artificial systems have esterase-like activity rather than lipase-like activity towards p-nitrophenyl esters. The designer peptides self-assembled into nanofibers with strong beta-sheet character. The extending histidine units and the hydrophobic edge of the fibrillar structure collectively form the active center of the artificial esterase. These artificial esterases show substrate specificity for short-chain acids esters. Moreover, 1-isopropoxy-4-nitrobenzene could function as a competitive inhibitor of hydrolysis of p-nitrophenyl acetate for an artificial esterase.
ESTHER : Liu_2022_Front.Chem_10_996641
PubMedSearch : Liu_2022_Front.Chem_10_996641
PubMedID: 36199662

Title : Effects of ABCG1 knockout on proteomic composition of HDL in mice on a chow diet and a high-fat diet - Wu_2022_Proteomics__e2100028
Author(s) : Wu Y , Chen L , Xie Z , Wang C , Zhang J , Yan X
Ref : Proteomics , :e2100028 , 2022
Abstract : ATP-binding cassette transporter G1 (ABCG1) is a cellular transmembrane protein that transports oxysterol efflux from cells to high-density lipoprotein (HDL) particles in the plasma. Previous studies have demonstrated that an ABCG1 deficiency exerts an antiatherosclerotic function through the effects of oxysterol accumulation in cells to enhance apoptosis and regulate inflammatory processes. However, whether the deficiency of ABCG1 and the corresponding changes in the efflux of oxysterols could take a series of impacts on the proteomic composition of HDL remains unclear. Here, plasma HDL of ABCG1(-/-) mice and their wild-type controls on a normal chow diet (NCD) or a high-fat diet (HFD) were isolated by ultracentrifugation. The proportion of 7-ketocholesterol and the proteomic composition of samples were comparatively analyzed by LC-MS/MS. In NCD-fed mice, lipid metabolism-related protein (arachidonate 12-lipoxygenase) and antioxidative protein (pantetheinase) exhibited increased accumulation, and inflammatory response protein (alpha-1-antitrypsin) was decreased in accumulation in ABCG1(-/-) mice HDL. In HFD-fed mice, fewer proteins were detected than that of NCD-fed mice. The ABCG1(-/-) mice HDL exhibited increased accumulation of lipid metabolism-related proteins (e.g., carboxylesterase 1C, apolipoprotein (apo)C-4) and decreased accumulation of alpha-1-antitrypsin, as well as significantly reduced proportion of 7-ketocholesterol. Additionally, positive correlations were found between 7-ketocholesterol and some essential proteins on HDL, such as alpha-1-antitrypsin, apoA-4, apoB-100, and serum amyloid A (SAA). These results suggest a detrimental impact of oxysterols on HDL composition, which might affect the antiatherosclerotic properties of HDL.
ESTHER : Wu_2022_Proteomics__e2100028
PubMedSearch : Wu_2022_Proteomics__e2100028
PubMedID: 35234362

Title : Design, synthesis, and evaluation of 8-aminoquinoline-melatonin derivatives as effective multifunctional agents for Alzheimer's disease - Chen_2022_Ann.Transl.Med_10_303
Author(s) : Chen Z , Yu X , Chen L , Xu L , Cai Y , Hou S , Zheng M , Liu F
Ref : Ann Transl Med , 10 :303 , 2022
Abstract : BACKGROUND: Alzheimer's disease (AD) is thought to be a complex, multifactorial syndrome with many related molecular lesions contributing to its pathogenesis. Thus, multi-target-directed ligands are considered an effective way of treating AD. This study sought to evaluate 8-aminoquinoline-melatonin derivatives as effective multifunctional agents for AD. METHODS: Thioflavin-T fluorescence assays were used to detect the inhibitory potency of 8-aminoquinoline-melatonin hybrids (a1-a5, b1-b5, and c1-c5) on self- and acetylcholinesterase (AChE)-induced amyloid-beta (Abeta) aggregation. The AChE and butyrylcholinesterase (BuChE) inhibitory potency within the compounds was evaluated by Ellman's assays. Methyl thiazolyl tetrazolium (MTT) assays were performed to evaluate the cytotoxicity of the compounds to C17.2 cells. MTT assay was used to detect the cell viability of HT22 cells to evaluate the antioxidant effect of the compounds. Metal chelation property was measured by ultraviolet-visible spectrophotometry. RESULTS: Compounds c3 and c5 had superior inhibitory activity against self-induced Abeta aggregation (with inhibitory rates of 41.4+/-2.1 and 25.5+/-3.2 at 10 microM, respectively) compared to the other compounds. Compounds in the carbamate group (i.e., a4, a5, b4, b5, c4, and c5) showed significant BuChE inhibitory activity and excellent selectivity over AChE. Most of the compounds exhibited low cytotoxicity in the C17.2 cells. Notably, a2, a3, b2, and b3 and series c (c1-c5) exhibited strong protective effects. Additionally, a3 and c1 specifically chelated with copper ions. CONCLUSIONS: Taking all of the promising results together, 8-aminoquinoline-melatonin hybrids can serve as lead molecules in the further development of new multi-functional anti-AD agents.
ESTHER : Chen_2022_Ann.Transl.Med_10_303
PubMedSearch : Chen_2022_Ann.Transl.Med_10_303
PubMedID: 35433950

Title : Structure-guided discovery of potent and oral soluble epoxide hydrolase inhibitors for the treatment of neuropathic pain - Du_2022_Acta.Pharm.Sin.B_12_1377
Author(s) : Du F , Cao R , Chen L , Sun J , Shi Y , Fu Y , Hammock BD , Zheng Z , Liu Z , Chen G
Ref : Acta Pharm Sin B , 12 :1377 , 2022
Abstract : Soluble epoxide hydrolase (sEH) is related to arachidonic acid cascade and is over-expressed in a variety of diseases, making sEH an attractive target for the treatment of pain as well as inflammatory-related diseases. A new series of memantyl urea derivatives as potent sEH inhibitors was obtained using our previous reported compound 4 as lead compound. A preferential modification of piperidinyl to 3-carbamoyl piperidinyl was identified for this series via structure-based rational drug design. Compound A20 exhibited moderate percentage plasma protein binding (88.6%) and better metabolic stability in vitro. After oral administration, the bioavailability of A20 was 28.6%. Acute toxicity test showed that A20 was well tolerated and there was no adverse event encountered at dose of 6.0 g/kg. Inhibitor A20 also displayed robust analgesic effect in vivo and dose-dependently attenuated neuropathic pain in rat model induced by spared nerve injury, which was better than gabapentin and sEH inhibitor (+/-)-EC-5026. In one word, the oral administration of A20 significantly alleviated pain and improved the health status of the rats, demonstrating that A20 was a promising candidate to be further evaluated for the treatment of neuropathic pain.
ESTHER : Du_2022_Acta.Pharm.Sin.B_12_1377
PubMedSearch : Du_2022_Acta.Pharm.Sin.B_12_1377
PubMedID: 35530144

Title : Development of 5-hydroxyl-1-azabenzanthrone derivatives as dual binding site and selective acetylcholinesterase inhibitors - Sun_2022_Eur.J.Med.Chem_234_114210
Author(s) : Sun X , Wang Y , Lei Z , Yue S , Chen L , Sun J
Ref : Eur Journal of Medicinal Chemistry , 234 :114210 , 2022
Abstract : A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase (eeAChE IC(50) = 0.045 microM; eeBuChE IC(50) = 19.68 microM; SI = 437.33). Most of the compounds showed cytoprotective effects on PC12 cells damaged by hydrogen peroxide, which might be related to their antioxidant activity. Further experiments confirmed that 16 exhibited anti-apoptotic effects at low concentrations and reduced the relative level of ROS generation in PC12 cells. The expression level of proteins related to antioxidant stress pathway in PC12 cells was relatively increased after administrated with 16, which may be beneficial to delay the progression of the disease. Moreover, 16 was evaluated to be safe in vivo and in vitro, and showed good overall pharmacokinetic performance and high bioavailability (Foral = 55.5%). Besides, 16 showed comparable performance in ameliorating the scopolamine-induced cognition impairment to donepezil. In addition, in vitro BBB permeability experiments confirmed that 16 had high BBB permeability.
ESTHER : Sun_2022_Eur.J.Med.Chem_234_114210
PubMedSearch : Sun_2022_Eur.J.Med.Chem_234_114210
PubMedID: 35303485

Title : Design, synthesis and insecticidal activity and mechanism research of Chasmanthinine derivatives - Song_2022_Sci.Rep_12_15290
Author(s) : Song Z , Li X , Xu K , Sun G , Yang L , Huang L , Liu J , Yin P , Huang S , Gao F , Zhou X , Chen L
Ref : Sci Rep , 12 :15290 , 2022
Abstract : Unrestricted reproduction and spread of pest had caused great damage to the quality and yield of crops in recent years. Besides the use of traditional chemical pesticides, natural products also make a huge contribution against pests. Chasmanthinine, a diterpenoid alkaloid isolated from Aconitum franchetii var. villosulum, shown extremely antifeedant activity against Spodoptera exigua. Therefore, a series of novel Chasmanthinine derivatives were synthesized and their biological activity was studied in this work. Compound 33 showed the strongest antifeedant activity (EC(50) = 0.10 mg/cm(2)) among all the test compounds. The mechanism research of 33 revealed that its antifeedant effect was related to the inhibition of carboxylesterase (CES), and proved the thiophene acyl group could form a strong binding effect with CES by molecular docking. Moreover, compound 10 exhibited the strongest cytotoxicity (IC(50) = 12.87 microM) against Sf9 cell line and moderate contact toxicity. The mechanism research indicated that compound 10 could induce Sf9 cells apoptosis. In summary, the results lay a foundation for the application of diterpene alkaloids in plant protection.
ESTHER : Song_2022_Sci.Rep_12_15290
PubMedSearch : Song_2022_Sci.Rep_12_15290
PubMedID: 36088472

Title : Screening models combining maternal characteristics and multiple markers for the early prediction of preeclampsia in pregnancy: a nested case-control study - Chen_2022_J.Obstet.Gynaecol__1
Author(s) : Chen L , Pi Y , Chang K , Luo S , Peng Z , Chen M , Yu L
Ref : J Obstet Gynaecol , :1 , 2022
Abstract : To identify maternal laboratory markers to predict the risk of preeclampsia (PE) in different stages of pregnancy, we analysed 67, 25, and 73, pregnancies developing PE at 11-13, 16-20, and 24-28 wks, respectively. Routine laboratory markers were measured in whole blood or serum and binary logistic regression analysis was used to identify predictive models. At 11-13 wks of gestation, patients who went on to develop PE showed significantly higher concentrations of alanine aminotransferase, aspartate aminotransferase, alpha-L-fucosidase, 5'-nucleotidase, glutamyl transpeptidase, cholinesterase, and uric acid; plateletcrit was also higher. At 16-20 wks, inhibin A concentration and plateletcrit were significantly elevated. At 24-28 wks, platelets, plateletcrit, and glucose concentration were significantly elevated. Logistic regression analysis showed that an elevation in 5'-nucleotidase was independently associated with PE at 11-13 wks. The combination of inhibin A, diastolic blood pressure, and body mass index was a significant predictor for PE at 16-20 wks, while the combination of glucose and systolic blood pressure was a significant predictor for PE at 24-28 wks. In conclusion, when combined with maternal characteristics, the measurement of 5'-nucleotidase, inhibin A, and glucose levels, represents a potentially valuable risk assessment for PE.Impact statementWhat is already known on this subject? Preeclampsia (PE) may be viewed as a spectrum of disorders with a severity that is reflected in the levels of specific biomarkers. Consequently, there is a clear need for additional biomarkers that can be used to stratify pregnancies as high or low risk soon after conception.What do the results of this study add? At 11-13 wks of gestation, maternal assays for platelets, plateletcrit, alanine aminotransferase, aspartate aminotransferase, alpha-L-fucosidase, 5'-nucleotidase, glutamyl transpeptidase, cholinesterase, and uric acid, demonstrated significantly higher values in patients with PE when compared with normal controls. Furthermore, assay results for inhibin A and platelets showed increased values at 16-20 wks of gestation. Assays performed at 24-28 wks of gestation revealed elevated levels of platelets, plateletcrit, and glucose. Our analysis indicated that increases in the levels of 5'-nucleotidase, inhibin A, and glucose, are effective and significant biomarkers that could be used in combination with maternal characteristics to screen for PE at 11-13, 16-20, and 24-28 wks of gestation, respectively. These findings provide a new basis for our understanding of the aetiology underlying PE.What are the implications of these findings for clinical practice and/or further research? Further studies that consider the entire population are now needed and should include the investigation of laboratory markers across different stages of pregnancy. Long-term follow up would also be necessary if we are to explore the full role of laboratory markers in the pathophysiology of PE.
ESTHER : Chen_2022_J.Obstet.Gynaecol__1
PubMedSearch : Chen_2022_J.Obstet.Gynaecol__1
PubMedID: 35634766

Title : Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress - Liu_2022_Nat.Cancer__
Author(s) : Liu X , Viswanadhapalli S , Kumar S , Lee TK , Moore A , Ma S , Chen L , Hsieh M , Li M , Sareddy GR , Parra K , Blatt EB , Reese TC , Zhao Y , Chang A , Yan H , Xu Z , Pratap UP , Liu Z , Roggero CM , Tan Z , Weintraub ST , Peng Y , Tekmal RR , Arteaga CL , Lippincott-Schwartz J , Vadlamudi RK , Ahn JM , Raj GV
Ref : Nat Cancer , : , 2022
Abstract : Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.
ESTHER : Liu_2022_Nat.Cancer__
PubMedSearch : Liu_2022_Nat.Cancer__
PubMedID: 35654861
Gene_locus related to this paper: human-LIPA

Title : A Novel Paper-Based Electrochemical Biosensor Based on N,O-Rich Covalent Organic Frameworks for Carbaryl Detection - Xiao_2022_Biosensors.(Basel)_12_
Author(s) : Xiao Y , Wu N , Wang L , Chen L
Ref : Biosensors (Basel) , 12 : , 2022
Abstract : A new N,O-rich covalent organic framework (COF(DHNDA-BTH)) was synthesized by an amine-aldehyde condensation reaction between 2,6-dialdehyde-1,5-dihydroxynaphthalene (DHNDA) and 1,3,5-phenyltriformylhydrazine (BTH) for carbaryl detection. The free NH, OH, and C=O groups of COF(DHNDA-BTH) not only covalently couples with acetylcholinesterase (AChE) into the pores of COF(DHNDA-BTH), but also greatly improves the catalytic activity of AChE in the constrained environment of COF(DHNDA-BTH)'s pore. Under the catalysis of AChE, the acetylthiocholine (ATCl) was decomposed into positively charged thiocholine (TCl), which was captured on the COF(DHNDA-BTH) modified electrode. The positive charges of TCl can attract anionic probe [Fe(CN)(6)](3-/4-) on the COF(DHNDA-BTH)-modified electrode to show a good oxidation peak at 0.25 V (versus a saturated calomel electrode). The carbaryl detection can inhibit the activity of AChE, resulting in the decrease in the oxidation peak. Therefore, a turn-off electrochemical carbaryl biosensor based on a flexible carbon paper electrode loaded with COF(DHNDA-BTH) and AChE was constructed using the oxidation peak of an anionic probe [Fe(CN)(6)](3-/4-) as the detection signal. The detection limit was 0.16 microM (S/N = 3), and the linear range was 0.48~35.0 microM. The sensor has good selectivity, repeatability, and stability, and has a good application prospect in pesticide detection.
ESTHER : Xiao_2022_Biosensors.(Basel)_12_
PubMedSearch : Xiao_2022_Biosensors.(Basel)_12_
PubMedID: 36291036

Title : Two new C18-diterpenoid alkaloids from Aconitum leucostomum Worosch - Zhou_2022_Chem.Biodivers__
Author(s) : Zhou X , Yang HB , Luo YY , Xu JB , Liu Y , Gao F , Huang S , Chen L
Ref : Chem Biodivers , : , 2022
Abstract : Two new lappaconitine-type C18-diterpenoid alkaloids, named as leucostosines C (1) and D (2), together with six known compounds (3-8), were isolated from the roots of Aconitum leucostomum Worosch. Their structures were elucidated by various spectroscopic analyses, including IR, HR-ESI-MS, NMR spectra and X-ray experiments. Leucostosine C is the first diterpenoid alkaloid bearing the 7-amino group. The isolated compounds were tested for the acetylcholinesterase (AChE) inhibitory effect and neuroprotective activity, none of them showed significant activities.
ESTHER : Zhou_2022_Chem.Biodivers__
PubMedSearch : Zhou_2022_Chem.Biodivers__
PubMedID: 36094326

Title : Changes and significance of serum monocyte chemoattractant protein-1 and Lp-PLA2 in patients with hypertension and coronary heart disease - Tian_2022_J.Pak.Med.Assoc_72_1114
Author(s) : Tian Y , Fan Y , Chen L , Sun M
Ref : J Pak Med Assoc , 72 :1114 , 2022
Abstract : OBJECTIVE: To explore the combined application value of serum monocyte chemoattractant protein-1 and lipoprotein-associated phospholipase A2 in the diagnosis of hypertension and coronary heart disease. METHODS: The cross-sectional case-control study was conducted at Baoji Hospital of Traditional Chinese medicine, Shaanxi, China, from April 2018 to May 2020, and comprised patients with suspected hypertension and coronary heart disease. Patients with both hypertension and coronary heart disease formed Group A, and those with simple hypertension formed Group B. Healthy individuals formed the control Group C. Receiver operating characteristic curve was used to evaluate the value of serum monocyte chemoattractant protein-1 combined with lipoprotein-associated phospholipase A2 in the diagnosis of hypertension complicated with coronary heart disease. Data was analysed using SPSS 25. RESULTS: Of the 306 subjects, there were 122(40%) in Group A; 68(55.7%) males and 54(44.3%) females with mean age 68.77+/-5.76 years. There were 92(30%) cases in Group B; 51(55.4%) males and 41(44.6%) females with mean age 68.80+/-5.28 years. Group C had 92(30%) cases; 50(54.3%) males and 42(45.7%) females with mean age 67.85+/-5.29 years. Serum monocyte chemoattractant protein-1 and lipoprotein-associated phospholipase A2 levels were higher in Group A than the other two groups (p<0.001), and the levels in patients with carotid plaque total score <2 were lower than those with carotid plaque total score >2 (p<0.001). Area under receiver operating characteristic curve of the combination of the serum markers was 0.883 (95% confidence interval: 0.837-0.929, p<0.001), which was greater than that of two serum markers alone (p<0.05). CONCLUSIONS: Monocyte chemoattractant protein-1 and lipoprotein-associated phospholipase A2 may be involved in pathogenesis of elevated blood pressure and coronary artery disease. Combined detection of the two serum markers can provide a certain basis for the diagnosis and treatment of hypertension and coronary heart disease.
ESTHER : Tian_2022_J.Pak.Med.Assoc_72_1114
PubMedSearch : Tian_2022_J.Pak.Med.Assoc_72_1114
PubMedID: 35751319
Gene_locus related to this paper: human-PLA2G7

Title : Acute thiamethoxam exposure induces hepatotoxicity and neurotoxicity in juvenile Chinese mitten crab (Eriocheir sinensis) - Yang_2022_Ecotoxicol.Environ.Saf_249_114399
Author(s) : 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
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.
ESTHER : Yang_2022_Ecotoxicol.Environ.Saf_249_114399
PubMedSearch : Yang_2022_Ecotoxicol.Environ.Saf_249_114399
PubMedID: 36508784

Title : Strigolactone signaling complex formation in yeast: A paradigm for studying hormone-induced receptor interaction with multiple downstream proteins - Yu_2022_Methods.Enzymol_674_519
Author(s) : Yu H , Yang L , Long H , Su X , Wang Y , Xing Q , Yao R , Zhang M , Chen L
Ref : Methods Enzymol , 674 :519 , 2022
Abstract : Strigolactones (SLs) are bioactive carotenoid derivatives which function as signaling molecules to regulate plant architecture, nutrient absorption and communication with other organisms. The alpha/beta-fold hydrolase, D14, hydrolyzes SLs, and the hydrolysis product activates D14 to bind to downstream signaling partners, including an E3 ubiquitin ligase MAX2 and SMXL6/7/8 proteins. What was not known was whether binding with one downstream partner would alter the affinity of D14 for other binding partners. Here, we developed an efficient yeast four-hybrid (Y4H) detection system and demonstrate that SL induces the interaction of D14 with both SMXL7 and MAX2 in a dose-dependent manner. Moreover, using our newly established yeast four-hybrid system, we found that the SL-induced D14 interaction with SMXL7 was strengthened by MAX2 while SMXL7 weakened the SL-induced D14 interaction with MAX2. Our findings provide novel insights into the regulatory effects of these signaling components and shed light on the molecular mechanism controlling the core SL signaling pathway. Furthermore, the heterologous yeast platform used for investigating SL complex formation has great potential to explore dynamic interactions in other signaling pathways or elucidate the unknown complex formation for biosynthesis of the parent carotenoids of SLs.
ESTHER : Yu_2022_Methods.Enzymol_674_519
PubMedSearch : Yu_2022_Methods.Enzymol_674_519
PubMedID: 36008019

Title : Biodegradation of diphenyl ether herbicide lactofen by Bacillus sp. YS-1 and characterization of two initial degrading esterases - Shang_2022_Sci.Total.Environ_806_151357
Author(s) : Shang N , Chen L , Cheng M , Tian Y , Huang X
Ref : Sci Total Environ , 806 :151357 , 2022
Abstract : The extensive use of the diphenyl ether herbicide lactofen in recent years has caused serious environmental problems. Therefore, detoxification and elimination of lactofen from the environment are urgently required. In this study, the lactofen-degrading strain Bacillus sp. YS-1 was isolated, which achieved a 97.6% degradation rate of 50 mg/L lactofen within 15 h. The ester bond of lactofen was hydrolyzed, which generated acifluorfen, and then, the nitro group was reduced to the amino group, which generated aminoacifluorfen. Finally, the amino group was acetylated, which formed acetylated aminoacifluorfen, a novel end product in the degradation of lactofen. The toxicity of acetylated aminoacifluorfen to the root and seedling growth of cucumber and sorghum was significantly decreased compared with that of lactofen. The two esterase genes rhoE and rapE, encoding two esterases responsible for lactofen hydrolysis to acifluorfen, were cloned and expressed. The amino acid sequences encoded by rhoE and rapE were 27.78% and 88.21% identical with known esterases, respectively. The optimum temperatures for RhoE and RapE degradation of lactofen were 35 degreesC and 25 degreesC, respectively, and both esterases displayed maximal activity at pH 8.0. Both RhoE and RapE prioritized the degradation of (S)-(+)-lactofen, (S)-(-)-quizalofop-ethyl, and (S)-(-)-diclofop-methyl. This study provided the resources of bacterial strain and hydrolyzing enzyme for the removal of lactofen from the environment and the bioremediation of herbicide-contaminated soil.
ESTHER : Shang_2022_Sci.Total.Environ_806_151357
PubMedSearch : Shang_2022_Sci.Total.Environ_806_151357
PubMedID: 34742792
Gene_locus related to this paper: bacsp-a0a6b9cu04 , 9baci-a0a0d7fsc6

Title : A New Berberine Preparation Protects Pancreatic Islet Cells from Apoptosis Mediated by Inhibition of Phospholipase A(2)\/p38 MAPK Pathway - Bi_2022_Bull.Exp.Biol.Med_173_346
Author(s) : Bi XJ , Lv YQ , Yang XH , Ge Y , Han H , Feng JS , Zhang M , Chen L , Xu MZ , Guan FY
Ref : Bulletin of Experimental Biology & Medicine , 173 :346 , 2022
Abstract : We studied an amorphous solid dispersion of berberine with absorption enhancer sodium caprate (Huang-Gui solid dispersion preparations, HGSD). A therapeutic effect of HGSD was revealed in mice with type 2 diabetes mellitus and palmitate-induced injury to MIN6 beta-cells. HGSD treatment (150 mg/kg) improved glucose metabolism and decreased beta-cell apoptosis in diabetic mice. Furthermore, the effective component of HGSD berberine significantly attenuated the palmitate-induced decrease in MIN6 beta-cells viability and insulin secretion. Moreover, molecular docking analysis and Western blotting showed that berberine decreased cell apoptosis and expression of group VIA phospholipase A(2) (iPLA(2)), p38 mitogen-activated protein kinase (p38 MAPK), and caspase-3. These data suggest that HGSD treatment protected beta-cells via inhibiting the iPLA(2)/p38 MAPK pathway.
ESTHER : Bi_2022_Bull.Exp.Biol.Med_173_346
PubMedSearch : Bi_2022_Bull.Exp.Biol.Med_173_346
PubMedID: 35852692

Title : Efficiency of donepezil in elderly patients undergoing orthopaedic surgery due to underlying post-operative cognitive dysfunction: study protocol for a multicentre randomised controlled trial - Zhu_2021_Trials_22_688
Author(s) : Zhu H , Cong L , Chen Y , Chen S , Chen L , Huang Z , Zhou J , Xiao J , Huang Y , Su D
Ref : Trials , 22 :688 , 2021
Abstract : BACKGROUND: Post-operative cognitive dysfunction (POCD) is an overarching term used to describe cognitive impairment identified in the preoperative or post-operative period. After surgical operations, older patients are particularly vulnerable to memory disturbances and other types of cognitive impairment. However, the pathogenesis of POCD remains unclear with no confirmed preventable or treatable strategy available. Our previous study demonstrated that the concentration of choline acetyl transferase in the cerebral spinal fluid was a predictive factor of POCD and that donepezil, which is an acetylcholinesterase inhibitor used in clinical settings for the treatment of Alzheimer's disease, can prevent learning and memory impairment after anaesthesia/surgery in aged mice. This study aimed to determine the critical role of donepezil in preventing cognitive impairment in elderly patients undergoing orthopaedic surgery. METHODS: A multicentre, double-blind, placebo-controlled, crossover clinical trial will be performed to assess the efficacy of donepezil in elderly patients undergoing orthopaedic surgery. Participants (n = 360) will receive donepezil (5 mg once daily) or placebo from 1 day prior to surgery until 5 days after surgery. Neuropsychological tests will be measured at 1 day before the operation and 1 week, 1 month, 6 months and 1 year after the operation. DISCUSSION: This research project mainly aimed to study the effects of donepezil in elderly patients undergoing orthopaedic surgery due to underlying POCD and to investigate the underlying physiological and neurobiological mechanisms of these effects. The results may provide important implications for the development of effective interfering strategies, specifically regarding cognitive dysfunction therapy using drugs. TRIAL REGISTRATION: NCT04423276 . Registered on 14 June 2020.
ESTHER : Zhu_2021_Trials_22_688
PubMedSearch : Zhu_2021_Trials_22_688
PubMedID: 34627332

Title : Identification of Conserved and Divergent Strigolactone Receptors in Sugarcane Reveals a Key Residue Crucial for Plant Branching Control - Hu_2021_Front.Plant.Sci_12_747160
Author(s) : Hu A , Zhao Q , Chen L , Zhao J , Wang Y , Feng K , Wu L , Xie M , Zhou X , Xiao L , Ming Z , Zhang M , Yao R
Ref : Front Plant Sci , 12 :747160 , 2021
Abstract : Strigolactones (SLs) are a class of important plant hormones mainly regulating plant architecture such as branching, which is crucial for crop yield. It is valuable to study SL signaling pathway and its physiological function in sugarcane, the most important sugar crop, for further molecular breeding. Here, two putative SL receptors SsD14a/b and the interacting F-box protein SsMAX2 were identified in Saccharum spontaneum. SL induced both SsD14a and SsD14b to interact with SsMAX2 in yeast. SsD14a, but not SsD14b, could bind with AtMAX2 and AtSMXL7/SsSMXL7. Overexpression of SsD14a or SsMAX2 rescued the increased branching phenotypes of Arabidopsis thaliana d14-1 or max2-3 mutants, respectively. Moreover, the crystal structure of N-terminal truncated SsD14a was solved, with an overall structure identical to AtD14 and OsD14 in the open state, consistent with its conserved branching suppression capacity in Arabidopsis. In line with the biochemical observations, SsD14b could not completely complement in d14-1 although these two SsD14 proteins have almost identical primary sequences except for very few residues. Complement with the combination of SsD14b and SsMAX2 still failed to rescue the d14-1 max2-3 double mutant multi-branching phenotype, indicating SsD14b-AtSMXL7 complex formation is required for regulating branching. Mutagenesis analyses revealed that residue R310 at alpha10 helix of SsD14a was crucial for the binding with SsSMXL7/AtSMXL7 but not SsMAX2. The site-equivalent single-residue P304R substitution enabled SsD14b to bind with AtMAX2 and AtSMXL7/SsSMXL7 and to rescue the phenotype of d14-1 max2-3 together with SsMAX2. Moreover, this conserved Arg residue across species including rice and Arabidopsis determined the activity of SL receptors through maintaining their interaction with SMXL repressors. Taken together, our work identified conserved and divergent strigolactone receptors in sugarcane core SL signaling pathway and revealed a key residue crucial for plant branching control.
ESTHER : Hu_2021_Front.Plant.Sci_12_747160
PubMedSearch : Hu_2021_Front.Plant.Sci_12_747160
PubMedID: 34858455
Gene_locus related to this paper: 9poal-a0a0d5nt23

Title : Molecular basis for high ligand sensitivity and selectivity of strigolactone receptors in Striga - Wang_2021_Plant.Physiol_185_1411
Author(s) : Wang Y , Yao R , Du X , Guo L , Chen L , Xie D , Smith SM
Ref : Plant Physiol , 185 :1411 , 2021
Abstract : Seeds of the root parasitic plant Striga hermonthica can sense very low concentrations of strigolactones (SLs) exuded from host roots. The S. hermonthica hyposensitive to light (ShHTL) proteins are putative SL receptors, among which ShHTL7 reportedly confers sensitivity to picomolar levels of SL when expressed in Arabidopsis thaliana. However, the molecular mechanism underlying ShHTL7 sensitivity is unknown. Here we determined the ShHTL7 crystal structure and quantified its interactions with various SLs and key interacting proteins. We established that ShHTL7 has an active-site pocket with broad-spectrum response to different SLs and moderate affinity. However, in contrast to other ShHTLs, we observed particularly high affinity of ShHTL7 for F-box protein AtMAX2. Furthermore, ShHTL7 interacted with AtMAX2 and with transcriptional regulator AtSMAX1 in response to nanomolar SL concentration. ShHTL7 mutagenesis analyses identified surface residues that contribute to its high-affinity binding to AtMAX2 and residues in the ligand binding pocket that confer broad-spectrum response to SLs with various structures. Crucially, yeast-three hybrid experiments showed that AtMAX2 confers responsiveness of the ShHTL7-AtSMAX1 interaction to picomolar levels of SL in line with the previously reported physiological sensitivity. These findings highlight the key role of SL-induced MAX2-ShHTL7-SMAX1 complex formation in determining the sensitivity to SL. Moreover, these data suggest a strategy to screen for compounds that could promote suicidal seed germination at physiologically relevant levels.
ESTHER : Wang_2021_Plant.Physiol_185_1411
PubMedSearch : Wang_2021_Plant.Physiol_185_1411
PubMedID: 33793945
Gene_locus related to this paper: strhe-ShHTL7

Title : Cholinesterase is Associated With Prognosis and Response to Chemotherapy in Advanced Gastric Cancer - Bi_2021_Pathol.Oncol.Res_27_580800
Author(s) : Bi Y , Zhang J , Zeng D , Chen L , Ye W , Yang Q , Ling Y
Ref : Pathol Oncol Res , 27 :580800 , 2021
Abstract : Background: Cholinesterase (CHE) is a routine serum biomarker in gastric cancer (GC). However, little research has been done on its clinical value in advanced GC. In addition, it is not clear whether it can be used as biomarker for the response and prognosis of advanced GC patients. Methods: Between Jan. 2013 and Dec. 2016, a total of 150 patients with advanced GC treated with first-line chemotherapy were admitted to Changzhou Tumor Hospital Affiliated to Soochow University. We retrospectively identified serum CHE level on the day before chemotherapy and at the end of chemotherapy and abstracted clinicopathologic features and treatment outcomes. Univariate and multivariate survival analyses were performed to assess the relationship between serum CHE levels and progression-free survival (PFS) and overall survival (OS). Results: A total of 150 advanced GC patients were included and divided into serum level <=5,000 IU/L and serum level <5,000 IU/L. CHE level lower than 5,000 IU/L was associated with poorer PFS (HR, 1.60; 95% CI, 1.141-2.243; p = 0.006), poorer OS (HR, 1.76; 95% CI, 1.228-2.515; p = 0.002) and trend of poorer response (HR, 0.56; 95% CI, 0.272-1.129; p = 0.104). In univariate and multivariate logistic regression analysis, only liver metastasis and PS score were significantly associated with objective response (p < 0.05). The medium PFS was 8.0 months in patients with post-treatment CHE increased vs. 3.8 months in patients with CHE decreased after chemotherapy (HR, 1.82; 95% CI 1.28-2.57; p = 0.0002). The medium OS was 13.1 months in patients with increased post-treatment CHE vs. 8.1 months in patients with decreased post-treatment CHE (HR, 1.87; 95% CI 1.29-2.71; p = 0.0002). Conclusion: Advanced GC with CHE levels below 5,000 IU/L was significantly associated with poor PFS and OS. The results suggested that CHE analysis before chemotherapy was a promising prognostic marker for advanced GC.
ESTHER : Bi_2021_Pathol.Oncol.Res_27_580800
PubMedSearch : Bi_2021_Pathol.Oncol.Res_27_580800
PubMedID: 34257526

Title : Synergistic enhancement of the emergency treatment effect of organophosphate poisoning by a supramolecular strategy - Chen_2021_Chem.Sci_12_5202
Author(s) : Chen J , Zhang Y , Chai Y , Meng Z , Chen L , Quan D , Wang Y , Meng Q , Li C
Ref : Chem Sci , 12 :5202 , 2021
Abstract : Poisoning by organophosphorus agents (OPs) is a serious public health issue across the world. These compounds irreversibly inhibit acetylcholinesterase (AChE), resulting in the accumulation of acetylcholine (ACh) and overstimulation of ACh receptors. A supramolecular detoxification system (SDS) has been designed with a view to deliver pyridine-2-aldoxime methochloride (PAM) with a synergistic inhibition effect on the ACh-induced hyperstimulation through host-guest encapsulation. NMR and fluorescence titration served to confirm the complexation between carboxylatopillar[6]arene (CP6A) and PAM as well as ACh with robust affinities. Patch-clamp studies proved that CP6A could exert an inhibition effect on the ACh-induced hyperstimulation of ACh receptors. Support for the feasibility of this strategy came from fluorescence imaging results. In vivo studies revealed that complexation by CP6A serves to increase the AChE reactivation efficiency of PAM. The formation of the PAM/CP6A complex contributed to enhance in a statistically significant way the ability of PAM not only to relieve symptoms of seizures but also to improve the survival ratio in paraoxon-poisoned model rats. These favorable findings are attributed to synergistic effects that PAM reactivates AChE to hydrolyze ACh and excess ACh is encapsulated in the cavity of CP6A to relieve cholinergic crisis symptoms.
ESTHER : Chen_2021_Chem.Sci_12_5202
PubMedSearch : Chen_2021_Chem.Sci_12_5202
PubMedID: 34163757

Title : Strigolactone mimic 2-nitrodebranone is highly active in Arabidopsis growth and development - Li_2021_Plant.J__
Author(s) : Li S , Li Y , Chen L , Zhang C , Wang F , Li H , Wang M , Wang Y , Nan F , Xie D , Yan J
Ref : Plant J , : , 2021
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.
ESTHER : Li_2021_Plant.J__
PubMedSearch : Li_2021_Plant.J__
PubMedID: 33860570

Title : Broad-spectrum pesticide screening by multiple cholinesterases and thiocholine sensors assembled high-throughput optical array system - Chen_2021_J.Hazard.Mater_402_123830
Author(s) : Chen L , Tian X , Li Y , Lu L , Nie Y , Wang Y
Ref : J Hazard Mater , 402 :123830 , 2021
Abstract : Accurate screening of organophosphorus and carbamates pesticides from the complex real sample is crucial for water quality analysis and food safety control. Herein, a simple, low-cost and accurate pesticides screening method based on a high-throughput optical array system assembled by multiple cholinesterases (ChE) and thiocholine (TCh) sensors is described. The detection mechanism is that the inhibition of ChE activity by pesticides reduces the TCh produced by the hydrolysis of butyryl/acetylthiocholine iodide, thus changing the fluorescence intensity of TCh sensor. The diverse response of ChEs to pesticides and different affinity of sensors to TCh ensure the high-throughput and distinguishable signal output, which allow the establishment of high discrete pesticide database with intra-cluster agglomeration and inter-cluster dispersion. By using the database, the screening of unknown real contaminated samples were successfully operated, and the screened pesticide species and concentrations were consistent with high-performance liquid chromatography. This screening strategy demonstrates the feasibility of replacing existing complex mass spectrometry-based screening strategy with simple optical analysis, providing a new idea for the development of simple accurate screening technologies for widespread organic pollutants including pesticides.
ESTHER : Chen_2021_J.Hazard.Mater_402_123830
PubMedSearch : Chen_2021_J.Hazard.Mater_402_123830
PubMedID: 33254811

Title : A new diterpenoid alkaloid from Delphinium gyalanum C. Marquand & Airy Shaw - Li_2021_Nat.Prod.Res__1
Author(s) : Li X , Ye M , Gao F , Zhou X , Chen L , Huang S
Ref : Nat Prod Res , :1 , 2021
Abstract : A new C(19)-diterpenoid alkaloid named gyalanutine A (1) and fourteen known compounds 2-15 were isolated from the plant of Delphinium gyalanum C. Marquand & Airy Shaw. Compound 1 displayed an unusual lycoctonine-type C(19)-diterpenoid alkaloid skeleton with the cleavage of N-C(19) and C(7)-C(17) bonds, and the construction of the N-C(7) bond. Structures were identified by multiple spectroscopic analyses including 1 D, 2 D NMR, IR and HR-ESI-MS. Compounds were tested for acetylcholinesterase inhibitory and anti-inflammatory activity.
ESTHER : Li_2021_Nat.Prod.Res__1
PubMedSearch : Li_2021_Nat.Prod.Res__1
PubMedID: 34241556

Title : Near-infrared fluorescent probe for evaluating the acetylcholinesterase effect in the aging process and dietary restriction via fluorescence imaging - He_2021_J.Mater.Chem.B__
Author(s) : He N , Yu L , Xu M , Huang Y , Wang X , Chen L , Yue S
Ref : J Mater Chem B , : , 2021
Abstract : Dietary restriction (DR), as a natural intervention, not only benefits the neuroendocrine system, but also has an antiaging action. Acetylcholinesterase (AChE) is one of the most important bioactive substances and plays a major part in choline changes in the aging process. Thus, we aim to evaluate the effect of DR on AChE in the brains of aging animals. In this study, we synthesize a NIR fluorescent probe BD-AChE for the real-time and in situ monitoring of AChE level changes in living cells and living mice, notably in brains. In situ visualization with BD-AChE verified a decrease in the AchE level in the brains of mice aging models. Evidently, the prepared probe has the excellent capability of measuring AChE variation in the brains of aging mice with DR via NIR fluorescence bioimaging, indicating that long-term DR can effectively affect AChE levels in the brain. The attenuation of AChE level in the brain of aging mice after DR could be helpful in infering the advantageous impact of DR on age-related neurodegenerative disease, as a better treatment alternative in the future.
ESTHER : He_2021_J.Mater.Chem.B__
PubMedSearch : He_2021_J.Mater.Chem.B__
PubMedID: 33666613

Title : Electro-Acupuncture Improve the Early Pattern Separation in Alzheimer's Disease Mice via Basal Forebrain-Hippocampus Cholinergic Neural Circuit - Li_2021_Front.Aging.Neurosci_13_770948
Author(s) : Li L , Li J , Dai Y , Yang M , Liang S , Wang Z , Liu W , Chen L , Tao J
Ref : Front Aging Neurosci , 13 :770948 , 2021
Abstract : OBJECTIVES: To explore the effect of electro-acupuncture (EA) treatment on pattern separation and investigate the neural circuit mechanism involved in five familial mutations (5 x FAD) mice. METHODS: Five familial mutations mice were treated with EA at Baihui (DU20) and Shenting (DU24) acupoints for 30 min each, lasting for 4 weeks. Cognitive-behavioral tests were performed to evaluate the effects of EA treatment on cognitive functions. (1)H-MRS, Nissl staining, immunohistochemistry, and immunofluorescence were performed to examine the cholinergic system alteration. Thioflavin S staining and 6E10 immunofluorescence were performed to detect the amyloid-beta (Abeta). Furthermore, hM4Di designer receptors exclusively activated by designer drugs (DREADDs) virus and long-term clozapine-N-oxide injection were used to inhibit the medial septal and vertical limb of the diagonal band and dentate gyrus (MS/VDB-DG) cholinergic neural circuit. Cognitive-behavioral tests and immunofluorescence were performed to investigate the cholinergic neural circuit mechanism of EA treatment improving cognition in 5 x FAD mice. RESULTS: Electro-acupuncture treatment significantly improved spatial recognition memory and pattern separation impairment, regulated cholinergic system via reduction neuron loss, upregulation of choline/creatine, choline acetyltransferase, vesicular acetylcholine transporter, and downregulation of enzyme acetylcholinesterase in 5 x FAD mice. Abeta deposition was reduced after EA treatment. Subsequently, the monosynaptic hM4Di DREADDs virus tracing and inhibiting strategy showed that EA treatment activates the MS/VDB-DG cholinergic neural circuit to improve the early pattern separation. In addition, EA treatment activates this circuit to upregulating M1 receptors positive cells and promoting hippocampal neurogenesis in the dentate gyrus (DG). CONCLUSION: Electro-acupuncture could improve the early pattern separation impairment by activating the MS/VDB-DG cholinergic neural circuit in 5 x FAD mice, which was related to the regulation of the cholinergic system and the promotion of neurogenesis by EA treatment.
ESTHER : Li_2021_Front.Aging.Neurosci_13_770948
PubMedSearch : Li_2021_Front.Aging.Neurosci_13_770948
PubMedID: 35185516

Title : Autistic-like behavior, spontaneous seizures, and increased neuronal excitability in a Scn8a mouse model - Wong_2021_Neuropsychopharmacology__
Author(s) : Wong JC , Grieco SF , Dutt K , Chen L , Thelin JT , Inglis GAS , Parvin S , Garraway SM , Xu X , Goldin AL , Escayg A
Ref : Neuropsychopharmacology , : , 2021
Abstract : Patients with SCN8A epileptic encephalopathy exhibit a range of clinical features, including multiple seizure types, movement disorders, and behavioral abnormalities, such as developmental delay, mild-to-severe intellectual disability, and autism. Recently, the de novo heterozygous SCN8A R1620L mutation was identified in an individual with autism, intellectual disability, and behavioral seizures without accompanying electrographic seizure activity. To date, the effects of SCN8A mutations that are primarily associated with behavioral abnormalities have not been studied in a mouse model. To better understand the phenotypic and functional consequences of the R1620L mutation, we used CRISPR/Cas9 technology to generate mice expressing the corresponding SCN8A amino acid substitution. Homozygous mutants exhibit tremors and a maximum lifespan of 22 days, while heterozygous mutants (RL/+) exhibit autistic-like behaviors, such as hyperactivity and learning and social deficits, increased seizure susceptibility, and spontaneous seizures. Current clamp analyses revealed a reduced threshold for firing action potentials in heterozygous CA3 pyramidal neurons and reduced firing frequency, suggesting that the R1620L mutation has both gain- and loss-of-function effects. In vivo calcium imaging using miniscopes in freely moving RL/+ mutants showed hyperexcitability of cortical excitatory neurons that is likely to increase seizure susceptibility. Finally, we found that oxcarbazepine and Huperzine A, a sodium channel blocker and reversible acetylcholinesterase inhibitor, respectively, were capable of conferring robust protection against induced seizures in RL/+ mutants. This mouse line will provide the opportunity to better understand the range of clinical phenotypes associated with SCN8A mutations and to develop new therapeutic approaches.
ESTHER : Wong_2021_Neuropsychopharmacology__
PubMedSearch : Wong_2021_Neuropsychopharmacology__
PubMedID: 33658654

Title : Improved production of recombinant Rhizomucor miehei lipase by coexpressing protein folding chaperones in Pichia pastoris, which triggered ER stress - Huang_2020_Bioengineered_11_375
Author(s) : Huang J , Zhao Q , Chen L , Zhang C , Bu W , Zhang X , Zhang K , Yang Z
Ref : Bioengineered , 11 :375 , 2020
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%.
ESTHER : Huang_2020_Bioengineered_11_375
PubMedSearch : Huang_2020_Bioengineered_11_375
PubMedID: 32175802
Gene_locus related to this paper: rhimi-lipas

Title : Ajmalicine and its Analogues against AChE and BuChE for the Management of Alzheimer's Disease: An In-silico study - Liu_2020_Curr.Pharm.Des__
Author(s) : Liu S , Dang M , Lei Y , Ahmad SS , Khalid M , Kamal MA , Chen L
Ref : Curr Pharm Des , : , 2020
Abstract : BACKGROUND: Alzheimer's disease (AD) is the most well-known reason for disability in persons aged greater than 65 years worldwide. AD influences the part of the brain that controls cognitive and noncognitive functions. OBJECTIVE: The study focuses on the screening of natural compounds for the inhibition of AChE and BuChE using a computational methodology. METHODS: We performed a docking-based virtual screening utilizing the 3D structure of AChE and BuChE to search for potential inhibitors for AD. In this work, a screened inhibitor Ajmalicine similarity search was carried out against a natural products database (Super Natural II). Lipinski rule of five was carried out and docking studies were performed between ligands and enzyme using 'Autodock4.2'. RESULTS: Two phytochemical compounds SN00288228 and SN00226692 were predicted for the inhibition of AChE and BuChE, respectively. The docking results revealed Ajmalicine, a prominent natural alkaloid, showing promising inhibitory potential against AChE and BuChE with the binding energy of - 9.02 and -8.89 kcal/mole respectively. However, SN00288228- AChE, and SN00226692-BuChE were found to have binding energy -9.88 and -9.54 kcal/mole, respectively. These selected phytochemical compounds showed better interactions in comparison to Ajmalicine with the target molecule. CONCLUSION: The current study verifies that SN00288228 and SN00226692 are more capable inhibitors of human AChE and BuChE as compared to Ajmalicine with reference to DeltaG values.
ESTHER : Liu_2020_Curr.Pharm.Des__
PubMedSearch : Liu_2020_Curr.Pharm.Des__
PubMedID: 32264807

Title : Lipase catalysis of alpha-linolenic acid-rich medium- and long-chain triacylglycerols from perilla oil and medium-chain triacylglycerols with reduced by-products - Huang_2020_J.Sci.Food.Agric_100_4565
Author(s) : Huang Z , Cao Z , Guo Z , Chen L , Wang Z , Sui X , Jiang L
Ref : J Sci Food Agric , 100 :4565 , 2020
Abstract : BACKGROUND: Medium- and long- chain triacylglycerols (MLCTs) are functional structural lipids that can provide the human body with essential fatty acids and a faster energy supply. This study aimed to prepare MLCTs rich in alpha-linolenic by enzymatic interesterification of perilla oil and medium-chain triacylglycerols (MCTs), catalyzed by Lipozyme RM IM, Lipozyme TL IM, Lipozyme 435, and Novozyme 435 respectively. RESULTS: The effects of lipase loading, concentration of MCTs, reaction temperature, and reaction time on the yield of MLCTs were investigated. It was found that the reaction achieved more than a 70% yield of MLCTs in triacylglycerols under the conditions of 400 g kg(-1) MCTs and 60 g kg(-1) lipase loading after equilibrium. A novel two-stage deodorization was also applied to purify the interesterification products. The triacylglycerols reach over 97% purity in the products with significant removal (P < 0.05) of the free fatty acids, and the trans fatty acids were strictly controlled at below 1%. There was more than 40% alpha-linolenic in the purified products, with long-chain fatty acids mostly occupying the desired sn-2 position in acylglycerols, which are more active in hydrolysis. CONCLUSION: A series of novel alpha-linolenic acid-rich medium- and long-chain triacylglycerols was prepared. Under appropriate reaction conditions, the yield of MLCTs in triacylglycerols was above 70%. A novel two-stage deodorization can be used to promote the elimination of free fatty acids and limit the generation of trans fatty acids.
ESTHER : Huang_2020_J.Sci.Food.Agric_100_4565
PubMedSearch : Huang_2020_J.Sci.Food.Agric_100_4565
PubMedID: 32419135

Title : Dietary administration of probiotic Lactobacillus rhamnosus modulates the neurological toxicities of perfluorobutanesulfonate in zebrafish - Liu_2020_Environ.Pollut_265_114832
Author(s) : Liu M , Song S , Hu C , Tang L , Lam JCW , Lam PKS , Chen L
Ref : Environ Pollut , 265 :114832 , 2020
Abstract : Perfluorobutanesulfonate (PFBS), an aquatic pollutant of emerging concern, is found to disturb the neural signaling along gut-brain axis, whereas probiotic additives have been applied to improve neuroendocrine function of teleosts. Both PFBS and probiotics can commonly target nervous system. However, whether and how probiotic bacteria can modulate the neurotoxicities of PFBS remain not explored. It is thus necessary to elucidate the probiotic modulation of PFBS neurotoxicity, which can provide implications to the application of probiotic bacteria in aquaculture industry. In the present study, adult zebrafish were exposed to 0, 10 and 100 mug/L PFBS with or without dietary administration of probiotic Lactobacillus rhamnosus. Interaction between PFBS and probiotic along gut-brain axis was examined, covering three dominant pathways (i.e., neurotransmission, immune response and hypothalamic-pituitary-adrenal (HPA) axis). The results showed that, compared to the single effects, PFBS and probiotic coexposure significantly altered the acetylcholinesterase activity and neurotransmitter profiles in gut and brain of zebrafish, with mild effects on neuronal integrity. Neurotransmitters closely correlated reciprocally in intestines, which, however, was distinct from the correlation profile in brains. In addition, PFBS and probiotic were combined to impact brain health through absorption of bacterial lipopolysaccharides and production of inflammatory cytokines. Relative to neurotransmission and immune signaling, HPA axis was not involved in the neurotoxicological interaction between PFBS and probiotic. Furthermore, it needs to point out that interactive modes between PFBS and probiotic varied a lot, depending on exposure concentrations, sex and toxic indices. Overall, the present study provided the first evidence that probiotic supplement could dynamically modulate the neurotoxicities of PFBS in teleost.
ESTHER : Liu_2020_Environ.Pollut_265_114832
PubMedSearch : Liu_2020_Environ.Pollut_265_114832
PubMedID: 32454362

Title : Structural basis for the inhibitor and substrate specificity of the unique Fph serine hydrolases of Staphylococcus aureus - Fellner_2020_ACS.Infect.Dis_6_2771
Author(s) : Fellner M , Lentz CS , Jamieson SA , Brewster JL , Chen L , Bogyo M , Mace PD
Ref : ACS Infect Dis , 6 :2771 , 2020
Abstract : Staphylococcus aureus is a prevalent bacterial pathogen in both community and hospital settings, and its treatment is made particularly difficult by resilience within biofilms. Within this niche, serine hydrolase enzymes play a key role in generating and maintaining the biofilm matrix. Activity-based profiling has previously identified a family of serine hydrolases, designated fluorophosphonate-binding hydrolases (Fphs), some of which contribute to the virulence of S. aureus in vivo. These ten Fph proteins have limited annotation, and have few, if any, characterized bacterial or mammalian homologs. This suggests unique hydrolase functions even within bacterial species. Here we report structures of one of the most abundant Fph family members, FphF. Our structures capture FphF alone, covalently bound to a substrate analog, and bound to small molecule inhibitors that occupy the hydrophobic substrate-binding pocket. In line with these findings, we show that FphF has promiscuous esterase activity towards hydrophobic lipid substrates. We present docking studies that characterize interactions of inhibitors and substrates within the active site environment, which can be extended to other Fph family members. Comparison of FphF to other esterases and the wider Fph protein family suggest that FphF forms a new esterase subfamily. Our data suggest that other Fph enzymes, including the virulence factor FphB, are likely to have more restricted substrate profiles than FphF. This work demonstrates a clear molecular rationale for the specificity of fluorophosphonate probes that target FphF and provides a structural template for the design of enhanced probes and inhibitors of the Fph family of serine hydrolases.
ESTHER : Fellner_2020_ACS.Infect.Dis_6_2771
PubMedSearch : Fellner_2020_ACS.Infect.Dis_6_2771
PubMedID: 32865965
Gene_locus related to this paper: staau-MW0741 , staau-MW2456 , staau-SA1143 , staau-SA2240 , staau-SA2306 , staau-SA2367 , staau-SA2422 , staau-SAV0457 , staau-SAV1793 , staau-SAV2188

Title : Discovery of Pyranoviolin A and Its Biosynthetic Gene Cluster in Aspergillus violaceofuscus - Wei_2020_Front.Microbiol_11_562063
Author(s) : Wei X , Chen L , Tang JW , Matsuda Y
Ref : Front Microbiol , 11 :562063 , 2020
Abstract : A new polyketide-non-ribosomal peptide hybrid molecule, pyranoviolin A (1), was discovered from the genome-sequenced fungus Aspergillus violaceofuscus CBS 115571 and was characterized to be the first pyranonigrin analog harboring the C-3 methoxy group. Examination of the genome sequence of the fungus identified a putative biosynthetic gene cluster of 1, which was designated as the pyv cluster. The gene deletion experiment of the polyketide synthase (PKS)-non-ribosomal peptide synthetase (NRPS) hybrid gene in the cluster confirmed the involvement of the pyv cluster in the pyranoviolin A biosynthesis. Finally, a plausible biosynthetic route leading to 1 has been proposed based on the bioinformatic analysis. Our study indicates that metabolite analysis of genome-sequenced microorganisms whose metabolites have been largely unexplored facilitates the discovery of new secondary metabolites along with their biosynthetic gene clusters.
ESTHER : Wei_2020_Front.Microbiol_11_562063
PubMedSearch : Wei_2020_Front.Microbiol_11_562063
PubMedID: 33117309
Gene_locus related to this paper: aspv1-pyvd

Title : Diterpenoid alkaloids from Aconitum anthoroideum that offer protection against MPP(+)-Induced apoptosis of SH-SY5Y cells and acetylcholinesterase inhibitory activity - Huang_2020_Phytochemistry_178_112459
Author(s) : Huang S , Zhang JF , Chen L , Gao F , Zhou XL
Ref : Phytochemistry , 178 :112459 , 2020
Abstract : Nine unprecedented diterpenoid alkaloid, including a diterpenoid alkaloid featuring a diterpenoid moiety, anthoroidine A; one bisditerpenoid alkaloid joined with a carbon-carbon single bond, anthoroidine B; three racemulosine-type C(20)-diterpenoid alkaloids, anthoroidines C-E; one hetidine-type C(20)-diterpenoid alkaloid, anthoroidine F; and three hetisine-type C(20)-diterpenoid alkaloids, anthoroidines G-I, together with ten known diterpenoid alkaloids were isolated from Aconitum anthoroideum DC. Their structures were established via detailed spectroscopic analyses. Most of the isolated compounds along with five known diterpenoid alkaloids obtained in a previous study were screened for neuroprotective activities and acetylcholinesterase inhibitory effects. Nominine showed potent protective activity against MPP(+)-induced apoptosis in SH-SY5Y cells, with a rescue rate of 34.4% (50 muM). Rotundifosine F showed a significant inhibitory activity against AChE (IC(50) = 0.3 muM). The structure-activity relationship of these alkaloids is also briefly discussed.
ESTHER : Huang_2020_Phytochemistry_178_112459
PubMedSearch : Huang_2020_Phytochemistry_178_112459
PubMedID: 32888673

Title : Colonization of Beauveria bassiana 08F04 in root-zone soil and its biocontrol of cereal cyst nematode (Heterodera filipjevi) - Zhang_2020_PLoS.One_15_e0232770
Author(s) : Zhang J , Fu B , Lin Q , Riley IT , Ding S , Chen L , Cui J , Yang L , Li H
Ref : PLoS ONE , 15 :e0232770 , 2020
Abstract : Cereal cyst nematodes cause serious yield losses of wheat in Hunaghuai winter wheat growing region in China. Beauveria bassiana 08F04 isolated from the surface of cysts is a promising biological control agent for cereal cyst nematodes. As the colonization capacity is a crucial criteria to assess biocontrol effectiveness for a microbial agent candidate, we aimed to label B. bassiana 08F04 for efficient monitoring of colonization in the soil. The binary pCAM-gfp plasmid containing sgfp and hph was integrated into B. bassiana 08F04 using the Agrobacterium tumefaciens-mediated transformation. The transformation caused a significant change in mycelial and conidial yields, and in extracellular chitinase activity in some transformants. The cultural filtrates of some transformants also decreased acetylcholinesterase activity and the survival of Heterodera filipjevi second-stage juveniles relative to the wild-type strain. One transformant (G10) had a growth rate and biocontrol efficacy similar to the wild-type strain, so it was used for a pilot study of B. bassiana colonization conducted over 13 weeks. Real-time PCR results and CFU counts revealed that the population of G10 increased quickly over the first 3 weeks, then decreased slowly over the following 4 weeks before stabilizing. In addition, the application of wild-type B. bassiana 08F04 and transformant G10 significantly reduced the number of H. filipjevi females in roots by 64.4% and 60.2%, respectively. The results of this study have practical applications for ecological, biological and functional studies of B. bassiana 08F04 and for bionematicide registration.
ESTHER : Zhang_2020_PLoS.One_15_e0232770
PubMedSearch : Zhang_2020_PLoS.One_15_e0232770
PubMedID: 32369513

Title : Rhizomucor miehei lipase-catalysed synthesis of cocoa butter equivalent from palm mid-fraction and stearic acid: Characteristics and feasibility as cocoa butter alternative - Huang_2020_Food.Chem__128407
Author(s) : Huang Z , Guo Z , Xie D , Cao Z , Chen L , Wang H , Jiang L , Shen Q
Ref : Food Chem , :128407 , 2020
Abstract : In this study, cocoa butter equivalents (CBEs) were prepared through enzymatic interesterification of palm mid-fraction (PMF) with stearic acid (SA). The reaction process parameters were experimented and the performance of the product was analysed. PMF and stearic acid (at a mass ratio of 1:2) were catalysed by 80 g kg(-1) enzyme loading of Lipozyme RM IM fromRhizomucor mieheiat 60 degreeC for 120 min. The yield of the CBE product was more than 92%, and the CBE resembled cocoa butter (CB) in terms of its triacylglycerol composition. The hardness of the CBE product was higher than that of CB at different storage temperatures, but this difference was not obvious at 25 degreeC. The polymorphic structures and SFC curve of the CBE were similar to those of the CB. In addition, the CBE could be mixed with CB in any ratio without an obvious eutectic phenomena. Up to 40% CBE could be added to CB without significantly affecting the thermodynamic properties of CB. Thus, replacing CB with the CBE product is feasible.
ESTHER : Huang_2020_Food.Chem__128407
PubMedSearch : Huang_2020_Food.Chem__128407
PubMedID: 33129620

Title : Increased cross-linking micelle retention in the brain of Alzheimer's disease mice by elevated asparagine endopeptidase protease responsive aggregation - Ren_2020_Biomater.Sci_8_6533
Author(s) : Ren J , Jiang F , Wang M , Hu H , Zhang B , Chen L , Dai F
Ref : Biomater Sci , 8 :6533 , 2020
Abstract : Current forms of medication for Alzheimer's disease (AD) provide a symptomatic benefit limited to those with early onset, but there is no single drug available for later stage patients. Given the recent failures of AD drugs in clinical trials, an intensive treatment strategy based on drug combination that is approved is attractive. At present, the greatest difficulty lies in the low accumulation of drugs in the brain. All hydrophilic drugs are limited by the physical and biochemical barriers within the blood-brain barrier and lipophilic drugs are often transported back into the blood by efflux pumps located in the blood-brain barrier. Here, we select elevated asparagine endopeptidase (AEP) as a target to trigger in situ cross-linking of small sized particles to form large sized drug clusters to block the efflux of the brain. Subsequently, responsive cross-linking micelles (RCMs) loaded with the acetylcholinesterase inhibitor, donepezil (DON), the microtubule therapeutic agent, Paclitaxel (PTX), and the glucose metabolism disorder regulator, insulin (INS) are investigated, with a focus on high levels of drug accumulation in the brain in AD. These smart multi-drug delivery RCMs provide a powerful system for AD treatment and can be adapted for other central nervous system (CNS) disorders.
ESTHER : Ren_2020_Biomater.Sci_8_6533
PubMedSearch : Ren_2020_Biomater.Sci_8_6533
PubMedID: 33111725

Title : Molecular Basis for the Biosynthesis of an Unusual Chain-Fused Polyketide Gregatin A - Wang_2020_J.Am.Chem.Soc_142_8464
Author(s) : Wang WG , Wang H , Du LQ , Li M , Chen L , Yu J , Cheng GG , Zhan MT , Hu QF , Zhang L , Yao M , Matsuda Y
Ref : Journal of the American Chemical Society , 142 :8464 , 2020
Abstract : Gregatin A (1) is a fungal polyketide featuring an alkylated furanone core, but the biosynthetic mechanism to furnish the intri-guing molecular skeleton has yet to be elucidated. Herein, we have identified the biosynthetic gene cluster of gregatin A (1) in Penicillium sp. sh18, and investigated the mechanism that produces the intriguing structure of 1 by in vivo and in vitro recon-stitution of its biosynthesis. Our study established the biosynthetic route leading to 1, and illuminated that 1 is generated by the fusion of two different polyketide chains, which are, amazingly, synthesized by a single PKS GrgA with the aid of a trans-acting enoylreductase GrgB. Chain fusion, as well as chain hydrolysis, is catalyzed by an alpha/beta hydrolase GrgF, hybridizing the C11 and C4 carbon chains by Claisen condensation. Finally, structural analysis and mutational experiments using GrgF provided insight into how the enzyme facilitates the unusual chain-fusing reaction. In unraveling a new biosynthetic strategy involving a bifunc-tional PKS and a polyketide fusing enzyme, our study expands our knowledge concerning fungal polyketide biosynthesis.
ESTHER : Wang_2020_J.Am.Chem.Soc_142_8464
PubMedSearch : Wang_2020_J.Am.Chem.Soc_142_8464
PubMedID: 32275405
Gene_locus related to this paper: pensq-GrgF

Title : In vitro biolayer interferometry analysis of acetylcholinesterase as a potential target of aryl-organophosphorus flame-retardants - Shi_2020_J.Hazard.Mater_409_124999
Author(s) : Shi Q , Guo W , Shen Q , Han J , Lei L , Chen L , Yang L , Feng C , Zhou B
Ref : J Hazard Mater , 409 :124999 , 2020
Abstract : Organophosphorus flame retardants (OPFRs) have been implicated as neurotoxicants, but their potential neurotoxicity and mechanisms remain poorly understood. Herein, we investigated the neurotoxicity of selected OPFRs using zebrafish as a model organism. Environmentally relevant concentrations (3-1500 nM) of three classes of OPFRs (aryl-OPFRs, chlorinated-OPFRs, and alkyl-OPFRs) were tested in zebrafish larvae (2-144 h post-fertilisation) alongside the neurotoxic chemical chlorpyrifos (CPF) that inhibits acetylcholinesterase (AChE). Exposure to aryl-OPFRs and CPF inhibited AChE activities, while chlorinated- and alkyl-OPFRs did not inhibit these enzymes. Biolayer interferometry (BLI) was used to probe interactions between OPFRs and AChE. The association and dissociation response curves showed that, like CPF, all three selected aryl-OPFRs, triphenyl phosphate (TPHP), tricresyl phosphate (TCP) and cresyl diphenyl phosphate (CDP), bound directly to AChE. The affinity constant (K(D)) for TPHP, TCP, CDP and CPF was 2.18 x 10(-4), 5.47 x 10(-5), 1.05 x 10(-4) and 1.70 x 10(-5) M, respectively. In addition, molecular docking revealed that TPHP, TCP, CDP and CPF bound to AChE with glide scores of - 7.8, - 8.3, - 8.1 and - 7.3, respectively. Furthermore, the calculated binding affinity between OPFRs and AChE correlated well with the K(D) values measured by BLI. The present study revealed that aryl-OPFRs can act as potent AChE inhibitors, and may therefore present a significant ecological risk to aquatic organisms.
ESTHER : Shi_2020_J.Hazard.Mater_409_124999
PubMedSearch : Shi_2020_J.Hazard.Mater_409_124999
PubMedID: 33454525

Title : Rational design and biological evaluation of a new class of thiazolopyridyl tetrahydroacridines as cholinesterase and GSK-3 dual inhibitors for Alzheimer's disease - Jiang_2020_Eur.J.Med.Chem_207_112751
Author(s) : Jiang X , Zhou J , Wang Y , Chen L , Duan Y , Huang J , Liu C , Chen Y , Liu W , Sun H , Feng F , Qu W
Ref : Eur Journal of Medicinal Chemistry , 207 :112751 , 2020
Abstract : A key factor in the success of the MTDLs drug discovery approach is the selection of suitable target proteins. Based on the results of our previous research regarding dual-target inhibitors of AChE/GSK-3beta and analysis of target proteins, in the current study, 28 hybrids were designed and synthesized. Docking studies allowed us to rationalize the binding mode of the synthesized compounds in both targets. In vitro enzyme inhibition studies identified compound GT15 as a lead molecule with preferential AChE/GSK-3beta inhibition (hAChE IC(50) = 1.2 +/- 0.1 nM; hGSK-3beta IC(50) = 22.2 +/- 1.4 nM). In addition, GT15 showed high kinase selectivity for GSK-3, except for DYRK1, with inhibition rate of 83.69% and 67.94% against DYRK1alpha and DYRK1beta at a concentration of 20 muM. The compound also exhibited good permeability across the blood-brain-barrier and ability to inhibit the phosphorylation of tau protein. Upon oral administration, GT15 exhibited promising cognitive improvement in the scopolamine-induced cognitive deficit mice in the Morris water maze model. These results suggest that AChE and GSK-3 based multitargeted approach have therapeutic potential for Alzheimer's disease.
ESTHER : Jiang_2020_Eur.J.Med.Chem_207_112751
PubMedSearch : Jiang_2020_Eur.J.Med.Chem_207_112751
PubMedID: 32950908

Title : An optimized acetylcholine sensor for monitoring in vivo cholinergic activity - Jing_2020_Nat.Methods_17_1139
Author(s) : Jing M , Li Y , Zeng J , Huang P , Skirzewski M , Kljakic O , Peng W , Qian T , Tan K , Zou J , Trinh S , Wu R , Zhang S , Pan S , Hires SA , Xu M , Li H , Saksida LM , Prado VF , Bussey TJ , Prado MAM , Chen L , Cheng H
Ref : Nat Methods , 17 :1139 , 2020
Abstract : The ability to directly measure acetylcholine (ACh) release is an essential step toward understanding its physiological function. Here we optimized the GRAB(ACh) (GPCR-activation-based ACh) sensor to achieve substantially improved sensitivity in ACh detection, as well as reduced downstream coupling to intracellular pathways. The improved version of the ACh sensor retains the subsecond response kinetics, physiologically relevant affinity and precise molecular specificity for ACh of its predecessor. Using this sensor, we revealed compartmental ACh signals in the olfactory center of transgenic flies in response to external stimuli including odor and body shock. Using fiber photometry recording and two-photon imaging, our ACh sensor also enabled sensitive detection of single-trial ACh dynamics in multiple brain regions in mice performing a variety of behaviors.
ESTHER : Jing_2020_Nat.Methods_17_1139
PubMedSearch : Jing_2020_Nat.Methods_17_1139
PubMedID: 32989318

Title : Preventive Effects of Different Fermentation Times of Shuidouchi on Diphenoxylate-Induced Constipation in Mice - Chen_2019_Foods_8_
Author(s) : Chen L , Zhang J , Suo H , Wang W , Wang H , Zhang Y , Hu Q , Zhao X , Li J
Ref : Foods , 8 : , 2019
Abstract : This study compares the prevention effects of Shuidouchi with different fermentation times on constipation in mice. Shuidouchi is a short-time fermented soybean product. By improving its processing technology, it can incur better biological activity and become a health food. The Shuidouchi-treated mice were evaluated using constipation-related kits, quantitative polymerase chain reaction (qPCR), and Western blot assays. After the mice were fed 72-h-fermented Shuidouchi (72-SDC) for 9 d, the defecation time to excrete the first black stool was lower than that of the control and 24-SDC and 48-SDC groups, but was much higher than that of the normal group. The gastrointestinal (GI) transit of the small intestine of the 72-SDC group was higher than that of the control and the 24-SDC and 48-SDC groups, but lower that of the normal group. Meanwhile, 72-SDC could significantly increase the levels of ghrelin, endothelin-1 (ET-1), vasoactive intestinal peptide (VIP), and acetylcholinesterase (AchE) in the serum of constipated mice compared to the levels in mice in the control group. Moreover, 72-SDC could raise c-Kit, stem cell factor (SCF), glial cell-derived neurotrophic factor (GNDF), neuronal nitric oxide synthase (nNOS), and endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA) and protein expression levels, and reduce transient receptor potential cation channel subfamily V member 1 (TRPV1) and inducible nitric oxide synthase (iNOS) expression levels in small-intestinal tissue compared to the levels in the control group. Meanwhile, 72-SDC also raised ghrelin mRNA expression in gastric tissue and transient receptor potential ankyrin 1 (TRPA1) mRNA expression in colon tissue compared to the control group mice; these effects were stronger than those of 24-SDC and 48-SDC. Shuidouchi has good preventative effects on constipation and performs best when fermented for at least 72 h.
ESTHER : Chen_2019_Foods_8_
PubMedSearch : Chen_2019_Foods_8_
PubMedID: 30832248

Title : Effects of Picrasma quassioides and its active constituents on Alzheimer's disease in vitro and in vivo - Guo_2019_Bioorg.Chem_92_103258
Author(s) : Guo E , Hu Y , Du T , Zhu H , Chen L , Qu W , Zhang J , Xie N , Liu W , Feng F , Xu J
Ref : Bioorg Chem , 92 :103258 , 2019
Abstract : Alzheimer disease (AD), a prevalent neurodegenerative disorder, is one of the leading causes of dementia. However, there is no effective drug for this disease to date. Picrasma quassioides (D.Don) Benn, a Chinese traditional medicine, was used mainly for the treatment of inflammation, fever, microbial infection and dysentery. In this paper, we reported that the EtOAc extract of Picrasma quassioides stems showed potential neuroprotective activities in l-glutamate-stimulated PC12 and Abeta25-35-stimulated SH-SY5Y cell models, as well as improved memory and cognitive abilities in AD mice induced by amyloid-beta peptide. Moreover, it was revealed that the anti-AD mechanism was related to suppressing neuroinflammatory and reducing Abeta1-42 deposition using ELISA assay kits. To clarify the active components of the EtOAc extract of Picrasma quassioides stems, a systematic phytochemistry study led to isolate and identify six beta-carboline alkaloids (1-6), seven canthin-6-one alkaloids (7-13), and five quassinoids (14-18). Among them, four beta-carbolines (1-3, and 6) and six canthin-6-ones (7-11, and 13) exhibited potential neuroprotective activities in vitro. Based on these date, the structure-activity relationships of alkaloids were discussed. Furthermore, molecular docking experiments showed that compounds 2 and 3 have high affinity for both of dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYPKIA) and butyrylcholinesterase (BuChE).
ESTHER : Guo_2019_Bioorg.Chem_92_103258
PubMedSearch : Guo_2019_Bioorg.Chem_92_103258
PubMedID: 31520892

Title : Pharmacological Effects of Verticine: Current Status - Yin_2019_Evid.Based.Complement.Alternat.Med_2019_2394605
Author(s) : Yin Z , Zhang J , Guo Q , Chen L , Zhang W , Kang W
Ref : Evid Based Complement Alternat Med , 2019 :2394605 , 2019
Abstract : Verticine is the major bioactive constituent of Fritillaria as a kind of Traditional Chinese Medicine. Pharmacological researches have reported various benefits of verticine, including anticancer, anti-inflammatory, protecting against acute lung injury, tracheobronchial relaxation, antitussive, expectorant, sedative, and analgesic activities, in addition to inhibiting proliferation of cultured orbital fibroblast, angiotensin converting enzyme (ACE), and acetylcholinesterase (AChE) and inhibiting hERG potassium channels. The underlying mechanisms of verticine are still under investigation. This review will comprehensively summarize the metabolism, biological activities, and possible mechanism of verticine.
ESTHER : Yin_2019_Evid.Based.Complement.Alternat.Med_2019_2394605
PubMedSearch : Yin_2019_Evid.Based.Complement.Alternat.Med_2019_2394605
PubMedID: 30956677

Title : Bioaccumulation, behavior changes and physiological disruptions with gender-dependent in lizards (Eremias argus) after exposure to glufosinate-ammonium and l-glufosinate-ammonium - Zhang_2019_Chemosphere_226_817
Author(s) : Zhang L , Chen L , Meng Z , Zhang W , Xu X , Wang Z , Qin Y , Deng Y , Liu R , Zhou Z , Diao J
Ref : Chemosphere , 226 :817 , 2019
Abstract : Reptiles, the most diverse taxon of terrestrial vertebrates, might be particularly vulnerable to soil pollution. Reptiles especially lizards have been rarely evaluated in ecotoxicological studies, and there is a very limited report for effects of soil pesticide contaminants on lizards. In this study, male and female lizards (Eremias argus) were exposed to Glufosinate-ammonium (GLA) and l- Glufosinate-ammonium (L-GLA) for 60 days. Slower sprint speed, higher frequency of turning back and reduced brain index were observed in treatment groups. The accumulation of GLA in the brain of lizard was higher than that of L-GLA. Moreover, the activities of neurotoxicity-related enzymes and biomarkers of oxidative stress were also investigated. In summary, the neurotoxic effects of lizards have been observed after exposure to GLA and L-GLA. Based on the result of the Integrated Biomarker Response (IBR), males were more sensitive to contaminants than females. On the other hand, the neurotoxic pathways by GLA and L-GLA triggered were slightly different: GLA mainly acted on glutamine synthetase (GS), acetylcholinesterase (AchE) and Catalase (CAT) and L-GLA aimed at AchE, Na(+)/K(+)-ATPase, Superoxide dismutase (SOD) and Malondialdehyde (MDA). In summary, the accumulation of GLA and L-GLA in lizard's brain induced neurotoxicity by altering the levels of enzymes related to nervous system and antioxidant activity and further resulted in the decrease of brain index and locomotor performance.
ESTHER : Zhang_2019_Chemosphere_226_817
PubMedSearch : Zhang_2019_Chemosphere_226_817
PubMedID: 30965253

Title : Synthesis and biological evaluation of calycanthaceous alkaloid analogs - Zheng_2019_Bioorg.Med.Chem__115088
Author(s) : Zheng S , Zhu R , Zhou X , Chen L , Bai H , Zhang J
Ref : Bioorganic & Medicinal Chemistry , :115088 , 2019
Abstract : Starting from 9-methyl-1,2,3,4,9,9a-hexahydro-4aH-pyrido[2,3-b]indol-4a-ol, or indole-3-acetonitrile, 40 new calycanthaceous alkaloid analogs were synthesized in excellent yields. The prepared compounds were evaluated for biological activity against acetylcholinesterase and a broad range of plant pathogen fungi. The results of bioassays indicated that the majority of tested compounds displayed comparable or better in vitro bioactivity than the positive control. Notably, compounds b8 and b9 showed higher activity against Verticillium dahlia than chlorothalonil, with MIC values of 62.5 and 7.81microgmL(-1), respectively. Compound b3 had a higher activity against Bacillus cereus, with a MIC value of 15.63microgmL(-1). Compounds c2 and c11 revealed potent activity against acetylcholinesterase, with MIC values of 0.01 and 0.1ngmL(-1), respectively. Analysis of the molecular docking modes of c2 and c11 with Torpedo californica acetylcholinesterase indicated a medium strong hydrogen bond interaction between the hydroxyl groups of both the ligands and the phenolic hydroxyl of Try121 at a distance of approximately 2.4A. The results obtained in this study will be useful for the further design and structural optimization of calycanthaceous alkaloids as potential agrochemical lead compounds for plant disease control.
ESTHER : Zheng_2019_Bioorg.Med.Chem__115088
PubMedSearch : Zheng_2019_Bioorg.Med.Chem__115088
PubMedID: 31521458

Title : Different construction strategies affected on the physiology of Pichia pastoris strains highly expressed lipase by transcriptional analysis of key genes - Huang_2019_Bioengineered_10_150
Author(s) : Huang J , Wang Q , Bu W , Chen L , Yang Z , Zheng W , Li Y , Li J
Ref : Bioengineered , 10 :150 , 2019
Abstract : We demonstrated previously that expression of Rhizomucor miehei lipase (RML) in Pichia pastoris could be significantly increased by addition of gene propeptide, optimized signal peptide codons and manipulation of gene dosage. In this study, effects of various strategies on the protein synthesis and secretion pathways were analyzed. Using nine strains previously constructed, we evaluated cell culture properties, enzymatic activities, and analyzed transcriptional levels of nine genes involved in protein synthesis and secretion pathways by qPCR. We observed that (i) Addition of propeptide decreased lipase folding stress by down-regulated four UPR-related genes. (ii) Signal peptide codons optimization had no effect on host with no change in the nine detected genes. (iii) Folding stress and limited transport capacity produced when rml gene dosage exceed 2. Different limiting factors on lipase expression in strains with different construction strategies were identified. This study provides a theoretical basis for further improving RML by transforming host.
ESTHER : Huang_2019_Bioengineered_10_150
PubMedSearch : Huang_2019_Bioengineered_10_150
PubMedID: 31079540

Title : Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction - Xu_2019_Lab.Invest_99_1078
Author(s) : Xu H , Chen L , Zhang X , Jiang X , Tian W , Yu W , Wang X , Tian J , Su D
Ref : Lab Invest , 99 :1078 , 2019
Abstract : Postoperative cognitive dysfunction (POCD) is consistently associated with increased morbidity and mortality. However, its mechanism remains poorly understood. We hypothesized that central cholinergic neuronal degeneration facilitates the development of POCD. The impact of anesthesia/surgery (appendectomy) on learning and memory and the levels of choline acetyltransferase (ChAT), acetylcholinesterase (AChE), vesicular acetylcholine transporter (VAChT), and choline transporter (CHT) in adult and aged mice were measured. Separate cohorts were analyzed after pretreatment with donepezil, an AChE inhibitor, in aged mice or with murine-p75-saporin (mu-p75-sap), a cholinergic-specific immunotoxin, in adult mice. Morris Water Maze was used to measure the learning and memory changes after anesthesia/surgery. Western blot was used to measure the changes in the protein levels of the biomarkers of the central cholinergic system. We found that anesthesia/surgery-induced memory decline and attenuation of central cholinergic biomarkers (ChAT and VAChT) in aged mice but not in adult mice. Donepezil pretreatment reduced central cholinergic impairment in the aged mice and prevented learning and memory declines after anesthesia/surgery. In contrast, when central cholinergic neurons were pre-injured with mu-p75-sap, cognitive dysfunction developed in the adult mice after anesthesia/surgery. These data suggest that central cholinergic neuronal degeneration facilitates the development of POCD.
ESTHER : Xu_2019_Lab.Invest_99_1078
PubMedSearch : Xu_2019_Lab.Invest_99_1078
PubMedID: 30626892

Title : Single-particle enumeration-based ultrasensitive enzyme activity quantification with fluorescent polymer nanoparticles - Han_2019_Nanoscale_11_14793
Author(s) : Han Y , Ye Z , Wang F , Chen T , Wei L , Chen L , Xiao L
Ref : Nanoscale , 11 :14793 , 2019
Abstract : Acetylcholinesterase (AChE) plays a vital role in nerve conduction through rapidly hydrolyzing the neurotransmitter acetylcholine (ACh) and is correlated with Alzheimer's disease. In this work, a label-free single-particle enumeration (SPE) method for the quantitative detection of acetylcholinesterase (AChE) activity is developed. The design is based on the fluorescence resonance energy transfer (FRET) between fluorescent conjugated polymer nanoparticles (FCPNPs) and MnO2 nanosheets. The fluorescence of FCPNPs can be effectively quenched by MnO2 nanosheets via hydrogen bonding interaction. In the presence of acetylcholinesterase (AChE), acetylthiocholine (ATCh) could be hydrolyzed to thiocholine (TCh), which can reduce MnO2 to Mn2+ and trigger the decomposition of MnO2 nanosheets. As a result, the fluorescence of FCPNPs is restored. Taking advantage of the superior brightness and stable fluorescence emission from individual FCPNPs, the accurate quantification of AChE is achieved by statistically counting the fluorescent particles on the glass slide surface. A linear range from 5 to 1600 muU mL-1 is obtained for AChE assay and the limit-of-detection (LOD) is 1.02 muU mL-1, which is far below the spectroscopic measurements in bulk solution. In the human serum sample, satisfactory recovery efficiencies are determined in a range of 91.0%-103.0%. Furthermore, pesticide carbaryl as an inhibitor of AChE activity was detected. The LOD is 1.12 pg mL-1 with linear responses ranging from 5 to 300 pg mL-1, which demonstrates the feasibility of this approach for AChE inhibitor screening. As a consequence, the label-free SPE-based method affords a promising platform for the sensitive detection of target molecules in the future.
ESTHER : Han_2019_Nanoscale_11_14793
PubMedSearch : Han_2019_Nanoscale_11_14793
PubMedID: 31353389

Title : Acute exposure to triphenyl phosphate (TPhP) disturbs ocular development and muscular organization in zebrafish larvae - Shi_2019_Ecotoxicol.Environ.Saf_179_119
Author(s) : Shi Q , Tsui MMP , Hu C , Lam JCW , Zhou B , Chen L
Ref : Ecotoxicology & Environmental Safety , 179 :119 , 2019
Abstract : Triphenyl phosphate (TPhP) is an organophosphate flame retardant that is frequently detected in the environments. TPhP exposure is known to cause developmental toxicity. However, the underlying molecular mechanisms remain underestimated. In the present study, zebrafish embryos were acutely exposed to 0, 4 and 100mug/L TPhP until 144h post-fertilization. Profiles of differentially expressed proteins were constructed using a shotgun proteomic. With the input of differential proteins, principal component analysis suggested different protein expression profiles for 4 and 100mug/L TPhP. Gene ontology and KEGG pathway analyses further found that effects of TPhP at 4mug/L targeted phagosome and lysosome activity, while 100mug/L TPhP mainly affected carbohydrate metabolism, muscular contraction and phagosome. Based on proteomic data, diverse bioassays were employed to ascertain the effects of TPhP on specific proteins and pathways. At gene and protein levels, expressions of critical visual proteins were significantly changed by TPhP exposure, including retinoschisin 1a, opsins and crystallins, implying the impairment of ocular development and function. TPhP exposure at 100mug/L also altered the abundances of diverse muscular proteins and disordered the assembly of muscle fibers. Effects of TPhP on visual development and motor activity may be combined to disturb larval swimming behavior. In summary, current results provided mechanistic clues to the developmental toxicities of TPhP. Future works are inspired to broaden the toxicological knowledge of TPhP based on current proteomic results.
ESTHER : Shi_2019_Ecotoxicol.Environ.Saf_179_119
PubMedSearch : Shi_2019_Ecotoxicol.Environ.Saf_179_119
PubMedID: 31035246

Title : Biodegradation of mycotoxin fumonisin B1 by a novel bacterial consortium SAAS79 - Zhao_2019_Appl.Microbiol.Biotechnol_103_7129
Author(s) : Zhao Z , Zhang Y , Gong A , Liu N , Chen S , Zhao X , Li X , Chen L , Zhou C , Wang J
Ref : Applied Microbiology & Biotechnology , 103 :7129 , 2019
Abstract : Fumonisin B1 (FB1) contamination in cereals and cereal products remains an important aspect of food safety because of its wide distribution and the potential health hazard. However, only a few microorganisms have been reported to effectively degrade FB1. In this present study, a bacterial consortium SAAS79 with highly FB1-degrading activity was isolated from the spent mushroom compost. The combination of antibiotic-driven selection and 16S rDNA sequencing identified the Pseudomonas genus as the key FB1-degrading member. The microbial consortium could degrade more than 90% of 10 microg/mL FB1 after incubation for 24 h at pH of 5-7 and temperature of 28-35 degreesC. The enzymes from the intracellular space were proved to be responsible for FB1 degradation, which eliminated about 90% of 10 microg/mL FB1 in 3 h. Besides, liquid chromatography time-of-flight mass spectrometry (LC-TOF/MS) analysis identified two degradation products of FB1, and their toxicity on the monkey kidney cells (MARC-145) was significantly lower (p < 0.05) compared with the parent FB1. Overall, the consortium SAAS79 and its crude enzymes may be a potential choice for the decontamination of FB1 in the feed and food industry. Also, the bacterial consortium provides a new source of genes for the development of enzymatic detoxification agent.
ESTHER : Zhao_2019_Appl.Microbiol.Biotechnol_103_7129
PubMedSearch : Zhao_2019_Appl.Microbiol.Biotechnol_103_7129
PubMedID: 31230101

Title : Fluorescent Triazole Urea Activity-Based Probes for the Single-Cell Phenotypic Characterization of Staphylococcus aureus - Chen_2019_Angew.Chem.Int.Ed.Engl_58_5643
Author(s) : Chen L , Keller LJ , Cordasco E , Bogyo M , Lentz CS
Ref : Angew Chem Int Ed Engl , 58 :5643 , 2019
Abstract : Phenotypically distinct cellular (sub)populations are clinically relevant for the virulence and antibiotic resistance of a bacterial pathogen, but functionally different cells are usually indistinguishable from each other. Herein, we introduce fluorescent activity-based probes as chemical tools for the single-cell phenotypic characterization of enzyme activity levels in Staphylococcus aureus. We screened a 1,2,3-triazole urea library to identify selective inhibitors of fluorophosphonate-binding serine hydrolases and lipases in S. aureus and synthesized target-selective activity-based probes. Molecular imaging and activity-based protein profiling studies with these probes revealed a dynamic network within this enzyme family involving compensatory regulation of specific family members and exposed single-cell phenotypic heterogeneity. We propose the labeling of enzymatic activities by chemical probes as a generalizable method for the phenotyping of bacterial cells at the population and single-cell level.
ESTHER : Chen_2019_Angew.Chem.Int.Ed.Engl_58_5643
PubMedSearch : Chen_2019_Angew.Chem.Int.Ed.Engl_58_5643
PubMedID: 30768830

Title : Distribution characteristics of sweat gland nerve fibres in normal humans identified by acetylcholinesterase histochemical staining - Ling_2019_Clin.Neurol.Neurosurg_189_105620
Author(s) : Ling L , Liu Y , Sun Y , Cai Y , Jiang Y , Chen L , He L , Xue J
Ref : Clin Neurol Neurosurg , 189 :105620 , 2019
Abstract : OBJECTIVE: To quantitatively analyze distribution characteristics of sweat gland nerve fibres (SGNF) in normal Chinese individuals for obtaining a reference for early diagnosis of peripheral neuropathy. PATIENTS AND METHODS: Skin biopsy samples were collected from 192 normal Chinese individuals and divided into six, four and two groups according to anatomic sites, age and gender, respectively. SGNF morphology was observed and SGNF density (SGNFD) was determined. RESULTS: There was a significant difference in SGNFD among different anatomic sites, age and gender. A degressive tendency was observed from proximal to distal anatomic sites. SGNFD was the lowest in subjects in the 21-40-year-old age group, but was the highest in subjects in the >61-year-old age group. Overall, SGNFD fluctuated with age. SGNFD in males was significantly higher than that in females. CONCLUSIONS: Distribution characteristics of SGNF in normal individuals may serve as a reference for early diagnosis of nerve fibre damage.
ESTHER : Ling_2019_Clin.Neurol.Neurosurg_189_105620
PubMedSearch : Ling_2019_Clin.Neurol.Neurosurg_189_105620
PubMedID: 31812030

Title : Long noncoding RNA ABHD11-AS1 promote cells proliferation and invasion of colorectal cancer via regulating the miR-1254-WNT11 pathway - He_2019_J.Cell.Physiol_234_12070
Author(s) : He D , Yue Z , Liu L , Fang X , Chen L , Han H
Ref : Journal of Cellular Physiology , 234 :12070 , 2019
Abstract : The purpose of our study was to investigate the effects of the long noncoding RNA (lncRNA) ABHD11-AS1 on colorectal cancer (CRC) progression and further explore its possible underlying mechanisms. In the study, we found that ABHD11-AS1 was highly expressed in CRC tissues and cell lines. High ABHD11-AS1 expression was correlated with poor overall survival of patients with CRC. ABHD11-AS1 knockdown reduced CRC cell proliferation, in vitro invasion, and in vivo tumor growth. Investigation of the underlying mechanism showed that ABHD11-AS1 could act as a molecular sponge of miR-1254, and WNT11 was a downstream target of miR-1254 in CRC. Moreover, there was a negative association between ABHD11-AS1 expression (or WNT11) and miR-1254 in CRC tissues. The rescue assays showed that WNT11 overexpression partially rescued the effects of ABHD11-AS1 inhibition on CRC progression. Thus, we demonstrated that ABHD11-AS1 promotes CRC progression through the miR-1254-WNT11 pathway, which provides a new insight into the therapeutic strategies for CRC.
ESTHER : He_2019_J.Cell.Physiol_234_12070
PubMedSearch : He_2019_J.Cell.Physiol_234_12070
PubMedID: 30537177
Gene_locus related to this paper: human-ABHD11

Title : Palmitoylation signaling: a novel mechanism of mitochondria dynamics and diverse pathologies -
Author(s) : Tang M , Lu L , Huang Z , Chen L
Ref : Acta Biochim Biophys Sin (Shanghai) , 50 :831 , 2018
PubMedID: 29924300

Title : Synthesis and Evaluation of Novel Ligustrazine Derivatives as Multi-Targeted Inhibitors for the Treatment of Alzheimer's Disease - Wu_2018_Molecules_23_
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
Ref : Molecules , 23 : , 2018
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.
ESTHER : Wu_2018_Molecules_23_
PubMedSearch : Wu_2018_Molecules_23_
PubMedID: 30301153

Title : Oxoisoaporphine Alkaloids: Prospective Anti-Alzheimer's Disease, Anticancer, and Antidepressant Agents - Zhang_2018_ChemMedChem_13_1262
Author(s) : Zhang J , Chen L , Sun J
Ref : ChemMedChem , 13 :1262 , 2018
Abstract : Oxoisoaporphine alkaloids are a family of oxoisoquinoline-derived alkaloids that were first isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It has been demonstrated that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and beta-amyloid inhibition, acting as a topoisomerase intercalator, monoamine oxidase A inhibition, and are expected to become anti-Alzheimer's disease, anticancer, and antidepressant drugs. This review provides an overview of natural sources, synthetic routes, bioactivities, structure-function relationship, and modification investigations into oxoisoaporphine alkaloids, with the aim of providing references to the structure-activity relationships for the design and development of oxoisoaporphine derivatives with higher efficacy and therapeutic potential.
ESTHER : Zhang_2018_ChemMedChem_13_1262
PubMedSearch : Zhang_2018_ChemMedChem_13_1262
PubMedID: 29696800

Title : Three-dimensional reconstructed eccrine sweat glands with vascularization and cholinergic and adrenergic innervation - Zhang_2018_J.Mol.Histol_49_339
Author(s) : Zhang M , Li H , Chen L , Fang S , Xie S , Lin C
Ref : J Mol Histol , 49 :339 , 2018
Abstract : Functional integrity of the regenerated tissues requires not only structural integrity but also vascularization and innervation. We previously demonstrated that the three-dimensional (3D) reconstructed eccrine sweat glands had similar structures as those of the native ones did, but whether the 3D reconstructed glands possessing vascularization and innervation was still unknown. In the study, Matrigel-embedded eccrine sweat gland cells were implanted under the inguinal skin. Ten weeks post-implantation, the vascularization, and innervation in the 10-week reconstructed eccrine sweat glands and native human eccrine sweat glands were detected by immunofluorescence staining. The results showed that the fluorescent signals of general neuronal marker protein gene product 9.5, adrenergic nerve fiber marker tyrosine hydroxylase, and cholinergic nerve fiber markers acetylcholinesterase and vasoactive intestinal peptide embraced the 3D reconstructed glands in circular patterns, as the signals appeared in native eccrine sweat glands. There were many CD31- and von Willebrand factor-positive vessels growing into the plugs. We demonstrated that the 3D reconstructed eccrine sweat glands were nourished by blood vessels, and we for the first time demonstrated that the engineering sweat glands were innervated by both cholinergic and adrenergic fibers. In conclusion, the 3D reconstructed eccrine sweat glands may have functions as the native ones do.
ESTHER : Zhang_2018_J.Mol.Histol_49_339
PubMedSearch : Zhang_2018_J.Mol.Histol_49_339
PubMedID: 29667149

Title : Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases - Kuhnert_2018_Environ.Microbiol_20_3325
Author(s) : Kuhnert E , Li Y , Lan N , Yue Q , Chen L , Cox RJ , An Z , Yokoyama K , Bills GF
Ref : Environ Microbiol , 20 :3325 , 2018
Abstract : Enfumafungin is a glycosylated fernene-type triterpenoid produced by the fungus Hormonema carpetanum. Its potent antifungal activity, mediated by its interaction with beta-1,3-glucan synthase and the fungal cell wall, has led to its development into the semi-synthetic clinical candidate, ibrexafungerp (=SCY-078). We report on the preliminary identification of the enfumafungin biosynthetic gene cluster (BGC) based on genome sequencing, phylogenetic reconstruction, gene disruption, and cDNA sequencing studies. Enfumafungin synthase (efuA) consists of a terpene cyclase domain (TC) fused to a glycosyltransferase (GT) domain and thus represents a novel multifunctional enzyme. Moreover, the TC domain bears a phylogenetic relationship to bacterial squalene-hopene cyclases (SHC) and includes a typical DXDD motif within the active centre suggesting that efuA evolved from SHCs. Phylogenetic reconstruction of the GT domain indicated that this portion of the fusion gene originated from fungal sterol GTs. Eleven genes flanking efuA are putatively involved in the biosynthesis, regulation, transport and self-resistance of enfumafungin and include an acetyltransferase, three P450 monooxygenases, a dehydrogenase, a desaturase and a reductase. A hypothetical scheme for enfumafungin assembly is proposed in which the E-ring is oxidatively cleaved to yield the four-ring system of enfumafungin. EfuA represents the first member of a widespread lineage of fungal SHCs.
ESTHER : Kuhnert_2018_Environ.Microbiol_20_3325
PubMedSearch : Kuhnert_2018_Environ.Microbiol_20_3325
PubMedID: 30051576
Gene_locus related to this paper: horcr-efuc , horcr-efuk

Title : Detoxification of diphenyl ether herbicide lactofen by Bacillus sp. Za and enantioselective characteristics of an esterase gene lacE - Zhang_2018_J.Hazard.Mater_341_336
Author(s) : Zhang J , Lu L , Chen F , Chen L , Yin J , Huang X
Ref : J Hazard Mater , 341 :336 , 2018
Abstract : A bacterial strain Za capable of degrading diphenyl ether herbicide lactofen was isolated and identified as Bacillus sp. This strain could degrade 94.8% of 50mgL-1 lactofen after 4days of inoculation in flasks. It was revealed that lactofen was initially hydrolyzed to desethyl lactofen, which was further transformed to acifluorfen, followed by the reduction of the nitro group to yield aminoacifluorfen. The phytotoxicity of the transformed product aminoacifluorfen to maize was decreased significantly compared with the lactofen. A gene lacE, encoding an esterase responsible for lactofen hydrolysis to desethyl lactofen and acifluorfen continuously, was cloned from Bacillus sp. Za. The deduced amino acid belonging to the esterase family VII contained a typical Ser-His-Asp/Glu catalytic triad and the conserved motifs GXSXG. The purified recombinant protein LacE displayed maximal esterase activity at 40 degrees C and pH 7.0. Additionally, LacE had broad substrate specificity and was capable of hydrolyzing p-nitrophenyl esters. The enantioselectivity of LacE during lactofen degradation was further studied, and the results indicated that the (S)-(+)-lactofen was degraded faster than the (R)-(-)-lactofen, which could illustrate the reported phenomenon that (S)-(+)-lactofen was preferentially degraded in soil and sediment.
ESTHER : Zhang_2018_J.Hazard.Mater_341_336
PubMedSearch : Zhang_2018_J.Hazard.Mater_341_336
PubMedID: 28802244
Gene_locus related to this paper: bacsu-pnbae

Title : Rice DWARF14 acts as an unconventional hormone receptor for strigolactone - Yao_2018_J.Exp.Bot_69_2355
Author(s) : Yao R , Wang L , Li Y , Chen L , Li S , Du X , Wang B , Yan J , Li J , Xie D
Ref : J Exp Bot , 69 :2355 , 2018
Abstract : Strigolactones (SLs) act as an important class of phytohormones to regulate plant shoot branching, and also serve as rhizosphere signals to mediate interactions of host plants with soil microbes and parasitic weeds. SL receptors in dicots, such as DWARF14 in Arabidopsis (AtD14), RMS3 in pea, and ShHTL7 in Striga, serve as unconventional receptors that hydrolyze SLs into a D-ring-derived intermediate CLIM and irreversibly bind CLIM to trigger SL signal transduction. Here, we show that D14 from the monocot rice can complement Arabidopsis d14 mutant and interact with the SL signaling components in Arabidopsis. Our results further reveal that rice D14, similar to SL receptors in dicots, also serves as an unconventional hormone receptor that generates and irreversibly binds the active form of SLs. These findings uncover the conserved functions of D14 proteins in monocots and dicots.
ESTHER : Yao_2018_J.Exp.Bot_69_2355
PubMedSearch : Yao_2018_J.Exp.Bot_69_2355
PubMedID: 29365172

Title : Acetylcholinesterase Inhibitor Donepezil Effects on Plasma beta-Hydroxybutyrate Levels in the Treatment of Alzheimer's Disease - Wan_2018_Curr.Alzheimer.Res_15_917
Author(s) : Wan L , Lu J , Fu J , Huang J , Yang Q , Xin B , Chen L , Huo Y , Zhong Y , Guo C
Ref : Curr Alzheimer Res , 15 :917 , 2018
Abstract : BACKGROUND: Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by a multi-factorial etiology that is not completely understood. Donepezil is a first-line acetylcholinesterase inhibitor used for the treatment of AD that has been found, in addition to its potent acetylcholinesterase inhibitory effect, to act through other non-cholinergic mechanisms such as affecting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma coactivator (PGC1alpha). Mitochondrial biogenesis and PGC-1alpha, at least in part, are associated with hepatic fatty acid oxidation and ketogenesis. Whether donepezil regulates ketogenesis in AD treatment remains unclear. Ketogenesis is important in the progression of AD and is a critical consideration during the therapeutic strategy selection for AD. Thus, our goals were to determine the differences in ketone bodies in patients with AD who were taking donepezil treatment and those who were not, to elucidate the potential effect of AD and donepezil therapy on ketone body metabolic parameters, and to discover the effect of donepezil therapy on ketogenesis in patients with AD. METHODS: Cross-sectional analysis was performed on plasma collected from 145 individuals, namely, elderly adults as healthy controls (n=30), newly diagnosed patients with AD (n=30), patients with AD who responded to donepezil therapy (n=48) and patients with AD who did not respond to donepezil therapy (n=37). Gas chromatography-mass spectrometry was performed to quantify the lipids in the plasma. The level of beta-hydroxybutyrate, a metabolite, was determined by liquid chromatographytandem mass spectrometry, and to gain further insight into the effect of donepezil on ketogenesis, the effects of donepezil were investigated in a mouse model. RESULTS: The level of beta-hydroxybutyrate decreased in AD patients, and donepezil elevated the plasma level of beta-hydroxybutyrate. Donepezil increased the plasma and liver levels of beta-hydroxybutyrate in mice as well as the hepatic expression of PGC-1alpha and the mitochondrial expression of HMG-CoA synthetase 2 (HMGCS2) in response to fasting, causing a subsequent increase in ketogenesis. CONCLUSIONS: Our study revealed that impaired ketogenesis is a metabolic feature of AD. Donepezil had effects on ketogenesis in mice and reversed the decrease in the level of beta-hydroxybutyrate found in patients with AD.
ESTHER : Wan_2018_Curr.Alzheimer.Res_15_917
PubMedSearch : Wan_2018_Curr.Alzheimer.Res_15_917
PubMedID: 29852870

Title : Irreversible strigolactone recognition: a non-canonical mechanism for hormone perception - Yao_2018_Curr.Opin.Plant.Biol_45_155
Author(s) : Yao R , Chen L , Xie D
Ref : Curr Opin Plant Biol , 45 :155 , 2018
Abstract : Unveiling of hormone perception is central to comprehending hormone action. It is generally recognized that an active hormone molecule binds its receptor to initiate hormone signaling, subsequently dissociates from its receptor without being changed, and then initiates the next round of hormone perception. However, recent studies discovered that the alpha/beta hydrolase DWARF14 serves as a non-canonical receptor for the plant hormone strigolactone (SL) to generate the active form of SL which remains covalently bound in an irreversible manner, triggering SL signal transduction. In this short review, we will discuss the recent advances in uncovering this unprecedented non-canonical mechanism for hormone perception.
ESTHER : Yao_2018_Curr.Opin.Plant.Biol_45_155
PubMedSearch : Yao_2018_Curr.Opin.Plant.Biol_45_155
PubMedID: 30014890
Gene_locus related to this paper: arath-AtD14

Title : IMA Genome-F 9: Draft genome sequence of Annulohypoxylon stygium, Aspergillus mulundensis, Berkeleyomyces basicola (syn. Thielaviopsis basicola), Ceratocystis smalleyi, two Cercospora beticola strains, Coleophoma cylindrospora, Fusarium fracticaudum, Phialophora cf. hyalina, and Morchella septimelata - Wingfield_2018_IMA.Fungus_9_199
Author(s) : Wingfield BD , Bills GF , Dong Y , Huang W , Nel WJ , Swalarsk-Parry BS , Vaghefi N , Wilken PM , An Z , de Beer ZW , De Vos L , Chen L , Duong TA , Gao Y , Hammerbacher A , Kikkert JR , Li Y , Li H , Li K , Li Q , Liu X , Ma X , Naidoo K , Pethybridge SJ , Sun J , Steenkamp ET , van der Nest MA , van Wyk S , Wingfield MJ , Xiong C , Yue Q , Zhang X
Ref : IMA Fungus , 9 :199 , 2018
Abstract : Draft genomes of the species Annulohypoxylon stygium, Aspergillus mulundensis, Berkeleyomyces basicola (syn. Thielaviopsis basicola), Ceratocystis smalleyi, two Cercospora beticola strains, Coleophoma cylindrospora, Fusarium fracticaudum, Phialophora cf. hyalina and Morchella septimelata are presented. Both mating types (MAT1-1 and MAT1-2) of Cercospora beticola are included. Two strains of Coleophoma cylindrospora that produce sulfated homotyrosine echinocandin variants, FR209602, FR220897 and FR220899 are presented. The sequencing of Aspergillus mulundensis, Coleophoma cylindrospora and Phialophora cf. hyalina has enabled mapping of the gene clusters encoding the chemical diversity from the echinocandin pathways, providing data that reveals the complexity of secondary metabolism in these different species. Overall these genomes provide a valuable resource for understanding the molecular processes underlying pathogenicity (in some cases), biology and toxin production of these economically important fungi.
ESTHER : Wingfield_2018_IMA.Fungus_9_199
PubMedSearch : Wingfield_2018_IMA.Fungus_9_199
PubMedID: 30018880
Gene_locus related to this paper: 9helo-a0a370tge3 , 9helo-a0a3d8spg6 , 9euro-a0a3d8t2t6 , 9euro-a0a3d8t644 , 9helo-a0a370te58 , 9helo-a0a370tt42 , 9helo-a0a370u2s4 , 9helo-a0a3d8s0y2 , 9helo-a0a3d8stp9 , 9helo-a0a370u370 , 9euro-a0a3d8rk78 , 9helo-a0a370tat5 , 9helo-a0a3d8qpi0

Title : ShHTL7 is a non-canonical receptor for strigolactones in root parasitic weeds -
Author(s) : Yao R , Wang F , Ming Z , Du X , Chen L , Wang Y , Zhang W , Deng H , Xie D
Ref : Cell Res , 27 :838 , 2017
PubMedID: 28059066
Gene_locus related to this paper: strhe-ShHTL7

Title : Research Advances and Detection Methodologies for Microbe-Derived Acetylcholinesterase Inhibitors: A Systemic Review - Su_2017_Molecules_22_
Author(s) : Su J , Liu H , Guo K , Chen L , Yang M , Chen Q
Ref : Molecules , 22 : , 2017
Abstract : Acetylcholinesterase inhibitors (AChEIs) are an attractive research subject owing to their potential applications in the treatment of neurodegenerative diseases. Fungi and bacteria are major producers of AChEIs. Their active ingredients of fermentation products include alkaloids, terpenoids, phenylpropanoids, and steroids. A variety of in vitro acetylcholinesterase inhibitor assays have been developed and used to measure the activity of acetylcholinesterases, including modified Ellman's method, thin layer chromatography bioautography, and the combined liquid chromatography-mass spectrometry/modified Ellman's method. In this review, we provide an overview of the different detection methodologies, the microbe-derived AChEIs, and their producing strains.
ESTHER : Su_2017_Molecules_22_
PubMedSearch : Su_2017_Molecules_22_
PubMedID: 28125001

Title : Deleterious Effect of Butyrylcholinesterase K-Variant in Donepezil Treatment of Mild Cognitive Impairment - Sokolow_2017_J.Alzheimers.Dis_56_229
Author(s) : Sokolow S , Li X , Chen L , Taylor KD , Rotter JI , Rissman RA , Aisen PS , Apostolova LG
Ref : J Alzheimers Dis , 56 :229 , 2017
Abstract : BACKGROUND: Donepezil is an acetylcholinesterase inhibitor frequently prescribed for the treatment of mild cognitive impairment (MCI) though not approved by the Food and Drug Administration for this indication. In Alzheimer's disease, butyrylcholinesterase (BChE) activity increases with disease progression and may replace acetylcholinesterase function. The most frequent polymorphism of BChE is the K-variant, which is associated with lower acetylcholine-hydrolyzing activity. BChE-K polymorphism has been studied in Alzheimer's disease progression and donepezil therapy, and has led to contradictory results. OBJECTIVES: To determine whether BChE-K genotype predicts response to donepezil in MCI.
METHODS: We examined the association between BChE-K genotype and changes in cognitive function using the data collected during the ADCS vitamin E/donepezil clinical trial in MCI.
RESULTS: We found significant interactions between BChE-K genotype and the duration of donepezil treatment, with increased changes in MMSE and CDR-SB scores compared to the common allele in MCI subjects treated during the 3-year trial. We found faster MMSE decline and CDR-SB rise in BChE-K homozygous individuals treated with donepezil compared to the untreated. We observed similar interactions between BChE-K genotype and steeper changes in MMSE and CDR-SB scores in APOE4 carriers treated with donepezil compared to controls. CONCLUSION: BChE-K polymorphisms are associated with deleterious changes in cognitive decline in MCI patients treated with donepezil for 3 years. This indicates that BChE-K genotyping should be performed to help identify subsets of subjects at risk for donepezil therapy, like those carrying APOE4. BChE-K and APOE4 carriers should not be prescribed off-label donepezil therapy for MCI management.
ESTHER : Sokolow_2017_J.Alzheimers.Dis_56_229
PubMedSearch : Sokolow_2017_J.Alzheimers.Dis_56_229
PubMedID: 27911294

Title : Endothelial Nox4-based NADPH oxidase regulates atherosclerosis via soluble epoxide hydrolase - Hu_2017_Biochim.Biophys.Acta_1863_1382
Author(s) : Hu P , Wu X , Khandelwal AR , Yu W , Xu Z , Chen L , Yang J , Weisbrod RM , Lee KSS , Seta F , Hammock BD , Cohen RA , Zeng C , Tong X
Ref : Biochimica & Biophysica Acta , 1863 :1382 , 2017
Abstract : Nox4-based NADPH oxidase is a major reactive oxygen species-generating enzyme in the vasculature, but its role in atherosclerosis remains controversial. OBJECTIVE: Our goal was to investigate the mechanisms of endothelial Nox4 in regulating atherosclerosis. APPROACH AND
RESULTS: Atherosclerosis-prone conditions (disturbed blood flow, type I diabetes, and Western diet) downregulated endothelial Nox4 mRNA in arteries. To address whether the downregulated endothelial Nox4 was directly involved in the development of atherosclerosis, we generated mice carrying a human Nox4 P437H dominant negative mutation (Nox4DN), driven by the endothelial specific promoter Tie-2, on atherosclerosis-prone genetic background (ApoE deficient mice) to mimic the effect of decreased endothelial Nox4. Nox4DN significantly increased type I diabetes-induced aortic stiffness and atherosclerotic lesions. Gene analysis indicated that soluble epoxide hydrolase 2 (sEH) was significantly upregulated in Nox4DN endothelial cells (EC). Inhibition of sEH activity in Nox4DN EC suppressed inflammation and macrophage adhesion to EC. On the contrary, overexpression of endothelial wild type Nox4 suppressed sEH, ameliorated Western diet-induced atherosclerosis and decreased aortic stiffness.
CONCLUSIONS: Atherosclerosis-prone conditions downregulated endothelial Nox4 to accelerate the progress of atherosclerosis, at least in part, by upregulating sEH to enhance inflammation.
ESTHER : Hu_2017_Biochim.Biophys.Acta_1863_1382
PubMedSearch : Hu_2017_Biochim.Biophys.Acta_1863_1382
PubMedID: 28185955

Title : Assessment of tissue-specific accumulation, elimination and toxic effects of dichlorodiphenyltrichloroethanes (DDTs) in carp through aquatic food web - Di_2017_Sci.Rep_7_2288
Author(s) : Di S , Liu R , Tian Z , Cheng C , Chen L , Zhang W , Zhou Z , Diao J
Ref : Sci Rep , 7 :2288 , 2017
Abstract : Microcosms containing DDT spiked-sediment, Tubifex tubifex and carp (Cyprinus carpio) were constructed to simulate a freshwater system. The accumulation, elimination and toxic effects of DDT (p,p'-DDT, o,p'-DDT), and its metabolites DDD (p,p'-DDD, o,p'-DDD) and DDE (p,p'-DDE, o,p'-DDE) were studied in T. tubifex and carp. Tissue/organ distributions of DDTs were also investigated in carp. The bioaccumulation and elimination of DDT differed in T. tubifex, carp and its tissues/organs. Unimodal or bimodal distributions were observed, and the concentrations of DDT metabolites (DDD and p,p'-DDE) increased over time. The carp organ with the highest concentrations of DDTs (DDT, DDD and DDE) was the gill. The largest mass distribution of DDTs was also in gill, followed by muscle and gastrointestinal tract. Maximum levels of DDTs in whole carp and carp muscle were 161 and 87 ng/g, respectively; therefore, the levels of DDTs observed in carp in this study were insufficient to constitute a health concern if present in fish for human consumption. Significant changes were observed in some biomarkers, including superoxide dismutase, catalase, glutathione-S-transferase, glutathione, and carboxylesterase, in T. tubifex and carp tissues during DDT exposure. Tissue-specific accumulation of DDTs in carp can be a key indicator of exposure to environmentally relevant concentrations.
ESTHER : Di_2017_Sci.Rep_7_2288
PubMedSearch : Di_2017_Sci.Rep_7_2288
PubMedID: 28536421

Title : Study of acetylcholinesterase activity and apoptosis in SH-SY5Y cells and mice exposed to ethanol - Sun_2017_Toxicology_384_33
Author(s) : Sun W , Chen L , Zheng W , Wei X , Wu W , Duysen EG , Jiang W
Ref : Toxicology , 384 :33 , 2017
Abstract : Ethanol is one of the most commonly abused psychotropic substances with deleterious effects on the central nervous system. Ethanol exposure during development results in the loss of neurons in brain regions and when exposed to ethanol cultured cells undergo apoptosis. To date no information is available on whether abnormally high AChE activity is characteristic of apoptosis in animals exposed to ethanol. The aims of the present study were to determine whether induction of AChE activity is associated with ethanol-induced apoptosis and to explore the mechanism of enhanced AChE activity induced by ethanol. For this purpose, in vitro and in vivo experiments were performed. AChE activity was quantified by spectrophotometry and apoptosis by flow cytometer in SH-SY5Y cells exposed to ethanol. The results showed that cells treated with 500mM ethanol for 24h had a 9-fold increase in apoptotic cells and a 6-fold increase in AChE activity compared with controls. Mice exposed acutely to 200mul of 20% ethanol daily on days 1-4 had elevated AChE activity in plasma on days 3-7. On day 4, plasma AChE activity was 2.4-fold higher than pretreatment activity. More apoptotic cells were found in the brains of treated mice compared to controls. Cells in brain sections that were positive in the TUNEL assay stained for AChE activity. In conclusion, AChE activity and apoptosis were induced in SH-SY5Y cells and mice treated with ethanol, which may indicate that increased AChE may related to apoptosis induced by ethanol. Unusually high AChE activity may be an effect marker of exposure to ethanol. The relationship between AChE and apoptosis might represent a novel mechanism of ethanol-associated neuronal injury.
ESTHER : Sun_2017_Toxicology_384_33
PubMedSearch : Sun_2017_Toxicology_384_33
PubMedID: 28427893

Title : Design, synthesis and biological evaluation of multifunctional tacrine-curcumin hybrids as new cholinesterase inhibitors with metal ions-chelating and neuroprotective property - Liu_2017_Bioorg.Med.Chem_25_2387
Author(s) : Liu Z , Fang L , Zhang H , Gou S , Chen L
Ref : Bioorganic & Medicinal Chemistry , 25 :2387 , 2017
Abstract : Total sixteen tacrine-curcumin hybrid compounds were designed and synthesized for the purpose of searching for multifunctional anti-Alzheimer agents. In vitro studies showed that these hybrid compounds showed good cholinesterase inhibitory activity. Particularly, the potency of K3-2 is even beyond tacrine. Some of the compounds exhibited different selectivity on acetylcholinesterase or butyrylcholinesterase due to the structural difference. Thus, the structure and activity relationship is summarized and further discussed based on molecular modeling studies. The ORAC and MTT assays indicated that the hybrid compounds possessed pronounced antioxidant activity and could effectively protect PC12 cells from the H2O2/Abeta42-induced toxicity. Moreover, the hybrid compounds also showed positive metal ions-chelating ability in vitro, suggesting a potential to halt ion-induced Abeta aggregation. All the obtained results demonstrated that the tacrine-curcumin hybrid compounds, in particular compound K3-2, can be considered as potential therapeutic agents for Alzheimer's disease.
ESTHER : Liu_2017_Bioorg.Med.Chem_25_2387
PubMedSearch : Liu_2017_Bioorg.Med.Chem_25_2387
PubMedID: 28302511

Title : Inhibition of the high affinity choline transporter enhances hyperalgesia in a rat model of chronic pancreatitis - Luo_2017_Biochem.Biophys.Res.Commun_488_204
Author(s) : Luo D , Chen L , Yu B
Ref : Biochemical & Biophysical Research Communications , 488 :204 , 2017
Abstract : BACKGROUND: The mechanisms underlying chronic and persistent pain associated with chronic pancreatitis (CP) are not completely understood. The cholinergic system is one of the major neural pathways of the pancreas. Meanwhile, this system plays an important role in chronic pain. We hypothesized that the high affinity choline transporter CHT1, which is a main determinant of cholinergic signaling capacity, is involved in regulating pain associated with CP.
METHODS: CP was induced by intraductal injection of 2% trinitrobenzene sulfonic acid (TNBS) in Sprague-Dawley rats. Pathological examination was used to evaluate the inflammation of pancreas and hyperalgesia was assessed by measuring the number of withdrawal events evoked by application of the von Frey filaments. CHT1 expression in pancreas-specific dorsal root ganglia (DRGs) was assessed through immunohistochemistry and western blotting. We also intraperitoneally injected the rats with hemicholinium-3 (HC-3, a specific inhibitor of CHT1). Then we observed its effects on the visceral hyperalgesia induced by CP, and on the acetylcholine (ACh) levels in the DRGs through using an acetylcholine/acetylcholinesterase assay kit.
RESULTS: Signs of CP were observed 21 days after TNBS injection. Rats subjected to TNBS infusions had increased sensitivity to mechanical stimulation of the abdomen. CHT1-immunoreactive cells were increased in the DRGs from rats with CP compared to naive or sham rats. Western blots indicated that CHT1 expression was significantly up-regulated in TNBS-treated rats when compared to naive or sham-operated rats at all time points following surgery. In the TNBS group, CHT1 expression was higher on day 28 than on day 7 or day 14, but there was no statistical difference in CHT1 expression on day 28 vs. day 21. Treatment with HC-3 (60 mug/kg, 80 mug/kg, or 100 mug/kg) markedly enhanced the mechanical hyperalgesia and reduced ACh levels in a dose-dependent manner in rats with CP. CONCLUSION: We report for the first time that CHT1 may be involved in pain modulation in CP, as it plays an important role in pain inhibition. Increased CHT1 activity or the up-regulation of its expression may be used to treat pain in patients with CP.
ESTHER : Luo_2017_Biochem.Biophys.Res.Commun_488_204
PubMedSearch : Luo_2017_Biochem.Biophys.Res.Commun_488_204
PubMedID: 28483526

Title : Chemical Composition and Acetylcholinesterase Inhibitory Activity of Essential Oils from Piper Species - Xiang_2017_J.Agric.Food.Chem_65_3702
Author(s) : Xiang CP , Han JX , Li XC , Li YH , Zhang Y , Chen L , Qu Y , Hao CY , Li HZ , Yang CR , Zhao SJ , Xu M
Ref : Journal of Agricultural and Food Chemistry , 65 :3702 , 2017
Abstract : The essential oils (EOs) derived from aromatic plants such as Piper species are considered to play a role in alleviating neuronal ailments that are associated with inhibition of acetylcholinesterase (AChE). The chemical compositions of 23 EOs prepared from 16 Piper spp. were analyzed by both gas chromatography with a flame ionization detector (GC-FID) and gas chromatography-mass spectrometry (GC-MS). A total of 76 compounds were identified in the EOs from the leaves and stems of 19 samples, while 30 compounds were detected in the EOs from the fruits of four samples. Sesquiterpenes and phenylpropanoids were found to be rich in these EOs, of which asaricin, caryophyllene, caryophyllene oxide, isospathulenol, (+)-spathulenol, and beta-bisabolene are the major constituents. The EOs from the leaves and stems of Piper austrosinense, P. puberulum, P. flaviflorum, P. betle, and P. hispidimervium showed strong AChE inhibitory activity with IC50 values in the range of 1.51 to 13.9 mg/mL. A thin-layer chromatography (TLC) bioautography assay was employed to identify active compound(s) in the most active EO from P. hispidimervium. The active compound was isolated and identified as asaricin, which gave an IC50 value of 0.44 +/- 0.02 mg/mL against AChE, comparable to galantamine with an IC50 0.15 +/- 0.01 mg/mL.
ESTHER : Xiang_2017_J.Agric.Food.Chem_65_3702
PubMedSearch : Xiang_2017_J.Agric.Food.Chem_65_3702
PubMedID: 28436658

Title : Colorimetric biosensor for the assay of paraoxon in environmental water samples based on the iodine-starch color reaction - Guo_2017_Anal.Chim.Acta_967_59
Author(s) : Guo L , Li Z , Chen H , Wu Y , Chen L , Song Z , Lin T
Ref : Anal Chim Acta , 967 :59 , 2017
Abstract : In this work, a new colorimetric biosensor for the assay of paraoxon was developed via the conventional iodine-starch color reaction and multi-enzyme cascade catalytic reactions. In the presence of acetylcholine chloride, acetylcholinesterase (AChE) and choline oxidase (ChO) catalyzed the formation of H2O2, which then activated horseradish peroxidase (HRP) to catalyze the oxidation of KI to produce an iodine-starch color reaction. Upon exposure to paraoxon, the catalytic activity of AChE was inhibited and less H2O2 generated, resulting in a decrease in the production of I2 and a drop in the intensity of solution color. This colorimetric biosensor showed high sensitivity for the assay of paraoxon with a limit of detection 4.7 ppb and was applied for the assay of paraoxon in spiked real samples. By employing the conventional iodine-starch color reaction, this biosensor has the potential of on-site assay of OPs residues in environmental samples.
ESTHER : Guo_2017_Anal.Chim.Acta_967_59
PubMedSearch : Guo_2017_Anal.Chim.Acta_967_59
PubMedID: 28390486

Title : Simultaneous bioremediation and biodetection of mercury ion through surface display of carboxylesterase E2 from Pseudomonas aeruginosa PA1 - Yin_2016_Water.Res_103_383
Author(s) : Yin K , Lv M , Wang Q , Wu Y , Liao C , Zhang W , Chen L
Ref : Water Res , 103 :383 , 2016
Abstract : Mercury is a toxic heavy metal and presents significant threats to organisms and natural ecosystems. Recently, the mercury remediation as well as its detection by environmental-friendly biotechnology has received increasing attention. In this study, carboxylesterase E2 from mercury-resistant strain Pseudomonas aeruginosa PA1 has been successfully displayed on the outer membrane of Escherichia coli Top10 bacteria to simultaneously adsorb and detect mercury ion (Hg2+). The transmission electron microscopy analysis shows that Hg2+ can be absorbed by carboxylesterase E2 and accumulated on the outer membrane of surface-displayed E. coli bacteria. The adsorption of Hg2+ followed a physicochemical, equilibrated and saturatable mechanism, which well fits the traditional Langmuir adsorption model. The surface-displayed system can be regenerated through regulating pH values. As its activity can be inhibited by Hg2+, carboxylesterase E2 has been used to detect the concentration of Hg2+ in water samples. The developed surface display system will be of great potential in the simultaneous bioremediation and biodetection of environmental mercury pollution.
ESTHER : Yin_2016_Water.Res_103_383
PubMedSearch : Yin_2016_Water.Res_103_383
PubMedID: 27486950

Title : Association between L55M polymorphism in Paraoxonase 1 and cancer risk: a meta-analysis based on 21 studies - Chen_2016_Onco.Targets.Ther_9_1151
Author(s) : Chen L , Lu W , Fang L , Xiong H , Wu X , Zhang M , Wu S , Yu D
Ref : Onco Targets Ther , 9 :1151 , 2016
Abstract : L55M polymorphism in Paraoxonase 1 (PON1) has been regarded as a risk factor for many cancer types. Nevertheless, the results remain controversial and inconclusive. We therefore performed a meta-analysis of all eligible case-control studies to evaluate the association between L55M polymorphism and cancer risk. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the associations. Finally, a total of 5,627 cases and 6,390 controls, arising from 21 case-control studies, were enrolled in our study. Significant associations between PON1-L55M polymorphism and overall cancer risk were identified in all genetic models. In the stratified analyses by cancer type, PON1-L55M polymorphism was a risk factor for breast cancer in all genetic models, prostate cancer in the heterozygote model (ML vs LL: OR =1.304, 95% CI =1.049-1.620, P heterogeneity=0.067), and ovarian cancer in the recessive model (MM vs ML/LL: OR =1.526, 95% CI =1.110-2.097, P heterogeneity=0.464). Similarly, an increased risk was also identified for the Caucasian population in the heterozygote comparison and homozygote models, and hospital-based controls in all genetic models. To sum up, our study suggests that the PON1-L55M allele increased the risk of cancer. Future well-designed studies with larger sample sizes are warranted to further verify these findings.
ESTHER : Chen_2016_Onco.Targets.Ther_9_1151
PubMedSearch : Chen_2016_Onco.Targets.Ther_9_1151
PubMedID: 27019599

Title : Ferulic acid-carbazole hybrid compounds: Combination of cholinesterase inhibition, antioxidant and neuroprotection as multifunctional anti-Alzheimer agents - Fang_2016_Bioorg.Med.Chem_24_886
Author(s) : Fang L , Chen M , Liu Z , Fang X , Gou S , Chen L
Ref : Bioorganic & Medicinal Chemistry , 24 :886 , 2016
Abstract : In order to search for novel multifunctional anti-Alzheimer agents, a series of ferulic acid-carbazole hybrid compounds were designed and synthesized. Ellman's assay revealed that the hybrid compounds showed moderate to potent inhibitory activity against the cholinesterases. Particularly, the AChE inhibition potency of compound 5k (IC50 1.9muM) was even 5-fold higher than that of galantamine. In addition, the target compounds showed pronounced antioxidant ability and neuroprotective property, especially against the ROS-induced toxicity. Notably, the neuroprotective effect of 5k was obviously superior to that of the mixture of ferulic acid and carbazole, indicating the therapeutic effect of the hybrid compound is better than the combination administration of the corresponding mixture.
ESTHER : Fang_2016_Bioorg.Med.Chem_24_886
PubMedSearch : Fang_2016_Bioorg.Med.Chem_24_886
PubMedID: 26795115

Title : Neuroligin-1 Knockdown Suppresses Seizure Activity by Regulating Neuronal Hyperexcitability - Fang_2016_Mol.Neurobiol_53_270
Author(s) : Fang M , Wei JL , Tang B , Liu J , Chen L , Tang ZH , Luo J , Chen GJ , Wang XF
Ref : Molecular Neurobiology , 53 :270 , 2016
Abstract : Abnormally synchronized synaptic transmission in the brain leads to epilepsy. Neuroligin-1 (NL1) is a synaptic cell adhesion molecule localized at excitatory synapses. NL1 modulates synaptic transmission and determines the properties of neuronal networks in the mammalian central nervous system. We showed that the expression of NL1 and its binding partner neurexin-1beta was increased in temporal lobe epileptic foci in patients and lithium-pilocarpine-treated epileptic rats. We investigated electrophysiological and behavioral changes in epileptic rats after lentivirally mediated NL1 knockdown in the hippocampus to determine whether NL1 suppression prevented seizures and, if so, to explore the probable underlying mechanisms. Our behavioral studies revealed that NL1 knockdown in epileptic rats reduced seizure severity and increased seizure latency. Whole-cell patch-clamp recordings of CA1 pyramidal neurons in hippocampal slices from NL1 knockdown epileptic rats revealed a decrease in spontaneous action potential frequency and a decrease in miniature excitatory postsynaptic current (mEPSC) frequency but not amplitude. The amplitude of N-methyl-D-aspartate receptor (NMDAR)-dependent EPSCs was also selectively decreased. Notably, NL1 knockdown reduced total NMDAR1 expression and the surface/total ratio in the hippocampus of epileptic rats. Taken together, these data indicate that NL1 knockdown in epileptic rats may reduce the frequency and severity of seizures and suppress neuronal hyperexcitability via changes in postsynaptic NMDARs.
ESTHER : Fang_2016_Mol.Neurobiol_53_270
PubMedSearch : Fang_2016_Mol.Neurobiol_53_270
PubMedID: 25428619

Title : Engineering of New Pneumocandin Side-Chain Analogues from Glarea lozoyensis by Mutasynthesis and Evaluation of Their Antifungal Activity - Chen_2016_ACS.Chem.Biol_11_2724
Author(s) : Chen L , Li Y , Yue Q , Loksztejn A , Yokoyama K , Felix EA , Liu X , Zhang N , An Z , Bills GF
Ref : ACS Chemical Biology , 11 :2724 , 2016
Abstract : Pneumocandins are lipohexapeptides of the echinocandin family that inhibit fungal 1,3-beta-glucan synthase. Most of the pathway steps have been identified previously. However, the lipoinitiation reaction has not yet been experimentally verified. Herein, we investigate the lipoinitiation step of pneumocandin biosynthesis in Glarea lozoyensis and demonstrate that the gene product, GLligase, catalyzes this step. Disruption of GLHYD, a gene encoding a putative type II thioesterase and sitting upstream of the pneumocandin acyl side chain synthase gene, GLPKS4, revealed that GLHYD was necessary for optimal function of GLPKS4 and to attain normal levels of pneumocandin production. Double disruption of GLHYD and GLPKS4 did not affect residual function of the GLligase or GLNRPS4. Mutasynthesis experiments with a gene disruption mutant of GLPKS4 afforded us an opportunity to test the substrate specificity of GLligase in the absence of its native polyketide side chain to diversify pneumocandins with substituted side chains. Feeding alternative side chain precursors yielded acrophiarin and four new pneumocandin congeners with straight C14, C15, and C16 side chains. A comprehensive biological evaluation showed that one compound, pneumocandin I (5), has elevated antifungal activity and similar hemolytic activity compared to pneumocandin B(0), the starting molecule for caspofungin. This study demonstrates that the lipoinitiation mechanism in pneumocandin biosynthesis involves interaction among a highly reducing PKS, a putative type II thioesterase, and an acyl AMP-ligase. A comparison of the SAR among pneumocandins with different-length acyl side chains demonstrated the potential for using GLligase for future engineering of new echinocandin analogues.
ESTHER : Chen_2016_ACS.Chem.Biol_11_2724
PubMedSearch : Chen_2016_ACS.Chem.Biol_11_2724
PubMedID: 27494047
Gene_locus related to this paper: glal2-glon

Title : A novel esterase from a marine mud metagenomic library for biocatalytic synthesis of short-chain flavor esters - Gao_2016_Microb.Cell.Fact_15_41
Author(s) : Gao W , Wu K , Chen L , Fan H , Zhao Z , Gao B , Wang H , Wei D
Ref : Microb Cell Fact , 15 :41 , 2016
Abstract : BACKGROUND: Marine mud is an abundant and largely unexplored source of enzymes with unique properties that may be useful for industrial and biotechnological purposes. However, since most microbes cannot be cultured in the laboratory, a cultivation-independent metagenomic approach would be advantageous for the identification of novel enzymes. Therefore, with the objective of screening novel lipolytic enzymes, a metagenomic library was constructed using the total genomic DNA extracted from marine mud.
RESULTS: Based on functional heterologous expression, 34 clones that showed lipolytic activity were isolated. The five clones with the largest halos were identified, and the corresponding genes were successfully overexpressed in Escherichia coli. Molecular analysis revealed that these encoded proteins showed 48-79 % similarity with other proteins in the GenBank database. Multiple sequence alignment and phylogenetic tree analysis classified these five protein sequences as new members of known families of bacterial lipolytic enzymes. Among them, EST4, which has 316 amino acids with a predicted molecular weight of 33.8 kDa, was further studied in detail due to its strong hydrolytic activity. Characterization of EST4 indicated that it is an alkaline esterase that exhibits highest hydrolytic activity towards p-nitrophenyl butyrate (specific activity: 1389 U mg(-1)) at 45 degrees C and pH 8.0. The half-life of EST4 is 55 and 46 h at 40 and 45 degrees C, respectively, indicating a relatively high thermostability. EST4 also showed remarkable stability in organic solvents, retaining 90 % of its initial activity when incubated for 12 h in the presence of hydrophobic alkanes. Furthermore, EST4 was used as an efficient whole-cell biocatalyst for the synthesis of short-chain flavor esters, showing high conversion rate and good tolerance for high substrate concentrations (up to 3.0 M). These results demonstrate a promising potential for industrial scaling-up to produce short-chain flavor esters at high substrate concentrations in non-aqueous media.
CONCLUSIONS: This manuscript reports unprecedented alcohol tolerance and conversion of an esterase biocatalyst identified from a marine mud metagenomic library. The high organic solvent tolerance and thermostability of EST4 suggest that it has great potential as a biocatalyst.
ESTHER : Gao_2016_Microb.Cell.Fact_15_41
PubMedSearch : Gao_2016_Microb.Cell.Fact_15_41
PubMedID: 26892801

Title : The Pseudomonas aeruginosa Type VI Secretion PGAP1-like Effector Induces Host Autophagy by Activating Endoplasmic Reticulum Stress - Jiang_2016_Cell.Rep_16_1502
Author(s) : Jiang F , Wang X , Wang B , Chen L , Zhao Z , Waterfield NR , Yang G , Jin Q
Ref : Cell Rep , 16 :1502 , 2016
Abstract : Pseudomonas aeruginosa is an opportunistic pathogen that regularly causes nosocomial infections in hospitalized patients. The type VI secretion system (T6SS) is responsible for the secretion of numerous virulence effector proteins that can both interfere with competing microbes and manipulate host cells.sHere, we report a detailed investigation of a P.saeruginosa H2-T6SS-dependent phospholipase effector, TplE, which acts as a trans-kingdom toxin. Delivery of TplE to the periplasmic space of rival bacteria leads to growth inhibition. Importantly, TplE, also contains a eukaryotic PGAP1-like domain, which targets the host ER apparatus, ultimately leading to disruption of the ER. TplE activity leads to the activation of the unfolded protein response (UPR) through the IRE1alpha-XBP1 pathway, enhancing autophagic flux. These findings indicate that this T6SS-delivered phospholipase effector is active against both prokaryotic and eukaryotic cellular targets, highlighting the T6SS as a versatile weapon in the Pseudomonas arsenal.
ESTHER : Jiang_2016_Cell.Rep_16_1502
PubMedSearch : Jiang_2016_Cell.Rep_16_1502
PubMedID: 27477276
Gene_locus related to this paper: pseae-PA1510

Title : Novel Tacrine-Benzofuran Hybrids as Potent Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease: Design, Synthesis, Biological Evaluation, and X-ray Crystallography - Zha_2016_J.Med.Chem_59_114
Author(s) : Zha X , Lamba D , Zhang L , Lou Y , Xu C , Kang D , Chen L , Xu Y , De Simone A , Samez S , Pesaresi A , Stojan J , Lopez MG , Egea J , Andrisano V , Bartolini M
Ref : Journal of Medicinal Chemistry , 59 :114 , 2016
Abstract : Twenty-six new tacrine-benzofuran hybrids were designed, synthesized, and evaluated in vitro on key molecular targets for Alzheimer's disease. Most hybrids exhibited good inhibitory activities on cholinesterases and beta-amyloid self-aggregation. Selected compounds displayed significant inhibition of human beta-secretase-1 (hBACE-1). Among the 26 hybrids, 2e showed the most interesting profile as a subnanomolar selective inhibitor of human acetylcholinesterase (hAChE) (IC50 = 0.86 nM) and a good inhibitor of both beta-amyloid aggregation (hAChE- and self-induced, 61.3% and 58.4%, respectively) and hBACE-1 activity (IC50 = 1.35 muM). Kinetic studies showed that 2e acted as a slow, tight-binding, mixed-type inhibitor, while X-ray crystallographic studies highlighted the ability of 2e to induce large-scale structural changes in the active-site gorge of Torpedo californica AChE (TcAChE), with significant implications for structure-based drug design. In vivo studies confirmed that 2e significantly ameliorates performances of scopolamine-treated ICR mice. Finally, 2e administration did not exhibit significant hepatotoxicity.
ESTHER : Zha_2016_J.Med.Chem_59_114
PubMedSearch : Zha_2016_J.Med.Chem_59_114
PubMedID: 26632651
Gene_locus related to this paper: torca-ACHE

Title : A Three-Dimensional Origami Paper-Based Device for Potentiometric Biosensing - Ding_2016_Angew.Chem.Int.Ed.Engl_55_13033
Author(s) : Ding J , Li B , Chen L , Qin W
Ref : Angew Chem Int Ed Engl , 55 :13033 , 2016
Abstract : Current paper-based potentiometric ion-sensing platforms are planar devices used for clinically relevant ions. These devices, however, have not been designed for the potentiometric biosensing of proteins or small molecule analytes. A three-dimensional origami paper-based device, in which a solid-contact ion-selective electrode is integrated with an all-solid-state reference electrode, is described for the first time. The device is made by impregnation of paper with appropriate bioreceptors and reporting reagents on different zones. By folding and unfolding the paper structures, versatile potentiometric bioassays can be performed. A USB-controlled miniaturized electrochemical detector can be used for simple and in situ measurements. Using butyrylcholinesterase as a model enzyme, the device has been successfully applied to the detection of enzyme activities and organophosphate pesticides involved in the enzymatic system as inhibitors. The proposed 3D origami paper device allows the potentiometric biosensing of proteins and small molecules in a simple, portable, and cost-effective way.
ESTHER : Ding_2016_Angew.Chem.Int.Ed.Engl_55_13033
PubMedSearch : Ding_2016_Angew.Chem.Int.Ed.Engl_55_13033
PubMedID: 27634584

Title : DWARF14 is a non-canonical hormone receptor for strigolactone - Yao_2016_Nature_536_469
Author(s) : Yao R , Ming Z , Yan L , Li S , Wang F , Ma S , Yu C , Yang M , Chen L , Li Y , Yan C , Miao D , Sun Z , Yan J , Sun Y , Wang L , Chu J , Fan S , He W , Deng H , Nan F , Li J , Rao Z , Lou Z , Xie D
Ref : Nature , 536 :469 , 2016
Abstract : Classical hormone receptors reversibly and non-covalently bind active hormone molecules, which are generated by biosynthetic enzymes, to trigger signal transduction. The alpha/beta hydrolase DWARF14 (D14), which hydrolyses the plant branching hormone strigolactone and interacts with the F-box protein D3/MAX2, is probably involved in strigolactone detection. However, the active form of strigolactone has yet to be identified and it is unclear which protein directly binds the active form of strigolactone, and in which manner, to act as the genuine strigolactone receptor. Here we report the crystal structure of the strigolactone-induced AtD14-D3-ASK1 complex, reveal that Arabidopsis thaliana (At)D14 undergoes an open-to-closed state transition to trigger strigolactone signalling, and demonstrate that strigolactone is hydrolysed into a covalently linked intermediate molecule (CLIM) to initiate a conformational change of AtD14 to facilitate interaction with D3. Notably, analyses of a highly branched Arabidopsis mutant d14-5 show that the AtD14(G158E) mutant maintains enzyme activity to hydrolyse strigolactone, but fails to efficiently interact with D3/MAX2 and loses the ability to act as a receptor that triggers strigolactone signalling in planta. These findings uncover a mechanism underlying the allosteric activation of AtD14 by strigolactone hydrolysis into CLIM, and define AtD14 as a non-canonical hormone receptor with dual functions to generate and sense the active form of strigolactone.
ESTHER : Yao_2016_Nature_536_469
PubMedSearch : Yao_2016_Nature_536_469
PubMedID: 27479325
Gene_locus related to this paper: arath-AtD14

Title : Conditional neuroligin-2 knockout in adult medial prefrontal cortex links chronic changes in synaptic inhibition to cognitive impairments - Liang_2015_Mol.Psychiatry_20_850
Author(s) : Liang J , Xu W , Hsu YT , Yee AX , Chen L , Sudhof TC
Ref : Mol Psychiatry , 20 :850 , 2015
Abstract : Abnormal activity in the medial prefrontal cortex (mPFC) is consistently observed in neuropsychiatric disorders, but the mechanisms involved remain unclear. Chronic aberrant excitation and/or inhibition of mPFC neurons were proposed to cause cognitive impairments. However, direct evidence for this hypothesis is lacking because it is technically challenging to control synaptic properties in a chronic and locally restricted, yet specific, manner. Here, we generated conditional knockout (cKO) mice of neuroligin-2 (Nlgn2), a postsynaptic cell-adhesion molecule of inhibitory synapses linked to neuropsychiatric disorders. cKO of Nlgn2 in adult mPFC rendered Nlgn2 protein undetectable after already 2-3 weeks, but induced major reductions in synaptic inhibition after only 6-7 weeks, and caused parallel impairments in anxiety, fear memory and social interaction behaviors. Moreover, cKO of Nlgn2 severely impaired behavioral stimulation of immediate-early gene expression in the mPFC, suggesting that chronic reduction in synaptic inhibition uncoupled the mPFC from experience-dependent inputs. Our results indicate that Nlgn2 is required for continuous maintenance of inhibitory synapses in the adult mPFC, and that chronic impairment of local inhibition disengages the mPFC from its cognitive functions by partially uncoupling the mPFC from experience-induced inputs.
ESTHER : Liang_2015_Mol.Psychiatry_20_850
PubMedSearch : Liang_2015_Mol.Psychiatry_20_850
PubMedID: 25824299

Title : Complete Genome Sequence of Elizabethkingia meningoseptica, Isolated from a T-Cell Non-Hodgkin's Lymphoma Patient - Sun_2015_Genome.Announc_3_e00673
Author(s) : Sun G , Wang L , Bao C , Li T , Ma L , Chen L
Ref : Genome Announc , 3 : , 2015
Abstract : An Elizabethkingia meningoseptica infection was detected at the end stage of a patient with T-cell non-Hodgkin's lymphoma. The complete genome of this isolated strain, FMS-007, was generated in one contig with a total size of 3,938,967 bp. A preliminary screening indicated that the genome contains drug resistance genes to aminoglycosides and beta-lactams. A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (CRISPR/Cas) system with 16 direct repeats and 15 spacers was identified.
ESTHER : Sun_2015_Genome.Announc_3_e00673
PubMedSearch : Sun_2015_Genome.Announc_3_e00673
PubMedID: 26112786
Gene_locus related to this paper: elimr-a0a0a2h0j3

Title : Bioactivities of phytochemicals in Araiostegia yunnanensis (Christ) - Chen_2015_Food.Chem_186_37
Author(s) : Chen L , Xu W , Shao R , Du X
Ref : Food Chem , 186 :37 , 2015
Abstract : The profile and bioactivity of phytochemicals in Araiostegia yunnanensis (Christ) Cop were investigated. The total flavonoids content in A. yunnanensis is about 84.90mg/g. By means of HPLC-DAD-ESI-MS, the main flavonoids in A. yunnanensis were tentatively identified as myricetin 3-O-rhamnosylglucoside, eriodictyol 7-O-rutinoside, quercetin 3-O-rutinoside, luteolin-7-O-apiosylglucoside, quercetin 3-O-rhamnosylgalactoside, and luteolin 7-O-glucoside. The extract (0.268mg/ml total flavonoids) from A. yunnanensis showed very strong superoxide anion radical scavenging potential and reducing power, which are higher than those of rutin (0.25mg/ml). The extract (0.268mg/ml total flavonoids) from A. yunnanensis exhibited similar DPPH scavenging activity with rutin (0.25mg/ml). However, rutin (0.25mg/ml) showed a significantly higher ABTS radical scavenging effect than that of the extract (0.268mg/ml total flavonoids) from A. yunnanensis. The methanol extract from A. yunnanensis showed obviously cytotoxic effects on A549 cells and it had no effect against acetylcholinesterase.
ESTHER : Chen_2015_Food.Chem_186_37
PubMedSearch : Chen_2015_Food.Chem_186_37
PubMedID: 25976789

Title : Genetic Manipulation of the Pneumocandin Biosynthetic Pathway for Generation of Analogues and Evaluation of Their Antifungal Activity - Li_2015_ACS.Chem.Biol_10_1702
Author(s) : Li Y , Chen L , Yue Q , Liu X , An Z , Bills GF
Ref : ACS Chemical Biology , 10 :1702 , 2015
Abstract : Pneumocandins are lipohexapeptides of the echinocandin family that potently interrupt fungal cell wall biogenesis by noncompetitive inhibition of 1,3-beta-glucan synthase. The pneumocandin biosynthetic gene cluster was previously elucidated by whole genome sequencing. In addition to the core nonribosomal peptide synthetase and polyketide synthase (GLNRPS4 and GLPKS4), the pneumocandin biosynthetic cluster includes two P450-type hemeprotein monooxygenase genes (GLP450-1 and GLP450-2) and four nonheme mononuclear iron oxygenase genes (GLOXY1, GLOXY2, GLOXY3, and GLOXY4), which function to biosynthesize and create the unusual sequence of hydroxylated amino acids of the mature pneumocandin peptide. Insertional inactivation of three of these genes (GLP450-1, GLP450-2, and GLOXY1) generated 13 different pneumocandin analogues that lack one, two, three, or four hydroxyl groups on 4R,5R-dihydroxy-ornithine and 3S,4S-dihydroxy-homotyrosine of the parent hexapeptide. Among them, seven analogues are previously unreported genetically engineered pneumocandins whose structures were established by NMR experiments. These new pneumocandins afforded a unique opportunity for side-by-side exploration of the effects of hydroxylation on pneumocandin antifungal activity. All of these cyclic lipopeptides showed potent antifungal activities, and two new metabolites pneumocandins F (3) and G (4) were more potent in vitro against Candida species and Aspergillus fumigatus than the principal fermentation products, pneumocandins A0 and B0.
ESTHER : Li_2015_ACS.Chem.Biol_10_1702
PubMedSearch : Li_2015_ACS.Chem.Biol_10_1702
PubMedID: 25879325
Gene_locus related to this paper: glal2-glon

Title : Engineering of Glarea lozoyensis for exclusive production of the pneumocandin B0 precursor of the antifungal drug caspofungin acetate - Chen_2015_Appl.Environ.Microbiol_81_1550
Author(s) : Chen L , Yue Q , Li Y , Niu X , Xiang M , Wang W , Bills GF , Liu X , An Z
Ref : Applied Environmental Microbiology , 81 :1550 , 2015
Abstract : Pneumocandins produced by the fungus Glarea lozoyensis are acylated cyclic hexapeptides of the echinocandin family. Pneumocandin B0 is the starting molecule for the first semisynthetic echinocandin antifungal drug, caspofungin acetate. In the wild-type strain, pneumocandin B0 is a minor fermentation product, and its industrial production was achieved by a combination of extensive mutation and medium optimization. The pneumocandin biosynthetic gene cluster was previously elucidated by a whole-genome sequencing approach. Knowledge of the biosynthetic cluster suggested an alternative way to produce exclusively pneumocandin B0. Disruption of GLOXY4, encoding a nonheme, alpha-ketoglutarate-dependent oxygenase, confirmed its involvement in l-leucine cyclization to form 4S-methyl-l-proline. The absence of 4S-methyl-l-proline abolishes pneumocandin A0 production, and 3S-hydroxyl-l-proline occupies the hexapeptide core's position 6, resulting in exclusive production of pneumocandin B0. Retrospective analysis of the GLOXY4 gene in a previously isolated pneumocandin B0-exclusive mutant (ATCC 74030) indicated that chemical mutagenesis disrupted the GLOXY4 gene function by introducing two amino acid mutations in GLOXY4. This one-step genetic manipulation can rationally engineer a high-yield production strain.
ESTHER : Chen_2015_Appl.Environ.Microbiol_81_1550
PubMedSearch : Chen_2015_Appl.Environ.Microbiol_81_1550
PubMedID: 25527531
Gene_locus related to this paper: glal2-glon

Title : Expression, Purification and Characterisation of Secreted Esterase Rv2525c from Mycobacterium tuberculosis - Dang_2015_Appl.Biochem.Biotechnol_176_1
Author(s) : Dang G , Chen L , Li Z , Deng X , Cui Y , Cao J , Yu S , Pang H , Liu S
Ref : Appl Biochem Biotechnol , 176 :1 , 2015
Abstract : Rv2525c from Mycobacterium tuberculosis belongs to the domain of unknown function (DUF) 1906 superfamily, but it also contains the motif G-X-S-X-G, the consensus active site sequence of the ester/lipid family. Biochemical analysis indicated that the mature Rv2525c protein is secreted. The discovery and characterisation of novel enzymes secreted by M. tuberculosis are vital for understanding the pathogenesis of the most important human bacterial pathogen. The proteome of M. tuberculosis contains over 400 potentially secreted proteins, of which the majority remain uncharacterised. In this study, we cloned and expressed the rv2525c gene in Escherichia coli and purified the recombinant protein using a three-step process (affinity chromatography, ion exchange chromatography, gel filtration chromatography), obtaining more than 99% pure protein. Mass spectrometry was performed to confirm that the purified protein was Rv2525c. Circular dichroism spectroscopy results showed that its conformation was stable at pH ranging from 6.0 to 8.0 and at temperatures <= 40 degrees C. Moreover, we tested the esterase activity using p-nitrophenyl esters (C2, C4, C6, C8, C12, C14, C16). This enzyme exhibited broad substrate acceptance, preferentially hydrolysing p-nitrophenyl butyrate (C4) at pH 7.0 and 37 degrees C. The dynamic activity test demonstrated that the optimal conditions were pH 8.0 and 38 degrees C. Site-directed mutagenesis studies revealed that Gly 113, Ser 115 and Gly 117 residues play catalytic roles in Rv2525c.
ESTHER : Dang_2015_Appl.Biochem.Biotechnol_176_1
PubMedSearch : Dang_2015_Appl.Biochem.Biotechnol_176_1
PubMedID: 25869294

Title : Identification and Characterization of Lipase Activity and Immunogenicity of LipL from Mycobacterium tuberculosis - Cao_2015_PLoS.One_10_e0138151
Author(s) : Cao J , Dang G , Li H , Li T , Yue Z , Li N , Liu Y , Liu S , Chen L
Ref : PLoS ONE , 10 :e0138151 , 2015
Abstract : Lipids and lipid-metabolizing esterases/lipases are highly important for the mycobacterial life cycle and, possibly, for mycobacterial virulence. In this study, we expressed 10 members of the Lip family of Mycobacterium tuberculosis. Among the 10 proteins, LipL displayed a significantly high enzymatic activity for the hydrolysis of long-chain lipids. The optimal temperature for the lipase activity of LipL was demonstrated to be 37 degrees C, and the optimal pH was 8.0. The lipase active center was not the conserved motif G-x-S-x-G, but rather the S-x-x-K and GGG motifs, and the key catalytic amino acid residues were identified as G50, S88, and K91, as demonstrated through site-directed mutagenesis experiments. A three-dimensional modeling structure of LipL was constructed, which showed that the GGG motif was located in the surface of a pocket structure. Furthermore, the subcellular localization of LipL was demonstrated to be on the mycobacterial surface by Western blot analysis. Our results revealed that the LipL protein could induce a strong humoral immune response in humans and activate a CD8+ T cell-mediated response in mice. Overall, our study identified and characterized a novel lipase denoted LipL from M. tuberculosis, and demonstrated that LipL functions as an immunogen that activates both humoral and cell-mediated responses.
ESTHER : Cao_2015_PLoS.One_10_e0138151
PubMedSearch : Cao_2015_PLoS.One_10_e0138151
PubMedID: 26398213
Gene_locus related to this paper: myctu-Rv1076 , myctu-Rv2485c , myctu-Rv3097c

Title : Outbred genome sequencing and CRISPR\/Cas9 gene editing in butterflies - Li_2015_Nat.Commun_6_8212
Author(s) : Li X , Fan D , Zhang W , Liu G , Zhang L , Zhao L , Fang X , Chen L , Dong Y , Chen Y , Ding Y , Zhao R , Feng M , Zhu Y , Feng Y , Jiang X , Zhu D , Xiang H , Feng X , Li S , Wang J , Zhang G , Kronforst MR , Wang W
Ref : Nat Commun , 6 :8212 , 2015
Abstract : Butterflies are exceptionally diverse but their potential as an experimental system has been limited by the difficulty of deciphering heterozygous genomes and a lack of genetic manipulation technology. Here we use a hybrid assembly approach to construct high-quality reference genomes for Papilio xuthus (contig and scaffold N50: 492 kb, 3.4 Mb) and Papilio machaon (contig and scaffold N50: 81 kb, 1.15 Mb), highly heterozygous species that differ in host plant affiliations, and adult and larval colour patterns. Integrating comparative genomics and analyses of gene expression yields multiple insights into butterfly evolution, including potential roles of specific genes in recent diversification. To functionally test gene function, we develop an efficient (up to 92.5%) CRISPR/Cas9 gene editing method that yields obvious phenotypes with three genes, Abdominal-B, ebony and frizzled. Our results provide valuable genomic and technological resources for butterflies and unlock their potential as a genetic model system.
ESTHER : Li_2015_Nat.Commun_6_8212
PubMedSearch : Li_2015_Nat.Commun_6_8212
PubMedID: 26354079
Gene_locus related to this paper: papxu-a0a194pj15 , papxu-a0a194q254 , papma-a0a194rdx2 , papxu-a0a194q858 , papxu-a0a194pyl3 , papxu-a0a194q337 , papma-a0a194r1p9 , papma-a0a194r6h1 , papxu-a0a194q1w8 , papma-a0a194ql80 , papma-a0a0n1ipl3 , papma-a0a194qm14

Title : Poster: Structural studies of nicotinic acetylcholine receptor alpha1 subunit and Fab35 complex to understand autoimmune disease of myasthenia gravis -
Author(s) : Noridomi K , Watanabe G , Hansen M , Chen L
Ref : Biochemical Pharmacology , 97 :627 , 2015

Title : Identification of Pathogenicity-Related Genes in Biofilm-Defective Acidovorax citrulli by Transposon Tn5 Mutagenesis - Luo_2015_Int.J.Mol.Sci_16_28050
Author(s) : Luo J , Qiu W , Chen L , Anjum SI , Yu M , Shan C , Ilyas M , Li B , Wang Y , Sun G
Ref : Int J Mol Sci , 16 :28050 , 2015
Abstract : Biofilm formation is important for virulence of a large number of plant pathogenic bacteria. Indeed, some virulence genes have been found to be involved in the formation of biofilm in bacterial fruit blotch pathogen Acidovorax citrulli. However, some virulent strains of A. citrulli were unable to format biofilm, indicating the complexity between biofilm formation and virulence. In this study, virulence-related genes were identified in the biofilm-defective strain A1 of A. citrulli by using Tn5 insertion, pathogenicity test, and high-efficiency thermal asymmetric interlaced PCR (hiTAIL-PCR). Results from this study indicated that 22 out of the obtained 301 mutants significantly decreased the virulence of strain A1 compared to the wild-type. Furthermore, sequence analysis indicated that the obtained 22 mutants were due to the insertion of Tn5 into eight genes, including Aave 4244 (cation diffusion facilitator family transporter), Aave 4286 (hypothetical protein), Aave 4189 (alpha/beta hydrolase fold), Aave 1911 (IMP dehydrogenase/GMP reductase domain), Aave 4383 (bacterial export proteins, family 1), Aave 4256 (Hsp70 protein), Aave 0003 (histidine kinase, DNA gyrase B, and HSP90-like ATPase), and Aave 2428 (pyridoxal-phosphate dependent enzyme). Furthermore, the growth of mutant Aave 2428 was unaffected and even increased by the change in incubation temperature, NaCl concentration and the pH of the LB broth, indicating that this gene may be directly involved in the bacterial virulence. Overall, the determination of the eight pathogenicity-related genes in strain A1 will be helpful to elucidate the pathogenesis of biofilm-defective A. citrulli.
ESTHER : Luo_2015_Int.J.Mol.Sci_16_28050
PubMedSearch : Luo_2015_Int.J.Mol.Sci_16_28050
PubMedID: 26602922

Title : (-)-Meptazinol-melatonin hybrids as novel dual inhibitors of cholinesterases and amyloid-beta aggregation with high antioxidant potency for Alzheimer's therapy - Cheng_2015_Bioorg.Med.Chem_23_3110
Author(s) : Cheng S , Zheng W , Gong P , Zhou Q , Xie Q , Yu L , Zhang P , Chen L , Li J , Chen J , Chen H
Ref : Bioorganic & Medicinal Chemistry , 23 :3110 , 2015
Abstract : The multifactorial pathogenesis of Alzheimer's disease (AD) implicates that multi-target-directed ligands (MTDLs) intervention may represent a promising therapy for AD. Amyloid-beta (Abeta) aggregation and oxidative stress, two prominent neuropathological hallmarks in patients, play crucial roles in the neurotoxic cascade of this disease. In the present study, a series of novel (-)-meptazinol-melatonin hybrids were designed, synthesized and biologically characterized as potential MTDLs against AD. Among them, hybrids 7-7c displayed higher dual inhibitory potency toward cholinesterases (ChEs) and better oxygen radical absorbance capacity (ORAC) than the parental drugs. Furthermore, compound 7c could effectively inhibit Abeta self-aggregation, showed favorable safety and the blood-brain barrier (BBB) permeability. Therefore, 7c may serve as a valuable candidate that is worthy of further investigations in the treatment of AD.
ESTHER : Cheng_2015_Bioorg.Med.Chem_23_3110
PubMedSearch : Cheng_2015_Bioorg.Med.Chem_23_3110
PubMedID: 26025073

Title : Disruption of the Arabidopsis Defense Regulator Genes SAG101, EDS1, and PAD4 Confers Enhanced Freezing Tolerance - Chen_2015_Mol.Plant_8_1536
Author(s) : Chen QF , Xu L , Tan WJ , Chen L , Qi H , Xie LJ , Chen MX , Liu BY , Yu LJ , Yao N , Zhang JH , Shu W , Xiao S
Ref : Mol Plant , 8 :1536 , 2015
Abstract : In Arabidopsis, three lipase-like regulators, SAG101, EDS1, and PAD4, act downstream of resistance protein-associated defense signaling. Although the roles of SAG101, EDS1, and PAD4 in biotic stress have been extensively studied, little is known about their functions in plant responses to abiotic stresses. Here, we show that SAG101, EDS1, and PAD4 are involved in the regulation of freezing tolerance in Arabidopsis. With or without cold acclimation, the sag101, eds1, and pad4 single mutants, as well as their double mutants, exhibited similarly enhanced tolerance to freezing temperatures. Upon cold exposure, the sag101, eds1, and pad4 mutants showed increased transcript levels of C-REPEAT/DRE BINDING FACTORs and their regulons compared with the wild type. Moreover, freezing-induced cell death and accumulation of hydrogen peroxide were ameliorated in sag101, eds1, and pad4 mutants. The sag101, eds1, and pad4 mutants had much lower salicylic acid (SA) and diacylglycerol (DAG) contents than the wild type, and exogenous application of SA and DAG compromised the freezing tolerance of the mutants. Furthermore, SA suppressed the cold-induced expression of DGATs and DGKs in the wild-type leaves. These findings indicate that SAG101, EDS1, and PAD4 are involved in the freezing response in Arabidopsis, at least in part, by modulating the homeostasis of SA and DAG.
ESTHER : Chen_2015_Mol.Plant_8_1536
PubMedSearch : Chen_2015_Mol.Plant_8_1536
PubMedID: 26149542

Title : A novel protein elicitor (SsCut) from Sclerotinia sclerotiorum induces multiple defense responses in plants - Zhang_2014_Plant.Mol.Biol_86_495
Author(s) : Zhang H , Wu Q , Cao S , Zhao T , Chen L , Zhuang P , Zhou X , Gao Z
Ref : Plant Mol Biol , 86 :495 , 2014
Abstract : In this study, we report the cloning of the SsCut gene encoding cutinase from Sclerotinia sclerotiorum. We isolated a 609-bp cDNA encoding a polypeptide of 202 amino acids with a molecular weight of 20.4 kDa. Heterologous expression of SsCut in Escherichia coli (His-SsCut) caused the formation of lesions in tobacco that closely resembled hypersensitive response lesions. Mutational analysis identified the C-terminal-half peptide and the same amino acids indispensable for both enzyme and elicitor activity. His-SsCut was caused cell death in Arabidopsis, soybean (Glycine max), oilseed rape (Brassica napus), rice (Oryza sativa), maize (Zea mays), and wheat (Triticum aestivum), indicating that both dicot and monocot species are responsive to the elicitor. Furthermore, the elicitation of tobacco was effective in the induction of the activities of hydrogen peroxide, phenylalanine ammonia-lyase, peroxides, and polyphenol oxidase. His-SsCut-treated plants exhibited enhanced resistance as indicated by a significant reduction in the number and size of S. sclerotiorum, Phytophthora sojae, and P. nicotianae lesions on leaves relative to controls. Real-time PCR results indicated that the expression of defense-related genes and genes involved in signal transduction were induced by His-SsCut. Our results demonstrate that SsCut is an elicitor that triggers defense responses in plants and will help to clarify its relationship to downstream signaling pathways that induce defense responses.
ESTHER : Zhang_2014_Plant.Mol.Biol_86_495
PubMedSearch : Zhang_2014_Plant.Mol.Biol_86_495
PubMedID: 25149470

Title : SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats - Chen_2014_Int.J.Neuropsychopharmacol_17_1295
Author(s) : Chen L , Deltheil T , Turle-Lorenzo N , Liberge M , Rosier C , Watabe I , Sreng L , Amalric M , Mourre C
Ref : Int J Neuropsychopharmacol , 17 :1295 , 2014
Abstract : Parkinson's disease has traditionally been viewed as a motor disorder caused by the loss of dopamine (DA) neurons. However, emotional and cognitive syndromes can precede the onset of the motor deficits and provide an opportunity for therapeutic intervention. Potassium channels have recently emerged as potential new targets in the treatment of Parkinson's disease. The selective blockade of small conductance calcium-activated K+ channels (SK channels) by apamin is known to increase burst firing in midbrain DA neurons and therefore DA release. We thus investigated the effects of systemic administration of apamin on the motor, cognitive deficits and anxiety present after bilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesions in rats. Apamin administration (0.1 or 0.3 mg/kg i.p.) counteracted the depression, anxiety-like behaviors evaluated on sucrose consumption and in the elevated plus maze, social recognition and spatial memory deficits produced by partial 6-OHDA lesions. Apamin also reduced asymmetric motor deficits on circling behavior and postural adjustments in the unilateral extensive 6-OHDA model. The partial 6-OHDA lesions (56% striatal DA depletion) produced 20% decrease of iodinated apamin binding sites in the substantia nigra pars compacta in correlation with the loss of tyrosine hydroxylase positive cells, without modifying apamin binding in brain regions receiving DAergic innervation. Striatal extracellular levels of DA, not detectable after 6-OHDA lesions, were enhanced by apamin treatment as measured by in vivo microdialysis. These results indicate that blocking SK channels may reinstate minimal DA activity in the striatum to alleviate the non-motor symptoms induced by partial striatal DA lesions.
ESTHER : Chen_2014_Int.J.Neuropsychopharmacol_17_1295
PubMedSearch : Chen_2014_Int.J.Neuropsychopharmacol_17_1295
PubMedID: 24661728

Title : Comparative safety of the antifouling compound butenolide and 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) to the marine medaka (Oryzias melastigma) - Chen_2014_Aquat.Toxicol_149C_116
Author(s) : Chen L , Ye R , Xu Y , Gao Z , Au DW , Qian PY
Ref : Aquat Toxicol , 149C :116 , 2014
Abstract : This study evaluated the potential adverse effects of butenolide, a promising antifouling compound, using the marine medaka (Oryzias melastigma), a model fish for marine ecotoxicology. The active ingredient used in the commercial antifoulant SeaNine 211, 4,5-dichloro-2-n-octyl-4-isothiazolin-3-one (DCOIT) was employed as the positive control. Adult marine medaka (4-month-old) were exposed to various concentrations of butenolide or DCOIT for 28 days and then depurated in clean seawater for 14 days (recovery). A suite of sensitive biomarkers, including hepatic oxidative stress, neuronal signal transmission, endocrine disruption, and reproductive function, was used to measure significant biological effects induced by the chemicals. Compared to DCOIT, chronic exposure to butenolide induced a lower extent of oxidative stress in the liver of male and female medaka. Furthermore, butenolide-exposed fish could recover faster from oxidative stress than fish exposed to DCOIT. Regarding neurotransmission, DCOIT significantly inhibited acetylcholinesterase (AChE) activity in the brain of both male and female medaka, whereas this was not significant for butenolide. In addition, plasma estradiol (E2) level was elevated and testosterone (T) level was decreased in male medaka exposed to DCOIT. This greatly imbalanced sex hormones ratio (E2/T) in exposed males, indicating that DCOIT is a potent endocrine disruptive chemical. In contrast, butenolide induced only moderate effects on sex hormone levels in exposed males, which could be gradually recovered during depuration. Moreover, the endocrine disruptive effect induced by butenolide did not affect normal development of offspring. In contrast, DCOIT-exposed fish exhibited a decrease of egg production and impaired reproductive success. Overall, the above findings demonstrated that chronic exposure to butenolide induced transient, reversible biological effect on marine medaka, while DCOIT could impair reproductive success of fish, as evident by clear alterations of the E2/T ratio. The relatively low toxicity of butenolide on marine biota highlights its promising application in the antifouling industry. The present findings also emphasize gender difference in fish susceptibility to chemical treatment (male>female), which is an important consideration for ecological risk assessment.
ESTHER : Chen_2014_Aquat.Toxicol_149C_116
PubMedSearch : Chen_2014_Aquat.Toxicol_149C_116
PubMedID: 24583292

Title : Molecular dissection of the evolution of carbapenem-resistant multilocus sequence type 258 Klebsiella pneumoniae - Deleo_2014_Proc.Natl.Acad.Sci.U.S.A_111_4988
Author(s) : Deleo FR , Chen L , Porcella SF , Martens CA , Kobayashi SD , Porter AR , Chavda KD , Jacobs MR , Mathema B , Olsen RJ , Bonomo RA , Musser JM , Kreiswirth BN
Ref : Proc Natl Acad Sci U S A , 111 :4988 , 2014
Abstract : Infections caused by drug-resistant bacteria are a major problem worldwide. Carbapenem-resistant Klebsiella pneumoniae, most notably isolates classified as multilocus sequence type (ST) 258, have emerged as an important cause of hospital deaths. ST258 isolates are predominantly multidrug resistant, and therefore infections caused by them are difficult to treat. It is not known why the ST258 lineage is the most prevalent cause of multidrug-resistant K. pneumoniae infections in the United States and other countries. Here we tested the hypothesis that carbapenem-resistant ST258 K. pneumoniae is a single genetic clone that has disseminated worldwide. We sequenced to closure the genomes of two ST258 clinical isolates and used these genomes as references for comparative genome sequencing of 83 additional clinical isolates recovered from patients at diverse geographic locations worldwide. Phylogenetic analysis of the SNPs in the core genome of these isolates revealed that ST258 K. pneumoniae organisms are two distinct genetic clades. This unexpected finding disproves the single-clone hypothesis. Notably, genetic differentiation between the two clades results from an approximately 215-kb region of divergence that includes genes involved in capsule polysaccharide biosynthesis. The region of divergence appears to be a hotspot for DNA recombination events, and we suggest that this region has contributed to the success of ST258 K. pneumoniae. Our findings will accelerate research on novel diagnostic, therapeutic, and vaccine strategies designed to prevent and/or treat infections caused by multidrug resistant K. pneumoniae.
ESTHER : Deleo_2014_Proc.Natl.Acad.Sci.U.S.A_111_4988
PubMedSearch : Deleo_2014_Proc.Natl.Acad.Sci.U.S.A_111_4988
PubMedID: 24639510
Gene_locus related to this paper: klep7-a6t9v6 , klep7-y1077 , klepn-a0a016qwx4 , klepn-w8uta0

Title : Protective effects of perindopril on d-galactose and aluminum trichloride induced neurotoxicity via the apoptosis of mitochondria-mediated intrinsic pathway in the hippocampus of mice - Yang_2014_Brain.Res.Bull_109_46
Author(s) : Yang W , Shi L , Chen L , Zhang B , Ma K , Liu Y , Qian Y
Ref : Brain Research Bulletin , 109 :46 , 2014
Abstract : Perindopril, an angiotensin converting enzyme inhibitor, has been reported to improve learning and memory in a mouse or rat model of Alzheimer's disease (AD) induced by injection of beta-amyloid protein. However, the exact mechanism of perindopril on the cognitive deficits is not fully understood. Our previous data have indicated that perindopril improves learning and memory in a mouse model of AD induced by d-galactose (d-gal) and aluminum trichloride (AlCl3) via inhibition of acetylcholinesterase activity and oxidative stress. Whether perindopril also inhibit apoptosis to prevent cognitive decline remains unknown in mice. Therefore, the present study explored the protective effects of perindopril in the hippocampus of mice further. Perindopril (0.5mg/kg/day) was administered intragastrically for 60 days after the mice were given a d-gal (150mg/kg/day) and AlCl3 (10mg/kg/day) intraperitoneally for 90 days. Then the expression of Bcl-2, Bax, Fas, FasL, caspase-3, caspase-8 and caspase-9 were analyzed by RT-PCR and western blotting in the hippocampus. Perindopril significantly decreased caspase-3 and caspase-9 activities, and elevated Bcl-2/Bax ratio in the hippocampus. However, the expression of Fas, FasL and caspase-8 did not change in the hippocampus whether treatment with d-gal and AlCl3 or perindopril. Taken together, the above findings indicated that perindopril inhibited apoptosis in the hippocampus may be another mechanism by which perindopril improves learning and memory functions in d-gal and AlCl3 treated mice.
ESTHER : Yang_2014_Brain.Res.Bull_109_46
PubMedSearch : Yang_2014_Brain.Res.Bull_109_46
PubMedID: 25290208

Title : Whole genome sequence of the Treponema pallidum subsp. endemicum strain Bosnia A: the genome is related to yaws treponemes but contains few loci similar to syphilis treponemes - Staudova_2014_PLoS.Negl.Trop.Dis_8_e3261
Author(s) : Staudova B , Strouhal M , Zobanikova M , Cejkova D , Fulton LL , Chen L , Giacani L , Centurion-Lara A , Bruisten SM , Sodergren E , Weinstock GM , Smajs D
Ref : PLoS Negl Trop Dis , 8 :e3261 , 2014
Abstract : BACKGROUND: T. pallidum subsp. endemicum (TEN) is the causative agent of bejel (also known as endemic syphilis). Clinical symptoms of syphilis and bejel are overlapping and the epidemiological context is important for correct diagnosis of both diseases. In contrast to syphilis, caused by T. pallidum subsp. pallidum (TPA), TEN infections are usually spread by direct contact or contaminated utensils rather than by sexual contact. Bejel is most often seen in western Africa and in the Middle East. The strain Bosnia A was isolated in 1950 in Bosnia, southern Europe. METHODOLOGY/PRINCIPAL FINDINGS: The complete genome of the Bosnia A strain was amplified and sequenced using the pooled segment genome sequencing (PSGS) method and a combination of three next-generation sequencing techniques (SOLiD, Roche 454, and Illumina). Using this approach, a total combined average genome coverage of 513x was achieved. The size of the Bosnia A genome was found to be 1,137,653 bp, i.e. 1.6-2.8 kbp shorter than any previously published genomes of uncultivable pathogenic treponemes. Conserved gene synteny was found in the Bosnia A genome compared to other sequenced syphilis and yaws treponemes. The TEN Bosnia A genome was distinct but very similar to the genome of yaws-causing T. pallidum subsp. pertenue (TPE) strains. Interestingly, the TEN Bosnia A genome was found to contain several sequences, which so far, have been uniquely identified only in syphilis treponemes. CONCLUSIONS/SIGNIFICANCE: The genome of TEN Bosnia A contains several sequences thought to be unique to TPA strains; these sequences very likely represent remnants of recombination events during the evolution of TEN treponemes. This finding emphasizes a possible role of repeated horizontal gene transfer between treponemal subspecies in shaping the Bosnia A genome.
ESTHER : Staudova_2014_PLoS.Negl.Trop.Dis_8_e3261
PubMedSearch : Staudova_2014_PLoS.Negl.Trop.Dis_8_e3261
PubMedID: 25375929
Gene_locus related to this paper: trepa-TP0902

Title : Whole-genome sequencing of cultivated and wild peppers provides insights into Capsicum domestication and specialization - Qin_2014_Proc.Natl.Acad.Sci.U.S.A_111_5135
Author(s) : Qin C , Yu C , Shen Y , Fang X , Chen L , Min J , Cheng J , Zhao S , Xu M , Luo Y , Yang Y , Wu Z , Mao L , Wu H , Ling-Hu C , Zhou H , Lin H , Gonzalez-Morales S , Trejo-Saavedra DL , Tian H , Tang X , Zhao M , Huang Z , Zhou A , Yao X , Cui J , Li W , Chen Z , Feng Y , Niu Y , Bi S , Yang X , Cai H , Luo X , Montes-Hernandez S , Leyva-Gonzalez MA , Xiong Z , He X , Bai L , Tan S , Liu D , Liu J , Zhang S , Chen M , Zhang L , Zhang Y , Liao W , Wang M , Lv X , Wen B , Liu H , Luan H , Yang S , Wang X , Xu J , Li X , Li S , Wang J , Palloix A , Bosland PW , Li Y , Krogh A , Rivera-Bustamante RF , Herrera-Estrella L , Yin Y , Yu J , Hu K , Zhang Z
Ref : Proc Natl Acad Sci U S A , 111 :5135 , 2014
Abstract : As an economic crop, pepper satisfies people's spicy taste and has medicinal uses worldwide. To gain a better understanding of Capsicum evolution, domestication, and specialization, we present here the genome sequence of the cultivated pepper Zunla-1 (C. annuum L.) and its wild progenitor Chiltepin (C. annuum var. glabriusculum). We estimate that the pepper genome expanded approximately 0.3 Mya (with respect to the genome of other Solanaceae) by a rapid amplification of retrotransposons elements, resulting in a genome comprised of approximately 81% repetitive sequences. Approximately 79% of 3.48-Gb scaffolds containing 34,476 protein-coding genes were anchored to chromosomes by a high-density genetic map. Comparison of cultivated and wild pepper genomes with 20 resequencing accessions revealed molecular footprints of artificial selection, providing us with a list of candidate domestication genes. We also found that dosage compensation effect of tandem duplication genes probably contributed to the pungent diversification in pepper. The Capsicum reference genome provides crucial information for the study of not only the evolution of the pepper genome but also, the Solanaceae family, and it will facilitate the establishment of more effective pepper breeding programs.
ESTHER : Qin_2014_Proc.Natl.Acad.Sci.U.S.A_111_5135
PubMedSearch : Qin_2014_Proc.Natl.Acad.Sci.U.S.A_111_5135
PubMedID: 24591624
Gene_locus related to this paper: capch-q75qh4 , capan-a0a1u8fuf5 , capan-a0a1u8gmz3 , capan-a0a1u8f879 , capan-a0a1u8ftr2 , capan-a0a1u8g8s6

Title : Inter-residue coupling contributes to high-affinity subtype-selective binding of alpha-bungarotoxin to nicotinic receptors - Sine_2013_Biochem.J_454_311
Author(s) : Sine SM , Huang S , Li SX , daCosta CJ , Chen L
Ref : Biochemical Journal , 454 :311 , 2013
Abstract : The crystal structure of a pentameric alpha7 ligand-binding domain chimaera with bound alpha-btx (alpha-bungarotoxin) showed that of the five conserved aromatic residues in alpha7, only Tyr184 in loop C of the ligand-binding site was required for high-affinity binding. To determine whether the contribution of Tyr184 depends on local residues, we generated mutations in an alpha7/5HT3A (5-hydroxytryptamine type 3A) receptor chimaera, individually and in pairs, and measured 125I-labelled alpha-btx binding. The results show that mutations of individual residues near Tyr184 do not affect alpha-btx affinity, but pairwise mutations decrease affinity in an energetically coupled manner. Kinetic measurements show that the affinity decreases arise through increases in the alpha-btx dissociation rate with little change in the association rate. Replacing loop C in alpha7 with loop C from the alpha-btx-insensitive alpha2 or alpha3 subunits abolishes high-affinity alpha-btx binding, but preserves acetylcholine-elicited single channel currents. However, in both the alpha2 and alpha3 construct, mutating either residue that flanks Tyr184 to its alpha7 counterpart restores high-affinity alpha-btx binding. Analogously, in alpha7, mutating both residues that flank Tyr184 to the alpha2 or alpha3 counterparts abolishes high-affinity alpha-btx binding. Thus interaction between Tyr184 and local residues contributes to high-affinity subtype-selective alpha-btx binding.
ESTHER : Sine_2013_Biochem.J_454_311
PubMedSearch : Sine_2013_Biochem.J_454_311
PubMedID: 23802200

Title : Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the clavicipitaceae reveals dynamics of alkaloid loci - Schardl_2013_PLoS.Genet_9_e1003323
Author(s) : Schardl CL , Young CA , Hesse U , Amyotte SG , Andreeva K , Calie PJ , Fleetwood DJ , Haws DC , Moore N , Oeser B , Panaccione DG , Schweri KK , Voisey CR , Farman ML , Jaromczyk JW , Roe BA , O'Sullivan DM , Scott B , Tudzynski P , An Z , Arnaoudova EG , Bullock CT , Charlton ND , Chen L , Cox M , Dinkins RD , Florea S , Glenn AE , Gordon A , Guldener U , Harris DR , Hollin W , Jaromczyk J , Johnson RD , Khan AK , Leistner E , Leuchtmann A , Li C , Liu J , Liu M , Mace W , Machado C , Nagabhyru P , Pan J , Schmid J , Sugawara K , Steiner U , Takach JE , Tanaka E , Webb JS , Wilson EV , Wiseman JL , Yoshida R , Zeng Z
Ref : PLoS Genet , 9 :e1003323 , 2013
Abstract : The fungal family Clavicipitaceae includes plant symbionts and parasites that produce several psychoactive and bioprotective alkaloids. The family includes grass symbionts in the epichloae clade (Epichloe and Neotyphodium species), which are extraordinarily diverse both in their host interactions and in their alkaloid profiles. Epichloae produce alkaloids of four distinct classes, all of which deter insects, and some-including the infamous ergot alkaloids-have potent effects on mammals. The exceptional chemotypic diversity of the epichloae may relate to their broad range of host interactions, whereby some are pathogenic and contagious, others are mutualistic and vertically transmitted (seed-borne), and still others vary in pathogenic or mutualistic behavior. We profiled the alkaloids and sequenced the genomes of 10 epichloae, three ergot fungi (Claviceps species), a morning-glory symbiont (Periglandula ipomoeae), and a bamboo pathogen (Aciculosporium take), and compared the gene clusters for four classes of alkaloids. Results indicated a strong tendency for alkaloid loci to have conserved cores that specify the skeleton structures and peripheral genes that determine chemical variations that are known to affect their pharmacological specificities. Generally, gene locations in cluster peripheries positioned them near to transposon-derived, AT-rich repeat blocks, which were probably involved in gene losses, duplications, and neofunctionalizations. The alkaloid loci in the epichloae had unusual structures riddled with large, complex, and dynamic repeat blocks. This feature was not reflective of overall differences in repeat contents in the genomes, nor was it characteristic of most other specialized metabolism loci. The organization and dynamics of alkaloid loci and abundant repeat blocks in the epichloae suggested that these fungi are under selection for alkaloid diversification. We suggest that such selection is related to the variable life histories of the epichloae, their protective roles as symbionts, and their associations with the highly speciose and ecologically diverse cool-season grasses.
ESTHER : Schardl_2013_PLoS.Genet_9_e1003323
PubMedSearch : Schardl_2013_PLoS.Genet_9_e1003323
PubMedID: 23468653
Gene_locus related to this paper: clap2-m1w2a8 , clap2-m1w555 , clap2-m1wa31 , clap2-m1whd2 , clap2-m1weh2 , clap2-m1w5y7 , clap2-m1wh11 , clap2-m1vyn7 , clap2-m1w670

Title : Hopeahainol A attenuates memory deficits by targeting beta-amyloid in APP\/PS1 transgenic mice - Zhu_2013_Aging.Cell_12_85
Author(s) : Zhu X , Ye L , Ge H , Chen L , Jiang N , Qian L , Li L , Liu R , Ji S , Zhang S , Jin J , Guan D , Fang W , Tan R , Xu Y
Ref : Aging Cell , 12 :85 , 2013
Abstract : Increasing evidence demonstrates that amyloid beta (Abeta) elicits mitochondrial dysfunction and oxidative stress, which contributes to the pathogenesis of Alzheimer's disease (AD). Identification of the molecules targeting Abeta is thus of particular significance in the treatment of AD. Hopeahainol A (HopA), a polyphenol with a novel skeleton obtained from Hopea hainanensis, is potentially acetylcholinesterase-inhibitory and anti-oxidative in H(2) O(2) -treated PC12 cells. In this study, we reported that HopA might bind to Abeta(1-42) directly and inhibit the Abeta(1-42) aggregation using a combination of molecular dynamics simulation, binding assay, transmission electron microscopic analysis and staining technique. We also demonstrated that HopA decreased the interaction between Abeta(1-42) and Abeta-binding alcohol dehydrogenase, which in turn reduced mitochondrial dysfunction and oxidative stress in vivo and in vitro. In addition, HopA was able to rescue the long-term potentiation induction by protecting synaptic function and attenuate memory deficits in APP/PS1 mice. Our data suggest that HopA might be a promising drug for therapeutic intervention in AD.
ESTHER : Zhu_2013_Aging.Cell_12_85
PubMedSearch : Zhu_2013_Aging.Cell_12_85
PubMedID: 23107435

Title : Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in the fungus Glarea lozoyensis - Chen_2013_BMC.Genomics_14_339
Author(s) : Chen L , Yue Q , Zhang X , Xiang M , Wang C , Li S , Che Y , Ortiz-Lopez FJ , Bills GF , Liu X , An Z
Ref : BMC Genomics , 14 :339 , 2013
Abstract : BACKGROUND: The antifungal therapy caspofungin is a semi-synthetic derivative of pneumocandin B0, a lipohexapeptide produced by the fungus Glarea lozoyensis, and was the first member of the echinocandin class approved for human therapy. The nonribosomal peptide synthetase (NRPS)-polyketide synthases (PKS) gene cluster responsible for pneumocandin biosynthesis from G. lozoyensis has not been elucidated to date. In this study, we report the elucidation of the pneumocandin biosynthetic gene cluster by whole genome sequencing of the G. lozoyensis wild-type strain ATCC 20868.
RESULTS: The pneumocandin biosynthetic gene cluster contains a NRPS (GLNRPS4) and a PKS (GLPKS4) arranged in tandem, two cytochrome P450 monooxygenases, seven other modifying enzymes, and genes for L-homotyrosine biosynthesis, a component of the peptide core. Thus, the pneumocandin biosynthetic gene cluster is significantly more autonomous and organized than that of the recently characterized echinocandin B gene cluster. Disruption mutants of GLNRPS4 and GLPKS4 no longer produced the pneumocandins (A0 and B0), and the Deltaglnrps4 and Deltaglpks4 mutants lost antifungal activity against the human pathogenic fungus Candida albicans. In addition to pneumocandins, the G. lozoyensis genome encodes a rich repertoire of natural product-encoding genes including 24 PKSs, six NRPSs, five PKS-NRPS hybrids, two dimethylallyl tryptophan synthases, and 14 terpene synthases.
CONCLUSIONS: Characterization of the gene cluster provides a blueprint for engineering new pneumocandin derivatives with improved pharmacological properties. Whole genome estimation of the secondary metabolite-encoding genes from G. lozoyensis provides yet another example of the huge potential for drug discovery from natural products from the fungal kingdom.
ESTHER : Chen_2013_BMC.Genomics_14_339
PubMedSearch : Chen_2013_BMC.Genomics_14_339
PubMedID: 23688303
Gene_locus related to this paper: glal2-s3cg73 , glal2-s3d2r4 , glal2-s3dmm6 , glal2-s3e306 , glal2-s3dl45 , glal2-s3d1r9 , glal2-s3e4a7 , glal2-s3ddr1 , glal2-s3ctz6 , glal2-s3dy35 , glal2-s3dws5 , glal2-s3df31 , glal2-s3d7q5 , glal2-s3cwz5 , glal2-s3dcn7 , glal2-s3dhj7 , glal2-s3dm96 , glal2-s3d6q1 , glal2-s3cv25 , glal2-s3e8v9 , glal2-s3crh2 , glal2-s3dde8 , glal2-s3cxt6 , glal2-s3da89 , glal2-s3ckn8 , glal2-s3d4y3 , glal2-s3ddw6 , glal2-s3dk02 , glal2-s3d048 , glal2-s3de12

Title : Complex between alpha-bungarotoxin and an alpha7 nicotinic receptor ligand-binding domain chimaera - Huang_2013_Biochem.J_454_303
Author(s) : Huang S , Li SX , Bren N , Cheng K , Gomoto R , Chen L , Sine SM
Ref : Biochemical Journal , 454 :303 , 2013
Abstract : To identify high-affinity interactions between long-chain alpha-neurotoxins and nicotinic receptors, we determined the crystal structure of the complex between alpha-btx (alpha-bungarotoxin) and a pentameric ligand-binding domain constructed from the human alpha7 AChR (acetylcholine receptor) and AChBP (acetylcholine-binding protein). The complex buries ~2000 A2 (1 A=0.1 nm) of surface area, within which Arg36 and Phe32 from finger II of alpha-btx form a pi-cation stack that aligns edge-to-face with the conserved Tyr184 from loop-C of alpha7, while Asp30 of alpha-btx forms a hydrogen bond with the hydroxy group of Tyr184. These inter-residue interactions diverge from those in a 4.2 A structure of alpha-ctx (alpha-cobratoxin) bound to AChBP, but are similar to those in a 1.94 A structure of alpha-btx bound to the monomeric alpha1 extracellular domain, although compared with the monomer-bound complex, the alpha-btx backbone exhibits a large shift relative to the protein surface. Mutational analyses show that replacing Tyr184 with a threonine residue abolishes high-affinity alpha-btx binding, whereas replacing with a phenylalanine residue maintains high affinity. Comparison of the alpha-btx complex with that coupled to the agonist epibatidine reveals structural rearrangements within the binding pocket and throughout each subunit. The overall findings highlight structural principles by which alpha-neurotoxins interact with nicotinic receptors.
ESTHER : Huang_2013_Biochem.J_454_303
PubMedSearch : Huang_2013_Biochem.J_454_303
PubMedID: 23800261

Title : [Risk factors of hepatorenal syndrome in patients with acute on chronic liver failure] - Zhang_2013_Zhonghua.Gan.Zang.Bing.Za.Zhi_21_743
Author(s) : Zhang DQ , Chen L , Gan QR , Lin QF , Pan C
Ref : Zhonghua Gan Zang Bing Za Zhi , 21 :743 , 2013
Abstract : OBJECTIVE: To identify the risk factors of hepatorenal syndrome in patients with hepatitis B virus (HBV)-related acute-on-chronic liver failure(ACLF).
METHODS: A total of 726 hospitalized patients with HBV-ACLF were retrospectively analyzed. Data of demographic and clinical parameters (sex, age, family history, and presence of liver cirrhosis and diabetes), common complications (spontaneous bacterial peritonitis, pulmonary infection, hepatic encephalopathy, and upper gastrointestinal hemorrhage), and baseline biochemical parameters (albumin, globulin, total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, cholesterol, cholinesterase, K+, Na+, plasma thromboplastin antecedent, alpha-fetoprotein, HBV DNA, white blood cell count, hemoglobin, and platelet count) were collected from the medical records database. Univariate and multiple regression analyses were performed to determine the risk factors of hepatorenal syndrome.
RESULTS: Multiple logistic regression analysis indicated that upper gastrointestinal hemorrhage [risk (R) = 1.313, relative hazard (RH) = 3.716, 95% confidence interval (CI): 2.156-6.404], hepatic encephalopathy (R = 1.120, RH = 3.065, 95% CI: 1.900-4.945), spontaneous bacterial peritonitis (R = 1.005, RH = 2.733, 95% CI: 1.379-5.417), pulmonary infection (R = 1.051, RH = 2.862, 95% CI: 1.783-4.592), and white blood cell count (R = 0.056, RH = 1.058, 95% CI: 1.010-1.107) were independent risk factors for hepatorenal syndrome development in patients with HBV-ACLF. CONCLUSION: Several risk factors were significantly associated with the development of hepatorenal syndrome in HBV-ACLF, including upper gastrointestinal hemorrhage, hepatic encephalopathy, spontaneous bacterial peritonitis, pulmonary infection, and elevated white blood cell count.
ESTHER : Zhang_2013_Zhonghua.Gan.Zang.Bing.Za.Zhi_21_743
PubMedSearch : Zhang_2013_Zhonghua.Gan.Zang.Bing.Za.Zhi_21_743
PubMedID: 24331631

Title : Beneficial effects of inhibition of soluble epoxide hydrolase on glucose homeostasis and islet damage in a streptozotocin-induced diabetic mouse model - Chen_2013_Prostaglandins.Other.Lipid.Mediat_104-105_42
Author(s) : Chen L , Fan C , Zhang Y , Bakri M , Dong H , Morisseau C , Maddipati KR , Luo P , Wang CY , Hammock BD , Wang MH
Ref : Prostaglandins Other Lipid Mediat , 104-105 :42 , 2013
Abstract : Soluble epoxide hydrolase (sEH) is an enzyme involved in the metabolism of endogenous inflammatory and anti-apoptotic mediators. In the present study, we determined the effects of the inhibition of sEH on glucose homeostasis and islet damage in mice treated with streptozotocin (STZ), a model of chemical-induced diabetes. STZ increased daily water intake and decreased visceral (spleen and pancreas) weight in mice; sEH inhibition in STZ mice decreased water intake, but did not affect visceral weight. Hyperglycemia induced by STZ treatment in mice was attenuated by inhibiting sEH. The beneficial effects of sEH inhibition were accompanied, after 2 and 4 weeks of initial administration, by improving glucose tolerance. In contrast, sEH inhibition did not affect insulin tolerance. Using LC/MS analysis, neither STZ nor STZ plus sEH inhibition affected pancreatic and plasma ratios of epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acids (DHETs), an index of EETs levels. Western blot analysis showed that mouse cytochrome P450 (CYP) 2C enzymes are the major epoxygenases in islets. On day 5 after initial STZ treatment, STZ induced islet cell apoptosis, while sEH inhibition in STZ mice significantly reduced islet cell apoptosis. These studies provide pharmacological evidence that inhibiting sEH activity provides significant protection against islet beta-cell damage and improves glucose homeostasis in STZ-induced diabetes.
ESTHER : Chen_2013_Prostaglandins.Other.Lipid.Mediat_104-105_42
PubMedSearch : Chen_2013_Prostaglandins.Other.Lipid.Mediat_104-105_42
PubMedID: 23247129

Title : Molecular cloning of a novel bioH gene from an environmental metagenome encoding a carboxylesterase with exceptional tolerance to organic solvents - Shi_2013_BMC.Biotechnol_13_13
Author(s) : Shi Y , Pan Y , Li B , He W , She Q , Chen L
Ref : BMC Biotechnol , 13 :13 , 2013
Abstract : ABSTRACT: BACKGROUND: BioH is one of the key enzymes to produce the precursor pimeloyl-ACP to initiate biotin biosynthesis de novo in bacteria. To date, very few bioH genes have been characterized. In this study, we cloned and identified a novel bioH gene, bioHx, from an environmental metagenome by a functional metagenomic approach. The bioHx gene, encoding an enzyme that is capable of hydrolysis of p-nitrophenyl esters of fatty acids, was expressed in Escherichia coli BL21 using the pET expression system. The biochemical property of the purified BioHx protein was also investigated.
RESULTS: Screening of an unamplified metagenomic library with a tributyrin-containing medium led to the isolation of a clone exhibiting lipolytic activity. This clone carried a 4,570-bp DNA fragment encoding for six genes, designated bioF, bioHx, fabG, bioC, orf5 and sdh, four of which were implicated in the de novo biotin biosynthesis. The bioHx gene encodes a protein of 259 aa with a calculated molecular mass of 28.60 kDa, displaying 24-39% amino acid sequence identity to a few characterized bacterial BioH enzymes. It contains a pentapeptide motif (Gly76-Trp77-Ser78-Met79-Gly80) and a catalytic triad (Ser78-His230-Asp202), both of which are characteristic for lipolytic enzymes. BioHx was expressed as a recombinant protein and characterized. The purified BioHx protein displayed carboxylesterase activity, and it was most active on p-nitrophenyl esters of fatty acids substrate with a short acyl chain (C4). Comparing BioHx with other known BioH proteins revealed interesting diversity in their sensitivity to ionic and nonionic detergents and organic solvents, and BioHx exhibited exceptional resistance to organic solvents, being the most tolerant one amongst all known BioH enzymes. This ascribed BioHx as a novel carboxylesterase with a strong potential in industrial applications.
CONCLUSIONS: This study constituted the first investigation of a novel bioHx gene in a biotin biosynthetic gene cluster cloned from an environmental metagenome. The bioHx gene was successfully cloned, expressed and characterized. The results demonstrated that BioHx is a novel carboxylesterase, displaying distinct biochemical properties with strong application potential in industry. Our results also provided the evidence for the effectiveness of functional metagenomic approach for identifying novel bioH genes from complex ecosystem.
ESTHER : Shi_2013_BMC.Biotechnol_13_13
PubMedSearch : Shi_2013_BMC.Biotechnol_13_13
PubMedID: 23413993

Title : Draft genome sequence of Alicyclobacillus hesperidum strain URH17-3-68 - Wang_2012_J.Bacteriol_194_6348
Author(s) : Wang P , Li L , Chen X , Jiang N , Liu G , Chen L , Xu J , Song H , Chen Z , Ma Y
Ref : Journal of Bacteriology , 194 :6348 , 2012
Abstract : Alicyclobacillus hesperidum is a thermoacidophilic bacterium. We isolated strain URH17-3-68 from hot spring sludge in Tengchong, Yunnan province, China. Its extracellular products include heat- and acid-stable enzymes which are important for industrial applications. Here we report the draft genome of this strain.
ESTHER : Wang_2012_J.Bacteriol_194_6348
PubMedSearch : Wang_2012_J.Bacteriol_194_6348
PubMedID: 23105079
Gene_locus related to this paper: 9bacl-h2esd6 , 9bacl-j9e7t9

Title : Draft genome of a Brazilian avian-pathogenic Escherichia coli strain and in silico characterization of virulence-related genes - Rojas_2012_J.Bacteriol_194_3023
Author(s) : Rojas TC , Parizzi LP , Tiba MR , Chen L , Pereira GA , Sangal V , Yang J , Yu J , Dias da Silveira W
Ref : Journal of Bacteriology , 194 :3023 , 2012
Abstract : Avian-pathogenic Escherichia coli (APEC) strains cause extraintestinal diseases in avian species. Here, we present the draft genome of an APEC strain (SCI-07) from Brazil that was isolated from skin lesions (gelatinous edema) on the head and periorbital tissues of a laying hen with swollen head syndrome.
ESTHER : Rojas_2012_J.Bacteriol_194_3023
PubMedSearch : Rojas_2012_J.Bacteriol_194_3023
PubMedID: 22582380
Gene_locus related to this paper: ecoli-IROD , ecoli-IROE , ecoli-ycfp , ecoli-YFBB , ecoli-ypt1 , ecoli-YfhR

Title : Human Mesenchymal Stem Cell Transfusion Is Safe and Improves Liver Function in Acute-on-Chronic Liver Failure Patients - Shi_2012_Stem.Cells.Transl.Med_1_725
Author(s) : Shi M , Zhang Z , Xu R , Lin H , Fu J , Zou Z , Zhang A , Shi J , Chen L , Lv S , He W , Geng H , Jin L , Liu Z , Wang FS
Ref : Stem Cells Transl Med , 1 :725 , 2012
Abstract : Acute-on-chronic liver failure (ACLF) is a severe, life-threatening complication, and new and efficient therapeutic strategies for liver failure are urgently needed. Mesenchymal stem cell (MSC) transfusions have been shown to reverse fulminant hepatic failure in mice and to improve liver function in patients with end-stage liver diseases. We assessed the safety and initial efficacy of umbilical cord-derived MSC (UC-MSC) transfusions for ACLF patients associated with hepatitis B virus (HBV) infection. A total of 43 ACLF patients were enrolled for this open-labeled and controlled study; 24 patients were treated with UC-MSCs, and 19 patients were treated with saline as controls. UC-MSC therapy was given three times at 4-week intervals. The liver function, adverse events, and survival rates were evaluated during the 48-week or 72-week follow-up period. No significant side effects were observed during the trial. The UC-MSC transfusions significantly increased the survival rates in ACLF patients; reduced the model for end-stage liver disease scores; increased serum albumin, cholinesterase, and prothrombin activity; and increased platelet counts. Serum total bilirubin and alanine aminotransferase levels were significantly decreased after the UC-MSC transfusions. UC-MSC transfusions are safe in the clinic and may serve as a novel therapeutic approach for HBV-associated ACLF patients.
ESTHER : Shi_2012_Stem.Cells.Transl.Med_1_725
PubMedSearch : Shi_2012_Stem.Cells.Transl.Med_1_725
PubMedID: 23197664

Title : The oyster genome reveals stress adaptation and complexity of shell formation - Zhang_2012_Nature_490_49
Author(s) : Zhang G , Fang X , Guo X , Li L , Luo R , Xu F , Yang P , Zhang L , Wang X , Qi H , Xiong Z , Que H , Xie Y , Holland PW , Paps J , Zhu Y , Wu F , Chen Y , Wang J , Peng C , Meng J , Yang L , Liu J , Wen B , Zhang N , Huang Z , Zhu Q , Feng Y , Mount A , Hedgecock D , Xu Z , Liu Y , Domazet-Loso T , Du Y , Sun X , Zhang S , Liu B , Cheng P , Jiang X , Li J , Fan D , Wang W , Fu W , Wang T , Wang B , Zhang J , Peng Z , Li Y , Li N , Chen M , He Y , Tan F , Song X , Zheng Q , Huang R , Yang H , Du X , Chen L , Yang M , Gaffney PM , Wang S , Luo L , She Z , Ming Y , Huang W , Huang B , Zhang Y , Qu T , Ni P , Miao G , Wang Q , Steinberg CE , Wang H , Qian L , Liu X , Yin Y
Ref : Nature , 490 :49 , 2012
Abstract : The Pacific oyster Crassostrea gigas belongs to one of the most species-rich but genomically poorly explored phyla, the Mollusca. Here we report the sequencing and assembly of the oyster genome using short reads and a fosmid-pooling strategy, along with transcriptomes of development and stress response and the proteome of the shell. The oyster genome is highly polymorphic and rich in repetitive sequences, with some transposable elements still actively shaping variation. Transcriptome studies reveal an extensive set of genes responding to environmental stress. The expansion of genes coding for heat shock protein 70 and inhibitors of apoptosis is probably central to the oyster's adaptation to sessile life in the highly stressful intertidal zone. Our analyses also show that shell formation in molluscs is more complex than currently understood and involves extensive participation of cells and their exosomes. The oyster genome sequence fills a void in our understanding of the Lophotrochozoa.
ESTHER : Zhang_2012_Nature_490_49
PubMedSearch : Zhang_2012_Nature_490_49
PubMedID: 22992520
Gene_locus related to this paper: cragi-k1qzk7 , cragi-k1rad0 , cragi-k1p6v9 , cragi-k1pa46 , cragi-k1pga2 , cragi-k1pp63 , cragi-k1pwa8 , cragi-k1q0b1.1 , cragi-k1q0b1.2 , cragi-k1q1h2 , cragi-k1q2z6 , cragi-k1qaj8 , cragi-k1qaw5 , cragi-k1qhl5 , cragi-k1qly1 , cragi-k1qqb1.1 , cragi-k1qqb1.2 , cragi-k1qs61 , cragi-k1qs99 , cragi-k1qwl6 , cragi-k1r068 , cragi-k1r0n3.1 , cragi-k1r0n3.2 , cragi-k1r0r4 , cragi-k1r1i9 , cragi-k1r8q9 , cragi-k1rgi1 , cragi-k1rig4 , cragi-k1s0a7.1 , cragi-k1s0a7.2 , cragi-k1s0a7.3 , cragi-k1q6q0 , cragi-k1rru1 , cragi-k1qfi4 , cragi-k1qvm5 , cragi-k1qq58 , cragi-k1qdc0 , cragi-k1r754 , cragi-k1pje5 , cragi-k1qca6 , cragi-k1qdt5 , cragi-k1qkz7 , cragi-k1rgd2 , cragi-k1puh6 , cragi-k1raz4 , cragi-k1qqj4 , cragi-k1rbs1

Title : Bone marrow-derived mesenchymal stem cells up-regulate acetylcholine receptor delta subunit through NRG\/ErbB3-mediated mitogen-activated protein kinase pathway - Chen_2012_Clin.Transl.Sci_5_27
Author(s) : Chen L , Jiang J , Xu J , Gu Y , Xu L
Ref : Clin Transl Sci , 5 :27 , 2012
Abstract : To investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on the expression of acetylcholine receptor delta subunit (AChRd), the murine skeletal muscle cell line Sol8 were grown in DMEM with 20% fetal bovine serum added with (conditional medium group) or without (control group) conditional medium of BMSC cells for 48 hours. RT-PCR and Western blot were performed to access the mRNA and protein levels of AChRd in Sol8 cells, respectively. Western blot was used to detect total and phosphorylated protein levels of Ras, Raf-1, Mek1/2, and Erk1/2, respectively. NRG-1 antibody added in conditional medium of BMSCs, si-ErbB3, and four Ras/Raf/MEK/ERK pathway inhibitors (FTS, Sulindac, U0126, and PD98059) were using to investigate the effect of AChRd levels. Our studies indicated that expression of AChRd was significantly enhanced in the conditional medium group when compared with those in control group and phosphorylation of Ras, Raf, Erk1/2 in Sol8 cells was also increased. Although gene silencing for ErbB3 gene, adding of NRG-1 antibody in conditional medium of BMSCs or treatment of Ras/Raf/MEK/ERK pathway inhibitors can down-regulate expression of AChRd and phosphorylation, which suggesting that the Ras/Raf/MEK/ERK pathway may be involved in BMSCs-induced expression of AChRd.
ESTHER : Chen_2012_Clin.Transl.Sci_5_27
PubMedSearch : Chen_2012_Clin.Transl.Sci_5_27
PubMedID: 22376253

Title : Acute exposure to DE-71: effects on locomotor behavior and developmental neurotoxicity in zebrafish larvae - Chen_2012_Environ.Toxicol.Chem_31_2338
Author(s) : Chen L , Huang C , Hu C , Yu K , Yang L , Zhou B
Ref : Environ Toxicol Chem , 31 :2338 , 2012
Abstract : The aim of the present study was to investigate the acute developmental neurotoxicity of polybrominated diphenyl ethers (PBDEs) in zebrafish larvae. From 2 to 120 h postfertilization zebrafish embryos were exposed to DE-71 (0, 31.0, 68.7, and 227.6 microg/L). The authors studied the locomotor behavior of larvae, involvement of the cholinergic system, and selected gene and protein expressions in the central nervous system. The results showed that low DE-71 concentration caused hyperactivity, whereas higher concentrations decreased activity during the dark period. During the light period, larval activity was significantly reduced in a concentration-dependent manner. In the cholinergic system, acetylcholinesterase activity significantly increased (10.7 and 12.4%) in the 68.7 and 227.6 microg/L exposure groups, respectively, and acetylcholine concentration accordingly decreased (60.5%) in the 227.6 microg/L exposure group. The mRNA expressions of genes encoding myelin basic protein, neuron microtubule protein (alpha1-tubulin), and sonic hedgehog a were significantly downregulated. Western blotting assay demonstrated that the protein concentration of alpha1-tubulin was also decreased. Overall, the present study demonstrated that acute exposure to PBDEs can disrupt the neurobehavior of zebrafish larvae and affect cholinergic neurotransmission and neuron development.
ESTHER : Chen_2012_Environ.Toxicol.Chem_31_2338
PubMedSearch : Chen_2012_Environ.Toxicol.Chem_31_2338
PubMedID: 22833361

Title : Prenatal Transfer of Polybrominated Diphenyl Ethers (PBDEs) Results in Developmental Neurotoxicity in Zebrafish Larvae - Chen_2012_Environ.Sci.Technol_46_9727
Author(s) : Chen L , Yu K , Huang C , Yu L , Zhu B , Lam PK , Lam JC , Zhou B
Ref : Environ Sci Technol , 46 :9727 , 2012
Abstract : Parental exposure to polybrominated diphenyl ethers (PBDEs) in animals has been found to be transferred to the offspring. The environmental health risk and toxicity to the offspring are still unclear. The objective of the present study was to identify environmentally relevant concentrations of PBDEs for parental exposure that would cause developmental neurotoxicity in the offspring. Adult zebrafish were exposed to environmentally relevant concentrations of DE-71 (0.16, 0.8, 4.0 ug/L) via water. The results showed that PBDE exposure did not affect larvae hatching, malformation, or survival. The residue of PBDEs was detected in F1 eggs upon parental exposure. Acetylcholinesterase (AChE) activity was significantly inhibited in F1 larvae. Genes of central nervous system development (e.g., myelin basic protein, synapsin IIa, alpha1-tubulin) were significantly downregulated in larvae. Protein levels of alpha1-tubulin and synapsin IIa were also reduced. Decreased locomotion activity was observed in the larvae. This study provides the first evidence that parental exposure to environmentally relevant concentrations of PBDEs could cause adverse effects on neurodevelopment in zebrafish offspring.
ESTHER : Chen_2012_Environ.Sci.Technol_46_9727
PubMedSearch : Chen_2012_Environ.Sci.Technol_46_9727
PubMedID: 22866812

Title : Increased genetic vulnerability to smoking at CHRNA5 in early-onset smokers - Hartz_2012_Arch.Gen.Psychiatry_69_854
Author(s) : Hartz SM , Short SE , Saccone NL , Culverhouse R , Chen L , Schwantes-An TH , Coon H , Han Y , Stephens SH , Sun J , Chen X , Ducci F , Dueker N , Franceschini N , Frank J , Geller F , Gubjartsson D , Hansel NN , Jiang C , Keskitalo-Vuokko K , Liu Z , Lyytikainen LP , Michel M , Rawal R , Rosenberger A , Scheet P , Shaffer JR , Teumer A , Thompson JR , Vink JM , Vogelzangs N , Wenzlaff AS , Wheeler W , Xiao X , Yang BZ , Aggen SH , Balmforth AJ , Baumeister SE , Beaty T , Bennett S , Bergen AW , Boyd HA , Broms U , Campbell H , Chatterjee N , Chen J , Cheng YC , Cichon S , Couper D , Cucca F , Dick DM , Foroud T , Furberg H , Giegling I , Gu F , Hall AS , Hallfors J , Han S , Hartmann AM , Hayward C , Heikkila K , Hewitt JK , Hottenga JJ , Jensen MK , Jousilahti P , Kaakinen M , Kittner SJ , Konte B , Korhonen T , Landi MT , Laatikainen T , Leppert M , Levy SM , Mathias RA , McNeil DW , Medland SE , Montgomery GW , Muley T , Murray T , Nauck M , North K , Pergadia M , Polasek O , Ramos EM , Ripatti S , Risch A , Ruczinski I , Rudan I , Salomaa V , Schlessinger D , Styrkarsdottir U , Terracciano A , Uda M , Willemsen G , Wu X , Abecasis G , Barnes K , Bickeboller H , Boerwinkle E , Boomsma DI , Caporaso N , Duan J , Edenberg HJ , Francks C , Gejman PV , Gelernter J , Grabe HJ , Hops H , Jarvelin MR , Viikari J , Kahonen M , Kendler KS , Lehtimaki T , Levinson DF , Marazita ML , Marchini J , Melbye M , Mitchell BD , Murray JC , Nothen MM , Penninx BW , Raitakari O , Rietschel M , Rujescu D , Samani NJ , Sanders AR , Schwartz AG , Shete S , Shi J , Spitz M , Stefansson K , Swan GE , Thorgeirsson T , Volzke H , Wei Q , Wichmann HE , Amos CI , Breslau N , Cannon DS , Ehringer M , Grucza R , Hatsukami D , Heath A , Johnson EO , Kaprio J , Madden P , Martin NG , Stevens VL , Stitzel JA , Weiss RB , Kraft P , Bierut LJ
Ref : Arch Gen Psychiatry , 69 :854 , 2012
Abstract : CONTEXT: Recent studies have shown an association between cigarettes per day (CPD) and a nonsynonymous single-nucleotide polymorphism in CHRNA5, rs16969968. OBJECTIVE: To determine whether the association between rs16969968 and smoking is modified by age at onset of regular smoking. DATA SOURCES: Primary data. STUDY SELECTION: Available genetic studies containing measures of CPD and the genotype of rs16969968 or its proxy. DATA EXTRACTION: Uniform statistical analysis scripts were run locally. Starting with 94,050 ever-smokers from 43 studies, we extracted the heavy smokers (CPD >20) and light smokers (CPD </=10) with age-at-onset information, reducing the sample size to 33,348. Each study was stratified into early-onset smokers (age at onset </=16 years) and late-onset smokers (age at onset >16 years), and a logistic regression of heavy vs light smoking with the rs16969968 genotype was computed for each stratum. Meta-analysis was performed within each age-at-onset stratum. DATA SYNTHESIS: Individuals with 1 risk allele at rs16969968 who were early-onset smokers were significantly more likely to be heavy smokers in adulthood (odds ratio [OR] = 1.45; 95% CI, 1.36-1.55; n = 13,843) than were carriers of the risk allele who were late-onset smokers (OR = 1.27; 95% CI, 1.21-1.33, n = 19,505) (P = .01). CONCLUSION: These results highlight an increased genetic vulnerability to smoking in early-onset smokers.
ESTHER : Hartz_2012_Arch.Gen.Psychiatry_69_854
PubMedSearch : Hartz_2012_Arch.Gen.Psychiatry_69_854
PubMedID: 22868939

Title : Whole genome sequences of three Treponema pallidum ssp. pertenue strains: yaws and syphilis treponemes differ in less than 0.2\% of the genome sequence - Cejkova_2012_PLoS.Negl.Trop.Dis_6_e1471
Author(s) : Cejkova D , Zobanikova M , Chen L , Pospisilova P , Strouhal M , Qin X , Mikalova L , Norris SJ , Muzny DM , Gibbs RA , Fulton LL , Sodergren E , Weinstock GM , Smajs D
Ref : PLoS Negl Trop Dis , 6 :e1471 , 2012
Abstract : BACKGROUND: The yaws treponemes, Treponema pallidum ssp. pertenue (TPE) strains, are closely related to syphilis causing strains of Treponema pallidum ssp. pallidum (TPA). Both yaws and syphilis are distinguished on the basis of epidemiological characteristics, clinical symptoms, and several genetic signatures of the corresponding causative agents. METHODOLOGY/PRINCIPAL FINDINGS: To precisely define genetic differences between TPA and TPE, high-quality whole genome sequences of three TPE strains (Samoa D, CDC-2, Gauthier) were determined using next-generation sequencing techniques. TPE genome sequences were compared to four genomes of TPA strains (Nichols, DAL-1, SS14, Chicago). The genome structure was identical in all three TPE strains with similar length ranging between 1,139,330 bp and 1,139,744 bp. No major genome rearrangements were found when compared to the four TPA genomes. The whole genome nucleotide divergence (d(A)) between TPA and TPE subspecies was 4.7 and 4.8 times higher than the observed nucleotide diversity (pi) among TPA and TPE strains, respectively, corresponding to 99.8% identity between TPA and TPE genomes. A set of 97 (9.9%) TPE genes encoded proteins containing two or more amino acid replacements or other major sequence changes. The TPE divergent genes were mostly from the group encoding potential virulence factors and genes encoding proteins with unknown function. CONCLUSIONS/SIGNIFICANCE: Hypothetical genes, with genetic differences, consistently found between TPE and TPA strains are candidates for syphilitic treponemes virulence factors. Seventeen TPE genes were predicted under positive selection, and eleven of them coded either for predicted exported proteins or membrane proteins suggesting their possible association with the cell surface. Sequence changes between TPE and TPA strains and changes specific to individual strains represent suitable targets for subspecies- and strain-specific molecular diagnostics.
ESTHER : Cejkova_2012_PLoS.Negl.Trop.Dis_6_e1471
PubMedSearch : Cejkova_2012_PLoS.Negl.Trop.Dis_6_e1471
PubMedID: 22292095
Gene_locus related to this paper: trepa-TP0902

Title : Ligand-binding domain of an alpha7-nicotinic receptor chimera and its complex with agonist - Li_2011_Nat.Neurosci_14_1253
Author(s) : Li SX , Huang S , Bren N , Noridomi K , Dellisanti CD , Sine SM , Chen L
Ref : Nat Neurosci , 14 :1253 , 2011
Abstract : The alpha(7) acetylcholine receptor (AChR) mediates pre- and postsynaptic neurotransmission in the central nervous system and is a potential therapeutic target in neurodegenerative, neuropsychiatric and inflammatory disorders. We determined the crystal structure of the extracellular domain of a receptor chimera constructed from the human alpha(7) AChR and Lymnaea stagnalis acetylcholine binding protein (AChBP), which shares 64% sequence identity and 71% similarity with native alpha(7). We also determined the structure with bound epibatidine, a potent AChR agonist. Comparison of the structures revealed molecular rearrangements and interactions that mediate agonist recognition and early steps in signal transduction in alpha(7) AChRs. The structures further revealed a ring of negative charge within the central vestibule, poised to contribute to cation selectivity. Structure-guided mutational studies disclosed distinctive contributions to agonist recognition and signal transduction in alpha(7) AChRs. The structures provide a realistic template for structure-aided drug design and for defining structure-function relationships of alpha(7) AChRs.
ESTHER : Li_2011_Nat.Neurosci_14_1253
PubMedSearch : Li_2011_Nat.Neurosci_14_1253
PubMedID: 21909087

Title : Theoretical study of the mechanism of proton transfer in the esterase EstB from Burkholderia gladioli - Chen_2011_J.Phys.Chem.B_115_13019
Author(s) : Chen L , Kong X , Liang Z , Ye F , Yu K , Dai W , Wu D , Luo C , Jiang H
Ref : J Phys Chem B , 115 :13019 , 2011
Abstract : Esterase EstB from Burkholderia gladioli belongs to a novel class of esterases homologous to penicillin binding proteins, notably DD-peptidase and class C beta-lactamases. It can cleave the side chain acetyl ester group from cephalosporins leaving the beta-lactam ring intact, which is a feature of relevance to industrial biocatalytic applications in the production of semisynthetic cephalosporin derivatives. Due to its important role as a potential biocatalyst in industry, the significance of EstB has been greatly appreciated. However, the molecular basis for those residues involving catalysis of EstB remains elusive. By analyzing the crystal structure of EstB, we identified a conserved water molecule in active-site cavity which might mediate an intramolecular proton transfer (PT) from Lys78 to Asp186 via Tyr133. Then a combined computational approach including molecular dynamics (MD) simulations and quantum mechanics/molecular mechanics (QM/MM) calculations was employed to explore this presumable PT mode in the native enzyme. A 30 ns MD simulation of the enzyme highlights the conserved H-bond network involving Lys78, Tyr133, Asp186, and the conserved water molecule in the active site. In particular, the water molecule did not exchange with bulk solvent, indicating its structural and functional relevance. The energy profile calculated by QM/MM approach displayed a notably low PT barrier (2.2 kcal/mol) and a dramatic energy difference (14.1 kcal/mol) in reactants versus immediate products, which implies that the proposed proton shuttle is concerted and energetically favorable. Our studies offer a reasonable pathway to yield a free base by assisting Lys78 deprotonation, thereby paving the way for future studies on Ser75 activation that is a critical step in catalysis by EstB, as well as biocatalyst development by rational attempts. This PT mode would also afford clues for the forthcoming investigation on acyltransferase LovD that is homologous to EstB.
ESTHER : Chen_2011_J.Phys.Chem.B_115_13019
PubMedSearch : Chen_2011_J.Phys.Chem.B_115_13019
PubMedID: 21910435

Title : Evaluation of pharmacokinetic parameters and dipeptidyl peptidase-4 inhibition following single doses of sitagliptin in healthy, young Japanese males - Herman_2011_Br.J.Clin.Pharmacol_71_429
Author(s) : Herman GA , Mistry GC , Yi B , Bergman AJ , Wang AQ , Zeng W , Chen L , Snyder K , Ruckle JL , Larson PJ , Davies MJ , Langdon RB , Gottesdiener KM , Wagner JA
Ref : British Journal of Clinical Pharmacology , 71 :429 , 2011
Abstract : AIMS: Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 (DPP-4) used to treat type 2 diabetes. The present aim was to evaluate pharmacokinetic (PK), pharmacodynamic (PD) and safety characteristics of sitagliptin following single doses in healthy, young Japanese males. METHODS: In this alternating two-panel, randomized, controlled double-blind study, six healthy Japanese male subjects (aged 20-46 years) in each panel received single oral doses of 5-400mg sitagliptin and two received placebo. Plasma and urine drug concentrations were measured from 0-48h post dose and plasma DPP-4 inhibition from 0-24h post dose. The results were compared with historical data from young, healthy non-Japanese males. RESULTS: Plasma concentrations of sitagliptin increased approximately in proportion to dose; maximum concentrations occurred 2-6h post-dose. The mean apparent terminal half-life for plasma sitagliptin was 9-14h, with the half-life slightly decreasing as the dose increased. The mean dose fraction excreted unchanged in the urine was 0.73-1.00. Ingestion of a traditional Japanese breakfast prior to dosing had only a minor effect on PK parameters. After correction for dilution and competition effects during assay, doses of sitagliptin >/=50mg resulted in weighted average DPP-4 inhibition from 0-24h post-dose >94% (without correction, >78%). No clinically meaningful differences in PK and DPP-4 inhibition parameters were found between Japanese and non-Japanese subjects. Sitagliptin was generally well tolerated and there were no serious adverse experiences or episodes of hypoglycaemia. CONCLUSIONS: The PK and PD findings from this study are consistent with once daily dosing of sitagliptin in Japanese patients with type 2 diabetes.
ESTHER : Herman_2011_Br.J.Clin.Pharmacol_71_429
PubMedSearch : Herman_2011_Br.J.Clin.Pharmacol_71_429
PubMedID: 21284702

Title : Selective repression of MEF2 activity by PKA-dependent proteolysis of HDAC4 - Backs_2011_J.Cell.Biol_195_403
Author(s) : Backs J , Worst BC , Lehmann LH , Patrick DM , Jebessa Z , Kreusser MM , Sun Q , Chen L , Heft C , Katus HA , Olson EN
Ref : Journal of Cell Biology , 195 :403 , 2011
Abstract : Histone deacetylase 4 (HDAC4) regulates numerous gene expression programs through its signal-dependent repression of myocyte enhancer factor 2 (MEF2) and serum response factor (SRF) transcription factors. In cardiomyocytes, calcium/calmodulin-dependent protein kinase II (CaMKII) signaling promotes hypertrophy and pathological remodeling, at least in part by phosphorylating HDAC4, with consequent stimulation of MEF2 activity. In this paper, we describe a novel mechanism whereby protein kinase A (PKA) overcomes CaMKII-mediated activation of MEF2 by regulated proteolysis of HDAC4. PKA induces the generation of an N-terminal HDAC4 cleavage product (HDAC4-NT). HDAC4-NT selectively inhibits activity of MEF2 but not SRF, thereby antagonizing the prohypertrophic actions of CaMKII signaling without affecting cardiomyocyte survival. Thus, HDAC4 functions as a molecular nexus for the antagonistic actions of the CaMKII and PKA pathways. These findings have implications for understanding the molecular basis of cardioprotection and other cellular processes in which CaMKII and PKA exert opposing effects.
ESTHER : Backs_2011_J.Cell.Biol_195_403
PubMedSearch : Backs_2011_J.Cell.Biol_195_403
PubMedID: 22042619

Title : Over-expression of human lipoprotein lipase in mouse mammary glands leads to reduction of milk triglyceride and delayed growth of suckling pups - Wang_2011_PLoS.One_6_e20895
Author(s) : Wang Y , Tong J , Li S , Zhang R , Chen L , Zheng M , Wang M , Liu G , Dai Y , Zhao Y , Li N
Ref : PLoS ONE , 6 :e20895 , 2011
Abstract : BACKGROUND: The mammary gland is a conserved site of lipoprotein lipase expression across species and lipoprotein lipase attachment to the luminal surface of mammary gland vascular endothelial cells has been implicated in the direction of circulating triglycerides into milk synthesis during lactation. PRINCIPAL FINDINGS: Here we report generation of transgenic mice harboring a human lipoprotein lipase gene driven by a mammary gland-specific promoter. Lipoprotein lipase levels in transgenic milk was raised to 0.16 mg/ml, corresponding to an activity of 8772.95 mU/ml. High lipoprotein lipase activity led to a significant reduction of triglyceride concentration in milk, but other components were largely unchanged. Normal pups fed with transgenic milk showed inferior growth performances compared to those fed with normal milk. CONCLUSION: Our study suggests a possibility to reduce the triglyceride content of cow milk using transgenic technology.
ESTHER : Wang_2011_PLoS.One_6_e20895
PubMedSearch : Wang_2011_PLoS.One_6_e20895
PubMedID: 21698114

Title : Genome analyses of Icelandic strains of Sulfolobus islandicus, model organisms for genetic and virus-host interaction studies - Guo_2011_J.Bacteriol_193_1672
Author(s) : Guo L , Brugger K , Liu C , Shah SA , Zheng H , Zhu Y , Wang S , Lillestol RK , Chen L , Frank J , Prangishvili D , Paulin L , She Q , Huang L , Garrett RA
Ref : Journal of Bacteriology , 193 :1672 , 2011
Abstract : The genomes of two Sulfolobus islandicus strains obtained from Icelandic solfataras were sequenced and analyzed. Strain REY15A is a host for a versatile genetic toolbox. It exhibits a genome of minimal size, is stable genetically, and is easy to grow and manipulate. Strain HVE10/4 shows a broad host range for exceptional crenarchaeal viruses and conjugative plasmids and was selected for studying their life cycles and host interactions. The genomes of strains REY15A and HVE10/4 are 2.5 and 2.7 Mb, respectively, and each genome carries a variable region of 0.5 to 0.7 Mb where major differences in gene content and gene order occur. These include gene clusters involved in specific metabolic pathways, multiple copies of VapBC antitoxin-toxin gene pairs, and in strain HVE10/4, a 50-kb region rich in glycosyl transferase genes. The variable region also contains most of the insertion sequence (IS) elements and high proportions of the orphan orfB elements and SMN1 miniature inverted-repeat transposable elements (MITEs), as well as the clustered regular interspaced short palindromic repeat (CRISPR)-based immune systems, which are complex and diverse in both strains, consistent with them having been mobilized both intra- and intercellularly. In contrast, the remainder of the genomes are highly conserved in their protein and RNA gene syntenies, closely resembling those of other S. islandicus and Sulfolobus solfataricus strains, and they exhibit only minor remnants of a few genetic elements, mainly conjugative plasmids, which have integrated at a few tRNA genes lacking introns. This provides a possible rationale for the presence of the introns.
ESTHER : Guo_2011_J.Bacteriol_193_1672
PubMedSearch : Guo_2011_J.Bacteriol_193_1672
PubMedID: 21278296
Gene_locus related to this paper: sulir-f0nbu1 , sulso-APEH1 , sulso-APEH3 , sulso-dlhh , sulir-f0ndq1

Title : The phospholipase A1 activity of lysophospholipase A-I links platelet activation to LPA production during blood coagulation - Bolen_2011_J.Lipid.Res_52_958
Author(s) : Bolen AL , Naren AP , Yarlagadda S , Beranova-Giorgianni S , Chen L , Norman D , Baker DL , Rowland MM , Best MD , Sano T , Tsukahara T , Liliom K , Igarashi Y , Tigyi G
Ref : J Lipid Res , 52 :958 , 2011
Abstract : Platelet activation initiates an upsurge in polyunsaturated (18:2 and 20:4) lysophosphatidic acid (LPA) production. The biochemical pathway(s) responsible for LPA production during blood clotting are not yet fully understood. Here we describe the purification of a phospholipase A(1) (PLA(1)) from thrombin-activated human platelets using sequential chromatographic steps followed by fluorophosphonate (FP)-biotin affinity labeling and proteomics characterization that identified acyl-protein thioesterase 1 (APT1), also known as lysophospholipase A-I (LYPLA-I; accession code O75608) as a novel PLA(1). Addition of this recombinant PLA(1) significantly increased the production of sn-2-esterified polyunsaturated LPCs and the corresponding LPAs in plasma. We examined the regioisomeric preference of lysophospholipase D/autotaxin (ATX), which is the subsequent step in LPA production. To prevent acyl migration, ether-linked regioisomers of oleyl-sn-glycero-3-phosphocholine (lyso-PAF) were synthesized. ATX preferred the sn-1 to the sn-2 regioisomer of lyso-PAF. We propose the following LPA production pathway in blood: 1) Activated platelets release PLA(1); 2) PLA(1) generates a pool of sn-2 lysophospholipids; 3) These newly generated sn-2 lysophospholipids undergo acyl migration to yield sn-1 lysophospholipids, which are the preferred substrates of ATX; and 4) ATX cleaves the sn-1 lysophospholipids to generate sn-1 LPA species containing predominantly 18:2 and 20:4 fatty acids.
ESTHER : Bolen_2011_J.Lipid.Res_52_958
PubMedSearch : Bolen_2011_J.Lipid.Res_52_958
PubMedID: 21393252

Title : Genome sequencing reveals insights into physiology and longevity of the naked mole rat - Kim_2011_Nature_479_223
Author(s) : Kim EB , Fang X , Fushan AA , Huang Z , Lobanov AV , Han L , Marino SM , Sun X , Turanov AA , Yang P , Yim SH , Zhao X , Kasaikina MV , Stoletzki N , Peng C , Polak P , Xiong Z , Kiezun A , Zhu Y , Chen Y , Kryukov GV , Zhang Q , Peshkin L , Yang L , Bronson RT , Buffenstein R , Wang B , Han C , Li Q , Chen L , Zhao W , Sunyaev SR , Park TJ , Zhang G , Wang J , Gladyshev VN
Ref : Nature , 479 :223 , 2011
Abstract : The naked mole rat (Heterocephalus glaber) is a strictly subterranean, extraordinarily long-lived eusocial mammal. Although it is the size of a mouse, its maximum lifespan exceeds 30 years, making this animal the longest-living rodent. Naked mole rats show negligible senescence, no age-related increase in mortality, and high fecundity until death. In addition to delayed ageing, they are resistant to both spontaneous cancer and experimentally induced tumorigenesis. Naked mole rats pose a challenge to the theories that link ageing, cancer and redox homeostasis. Although characterized by significant oxidative stress, the naked mole rat proteome does not show age-related susceptibility to oxidative damage or increased ubiquitination. Naked mole rats naturally reside in large colonies with a single breeding female, the 'queen', who suppresses the sexual maturity of her subordinates. They also live in full darkness, at low oxygen and high carbon dioxide concentrations, and are unable to sustain thermogenesis nor feel certain types of pain. Here we report the sequencing and analysis of the naked mole rat genome, which reveals unique genome features and molecular adaptations consistent with cancer resistance, poikilothermy, hairlessness and insensitivity to low oxygen, and altered visual function, circadian rythms and taste sensing. This information provides insights into the naked mole rat's exceptional longevity and ability to live in hostile conditions, in the dark and at low oxygen. The extreme traits of the naked mole rat, together with the reported genome and transcriptome information, offer opportunities for understanding ageing and advancing other areas of biological and biomedical research.
ESTHER : Kim_2011_Nature_479_223
PubMedSearch : Kim_2011_Nature_479_223
PubMedID: 21993625
Gene_locus related to this paper: hetga-g5amh8 , hetga-g5an68 , hetga-g5anw7 , hetga-g5as32 , hetga-g5atg6 , hetga-g5b5b7 , hetga-g5b9m6 , hetga-g5bdh8 , hetga-g5bmv3 , hetga-g5bp66 , hetga-g5bp67 , hetga-g5bp68 , hetga-g5bpp3 , hetga-g5bsd4 , hetga-g5bul0 , hetga-g5bw29 , hetga-g5bze3 , hetga-g5c6q5 , hetga-g5bfw4 , hetga-g5b832 , hetga-g5c6q8 , hetga-g5bj87 , hetga-a0a0p6jix7 , hetga-g5c108 , hetga-g5c109 , hetga-g5c110 , hetga-g5arh0 , hetga-g5aua1 , hetga-g5are8 , hetga-g5ax31 , hetga-a0a0p6jud6 , hetga-g5b7v3 , hetga-a0a0p6jw61 , hetga-a0a0p6jdl4 , hetga-g5bg83 , hetga-g5bcu5 , hetga-g5bvp0 , hetga-g5b8m7 , hetga-g5b709 , hetga-g5bt99 , hetga-g5b4q4

Title : Complete genome sequence of Treponema paraluiscuniculi, strain Cuniculi A: the loss of infectivity to humans is associated with genome decay - Smajs_2011_PLoS.One_6_e20415
Author(s) : Smajs D , Zobanikova M , Strouhal M , Cejkova D , Dugan-Rocha S , Pospisilova P , Norris SJ , Albert T , Qin X , Hallsworth-Pepin K , Buhay C , Muzny DM , Chen L , Gibbs RA , Weinstock GM
Ref : PLoS ONE , 6 :e20415 , 2011
Abstract : Treponema paraluiscuniculi is the causative agent of rabbit venereal spirochetosis. It is not infectious to humans, although its genome structure is very closely related to other pathogenic Treponema species including Treponema pallidum subspecies pallidum, the etiological agent of syphilis. In this study, the genome sequence of Treponema paraluiscuniculi, strain Cuniculi A, was determined by a combination of several high-throughput sequencing strategies. Whereas the overall size (1,133,390 bp), arrangement, and gene content of the Cuniculi A genome closely resembled those of the T. pallidum genome, the T. paraluiscuniculi genome contained a markedly higher number of pseudogenes and gene fragments (51). In addition to pseudogenes, 33 divergent genes were also found in the T. paraluiscuniculi genome. A set of 32 (out of 84) affected genes encoded proteins of known or predicted function in the Nichols genome. These proteins included virulence factors, gene regulators and components of DNA repair and recombination. The majority (52 or 61.9%) of the Cuniculi A pseudogenes and divergent genes were of unknown function. Our results indicate that T. paraluiscuniculi has evolved from a T. pallidum-like ancestor and adapted to a specialized host-associated niche (rabbits) during loss of infectivity to humans. The genes that are inactivated or altered in T. paraluiscuniculi are candidates for virulence factors important in the infectivity and pathogenesis of T. pallidum subspecies.
ESTHER : Smajs_2011_PLoS.One_6_e20415
PubMedSearch : Smajs_2011_PLoS.One_6_e20415
PubMedID: 21655244
Gene_locus related to this paper: trepa-TP0902

Title : Crystal structure of a triacylglycerol lipase from Penicillium expansum at 1.3 A determined by sulfur SAD -
Author(s) : Bian C , Yuan C , Chen L , Meehan EJ , Jiang L , Huang Z , Lin L , Huang M
Ref : Proteins , 78 :1601 , 2010
PubMedID: 20146362
Gene_locus related to this paper: penex-Q9HFW6

Title : A catalog of reference genomes from the human microbiome - Nelson_2010_Science_328_994
Author(s) : Nelson KE , Weinstock GM , Highlander SK , Worley KC , Creasy HH , Wortman JR , Rusch DB , Mitreva M , Sodergren E , Chinwalla AT , Feldgarden M , Gevers D , Haas BJ , Madupu R , Ward DV , Birren BW , Gibbs RA , Methe B , Petrosino JF , Strausberg RL , Sutton GG , White OR , Wilson RK , Durkin S , Giglio MG , Gujja S , Howarth C , Kodira CD , Kyrpides N , Mehta T , Muzny DM , Pearson M , Pepin K , Pati A , Qin X , Yandava C , Zeng Q , Zhang L , Berlin AM , Chen L , Hepburn TA , Johnson J , McCorrison J , Miller J , Minx P , Nusbaum C , Russ C , Sykes SM , Tomlinson CM , Young S , Warren WC , Badger J , Crabtree J , Markowitz VM , Orvis J , Cree A , Ferriera S , Fulton LL , Fulton RS , Gillis M , Hemphill LD , Joshi V , Kovar C , Torralba M , Wetterstrand KA , Abouellleil A , Wollam AM , Buhay CJ , Ding Y , Dugan S , Fitzgerald MG , Holder M , Hostetler J , Clifton SW , Allen-Vercoe E , Earl AM , Farmer CN , Liolios K , Surette MG , Xu Q , Pohl C , Wilczek-Boney K , Zhu D
Ref : Science , 328 :994 , 2010
Abstract : The human microbiome refers to the community of microorganisms, including prokaryotes, viruses, and microbial eukaryotes, that populate the human body. The National Institutes of Health launched an initiative that focuses on describing the diversity of microbial species that are associated with health and disease. The first phase of this initiative includes the sequencing of hundreds of microbial reference genomes, coupled to metagenomic sequencing from multiple body sites. Here we present results from an initial reference genome sequencing of 178 microbial genomes. From 547,968 predicted polypeptides that correspond to the gene complement of these strains, previously unidentified ("novel") polypeptides that had both unmasked sequence length greater than 100 amino acids and no BLASTP match to any nonreference entry in the nonredundant subset were defined. This analysis resulted in a set of 30,867 polypeptides, of which 29,987 (approximately 97%) were unique. In addition, this set of microbial genomes allows for approximately 40% of random sequences from the microbiome of the gastrointestinal tract to be associated with organisms based on the match criteria used. Insights into pan-genome analysis suggest that we are still far from saturating microbial species genetic data sets. In addition, the associated metrics and standards used by our group for quality assurance are presented.
ESTHER : Nelson_2010_Science_328_994
PubMedSearch : Nelson_2010_Science_328_994
PubMedID: 20489017
Gene_locus related to this paper: strp2-q04l35 , strpn-AXE1 , strpn-pepx

Title : The genome of a songbird - Warren_2010_Nature_464_757
Author(s) : Warren WC , Clayton DF , Ellegren H , Arnold AP , Hillier LW , Kunstner A , Searle S , White S , Vilella AJ , Fairley S , Heger A , Kong L , Ponting CP , Jarvis ED , Mello CV , Minx P , Lovell P , Velho TA , Ferris M , Balakrishnan CN , Sinha S , Blatti C , London SE , Li Y , Lin YC , George J , Sweedler J , Southey B , Gunaratne P , Watson M , Nam K , Backstrom N , Smeds L , Nabholz B , Itoh Y , Whitney O , Pfenning AR , Howard J , Volker M , Skinner BM , Griffin DK , Ye L , McLaren WM , Flicek P , Quesada V , Velasco G , Lopez-Otin C , Puente XS , Olender T , Lancet D , Smit AF , Hubley R , Konkel MK , Walker JA , Batzer MA , Gu W , Pollock DD , Chen L , Cheng Z , Eichler EE , Stapley J , Slate J , Ekblom R , Birkhead T , Burke T , Burt D , Scharff C , Adam I , Richard H , Sultan M , Soldatov A , Lehrach H , Edwards SV , Yang SP , Li X , Graves T , Fulton L , Nelson J , Chinwalla A , Hou S , Mardis ER , Wilson RK
Ref : Nature , 464 :757 , 2010
Abstract : The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour.
ESTHER : Warren_2010_Nature_464_757
PubMedSearch : Warren_2010_Nature_464_757
PubMedID: 20360741
Gene_locus related to this paper: taegu-b5fyu7 , taegu-BCHE , taegu-h0z4h9 , taegu-h0z9w8 , taegu-h0zat6 , taegu-h0ze48 , taegu-h0zha8 , taegu-h0zkr8 , taegu-h0zqp3 , taegu-h0zz82 , taegu-h0zqs1 , taegu-h0yy64 , taegu-h0yv40 , taegu-h0yyt1 , taegu-h0zcc8 , taegu-h0z3k5 , taegu-h0yw95 , taegu-h0zkm7 , taegu-h1a198 , taegu-h0z6w2 , taegu-h0zl93 , taegu-h0zt33 , taegu-h0yp71 , taegu-h0ypu5 , taegu-h1a048 , taegu-h0ztq1 , fical-u3kau2 , 9pass-a0a093qu66 , taegu-h0z7g0 , fical-u3jnn0 , taegu-h0zb80 , taegu-h0zb89 , taegu-h0z994 , taegu-h0ztj6

Title : Complete genome sequence of the extremophilic Bacillus cereus strain Q1 with industrial applications - Xiong_2009_J.Bacteriol_191_1120
Author(s) : Xiong Z , Jiang Y , Qi D , Lu H , Yang F , Yang J , Chen L , Sun L , Xu X , Xue Y , Zhu Y , Jin Q
Ref : Journal of Bacteriology , 191 :1120 , 2009
Abstract : Bacillus cereus strain Q1 was isolated from a deep-subsurface oil reservoir in the Daqing oil field in northeastern China. This strain is able to produce biosurfactants and to survive in extreme environments. Here we report the finished and annotated genome sequence of this organism.
ESTHER : Xiong_2009_J.Bacteriol_191_1120
PubMedSearch : Xiong_2009_J.Bacteriol_191_1120
PubMedID: 19060151
Gene_locus related to this paper: bacah-a0rer5 , bacan-BA0954 , bacan-BA3703 , bacan-BA4338 , bacan-BA5009 , bacan-DHBF , bacc1-q73br9 , bacce-BC0192 , bacce-BC0968 , bacce-BC1788 , bacce-BC2141 , bacce-BC2171 , bacce-BC4102 , bacce-BC4854 , bacce-BC4862 , bacce-BC5130 , bacce-c2mr40 , bacce-PHAC , bacce-q72yu1 , bacce-q736x9 , baccq-b9j170 , baccr-pepx , baccz-q636u4 , bacti-q3elq7

Title : The genome sequence of taurine cattle: a window to ruminant biology and evolution - Elsik_2009_Science_324_522
Author(s) : Elsik CG , Tellam RL , Worley KC , Gibbs RA , Muzny DM , Weinstock GM , Adelson DL , Eichler EE , Elnitski L , Guigo R , Hamernik DL , Kappes SM , Lewin HA , Lynn DJ , Nicholas FW , Reymond A , Rijnkels M , Skow LC , Zdobnov EM , Schook L , Womack J , Alioto T , Antonarakis SE , Astashyn A , Chapple CE , Chen HC , Chrast J , Camara F , Ermolaeva O , Henrichsen CN , Hlavina W , Kapustin Y , Kiryutin B , Kitts P , Kokocinski F , Landrum M , Maglott D , Pruitt K , Sapojnikov V , Searle SM , Solovyev V , Souvorov A , Ucla C , Wyss C , Anzola JM , Gerlach D , Elhaik E , Graur D , Reese JT , Edgar RC , McEwan JC , Payne GM , Raison JM , Junier T , Kriventseva EV , Eyras E , Plass M , Donthu R , Larkin DM , Reecy J , Yang MQ , Chen L , Cheng Z , Chitko-McKown CG , Liu GE , Matukumalli LK , Song J , Zhu B , Bradley DG , Brinkman FS , Lau LP , Whiteside MD , Walker A , Wheeler TT , Casey T , German JB , Lemay DG , Maqbool NJ , Molenaar AJ , Seo S , Stothard P , Baldwin CL , Baxter R , Brinkmeyer-Langford CL , Brown WC , Childers CP , Connelley T , Ellis SA , Fritz K , Glass EJ , Herzig CT , Iivanainen A , Lahmers KK , Bennett AK , Dickens CM , Gilbert JG , Hagen DE , Salih H , Aerts J , Caetano AR , Dalrymple B , Garcia JF , Gill CA , Hiendleder SG , Memili E , Spurlock D , Williams JL , Alexander L , Brownstein MJ , Guan L , Holt RA , Jones SJ , Marra MA , Moore R , Moore SS , Roberts A , Taniguchi M , Waterman RC , Chacko J , Chandrabose MM , Cree A , Dao MD , Dinh HH , Gabisi RA , Hines S , Hume J , Jhangiani SN , Joshi V , Kovar CL , Lewis LR , Liu YS , Lopez J , Morgan MB , Nguyen NB , Okwuonu GO , Ruiz SJ , Santibanez J , Wright RA , Buhay C , Ding Y , Dugan-Rocha S , Herdandez J , Holder M , Sabo A , Egan A , Goodell J , Wilczek-Boney K , Fowler GR , Hitchens ME , Lozado RJ , Moen C , Steffen D , Warren JT , Zhang J , Chiu R , Schein JE , Durbin KJ , Havlak P , Jiang H , Liu Y , Qin X , Ren Y , Shen Y , Song H , Bell SN , Davis C , Johnson AJ , Lee S , Nazareth LV , Patel BM , Pu LL , Vattathil S , Williams RL, Jr. , Curry S , Hamilton C , Sodergren E , Wheeler DA , Barris W , Bennett GL , Eggen A , Green RD , Harhay GP , Hobbs M , Jann O , Keele JW , Kent MP , Lien S , McKay SD , McWilliam S , Ratnakumar A , Schnabel RD , Smith T , Snelling WM , Sonstegard TS , Stone RT , Sugimoto Y , Takasuga A , Taylor JF , Van Tassell CP , Macneil MD , Abatepaulo AR , Abbey CA , Ahola V , Almeida IG , Amadio AF , Anatriello E , Bahadue SM , Biase FH , Boldt CR , Carroll JA , Carvalho WA , Cervelatti EP , Chacko E , Chapin JE , Cheng Y , Choi J , Colley AJ , de Campos TA , De Donato M , Santos IK , de Oliveira CJ , Deobald H , Devinoy E , Donohue KE , Dovc P , Eberlein A , Fitzsimmons CJ , Franzin AM , Garcia GR , Genini S , Gladney CJ , Grant JR , Greaser ML , Green JA , Hadsell DL , Hakimov HA , Halgren R , Harrow JL , Hart EA , Hastings N , Hernandez M , Hu ZL , Ingham A , Iso-Touru T , Jamis C , Jensen K , Kapetis D , Kerr T , Khalil SS , Khatib H , Kolbehdari D , Kumar CG , Kumar D , Leach R , Lee JC , Li C , Logan KM , Malinverni R , Marques E , Martin WF , Martins NF , Maruyama SR , Mazza R , McLean KL , Medrano JF , Moreno BT , More DD , Muntean CT , Nandakumar HP , Nogueira MF , Olsaker I , Pant SD , Panzitta F , Pastor RC , Poli MA , Poslusny N , Rachagani S , Ranganathan S , Razpet A , Riggs PK , Rincon G , Rodriguez-Osorio N , Rodriguez-Zas SL , Romero NE , Rosenwald A , Sando L , Schmutz SM , Shen L , Sherman L , Southey BR , Lutzow YS , Sweedler JV , Tammen I , Telugu BP , Urbanski JM , Utsunomiya YT , Verschoor CP , Waardenberg AJ , Wang Z , Ward R , Weikard R , Welsh TH, Jr. , White SN , Wilming LG , Wunderlich KR , Yang J , Zhao FQ
Ref : Science , 324 :522 , 2009
Abstract : To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production.
ESTHER : Elsik_2009_Science_324_522
PubMedSearch : Elsik_2009_Science_324_522
PubMedID: 19390049
Gene_locus related to this paper: bovin-2neur , bovin-a0jnh8 , bovin-a5d7b7 , bovin-ACHE , bovin-balip , bovin-dpp4 , bovin-dpp6 , bovin-e1bi31 , bovin-e1bn79 , bovin-est8 , bovin-f1mbd6 , bovin-f1mi11 , bovin-f1mr65 , bovin-f1n1l4 , bovin-g3mxp5 , bovin-q0vcc8 , bovin-q2kj30 , bovin-q3t0r6 , bovin-thyro

Title : The mosaic genome structure of the Wolbachia wRi strain infecting Drosophila simulans - Klasson_2009_Proc.Natl.Acad.Sci.U.S.A_106_5725
Author(s) : Klasson L , Westberg J , Sapountzis P , Naslund K , Lutnaes Y , Darby AC , Veneti Z , Chen L , Braig HR , Garrett R , Bourtzis K , Andersson SG
Ref : Proc Natl Acad Sci U S A , 106 :5725 , 2009
Abstract : The obligate intracellular bacterium Wolbachia pipientis infects around 20% of all insect species. It is maternally inherited and induces reproductive alterations of insect populations by male killing, feminization, parthenogenesis, or cytoplasmic incompatibility. Here, we present the 1,445,873-bp genome of W. pipientis strain wRi that induces very strong cytoplasmic incompatibility in its natural host Drosophila simulans. A comparison with the previously sequenced genome of W. pipientis strain wMel from Drosophila melanogaster identified 35 breakpoints associated with mobile elements and repeated sequences that are stable in Drosophila lines transinfected with wRi. Additionally, 450 genes with orthologs in wRi and wMel were sequenced from the W. pipientis strain wUni, responsible for the induction of parthenogenesis in the parasitoid wasp Muscidifurax uniraptor. The comparison of these A-group Wolbachia strains uncovered the most highly recombining intracellular bacterial genomes known to date. This was manifested in a 500-fold variation in sequence divergences at synonymous sites, with different genes and gene segments supporting different strain relationships. The substitution-frequency profile resembled that of Neisseria meningitidis, which is characterized by rampant intraspecies recombination, rather than that of Rickettsia, where genes mostly diverge by nucleotide substitutions. The data further revealed diversification of ankyrin repeat genes by short tandem duplications and provided examples of horizontal gene transfer across A- and B-group strains that infect D. simulans. These results suggest that the transmission dynamics of Wolbachia and the opportunity for coinfections have created a freely recombining intracellular bacterial community with mosaic genomes.
ESTHER : Klasson_2009_Proc.Natl.Acad.Sci.U.S.A_106_5725
PubMedSearch : Klasson_2009_Proc.Natl.Acad.Sci.U.S.A_106_5725
PubMedID: 19307581

Title : Complete genome sequence of Haemophilus parasuis SH0165 - Yue_2009_J.Bacteriol_191_1359
Author(s) : Yue M , Yang F , Yang J , Bei W , Cai X , Chen L , Dong J , Zhou R , Jin M , Jin Q , Chen H
Ref : Journal of Bacteriology , 191 :1359 , 2009
Abstract : Haemophilus parasuis is the causative agent of Glasser's disease, which produces big losses in swine populations worldwide. H. parasuis SH0165, belonging to the dominant serovar 5 in China, is a clinically isolated strain with high-level virulence. Here, we report the first completed genome sequence of this species.
ESTHER : Yue_2009_J.Bacteriol_191_1359
PubMedSearch : Yue_2009_J.Bacteriol_191_1359
PubMedID: 19074396
Gene_locus related to this paper: haepr-b0qsi5 , haepr-b0qve9 , haeps-b8f6u1 , haeps-b8f692 , haeps-b8f714

Title : Genome analysis of the platypus reveals unique signatures of evolution - Warren_2008_Nature_453_175
Author(s) : Warren WC , Hillier LW , Marshall Graves JA , Birney E , Ponting CP , Grutzner F , Belov K , Miller W , Clarke L , Chinwalla AT , Yang SP , Heger A , Locke DP , Miethke P , Waters PD , Veyrunes F , Fulton L , Fulton B , Graves T , Wallis J , Puente XS , Lopez-Otin C , Ordonez GR , Eichler EE , Chen L , Cheng Z , Deakin JE , Alsop A , Thompson K , Kirby P , Papenfuss AT , Wakefield MJ , Olender T , Lancet D , Huttley GA , Smit AF , Pask A , Temple-Smith P , Batzer MA , Walker JA , Konkel MK , Harris RS , Whittington CM , Wong ES , Gemmell NJ , Buschiazzo E , Vargas Jentzsch IM , Merkel A , Schmitz J , Zemann A , Churakov G , Kriegs JO , Brosius J , Murchison EP , Sachidanandam R , Smith C , Hannon GJ , Tsend-Ayush E , McMillan D , Attenborough R , Rens W , Ferguson-Smith M , Lefevre CM , Sharp JA , Nicholas KR , Ray DA , Kube M , Reinhardt R , Pringle TH , Taylor J , Jones RC , Nixon B , Dacheux JL , Niwa H , Sekita Y , Huang X , Stark A , Kheradpour P , Kellis M , Flicek P , Chen Y , Webber C , Hardison R , Nelson J , Hallsworth-Pepin K , Delehaunty K , Markovic C , Minx P , Feng Y , Kremitzki C , Mitreva M , Glasscock J , Wylie T , Wohldmann P , Thiru P , Nhan MN , Pohl CS , Smith SM , Hou S , Nefedov M , de Jong PJ , Renfree MB , Mardis ER , Wilson RK
Ref : Nature , 453 :175 , 2008
Abstract : We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation.
ESTHER : Warren_2008_Nature_453_175
PubMedSearch : Warren_2008_Nature_453_175
PubMedID: 18464734
Gene_locus related to this paper: ornan-f6s0q0 , ornan-f6ty74 , ornan-f6u2k2 , ornan-f6uve1 , ornan-f6vpb6 , ornan-f6ybp3 , ornan-f7bgu8 , ornan-f7ct41 , ornan-f7cza1 , ornan-f7ejp8 , ornan-f7exu1 , ornan-f7f392 , ornan-f7f9y6 , ornan-f6ve87 , ornan-f7f1d9 , ornan-f6z3l1 , ornan-f6r3f9 , ornan-f6r3g8 , ornan-f6vs71 , ornan-f7g4v8

Title : Large scale variation in Enterococcus faecalis illustrated by the genome analysis of strain OG1RF - Bourgogne_2008_Genome.Biol_9_R110
Author(s) : Bourgogne A , Garsin DA , Qin X , Singh KV , Sillanpaa J , Yerrapragada S , Ding Y , Dugan-Rocha S , Buhay C , Shen H , Chen G , Williams G , Muzny D , Maadani A , Fox KA , Gioia J , Chen L , Shang Y , Arias CA , Nallapareddy SR , Zhao M , Prakash VP , Chowdhury S , Jiang H , Gibbs RA , Murray BE , Highlander SK , Weinstock GM
Ref : Genome Biol , 9 :R110 , 2008
Abstract : BACKGROUND: Enterococcus faecalis has emerged as a major hospital pathogen. To explore its diversity, we sequenced E. faecalis strain OG1RF, which is commonly used for molecular manipulation and virulence studies. RESULTS: The 2,739,625 base pair chromosome of OG1RF was found to contain approximately 232 kilobases unique to this strain compared to V583, the only publicly available sequenced strain. Almost no mobile genetic elements were found in OG1RF. The 64 areas of divergence were classified into three categories. First, OG1RF carries 39 unique regions, including 2 CRISPR loci and a new WxL locus. Second, we found nine replacements where a sequence specific to V583 was substituted by a sequence specific to OG1RF. For example, the iol operon of OG1RF replaces a possible prophage and the vanB transposon in V583. Finally, we found 16 regions that were present in V583 but missing from OG1RF, including the proposed pathogenicity island, several probable prophages, and the cpsCDEFGHIJK capsular polysaccharide operon. OG1RF was more rapidly but less frequently lethal than V583 in the mouse peritonitis model and considerably outcompeted V583 in a murine model of urinary tract infections. CONCLUSION: E. faecalis OG1RF carries a number of unique loci compared to V583, but the almost complete lack of mobile genetic elements demonstrates that this is not a defining feature of the species. Additionally, OG1RF's effects in experimental models suggest that mediators of virulence may be diverse between different E. faecalis strains and that virulence is not dependent on the presence of mobile genetic elements.
ESTHER : Bourgogne_2008_Genome.Biol_9_R110
PubMedSearch : Bourgogne_2008_Genome.Biol_9_R110
PubMedID: 18611278
Gene_locus related to this paper: entfa-EF0101 , entfa-EF0449 , entfa-EF1236 , entfa-EF2618 , entfa-q5j1l4 , entfl-e2z7d4

Title : Lead optimization and insecticidal activity of analogues of daphneolone isolated from Stellera chamaejasme L. - Chen_2007_Pest.Manag.Sci_63_928
Author(s) : Chen L , Wang X , Lu T , Hou T
Ref : Pest Manag Sci , 63 :928 , 2007
Abstract : Starting from the chemical structure of the botanical aphicides 1,5-diphenyl-1-pentanone and 1,5-diphenyl-2-penten-1-one, extracted from Stellera chamaejasme L., the authors designed and synthesized a series of novel compounds following the concept of bioisosterism. Their structures were established on the basis of 1H NMR and GC-MS spectra, and the insecticidal activities of the compounds were evaluated against Aphis gossypii Glover. The results demonstrated that the substitution of a heterocycle for the phenyl ring was favourable. Thus, further modification of compound 2n, containing a furan ring, which showed excellent activity (LC50 = 0.85 g L-1), is of some promise.
ESTHER : Chen_2007_Pest.Manag.Sci_63_928
PubMedSearch : Chen_2007_Pest.Manag.Sci_63_928

Title : Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects - Krishna_2007_J.Clin.Pharmacol_47_165
Author(s) : Krishna R , Bergman A , Larson P , Cote J , Lasseter K , Dilzer S , Wang A , Zeng W , Chen L , Wagner J , Herman G
Ref : Journal of Clinical Pharmacology , 47 :165 , 2007
Abstract : Sitagliptin (MK-0431) is an orally active, potent, and selective dipeptidyl peptidase-4 inhibitor used for the treatment of patients with type 2 diabetes mellitus. Sitagliptin has been shown to be a substrate for P-glycoprotein in preclinical studies. Cyclosporine was used as a probe P-glycoprotein inhibitor at a high dose to evaluate the potential effect of potent P-glycoprotein inhibition on single-dose sitagliptin pharmacokinetics in healthy male subjects. Eight healthy young men received a single oral 600-mg dose of cyclosporine with a single 100-mg oral sitagliptin dose and a single oral 100-mg sitagliptin dose alone in an open-label, randomized, 2-period, crossover study. Single doses of sitagliptin with or without single doses of cyclosporine were generally well tolerated. The sitagliptin AUC(0-infinity) geometric mean ratio was 1.29 with a 90% confidence interval of (1.24, 1.34). The sitagliptin Cmax geometric mean ratio was 1.68 with a 90% confidence interval of (1.35, 2.08). Cyclosporine coadministration did not appear to affect apparent sitagliptin renal clearance, t(1/2), or C(24 h), suggesting that effects of these high doses of cyclosporine are more likely due to enhanced absorption of sitagliptin, potentially through inhibition of intestinal P-glycoprotein. These results rationalize the use of a single high-dose cyclosporine as a probe inhibitor of P-glycoprotein for compound candidates whose elimination is less dependent on CYP3A4-mediated metabolism.
ESTHER : Krishna_2007_J.Clin.Pharmacol_47_165
PubMedSearch : Krishna_2007_J.Clin.Pharmacol_47_165
PubMedID: 17244767

Title : Expression of LPL in endothelial-intact artery results in lipid deposition and vascular cell adhesion molecule-1 upregulation in both LPL and ApoE-deficient mice - Wang_2007_Arterioscler.Thromb.Vasc.Biol_27_197
Author(s) : Wang J , Xian X , Huang W , Chen L , Wu L , Zhu Y , Fan J , Ross C , Hayden MR , Liu G
Ref : Arterioscler Thromb Vasc Biol , 27 :197 , 2007
Abstract : OBJECTIVE: Overexpression of lipoprotein lipase (LPL) in deendothelialized artery led to profound localized lipid deposition. In this study the role of LPL in atherogenesis in endothelial-intact carotid arteries was assessed in genetically hyperlipidemic LPL- and ApoE-deficient mice. METHODS AND RESULTS: Human wild-type LPL (hLPLwt), catalytically inactive LPL (hLPL194), or control alkaline phosphatase (hAP) were expressed in endothelial-intact carotid arteries via adenoviral vectors. Compared with Ad-hAP, lipid deposition in the arterial wall increased 10.0- and 5.1-fold for Ad-hLPLwt and Ad-hLPL194 in LPL-deficient mice, and 10.6- and 6.2-fold in ApoE-deficient mice, respectively. Vascular cell adhesion molecule-1 (VCAM-1) was upregulated in Ad-hLPLwt and Ad-hLPL194 transferred arteries. CONCLUSIONS: Endothelial cell associated LPL, either active or inactive, in the arterial wall is a strong proatherosclerotic factor in both LPL- and ApoE-deficient mice.
ESTHER : Wang_2007_Arterioscler.Thromb.Vasc.Biol_27_197
PubMedSearch : Wang_2007_Arterioscler.Thromb.Vasc.Biol_27_197
PubMedID: 17038632

Title : Structure of the minimized alpha\/beta-hydrolase fold protein from Thermus thermophilus HB8 - Xie_2007_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_63_993
Author(s) : Xie Y , Takemoto C , Kishishita S , Uchikubo-Kamo T , Murayama K , Chen L , Liu ZJ , Wang BC , Manzoku M , Ebihara A , Kuramitsu S , Shirouzu M , Yokoyama S
Ref : Acta Crystallographica Sect F Struct Biol Cryst Commun , 63 :993 , 2007
Abstract : The gene encoding TTHA1544 is a singleton found in the Thermus thermophilus HB8 genome and encodes a 131-amino-acid protein. The crystal structure of TTHA1544 has been determined at 2.0 A resolution by the single-wavelength anomalous dispersion method in order to elucidate its function. There are two molecules in the asymmetric unit. Each molecule consists of four alpha-helices and six beta-strands, with the beta-strands composing a central beta-sheet. A structural homology search revealed that the overall structure of TTHA1544 resembles the alpha/beta-hydrolase fold, although TTHA1544 lacks the catalytic residues of a hydrolase. These results suggest that TTHA1544 represents the minimized alpha/beta-hydrolase fold and that an additional component would be required for its activity.
ESTHER : Xie_2007_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_63_993
PubMedSearch : Xie_2007_Acta.Crystallogr.Sect.F.Struct.Biol.Cryst.Commun_63_993
PubMedID: 18084077
Gene_locus related to this paper: teth8-Q5SI36

Title : The genome of Hyperthermus butylicus: a sulfur-reducing, peptide fermenting, neutrophilic Crenarchaeote growing up to 108 degrees C - Brugger_2007_Archaea_2_127
Author(s) : Brugger K , Chen L , Stark M , Zibat A , Redder P , Ruepp A , Awayez M , She Q , Garrett RA , Klenk HP
Ref : Archaea , 2 :127 , 2007
Abstract : Hyperthermus butylicus, a hyperthermophilic neutrophile and anaerobe, is a member of the archaeal kingdom Crenarchaeota. Its genome consists of a single circular chromosome of 1,667,163 bp with a 53.7% G+C content. A total of 1672 genes were annotated, of which 1602 are protein-coding, and up to a third are specific to H. butylicus. In contrast to some other crenarchaeal genomes, a high level of GUG and UUG start codons are predicted. Two cdc6 genes are present, but neither could be linked unambiguously to an origin of replication. Many of the predicted metabolic gene products are associated with the fermentation of peptide mixtures including several peptidases with diverse specificities, and there are many encoded transporters. Most of the sulfur-reducing enzymes, hydrogenases and electron-transfer proteins were identified which are associated with energy production by reducing sulfur to H(2)S. Two large clusters of regularly interspaced repeats (CRISPRs) are present, one of which is associated with a crenarchaeal-type cas gene superoperon; none of the spacer sequences yielded good sequence matches with known archaeal chromosomal elements. The genome carries no detectable transposable or integrated elements, no inteins, and introns are exclusive to tRNA genes. This suggests that the genome structure is quite stable, possibly reflecting a constant, and relatively uncompetitive, natural environment.
ESTHER : Brugger_2007_Archaea_2_127
PubMedSearch : Brugger_2007_Archaea_2_127
PubMedID: 17350933

Title : Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers - Bergman_2006_Clin.Ther_28_55
Author(s) : Bergman AJ , Stevens C , Zhou Y , Yi B , Laethem M , De Smet M , Snyder K , Hilliard D , Tanaka W , Zeng W , Tanen M , Wang AQ , Chen L , Winchell G , Davies MJ , Ramael S , Wagner JA , Herman GA
Ref : Clin Ther , 28 :55 , 2006
Abstract : BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin.
METHODS: This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis.
RESULTS: Seventy subjects were enrolled (mean age, 32.9 years [range, 18-45 years]; mean weight, 79.7 kg [range, 63.4-97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T(max), C(max), and t((1/2))) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05-1.29), and the apparent terminal elimination t((1/2)) was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was approximately 70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was > or = 80% for doses of > or = 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by approximately 2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported.
CONCLUSIONS: The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.
ESTHER : Bergman_2006_Clin.Ther_28_55
PubMedSearch : Bergman_2006_Clin.Ther_28_55
PubMedID: 16490580

Title : Localized vessel expression of lipoprotein lipase in rabbits leads to rapid lipid deposition in the balloon-injured arterial wall - Wu_2006_Atherosclerosis_187_65
Author(s) : Wu X , Wang J , Fan J , Chen M , Chen L , Huang W , Liu G
Ref : Atherosclerosis , 187 :65 , 2006
Abstract : Recent studies on mice demonstrated that lipoprotein lipase (LPL) located in the arterial wall might play a pro-atherogenic role. There are major differences between humans and mice in lipoprotein metabolism and in susceptibility to atherosclerosis. We have therefore used rabbits fed normal chow diet as a model to assess such localized effects by adenovirus-mediated gene transfer of human catalytically active wild type LPL (hLPLwt) and an inactive mutant (hLPL194) to balloon-injured carotid arteries. By morphometric analysis on cryosections stained with Oil Red O (ORO) we found 7- and 4-fold increases, respectively, of lipid deposition in the arterial walls 7 days after infection with adenovirus expressing hLPLwt or hLPL194, when compared with a virus expressing human alkaline phosphatase (hAP) as control. Macrophages were detected in the arteries expressing both forms of LPL, but apoB was only found in arteries expressing hLPLwt. Expression of the LPL gene products was transient and was gone after 2 weeks, but the accumulated lipid deposits remained between the neointimal and the media layers even after 8 weeks. Our data demonstrate that expression of LPL in the arterial wall (with or without lipase activity) leads to lipid accumulation in balloon-injured rabbit arteries, and could result in enhanced formation of atherosclerotic lesions.
ESTHER : Wu_2006_Atherosclerosis_187_65
PubMedSearch : Wu_2006_Atherosclerosis_187_65
PubMedID: 16191430

Title : Chronic oral nicotine normalizes dopaminergic function and synaptic plasticity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned primates - Quik_2006_J.Neurosci_26_4681
Author(s) : Quik M , Chen L , Parameswaran N , Xie X , Langston JW , McCallum SE
Ref : Journal of Neuroscience , 26 :4681 , 2006
Abstract : Our recent studies show that chronic oral nicotine partially protects against striatal damage in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman primates. To identify the cellular changes associated with this protective action, we investigated the effects of nicotine treatment on stimulus-evoked dopamine release, dopamine turnover, and synaptic plasticity in striatum from lesioned and unlesioned animals. Monkeys were chronically (6 months) treated with nicotine in the drinking water and subsequently lesioned with the dopaminergic neurotoxin MPTP (6 months) while nicotine was continued. Nigrostriatal damage increased nicotinic acetylcholine receptor (nAChR)-mediated fractional dopamine release from residual terminals, primarily through changes in alpha3*/alpha6* nAChRs. In contrast, fractional receptor-evoked dopamine release was similar to control in unlesioned and lesioned animals with chronic oral nicotine. Long-term nicotine administration also attenuated the enhanced K(+)-evoked fractional dopamine release from synaptosomes of MPTP-lesioned animals, suggesting that nicotine treatment had a generalized effect on dopaminergic function. This premise was further supported by experiments showing that nicotine dosing decreased the elevated dopamine turnover that occurs after nigrostriatal damage. We next investigated changes in synaptic plasticity with lesioning and nicotine treatment. Nicotine treatment alone enhanced synaptic plasticity by lowering the threshold for long-term depression (LTD) in the corticostriatal pathway. MPTP lesioning led to a loss of LTD, a measure of short-term synaptic plasticity. In contrast, LTD was preserved in nicotine-treated lesioned animals. Thus, the present data show that the disruptions in striatal dopaminergic function after nigrostriatal damage were attenuated with chronic nicotine administration. These cellular alterations may underlie the ability of nicotine to maintain/restore normal function with nigrostriatal damage.
ESTHER : Quik_2006_J.Neurosci_26_4681
PubMedSearch : Quik_2006_J.Neurosci_26_4681
PubMedID: 16641249

Title : Complete genome sequence of Shigella flexneri 5b and comparison with Shigella flexneri 2a - Nie_2006_BMC.Genomics_7_173
Author(s) : Nie H , Yang F , Zhang X , Yang J , Chen L , Wang J , Xiong Z , Peng J , Sun L , Dong J , Xue Y , Xu X , Chen S , Yao Z , Shen Y , Jin Q
Ref : BMC Genomics , 7 :173 , 2006
Abstract : BACKGROUND: Shigella bacteria cause dysentery, which remains a significant threat to public health. Shigella flexneri is the most common species in both developing and developed countries. Five Shigella genomes have been sequenced, revealing dynamic and diverse features. To investigate the intra-species diversity of S. flexneri genomes further, we have sequenced the complete genome of S. flexneri 5b strain 8401 (abbreviated Sf8401) and compared it with S. flexneri 2a (Sf301).
RESULTS: The Sf8401 chromosome is 4.5-Mb in size, a little smaller than that of Sf301, mainly because the former lacks the SHI-1 pathogenicity island (PAI). Compared with Sf301, there are 6 inversions and one translocation in Sf8401, which are probably mediated by insertion sequences (IS). There are clear differences in the known PAIs between these two genomes. The bacteriophage SfV segment remaining in SHI-O of Sf8401 is clearly larger than the remnants of bacteriophage SfII in Sf301. SHI-1 is absent from Sf8401 but a specific related protein is found next to the pheV locus. SHI-2 is involved in one intra-replichore inversion near the origin of replication, which may change the expression of iut/iuc genes. Moreover, genes related to the glycine-betaine biosynthesis pathway are present only in Sf8401 among the known Shigella genomes. CONCLUSION: Our data show that the two S. flexneri genomes are very similar, which suggests a high level of structural and functional conservation between the two serotypes. The differences reflect different selection pressures during evolution. The ancestor of S. flexneri probably acquired SHI-1 and SHI-2 before SHI-O was integrated and the serotypes diverged. SHI-1 was subsequently deleted from the S. flexneri 5b genome by recombination, but stabilized in the S. flexneri 2a genome. These events may have contributed to the differences in pathogenicity and epidemicity between the two serotypes of S. flexneri.
ESTHER : Nie_2006_BMC.Genomics_7_173
PubMedSearch : Nie_2006_BMC.Genomics_7_173
PubMedID: 16822325
Gene_locus related to this paper: shifl-AES , shifl-BIOH , shifl-entf , shifl-FES , shifl-PTRB , shifl-S2753 , shifl-SF1808 , shifl-SF3046 , shifl-yafa , shifl-YBFF , shifl-YCDJ , shifl-ycfp , shifl-YCJY , shifl-YFBB , shifl-YHET , shifl-YIEL , shifl-YJFP , shifl-YPFH , shiss-yeiG , shiss-yqia

Title : Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects - Herman_2006_J.Clin.Pharmacol_46_876
Author(s) : Herman GA , Bergman A , Liu F , Stevens C , Wang AQ , Zeng W , Chen L , Snyder K , Hilliard D , Tanen M , Tanaka W , Meehan AG , Lasseter K , Dilzer S , Blum R , Wagner JA
Ref : Journal of Clinical Pharmacology , 46 :876 , 2006
Abstract : Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post-oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.
ESTHER : Herman_2006_J.Clin.Pharmacol_46_876
PubMedSearch : Herman_2006_J.Clin.Pharmacol_46_876
PubMedID: 16855072

Title : Polymorphisms for microsomal epoxide hydrolase and genetic susceptibility to COPD - Park_2005_Int.J.Mol.Med_15_443
Author(s) : Park JY , Chen L , Wadhwa N , Tockman MS
Ref : Int J Mol Med , 15 :443 , 2005
Abstract : Although smoking is the major causal factor in the development of chronic obstructive pulmonary disease (COPD), only 10-20% of chronic heavy cigarette smokers develop symptomatic COPD, which suggests the presence of genetic susceptibility. The human microsomal epoxide hydrolase (EH) is a metabolizing enzyme which involves the process of numerous reactive epoxide intermediates and contains polymorphic alleles which are associated with altered EH activity and may be linked to increased risk for COPD. To determine whether the EH polymorphisms contributed to increased risk for COPD, prevalence of the EH codons 113 and 139 polymorphisms were compared between COPD patients and controls by a PCR-RFLP analysis using genomic DNA isolated from 131 COPD patients and 262 individually matched controls by age (+/-5 years) among Caucasians with 2:1 ratio. Significantly increased risk for COPD was observed for subjects with the EH(113His/His) genotypes (OR=2.4, 95% CI=1.1-5.1). These results were consistent with the fact that a significant trend towards increased risk was observed with predicted less protective EH codon 113 genotypes (p=0.03, trend test). A similar association was not observed for EH codon 139 polymorphism. As expected, a significant correlation between smoking dose and severity of COPD was observed (p<0.001). These results suggest that EH codon 113 polymorphism may modify risk for COPD.
ESTHER : Park_2005_Int.J.Mol.Med_15_443
PubMedSearch : Park_2005_Int.J.Mol.Med_15_443
PubMedID: 15702235

Title : Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter - Nam_2005_Proc.Natl.Acad.Sci.U.S.A_102_6137
Author(s) : Nam CI , Chen L
Ref : Proc Natl Acad Sci U S A , 102 :6137 , 2005
Abstract : Presynaptic and postsynaptic differentiation occurs at axodendritic contacts between CNS neurons. Synaptic adhesion mediated by synaptic cell adhesion molecule (SynCAM) and beta-neurexins/neuroligins triggers presynaptic differentiation. The signals that trigger postsynaptic differentiation are, however, unknown. Here we report that beta-neurexin expressed in nonneuronal cells induced postsynaptic density (PSD)-95 clustering in contacting dendrites of hippocampal neurons. The effect is specific to beta-neurexin and was not observed with other synaptic cell adhesion molecules such as N-cadherin or SynCAM. NMDA receptors, but not alpha-amino-3-hydroxyl-5-methyl-4-isoxazolepropionate receptors (AMPARs), were recruited to this beta-neurexin-induced PSD-95 scaffold. Remarkably, AMPARs were inserted into this scaffold upon glutamate application or expression of a constitutively active form of calmodulin kinase II in neurons. Expression of a dominant-negative neuroligin-1 in cultured neurons markedly reduced the sizes and densities of PSD-95 puncta and AMPAR clusters. In addition, excitatory, but not inhibitory, synaptic functions were impaired in these neurons, confirming that PSD-95/neuroligin-1 interaction is involved in postsynaptic assembly at glutamatergic synapses. These results demonstrate that postsynaptic assembly of the glutamatergic synapse may be initiated by presynaptic beta-neurexin and that glutamate release also is required for maturation of synapses.
ESTHER : Nam_2005_Proc.Natl.Acad.Sci.U.S.A_102_6137
PubMedSearch : Nam_2005_Proc.Natl.Acad.Sci.U.S.A_102_6137
PubMedID: 15837930
Gene_locus related to this paper: human-NLGN1

Title : The genome of Sulfolobus acidocaldarius, a model organism of the Crenarchaeota - Chen_2005_J.Bacteriol_187_4992
Author(s) : Chen L , Brugger K , Skovgaard M , Redder P , She Q , Torarinsson E ,