Xu Y

General

Full name : Xu Yechun

First name : Yechun

Mail : Shanghai Institute of Materia Medica\; Chinese Academy of Sciences\; Drug Discovery and Design Center\; #646 Songtao Load\; Shanghai\; 201203

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Country : China

Email : ycxu@mail.shcnc.ac.cn

Phone : +862150801267

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References (239)

Title : Photosensitization enables Pauson-Khand-type reactions with nitrenes - Li_2024_Science_383_498
Author(s) : Li F , Zhu WF , Empel C , Datsenko O , Kumar A , Xu Y , Ehrler JHM , Atodiresei I , Knapp S , Mykhailiuk PK , Proschak E , Koenigs RM
Ref : Science , 383 :498 , 2024
Abstract : The Pauson-Khand reaction has in the past 50 years become one of the most common cycloaddition reactions in chemistry. Coupling two unsaturated bonds with carbon monoxide, the transformation remains limited to CO as a C(1) building block. Herein we report analogous cycloaddition reactions with nitrenes as an N(1) unit. The reaction of a nonconjugated diene with a nitrene precursor produces bicyclic bioisosteres of common saturated heterocycles such as piperidine, morpholine, and piperazine. Experimental and computational mechanistic studies support relaying of the diradical nature of triplet nitrene into the Pi-system. We showcase the reaction's utility in late-stage functionalization of drug compounds and discovery of soluble epoxide hydrolase inhibitors.
ESTHER : Li_2024_Science_383_498
PubMedSearch : Li_2024_Science_383_498
PubMedID: 38301027
Gene_locus related to this paper: human-EPHX2

Title : The m(6)A modification mediated-lncRNA POU6F2-AS1 reprograms fatty acid metabolism and facilitates the growth of colorectal cancer via upregulation of FASN - Jiang_2024_Mol.Cancer_23_55
Author(s) : Jiang T , Qi J , Xue Z , Liu B , Liu J , Hu Q , Li Y , Ren J , Song H , Xu Y , Xu T , Fan R , Song J
Ref : Mol Cancer , 23 :55 , 2024
Abstract : BACKGROUND: Long noncoding RNAs (lncRNAs) have emerged as key players in tumorigenesis and tumour progression. However, the biological functions and potential mechanisms of lncRNAs in colorectal cancer (CRC) are unclear. METHODS: The novel lncRNA POU6F2-AS1 was identified through bioinformatics analysis, and its expression in CRC patients was verified via qRT-PCR and FISH. In vitro and in vivo experiments, such as BODIPY staining, Oil Red O staining, triglyceride (TAG) assays, and liquid chromatography mass spectrometry (LC-MS) were subsequently performed with CRC specimens and cells to determine the clinical significance, and functional roles of POU6F2-AS1. Biotinylated RNA pull-down, RIP, Me-RIP, ChIP, and patient-derived organoid (PDO) culture assays were performed to confirm the underlying mechanism of POU6F2-AS1. RESULTS: The lncRNA POU6F2-AS1 is markedly upregulated in CRC and associated with adverse clinicopathological features and poor overall survival in CRC patients. Functionally, POU6F2-AS1 promotes the growth and lipogenesis of CRC cells both in vitro and in vivo. Mechanistically, METTL3-induced m(6)A modification is involved in the upregulation of POU6F2-AS1. Furthermore, upregulated POU6F2-AS1 could tether YBX1 to the FASN promoter to induce transcriptional activation, thus facilitating the growth and lipogenesis of CRC cells. CONCLUSIONS: Our data revealed that the upregulation of POU6F2-AS1 plays a critical role in CRC fatty acid metabolism and might provide a novel promising biomarker and therapeutic target for CRC.
ESTHER : Jiang_2024_Mol.Cancer_23_55
PubMedSearch : Jiang_2024_Mol.Cancer_23_55
PubMedID: 38491348

Title : Neuroligin-3-Mediated Synapse Formation Strengthens Interactions between Hippocampus and Barrel Cortex in Associative Memory - Xiao_2024_Int.J.Mol.Sci_25_
Author(s) : Xiao H , Xu Y , Cui S , Wang JH
Ref : Int J Mol Sci , 25 : , 2024
Abstract : Memory traces are believed to be broadly allocated in cerebral cortices and the hippocampus. Mutual synapse innervations among these brain areas are presumably formed in associative memory. In the present study, we have used neuronal tracing by pAAV-carried fluorescent proteins and neuroligin-3 mRNA knockdown by shRNAs to examine the role of neuroligin-3-mediated synapse formation in the interconnection between primary associative memory cells in the sensory cortices and secondary associative memory cells in the hippocampus during the acquisition and memory of associated signals. Our studies show that mutual synapse innervations between the barrel cortex and the hippocampal CA3 region emerge and are upregulated after the memories of associated whisker and odor signals come into view. These synapse interconnections are downregulated by a knockdown of neuroligin-3-mediated synapse linkages. New synapse interconnections and the strengthening of these interconnections appear to endorse the belief in an interaction between the hippocampus and sensory cortices for memory consolidation.
ESTHER : Xiao_2024_Int.J.Mol.Sci_25_
PubMedSearch : Xiao_2024_Int.J.Mol.Sci_25_
PubMedID: 38255783
Gene_locus related to this paper: human-NLGN3

Title : Molecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis - Hong_2024_Nat.Commun_15_8
Author(s) : Hong J , Li T , Chao Y , Xu Y , Zhu Z , Zhou Z , Gu W , Qu Q , Li D
Ref : Nat Commun , 15 :8 , 2024
Abstract : The secretion and quality control of glycosylphosphatidylinositol-anchored proteins (GPI-APs) necessitates post-attachment remodeling initiated by the evolutionarily conserved PGAP1, which deacylates the inositol in nascent GPI-APs. Impairment of PGAP1 activity leads to developmental diseases in humans and fatality and infertility in animals. Here, we present three PGAP1 structures (2.66-2.84 A), revealing its 10-transmembrane architecture and product-enzyme interaction details. PGAP1 holds GPI-AP acyl chains in an optimally organized, guitar-shaped cavity with apparent energetic penalties from hydrophobic-hydrophilic mismatches. However, abundant glycan-mediated interactions in the lumen counterbalance these repulsions, likely conferring substrate fidelity and preventing off-target hydrolysis of bulk membrane lipids. Structural and biochemical analyses uncover a serine hydrolase-type catalysis with atypical features and imply mechanisms for substrate entrance and product release involving a drawing compass movement of GPI-APs. Our findings advance the mechanistic understanding of GPI-AP remodeling.
ESTHER : Hong_2024_Nat.Commun_15_8
PubMedSearch : Hong_2024_Nat.Commun_15_8
PubMedID: 38167496
Gene_locus related to this paper: chatd-g0s652 , human-PGAP1

Title : Expanding the clinical spectrum of anti-DPPX encephalitis: a multicenter retrospective study - Gao_2024_Front.Neurosci_18_1379933
Author(s) : Gao Y , Zhang Y , Chunyu H , Xu Y , Wang Y , Liu S , Chang J , Tang B , Xu C , Lu Y , Zhou J , Kong X , Zhu X , Chen S , Zhou Q , Meng H
Ref : Front Neurosci , 18 :1379933 , 2024
Abstract : OBJECTIVE: Anti-dipeptidyl-peptidase-like protein-6 (DPPX) encephalitis is a rare autoimmune encephalitis, and clinical and experimental information regarding this disease is limited. We conducted this study to comprehensively describe the clinical characteristics, ancillary test results, neuroimaging results, and treatment response in a group of Chinese patients with anti-DPPX encephalitis for better understanding this disease. METHODS: We recruited 14 patients who tested positive for anti-DPPX antibodies in the serum and/or cerebrospinal fluid from 11 medical centers between March 2021 and June 2023. This retrospective study evaluated data on symptoms, autoantibody test, auxiliary examinations, treatments, and outcomes. RESULTS: The average age at diagnosis was 45.93 +/- 4.62 years (range: 11-72 years), and 9 of the 14 patients were males. The main symptoms included cognitive impairment (50.0%, 7/14), central nervous system hyperexcitability (42.9%, 6/14), gastrointestinal dysfunction (35.7%, 5/14), and psychiatric disorders (35.7%, 5/14). Notably, we discovered specific findings on (18)F-fluorodeoxyglucose positron-emission tomography (PET)/magnetic resonance imaging in two patients. Co-existing autoantibodies were identified in two patients. Parainfection was identified in four patients. One patient had other autoimmune diseases, and one had tumor. Eleven patients received immunotherapy and most patients improved at discharge. Surprisingly, three male patients but no female patients relapsed during the 6 months of follow-up. CONCLUSION: The development and outcome of anti-DPPX encephalitis are variable. Male patients were predominant in our cohort. The most common symptoms were the classical triad of prodromal gastrointestinal dysfunction, cognitive and mental disorders, and central nervous system hyperexcitability. Infections, immune dysregulation, and tumors may be important etiologies. Long-term monitoring of disease development should be done in male patients. Overall, our results highlight novel clinical characteristics of anti-DPPX encephalitis.
ESTHER : Gao_2024_Front.Neurosci_18_1379933
PubMedSearch : Gao_2024_Front.Neurosci_18_1379933
PubMedID: 38756408
Gene_locus related to this paper: human-DPP6

Title : Depletion of ApoA5 aggravates spontaneous and diet-induced nonalcoholic fatty liver disease by reducing hepatic NR1D1 in hamsters - Guo_2024_Theranostics_14_2036
Author(s) : Guo J , Miao G , Zhang W , Shi H , Lai P , Xu Y , Zhang L , Chen G , Han Y , Zhao Y , Liu G , Wang Y , Huang W , Xian X
Ref : Theranostics , 14 :2036 , 2024
Abstract : Background: ApoA5 mainly synthesized and secreted by liver is a key modulator of lipoprotein lipase (LPL) activity and triglyceride-rich lipoproteins (TRLs). Although the role of ApoA5 in extrahepatic triglyceride (TG) metabolism in circulation has been well documented, the relationship between ApoA5 and nonalcoholic fatty liver disease (NAFLD) remains incompletely understood and the underlying molecular mechanism still needs to be elucidated. Methods: We used CRISPR/Cas9 gene editing to delete Apoa5 gene from Syrian golden hamster, a small rodent model replicating human metabolic features. Then, the ApoA5-deficient (ApoA5(-/-)) hamsters were used to investigate NAFLD with or without challenging a high fat diet (HFD). Results: ApoA5(-/-) hamsters exhibited hypertriglyceridemia (HTG) with markedly elevated TG levels at 2300 mg/dL and hepatic steatosis on a regular chow diet, accompanied with an increase in the expression levels of genes regulating lipolysis and small adipocytes in the adipose tissue. An HFD challenge predisposed ApoA5(-/-) hamsters to severe HTG (sHTG) and nonalcoholic steatohepatitis (NASH). Mechanistic studies in vitro and in vivo revealed that targeting ApoA5 disrupted NR1D1 mRNA stability in the HepG2 cells and the liver to reduce both mRNA and protein levels of NR1D1, respectively. Overexpression of human NR1D1 by adeno-associated virus 8 (AAV8) in the livers of ApoA5(-/-) hamsters significantly ameliorated fatty liver without affecting plasma lipid levels. Moreover, restoration of hepatic ApoA5 or activation of UCP1 in brown adipose tissue (BAT) by cold exposure or CL316243 administration could significantly correct sHTG and hepatic steatosis in ApoA5(-/-) hamsters. Conclusions: Our data demonstrate that HTG caused by ApoA5 deficiency in hamsters is sufficient to elicit hepatic steatosis and HFD aggravates NAFLD by reducing hepatic NR1D1 mRNA and protein levels, which provides a mechanistic link between ApoA5 and NAFLD and suggests the new insights into the potential therapeutic approaches for the treatment of HTG and the related disorders due to ApoA5 deficiency in the clinical trials in future.
ESTHER : Guo_2024_Theranostics_14_2036
PubMedSearch : Guo_2024_Theranostics_14_2036
PubMedID: 38505614

Title : Three-in-One Peptide Prodrug with Targeting, Assembly and Release Properties for Overcoming Bacterium-Induced Drug Resistance and Potentiating Anti-Cancer Immune Response - Gao_2024_Adv.Mater__e2312153
Author(s) : Gao G , Jiang YW , Chen J , Xu X , Sun X , Xu H , Liang G , Liu X , Zhan W , Wang M , Xu Y , Zheng J , Wang G
Ref : Adv Mater , :e2312153 , 2024
Abstract : The presence of bacteria in tumor results in chemotherapeutic drug resistance and weakens the immune response in colorectal cancer. To overcome bacterium-induced chemotherapeutic drug resistance and potentiate anti-tumor immunity, herein we rationally design a novel molecule Biotin-Lys(SA-Cip-OH)-Lys(SA-CPT)-Phe-Phe-Nap (Biotin-Cip-CPT-Nap) containing four functional motifs (i.e., a biotin motif for targeting, Phe-Phe(-Nap) motif for self-assembly, ciprofloxacin derivative (Cip-OH) motif for antibacterial effect, and camptothecin (CPT) motif for chemotherapy). Using the designed molecule, a novel strategy of intracellular enzymatic nanofiber formation and synergistic antibacterium-enhanced chemotherapy and immunotherapy is achieved. Under endocytosis mediated by highly expressed biotin receptor in colorectal cancer cell membrane and the catalysis of highly expressed carboxylesterase in the cytoplasm, this novel molecule can be transformed into Biotin-Nap, which self-assembled into nanofibers. Meanwhile, antibiotic ciprofloxacin derivative (Cip-OH) and chemotherapeutic drug camptothecin (CPT) are released, overcoming bacterium-induced drug resistance and enhancing the therapeutic efficacy of immunotherapy towards colorectal cancer. This work offers a feasible strategy for the design of novel multifunctional prodrugs to improve the efficiency of colorectal cancer treatment. This article is protected by copyright. All rights reserved.
ESTHER : Gao_2024_Adv.Mater__e2312153
PubMedSearch : Gao_2024_Adv.Mater__e2312153
PubMedID: 38444205

Title : Inquiry lipaseoring the mechanism of pancreatic lipase inhibition by isovitexin based on multispectral method and enzyme inhibition assay - Yu_2024_Luminescence_39_e4765
Author(s) : Yu H , Xing Z , Jia K , Li S , Xu Y , Zhao P , Zhu X
Ref : Luminescence , 39 :e4765 , 2024
Abstract : Isovitexin is a main natural flavonoid component in various plants. Currently, the inhibitory effect of isovitexin on pancreatic lipase (PL) and its mechanism have not been elucidated yet. In the present study, we investigated the inhibitory effect of isovitexin on PL, as well as its interaction mechanism, using enzyme inhibition methods, spectroscopic analysis, and molecular simulations. Results showed that isovitexin possessed significant PL inhibitory activity, with IC(50) values of 0.26 +/- 0.02 mM. The interaction between isovitexin and PL was dominated by static quenching, and mainly through hydrogen bonding and hydrophobic interaction forces. Analysis of fluorescence spectroscopy confirmed that isovitexin binding altered the conformation of the PL. Circular dichroism (CD) spectrum indicated that isovitexin altered the secondary structure of PL by decreasing the alpha-helix content and increasing the beta-fold content. Molecular simulations further characterize the conformational changes produced by the interaction between isovitexin with PL. The performed study may provide a new insight into the inhibitory mechanism of isovitexin as a novel PL inhibitor.
ESTHER : Yu_2024_Luminescence_39_e4765
PubMedSearch : Yu_2024_Luminescence_39_e4765
PubMedID: 38769927

Title : ANGPTL3 is a novel HDL component that regulates HDL function - Yang_2024_J.Transl.Med_22_263
Author(s) : Yang L , Wang Y , Xu Y , Li K , Yin R , Zhang L , Wang D , Wei L , Lang J , Cheng Y , Wang L , Ke J , Zhao D
Ref : J Transl Med , 22 :263 , 2024
Abstract : BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is secreted by hepatocytes and inhibits lipoprotein lipase and endothelial lipase activity. Previous studies reported the correlation between plasma ANGPTL3 levels and high-density lipoprotein (HDL). Recently ANGPTL3 was found to preferentially bind to HDL in healthy human circulation. Here, we examined whether ANGPTL3, as a component of HDL, modulates HDL function and affects HDL other components in human and mice with non-diabetes or type 2 diabetes mellitus. METHODS: HDL was isolated from the plasma of female non-diabetic subjects and type-2 diabetic mellitus (T2DM) patients. Immunoprecipitation, western blot, and ELISA assays were used to examine ANGPTL3 levels in HDL. Db/m and db/db mice, AAV virus mediated ANGPTL3 overexpression and knockdown models and ANGPTL3 knockout mice were used. The cholesterol efflux capacity induced by HDL was analyzed in macrophages preloaded with fluorescent cholesterol. The anti-inflammation capacity of HDL was assessed using flow cytometry to measure VCAM-1 and ICAM-1 expression levels in TNF-alpha-stimulated endothelial cells pretreated with HDL. RESULTS: ANGPTL3 was found to bind to HDL and be a component of HDL in both non-diabetic subjects and T2DM patients. Flag-ANGPTL3 was found in the HDL of transgenic mice overexpressing Flag-ANGPTL3. ANGPLT3 of HDL was positively associated with cholesterol efflux in female non-diabetic controls (r = 0.4102, p = 0.0117) but not in female T2DM patients (r = - 0.1725, p = 0.3224). Lower ANGPTL3 levels of HDL were found in diabetic (db/db) mice compared to control (db/m) mice and were associated with reduced cholesterol efflux and inhibition of VCAM-1 and ICAM-1 expression in endothelial cells (p < 0.05 for all). Following AAV-mediated ANGPTL3 cDNA transfer in db/db mice, ANGPTL3 levels were found to be increased in HDL, and corresponded to increased cholesterol efflux and decreased ICAM-1 expression. In contrast, knockdown of ANGPTL3 levels in HDL by AAV-mediated shRNA transfer led to a reduction in HDL function (p < 0.05 for both). Plasma total cholesterol, total triglycerides, HDL-c, protein components of HDL and the cholesterol efflux function of HDL were lower in ANGPTL3-/- mice than ANGPTL3+/+ mice, suggesting that ANGPTL3 in HDL may regulate HDL function by disrupting the balance of protein components in HDL. CONCLUSION: ANGPTL3 was identified as a component of HDL in humans and mice. ANGPTL3 of HDL regulated cholesterol efflux and the anti-inflammatory functions of HDL in T2DM mice. Both the protein components of HDL and cholesterol efflux capacity of HDL were decreased in ANGPTL3-/- mice. Our findings suggest that ANGPTL3 in HDL may regulate HDL function by disrupting the balance of protein components in HDL. Our study contributes to a more comprehensive understanding of the role of ANGPTL3 in lipid metabolism.
ESTHER : Yang_2024_J.Transl.Med_22_263
PubMedSearch : Yang_2024_J.Transl.Med_22_263
PubMedID: 38462608

Title : AAV-mediated hepatic expression of LPL ameliorates severe hypertriglyceridemia and its related acute pancreatitis in Gpihbp1 deficient mice and rats - Yuan_2023_Mol.Ther__
Author(s) : Yuan C , Xu Y , Lu G , Hu Y , Mao W , Ke L , Tong Z , Xia Y , Ma S , Dong X , Xian X , Wu X , Liu G , Li B , Li W
Ref : Mol Ther , : , 2023
Abstract : GPIHBP1 plays an important role in the hydrolysis of triglyceride (TG) lipoproteins by lipoprotein lipases (LPL). However, Gpihbp1 knockout mice did not develop hypertriglyceridemia (HTG) during the suckling period but developed severe HTG after weaning on a chow diet. It has been postulated that LPL expression in the liver of suckling mice may be involved. To determine whether hepatic LPL expression could correct severe HTG in Gpihbp1 deficiency, liver-targeted LPL expression was achieved via intravenous administration of the adeno-associated virus (AAV)-human LPL gene, and the effects of AAV-LPL on HTG and HTG-related acute pancreatitis (HTG-AP) were observed. Suckling Gpihbp1(-/-) mice with high hepatic LPL expression did not develop HTG, whereas Gpihbp1(-/-) rat pups, without hepatic LPL expression developed severe HTG. AAV-mediated liver-targeted LPL expression dose-dependently decreased plasma TG levels in Gpihbp1(-/-) mice and rats, increased post-heparin plasma LPL mass and activity, decreased mortality in Gpihbp1(-/-) rat pups, and reduced the susceptibility and severity of both Gpihbp1(-/-) animals to HTG-AP. However, the muscle expression of AAV-LPL had no significant effect on HTG. Targeted expression of LPL in the liver showed no obvious adverse reactions. Thus, liver-targeted LPL expression may be a new therapeutic approach for HTG-AP caused by GPIHBP1 deficiency.
ESTHER : Yuan_2023_Mol.Ther__
PubMedSearch : Yuan_2023_Mol.Ther__
PubMedID: 37974401

Title : Genome wide identification of GDSL gene family explores a novel GhirGDSL26 gene enhancing drought stress tolerance in cotton - Liu_2023_BMC.Plant.Biol_23_14
Author(s) : Liu J , Wang H , Khan A , Xu Y , Hou Y , Wang Y , Zhou Z , Zheng J , Liu F , Cai X
Ref : BMC Plant Biol , 23 :14 , 2023
Abstract : BACKGROUND: Current climate change scenarios are posing greater threats to the growth and development of plants. Thus, significant efforts are required that can mitigate the negative effects of drought on the cotton plant. GDSL esterase/lipases can offer an imperative role in plant development and stress tolerance. However, thesystematic and functional roles of the GDSL gene family, particularly in cotton under water deficit conditions have not yet been explored. RESULTS: In this study, 103, 103, 99, 198, 203, 239, 249, and 215 GDSL proteins were identified in eight cotton genomes i.e., Gossypium herbaceum (A1), Gossypium arboretum (A2), Gossypium raimondii (D5), Gossypium hirsutum (AD1), Gossypium barbadense (AD2), Gossypium tomentosum (AD3), Gossypium mustelinum (AD4), Gossypium darwinii (AD5), respectively. A total of 198 GDSL genes of Gossypium hirsutum were divided into eleven clades using phylogenetic analysis, and the number of GhirGDSL varied among different clades. The cis-elements analysis showed that GhirGDSL gene expression was mainly related to light, plant hormones, and variable tense environments. Combining the results of transcriptome and RT-qPCR, GhirGDSL26 (Gh_A01G1774), a highly up-regulated gene, was selected for further elucidating its tole in drought stress tolerance via estimating physiological and biochemical parameters. Heterologous expression of the GhirGDSL26 gene in Arabidopsis thaliana resulted in a higher germination and survival rates, longer root lengths, lower ion leakage and induced stress-responsive genes expression under drought stress. This further highlighted that overexpressed plants had a better drought tolerance as compared to the wildtype plants. Moreover, 3, 3'-diaminobenzidine (DAB) and Trypan staining results indicated reduced oxidative damage, less cell membrane damage, and lower ion leakage in overexpressed plants as compared to wild type. Silencing of GhirGDSL26 in cotton via VIGS resulting in a susceptible phenotype, higher MDA and H(2)O(2) contents, lower SOD activity, and proline content. CONCLUSION: Our results demonstrated that GhirGDSL26 plays a critical role in cotton drought stress tolerance. Current findings enrich our knowledge of GDSL genes in cotton and provide theoretical guidance and excellent gene resources for improving drought tolerance in cotton.
ESTHER : Liu_2023_BMC.Plant.Biol_23_14
PubMedSearch : Liu_2023_BMC.Plant.Biol_23_14
PubMedID: 36609252

Title : Didepside Formation by the Nonreducing Polyketide Synthase Preu6 of Preussia isomera Requires Interaction of Starter Acyl Transferase and Thioesterase Domains - Liu_2023_Angew.Chem.Int.Ed.Engl_62_e202214379
Author(s) : Liu Q , Zhang D , Gao S , Cai X , Yao M , Xu Y , Gong Y , Zheng K , Mao Y , Yang L , Yang D , Molnar I , Yang X
Ref : Angew Chem Int Ed Engl , 62 :e202214379 , 2023
Abstract : Orsellinic acid (OA) derivatives are produced by filamentous fungi using nonreducing polyketide synthases (nrPKSs). The chain-releasing thioesterase (TE) domains of such nrPKSs were proposed to also catalyze dimerization to yield didepsides, such as lecanoric acid. Here, we use combinatorial domain exchanges, domain dissections and reconstitutions to reveal that the TE domain of the lecanoric acid synthase Preu6 of Preussia isomera must collaborate with the starter acyl transferase (SAT) domain from the same nrPKS. We show that artificial SAT-TE fusion proteins are highly effective catalysts and reprogram the ketide homologation chassis to form didepsides. We also demonstrate that dissected SAT and TE domains of Preu6 physically interact, and SAT and TE domains of OA-synthesizing nrPKSs may co-evolve. Our work highlights an unexpected domain-domain interaction in nrPKSs that must be considered for the combinatorial biosynthesis of unnatural didepsides, depsidones, and diphenyl ethers.
ESTHER : Liu_2023_Angew.Chem.Int.Ed.Engl_62_e202214379
PubMedSearch : Liu_2023_Angew.Chem.Int.Ed.Engl_62_e202214379
PubMedID: 36484777
Gene_locus related to this paper: preis-preu6

Title : Wwl70-induced ABHD6 inhibition attenuates memory deficits and pathological phenotypes in APPswe\/PS1dE9 mice - Xue_2023_Pharmacol.Res__106864
Author(s) : Xue Z , Ye L , Ge J , Lan Z , Zou X , Mao C , Bao X , Yu L , Xu Y , Zhu X
Ref : Pharmacol Res , :106864 , 2023
Abstract : Synaptic dysfunction plays a crucial role in the pathogenesis of Alzheimer's disease (AD). alpha/beta-hydrolase domain-containing 6 (ABHD6) contributes to synaptic dysfunctions, and ABHD6 inhibition has shown potential therapeutic value in neurological disorders. However, the role of ABHD6 in AD has not been fully defined. In this study, we demonstrated that adeno-associated virus (AAV) mediated shRNA targeting ABHD6 in hippocampal neurons attenuated synaptic dysfunction and memory impairment of APPswe/PS1dE9 (APP/PS1) mice, while it didn't affect the amyloid-beta (Abeta) levels and neuroinflammation in the brains. In addition, intraperitoneal injection of wwl70, a specific inhibitor of ABHD6, improved synaptic plasticity and memory function in APP/PS1 mice, which might attribute to the activation of endogenous cannabinoid signaling. Furthermore, wwl70 significantly decreased the Abeta levels and neuroinflammation in the hippocampus of AD mice, and enhanced Abeta phagocytized by microglia. In conclusion, for the first time our data have shown that ABHD6 inhibition might be a promising strategy for AD treatment, and wwl70 is a potential candidate for AD drug development pipeline.
ESTHER : Xue_2023_Pharmacol.Res__106864
PubMedSearch : Xue_2023_Pharmacol.Res__106864
PubMedID: 37480972
Gene_locus related to this paper: human-ABHD6 , mouse-ABHD6

Title : Combined-methods elucidate the multi-organ toxicity of cylindrospermopsin (CYN) on Daphnia magna - He_2023_Environ.Pollut__121250
Author(s) : He Z , Chen Y , Huo D , Gao J , Xu Y , Yang R , Yang Y , Yu G
Ref : Environ Pollut , :121250 , 2023
Abstract : Global water bodies are now at risk from inevitable cyanobacterial blooms and their production of multiple cyanotoxins, in particular cylindrospermopsin (CYN). However, research on the CYN toxicity and its molecular mechanisms is still limited, whilst the responses of aquatic species against CYN are uncovered. By integrating behavioral observations, chemical detections and transcriptome analysis, this study demonstrated that CYN exerted multi-organ toxicity to model species, Daphnia magna. The present study confirmed that CYN could cause protein inhibition by undermining total protein contents, and altered the gene expression related to proteolysis. Meantime, CYN induced oxidative stress by increasing reactive oxidative species (ROS) level, decreasing the glutathione (GSH) concentration, and interfered with protoheme formation process molecularly. Neurotoxicity led by CYN was solidly determined by abnormal swimming patterns, reduced acetylcholinesterase (AChE), and downward expression of muscarinic acetylcholine receptor (CHRM). Importantly, for the first time, this research determined CYN directly interfered with energy metabolism in cladocerans. CYN distinctively reduced filtration and ingestion rate by targeting on heart and thoracic limbs, which declined the energy intake, and could be further displayed by the reduction of motional strength and the trypsin concentration. These phenotypic alterations were supported by transcriptomic profile, including the down-regulation of oxidative phosphorylation and ATP synthesis. Moreover, CYN was speculated to trigger the self-defense responses of D. magna, known as "abandon-ship" by moderating lipid metabolism and distribution. This study, overall, comprehensively demonstrated the CYN toxicity and the responses of D. magna against it, which is of great significance to the advancements of CYN toxicity knowledge.
ESTHER : He_2023_Environ.Pollut__121250
PubMedSearch : He_2023_Environ.Pollut__121250
PubMedID: 36813104

Title : Associative memory neurons of encoding multi-modal signals are recruited by neuroligin-3-mediated new synapse formation - Xu_2023_Elife_12_
Author(s) : Xu Y , Cui TL , Li JY , Chen B , Wang JH
Ref : Elife , 12 : , 2023
Abstract : The joint storage and reciprocal retrieval of learnt associated signals are presumably encoded by associative memory cells. In the accumulation and enrichment of memory contents in lifespan, a signal often becomes a core signal associatively shared for other signals. One specific group of associative memory neurons that encode this core signal likely interconnects multiple groups of associative memory neurons that encode these other signals for their joint storage and reciprocal retrieval. We have examined this hypothesis in a mouse model of associative learning by pairing the whisker tactile signal sequentially with the olfactory signal, the gustatory signal, and the tail-heating signal. Mice experienced this associative learning show the whisker fluctuation induced by olfactory, gustatory, and tail-heating signals, or the other way around, that is, memories to multi-modal associated signals featured by their reciprocal retrievals. Barrel cortical neurons in these mice become able to encode olfactory, gustatory, and tail-heating signals alongside the whisker signal. Barrel cortical neurons interconnect piriform, S1-Tr, and gustatory cortical neurons. With the barrel cortex as the hub, the indirect activation occurs among piriform, gustatory, and S1-Tr cortices for the second-order associative memory. These associative memory neurons recruited to encode multi-modal signals in the barrel cortex for associative memory are downregulated by neuroligin-3 knockdown. Thus, associative memory neurons can be recruited as the core cellular substrate to memorize multiple associated signals for the first-order and the second-order of associative memories by neuroligin-3-mediated synapse formation, which constitutes neuronal substrates of cognitive activities in the field of memoriology.
ESTHER : Xu_2023_Elife_12_
PubMedSearch : Xu_2023_Elife_12_
PubMedID: 38047770

Title : Artificial Intelligence Aided Lipase Production and Engineering for Enzymatic Performance Improvement - Ge_2023_J.Agric.Food.Chem__
Author(s) : Ge F , Chen G , Qian M , Xu C , Liu J , Cao J , Li X , Hu D , Xu Y , Xin Y , Wang D , Zhou J , Shi H , Tan Z
Ref : Journal of Agricultural and Food Chemistry , : , 2023
Abstract : With the development of artificial intelligence (AI), tailoring methods for enzyme engineering have been widely expanded. Additional protocols based on optimized network models have been used to predict and optimize lipase production as well as properties, namely, catalytic activity, stability, and substrate specificity. Here, different network models and algorithms for the prediction and reforming of lipase, focusing on its modification methods and cases based on AI, are reviewed in terms of both their advantages and disadvantages. Different neural networks coupled with various algorithms are usually applied to predict the maximum yield of lipase by optimizing the external cultivations for lipase production, while one part is used to predict the molecule variations affecting the properties of lipase. However, few studies have directly utilized AI to engineer lipase by affecting the structure of the enzyme, and a set of research gaps needs to be explored. Additionally, future perspectives of AI application in enzymes, including lipase engineering, are deduced to help the redesign of enzymes and the reform of new functional biocatalysts. This review provides a new horizon for developing effective and innovative AI tools for lipase production and engineering and facilitating lipase applications in the food industry and biomass conversion.
ESTHER : Ge_2023_J.Agric.Food.Chem__
PubMedSearch : Ge_2023_J.Agric.Food.Chem__
PubMedID: 37800676

Title : Molecular insights into the catalytic mechanism of plasticizer degradation by a monoalkyl phthalate hydrolase - Chen_2023_Commun.Chem_6_45
Author(s) : Chen Y , Wang Y , Xu Y , Sun J , Yang L , Feng C , Wang J , Zhou Y , Zhang ZM
Ref : Commun Chem , 6 :45 , 2023
Abstract : Phthalate acid esters (PAEs), a group of xenobiotic compounds used extensively as plasticizers, have attracted increasing concern for adverse effects to human health and the environment. Microbial degradation relying on PAE hydrolases is a promising treatment. However, only a limited number of PAE hydrolases were characterized to date. Here we report the structures of MehpH, a monoalkyl phthalate (MBP) hydrolase that catalyzes the reaction of MBP to phthalic acid and the corresponding alcohol, in apo and ligand-bound form. The structures reveal a positively-charged catalytic center, complementary to the negatively-charged carboxyl group on MBP, and a penetrating tunnel that serves as exit of alcohol. The study provides a first glimpse into the enzyme-substrate binding model for PAE hydrolases, leading strong support to the development of better enzymes in the future.
ESTHER : Chen_2023_Commun.Chem_6_45
PubMedSearch : Chen_2023_Commun.Chem_6_45
PubMedID: 36859434
Gene_locus related to this paper: 9acto-q2mhh5

Title : Fabrication and Enzymatic Disorganization of Multiresponse Worm-Like Micelles - Xu_2023_Langmuir__
Author(s) : Xu Y , Liu X
Ref : Langmuir , : , 2023
Abstract : How to fabricate multiresponse worm-like micelles (WLMs) and the corresponding green disposal is still challenging. A strategy of fabricating the surfactant-based WLMs that can respond simultaneously to light, heat, and pH was developed by using triple-response sodium (E)-2-(4-(phenyldiazenyl)phenoxy) acetate (AzoNa) and butyrylcholinesterase (BChE)-hydrolyzable palmitoylcholine bromide (PCB). Under the optimal molar ratio of AzoNa to PCB (-0.5), the PCB-AzoNa WLMs formed with a maximum zero-shear viscosity ((0)) value of about 2.1 x 10(5) mPa.s and an average diameter (D) of 4.1 +/- 0.6 nm under conditions of 37 degreesC and pH 7.4. After irradiated with 365 nm UV light for 80 min, AzoNa underwent the trans-to-cis transition, by which the PCB-AzoNa WLMs was destroyed; however, the PCB-AzoNa WLMs could be reformed upon the irradiation of 455 nm blue light for 18 h or heating at 70 degreesC for 45 min due to the cis-to-trans isomerization of AzoNa. When pH changed from 7.4 to 2.0, the PCB-AzoNa WLMs was destroyed rapidly because of the conversion of AzoNa to the acid form of AzoH, whereas the PCB-AzoNa WLMs could be reformed after pH was restored to 7.4. The multiple responsiveness of the PCB-AzoNa WLMs was reversible due to the reversible trans-cis isomerization or protonation of AzoNa. Besides, the average D values of light, heat, and pH-regenerated PCB-AzoNa WLMs were 4.2 +/- 0.7, 4.0 +/- 0.7, and 4.0 +/- 0.6 nm, respectively. Finally, the PCB-AzoNa WLMs could be enzymatically disorganized under conditions of 37 degreesC and pH 7.4 due to the BChE-catalyzed hydrolysis of PCB. We hope that the fabrication and enzymatic disorganization strategies for PCB-based multiresponse WLMs presented here will find potential applications in the formulation of antimicrobial household and personal care products containing PCB and in the green disposal of viscous waste containing PCB.
ESTHER : Xu_2023_Langmuir__
PubMedSearch : Xu_2023_Langmuir__
PubMedID: 38134447

Title : Chromium exposure altered metabolome and microbiome-associated with neurotoxicity in zebrafish - Yan_2023_J.Appl.Toxicol__
Author(s) : Yan T , Xu Y , Zhu Y , Jiang P , Zhang Z , Li L , Wu Q
Ref : J Appl Toxicol , : , 2023
Abstract : In recent years, chromium (Cr) has been found to induce neurotoxicity. However, the underlying mechanism remains unclear. This study aimed to investigate the effects of chromium exposure on the metabolome and microbiome that may contribute to neurotoxicity in juvenile zebrafish. Zebrafish embryos were exposed to 1mg/L Cr (III) and 1mg/L Cr (VI) for seven days, respectively. Swimming distance and locomotor behavior was decreased, and acetylcholinesterase activity was reduced in Cr-exposed groups. Total cholesterol levels were decreased in Cr-exposed groups. The differential-expressed metabolites due to Cr exposure were mainly enriched in primary bile acid biosynthesis, which indicated that Cr exposure may promote cholesterol conversion. The abundance of Bacteroidetes decreased and the abundance of Actinomycetes increased in Cr- exposed groups, as compared to that in the control group. At the genus level, the abundance of Acinetobacter, Acidophorax, Mycobacterium, Aeromonas, Hydrophagophaga and Brevundimonas increased, whereas Chryseobacterium, Pseudomonas, Delftia and Ancylobacter decreased in the Cr-exposed groups. Analysis of the correlation between gut microbiota and bile acid metabolites showed that changes of gut microbial community due to Cr exposure may be related to secondary bile acid metabolism. Collectively, chromium exposure may disturb cholesterol metabolism, including primary bile acid and microbiota-related secondary bile acid metabolism. This study provides potential mechanism of the effects of chromium on neurotoxicity based on modulation of metabolome and gut microbiota diversity, which needs further verification.
ESTHER : Yan_2023_J.Appl.Toxicol__
PubMedSearch : Yan_2023_J.Appl.Toxicol__
PubMedID: 36727205

Title : Purification, identification and hypolipidemic activities of three novel hypolipidemic peptides from tea protein - Ye_2023_Food.Res.Int_165_112450
Author(s) : Ye H , Xu Y , Sun Y , Liu B , Chen B , Liu G , Cao Y , Miao J
Ref : Food Res Int , 165 :112450 , 2023
Abstract : In this study, hypolipidemic peptides were obtained from tea protein by enzymatic hydrolysis, ultrafiltration and high-performance liquid chromatography. Subsequently, the hypolipidemic peptides were identified by mass spectrometry and screened through molecular docking technology, and the hypolipidemic activities and mechanisms of the active peptides were explored. The results showed that the hydrolysate of hypolipidemic peptides obtained by pepsin hydrolysis for 3 h had good bile salt binding ability. After purification, identification and molecular docking screening, three novel hypolipidemic peptides FLF, IYF and QIF were obtained. FLF, IYF and QIF can interact with the receptor proteins 1LPB and 1F6W through hydrogen bonds, Pi-Pi bonds, hydrophobic interactions and van der Waals forces, thus exerting hypolipidemic activities. Activity studies showed that, compared with the positive controls, FLF, IYF and QIF had excellent sodium taurocholate binding abilities, pancreatic lipase inhibitory activities and cholesterol esterase inhibitory activities. Moreover, FLF, IYF and QIF can effectively inhibit lipogenic differentiation of 3T3-L1 preadipocytes, reduce intracellular lipid and low-density lipoprotein content and increase high-density lipoprotein content. These results indicated that the three novel hypolipidemic peptides screened in this study had excellent hypolipidemic activities and were expected to be used as natural-derived hypolipidemic active ingredients for the development and application in functional foods.
ESTHER : Ye_2023_Food.Res.Int_165_112450
PubMedSearch : Ye_2023_Food.Res.Int_165_112450
PubMedID: 36869471

Title : Physiologically based pharmacokinetic modeling of candesartan to predict the exposure in hepatic and renal impairment and elderly populations - Guo_2023_Ther.Adv.Drug.Saf_14_20420986231220222
Author(s) : Guo L , Zhu X , Zhang L , Xu Y
Ref : Ther Adv Drug Safety , 14 :20420986231220222 , 2023
Abstract : BACKGROUND: Candesartan cilexetil is a widely used angiotensin II receptor blocker with minimal adverse effects and high tolerability for the treatment of hypertension. Candesartan is administered orally as the prodrug candesartan cilexetil, which is wholly and swiftly converted to the active metabolite candesartan by carboxylesterase during absorption in the intestinal tract. In populations with renal or hepatic impairment, candesartan's pharmacokinetic (PK) behavior may be altered, necessitating dosage adjustments. OBJECTIVES: This study was conducted to examine how the physiologically based PK (PBPK) model characterizes the PKs of candesartan in adult and geriatric populations and to predict the PKs of candesartan in elderly populations with renal and hepatic impairment. DESIGN: After developing PBPK models using the reported physicochemical properties of candesartan and clinical data, these models were validated using data from clinical investigations involving various dose ranges. METHODS: Comparing predicted and observed blood concentration data and PK parameters was used to assess the fit performance of the models. RESULTS: Doses should be reduced to approximately 94% of Chinese healthy adults for the Chinese healthy elderly population; approximately 92%, 68%, and 64% of that of the Chinese healthy adult dose in elderly populations with mild, moderate, and severe renal impairment, respectively; and approximately 72%, 71%, and 52% of that of the Chinese healthy adult dose in elderly populations with Child-Pugh-A, Child-Pugh-B, and Child-Pugh-C hepatic impairment, respectively. CONCLUSION: The results suggest that the PBPK model of candesartan can be utilized to optimize dosage regimens for special populations.
ESTHER : Guo_2023_Ther.Adv.Drug.Saf_14_20420986231220222
PubMedSearch : Guo_2023_Ther.Adv.Drug.Saf_14_20420986231220222
PubMedID: 38157240

Title : Chemically programmed STING-activating nano-liposomal vesicles improve anticancer immunity - Chen_2023_Nat.Commun_14_4584
Author(s) : Chen X , Meng F , Xu Y , Li T , Wang H
Ref : Nat Commun , 14 :4584 , 2023
Abstract : The often immune-suppressive tumor microenvironment (TME) may hinder immune evasion and response to checkpoint blockade therapies. Pharmacological activation of the STING pathway does create an immunologically hot TME, however, systemic delivery might lead to undesired off-target inflammatory responses. Here, we generate a small panel of esterase-activatable pro-drugs based on the structure of the non-nucleotide STING agonist MSA-2 that are subsequently stably incorporated into a liposomal vesicle for intravenous administration. The pharmacokinetic properties and immune stimulatory capacity of pro-drugs delivered via liposomes (SAProsomes) are enhanced compared to the free drug form. By performing efficacy screening among the SAProsomes incorporating different pro-drugs in syngeneic mouse tumor models, we find that superior therapeutic performance relies on improved delivery to the desired tumor and lymphoid compartments. The best candidate, SAProsome-3, highly stimulates secretion of inflammatory cytokines and creates a tumoricidal immune landscape. Notably, upon application to breast cancer or melanoma mouse models, SAProsome-3 elicits durable remission of established tumors and postsurgical tumor-free survival while decreasing metastatic burden without significant systemic toxicity. In summary, our work establishes the proof of principle for a better targeted and more efficient and safe STING agonist therapy.
ESTHER : Chen_2023_Nat.Commun_14_4584
PubMedSearch : Chen_2023_Nat.Commun_14_4584
PubMedID: 37524727

Title : Lysosomal phospholipase A2 contributes to the biosynthesis of the atypical late endosome lipid bis(monoacylglycero)phosphate - Chen_2023_Commun.Biol_6_210
Author(s) : Chen J , Cazenave-Gassiot A , Xu Y , Piroli P , Hwang R, Jr. , DeFreitas L , Chan RB , Di Paolo G , Nandakumar R , Wenk MR , Marquer C
Ref : Commun Biol , 6 :210 , 2023
Abstract : The late endosome/lysosome (LE/Lys) lipid bis(monoacylglycero)phosphate (BMP) plays major roles in cargo sorting and degradation, regulation of cholesterol and intercellular communication and has been linked to viral infection and neurodegeneration. Although BMP was initially described over fifty years ago, the enzymes regulating its synthesis remain unknown. The first step in the BMP biosynthetic pathway is the conversion of phosphatidylglycerol (PG) into lysophosphatidylglycerol (LPG) by a phospholipase A2 (PLA2) enzyme. Here we report that this enzyme is lysosomal PLA2 (LPLA2). We show that LPLA2 is sufficient to convert PG into LPG in vitro. We show that modulating LPLA2 levels regulates BMP levels in HeLa cells, and affects downstream pathways such as LE/Lys morphology and cholesterol levels. Finally, we show that in a model of Niemann-Pick disease type C, overexpressing LPLA2 alleviates the LE/Lys cholesterol accumulation phenotype. Altogether, we shed new light on BMP biosynthesis and contribute tools to regulate BMP-dependent pathways.
ESTHER : Chen_2023_Commun.Biol_6_210
PubMedSearch : Chen_2023_Commun.Biol_6_210
PubMedID: 36823305
Gene_locus related to this paper: human-PLA2G15

Title : IL-33 Downregulates Hepatic Carboxylesterase 1 in Acute Liver Injury via Macrophage-derived Exosomal miR-27b-3p - Gao_2023_J.Clin.Transl.Hepatol_11_1130
Author(s) : Gao P , Li M , Lu J , Xiang D , Wang X , Xu Y , Zu Y , Guan X , Li G , Zhang C
Ref : J Clin Transl Hepatol , 11 :1130 , 2023
Abstract : BACKGROUND AND AIMS: We previously reported that carboxylesterase 1 (CES1) expression was suppressed following liver injury. The study aimed to explore the role of interleukin (IL)-33 in liver injury and examine the mechanism by which IL-33 regulates CES1. METHODS: IL-33 and CES1 levels were determined in the livers of patients and lipopolysaccharide (LPS)-, acetaminophen (APAP)-treated mice. We constructed IL-33 and ST2 knockout (KO) mice. ST2-enriched immune cells in livers were screened to identify the responsible cells. Macrophage-derived exosome (MDE) activity was tested by adding exosome inhibitors. Micro-RNAs (miRs) were extracted from control and IL-33-stimulated MDEs (IL-33-MDEs) and subjected miR sequencing (miR-Seq). Candidate miR was tested in vitro and in vivo and its binding of a target gene was assessed by luciferase reporter assays. Lentivirus-vector cellular transfection and transcript silencing were used to examine pathways mediating IL-33 suppression of miR-27b-3p. RESULTS: Patient liver IL-33 and CES1 expression levels were inversely correlated. CES1 downregulation in liver injury was rescued in both IL-33-deficient and ST2 KO mice. Macrophages were shown to be responsible for IL-33 effects. IL-33-MDEs reduced CES1 levels in hepatocytes. Exosomal miR-Seq and qRT-PCR demonstrated increased miR-27b-3p levels in IL-33-MDEs; miR-27b-3p was implicated in Nrf2 targeting. IL-33 inhibition of miR-27b-3p was found to be GATA3-dependent. CONCLUSIONS: IL-33-ST2-GATA3 pathway signaling increases miR-27b-3p content in MDEs, which upon being internalized by hepatocytes reduce CES1 expression by inhibiting Nrf2. The elucidation of this mechanism in this study contributes to a better understanding of CES1 dysregulation in liver injury.
ESTHER : Gao_2023_J.Clin.Transl.Hepatol_11_1130
PubMedSearch : Gao_2023_J.Clin.Transl.Hepatol_11_1130
PubMedID: 37577217

Title : Dinotefuran induces oxidative stress and autophagy on Bombyx mori silk gland: Toxic effects and implications for nontarget organisms - Huang_2023_Environ.Pollut_336_122470
Author(s) : Huang Y , Zou S , Zhan P , Hao Z , Lu Q , Jing W , Li Y , Xu Y , Wang H
Ref : Environ Pollut , 336 :122470 , 2023
Abstract : Dinotefuran, a third-generation neonicotinoid insecticide, is widely utilized in agriculture for pest control; however, its environmental consequences and risks to non-target organisms remain largely unknown. Bombyx mori is an economically important insect and a good toxic detector for environmental assessments. In this study, ultrastructure analysis showed that dinotefuran exposure caused an increase in autophagic vesicles in the silk gland. Dinotefuran exposure triggered elevated levels of oxidative stress in silk glands. Reactive oxygen species, oxidized glutathione disulfide, glutathione peroxidase, the activities of UDP glucuronosyl-transferase and carboxylesterase were induced in the middle silk gland, while malondialdehyde, reactive oxygen species, superoxide dismutase oxidized glutathione disulfide were increased in the posterior silk gland. Global transcription patterns revealed the physiological responses were induced by dinotefuran. Dinotefuran exposure substantially induced the expression levels of many genes involved in the mTOR and PI3K - Akt signaling pathways in the middle silk gland, whereas many differentially expressed genes involved in fatty acid and pyrimidine metabolism were found in the posterior silk gland. Additionally, functional, ultrastructural, and transcriptomic analysis indicate that dinotefuran exposure induced an increase of autophagy in the silk gland. This study illuminates the toxicity effects of dinotefuran exposure on silkworms and provides new insights into the underlying molecular toxicity mechanisms of dinotefuran to nontarget organisms.
ESTHER : Huang_2023_Environ.Pollut_336_122470
PubMedSearch : Huang_2023_Environ.Pollut_336_122470
PubMedID: 37657723

Title : Biochemical toxicity and transcriptome aberration induced by dinotefuran in Bombyx mori - Xu_2022_Environ.Pollut__119562
Author(s) : Xu S , Hao Z , Li Y , Zhou Y , Shao R , Chen R , Zheng M , Xu Y , Wang H
Ref : Environ Pollut , :119562 , 2022
Abstract : Dinotefuran is a third-generation neonicotinoid pesticide and is increasingly used in agricultural production, which has adverse effects on nontarget organisms. However, the research on the impact of dinotefuran on nontarget organisms is still limited. Here the toxic effects of dinotefuran on an economic lepidopteran model insect, Bombyx mori, were investigated. Exposure to different doses of dinotefuran caused physiological disorders or death. Cytochrome P450, glutathione S-transferase, carboxylesterase, and UDP glycosyl-transferase activities were induced in the fat body at early stages after dinotefuran exposure. By contrast, only glutathione S-transferase activity was increased in the midgut. To overcome the lack of sensitivity of the biological assays at the individual organism level, RNA sequencing was performed to measure differential expressions of mRNA from silkworm larvae after dinotefuran exposure. Differential gene expression profiling revealed that various detoxification enzyme genes were significantly increased after dinotefuran exposure, which was consistent with the upregulation of the detoxifying enzyme. The global transcriptional pattern showed that the physiological responses induced by dinotefuran toxicity involved multiple cellular processes, including energy metabolism, oxidative stress, detoxification, and other fundamental physiological processes. Many metabolism processes, such as carbon metabolism, fatty acid biosynthesis, pyruvate metabolism, and the citrate cycle, were partially repressed in the midgut or fat body. Furthermore, dinotefuran significantly activated the MAPK/CREB, CncC/Keap1, PI3K/Akt, and Toll/IMD pathways. The links between physiological, biochemical toxicity and comparative transcriptomic analysis facilitated the systematic understanding of the integrated biological toxicity of dinotefuran. This study provides a holistic view of the toxicity and detoxification metabolism of dinotefuran in silkworm and other organisms.
ESTHER : Xu_2022_Environ.Pollut__119562
PubMedSearch : Xu_2022_Environ.Pollut__119562
PubMedID: 35659910

Title : Baoshanmycin and a New Furanone Derivative from a Soil-Derived Actinomycete, Amycolatopsis sp. YNNP 00208 - Qian_2022_Chem.Biodivers__e202200064
Author(s) : Qian MA , Yang YB , Hu BY , Xu Y , Wang ZH , Li QY , Gao YH , Luo XD , Zhao LX
Ref : Chem Biodivers , :e202200064 , 2022
Abstract : Actinomycetes have being regarded as a treasure reservoir of various bioactive secondary metabolites and devoted many antibiotics in clinicals. Amycolatopsis sp. YNNP 00208 was isolated from a soil sample collected in Gaoligong Mountain area, Yunnan Province, China. Chemical investigation of its fermentation broth led to a new amide, baoshanmycin (1), and a new furanone derivative, 3-(1,3-dihydroxybutyl)-4-methylfuran-2(H)-one (2), together with eight known compounds, including two amides (3-4), four cyclic dipeptides (5-8), and two deoxyribonucleosides (9-10). Their structures were established on basis of the 1D- and 2D-NMR spectroscopic data, along with the HR-ESI-MS experiments. Baoshanmycin (1) showed moderate antimicrobial activities against Candida albicans, and weak activities against Staphylococcus aureus, multi-drug resistant Staphylococcus aureus, Bacillus subtilis, Listeria monocytogenes, fluconazole-resistant Candida albicans. Baoshanmycin (1) presented strong antioxidant activity and moderate anti-acetylcholinesterase activity. The other compound 3-(1,3-dihydroxybutyl)-4-methylfuran-2(H)-one (2) and the known compounds (3-10) showed moderate antioxidant activity.
ESTHER : Qian_2022_Chem.Biodivers__e202200064
PubMedSearch : Qian_2022_Chem.Biodivers__e202200064
PubMedID: 35333437

Title : Comprehensive analysis of the carboxylesterase gene reveals that NtCXE22 regulates axillary bud growth through strigolactone metabolism in tobacco - Wang_2022_Front.Plant.Sci_13_1019538
Author(s) : Wang L , Xie X , Xu Y , Li Z , Xu G , Cheng L , Yang J , Li L , Pu W , Cao P
Ref : Front Plant Sci , 13 :1019538 , 2022
Abstract : Carboxylesterases (CXE) are a class of hydrolytic enzymes with alpha/beta-folding domains that play a vital role in plant growth, development, stress response, and activation of herbicide-active substances. In this study, 49 Nicotiana tabacum L. CXE genes (NtCXEs) were identified using a sequence homology search. The basic characteristics, phylogenetic evolution, gene structure, subcellular location, promoter cis-elements, and gene expression patterns of the CXE family were systematically analyzed. RNA-seq data and quantitative real-time PCR showed that the expression level of CXEs was associated with various stressors and hormones; gene expression levels were significantly different among the eight tissues examined and at different developmental periods. As a new class of hormones, strigolactones (SLs) are released from the roots of plants and can control the germination of axillary buds.NtCXE7, NtCXE9, NtCXE22, and NtCXE24 were homologous to Arabidopsis SLs hydrolase AtCXE15, and changes in their expression levels were induced by topping and by GR24 (a synthetic analogue of strigolactone). Further examination revealed that NtCXE22-mutant (ntcxe22) plants generated by CRISPR-Cas9 technology had shorter bud outgrowth with lower SLs content. Validation of NtCXE22 was also performed in NtCCD8-OE plants (with fewer axillary buds) and in ntccd8 mutant plants (with more axillary buds). The results suggest that NtCXE22 may act as an efficient SLs hydrolase and affects axillary bud development, thereby providing a feasible method for manipulating endogenous SLs in crops and ornamental plants.
ESTHER : Wang_2022_Front.Plant.Sci_13_1019538
PubMedSearch : Wang_2022_Front.Plant.Sci_13_1019538
PubMedID: 36600915
Gene_locus related to this paper: tobac-NtCXE49 , tobac-NtCXE48 , tobac-NtCXE46 , tobac-NtCXE44 , tobac-NtCXE41 , tobac-NtCXE40 , tobac-NtCXE39 , tobac-NtCXE38 , tobac-NtCXE36 , tobac-NtCXE34 , tobac-NtCXE33 , tobac-NtCXE28 , tobac-NtCXE27 , tobac-NtCXE26 , tobac-NtCXE25 , tobac-NtCXE24 , tobac-NtCXE23 , tobac-NtCXE21 , tobac-NtCXE19 , tobac-NtCXE18 , tobac-NtCXE17 , tobac-NtCXE15 , tobac-NtCXE14 , tobac-NtCXE13 , tobac-NtCXE12 , tobac-NtCXE11 , tobac-NtCXE10 , tobac-NtCXE8 , tobac-NtCXE7 , tobac-NtCXE6 , tobac-NtCXE5 , tobac-NtCXE4 , tobac-NtCXE3 , tobac-NtCXE2 , tobac-NtCXE1 , tobac-NtCXE30 , tobac-NtCXE32 , tobac-NtCXE22 , tobac-NtCXE29 , tobac-NtCXE35 , tobac-NtCXE45

Title : Cloning and Functional Characterization of the Polyketide Synthases Based on Genome Mining of Preussia isomera XL-1326 - Liu_2022_Front.Microbiol_13_819086
Author(s) : Liu Q , Zhang D , Xu Y , Gao S , Gong Y , Cai X , Yao M , Yang X
Ref : Front Microbiol , 13 :819086 , 2022
Abstract : Fungal polyketides (PKs) are one of the largest families of structurally diverse bioactive natural products biosynthesized by multidomain megasynthases, in which thioesterase (TE) domains act as nonequivalent decision gates determining both the shape and the yield of the polyketide intermediate. The endophytic fungus Preussia isomera XL-1326 was discovered to have an excellent capacity for secreting diverse bioactive PKs, i.e., the hot enantiomers (+/-)-preuisolactone A with antibacterial activity, the single-spiro minimoidione B with alpha-glucosidase inhibition activity, and the uncommon heptaketide setosol with antifungal activity, which drive us to illustrate how the unique PKs are biosynthesized. In this study, we first reported the genome sequence information of P. isomera. Based on genome mining, we discovered nine transcriptionally active genes encoding polyketide synthases (PKSs), Preu1-Preu9, of which those of Preu3, Preu4, and Preu6 were cloned and functionally characterized due to possessing complete sets of synthetic and release domains. Through heterologous expression in Saccharomyces cerevisiae, Preu3 and Preu6 could release high yields of orsellinic acid (OA) derivatives [3-methylorsellinic acid (3-MOA) and lecanoric acid, respectively]. Correspondingly, we found that Preu3 and Preu6 were clustered into OA derivative synthase groups by phylogenetic analysis. Next, with TE domain swapping, we constructed a novel "non-native" PKS, Preu6-TE(Preu3), which shared a very low identity with OA synthase, OrsA, from Aspergillus nidulans but could produce a large amount of OA. In addition, with the use of Preu6-TE(Preu3), we synthesized methyl 3-methylorsellinate (synthetic oak moss of great economic value) from 3-MOA as the substrate, and interestingly, 3-MOA exhibited remarkable antibacterial activities, while methyl 3-methylorsellinate displayed broad-spectrum antifungal activity. Taken together, we identified two novel PKSs to biosynthesize 3-MOA and lecanoric acid, respectively, with information on such kinds of PKSs rarely reported, and constructed one novel "non-native" PKS to largely biosynthesize OA. This work is our first step to explore the biosynthesis of the PKs in P. isomera, and it also provides a new platform for high-level environment-friendly production of OA derivatives and the development of new antimicrobial agents.
ESTHER : Liu_2022_Front.Microbiol_13_819086
PubMedSearch : Liu_2022_Front.Microbiol_13_819086
PubMedID: 35602042
Gene_locus related to this paper: preis-preu6

Title : Molecular mechanism of LIP05 derived from Monascus purpureus YJX-8 for synthesizing fatty acid ethyl esters under aqueous phase - Zhao_2022_Front.Microbiol_13_1107104
Author(s) : Zhao J , Xu Y , Lu H , Zhao D , Zheng J , Lin M , Liang X , Ding Z , Dong W , Yang M , Li W , Zhang C , Sun B , Li X
Ref : Front Microbiol , 13 :1107104 , 2022
Abstract : Fatty acid ethyl esters are important flavor chemicals in strong-flavor Baijiu. Monascus purpureus YJX-8 is recognized as an important microorganism for ester synthesis in the fermentation process. Enzyme LIP05 from YJX-8 can efficiently catalyze the synthesis of fatty acid ethyl esters under aqueous phase, but the key catalytic sites affecting esterification were unclear. The present work combined homology modeling, molecular dynamics simulation, molecular docking and site-directed mutation to analyze the catalytic mechanism of LIP05. Protein structure modeling indicated LIP05 belonged to alpha/beta fold hydrolase, contained a lid domain and a core catalytic pocket with conserved catalytic triad Ser150-His215-Asp202, and the oxyanion hole composed of Gly73 and Thr74. Ile30 and Leu37 of the lid domain were found to affect substrate specificity. The Pi-bond stacking between Tyr116 and Tyr149 played an important role in stabilizing the catalytic active center of LIP05. Tyr116 and Ile204 determined the substrate spectrum by composing the substrate-entrance channel. Residues Leu83, Ile204, Ile211 and Leu216 were involved in forming the hydrophobic substrate-binding pocket through steric hindrance and hydrophobic interaction. The catalytic mechanism for esterification in aqueous phase of LIP05 was proposed and provided a reference for clarifying the synthesis of fatty acid ethyl esters during the fermentation process of strong-flavor Baijiu.
ESTHER : Zhao_2022_Front.Microbiol_13_1107104
PubMedSearch : Zhao_2022_Front.Microbiol_13_1107104
PubMedID: 36713181

Title : Evaluation on the Metabolic Activity of Two Carboxylesterase Isozymes in Mouse Liver Microsomes by a LC-MS\/MS Method - Lan_2022_J.Chromatogr.Sci__
Author(s) : Lan L , Li M , Xu Y , Ren X , Zhang C
Ref : Journal of Chromatography Sci , : , 2022
Abstract : An applicable method for the precise measurement of major carboxylesterase (CESs) activity in liver still limited. Clopidogrel and irinotecan are specific substrates for CES1 and CES2, respectively. Clopidogrel is metabolized to the inactive metabolite clopidogrel carboxylate (CCAM) by CES1. Irinotecan is metabolized to the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) by CES2. In the present study, the LC-MS/MS method for the determination of CCAM and SN-38 were separately developed to characterize the metabolic activities of CES1 and CES2 in mouse liver microsomal. CCAM was separated on a Ecosil ODS column with an isocratic mobile phase consisted of 5smmol/L ammonium formate and 0.1% formic acid in water and acetonitrile (15:85, V:V) at a flow rate of 0.4mL/min. SN-38 was separated on a Waters symmetry C18 column with an gradient mobile phase consisted of 5smmol/L ammonium formate and 0.1% formic acid in water and acetonitrile at a flow rate of 0.3smL/min. Calibration curves were linear within the concentration range of 100-20,000sng/mL for CCAM and 1-200sng/mL for SN-38. The results of method showed excellent accuracy and precision. The recovery rate, matrix effect and stability inspection results were within the acceptance criteria. The optimized incubation conditions were as follows: protein concentration of microsomes were all 0.1smg/mL, incubation time was 60smin for clopidogrel and 30smin for irinotecan, respectively. This method was sensitive and applicable for the determination of the activity of CESs in the mouse liver microsomes.
ESTHER : Lan_2022_J.Chromatogr.Sci__
PubMedSearch : Lan_2022_J.Chromatogr.Sci__
PubMedID: 36585777

Title : The Relationship Between Zinc Deficiency and Hepatocellular Carcinoma Associated with Hepatitis B Liver Cirrhosis: A 10-year Follow-up Study - Wang_2022_Biol.Trace.Elem.Res__
Author(s) : Wang S , Fan X , Gao Y , Zuo L , Hong M , Xu Y
Ref : Biol Trace Elem Res , : , 2022
Abstract : Our aim is to evaluate the serum zinc levels in Hepatitis B liver cirrhosis patients and clarify the relationship between the serum zinc levels and the development of hepatocellular carcinoma (HCC). From January 2009 to December 2019, 295 included patients diagnosed with Hepatitis B liver cirrhosis received nucleos(t)ide analogues (NUCs) therapy at China-Japan Union Hospital of Jilin University. Their comprehensive medical records were retrospectively analyzed, and to analyze the relationship between hypozincemia and hepatitis B-related HCC. Twenty-eight of 295 patients (9.49%) developed HCC during an observation period of the median follow-up time was 42 months. Compared with the non-zinc deficiency group, the zinc deficiency group is older, has a higher proportion of hepatic encephalopathy, higher levels of aspartate aminotransferase(AST), international normalized ratio(INR) and TB, and lower levels of cholinesterase (CHE), creatinine, and platelet counts (P< 0.05). Multivariate analysis showed that zine (HR=0.854, 95%CI 0.725-1.007; P=0.061), zinc is not significant for reducing the incidence of HCC, as liver disease progresses, the proportion of zinc deficiency is getting higher and higher, Child-Pugh C. The proportion of grade zinc deficiency accounted for 64.86%. Child-Pugh grade C was more than Child-Pugh grade B and A, p<0.001. Zinc deficiency is associated with hepatic encephalopathy, and other complications related to hepatitis B and liver cirrhosis. But the relationship with hepatocellular carcinoma still needs further study.
ESTHER : Wang_2022_Biol.Trace.Elem.Res__
PubMedSearch : Wang_2022_Biol.Trace.Elem.Res__
PubMedID: 35247138

Title : Esterase-responsive and size-optimized prodrug nanoparticles for effective intracranial drug delivery and glioblastoma treatment - Ye_2022_Nanomedicine__102581
Author(s) : Ye Z , Gao L , Cai J , Wang Y , Li Y , Tong S , Yan T , Sun Q , Qi Y , Xu Y , Jiang H , Zhang S , Zhao L , Chen Q
Ref : Nanomedicine , :102581 , 2022
Abstract : Glioblastoma multiforme (GBM) is the intracranial malignancy with the highest rates of morbidity and mortality. Chemotherapy is often ineffective against GBM due to the presence of the blood-brain barrier (BBB); however, the application of nanotechnology is expected to overcome this limitation. Poly(lactic-co-glycolic acid) (PLGA) is a degradable and nontoxic functional polymer with good biocompatibility that is widely used in the pharmaceutical industry. Previous studies have shown that the ability of PLGA nanoparticles (NPs) to penetrate the BBB is largely determined by their size; however, determination of the optimal PLGA NP size requires further research. Here, we report a tandutinib-based prodrug (proTan), which responds to the GBM microenvironment, that was combined with NPs to overcome the BBB. AMD3100-PLGA NPs loaded with proTan inhibited tumor growth and effectively prolonged the survival of tumor-bearing mice.
ESTHER : Ye_2022_Nanomedicine__102581
PubMedSearch : Ye_2022_Nanomedicine__102581
PubMedID: 35811067

Title : Transcriptome analysis reveals differential effects of beta-cypermethrin and fipronil insecticides on detoxification mechanisms in Solenopsis invicta - Siddiqui_2022_Front.Physiol_13_1018731
Author(s) : Siddiqui JA , Luo Y , Sheikh UAA , Bamisile BS , Khan MM , Imran M , Hafeez M , Ghani MI , Lei N , Xu Y
Ref : Front Physiol , 13 :1018731 , 2022
Abstract : Insecticide resistance poses many challenges in insect pest control, particularly in the control of destructive pests such as red imported fire ants (Solenopsis invicta). In recent years, beta-cypermethrin and fipronil have been extensively used to manage invasive ants, but their effects on resistance development in S. invicta are still unknown. To investigate resistance development, S. invicta was collected from populations in five different cities in Guangdong, China. The results showed 105.71- and 2.98-fold higher resistance against fipronil and beta-cypermethrin, respectively, in the Guangzhou population. The enzymatic activities of acetylcholinesterase, carboxylases, and glutathione S-transferases significantly increased with increasing beta-cypermethrin and fipronil concentrations. Transcriptomic analysis revealed 117 differentially expressed genes (DEGs) in the BC-ck vs. BC-30 treatments (39 upregulated and 78 downregulated), 109 DEGs in F-ck vs. F-30 (33 upregulated and 76 downregulated), and 499 DEGs in BC-30 vs. F-30 (312 upregulated and 187 downregulated). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that DEGs associated with insecticide resistance were significantly enriched in metabolic pathways, the AMPK signaling pathway, the insulin signaling pathway, carbon metabolism, peroxisomes, fatty acid metabolism, drug metabolism enzymes and the metabolism of xenobiotics by cytochrome P450. Furthermore, we found that DEGs important for insecticide detoxification pathways were differentially regulated under both insecticide treatments in S. invicta. Comprehensive transcriptomic data confirmed that detoxification enzymes play a significant role in insecticide detoxification and resistance development in S. invicta in Guangdong Province. Numerous identified insecticide-related genes, GO terms, and KEGG pathways indicated the resistance of S. invicta workers to both insecticides. Importantly, this transcriptome profile variability serves as a starting point for future research on insecticide risk evaluation and the molecular mechanism of insecticide detoxification in invasive red imported fire ants.
ESTHER : Siddiqui_2022_Front.Physiol_13_1018731
PubMedSearch : Siddiqui_2022_Front.Physiol_13_1018731
PubMedID: 36277215

Title : Lipase-Catalyzed Phospha-Michael Addition Reactions under Mild Conditions - Xu_2022_Molecules_27_7798
Author(s) : Xu Y , Li F , Ma J , Li J , Xie H , Wang C , Chen P , Wang L
Ref : Molecules , 27 :7798 , 2022
Abstract : Organophosphorus compounds are the core structure of many active natural products. The synthesis of these compounds is generally achieved by metal catalysis requiring specifically functionalized substrates or harsh conditions. Herein, we disclose the phospha-Michael addition reaction of biphenyphosphine oxide with various substituted beta-nitrostyrenes or benzylidene malononitriles. This biocatalytic strategy provides a direct route for the synthesis of C-P bonds with good functional group compatibility and simple and practical operation. Under the optimal conditions (styrene (0.5 mmol), biphenyphosphine oxide (0.5 mmol), Novozym 435 (300 U), and EtOH (1 mL)), lipase leads to the formation of organophosphorus compounds in yields up to 94% at room temperature. Furthermore, we confirm the role of the catalytic triad of lipase in this phospha-Michael addition reaction. This new biocatalytic system will have broad applications in organic synthesis.
ESTHER : Xu_2022_Molecules_27_7798
PubMedSearch : Xu_2022_Molecules_27_7798
PubMedID: 36431898

Title : Traditional Chinese medicine promotes the control and treatment of dementia - Tao_2022_Front.Pharmacol_13_1015966
Author(s) : Tao P , Xu W , Gu S , Shi H , Wang Q , Xu Y
Ref : Front Pharmacol , 13 :1015966 , 2022
Abstract : Dementia is a syndrome that impairs learning and memory. To date, there is no effective therapy for dementia. Current prescription drugs, such as cholinesterase inhibitors, fail to improve the condition of dementia and are often accompanied by severe adverse effects. In recent years, the number of studies into the use of traditional Chinese medicine (TCM) for dementia treatment has increased, revealing a formula that could significantly improve memory and cognitive dysfunctions in animal models. TCM showed fewer adverse effects, lower costs, and improved suitability for long-term use compared with currently prescribed drugs. Due to the complexity of ingredients and variations in bioactivity of herbal medicines, the multi-target nature of the traditional Chinese formula affected the outcome of dementia therapy. Innovations in TCM will create a platform for the development of new drugs for the prevention and treatment of dementia, further strengthening and enhancing the current influence of TCM.
ESTHER : Tao_2022_Front.Pharmacol_13_1015966
PubMedSearch : Tao_2022_Front.Pharmacol_13_1015966
PubMedID: 36304171

Title : Simultaneous Inhibitory Effects of All-Trans Astaxanthin on Acetylcholinesterase and Oxidative Stress - Wang_2022_Mar.Drugs_20_
Author(s) : Wang X , Zhang T , Chen X , Xu Y , Li Z , Yang Y , Du X , Jiang Z , Ni H
Ref : Mar Drugs , 20 : , 2022
Abstract : Alzheimers disease is a global neurodegenerative health concern. To prevent the disease, the simultaneous inhibition of acetylcholinesterase and oxidative stress is an efficient approach. In this study, the inhibition effect of all-trans astaxanthin mainly from marine organisms on acetylcholinesterase and oxidative stress was evaluated by a chemical-based method in vitro and cell assay model. The results show that all-trans astaxanthin was a reversible competitive inhibitor and exhibited a strong inhibition effect with half inhibitory concentration (IC(50) value) of 8.64 micromol/L. Furthermore, all-trans astaxanthin inhibited oxidative stress through reducing malondialdehyde content and increasing the activity of superoxide dismutase as well as catalase. All-trans astaxanthin could induce the changes of the secondary structure to reduce acetylcholinesterase activity. Molecular-docking analysis reveals that all-trans astaxanthin prevented substrate from binding to acetylcholinesterase by occupying the space of the active pocket to cause the inhibition. Our finding suggests that all-trans astaxanthin might be a nutraceutical supplement for Alzheimers disease prevention.
ESTHER : Wang_2022_Mar.Drugs_20_
PubMedSearch : Wang_2022_Mar.Drugs_20_
PubMedID: 35447920

Title : Biological activities and gene expression of detoxifying enzymes in Tribolium castaneum induced by Moutan cortex essential oil - Li_2022_J.Toxicol.Environ.Health.A__1
Author(s) : Li X , Xu Y , Liu J , Yu X , Zhang W , You C
Ref : J Toxicol Environ Health A , :1 , 2022
Abstract : Tribolium castaneum is one of the most harmful storage pests in the world. The aim of this study was to determine the chemical composition, repellent, and contact activities of Moutan cortex essential oil against this insect pest. In addition, the effects of Moutan cortex were examined on the expressions of three major detoxifying enzyme genes in T. castaneum. Four components were identified in this essential oil by gas chromatography-mass spectrometry (GC-MS), which was predominantly paeonol (99.13%). Paeonol exerted significant repellent activity against T. castaneum, which was more potent than the positive control N.N-diethyl-meta-toluamide (DEET). The most significant contact toxicity was observed at 24 h after exposure to paeonol. Further, quantitative real-time PCR (qRT-PCR) was used to assess expression changes in three detoxification enzyme genes in T. castaneum, including carboxylesterase (CarE), glutathione S-transferase (Gst) and cytochrome P4506BQ8 (Cyp6bq8). Among these, Gst was most highly up-regulated after treatment with paeonol with the highest expression level of 4.9-fold (Rps18 as internal reference gene) greater than control at 24 h following treatment. Data indicated that Gst might play a critical role in metabolic detoxification of toxic xenobiotics. Taken together, our findings might lay a foundation for development of paeonol as a potential natural repellent or pesticide to control storage pests.
ESTHER : Li_2022_J.Toxicol.Environ.Health.A__1
PubMedSearch : Li_2022_J.Toxicol.Environ.Health.A__1
PubMedID: 35435144

Title : Comprehensive Detoxification Mechanism Assessment of Red Imported Fire Ant (Solenopsis invicta) against Indoxacarb - Siddiqui_2022_Molecules_27_
Author(s) : Siddiqui JA , Zhang Y , Luo Y , Bamisile BS , Rehman NU , Islam W , Qasim M , Jiang Q , Xu Y
Ref : Molecules , 27 : , 2022
Abstract : The red imported fire ant (Solenopsis invicta) is one of the deadliest invasive ant species that threatens the world by disrupting biodiversity, important functions within a natural ecosystem, and community structure. They are responsible for huge economic losses in the infested countries every year. Synthetic insecticides, especially indoxacarb, have been broadly used to control S. invicta for many years. However, the biochemical response of S. invicta to indoxacarb remains largely undiscovered. Here, we used the sublethal doses of indoxacarb on the S. invicta collected from the eight different cities of Southern China. The alteration in the transcriptome profile of S. invicta following sublethal dosages of indoxacarb was characterized using high-throughput RNA-seq technology. We created 2 libraries, with 50.93 million and 47.44 million clean reads for indoxacarb treatment and control, respectively. A total of 2018 unigenes were regulated after insecticide treatment. Results indicated that a total of 158 differentially expressed genes (DEGs) were identified in the indoxacarb-treated group, of which 100 were significantly upregulated and 58 were downregulated, mostly belonging to the detoxification enzymes, such as AChE, CarE, and GSTs. Furthermore, results showed that most of these DEGs were found in several KEGG pathways, including steroid biosynthesis, other drug metabolizing enzymes, glycerolipid metabolism, chemical carcinogenesis, drug-metabolizing cytochrome P450, glutathione metabolism, glycerophospholipid metabolism, glycolysis/gluconeogenesis, and metabolism of xenobiotics. Together, these findings indicated that indoxacarb causes significant alteration in the transcriptome profile and signaling pathways of S. invicta, providing a foundation for further molecular inquiry.
ESTHER : Siddiqui_2022_Molecules_27_
PubMedSearch : Siddiqui_2022_Molecules_27_
PubMedID: 35164134

Title : The dark side of synaptic proteins in tumours - Li_2022_Br.J.Cancer__
Author(s) : Li J , Xu Y , Zhu H , Wang Y , Li P , Wang D
Ref : Br J Cancer , : , 2022
Abstract : Research in the past decade has uncovered the essential role of the nervous system in the tumour microenvironment. The recent advances in cancer neuroscience, especially the discovery of neuron-tumour synaptic/perisynaptic structures, have revealed the dark side of synaptic proteins in the progression of brain tumours. Here, we provide an overview of the synaptic proteins expressed by tumour cells and analyse their molecular functions and organisation by comparing them with neuronal synaptic proteins. We focus on the studies of neuroligin-3, the glutamate receptors AMPAR and NMDAR and the synaptic scaffold protein DLGAP1, for their newly discovered regulatory role in the proliferation and progression of tumours. Progress in cancer neuroscience has brought novel insights into the treatment of cancers. In the last part of this review, we discuss the therapeutical strategies targeting synaptic proteins and the current challenges and possible toolkits regarding their clinical application in cancer treatment. Our understanding of cancer neuroscience is still in its infancy; deeper investigation of how tumour cells co-opt synaptic signaling will help fulfil the therapeutical potential of the synaptic proteins as promising anti-tumour targets.
ESTHER : Li_2022_Br.J.Cancer__
PubMedSearch : Li_2022_Br.J.Cancer__
PubMedID: 35624299

Title : Enzyme catalyzes ester bond synthesis and hydrolysis: The key step for sustainable usage of plastics - Lai_2022_Front.Microbiol_13_1113705
Author(s) : Lai J , Huang H , Lin M , Xu Y , Li X , Sun B
Ref : Front Microbiol , 13 :1113705 , 2022
Abstract : Petro-plastic wastes cause serious environmental contamination that require effective solutions. Developing alternatives to petro-plastics and exploring feasible degrading methods are two solving routes. Bio-plastics like polyhydroxyalkanoates (PHAs), polylactic acid (PLA), polycaprolactone (PCL), poly (butylene succinate) (PBS), poly (ethylene furanoate) s (PEFs) and poly (ethylene succinate) (PES) have emerged as promising alternatives. Meanwhile, biodegradation plays important roles in recycling plastics (e.g., bio-plastics PHAs, PLA, PCL, PBS, PEFs and PES) and petro-plastics poly (ethylene terephthalate) (PET) and plasticizers in plastics (e.g., phthalate esters, PAEs). All these bio- and petro-materials show structure similarity by connecting monomers through ester bond. Thus, this review focused on bio-plastics and summarized the sequences and structures of the microbial enzymes catalyzing ester-bond synthesis. Most of these synthetic enzymes belonged to alpha/beta-hydrolases with conserved serine catalytic active site and catalyzed the polymerization of monomers by forming ester bond. For enzymatic plastic degradation, enzymes about PHAs, PBS, PCL, PEFs, PES and PET were discussed, and most of the enzymes also belonged to the alpha/beta hydrolases with a catalytic active residue serine, and nucleophilically attacked the ester bond of substrate to generate the cleavage of plastic backbone. Enzymes hydrolysis of the representative plasticizer PAEs were divided into three types (I, II, and III). Type I enzymes hydrolyzed only one ester-bond of PAEs, type II enzymes catalyzed the ester-bond of mono-ester phthalates, and type III enzymes hydrolyzed di-ester bonds of PAEs. Divergences of catalytic mechanisms among these enzymes were still unclear. This review provided references for producing bio-plastics, and degrading or recycling of bio- and petro-plastics from an enzymatic point of view.
ESTHER : Lai_2022_Front.Microbiol_13_1113705
PubMedSearch : Lai_2022_Front.Microbiol_13_1113705
PubMedID: 36713200

Title : Three enigmatic BioH isoenzymes are programmed in the early stage of mycobacterial biotin synthesis, an attractive anti-TB drug target - Xu_2022_PLoS.Pathog_18_e1010615
Author(s) : Xu Y , Yang J , Li W , Song S , Shi Y , Wu L , Sun J , Hou M , Wang J , Jia X , Zhang H , Huang M , Lu T , Gan J , Feng Y
Ref : PLoS Pathog , 18 :e1010615 , 2022
Abstract : Tuberculosis (TB) is one of the leading infectious diseases of global concern, and one quarter of the world's population are TB carriers. Biotin metabolism appears to be an attractive anti-TB drug target. However, the first-stage of mycobacterial biotin synthesis is fragmentarily understood. Here we report that three evolutionarily-distinct BioH isoenzymes (BioH1 to BioH3) are programmed in biotin synthesis of Mycobacterium smegmatis. Expression of an individual bioH isoform is sufficient to allow the growth of an Escherichia coli deltabioH mutant on the non-permissive condition lacking biotin. The enzymatic activity in vitro combined with biotin bioassay in vivo reveals that BioH2 and BioH3 are capable of removing methyl moiety from pimeloyl-ACP methyl ester to give pimeloyl-ACP, a cognate precursor for biotin synthesis. In particular, we determine the crystal structure of dimeric BioH3 at 2.27A, featuring a unique lid domain. Apart from its catalytic triad, we also dissect the substrate recognition of BioH3 by pimeloyl-ACP methyl ester. The removal of triple bioH isoforms (deltabioH1/2/3) renders M. smegmatis biotin auxotrophic. Along with the newly-identified Tam/BioC, the discovery of three unusual BioH isoforms defines an atypical 'BioC-BioH(3)' paradigm for the first-stage of mycobacterial biotin synthesis. This study solves a long-standing puzzle in mycobacterial nutritional immunity, providing an alternative anti-TB drug target.
ESTHER : Xu_2022_PLoS.Pathog_18_e1010615
PubMedSearch : Xu_2022_PLoS.Pathog_18_e1010615
PubMedID: 35816546
Gene_locus related to this paper: mycs2-a0r6y0

Title : Preparation, characterization and bioactivities of selenized polysaccharides from Lonicera caerulea L. fruits - Shao_2022_Int.J.Biol.Macromol__
Author(s) : Shao C , Zhong J , Liu J , Yang Y , Li M , YangYu , Xu Y , Wang L
Ref : Int J Biol Macromol , : , 2022
Abstract : Native polysaccharide was obtained from Lonicera caerulea L. fruits (PLP). Two selenized polysaccharides (PSLP-1 and PSLP-2) were synthesized by the microwave-assisted HNO(3)-Na(2)SeO(3) method, where the selenium (Se) contents were 228 +/-24 and 353 +/- 36 microg/g, respectively. The molecular weights of PLP, PSLP-1, and PSLP-2 were 5.9 10(4), 5.6 10(4), and 5.1 10(4) kDa, respectively. PSLP-1 and PSLP-2 contained the same type of monosaccharides as PLP but with different molar ratios. The main chain structure of the native polysaccharide was not changed after selenization. PLP, PSLP-1, and PSLP-2 contained the same six types of glycosidic bonds. Bioactivity assays revealed that the two selenized polysaccharides possessed better antioxidant activities than PLP, but their bile acid-binding abilities and inhibitory activities on acetylcholinesterase (AChE) had weakened. In summary, PLP, PSLP-1, and PSLP-2 may be promising Se supplements in functional foods and inhibitors for the treatment of AChE.
ESTHER : Shao_2022_Int.J.Biol.Macromol__
PubMedSearch : Shao_2022_Int.J.Biol.Macromol__
PubMedID: 36403769

Title : Analysis of transcript-wide profile regulated by microsatellite instability of colorectal cancer - Xu_2022_Ann.Transl.Med_10_169
Author(s) : Xu Y , Wang X , Chu Y , Li J , Wang W , Hu X , Zhou F , Zhang H , Zhou L , Kuai R , Jin Y , Yang D , Peng H
Ref : Ann Transl Med , 10 :169 , 2022
Abstract : BACKGROUND: Microsatellite instability-high (MSI-H) is a form of genomic instability present in 15% of colorectal cancer (CRC) cases. Several differential gene analyses have been conducted on CRC; however, none have specifically explored the differentially expressed genes in MSI-H CRC. Research on the different gene expressions between MSI-H CRC and microsatellite stable (MSS) CRC, and their different patterns of metastasis will provide invaluable insights for diagnosis, prognosis, and treatment. METHODS: In this study, the differential expression of 46,602 genes were analyzed across 613 different tissue samples from The Cancer Genome Atlas (TCGA)-colon adenocarcinoma (COAD) and TCGA-rectum adenocarcinoma (READ) as part of a gene association analysis. R package TCGAbiolinks (version 2.18.0) was used to download the data set, and DESeq2 (version 1.30.1) was used for the differential gene analysis. The resulting genes were then analyzed for shared pathways with R package clusterProfiler (version 3.0.4). RESULTS: A total of 237 significantly differentially expressed genes (P(adj)<0.05) were found between MSI-H and MSS CRC. Differentially expressed genes include insulin like growth factor 2 (IGF2) and fibroblast growth factor 3 (FGF3), and the enriched pathways mostly involve hearing, digestive regulation, and neurogenesis.463 differentially expressed genes were found between metastatic and non-metastatic CRC. Notably differentially expressed genes in metastatic CRC include DEAD-box helicase 53 (DDX53) and adiponectin, C1Q and collagen domain containing (ADIPOQ), and enriched pathways include the immune system, cell adhesion, and cell signaling. For MSI-H CRC, a total of 34 genes were significantly differently expressed between metastatic and non-metastatic CRC. These include notum, palmitoleoyl-protein carboxylesterase (NOTUM), serpin family B member 2 (SERPINB2), and several keratin (KRT) genes, and the pathway analysis showed the major enrichment of the hormonal and secretion and regulation pathways. Of the differentially expressed genes in metastatic CRC, 25 were immunity related and include fatty acid binding protein 4 (FABP4), and the pathway analysis showed the enrichment of humoral immunity and lymphocyte regulation. CONCLUSIONS: Of the biologically plausible differentially expressed genes, the most notable were NOTUM, KRT6A, KRT14, SERPINB2, and serum amyloid A1 (SAA1). NOTUM, KRT6A, and KRT14 are active in the Wnt pathway. All five are also involved in various inflammation pathways.
ESTHER : Xu_2022_Ann.Transl.Med_10_169
PubMedSearch : Xu_2022_Ann.Transl.Med_10_169
PubMedID: 35280417

Title : Novel cannabidiol-carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease - Jiang_2021_Eur.J.Med.Chem_223_113735
Author(s) : Jiang X , Zhang Z , Zuo J , Wu C , Zha L , Xu Y , Wang S , Shi J , Liu XH , Zhang J , Tang W
Ref : Eur Journal of Medicinal Chemistry , 223 :113735 , 2021
Abstract : Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC(50) = 5.3 nM, SI > 4000), superior to CBD (IC(50) = 0.67 microM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (K(d) = 13 nM, k(2) = 0.26 min(-1)), showing good drug-like properties. In vivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Abeta(1-42) (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.
ESTHER : Jiang_2021_Eur.J.Med.Chem_223_113735
PubMedSearch : Jiang_2021_Eur.J.Med.Chem_223_113735
PubMedID: 34371367

Title : Micro-Aqueous Organic System: A Neglected Model in Computational Lipase Design? - Wang_2021_Biomolecules_11_
Author(s) : Wang S , Xu Y , Yu XW
Ref : Biomolecules , 11 : , 2021
Abstract : Water content is an important factor in lipase-catalyzed reactions in organic media but is frequently ignored in the study of lipases by molecular dynamics (MD) simulation. In this study, Candida antarctica lipase B, Candida rugosa lipase and Rhizopus chinensis lipase were used as research models to explore the mechanisms of lipase in micro-aqueous organic solvent (MAOS) media. MD simulations indicated that lipases in MAOS systems showed unique conformations distinguished from those seen in non-aqueous organic solvent systems. The position of water molecules aggregated on the protein surface in MAOS media is the major determinant of the unique conformations of lipases and particularly impacts the distribution of hydrophilic and hydrophobic amino acids on the lipase surface. Additionally, two maxima were observed in the water-lipase radial distribution function in MAOS systems, implying the formation of two water shells around lipase in these systems. The energy landscapes of lipases along solvent accessible areas of catalytic residues and the minimum energy path indicated the dynamic open states of lipases in MAOS systems differ from those in other solvent environments. This study confirmed the necessity of considering the influence of the microenvironment on MD simulations of lipase-catalyzed reactions in organic media.
ESTHER : Wang_2021_Biomolecules_11_
PubMedSearch : Wang_2021_Biomolecules_11_
PubMedID: 34200257

Title : The novel therapeutic strategy of vilazodone-donepezil chimeras as potent triple-target ligands for the potential treatment of Alzheimer's disease with comorbid depression - Li_2021_Eur.J.Med.Chem_229_114045
Author(s) : Li X , Li J , Huang Y , Gong Q , Fu Y , Xu Y , Huang J , You H , Zhang D , Mao F , Zhu J , Wang H , Zhang H
Ref : Eur Journal of Medicinal Chemistry , 229 :114045 , 2021
Abstract : Depression is one of the most frequent comorbid psychiatric symptoms of Alzheimer's disease (AD), and no efficacious drugs have been approved specifically for this purpose thus far. Herein, we proposed a novel therapeutic strategy that merged the key pharmacophores of the antidepressant vilazodone (5-HT(1A) receptor partial agonist and serotonin transporter inhibitor) and the anti-AD drug donepezil (acetylcholinesterase inhibitor) together to develop a series of multi-target-directed ligands for potential therapy of the comorbidity of AD and depression. Accordingly, 55 vilazodone-donepezil chimeric derivatives were designed and synthesized, and their triple-target activities against acetylcholinesterase, 5-HT(1A) receptor, and serotonin transporter were systematically evaluated. Among them, compound 5 displayed strong triple-target bioactivities in vitro, low hERG potassium channel inhibition and acceptable brain distribution. Importantly, oral intake of 5 mg/kg of the compound 5 dihydrochloride significantly alleviated the depressive symptoms and ameliorated cognitive dysfunction in mouse models. In brief, these results highlight vilazodone-donepezil chimeras as a prospective therapeutic approach for the treatment of the comorbidity of AD and depression.
ESTHER : Li_2021_Eur.J.Med.Chem_229_114045
PubMedSearch : Li_2021_Eur.J.Med.Chem_229_114045
PubMedID: 34922191

Title : An efficient phthalate ester-degrading Bacillus subtilis: Degradation kinetics, metabolic pathway, and catalytic mechanism of the key enzyme - Xu_2021_Environ.Pollut_273_116461
Author(s) : Xu Y , Liu X , Zhao J , Huang H , Wu M , Li X , Li W , Sun X , Sun B
Ref : Environ Pollut , 273 :116461 , 2021
Abstract : Phthalate ester pollution in the environment and food chain is frequently reported. Microbial treatment is a green and efficient method for solving this problem. The isolation and systematic investigation of microorganisms generally recognized as safe (GRAS) will provide useful resources. A GRAS Bacillus subtilis strain, BJQ0005, was isolated from Baijiu fermentation starter and efficiently degraded phthalate esters (PAEs). The half-lives for di-isobutyl phthalate, di-butyl phthalate and di-(2-ethylhexyl) phthalate were 3.93, 4.28, and 25.49 h, respectively, from the initial amount of 10 mg per 10 mL reaction mixture, which are records using wild-type strains. Genome sequencing and metabolic intermediate analysis generated the whole metabolic pathway. Eighteen enzymes from the alpha/beta hydrolase family were expressed. Enzymes GTW28_09400 and GTW28_13725 were capable of single ester bond hydrolysis of PAEs, while GTW28_17760 hydrolyzed di-ester bonds of PAEs. Using molecular docking, a possible mechanism affecting enzymatic ester bond hydrolysis of mono-butyl phthalate was proposed of GTW28_17760. The carboxyl group generated by the first hydrolysis step interacted with histidine in the catalytic active center, which negatively affected enzymatic hydrolysis. Isolation and systematic investigation of the PAE degradation characteristics of B. subtilis will promote the green and safe treatment of PAEs in the environment and food industry.
ESTHER : Xu_2021_Environ.Pollut_273_116461
PubMedSearch : Xu_2021_Environ.Pollut_273_116461
PubMedID: 33485001
Gene_locus related to this paper: bacsu-pnbae

Title : Genome-Wide Identification of Tannase Genes and Their Function of Wound Response and Astringent Substances Accumulation in Juglandaceae - Wang_2021_Front.Plant.Sci_12_664470
Author(s) : Wang J , Wang K , Lyu S , Huang J , Huang C , Xing Y , Wang Y , Xu Y , Li P , Hong J , Xi J , Si X , Ye H , Li Y
Ref : Front Plant Sci , 12 :664470 , 2021
Abstract : Tannins are important polyphenol compounds with different component proportions in different plant species. The plants in the Juglandaceae are rich in tannins, including condensed tannins and hydrolyzable tannins. In this study, we identified seven tannase genes (TAs) responsible for the tannin metabolism from walnut, pecan, and Chinese hickory, and three nut tree species in the Juglandaceae, which were divided into two groups. The phylogenetic and sequence analysis showed that TA genes and neighboring clade genes (TA-like genes) had similar sequences compared with other carboxylesterase genes, which may be the origin of TA genes produced by tandem repeat. TA genes also indicated higher expressions in leaf than other tissues and were quickly up-regulated at 3 h after leaf injury. During the development of the seed coat, the expression of the synthesis-related gene GGTs and the hydrolase gene TAs was continuously decreased, resulting in the decrease of tannin content in the dry sample of the seed coat of Chinese hickory. However, due to the reduction in water content during the ripening process, the tannin content in fresh sample increased, so the astringent taste was obvious at the mature stage. In addition, the CcGGTs' expression was higher than CiGGTs in the initiation of development, but CcTAs continued to be down-regulated while CiTA2a and CiTA2b were up-regulated, which may bring about the significant differences in tannin content and astringent taste between Chinese hickory and pecan. These results suggested the crucial role of TAs in wound stress of leaves and astringent ingredient accumulation in seed coats of two nut tree species in the Juglandaceae.
ESTHER : Wang_2021_Front.Plant.Sci_12_664470
PubMedSearch : Wang_2021_Front.Plant.Sci_12_664470
PubMedID: 34079571
Gene_locus related to this paper: camsi-CsTA

Title : Expression of Drosophila melanogaster acetylcholinesterase (DmAChE) gene splice variants in Pichia pastoris and evaluation of its sensitivity to organophosphorus pesticides - Shi_2021_J.Zhejiang.Univ.Sci.B_22_204
Author(s) : Shi L , Yang F , Xu Y , Wang S
Ref : J Zhejiang Univ Sci B , 22 :204 , 2021
Abstract : Acetylcholinesterase (AChE) is a key enzyme used to detect organophosphorus pesticide residues by the enzyme inhibition method. An accidental discovery of a mutant strain with AChE activity was made in our laboratory during the process of AChE expression by Pichia pastoris. The pPIC9K-Drosophila melanogaster acetylcholinesterase (DmAChE)-like expression vector was constructed by codon optimization of this mutant strain, which was transformed into P. pastoris GS115, and positive clones were selected on yeast peptone dextrose (YPD) plate with G418 at 4.0 mg/mL. The GS115-pPIC9K-DmAChE-like strain was subjected to 0.5% methanol induction expression for 120 h, with a protein band at 4.3 kDa found by the tricine-sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) pattern of the fermentation supernatant. After preliminary purification by ammonium sulfate precipitation, the enzyme activity was detected to be 76.9 U/(mL min). In addition, the pesticide sensitivity test proved that DmAChE-like is selective and sensitive to organophosphorus pesticides.
ESTHER : Shi_2021_J.Zhejiang.Univ.Sci.B_22_204
PubMedSearch : Shi_2021_J.Zhejiang.Univ.Sci.B_22_204
PubMedID: 33719225

Title : Antioxidant Effects of Sophora davidi (Franch.) Skeels on d-Galactose-Induced Aging Model in Mice via Activating the SIRT1\/p53 Pathway - Lin_2021_Front.Pharmacol_12_754554
Author(s) : Lin B , Xu D , Wu S , Qi S , Xu Y , Liu X , Zhang X , Chen C
Ref : Front Pharmacol , 12 :754554 , 2021
Abstract : This study investigated the protective effect of Sophora davidi (Franch.) Skeels fruits extract (SDE) on d-galactose-induced acute aging in mice. Ultra performance liquid chromatography coupled with tine-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to identify the composition of compounds in SDE. KM mice were divided stochastically into the normal control group (NC, saline), d-galactose (D-gal) model group, vitamin C (Vc) group (positive control), low-, medium-and high-dose SDE treat groups. After 28 days administration and fasting overnight, the serum, liver, and brain samples of mice were collected. The levels of inducible nitric oxide synthase (iNOS), acetylcholinesterase (AChE) activity in the brain, malondialdehyde (MDA) and reduced glutathione (GSH) content, superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) activity in the liver and brain were measured. Immunohistochemistry was applied to detect silent information regulator 1 (SIRT1) and p53 protein expression in the liver and brain, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of nuclear factor kappaB (NF-kappaB), tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), interleukin-1beta (IL-1beta), and anti-aging factor Klotho in the liver and brain. The results showed that UPLC-Q-TOF/MS identified 78 compounds in SDE. SDE could reduce the iNOS activity in serum and AChE activity in the brain, upregulate the levels of SOD, T-AOC and GSH in liver and brain, and debase the MDA content in liver and brain. SDE could downregulate the mRNA expressions of TNF-alpha, NF-kB, IL-1beta, and IL-6 in the liver and brain, and elevate the mRNA expression of Klotho. SDE improved the pathological changes of the liver and brain induced by D-gal, increased the expression of SIRT1 protein in the liver and brain, and inhibited the expression of p53 protein induced by D-gal. To summarize, SDE demonstrated clear anti-aging effect, and its mechanism may be relevant to the activation of the SIRT1/p53 signal pathway.
ESTHER : Lin_2021_Front.Pharmacol_12_754554
PubMedSearch : Lin_2021_Front.Pharmacol_12_754554
PubMedID: 34938181

Title : BMP4 and WNT signaling interact to promote mouse tracheal mesenchyme morphogenesis - Bottasso_2021_Am.J.Physiol.Lung.Cell.Mol.Physiol__
Author(s) : Bottasso Arias N , Leesman L , Burra K , Snowball J , Shah RM , Mohanakrishnan M , Xu Y , Sinner D
Ref : American Journal of Physiology Lung Cell Mol Physiol , : , 2021
Abstract : Tracheobronchomalacia and Complete Tracheal Rings are congenital malformations of the trachea associated with morbidity and mortality for which the etiology remains poorly understood. Epithelial expression of Wls (a cargo receptor mediating Wnt ligand secretion) by tracheal cells is essential for patterning the embryonic mouse trachea's cartilage and muscle. RNA sequencing indicated that Wls differentially modulated the expression of BMP signaling molecules. We tested whether BMP signaling, induced by epithelial Wnt ligands, mediates cartilage formation. Deletion of Bmp4 from respiratory tract mesenchyme impaired tracheal cartilage formation that was replaced by ectopic smooth muscle, recapitulating the phenotype observed after epithelial deletion of Wls in the embryonic trachea. Ectopic muscle was caused in part by anomalous differentiation and proliferation of smooth muscle progenitors rather than tracheal cartilage progenitors. Mesenchymal deletion of Bmp4 impaired expression of Wnt/beta-catenin target genes, including targets of WNTsignaling: Notum, and Axin2. In vitro, rBMP4 rescued the expression of Notum in Bmp4 deficient tracheal mesenchymal cells and induced Notum promoter activity via SMAD1/5. RNA sequencing of Bmp4 deficient tracheas identified genes essential for chondrogenesis and muscle development co-regulated by BMP and WNT signaling. During tracheal morphogenesis, WNT signaling induces Bmp4 in mesenchymal progenitors to promote cartilage differentiation and restrict trachealis muscle. In turn, Bmp4 differentially regulates the expression of Wnt/beta-catenin targets to attenuate mesenchymal WNT signaling and to further support chondrogenesis.
ESTHER : Bottasso_2021_Am.J.Physiol.Lung.Cell.Mol.Physiol__
PubMedSearch : Bottasso_2021_Am.J.Physiol.Lung.Cell.Mol.Physiol__
PubMedID: 34851738

Title : Kuwanon G protects HT22 cells from advanced glycation end product-induced damage - Gan_2021_Exp.Ther.Med_21_425
Author(s) : Gan WJ , Gao CL , Zhang WQ , Gu JL , Zhao TT , Guo HL , Zhou H , Xu Y , Yu LL , Li LF , Gui DK , Xu YH
Ref : Exp Ther Med , 21 :425 , 2021
Abstract : The incidence of diabetic encephalopathy is increasing as the population ages. Evidence suggests that formation and accumulation of advanced glycation end products (AGEs) plays a pivotal role in disease progression, but limited research has been carried out in this area. A previous study demonstrated that Kuwanon G (KWG) had significant anti-oxidative stress and anti-inflammatory properties. As AGEs are oxidative products and inflammation is involved in their generation it is hypothesized that KWG may have effects against AGE-induced neuronal damage. In the present study, mouse hippocampal neuronal cell line HT22 was used. KWG was shown to significantly inhibit AGE-induced cell apoptosis in comparison with a control treatment, as determined by both MTT and flow cytometry. Compared with the AGEs group, expression of pro-apoptotic protein Bax was reduced and expression of anti-apoptotic protein Bcl-2 was increased in the AGEs + KWG group. Both intracellular and extracellular levels of acetylcholine and choline acetyltransferase were significantly elevated after KWG administration in comparison with controls whilethe level of acetylcholinesterase decreased. These changes in protein expression were accompanied by increased levels of superoxide dismutase and glutathione peroxidase synthesis and reduced production of malondialdehyde and reactive oxygen species. Intracellular signaling pathway protein levels were determined by western blot and immunocytochemistry. KWG administration was found to prevent AGE-induced changes to the phosphorylation levels of Akt, IkappaB-alpha, glycogen synthase kinase 3 (GSK3)-alpha and beta, p38 MAPK and NF-kappaB p65 suggesting a potential neuroprotective effect of KWG against AGE-induced damage was via the PI3K/Akt/GSK3alphabeta signaling pathway. The findings of the present study suggest that KWG may be a potential treatment for diabetic encephalopathy.
ESTHER : Gan_2021_Exp.Ther.Med_21_425
PubMedSearch : Gan_2021_Exp.Ther.Med_21_425
PubMedID: 33747164

Title : IL-6 downregulates hepatic carboxylesterases via NF-kappaB activation in dextran sulfate sodium-induced colitis - Li_2021_Int.Immunopharmacol_99_107920
Author(s) : Li M , Lan L , Zhang S , Xu Y , He W , Xiang D , Liu D , Ren X , Zhang C
Ref : Int Immunopharmacol , 99 :107920 , 2021
Abstract : Ulcerative colitis (UC) is associated with increased levels of inflammatory factors, which is attributed to the abnormal expression and activity of enzymes and transporters in the liver, affecting drug disposition in vivo. This study aimed to examine the impact of intestinal inflammation on the expression of hepatic carboxylesterases (CESs) in a mouse model of dextran sulfate sodium (DSS)-induced colitis. Two major CESs isoforms, CES1 and CES2, were down-regulated, accompanied by decreases in hepatic microsomal metabolism of clopidogrel and irinotecan. Meanwhile, IL-6 levels significantly increased compared with other inflammatory factors in the livers of UC mice. In contrast, using IL-6 antibody simultaneously reversed the down-regulation of CES1, CES2, pregnane X receptor (PXR), and constitutive androstane receptor (CAR), as well as the nuclear translocation of NF-kappaB in the liver. We further confirmed that treatment with NF-kappaB inhibitor abolished IL-6-induced down-regulation of CES1, CES2, PXR, and CAR in vitro. Thus, it was concluded that IL-6 represses hepatic CESs via the NF-kappaB pathway in DSS-induced colitis. These findings indicate that caution should be exercised concerning the proper and safe use of therapeutic drugs in patients with UC.
ESTHER : Li_2021_Int.Immunopharmacol_99_107920
PubMedSearch : Li_2021_Int.Immunopharmacol_99_107920
PubMedID: 34217990

Title : High specific immobilization of His-tagged recombinant Microbacterium esterase by Ni-NTA magnetic chitosan microspheres for efficient synthesis of key chiral intermediate of d-biotin - He_2021_Bioprocess.Biosyst.Eng__
Author(s) : He S , Wu X , Ma B , Xu Y
Ref : Bioprocess Biosyst Eng , : , 2021
Abstract : The novel Ni-NTA-functionalized magnetic chitosan microspheres (MCS-NTA-Ni) were prepared via amino functionalization of MCS with epichlorohydrin and ethylenediamine, followed by the introduction of the aldehyde groups and NTA in turn, and nickel (II) ions were chelated in the end. MCS-NTA-Ni contained numerous long-armed NTA-Ni surface groups, ensuring high enzyme loading and providing more space and flexibility to attach enzymes and maintain their activity. This microsphere can have highly selective adsorption of his-tagged recombinant protein. The his-tagged recombinant Microbacterium esterase of E. coli BL21 (DE3)/pET21a-EstSIT01 was first immobilized on MCS-NTA-Ni by affinity fixation, giving high immobilization yield (90.1%) and enzyme loading (120 mg/g). Compared with free esterase, the immobilized esterase was found to exhibit higher pH stability and thermal stability. In addition, the immobilized esterase had excellent reusability for the synthesis of key chiral intermediate of d-biotin and the substrate conversion could still keep 100% after 8 cycles continuously.
ESTHER : He_2021_Bioprocess.Biosyst.Eng__
PubMedSearch : He_2021_Bioprocess.Biosyst.Eng__
PubMedID: 34089090

Title : Data for the lipase catalyzed synthesis of cyano-containing multi-substituted indoles - Li_2021_Data.Brief_36_107045
Author(s) : Li F , Xu Y , Wang C , Zhao R , Wang L
Ref : Data Brief , 36 :107045 , 2021
Abstract : The data presented here are related to the research paper entitled "Efficient Synthesis of Cyano-containing Multi-substituted Indoles Catalyzed by Lipase" [1]. In this data article, the lipase catalyzed synthetic procedures for the preparation of multi-substituted indoles and their derivatives were described. In total, 11 compounds were obtained and the optimum pH, reaction time and substrate ratio were screened through this study.
ESTHER : Li_2021_Data.Brief_36_107045
PubMedSearch : Li_2021_Data.Brief_36_107045
PubMedID: 33997196

Title : Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate - Zhou_2021_J.Med.Chem_64_1844
Author(s) : Zhou Y , Fu Y , Yin W , Li J , Wang W , Bai F , Xu S , Gong Q , Peng T , Hong Y , Zhang D , Liu Q , Xu Y , Xu HE , Zhang H , Jiang H , Liu H
Ref : Journal of Medicinal Chemistry , 64 :1844 , 2021
Abstract : The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
ESTHER : Zhou_2021_J.Med.Chem_64_1844
PubMedSearch : Zhou_2021_J.Med.Chem_64_1844
PubMedID: 33570950
Gene_locus related to this paper: human-ACHE

Title : Construction and characterization of CRISPR\/Cas9 knockout rat model of carboxylesterase 2a gene - Liu_2021_Mol.Pharmacol__2
Author(s) : Liu J , Shang X , Huang S , Xu Y , Lu J , Zhang Y , Liu Z , Wang X
Ref : Molecular Pharmacology , : , 2021
Abstract : Carboxylesterase 2 (CES2), an important metabolic enzyme, plays a critical role in drug biotransformation and lipid metabolism. Although CES2 is very important, few animal models have been generated to study its properties and functions. Rat Ces2 is similar to human CES2A-CES3A-CES4A gene cluster, with highly similar gene structure, function and substrate. In this report, CRISPR/Cas9 technology was firstly used to knock out rat Ces2a, a main subtype of Ces2 mostly distributed in liver and intestine. This model showed the absence of CES2A protein expression in liver. Further pharmacokinetic studies of diltiazem, a typical substrate of CES2A, confirmed the loss of function of CES2A both in vivo and in vitro. At the same time, the expression of CES2C and CES2J protein in liver decreased significantly. The body and liver weight of Ces2a knockout rats also increased, but the food intake did not change. Moreover, the deficiency of Ces2a led to obesity, insulin resistance and liver fat accumulation, which are consistent with the symptoms of nonalcoholic fatty liver disease (NAFLD). Therefore, this rat model is not only a powerful tool to study drug metabolism mediated by CES2, but also a good disease model to study NAFLD. Significance Statement Human CES2 plays a key role in the first-pass hydrolysis metabolism of most oral prodrugs as well as lipid metabolism. In this study, CRISPR/Cas9 technology was used to knock out Ces2a gene in rats for the first time. This model can be used not only in the study of drug metabolism and pharmacokinetics, but also as a disease model of NAFLD and other metabolic disorder.
ESTHER : Liu_2021_Mol.Pharmacol__2
PubMedSearch : Liu_2021_Mol.Pharmacol__2
PubMedID: 34503976
Gene_locus related to this paper: ratno-LOC246252

Title : Key Metabolic Enzymes Involved in Remdesivir Activation in Human Lung Cells - Li_2021_Antimicrob.Agents.Chemother__AAC0060221
Author(s) : Li R , Liclican A , Xu Y , Pitts J , Niu C , Zhang J , Kim C , Zhao X , Soohoo D , Babusis D , Yue Q , Ma B , Murray BP , Subramanian R , Xie X , Zou J , Bilello JP , Li L , Schultz BE , Sakowicz R , Smith BJ , Shi PY , Murakami E , Feng JY
Ref : Antimicrobial Agents & Chemotherapy , :AAC0060221 , 2021
Abstract : Remdesivir (RDV; GS-5734; Veklury(a)), the first FDA-approved antiviral to treat COVID-19, is a single diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV is taken up in the target cells and metabolized in multiple steps to form the active nucleoside triphosphate (TP) (GS-443902), which in turn acts as a potent and selective inhibitor of multiple viral RNA polymerases. In this report, we profiled the key enzymes involved in the RDV metabolic pathway with multiple parallel approaches: (1) bioinformatic analysis of nucleoside/tide metabolic enzyme mRNA expression using public human tissue and lung single-cell RNAseq datasets; (2) protein and mRNA quantification of enzymes in human lung tissue and primary lung cells; (3) biochemical studies on the catalytic rate of key enzymes; (4) effects of specific enzyme inhibitors on the GS-443902 formation; and (5) the effects of these inhibitors on RDV antiviral activity against SARS-CoV-2 in cell culture. Our data collectively demonstrated that carboxylesterase 1 (CES1) and cathepsin A (CatA) are enzymes involved in hydrolyzing RDV to its alanine intermediate Met X, which is further hydrolyzed to the monophosphate form by histidine triad nucleotide-binding protein 1 (HINT1). The monophosphate is then consecutively phosphorylated to diphosphate and triphosphate by cellular phosphotransferases. Our data support the hypothesis that the unique properties of RDV prodrug not only allow lung-specific accumulation critical for the treatment of respiratory viral infection such as COVID-19, they also enable efficient intracellular metabolism of RDV and its Met X to monophosphate and successive phosphorylation to form the active TP in disease-relevant cells.
ESTHER : Li_2021_Antimicrob.Agents.Chemother__AAC0060221
PubMedSearch : Li_2021_Antimicrob.Agents.Chemother__AAC0060221
PubMedID: 34125594

Title : Nutritional Status and Body Composition in Wilson Disease: A Cross-Sectional Study From China - Geng_2021_Front.Nutr_8_790520
Author(s) : Geng H , Wang S , Jin Y , Cheng N , Song B , Shu S , Li B , Han Y , Gao L , Ding Z , Xu Y , Wang X , Ma Z , Sun Y
Ref : Front Nutr , 8 :790520 , 2021
Abstract : Background: Abnormal nutritional status is frequently seen in patients with chronic diseases. To date, no study has investigated the detailed characteristics of abnormal nutritional status among Wilson's disease (WD) patients in the Chinese cohort. This study aimed to describe the nutritional status of WD patients, with a particular focus on the differences between patients with different phenotypes. Methods: The study subjects comprised 119 healthy controls, 129 inpatients (hepatic subtype, n = 34; neurological subtype, n = 95) who were being treated at the affiliated hospital of the Institute of Neurology, Anhui University of Chinese Medicine. All of the subjects were assessed for body composition by using bioelectrical impedance analysis. All WD patients received anthropometry, nutritional risk screening 2002 (NRS2002), and laboratory test (hemocyte and serum biomarkers) additionally. Results: Compared with healthy controls, the fat mass and rate of total body and trunk were significantly higher in WD patients (P < 0.001), the muscle and skeletal muscle mass of total body and trunk were significantly lower in WD patients (P < 0.001). Compared with hepatic subtype patients, the fat mass and rate of total body, trunk, and limbs were significantly lower in neurological subtype patients (P<0.01); while there were no significant differences in muscle and skeletal muscle between these two subtypes. The overall prevalence of abnormal nutritional status in WD patients was 43.41% (56/129). The prevalence of high-nutritional risk and overweight in WD patients was 17.83% (23 of 129) and 25.58% (33 of 129), respectively. Compare with patients with high nutritional risk, macro platelet ratio, alkaline phosphatase, the basal metabolic rate (p < 0.05), creatinine, trunk fat rate (p < 0.01) and appendicular skeletal muscle mass (p < 0.001) were significantly higher in patients without nutritional risk (p < 0.001). Patients with a high nutritional risk tend to have a lower cholinesterase concentration (x (2) = 4.227, p < 0.05). Conclusion: Both patients with H-subtype and N-subtype are prone to have an abnormal nutritional status. Longitudinal studies are required to investigate if nutritional status and body composition could reflect prognosis in WD patients, and which of these body composition indexes contribute to malnutrition and worse prognosis.
ESTHER : Geng_2021_Front.Nutr_8_790520
PubMedSearch : Geng_2021_Front.Nutr_8_790520
PubMedID: 35036410

Title : Identification and structure-activity relationship exploration of uracil-based benzoic acid and ester derivatives as novel dipeptidyl Peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus - Li_2021_Eur.J.Med.Chem_225_113765
Author(s) : Li Q , Deng X , Jiang N , Meng L , Xing J , Jiang W , Xu Y
Ref : Eur Journal of Medicinal Chemistry , 225 :113765 , 2021
Abstract : Our previously reported carboxyl-containing DPP-4 inhibitors were highly potent but were poorly bioavailable. Esters of the carboxyl analogs exhibited a significant DPP-4 potency loss albeit with enhanced oral absorption. Herein, we described identification and structure-activity relationship (SAR) exploration of a novel series of benzoic acid and ester derivatives as low single-digit nanomolar DPP-4 inhibitors. Importantly, the esters displayed comparable activities to the acids counterparts. Molecular simulation revealed that ester adopts a similar binding mode to acid. Moreover, the selected esters and acids demonstrated high selectivity and low cytotoxicity, as well as good metabolic stability. And more importantly, the esters possessed excellent pharmacokinetic profiles for oral administration. The best compound ester 19b demonstrated long DPP-4 inhibition in vivo, and robustly improved the glucose tolerance in normal and db/db mice while ensuring glucose-lowering potency in chronic treatment. Our results supported that the compound 19b can be served as a potential candidate for the treatment of type 2 diabetes.
ESTHER : Li_2021_Eur.J.Med.Chem_225_113765
PubMedSearch : Li_2021_Eur.J.Med.Chem_225_113765
PubMedID: 34399391

Title : Hepatocyte-Specific Expression of Human Carboxylesterase 1 Attenuates Diet-Induced Steatohepatitis and Hyperlipidemia in Mice - Xu_2020_Hepatol.Commun_4_527
Author(s) : Xu Y , Zhu Y , Bawa FC , Hu S , Pan X , Yin L , Zhang Y
Ref : Hepatol Commun , 4 :527 , 2020
Abstract : Rodents have at least five carboxylesterase 1 (Ces1) genes, whereas there is only one CES1 gene in humans, raising the question as to whether human CES1 and mouse Ces1 genes share the same functions. In this study, we investigate the role of human CES1 in the development of steatohepatitis or dyslipidemia in C57BL/6 mice. Hepatocyte-specific expression of human CES1 prevented Western diet or alcohol-induced steatohepatitis and hyperlipidemia. Mechanistically, human CES1 induced lipolysis and fatty acid oxidation, leading to a reduction in hepatic triglyceride and free fatty acid levels. Human CES1 also reduced hepatic-free cholesterol levels and induced low-density lipoprotein receptor. In addition, human CES1 induced hepatic lipoprotein lipase and apolipoprotein C-II expression. Conclusion: Hepatocyte-specific overexpression of human CES1 attenuates diet-induced steatohepatitis and hyperlipidemia.
ESTHER : Xu_2020_Hepatol.Commun_4_527
PubMedSearch : Xu_2020_Hepatol.Commun_4_527
PubMedID: 32258948

Title : Identification of Highly Selective Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors by a Covalent Fragment-Based Approach - Huang_2020_J.Med.Chem_63_7052
Author(s) : Huang F , Hu H , Wang K , Peng C , Xu W , Zhang Y , Gao J , Liu Y , Zhou H , Huang R , Li M , Shen J , Xu Y
Ref : Journal of Medicinal Chemistry , 63 :7052 , 2020
Abstract : Covalent ligands are of great interest as therapeutic drugs or biochemical tools. Here, we reported the discovery of highly selective and irreversible inhibitors of lipoprotein-associated phospholipase A2 (Lp-PLA2) using a covalent fragment-based approach. The crystal structure of Lp-PLA2 in complex with a covalent fragment not only reveals the covalent reaction mechanism but also provides a good starting point to design compound 8, which has a more than 130,000-fold and 3900-fold increase in potency and selectivity, respectively, compared to those of the covalent fragment. Furthermore, fluorescent probes with high selectivity and sensitivity are developed to characterize Lp-PLA2 and its enzymatic activity in vitro or even in living cells in a way more convenient than immunoblotting tests or immunofluorescence imaging. Overall, we provide a paradigm for application of the covalent fragment-based strategy in covalent ligand discovery and the advantage of enol-cyclocarbamate as a new warhead in designing covalent inhibitors of serine hydrolases.
ESTHER : Huang_2020_J.Med.Chem_63_7052
PubMedSearch : Huang_2020_J.Med.Chem_63_7052
PubMedID: 32459096
Gene_locus related to this paper: human-PLA2G7

Title : Improved Homologous Expression of the Acidic Lipase from Aspergillus niger - Zhu_2020_J.Microbiol.Biotechnol_30_196
Author(s) : Zhu SY , Xu Y , Yu XW
Ref : J Microbiol Biotechnol , 30 :196 , 2020
Abstract : In this study, the acidic lipase from Aspergillus niger (ANL) was homologously expressed in A. niger. The expression of ANL was significantly improved by the expression of the native ANL with the introns, the addition of the Kozak sequence and the optimization of the signal sequences. When the cDNA sequence of ANL fused with the glaA signal was expressed under the gpdA promoter in A. niger, no lipase activity could be detected. We then tried to improve the expression by using the full-length ANL gene containing three introns, and the lipase activity in the supernatant reached 75.80 U/ml, probably as a result of a more stable mRNA structure. The expression was further improved to 100.60 U/ml by introducing a Kozak sequence around the start codon due to a higher translation efficiency. Finally, the effects of three signal sequences including the cbhI signal, the ANL signal and the glaA signal on the lipase expression were evaluated. The transformant with the cbhI signal showed the highest lipase activity (314.67 U/ml), which was 1.90-fold and 3.13-fold higher than those with the ANL signal and the glaA signal, respectively. The acidic lipase was characterized and its highest activity was detected at pH 3.0 and a temperature of 45 degrees C. These results provided promising strategies for the production of the acidic lipase from A. niger.
ESTHER : Zhu_2020_J.Microbiol.Biotechnol_30_196
PubMedSearch : Zhu_2020_J.Microbiol.Biotechnol_30_196
PubMedID: 31752069

Title : Hepatocyte-specific Expression of Human Carboxylesterase 2 Attenuates Non-alcoholic Steatohepatitis in Mice - Xu_2020_Am.J.Physiol.Gastrointest.Liver.Physiol__
Author(s) : Xu Y , Pan X , Hu S , Zhu Y , Cassim Bawa F , Li Y , Yin L , Zhang Y
Ref : American Journal of Physiology Gastrointest Liver Physiol , : , 2020
Abstract : Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were i.v. injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced non-alcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/db mice. Human CES2 also improved glucose tolerance and insulin sensitivity. Mechanistically, human CES2 reduced hepatic triglyceride and free fatty acid levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis via suppression of sterol regulatory element-binding protein 1. Furthermore, human CES2 overexpression improved mitochondrial respiration and glycolytic function, and inhibited gluconeogenesis, lipid peroxidation, apoptosis and inflammation. Our data suggest that hepatocyte-specific expression of human CES2 prevents and reverses steatohepatitis. Targeting hepatic CES2 may be an attractive strategy for treatment of NAFLD.
ESTHER : Xu_2020_Am.J.Physiol.Gastrointest.Liver.Physiol__
PubMedSearch : Xu_2020_Am.J.Physiol.Gastrointest.Liver.Physiol__
PubMedID: 33325808

Title : Scocycamides, a Pair of Macrocyclic Dicaffeoylspermidines with Butyrylcholinesterase Inhibition and Antioxidation Activity from the Roots of Scopolia tangutica - Wang_2020_Org.Lett_22_8240
Author(s) : Wang JX , Zhao YP , Du NN , Han Y , Li H , Wang R , Xu Y , Liu YF , Liang XM
Ref : Org Lett , 22 :8240 , 2020
Abstract : A pair of new macrocyclic spermidine alkaloids, (+)-(S)-scocycamide and (-)-(R)-scocycamide, were isolated from the roots of Scopolia tangutica. Their structures were established by extensive spectroscopic data, electronic circular dichroism analyses, and chemical synthesis. They featured a unique 6/18 fused bicyclic framework with spermidine and catechol units, representing a new subtype of natural spermidine alkaloids. A plausible biosynthetic pathway was also proposed. They inhibited butyrylcholinesterase and exhibited antioxidant capacity, suggesting beneficial constituents against Alzheimer's disease and oxidation.
ESTHER : Wang_2020_Org.Lett_22_8240
PubMedSearch : Wang_2020_Org.Lett_22_8240
PubMedID: 33021797

Title : Efficient synthesis of cyano-containing multi-substituted indoles catalyzed by lipase - Li_2020_Bioorg.Chem_107_104583
Author(s) : Li F , Xu Y , Wang C , Zhao R , Wang L
Ref : Bioorg Chem , 107 :104583 , 2020
Abstract : BACKGROUND: Indoles are important bioactive compounds that have been extensively studied in organic chemistry. In this work, a green and efficient process for the synthesis of Indoles from 1,3-diketones with fumaronitrile was developed. RESULTS: Under optimal conditions (1,3-diketones (0.5 mmol), fumaronitrile (1 mmol), water (2 ml), lipase (15 mg), 30 degreesC, 24 h), high yields and satisfactory regioselectivity of cyano-containing multi-substituted indoles could be obtained when CRL (C. rugosa lipase) was used as the catalyst. CONCLUSION: This enzymatic method demonstrates the great potential for the synthesis of indoles and extends the application of enzyme in organic synthesis.
ESTHER : Li_2020_Bioorg.Chem_107_104583
PubMedSearch : Li_2020_Bioorg.Chem_107_104583
PubMedID: 33421956

Title : Characterization of the diversification of phospholipid:diacylglycerol acyltransferases in the green lineage - Falarz_2020_Plant.J_103_2025
Author(s) : Falarz LJ , Xu Y , Caldo KMP , Garroway CJ , Singer SD , Chen G
Ref : Plant J , 103 :2025 , 2020
Abstract : Triacylglycerols have important physiological roles in photosynthetic organisms, and are widely used as food, feed and industrial materials in our daily life. Phospholipid:diacylglycerol acyltransferase (PDAT) is the pivotal enzyme catalyzing the acyl-CoA-independent biosynthesis of triacylglycerols, which is unique in plants, algae and fungi, but not in animals, and has essential functions in plant and algal growth, development and stress responses. Currently, this enzyme has yet to be examined in an evolutionary context at the level of the green lineage. Some fundamental questions remain unanswered, such as how PDATs evolved in photosynthetic organisms and whether the evolution of terrestrial plant PDATs from a lineage of charophyte green algae diverges in enzyme function. As such, we used molecular evolutionary analysis and biochemical assays to address these questions. Our results indicated that PDAT underwent divergent evolution in the green lineage: PDATs exist in a wide range of plants and algae, but not in cyanobacteria. Although PDATs exhibit the conservation of several features, phylogenetic and selection-pressure analyses revealed that overall they evolved to be highly divergent, driven by different selection constraints. Positive selection, as one major driving force, may have resulted in enzymes with a higher functional importance in land plants than green algae. Further structural and mutagenesis analyses demonstrated that some amino acid sites under positive selection are critically important to PDAT structure and function, and may be central in lecithin:cholesterol acyltransferase family enzymes in general.
ESTHER : Falarz_2020_Plant.J_103_2025
PubMedSearch : Falarz_2020_Plant.J_103_2025
PubMedID: 32538516

Title : A Dual-Protein Cascade Reaction for the Regioselective Synthesis of Quinoxalines - Li_2020_Org.Lett__
Author(s) : Li F , Tang X , Xu Y , Wang C , Wang Z , Li Z , Wang L
Ref : Org Lett , : , 2020
Abstract : In this work, an efficient dual-protein (lipase and hemoglobin) system was successfully constructed for the regioselective synthesis of quinoxalines in water. A set of quinoxalines were obtained in high yields under optimal reaction conditions. This dual-protein method exhibited a regioselectivity higher than those of previously reported methods. This study not only provides a green and mild strategy for the synthesis of quinoxalines but also expands the application of lipase and hemoglobin in organic synthesis.
ESTHER : Li_2020_Org.Lett__
PubMedSearch : Li_2020_Org.Lett__
PubMedID: 32337998

Title : Discovery of nitazoxanide-based derivatives as autophagy activators for the treatment of Alzheimer's disease - Li_2020_Acta.Pharm.Sin.B_10_646
Author(s) : Li X , Lu J , Xu Y , Wang J , Qiu X , Fan L , Li B , Liu W , Mao F , Zhu J , Shen X , Li J
Ref : Acta Pharm Sin B , 10 :646 , 2020
Abstract : Drug repurposing is an efficient strategy for new drug discovery. Our latest study found that nitazoxanide (NTZ), an approved anti-parasite drug, was an autophagy activator and could alleviate the symptom of Alzheimer's disease (AD). In order to further improve the efficacy and discover new chemical entities, a series of NTZ-based derivatives were designed, synthesized, and evaluated as autophagy activator against AD. All compounds were screened by the inhibition of phosphorylation of p70S6K, which was the direct substrate of mammalian target of rapamycin (mTOR) and its phosphorylation level could reflect the mTOR-dependent autophagy level. Among these analogs, compound 22 exhibited excellent potency in promoting beta-amyloid (Abeta) clearance, inhibiting tau phosphorylation, as well as stimulating autophagy both in vitro and in vivo. What's more, 22 could effectively improve the memory and cognitive impairments in APP/PS1 transgenic AD model mice. These results demonstrated that 22 was a potential candidate for the treatment of AD.
ESTHER : Li_2020_Acta.Pharm.Sin.B_10_646
PubMedSearch : Li_2020_Acta.Pharm.Sin.B_10_646
PubMedID: 32322468

Title : A magnetic SERS immunosensor for highly sensitive and selective detection of human carboxylesterase 1 in human serum samples - Feng_2020_Anal.Chim.Acta_1097_176
Author(s) : Feng J , Xu Y , Huang W , Kong H , Li Y , Cheng H , Li L
Ref : Anal Chim Acta , 1097 :176 , 2020
Abstract : Hepatocellular carcinoma (HCC) is a common and lethal cancer. New serum markers for detecting HCC are urgently needed. Human carboxylesterase 1 (hCE1) is an important member of the serine hydrolase superfamily and is closely related to the occurrence of HCC. It can be used as a good serum marker for early diagnosis of HCC. Here, we developed a surface enhanced Raman scattering (SERS)- based magnetic immunosensor that specifically recognizes and detects trace amounts of hCE1 in human serum via a sandwich structure consisting of a SERS tags, magnetic supporting substrates, and target antigen (hCE1). The SERS tags are 4-mercaptobenzoic acid (4-MBA)-labeled AgNPs, and the SERS supporting substrates are composed of a raspberry-like morphology of Fe3O4@SiO2@AgNPs magnetic nanocomposites surface-functionalized with a hCE1 antibody. The prepared SERS magnetic immunosensor exhibits excellent selectivity and extremely high sensitivity for hCE1 detection. The SERS signal and logarithm of hCE1 concentration presented a wide linear response range of 0.1ngmL(-1) to 1.0mgmL(-1), and the detection limit of hCE1 was 0.1ngmL(-1). The results indicate that the immunosensor can be used for the rapid determination of hCE1 in human serum without a complicated sample pre-treatment. Furthermore, the immunosensor has good reproducibility and stability, and has a promising prospect for the quantitative detection of other tumor markers in early clinical diagnosis.
ESTHER : Feng_2020_Anal.Chim.Acta_1097_176
PubMedSearch : Feng_2020_Anal.Chim.Acta_1097_176
PubMedID: 31910958

Title : Design, synthesis and evaluation of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors - Xu_2020_Bioorg.Med.Chem.Lett_30_126985
Author(s) : Xu Y , Jian MM , Han C , Yang K , Bai LG , Cao F , Ma ZY
Ref : Bioorganic & Medicinal Chemistry Lett , 30 :126985 , 2020
Abstract : A series of new 4-arylthiazole-2-amine derivatives as acetylcholinesterase inhibitors (AChEIs) were designed and synthesized, Furthermore, their inhibitory activities against acetylcholinesterase in vitro were tested by Ellman spectrophotometry, and the results of inhibitory activity test showed that most of them had a certain acetylcholinesterase inhibitory activity in vitro. Moreover, the IC50 value of compound 4f was to 0.66 muM, which was higher than that of Rivastigmine and Huperzine-A as reference compounds, and it had a weak inhibitory effect on butyrylcholinesterase. The potential binding mode of compound 4f with AChE was investigated by the molecular docking, and the results showed that 4f was strongly bound up with AChE with the optimal conformation, in addition, their binding energy reached -11.27 Kcal*mol(-1). At last, in silico molecular property of the synthesized compounds were predicted by using Molinspiration online servers. It can be concluded that the lead AChEIs compound 4f presented satisfactory drug-like characteristics.
ESTHER : Xu_2020_Bioorg.Med.Chem.Lett_30_126985
PubMedSearch : Xu_2020_Bioorg.Med.Chem.Lett_30_126985
PubMedID: 32008906

Title : Discovery of anthocyanins from cranberry extract as pancreatic lipase inhibitors using a combined approach of ultrafiltration, molecular simulation and spectroscopy - Xie_2020_Food.Funct_11_8527
Author(s) : Xie L , Xie J , Xu Y , Chen W
Ref : Food Funct , 11 :8527 , 2020
Abstract : Obesity is a chronic disease that has been causing serious problems all over the world. However, there is a lack of available therapeutic approaches to treat obesity. The FDA-approved drug orlistat has severe side effects, such as abdominal pain, flatulence and oily stool. As the therapeutic target of orlistat is pancreatic lipase, there is an urgent need for discovery of new pancreatic lipase inhibitors from natural sources that have reduced side effects compared with orlistat. In this study, ultrafiltration in combination with molecular simulation and spectroscopy was reported as an effective approach for identifying new pancreatic lipase inhibitors from anthocyanin-rich berry sources. Using this approach, four monomeric anthocyanins cyanidin-3-O-arabinoside (C3A), cyanidin-3-O-galactoside (C3Ga), peonidin-3-O-arabinoside (Pn3A) and peonidin-3-O-galactoside (Pn3Ga) from cranberries were discovered as potent pancreatic lipase inhibitors. These four cranberry anthocyanins were shown to form hydrophobic interactions and hydrogen bonds with pocket amino acid residues in molecular docking and molecular dynamics simulations. C3A showed greater impact on secondary structures of the enzyme and showed higher binding capacity with the enzyme compared with C3Ga, Pn3A and Pn3Ga as observed by CD and fluorescence spectroscopy. The structure-activity relationships were then investigated and summarized as both the structures of the B ring and glycosyl group were related to the inhibitory activities of anthocyanins. In short, our results suggested that cranberry anthocyanins could be developed as food supplements to facilitate the prevention and treatment of obesity.
ESTHER : Xie_2020_Food.Funct_11_8527
PubMedSearch : Xie_2020_Food.Funct_11_8527
PubMedID: 33000849

Title : Genome sequencing of the Australian wild diploid species Gossypium australe highlights disease resistance and delayed gland morphogenesis - Cai_2020_Plant.Biotechnol.J_18_814
Author(s) : Cai Y , Cai X , Wang Q , Wang P , Zhang Y , Cai C , Xu Y , Wang K , Zhou Z , Wang C , Geng S , Li B , Dong Q , Hou Y , Wang H , Ai P , Liu Z , Yi F , Sun M , An G , Cheng J , Shi Q , Xie Y , Shi X , Chang Y , Huang F , Chen Y , Hong S , Mi L , Sun Q , Zhang L , Zhou B , Peng R , Zhang X , Liu F
Ref : Plant Biotechnol J , 18 :814 , 2020
Abstract : The diploid wild cotton species Gossypium australe possesses excellent traits including resistance to disease and delayed gland morphogenesis, and has been successfully used for distant breeding programmes to incorporate disease resistance traits into domesticated cotton. Here, we sequenced the G. australe genome by integrating PacBio, Illumina short read, BioNano (DLS) and Hi-C technologies, and acquired a high-quality reference genome with a contig N50 of 1.83 Mb and a scaffold N50 of 143.60 Mb. We found that 73.5% of the G. australe genome is composed of various repeat sequences, differing from those of G. arboreum (85.39%), G. hirsutum (69.86%) and G. barbadense (69.83%). The G. australe genome showed closer collinear relationships with the genome of G. arboreum than G. raimondii and has undergone less extensive genome reorganization than the G. arboreum genome. Selection signature and transcriptomics analyses implicated multiple genes in disease resistance responses, including GauCCD7 and GauCBP1, and experiments revealed induction of both genes by Verticillium dahliae and by the plant hormones strigolactone (GR24), salicylic acid (SA) and methyl jasmonate (MeJA). Experiments using a Verticillium-resistant domesticated G. barbadense cultivar confirmed that knockdown of the homologues of these genes caused a significant reduction in resistance against Verticillium dahliae. Moreover, knockdown of a newly identified gland-associated gene GauGRAS1 caused a glandless phenotype in partial tissues using G. australe. The G. australe genome represents a valuable resource for cotton research and distant relative breeding as well as for understanding the evolutionary history of crop genomes.
ESTHER : Cai_2020_Plant.Biotechnol.J_18_814
PubMedSearch : Cai_2020_Plant.Biotechnol.J_18_814
PubMedID: 31479566
Gene_locus related to this paper: gosra-a0a0d2pzd7

Title : Amino acid, fatty acid, and carbohydrate metabolomic profiles with ginsenoside-induced insecticidal efficacy against Ostrinia furnacalis (Guenee) - Liu_2020_J.Ginseng.Res_44_544
Author(s) : Liu S , Wang X , Zhang R , Song M , Zhang N , Li W , Wang Y , Xu Y , Zhang L
Ref : J Ginseng Res , 44 :544 , 2020
Abstract : Background: Previous studies have shown the insecticidal efficacy of ginsenosides. In the present study, we aimed to investigate the metabolic mechanism related to the inhibitory effect of panaxadiol saponins (PDSs) against the Asian corn borer Ostrinia furnacalis (Guenee). Methods: Third instar larvae of O. furnacalis were fed normal diets with different concentrations of PDSs for 4 days. The consumption index, relative growth rate, approximate digestibility, and conversion of ingested and digested food were recorded. A targeted gas chromatography-mass spectrometry assay was performed to detect the profiles of amino acids, fatty acids, and carbohydrates in larvae of O. furnacalis. In addition, the activity of detoxification-related enzymes was determined. Results and Conclusions: PDSs decreased the consumption index, relative growth rate, approximate digestibility, and conversion of ingested and digested food in the 3rd instar larvae of O. furnacalis in a dose-dependent manner. PDSs decreased 15 free amino acids, 16 free fatty acids, and 5 carbohydrates and increased the levels of palmitoleic acid, palmitic acid, and 9-octadecenoic acid in the 3rd instar larvae. The activity of detoxification-related enzymes, such as acetylcholinesterase, glutathione S-transferase, cytochrome P450, carboxylesterase, trehalase, acid phosphatase, and alkaline phosphatase, was reduced in a dose-dependent manner in the 3rd instar larvae exposed to PDSs. These data confirmed the inhibitory effect of PDSs against growth, food utilization, and detoxification in the 3rd instar larvae of O. furnacalis and the potential for using PDSs as an efficient tool for insect pest management for O. furnacalis larvae.
ESTHER : Liu_2020_J.Ginseng.Res_44_544
PubMedSearch : Liu_2020_J.Ginseng.Res_44_544
PubMedID: 32617034

Title : The rs1051931 G>A Polymorphism in the PLA2G7 Gene Confers Resistance to Immunoglobulin Therapy in Kawasaki Disease in a Southern Chinese Population - Gu_2020_Front.Pediatr_8_338
Author(s) : Gu X , Lin W , Xu Y , Che D , Tan Y , Lu Z , Pi L , Fu L , Zhou H , Jiang Z
Ref : Front Pediatr , 8 :338 , 2020
Abstract : Background: Kawasaki disease (KD) is a common cardiovascular disease in infants and young children, with fever, rash, and conjunctivitis as the main clinical manifestations, which can lead to the occurrence of coronary aneurysms. Intravenous immunoglobulin (IVIG) is the preferred treatment for KD patients, but 10-20% of patients are resistant to IVIG. Lipoprotein-associated phospholipase A 2 (Lp-PLA2) is a potential therapeutic target for coronary atherosclerotic heart disease, and the polymorphism of Phospholipase A2 Group VII (PLA2G7) is closely related to the activity of Lp-PLA2, of which rs1051931 is the strongest. Therefore, the rs1051931 polymorphism may be a predictor of IVIG resistance in KD patients. Methods: A total of 760 KD cases, including 148 IVIG-resistant patients and 612 IVIG-responsive patients, were genotyped for rs1051931 in PLA2G7, we compared the effects of rs1051931 on IVIG treatment in KD patients by odds ratios (OR) and 95% confidence interval (CI). Results: The homozygous mutation AA may be a protective factor for IVIG resistance in KD patients (adjusted OR = 3.47, 95% CI = 1.14-10.57, P = 0.0284) and is more evident in patients with KD aged <60 months (adjusted OR = 3.68, 95% CI = 1.10-12.28, P = 0.0399). Conclusions: The PLA2G7 rs1051931 G>A polymorphism may be suitable as a biomarker for the diagnosis or prognosis of IVIG resistance in KD in a southern Chinese population.
ESTHER : Gu_2020_Front.Pediatr_8_338
PubMedSearch : Gu_2020_Front.Pediatr_8_338
PubMedID: 32656171
Gene_locus related to this paper: human-PLA2G7

Title : Engineering of a thermo-alkali-stable lipase from Rhizopus chinensis by rational design of a buried disulfide bond and combinatorial mutagenesis - Wang_2020_J.Ind.Microbiol.Biotechnol_47_1019
Author(s) : Wang R , Wang S , Xu Y , Yu X
Ref : J Ind Microbiol Biotechnol , 47 :1019 , 2020
Abstract : To improve the thermostability of the lipase (r27RCL) from Rhizopus chinensis through rational design, a newly introduced buried disulfide bond F223C/G247C was proved to be beneficial to thermostability. Interestingly, F223C/G247C was also found to improve the alkali tolerance of the lipase. Subsequently, six other thermostabilizing mutations from our previous work were integrated into the mutant F223C/G247C, leading to a thermo-alkali-stable mutant m32. Compared to the wild-type lipase, the associative effect of the beneficial mutations showed significant improvements on the thermostability of m32, with a 74.7-fold increase in half-life at 60 degreesC, a 21.2 degreesC higher [Formula: see text] value and a 10 degreesC elevation in optimum temperature. The mutated m32 was also found stable at pH 9.0-10.0. Furthermore, the molecular dynamics simulations of m32 indicated that its rigidity was enhanced due to the decreased solvent-accessible surface area, a newly formed salt bridge, and the increased deltadeltaG values.
ESTHER : Wang_2020_J.Ind.Microbiol.Biotechnol_47_1019
PubMedSearch : Wang_2020_J.Ind.Microbiol.Biotechnol_47_1019
PubMedID: 33070231
Gene_locus related to this paper: rhich-a3fm73

Title : Significant improvement in catalytic activity and enantioselectivity of a Phaseolus vulgaris epoxide hydrolase, PvEH3, towards ortho-cresyl glycidyl ether based on the semi-rational design - Zhang_2020_Sci.Rep_10_1680
Author(s) : Zhang C , Liu Y , Li C , Xu Y , Su Y , Li J , Zhao J , Wu M
Ref : Sci Rep , 10 :1680 , 2020
Abstract : The investigation of substrate spectrum towards five racemic (rac-) aryl glycidyl ethers (1a-5a) indicated that E. coli/pveh3, an E. coli BL21(DE3) transformant harboring a PvEH3-encoding gene pveh3, showed the highest EH activity and enantiomeric ratio (E) towards rac-3a. For efficiently catalyzing the kinetic resolution of rac-3a, the activity and E value of PvEH3 were further improved by site-directed mutagenesis of selected residues. Based on the semi-rational design of an NC-loop in PvEH3, four single-site variants of pveh3 were amplified by PCR, and intracellularly expressed in E. coli BL21(DE3), respectively. E. coli/pveh3(E134K) and /pveh3(T137P) had the enhanced EH activities of 15.3 +/- 0.4 and 16.1 +/- 0.5 U/g wet cell as well as E values of 21.7 +/- 1.0 and 21.2 +/- 1.1 towards rac-3a. Subsequently, E. coli/pveh3(E134K/T137P) harboring a double-site variant gene was also constructed, having the highest EH activity of 22.4 +/- 0.6 U/g wet cell and E value of 24.1 +/- 1.2. The specific activity of the purified PvEH3(E134K/T137P) (14.5 +/- 0.5 U/mg protein) towards rac-3a and its catalytic efficiency (k(cat)/K(m) of 5.67 mM(-1) s(-1)) for (S)-3a were 1.7- and 3.54-fold those (8.4 +/- 0.3 U/mg and 1.60 mM(-1) s(-1)) of PvEH3. The gram-scale kinetic resolution of rac-3a using whole wet cells of E. coli/pveh3(E134K/T137P) was performed at 20 degC for 7.0 h, producing (R)-3a with 99.4% ee(s) and 38.5 +/- 1.2% yield. Additionally, the mechanism of PvEH3(E134K/T137P) with remarkably improved E value was analyzed by molecular docking simulation.
ESTHER : Zhang_2020_Sci.Rep_10_1680
PubMedSearch : Zhang_2020_Sci.Rep_10_1680
PubMedID: 32015448
Gene_locus related to this paper: phavu-PvEH3

Title : Enhancing the thermostability of Rhizopus chinensis lipase by rational design and MD simulations - Wang_2020_Int.J.Biol.Macromol_60_1189
Author(s) : Wang R , Wang S , Xu Y , Yu X
Ref : Int J Biol Macromol , 60 :1189 , 2020
Abstract : To improve the thermostability of r27RCL from Rhizopus chinensis and broaden its industrial applications, we used rational design (FoldX) according to DeltaDeltaG calculation to predict mutations. Four thermostable variants S142A, D217V, Q239F, and S250Y were screened out and then combined together to generate a quadruple-mutation (S142A/D217V/Q239F/S250Y) variant, called m31. m31 exhibited enhanced thermostability with a 41.7-fold longer half-life at 60 degrees C, a 5 degrees C higher of topt, and 15.8 degrees C higher of T30 50 compared to that of r27RCL expressed in P. pastoris. Molecular dynamics simulations were conducted to analyze the mechanism of the thermostable mutant. The results indicated that the rigidity of m31 was improved due to the decreased solvent accessible surface area, a newly formed salt bridge of Glu292:His171, and the increased DeltaDeltaG of m31. According to the root-mean-square-fluctuation analysis, three positive mutations S142A, D217V, and Q239F located in the thermal weak regions and greatly decreased the distribution of thermal-fluctuated regions of m31, compared to that of r27RCL. These results suggested that to simultaneously implement MD simulations and DeltaDeltaG-based rational approaches will be more accurate and efficient for the improvement of enzyme thermostability.
ESTHER : Wang_2020_Int.J.Biol.Macromol_60_1189
PubMedSearch : Wang_2020_Int.J.Biol.Macromol_60_1189
PubMedID: 32485250
Gene_locus related to this paper: rhich-a3fm73

Title : The structure-based optimization of delta-sultone-fused pyrazoles as selective BuChE inhibitors - Zhang_2020_Eur.J.Med.Chem_201_112273
Author(s) : Zhang Z , Min J , Chen M , Jiang X , Xu Y , Qin H , Tang W
Ref : Eur Journal of Medicinal Chemistry , 201 :112273 , 2020
Abstract : Structure-based optimization was conducted to improve the potency and selectivity of BuChE inhibitors with delta-sulfonolactone-fused pyrazole scaffold. By mimicking the hydrophobic interactions of donepezil at PAS, the introduction of a tertiary benzylamine at 5-position can significantly increase BuChE inhibitory activity. Compounds C4 and C6 were identified as high selective nanomolar BuChE inhibitors (IC50 = 8.3 and 7.7 nM, respectively), which exhibited mild antioxidant capacity, nontoxicity, lipophilicity and neuroprotective activity. Kinetic studies showed that BuChE inhibition of compound C6 was mixed-type against BuChE (Ki = 24 nM) and >2000-fold selectivity for BuChE over AChE. The proposed binding mode of new inhibitors was consistent with the results of structure-activity relationship analysis.
ESTHER : Zhang_2020_Eur.J.Med.Chem_201_112273
PubMedSearch : Zhang_2020_Eur.J.Med.Chem_201_112273
PubMedID: 32569925

Title : Biodegradation of phthalate esters by Paracoccus kondratievae BJQ0001 isolated from Jiuqu (Baijiu fermentation starter) and identification of the ester bond hydrolysis enzyme - Xu_2020_Environ.Pollut_263_114506
Author(s) : Xu Y , Minhazul K , Wang X , Liu X , Li X , Meng Q , Li H , Zhang C , Sun X , Sun B
Ref : Environ Pollut , 263 :114506 , 2020
Abstract : Phthalate ester (PAE) pollution is an increasing problem globally. Paracoccus kondratievae BJQ0001 was isolated from the fermentation starter of Baijiu and showed an efficient degradation capability toward PAEs. To our poor knowledge, this is the first report of a P. kondratievae strain capable of degrading PAEs. The first complete genome sequence of P. kondratievae was presented without gaps, and composed of two circular chromosomes and one plasmid. The species simultaneously degraded di-methyl phthalate (DMP), di-ethyl phthalate (DEP), di-butyl phthalate (DBP), di-isobutyl phthalate (DIBP) and di-(2-ethylhexyl) phthalate (DEHP), with DMP and DEP as the preferred substrates. The half-life (t(1/2)) of DMP was only 6.34 h with an initial concentration of 200 mg/L. Combined with gene annotation and metabolic intermediate analysis, a metabolic pathway was proposed for the species. Benzoic acid, the intermediate of anaerobic PAE metabolism, was identified in the aerobic degradation process. Two key enzymes for alkyl ester bond hydrolysis were obtained, and belonged to families IV and VI of hydrolases, respectively. These results will promote the investigation of PAE degradation by P. kondratievae, and provide useful information for improving the quality control of food and environmental PAE treatment.
ESTHER : Xu_2020_Environ.Pollut_263_114506
PubMedSearch : Xu_2020_Environ.Pollut_263_114506
PubMedID: 32268225
Gene_locus related to this paper: 9rhob-a0a5p8jcg2 , 9rhob-a0a5p8jaa4

Title : Discovery and development of a novel short-chain fatty acid ester synthetic biocatalyst under aqueous phase from Monascus purpureus isolated from Baijiu - Xu_2020_Food.Chem_338_128025
Author(s) : Xu Y , Wang X , Liu X , Li X , Zhang C , Li W , Sun X , Wang W , Sun B
Ref : Food Chem , 338 :128025 , 2020
Abstract : Short-chain fatty acid esters are important flavor chemicals in Chinese traditional fermented Baijiu. Monascus purpureus was recognized as an important microorganism contributing to ester synthesis. However, the molecular basis for ester synthesis was still lacking. The present work combined genome sequencing, transcriptome sequencing, gene library construction, and enzyme engineering to discover a novel catalyst from M. purpureus (isolated from Baijiu fermentation starter). Enzyme LIP05, belonging to the alpha/beta hydrolase family, was identified to synthesize short-chain fatty acid esters under aqueous phase. After deleting the lid domain of LIP05, the synthesis of ethyl pentanoate, ethyl hexanoate, ethyl octanoate, or ethyl decanoate was achieved. Ethyl octanoate with the highest conversion ratio of 93.7% was obtained with the assistance of ultrasound. The study reveals the molecular basis for synthesizing short-chain fatty acid esters by M. purpureus and will promote the application of the species or the enzyme in food industry.
ESTHER : Xu_2020_Food.Chem_338_128025
PubMedSearch : Xu_2020_Food.Chem_338_128025
PubMedID: 32927200
Gene_locus related to this paper: monpu-a0a507qkl5

Title : HEV-LFS : A novel scoring model for patients with hepatitis E virus-related liver failure - Wu_2019_J.Viral.Hepat_26_1334
Author(s) : Wu J , Guo N , Zhang X , Xiong C , Liu J , Xu Y , Fan J , Yu J , Zhao X , Liu B , Wang W , Zhang J , Cao H , Li L
Ref : J Viral Hepat , 26 :1334 , 2019
Abstract : A noninvasive assessment method for acute or acute-on-chronic liver failure in patients with hepatitis E virus (HEV) infection is urgently needed. We aimed to develop a scoring model for diagnosing HEV patients who developed liver failure (HEV-LF) at different stages. A cross-sectional set of 350 HEV-LF patients were identified and enrolled, and the Guidelines for Diagnosis and Treatment of Liver Failure in China and the Asian Pacific Association for the Study of the Liver were adopted as references. HEV-LFS , a novel scoring model that incorporates data on cholinesterase (CHE), urea nitrogen (UREA), platelets and international normalized ratio was developed using a derived dataset. For diagnosing HEV-LF stages F1 to F3, the HEV-LFS scoring model (F1: 0.87; F2: 0.90; F3: 0.92) had a significantly higher AUROC than did the CLIF-C-ACLFs (F1: 0.65; F2: 0.56; F3: 0.51) and iMELD (F1: 0.70; F2: 0.57; F3: 0.51) scoring models, of which the HEV-LFS scoring model had the best sensitivity and specificity. In addition, the HEV-LFS scoring model was correlated with mortality, length of hospitalization and ICU stay. As the GDTLF score increased, the CHE level decreased and the UREA increased gradually. Encouragingly, a calibration curve showed good agreement between the derivation and validation sets. Notably, we also established a nomogram to facilitate the practical operability of the HEV-LFS scoring model in clinical settings. In conclusion, both CHE and UREA may be indicators for HEV-LF patients. The HEV-LFS scoring model is an efficient and accessible model for classifying HEV-LF at different stages.
ESTHER : Wu_2019_J.Viral.Hepat_26_1334
PubMedSearch : Wu_2019_J.Viral.Hepat_26_1334
PubMedID: 31294523

Title : A transcriptomics-based analysis of the toxicity mechanisms of gabapentin to zebrafish embryos at realistic environmental concentrations - He_2019_Environ.Pollut_251_746
Author(s) : He Y , Li X , Jia D , Zhang W , Zhang T , Yu Y , Xu Y , Zhang Y
Ref : Environ Pollut , 251 :746 , 2019
Abstract : Gabapentin (GPT) has become an emerging contaminant in aquatic environments due to its wide application in medical treatment all over the world. In this study, embryos of zebrafish were exposed to gabapentin at realistically environmental concentrations, 0.1mug/L and 10mug/L, so as to evaluate the ecotoxicity of this emergent contaminant. The transcriptomics profiling of deep sequencing was employed to illustrate the mechanisms. The zebrafish (Danio rerio) embryo were exposed to GPT from 12 hpf to 96 hpf resulting in 136 and 750 genes differentially expressed, respectively. The results of gene ontology (GO) analysis and the Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis illustrated that a large amount of differentially expressed genes (DEGs) were involved in the antioxidant system, the immune system and the nervous system. RT-qPCR was applied to validate the results of RNA-seq, which provided direct evidence that the selected genes involved in those systems mentioned above were all down-regulated. Acetylcholinesterase (AChE), lysozyme (LZM) and the content of C-reactive protein (CRP) were decreased at the end of exposure, which is consistent with the transcriptomics results. The overall results of this study demonstrate that GPT simultaneously affects various vital functionalities of zebrafish at early developmental stage, even at environmentally relevant concentrations.
ESTHER : He_2019_Environ.Pollut_251_746
PubMedSearch : He_2019_Environ.Pollut_251_746
PubMedID: 31121539

Title : Vitamin E Ameliorates Lipid Metabolism in Mice with Nonalcoholic Fatty Liver Disease via Nrf2\/CES1 Signaling Pathway - He_2019_Dig.Dis.Sci_64_3182
Author(s) : He W , Xu Y , Ren X , Xiang D , Lei K , Zhang C , Liu D
Ref : Digestive Diseases & Sciences , 64 :3182 , 2019
Abstract : BACKGROUND: Vitamin E has been reported to have a beneficial effect on nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanism of action has not yet been clearly defined. AIM: We aimed to evaluate the effects and mechanisms of vitamin E on lipid and glucose homeostasis both in vivo and in vitro. METHODS: An NAFLD model was established in C57BL/6 mice fed a 30% fructose solution for 8 weeks. Subsequently, NAFLD mice were given vitamin E (70 mg/kg) for 2 weeks. In addition, L02 cells were treated with 5 mM fructose and 100 nM vitamin E to explore the potential mechanisms of action. RESULTS: Vitamin E reversed the impaired glucose tolerance of fructose-treated mice. Histopathological examination showed that liver steatosis was significantly relieved in vitamin E-treated mice. These effects may be attributed to the upregulation of nuclear factor erythroid-2-related factor 2 (Nrf2), carboxylesterase 1 (CES1), and downregulated proteins involved in lipid synthesis by vitamin E treatment. In vivo, vitamin E also significantly reduced lipid accumulation in fructose-treated L02 cells, and the Nrf2 inhibitor ML385 reversed the protective effects of vitamin E. CONCLUSION: These data indicated that the therapeutic effects of vitamin E on lipid and glucose homeostasis may be associated with activation of the Nrf2/CES1 signaling pathway.
ESTHER : He_2019_Dig.Dis.Sci_64_3182
PubMedSearch : He_2019_Dig.Dis.Sci_64_3182
PubMedID: 31076985

Title : Structural and functional analyses of the lipase CinB from Enterobacter asburiae - Shang_2019_Biochem.Biophys.Res.Commun_519_274
Author(s) : Shang F , Lan J , Liu W , Chen Y , Wang L , Zhao J , Chen J , Gao P , Ha NC , Quan C , Nam KH , Xu Y
Ref : Biochemical & Biophysical Research Communications , 519 :274 , 2019
Abstract : Lipases are widely present in various plants, animals and microorganisms, constituting a large category of enzymes. They have the ability to catalyze the cleavage of ester bonds. The lipase CinB from Enterobacter asburiae (E. asburiae) is an acetyl esterase. The primary amino acid sequence suggests that the EaCinB protein belongs to the alpha/beta-hydrolase (ABH) superfamily of the esterase/lipase superfamily. However, its molecular functions have not yet been determined. Here, we report the crystal structure of E. asburiae CinB at a 1.45A resolution. EaCinB contains a signal peptide, cap domain and catalytic domain. The active site of EaCinB contains the catalytic triad (Ser180-His307-Asp277) on the catalytic domain. The oxyanion hole is composed of Gly106 and Gly107 within the conserved sequence motif HGGG (amino acid residues 106-109). The substrate is accessible between the alpha1 and alpha2 helices or the alpha1 helix and catalytic domain. Narrow substrate pockets are formed by the alpha2 helix of the cap domain. Site-directed mutagenesis showed that EaCinB-W208H exhibits a higher catalytic ability than EaCinB-WT by approximately nine times. Our results provide insight into the molecular function of EaCinB.
ESTHER : Shang_2019_Biochem.Biophys.Res.Commun_519_274
PubMedSearch : Shang_2019_Biochem.Biophys.Res.Commun_519_274
PubMedID: 31493870
Gene_locus related to this paper: entas-cinB

Title : Discovery of delta-sultone-fused pyrazoles for treating Alzheimer's disease: Design, synthesis, biological evaluation and SAR studies - Xu_2019_Eur.J.Med.Chem_181_111598
Author(s) : Xu Y , Zhang Z , Jiang X , Chen X , Wang Z , Alsulami H , Qin HL , Tang W
Ref : Eur Journal of Medicinal Chemistry , 181 :111598 , 2019
Abstract : A class of novel delta-sulfonolactone-fused pyrazole scaffold was prepared via sulfur (VI) fluoride exchange (SuFEx) chemistry using aryl sulfonyl fluorides and pyrazolones. Enzyme screening revealed their cholinesterase inhibitory activity, among them, compounds 4a, 5a and 5d were identified as highly selective submicromolar BuChE inhibitors (IC50=0.20, 0.46 and 0.42muM, respectively), which exhibited nontoxicity, lipophilicity and remarkable neuroprotective activity. Kinetic studies showed that BuChE inhibition of compounds 5a and 5d was reversible, mixed-type and non-competitive inhibition against BuChE (Ki=145nM and 60nM, respectively). Compound 5d can be accommodated into hBuChE via pi-S interaction and hydrophobic interactions. The title compounds are potentially symptomatic treatment in progressive Alzheimer's disease.
ESTHER : Xu_2019_Eur.J.Med.Chem_181_111598
PubMedSearch : Xu_2019_Eur.J.Med.Chem_181_111598
PubMedID: 31415981

Title : Preparation of lipase cross-linked enzyme aggregates in octyl-modified mesocellular foams - Jin_2019_Int.J.Biol.Macromol_130_342
Author(s) : Jin W , Xu Y , Yu XW
Ref : Int J Biol Macromol , 130 :342 , 2019
Abstract : Lipase r27RCL from Rhizopus chinensis was immobilized onto octyl-modified mesocellular foams (MCFs-C8) via two-step process of enzyme adsorption and cross-linking. Oxidized gum arabic was used as substitute for harmful glutaraldehyde to improve catalytic performance of immobilized enzyme for catalysis in non-aqueous phase. The parameters like aldehyde concentration, cross-linking time were optimized. Cross-linked enzyme aggregates (CLEAs) of lipase r27RCL prepared in MCFs-C8 by using oxidized gum arabic (GA-CLEAs@MCFs-C8) showed the highest esterification activity (145 micromol min(-1) mg(-1) protein) compared with lipase adsorbed onto MCFs-C8 (MCFs-C8-r27RCL) (98 micromol min(-1) mg(-1) protein), CLEAs of lipase in MCFs-C8 by glutaraldehyde (G-CLEAs@MCFs-C8) (88 micromol min(-1) mg(-1) protein) and immobilized lipase onto octyl/epoxy (1,1, v/v) modified MCFs (MCFs-octyl-epoxy-r27RCL) (35 micromol min(-1) mg(-1) protein). Moreover, GA-CLEAs@MCFs-C8 exhibited excellent thermal and mechanical stability, and could still maintain 69% of initial activity after 5 time cycles.
ESTHER : Jin_2019_Int.J.Biol.Macromol_130_342
PubMedSearch : Jin_2019_Int.J.Biol.Macromol_130_342
PubMedID: 30825565

Title : Synthesis of cocoa butter substitutes from Cinnamomum camphora seed oil and fully hydrogenated palm oil by enzymatic interesterification - Ma_2019_J.Food.Sci.Technol_56_835
Author(s) : Ma X , Hu Z , Mao J , Xu Y , Zhu X , Xiong H
Ref : J Food Sci Technol , 56 :835 , 2019
Abstract : Cinnamomum camphora trees have a vast range of distribution in southern China and the seed oil has unique fatty acid (FA) properties and various bio-activities. In this work, Cinnamomum camphora seed oil (CCSO) was utilized to synthesize value-added cocoa butter substitute (CBS) by enzymatic interesterification. The synthesis was conducted in a solvent-free system by blending CCSO with fully hydrogenated palm oil under the catalysis of Lipozyme RM IM. The reacted products were assessed with physicochemical properties, i.e. FA composition, slip melting point (SMP), triacylglycerol (TAG), crystal polymorphism, microstructure, melting and crystallization properties and solid fat content (SFC). It showed that MCFAs (capric acid plus lauric acid) was the main fatty acid in products, accounting for over 45%. Comparing to physical blends, some novel TAG species such as LaLaLa and LaMLa/LaLaM were observed after enzymatic interesterification whereas SSS TAGs were reduced. IP presented a ball-like, well-distributed and nearly round crystal microstructure and a smaller crystal size. Moreover, it should be mentioned that SFC of IP ranging from 31.85 to 38.47% at 25 degreeC with most beta' crystal forms, was beneficial to improve the spreadability in term of confectionery products and baked goods. The SMP of the interesterified products was 35.75-36.15 degreeC which closed to the commercial CBS. Hence, the products synthesized can be used to as CBS, and the results in this study also showed CCSO have value-added applications.
ESTHER : Ma_2019_J.Food.Sci.Technol_56_835
PubMedSearch : Ma_2019_J.Food.Sci.Technol_56_835
PubMedID: 30906041

Title : Ultrasensitive and visible light-responsive photoelectrochemical aptasensor for edifenphos based on Zinc phthalocyanine sensitized MoS2 nanosheets - Ding_2019_Biosens.Bioelectron__111867
Author(s) : Ding L , Jiang D , Wen Z , Xu Y , Guo Y , Ding C , Wang K
Ref : Biosensors & Bioelectronics , :111867 , 2019
Abstract : Developing a simple, rapid detection method for the analysis of edifenphos (EDI) is crucial due to its residue is harmful to acetylcholinesterase on the human cellular system, and cause a lot of complications. Herein, we synthesized visible light-responsive MoS2 nanosheets decorated with Zinc phthalocyanine (ZnPc) nanoparticles (ZnPc/n-MoS2). Due to the sensitization of ZnPc nanoparticles, the resulting ZnPc/n-MoS2 exhibited narrower energy bandgap and efficient charge transfer. Especially, the carrier lifetime of ZnPc/n-MoS2 is 2 more times longer than n-MoS2, and the photocurrent intensity of ZnPc/n-MoS2 is 24 times of n-MoS2 and 22 times of ZnPc nanoparticles under visible light irradiation. Further, a visible light-responsive ultrasensitive photoelectrochemical (PEC) aptasensor for selectivity recognition of EDI was triumphantly established by using EDI aptamer as a biorecognition element, which exhibited a wide linear ranking from 5ngL(-1) to 10mugL(-1) (R(2)=0.996) and a low detection limit of 1.667ngL(-1) (S/N=3). The splendid performance of the ZnPc/n-MoS2 nanosheet ultrasensitive sensing platform can be applied to detect the concentration of EDI in food, biomedical and environmental analysis.
ESTHER : Ding_2019_Biosens.Bioelectron__111867
PubMedSearch : Ding_2019_Biosens.Bioelectron__111867
PubMedID: 31748191

Title : Synthesis, preliminarily biological evaluation and molecular docking study of new Olaparib analogues as multifunctional PARP-1 and cholinesterase inhibitors - Gao_2019_J.Enzyme.Inhib.Med.Chem_34_150
Author(s) : Gao CZ , Dong W , Cui ZW , Yuan Q , Hu XM , Wu QM , Han X , Xu Y , Min ZL
Ref : J Enzyme Inhib Med Chem , 34 :150 , 2019
Abstract : A series of new Olaparib derivatives was designed and synthesized, and their inhibitory activities against poly (ADP-ribose) polymerases-1 (PARP-1) enzyme and cancer cell line MDA-MB-436 in vitro were evaluated. The results showed that compound 5l exhibited the most potent inhibitory effects on PARP-1 enzyme (16.10 +/- 1.25 nM) and MDA-MB-436 cancer cell (11.62 +/- 2.15 muM), which was close to that of Olaparib. As a PARP-1 inhibitor had been reported to be viable to neuroprotection, in order to search for new multitarget-directed ligands (MTDLs) for the treatment of Alzheimer's disease (AD), the inhibitory activities of the synthesized compounds against the enzymes AChE (from electric eel) and BChE (from equine serum) were also tested. Compound 5l displayed moderate BChE inhibitory activity (9.16 +/- 0.91 muM) which was stronger than neostigmine (12.01 +/- 0.45 muM) and exhibited selectivity for BChE over AChE to some degree. Molecular docking studies indicated that 5l could bind simultaneously to the catalytic active of PARP-1, but it could not interact well with huBChE. For pursuit of PARP-1 and BChE dual-targeted inhibitors against AD, small and flexible non-polar groups introduced to the compound seemed to be conducive to improving its inhibitory potency on huBChE, while keeping phthalazine-1-one moiety unchanged which was mainly responsible for PARP-1 inhibitory activity. Our research gave a clue to search for new agents based on AChE and PARP-1 dual-inhibited activities to treat Alzheimer's disease.
ESTHER : Gao_2019_J.Enzyme.Inhib.Med.Chem_34_150
PubMedSearch : Gao_2019_J.Enzyme.Inhib.Med.Chem_34_150
PubMedID: 30427217

Title : High-level expression of Aspergillus niger lipase in Pichia pastoris: Characterization and gastric digestion in vitro - Zhang_2019_Food.Chem_274_305
Author(s) : Zhang XF , Ai YH , Xu Y , Yu XW
Ref : Food Chem , 274 :305 , 2019
Abstract : The low expression level of acidic lipases from Aspergillus sp. remains a major obstacle for their use in industrial applications. In this study, fusion expression with three fusion partners was investigated to enhance the expression level of an acidic lipase from A. niger (ANL) in Pichia pastoris. When fused with a small ubiquitin-related modifier (SUMO), designated SANL, the highest activity reached 960+/-40U/mL in a 3L fermenter, which was 1.85-fold higher than that of the parent ANL. SANL exhibited its maximum activity at pH 2.5 and had lower Km and higher kcat/Km values than those of ANL. In gastrointestinal digestion experiments, SANL was resistant to pepsin and had high hydrolytic activity against triolein from pH 3.0 to 6.0. However, SANL was significantly inhibited by NaTDC above its CMC, which may limit its application for intestinal digestion, but allow it to remain suitable for gastric digestion.
ESTHER : Zhang_2019_Food.Chem_274_305
PubMedSearch : Zhang_2019_Food.Chem_274_305
PubMedID: 30372943

Title : Structural insight into the carboxylesterase BioH from Klebsiella pneumoniae - Wang_2019_Biochem.Biophys.Res.Commun_520_538
Author(s) : Wang L , Chen Y , Shang F , Liu W , Lan J , Gao P , Ha NC , Nam KH , Dong Y , Quan C , Xu Y
Ref : Biochemical & Biophysical Research Communications , 520 :538 , 2019
Abstract : The BioH carboxylesterase which is a typical alpha/beta-hydrolase enzyme involved in biotin synthetic pathway in most bacteria. BioH acts as a gatekeeper and blocks the further elongation of its substrate. In the pathogen Klebsiella pneumoniae, BioH plays a critical role in the biosynthesis of biotin. To better understand the molecular function of BioH, we determined the crystal structure of BioH from K. pneumoniae at 2.26A resolution using X-ray crystallography. The structure of KpBioH consists of an alpha-beta-alpha sandwich domain and a cap domain. B-factor analysis revealed that the alpha-beta-alpha sandwich domain is a rigid structure, while the loops in the cap domain shows the structural flexibility. The active site of KpBioH contains the catalytic triad (Ser82-Asp207-His235) on the interface of the alpha-beta-alpha sandwich domain, which is surrounded by the cap domain. Size exclusion chromatography shows that KpBioH prefers the monomeric state in solution, whereas two-fold symmetric dimeric formation of KpBioH was observed in the asymmetric unit, the conserved Cys31-based disulfide bonds can maintain the irreversible dimeric formation of KpBioH. Our study provides important structural insight for understanding the molecular mechanisms of KpBioH and its homologous proteins.
ESTHER : Wang_2019_Biochem.Biophys.Res.Commun_520_538
PubMedSearch : Wang_2019_Biochem.Biophys.Res.Commun_520_538
PubMedID: 31615653
Gene_locus related to this paper: klep3-bioh

Title : Musa balbisiana genome reveals subgenome evolution and functional divergence - Wang_2019_Nat.Plants_5_810
Author(s) : Wang Z , Miao H , Liu J , Xu B , Yao X , Xu C , Zhao S , Fang X , Jia C , Wang J , Zhang J , Li J , Xu Y , Ma W , Wu Z , Yu L , Yang Y , Liu C , Guo Y , Sun S , Baurens FC , Martin G , Salmon F , Garsmeur O , Yahiaoui N , Hervouet C , Rouard M , Laboureau N , Habas R , Ricci S , Peng M , Guo A , Xie J , Li Y , Ding Z , Yan Y , Tie W , D'Hont A , Hu W , Jin Z
Ref : Nat Plants , 5 :810 , 2019
Abstract : Banana cultivars (Musa ssp.) are diploid, triploid and tetraploid hybrids derived from Musa acuminata and Musa balbisiana. We presented a high-quality draft genome assembly of M. balbisiana with 430 Mb (87%) assembled into 11 chromosomes. We identified that the recent divergence of M. acuminata (A-genome) and M. balbisiana (B-genome) occurred after lineage-specific whole-genome duplication, and that the B-genome may be more sensitive to the fractionation process compared to the A-genome. Homoeologous exchanges occurred frequently between A- and B-subgenomes in allopolyploids. Genomic variation within progenitors resulted in functional divergence of subgenomes. Global homoeologue expression dominance occurred between subgenomes of the allotriploid. Gene families related to ethylene biosynthesis and starch metabolism exhibited significant expansion at the pathway level and wide homoeologue expression dominance in the B-subgenome of the allotriploid. The independent origin of 1-aminocyclopropane-1-carboxylic acid oxidase (ACO) homoeologue gene pairs and tandem duplication-driven expansion of ACO genes in the B-subgenome contributed to rapid and major ethylene production post-harvest in allotriploid banana fruits. The findings of this study provide greater context for understanding fruit biology, and aid the development of tools for breeding optimal banana cultivars.
ESTHER : Wang_2019_Nat.Plants_5_810
PubMedSearch : Wang_2019_Nat.Plants_5_810
PubMedID: 31308504
Gene_locus related to this paper: musam-m0tuu7 , musam-a0a804kav5

Title : Comparative transcriptome profiling reveals candidate genes related to insecticide resistance of Glyphodes pyloalis - Su_2019_Bull.Entomol.Res__1
Author(s) : Su H , Gao Y , Liu Y , Li X , Liang Y , Dai X , Xu Y , Zhou Y , Wang H
Ref : Bull Entomol Res , :1 , 2019
Abstract : Glyphodes pyloalis Walker (Lepidoptera: Pyralididae) is a common pest in sericulture and has developed resistance to different insecticides. However, the mechanisms involved in insecticide resistance of G. pyloalis are poorly understood. Here, we present the first whole-transcriptome analysis of differential expression genes in insecticide-resistant and susceptible G. pyloalis. Clustering and enrichment analysis of DEGs revealed several biological pathways and enriched Gene Ontology terms were related to detoxification or insecticide resistance. Genes involved in insecticide metabolic processes, including cytochrome P450, glutathione S-transferases and carboxylesterase, were identified in the larval midgut of G. pyloalis. Among them, CYP324A19, CYP304F17, CYP6AW1, CYP6AB10, GSTs5, and AChE-like were significantly increased after propoxur treatment, while CYP324A19, CCE001c, and AChE-like were significantly induced by phoxim, suggesting that these genes were involved in insecticide metabolism. Furthermore, the sequence variation analysis identified 21 single nucleotide polymorphisms within CYP9A20, CYP6AB47, and CYP6AW1. Our findings reveal many candidate genes related to insecticide resistance of G. pyloalis. These results provide novel insights into insecticide resistance and facilitate the development of insecticides with greater specificity to G. pyloalis.
ESTHER : Su_2019_Bull.Entomol.Res__1
PubMedSearch : Su_2019_Bull.Entomol.Res__1
PubMedID: 31217039

Title : Genome-wide association studies reveal genetic loci associated with plasma cholinesterase activity in ducks - Xu_2019_Anim.Genet_50_287
Author(s) : Xu Y , Liu H , Jiang Y , Fan W , Hu J , Zhang Y , Guo Z , Xie M , Huang W , Liu X , Zhou Z , Hou S
Ref : Anim Genet , 50 :287 , 2019
Abstract : Plasma cholinesterase (PCHE) activity is an important auxiliary test in human clinical medicine. It can distinguish liver diseases from non-liver diseases and help detect organophosphorus poisoning. Animal experiments have confirmed that PCHE activity is associated with obesity and hypertension and changes with physiological changes in an animal's body. The objective of this study was to locate the genetic loci responsible for PCHE activity variation in ducks. PCHE activity of Pekin duck x mallard F2 ducks at 3 and 8 weeks of age were analyzed, and genome-wide association studies were conducted. A region of about 1.5 Mb (21.8-23.3 Mb) on duck chromosome 9 was found to be associated with PCHE activity at both 3 and 8 weeks of age. The top SNP, g.22643979C>T in the butyrylcholinesterase (BCHE) gene, was most highly associated with PCHE activity at 3 weeks (-logP = 21.45) and 8 weeks (-logP = 27.60) of age. For the top SNP, the strong associations of CC and CT genotypes with low PCHE activity and the TT genotype with high PCHE activity indicates the dominant inheritance of low PCHE activity. Problems with block inheritance or linkage exist in this region. This study supports that BCHE is a functional gene for determining PCHE levels in ducks and that the genetic variations around this gene can cause phenotypic variations of PCHE activity.
ESTHER : Xu_2019_Anim.Genet_50_287
PubMedSearch : Xu_2019_Anim.Genet_50_287
PubMedID: 30994195
Gene_locus related to this paper: anapl-BCHE

Title : Structural Basis by Which the N-Terminal Polypeptide Segment of Rhizopus chinensis Lipase Regulates Its Substrate Binding Affinity - Zhang_2019_Biochemistry_58_3943
Author(s) : Zhang M , Yu XW , Xu Y , Guo RT , Swapna GVT , Szyperski T , Hunt JF , Montelione GT
Ref : Biochemistry , 58 :3943 , 2019
Abstract : Members of an important group of industrial enzymes, Rhizopus lipases, exhibit valuable hydrolytic features that underlie their biological functions. Particularly important is their N-terminal polypeptide segment (NTPS), which is required for secretion and proper folding but is removed in the process of enzyme maturation. A second common feature of this class of lipases is the alpha-helical "lid", which regulates the accessibility of the substrate to the enzyme active site. Some Rhizopus lipases also exhibit "interfacial activation" by micelle and/or aggregate surfaces. While it has long been recognized that the NTPS is critical for function, its dynamic features have frustrated efforts to characterize its structure by X-ray crystallography. Here, we combine nuclear magnetic resonance spectroscopy and X-ray crystallography to determine the structure and dynamics of Rhizopus chinensis lipase (RCL) with its 27-residue NTPS prosequence (r27RCL). Both r27RCL and the truncated mature form of RCL (mRCL) exhibit biphasic interfacial activation kinetics with p-nitrophenyl butyrate (pNPB). r27RCL exhibits a substrate binding affinity significantly lower than that of mRCL due to stabilization of the closed lid conformation by the NTPS. In contrast to previous predictions, the NTPS does not enhance lipase activity by increasing surface hydrophobicity but rather inhibits activity by forming conserved interactions with both the closed lid and the core protein structure. Single-site mutations and kinetic studies were used to confirm that the NTPS serves as internal competitive inhibitor and to develop a model of the associated process of interfacial activation. These structure-function studies provide the basis for engineering RCL lipases with enhanced catalytic activities.
ESTHER : Zhang_2019_Biochemistry_58_3943
PubMedSearch : Zhang_2019_Biochemistry_58_3943
PubMedID: 31436959
Gene_locus related to this paper: rhich-a3fm73

Title : Rational Design of Novel Selective Dual-Target Inhibitors of Acetylcholinesterase and Monoamine Oxidase B as Potential Anti-Alzheimer's Disease Agents - Xu_2019_ACS.Chem.Neurosci_10_482
Author(s) : Xu Y , Zhang J , Wang H , Mao F , Bao K , Liu W , Zhu J , Li X , Zhang H , Li J
Ref : ACS Chem Neurosci , 10 :482 , 2019
Abstract : Multifunctional agents aiming at cholinesterases (ChEs) and monoamine oxidases (MAOs) are promising therapy for Alzheimer's disease (AD). Herein, a series of novel propargylamine-modified pyrimidinylthiourea derivatives (1-4) were designed and synthesized as dual inhibitors of ChEs and MAOs with other functions against AD. Most of these derivatives inhibited ChEs and MAOs with IC50 values in the micro- or nanomolar ranges. Compound 1c displayed the dual functional profile of targeting the AChE (IC50 = 0.032 +/- 0.007 muM) and MAO-B (IC50 = 2.117 +/- 0.061 muM), along with the improved blood-brain barrier (BBB) permeability, antioxidant ability, and good copper chelating property in vitro. Animal studies showed that compound 1c.HCl could inhibit the cerebral AChE/MAO-B activities and alleviate scopolamine-induced cognitive impairment in mice. Combined with good oral bioavailability ( F = 45.55%), these findings demonstrated that compound 1c may be a potent brain permeable multifunctional candidate for the treatment of AD.
ESTHER : Xu_2019_ACS.Chem.Neurosci_10_482
PubMedSearch : Xu_2019_ACS.Chem.Neurosci_10_482
PubMedID: 30110536

Title : FSH1 regulates the phenotype and pathogenicity of the pathogenic dermatophyte Microsporum canis - Zhang_2019_Int.J.Mol.Med_44_2047
Author(s) : Zhang F , Tan C , Xu Y , Yang G
Ref : Int J Mol Med , 44 :2047 , 2019
Abstract : Microsporum canis (M. canis) is a common pathogen that causes tinea capitis and is present worldwide. The incidence of M. canis infection, particularly tinea capitis, has been increasing in China. In our previous studies, family of serine hydrolases 1 (FSH1) was identified as a potential virulence factor in tinea capitis infection caused by M. canis. To determine the function of this gene in M. canis, FSH1 was knocked down using doublestranded RNA interference mediated by Agrobacterium tumefaciens. Reverse transcriptionquantitative PCR analysis was used to confirm gene knockdown. Loss of FSH1 expression by RNAi resulted in a minor phenotype alteration, but M. canis pathogenicity in guinea pig cutaneous infection was decreased compared with the wildtype strain. To the best of our knowledge, the present study is the first to demonstrate that FSH1 is associated with macroconidia septa formation and is an important contributor to M. canis virulence. These findings may advance the understanding of the function of the FSH1 gene and provide a foundation for future studies on macroconidia septa formation and pathogenicity of M. canis.
ESTHER : Zhang_2019_Int.J.Mol.Med_44_2047
PubMedSearch : Zhang_2019_Int.J.Mol.Med_44_2047
PubMedID: 31573050
Gene_locus related to this paper: artot-a0a516ux40

Title : Triazole Ureas Covalently Bind to Strigolactone Receptor and Antagonize Strigolactone Responses - Nakamura_2019_Mol.Plant_12_44
Author(s) : Nakamura H , Hirabayashi K , Miyakawa T , Kikuzato K , Hu W , Xu Y , Jiang K , Takahashi I , Niiyama R , Dohmae N , Tanokura M , Asami T
Ref : Mol Plant , 12 :44 , 2019
Abstract : Strigolactones, a class of plant hormones with multiple functions, mediate plant-plant and plant-microorganism communications in the rhizosphere. In this study, we developed potent strigolactone antagonists, which covalently bind to the strigolactone receptor D14, by preparing an array of triazole urea compounds. Using yeast two-hybrid and rice-tillering assays, we identified a triazole urea compound KK094 as a potent inhibitor of strigolactone receptors. Liquid chromatography-tandem mass spectrometry analysis and X-ray crystallography revealed that KK094 was hydrolyzed by D14, and that a reaction product of this degradation covalently binds to the Ser residue of the catalytic triad of D14. Furthermore, we identified two triazole urea compounds KK052 and KK073, whose effects on D14-D53/D14-SLR1 complex formation were opposite due to the absence (KK052) or presence (KK073) of a trifluoromethyl group on their phenyl ring. These results demonstrate that triazole urea compounds are potentially powerful tools for agricultural application and may be useful for the elucidation of the complicated mechanism underlying strigolactone perception.
ESTHER : Nakamura_2019_Mol.Plant_12_44
PubMedSearch : Nakamura_2019_Mol.Plant_12_44
PubMedID: 30391752
Gene_locus related to this paper: orysj-Q10QA5

Title : Characterization of a novel deep-sea microbial esterase EstC10 and its use in the generation of (R)-methyl2-chloropropionate - Gong_2018_J.Ocean.Limnol_36_473
Author(s) : Gong Y , Ma S , Wang Y , Xu Y , Sun A , Zhang Y , Hu Y
Ref : J Ocean Limnol , 36 :473 , 2018
Abstract : A novel esterase EstC10 from Bacillus sp. CX01 isolated from the deep sea of the Western Pacific Ocean and the functionalities of EstC10 was characterized. At present, the reports about the kinetic resolution of racemic methyl 2-chloropropionate were quite rare. So we developed deep-sea microbial esterase EstC10 as a novel biocatalyst in the kinetic resolution of racemic methyl 2-chloropropionate and generate (R)-methyl 2-chloropropionate with high enantiomeric excess (>99%) after the optimization of process parameters such as pH, temperature, organic co-solvents, surfactants, substrate concentration and reaction time. Notably, the optimal substrate concentration (80 mmol/L) of esterase EstC10 was higher than the kinetic resolution of another esterase, Est12-7 (50 mmol/L). The novel microbial esterase EstC10 identified from the deep sea was a promising green biocatalyst in the generation of (R)-methyl 2-chloropropionate as well of many other valuable chiral chemicals in industry.
ESTHER : Gong_2018_J.Ocean.Limnol_36_473
PubMedSearch : Gong_2018_J.Ocean.Limnol_36_473
PubMedID:
Gene_locus related to this paper: bacld-q65eq1

Title : Structural analysis of HTL and D14 proteins reveals the basis for ligand selectivity in Striga - Xu_2018_Nat.Commun_9_3947
Author(s) : Xu Y , Miyakawa T , Nosaki S , Nakamura A , Lyu Y , Nakamura H , Ohto U , Ishida H , Shimizu T , Asami T , Tanokura M
Ref : Nat Commun , 9 :3947 , 2018
Abstract : HYPOSENSITIVE TO LIGHT (HTL) and DWARF14 (D14) mediate the perception of karrikin and strigolactone, which stimulates germination of the parasitic weed Striga. However, their role in parasitic seeds is poorly understood, and the basis for their differing responsiveness remains unclear. Here, we show that Striga hermonthica HTL proteins (ShHTLs) in 'conserved' and 'intermediate' clades are able to bind karrikin. The 'divergent' clade is able to hydrolyze strigolactone. Unexpectedly, we find that ShD14 is also capable of hydrolyzing strigolactone. Through comparative analysis of ShHTLs and ShD14 crystal structures, we provide insights into the basis for their selectivity. Moreover, we show that both ShD14 and divergent clade ShHTLs, but not conserved and intermediate clade ShHTLs, can interact with the putative downstream signaling component ShMAX2 in the presence of the synthetic strigolactone, rac-GR24. These findings provide insight into how strigolactone is perceived and how ligand specificity is determined.
ESTHER : Xu_2018_Nat.Commun_9_3947
PubMedSearch : Xu_2018_Nat.Commun_9_3947
PubMedID: 30258184
Gene_locus related to this paper: strhe-ShD14 , strhe-ShHTL4 , strhe-ShHTL1 , strhe-ShHTL7

Title : Butyrylcholinesterase Levels on Admission Predict Severity and 12-Month Mortality in Hospitalized AIDS Patients - Xu_2018_Mediators.Inflamm_2018_5201652
Author(s) : Xu L , Zhu B , Huang Y , Yang Z , Sun J , Xu Y , Zheng J , Kinloch S , Yin MT , Weng H , Wu N
Ref : Mediators Inflamm , 2018 :5201652 , 2018
Abstract : Background: Butyrylcholinesterase (BChE) is synthesized mainly in the liver and an important marker in many infectious/inflammatory diseases, but its role in acquired immunodeficiency syndrome (AIDS) patients is not clear. We wished to ascertain if BChE level is associated with the progression/prognosis of AIDS patients. Methods: BChE levels (in U/L) were measured in 505 patients; <4500 was defined as "low" and >/=4500 as "normal." Associations between BChE level and CD4 count, WHO stage, body mass index (BMI), C-reactive protein (CRP) level, and duration of hospitalization were assessed. Kaplan-Meier curves and Cox proportional hazards model were used to assess associations between low BChE levels and mortality, after adjustment for age, CD4 count, WHO stage, and laboratory parameters. Results: A total of 129 patients (25.5%) had a lower BChE level. BChE was closely associated with CD4 count, WHO stage, CRP level, and BMI (all P < 0.001). Eighty-four patients (16.6%) died in the first year of follow-up. One-year survival was 64.5 +/- 4.5% for patients with low BChE and 87.6 +/- 1.8% for those with normal BChE (log-rank, P < 0.001). After adjustment for sex, age, BMI, WHO stage, and CD4 count, as well as serum levels of hemoglobin, sodium, and albumin, the hazard ratio was 1.8 (95% confidence interval, 1.0-3.2) for patients with a low BChE compared with those with a normal BChE (P = 0.035). Conclusion: BChE level is associated with HIV/AIDS severity and is an independent risk factor for increased mortality in AIDS patients.
ESTHER : Xu_2018_Mediators.Inflamm_2018_5201652
PubMedSearch : Xu_2018_Mediators.Inflamm_2018_5201652
PubMedID: 29736152

Title : Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease - Mao_2018_ACS.Chem.Neurosci_9_328
Author(s) : Mao F , Wang H , Ni W , Zheng X , Wang M , Bao K , Ling D , Li X , Xu Y , Zhang H , Li J
Ref : ACS Chem Neurosci , 9 :328 , 2018
Abstract : Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w.Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.
ESTHER : Mao_2018_ACS.Chem.Neurosci_9_328
PubMedSearch : Mao_2018_ACS.Chem.Neurosci_9_328
PubMedID: 29068218

Title : Enhanced lincomycin production by co-overexpression of metK1 and metK2 in Streptomyces lincolnensis - Xu_2018_J.Ind.Microbiol.Biotechnol_45_345
Author(s) : Xu Y , Tan G , Ke M , Li J , Tang Y , Meng S , Niu J , Wang Y , Liu R , Wu H , Bai L , Zhang L , Zhang B
Ref : J Ind Microbiol Biotechnol , 45 :345 , 2018
Abstract : Streptomyces lincolnensis is generally utilized for the production of lincomycin A (Lin-A), a clinically useful antibiotic to treat Gram-positive bacterial infections. Three methylation steps, catalyzed by three different S-adenosylmethionine (SAM)-dependent methyltransferases, are required in the biosynthesis of Lin-A, and thus highlight the significance of methyl group supply in lincomycin production. In this study, we demonstrate that externally supplemented SAM cannot be taken in by cells and therefore does not enhance Lin-A production. Furthermore, bioinformatics and in vitro enzymatic assays revealed there exist two SAM synthetase homologs, MetK1 (SLCG_1651) and MetK2 (SLCG_3830) in S. lincolnensis that could convert L-methionine into SAM in the presence of ATP. Even though we attempted to inactivate metK1 and metK2, only metK2 was deleted in S. lincolnensis LCGL, named as DeltametK2. Following a reduction of the intracellular SAM concentration, DeltametK2 mutant exhibited a significant decrease of Lin-A in comparison to its parental strain. Individual overexpression of metK1 or metK2 in S. lincolnensis LCGL either elevated the amount of intracellular SAM, concomitant with 15% and 22% increase in Lin-A production, respectively. qRT-PCR assays showed that overexpression of either metK1 or metK2 increased the transcription of lincomycin biosynthetic genes lmbA and lmbR, and regulatory gene lmbU, indicating SAM may also function as a transcriptional activator. When metK1 and metK2 were co-expressed, Lin-A production was increased by 27% in LCGL, while by 17% in a high-yield strain LA219X.
ESTHER : Xu_2018_J.Ind.Microbiol.Biotechnol_45_345
PubMedSearch : Xu_2018_J.Ind.Microbiol.Biotechnol_45_345
PubMedID: 29574602
Gene_locus related to this paper: strln-a0a1b1ma73 , strln-a0a1b1m575

Title : YbtT is a low-specificity type II thioesterase that maintains production of the metallophore yersiniabactin in pathogenic enterobacteria - Ohlemacher_2018_J.Biol.Chem_293_19572
Author(s) : Ohlemacher SI , Xu Y , Kober DL , Malik M , Nix JC , Brett TJ , Henderson JP
Ref : Journal of Biological Chemistry , 293 :19572 , 2018
Abstract : Clinical isolates of Yersinia, Klebsiella, and Escherichia coli frequently secrete the small molecule metallophore yersiniabactin (Ybt), which passivates and scavenges transition metals during human infections. YbtT is encoded within the Ybt biosynthetic operon and is critical for full Ybt production in bacteria. However, its biosynthetic function has been unclear because it is not essential for Ybt production by the in vitro reconstituted nonribosomal peptide synthetase/polyketide synthase (NRPS/PKS) pathway. Here, we report the structural and biochemical characterization of YbtT. YbtT structures at 1.4-1.9 A resolution possess a serine hydrolase catalytic triad and an associated substrate chamber with features similar to those previously reported for low-specificity type II thioesterases (TEIIs). We found that YbtT interacts with the two major Ybt biosynthetic proteins, HMWP1 (high-molecular-weight protein 1) and HMWP2 (high-molecular-weight protein 2), and hydrolyzes a variety of aromatic and acyl groups from their phosphopantetheinylated carrier protein domains. In vivo YbtT titration in uropathogenic E. coli revealed a distinct optimum for Ybt production consistent with a tradeoff between clearing both stalled inhibitory intermediates and productive Ybt precursors from HMWP1 and HMWP2. These results are consistent with a model in which YbtT maintains cellular Ybt biosynthesis by removing nonproductive, inhibitory thioesters that form aberrantly at multiple sites on HMWP1 and HMWP2.
ESTHER : Ohlemacher_2018_J.Biol.Chem_293_19572
PubMedSearch : Ohlemacher_2018_J.Biol.Chem_293_19572
PubMedID: 30355735
Gene_locus related to this paper: yerpe-YBTT

Title : Rationally Designed Strigolactone Analogs as Antagonists of the D14 Receptor - Takeuchi_2018_Plant.Cell.Physiol_59_1545
Author(s) : Takeuchi J , Jiang K , Hirabayashi K , Imamura Y , Wu Y , Xu Y , Miyakawa T , Nakamura H , Tanokura M , Asami T
Ref : Plant Cell Physiol , 59 :1545 , 2018
Abstract : Strigolactones (SLs) are plant hormones that inhibit shoot branching and act as signals in communications with symbiotic fungi and parasitic weeds in the rhizosphere. SL signaling is mediated by DWARF14 (D14), which is an alpha/beta-hydrolase that cleaves SLs into an ABC tricyclic lactone and a butenolide group (i.e. D-ring). This cleavage reaction (hydrolysis and dissociation) is important for inducing the interaction between D14 and its target proteins, including D3 and D53. In this study, a hydrolysis-resistant SL analog was predicted to inhibit the activation of the D14 receptor, thereby disrupting the SL signaling pathway. To test this prediction, carba-SL compounds, in which the ether oxygen of the D-ring or the phenol ether oxygen of the SL agonist (GR24 or 4-bromo debranone) was replaced with a methylene group, were synthesized as novel D14 antagonists. Subsequent biochemical and physiological studies indicated that carba-SLs blocked the interaction between D14 and D53 by inhibiting D14 hydrolytic activity. They also suppressed the SL-induced inhibition of rice tiller outgrowths. Additionally, carba-SLs antagonized the SL response in a Striga parasitic weed species. Structural analyses revealed that the D-ring of 7'-carba-4BD was hydrolyzed by D14 but did not dissociate from the 4BD skeleton. Thus, 7'-carba-4BD functioned as an antagonist rather than an agonist. Thus, the hydrolysis of the D-ring of SLs may be insufficient for activating the receptor. This study provides data relevant to designing SL receptor antagonists.
ESTHER : Takeuchi_2018_Plant.Cell.Physiol_59_1545
PubMedSearch : Takeuchi_2018_Plant.Cell.Physiol_59_1545
PubMedID: 29727000
Gene_locus related to this paper: arath-AtD14 , arath-KAI2.D14L

Title : Backbone and Ile-delta1, Leu, Val methyl (1)H, (15)N, and (13)C, chemical shift assignments for Rhizopus chinensis lipase - Zhang_2018_Biomol.NMR.Assign_12_63
Author(s) : Zhang M , Yu XW , Swapna GVT , Liu G , Xiao R , Xu Y , Montelione GT
Ref : Biomol NMR Assign , 12 :63 , 2018
Abstract : Lipase r27RCL is a 296-residue, 33 kDa monomeric enzyme with high ester hydrolysis activity, which has significant applications in the baking, paper and leather industries. The lipase gene proRCL from Rhizopus microsporus var. chinensis (also Rhizopus chinensis) CCTCC M201021 was cloned as a fusion construct C-terminal to a maltose-binding protein (MBP) tag, and expressed as MBP-proRCL in an Escherichia coli BL21 trxB (DE3) expression system with uniform (2)H,(13)C,(15)N-enrichment and Ile-delta1, Leu, and Val (13)CH3 methyl labeling. The fusion protein was hydrolyzed by Kex2 protease at the recognition site Lys-Arg between residues -29 and -28 of the prosequence, producing the enzyme form called r27RCL. Here we report extensive backbone (1)H, (15)N, and (13)C, as well as Ile-delta1, Leu, and Val side chain methyl, NMR resonance assignments for r27RCL.
ESTHER : Zhang_2018_Biomol.NMR.Assign_12_63
PubMedSearch : Zhang_2018_Biomol.NMR.Assign_12_63
PubMedID: 28929427
Gene_locus related to this paper: rhich-a3fm73

Title : Identification and characterization of a novel alkalistable and salt-tolerant esterase from the deep-sea hydrothermal vent of the East Pacific Rise - Yang_2018_Microbiolopen_7_e00601
Author(s) : Yang X , Wu L , Xu Y , Ke C , Hu F , Xiao X , Huang J
Ref : Microbiologyopen , 7 :e00601 , 2018
Abstract : A novel esterase gene selected from metagenomic sequences of deep-sea hydrothermal vents was successfully expressed in Escherichia coli. The recombinant protein (est-OKK), which belongs to the lipolytic enzyme family V, exhibited high activity toward pNP-esters with short acyl chains and especially p-nitrophenyl butyrate. Site-mutagenesis results confirmed that est-OKK contains the nonclassical catalytic tetrad predicted by alignment and computational modeling. The est-OKK protein is a moderately thermophilic enzyme that is relatively thermostable, and highly salt-tolerant, which remained stable in 3 mol/L NaCl for 6 hr. The est-OKK protein showed the considerable alkalistability, displayed optimal activity at pH 9.0 and maintained approximately 70% of its residual activity after incubation at pH 10 for 4 hr. Furthermore, the est-OKK activity was strongly resistant to a variety of metal ions such as Co(2+) , Zn(2+) , Fe(2+) , Na(+) , and K(+) ; nonionic detergents such as Tween-20, Tween-80; and organic solvents such as acetone and isopropanol. Taken together, the novel esterase with unique characteristics may give us a new insight into the family V of lipolytic enzymes, and could be a highly valuable candidate for biotechnological applications such as organic synthesis reactions or food and pharmaceutical industries.
ESTHER : Yang_2018_Microbiolopen_7_e00601
PubMedSearch : Yang_2018_Microbiolopen_7_e00601
PubMedID: 29504251
Gene_locus related to this paper: 9bact-a0a2s1gux0

Title : Molecular cloning, characterization and expression analysis of two juvenile hormone esterase-like carboxylesterase cDNAs in Chinese mitten crab, Eriocheir sinensis - Xu_2017_Comp.Biochem.Physiol.B.Biochem.Mol.Biol_205_46
Author(s) : Xu Y , Zhao M , Deng Y , Yang Y , Li X , Lu Q , Ge J , Pan J , Xu Z
Ref : Comparative Biochemistry & Physiology B Biochem Mol Biol , 205 :46 , 2017
Abstract : Precise regulation of methyl farnesoate (MF) titer is of prime importance throughout the crustacean life-cycle. Although the synthetic pathway of MF is well-documented, little is known about its degradation and recycling in crustaceans. Juvenile hormone esterase-like (JHE-like) carboxylesterase (CXE) is a key enzyme in MF degradation, thus playing a significant role in regulating the MF titer. We identified and characterized two cDNAs, Es-CXE1 and Es-CXE2, encoding JHE-like CXEs in Chinese mitten crab. Full-length cDNAs of Es-CXE1 and Es-CXE2 encode proteins composed of 584 and 597 amino acids, respectively, both of which contain a typical carboxylesterase domain. Alignment and phylogenetic analyses revealed that the Es-CXEs are highly similar to those of other crustaceans. To further validate their functions, we evaluated the mRNA expression patterns of the Es-CXEs in various tissues and in different physiological conditions. Tissue-specific expression analysis showed that the two Es-CXEs were predominantly expressed in the hepatopancreas and ovaries, which are the major tissues for MF metabolism. Es-CXE2 expression levels in the hepatopancreas and ovaries were about 100 and 25-fold higher, than the respective Es-CXE1 expressions. During ovarian rapid development stage, the global expressions of Es-CXEs were up-regulated in the hepatopancreas and down-regulated in the ovaries. After eyestalk ablation (ESA), the mRNA expressions of the two Es-CXEs were up-regulated in the hepatopancreas, further indicating their potential in degrading MF. Taken together, our results suggest that Es-CXEs, the key component of the juvenile hormone degradation pathway, may play vital roles in the development and reproduction of the Chinese mitten crab.
ESTHER : Xu_2017_Comp.Biochem.Physiol.B.Biochem.Mol.Biol_205_46
PubMedSearch : Xu_2017_Comp.Biochem.Physiol.B.Biochem.Mol.Biol_205_46
PubMedID: 28077333
Gene_locus related to this paper: erisi-a0a1l5jht6

Title : Global inactivation of carboxylesterase 1 (Ces1\/Ces1g) protects against atherosclerosis in Ldlr (-\/-) mice - Xu_2017_Sci.Rep_7_17845
Author(s) : Xu J , Xu Y , Yin L , Zhang Y
Ref : Sci Rep , 7 :17845 , 2017
Abstract : Atherosclerotic cardiovascular disease is a leading cause of death in the western world. Increased plasma triglyceride and cholesterol levels are major risk factors for this disease. Carboxylesterase 1 (Ces1/Ces1g) has been shown to play a role in metabolic control. So far, the role of mouse Ces1/Ces1g deficiency in atherosclerosis is not elucidated. We generated Ces1/Ces1g (-/-) mice. Compared to wild-type mice, Ces1/Ces1g (-/-) mice had reduced plasma cholesterol levels. We then generated Ces1g (-/-) Ldlr (-/-) double knockout (DKO) mice, which were fed a Western diet for 16 weeks. Compared to Ldlr (-/-) mice, DKO mice displayed decreased plasma cholesterol and TG levels and reduced atherosclerotic lesions. Interestingly, knockdown of hepatic Ces1/Ces1g in Apoe (-/-) mice resulted in hyperlipidemia and exacerbated Western diet-induced atherogenesis. Mechanistically, global inactivation of Ces1/Ces1g inhibited intestinal cholesterol and fat absorption and Niemann-Pick C1 like 1 expression, and increased macrophage cholesterol efflux by inducing ATP-binding cassette subfamily A member 1 (ABCA1) and ABCG1. Ces1/Ces1g ablation also promoted M2 macrophage polarization and induced hepatic cholesterol 7alpha-hydroxylase and sterol 12alpha-hydroxylase expression. In conclusion, global loss of Ces1/Ces1g protects against the development of atherosclerosis by inhibiting intestinal cholesterol and triglyceride absorption and promoting macrophage cholesterol efflux.
ESTHER : Xu_2017_Sci.Rep_7_17845
PubMedSearch : Xu_2017_Sci.Rep_7_17845
PubMedID: 29259301
Gene_locus related to this paper: mouse-Ces1g

Title : Gorge Motions of Acetylcholinesterase Revealed by Microsecond Molecular Dynamics Simulations - Cheng_2017_Sci.Rep_7_3219
Author(s) : Cheng S , Song W , Yuan X , Xu Y
Ref : Sci Rep , 7 :3219 , 2017
Abstract : Acetylcholinesterase, with a deep, narrow active-site gorge, attracts enormous interest due to its particularly high catalytic efficiency and its inhibitors used for treatment of Alzheimer's disease. To facilitate the massive pass-through of the substrate and inhibitors, "breathing" motions to modulate the size of the gorge are an important prerequisite. However, the molecular mechanism that governs such motions is not well explored. Here, to systematically investigate intrinsic motions of the enzyme, we performed microsecond molecular dynamics simulations on the monomer and dimer of Torpedo californica acetylcholinesterase (TcAChE) as well as the complex of TcAChE bound with the drug E2020. It has been revealed that protein-ligand interactions and dimerization both keep the gorge in bulk, and opening events of the gorge increase dramatically compared to the monomer. Dynamics of three subdomains, S3, S4 and the Omega-loop, are tightly associated with variations of the gorge size while the dynamics can be changed by ligand binding or protein dimerization. Moreover, high correlations among these subdomains provide a basis for remote residues allosterically modulating the gorge motions. These observations are propitious to expand our understanding of protein structure and function as well as providing clues for performing structure-based drug design.
ESTHER : Cheng_2017_Sci.Rep_7_3219
PubMedSearch : Cheng_2017_Sci.Rep_7_3219
PubMedID: 28607438

Title : Structure-Guided Discovery of Novel, Potent, and Orally Bioavailable Inhibitors of Lipoprotein-Associated Phospholipase A2 - Liu_2017_J.Med.Chem_60_10231
Author(s) : Liu Q , Huang F , Yuan X , Wang K , Zou Y , Shen J , Xu Y
Ref : Journal of Medicinal Chemistry , 60 :10231 , 2017
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a promising therapeutic target for atherosclerosis, Alzheimer's disease, and diabetic macular edema. Here we report the identification of novel sulfonamide scaffold Lp-PLA2 inhibitors derived from a relatively weak fragment. Similarity searching on this fragment followed by molecular docking leads to the discovery of a micromolar inhibitor with a 300-fold potency improvement. Subsequently, by the application of a structure-guided design strategy, a successful hit-to-lead optimization was achieved and a number of Lp-PLA2 inhibitors with single-digit nanomolar potency were obtained. After preliminary evaluation of the properties of drug-likeness in vitro and in vivo, compound 37 stands out from this congeneric series of inhibitors for good inhibitory activity and favorable oral bioavailability in male Sprague-Dawley rats, providing a quality candidate for further development. The present study thus clearly demonstrates the power and advantage of integrally employing fragment screening, crystal structures determination, virtual screening, and medicinal chemistry in an efficient lead discovery project, providing a good example for structure-based drug design.
ESTHER : Liu_2017_J.Med.Chem_60_10231
PubMedSearch : Liu_2017_J.Med.Chem_60_10231
PubMedID: 29193967
Gene_locus related to this paper: human-PLA2G7

Title : Novel Vilazodone-Tacrine Hybrids as Potential Multitarget-Directed Ligands for the Treatment of Alzheimer's Disease Accompanied with Depression: Design, Synthesis, and Biological Evaluation - Li_2017_ACS.Chem.Neurosci_8_2708
Author(s) : Li X , Wang H , Xu Y , Liu W , Gong Q , Wang W , Qiu X , Zhu J , Mao F , Zhang H , Li J
Ref : ACS Chem Neurosci , 8 :2708 , 2017
Abstract : Depression is one of the most frequent psychiatric complications of Alzheimer's disease (AD), affecting up to 50% of the patients. A novel series of hybrid molecules were designed and synthesized by combining the pharmacophoric features of vilazodone and tacrine as potential multitarget-directed ligands for the treatment of AD with depression. In vitro biological assays were conducted to evaluate the compounds; among the 30 hybrids, compound 1e showed relatively balanced profiles between acetylcholinesterase inhibition (IC50 = 3.319 +/- 0.708 muM), 5-HT1A agonist (EC50 = 107 +/- 37 nM), and 5-HT reuptake inhibition (IC50 = 76.3 +/- 33 nM). Compound 1e displayed tolerable hepatotoxicity and moderate hERG inhibition activity, and could penetrate the blood-brain barrier in vivo. Furthermore, an oral intake of 30 mg/kg 1e.HCl could significantly improve the cognitive function of scopolamine-induced amnesia mice and alleviate the depressive symptom in tail suspension test. The effectivity of 1e validates the rationality of our design strategy.
ESTHER : Li_2017_ACS.Chem.Neurosci_8_2708
PubMedSearch : Li_2017_ACS.Chem.Neurosci_8_2708
PubMedID: 28872831

Title : Computational Studies on Acetylcholinesterases - Xu_2017_Molecules_22_
Author(s) : Xu Y , Cheng S , Sussman JL , Silman I , Jiang H
Ref : Molecules , 22 : , 2017
Abstract : Functions of biomolecules, in particular enzymes, are usually modulated by structural fluctuations. This is especially the case in a gated diffusion-controlled reaction catalyzed by an enzyme such as acetylcholinesterase. The catalytic triad of acetylcholinesterase is located at the bottom of a long and narrow gorge, but it catalyzes the extremely rapid hydrolysis of the neurotransmitter, acetylcholine, with a reaction rate close to the diffusion-controlled limit. Computational modeling and simulation have produced considerable advances in exploring the dynamical and conformational properties of biomolecules, not only aiding in interpreting the experimental data, but also providing insights into the internal motions of the biomolecule at the atomic level. Given the remarkably high catalytic efficiency and the importance of acetylcholinesterase in drug development, great efforts have been made to understand the dynamics associated with its functions by use of various computational methods. Here, we present a comprehensive overview of recent computational studies on acetylcholinesterase, expanding our views of the enzyme from a microstate of a single structure to conformational ensembles, strengthening our understanding of the integration of structure, dynamics and function associated with the enzyme, and promoting the structure-based and/or mechanism-based design of new inhibitors for it.
ESTHER : Xu_2017_Molecules_22_
PubMedSearch : Xu_2017_Molecules_22_
PubMedID: 28796192

Title : Karyotype Stability and Unbiased Fractionation in the Paleo-Allotetraploid Cucurbita Genomes - Sun_2017_Mol.Plant_10_1293
Author(s) : Sun H , Wu S , Zhang G , Jiao C , Guo S , Ren Y , Zhang J , Zhang H , Gong G , Jia Z , Zhang F , Tian J , Lucas WJ , Doyle JJ , Li H , Fei Z , Xu Y
Ref : Mol Plant , 10 :1293 , 2017
Abstract : The Cucurbita genus contains several economically important species in the Cucurbitaceae family. Here, we report high-quality genome sequences of C. maxima and C. moschata and provide evidence supporting an allotetraploidization event in Cucurbita. We are able to partition the genome into two homoeologous subgenomes based on different genetic distances to melon, cucumber, and watermelon in the Benincaseae tribe. We estimate that the two diploid progenitors successively diverged from Benincaseae around 31 and 26 million years ago (Mya), respectively, and the allotetraploidization happened at some point between 26 Mya and 3 Mya, the estimated date when C. maxima and C. moschata diverged. The subgenomes have largely maintained the chromosome structures of their diploid progenitors. Such long-term karyotype stability after polyploidization has not been commonly observed in plant polyploids. The two subgenomes have retained similar numbers of genes, and neither subgenome is globally dominant in gene expression. Allele-specific expression analysis in the C. maxima x C. moschata interspecific F(1) hybrid and their two parents indicates the predominance of trans-regulatory effects underlying expression divergence of the parents, and detects transgressive gene expression changes in the hybrid correlated with heterosis in important agronomic traits. Our study provides insights into polyploid genome evolution and valuable resources for genetic improvement of cucurbit crops.
ESTHER : Sun_2017_Mol.Plant_10_1293
PubMedSearch : Sun_2017_Mol.Plant_10_1293
PubMedID: 28917590
Gene_locus related to this paper: cucma-a0a6j1jlb1 , cucma-a0a6j1i8e2 , cucma-a0a6j1hwl6

Title : The pomegranate (Punica granatum L.) genome and the genomics of punicalagin biosynthesis - Qin_2017_Plant.J_91_1108
Author(s) : Qin G , Xu C , Ming R , Tang H , Guyot R , Kramer EM , Hu Y , Yi X , Qi Y , Xu X , Gao Z , Pan H , Jian J , Tian Y , Yue Z , Xu Y
Ref : Plant J , 91 :1108 , 2017
Abstract : Pomegranate (Punica granatum L.) is a perennial fruit crop grown since ancient times that has been planted worldwide and is known for its functional metabolites, particularly punicalagins. We have sequenced and assembled the pomegranate genome with 328 Mb anchored into nine pseudo-chromosomes and annotated 29 229 gene models. A Myrtales lineage-specific whole-genome duplication event was detected that occurred in the common ancestor before the divergence of pomegranate and Eucalyptus. Repetitive sequences accounted for 46.1% of the assembled genome. We found that the integument development gene INNER NO OUTER (INO) was under positive selection and potentially contributed to the development of the fleshy outer layer of the seed coat, an edible part of pomegranate fruit. The genes encoding the enzymes for synthesis and degradation of lignin, hemicelluloses and cellulose were also differentially expressed between soft- and hard-seeded varieties, reflecting differences in their accumulation in cultivars differing in seed hardness. Candidate genes for punicalagin biosynthesis were identified and their expression patterns indicated that gallic acid synthesis in tissues could follow different biochemical pathways. The genome sequence of pomegranate provides a valuable resource for the dissection of many biological and biochemical traits and also provides important insights for the acceleration of breeding. Elucidation of the biochemical pathway(s) involved in punicalagin biosynthesis could assist breeding efforts to increase production of this bioactive compound.
ESTHER : Qin_2017_Plant.J_91_1108
PubMedSearch : Qin_2017_Plant.J_91_1108
PubMedID: 28654223
Gene_locus related to this paper: prupe-a0a251r634 , pungr-a0a218xv87 , pungr-a0a218xi98 , pungr-a0a218wma5 , pungr-a0a218w0a8 , pungr-a0a218w138 , pungr-a0a218w7t6 , pungr-a0a218weu3 , pungr-a0a218xzu6

Title : Lipases from the genus Rhizopus: Characteristics, expression, protein engineering and application - Yu_2016_Prog.Lipid.Res_64_57
Author(s) : Yu XW , Xu Y , Xiao R
Ref : Prog Lipid Res , 64 :57 , 2016
Abstract : Lipases are versatile catalysts that hydrolyze ester bonds of water-insoluble glycerides or carry out reversible reactions at the water/lipid interface. The remarkable characteristics of lipases from the genus Rhizopus are their high sn-1,3-positional specificity, enantioselectivity and activity in nonaqueous media, which make them one of the most desirable enzymes for many applications, including lipid modification and biodiesel and chiral organic compound synthesis. sn-1,3-Position-specific Rhizopus lipases are particularly useful for the production of structured triacylglycerols. Significant progress has been made regarding lipases from the genus Rhizopus, including gene sequencing, elucidation of the protein structure and catalytic function, heterologous expression and redesigning Rhizopus lipases for valuable properties, which is receiving increasing academic and industrial attention. In this review, we present a comprehensive overview of Rhizopus lipases, focusing on (a) the characteristics of Rhizopus lipases, (b) Rhizopus lipase genes and structural features, (c) strategies for heterologous expression of Rhizopus lipase genes in yeast system, (d) progress in protein engineering for the improvement of the properties of Rhizopus lipases, and (e) development of biotechnological applications.
ESTHER : Yu_2016_Prog.Lipid.Res_64_57
PubMedSearch : Yu_2016_Prog.Lipid.Res_64_57
PubMedID: 27497512

Title : NDRG1 overexpression promotes the progression of esophageal squamous cell carcinoma through modulating Wnt signaling pathway - Ai_2016_Cancer.Biol.Ther_17_943
Author(s) : Ai R , Sun Y , Guo Z , Wei W , Zhou L , Liu F , Hendricks DT , Xu Y , Zhao X
Ref : Cancer Biol Ther , 17 :943 , 2016
Abstract : N-myc down-regulated gene 1 (NDRG1) has been shown to regulate tumor growth and metastasis in various malignant tumors and also to be dysregulated in esophageal squamous cell carcinoma (ESCC). Here, we show that NDRG1 overexpression (91.9%, 79/86) in ESCC tumor tissues is associated with poor overall survival of esophageal cancer patients. When placed in stable transfectants of the KYSE 30 ESCC cell line generated by lentiviral transduction with the ectopic overexpression of NDRG1, the expression of transducin-like enhancer of Split 2 (TLE2) was decreased sharply, however beta-catenin was increased. Mechanistically, NDRG1 physically associates with TLE2 and beta-catenin to affect the Wnt pathway. RNA interference and TLE2 overexpression studies demonstrate that NDRG1 fails to active Wnt pathway compared with isogenic wild-type controls. Strikingly, NDRG1 overexpression induces the epithelial mesenchymal transition (EMT) through activating the Wnt signaling pathway in ESCC cells, decreased the expression of E-cadherin and enhanced the expression of Snail. Our study elucidates a mechanism of NDRG1-regulated Wnt pathway activation and EMT via affecting TLE2 and beta-catenin expression in esophageal cancer cells. This indicates a pro-oncogenic role for NDRG1 in esophageal cancer cells whereby it modulates tumor progression.
ESTHER : Ai_2016_Cancer.Biol.Ther_17_943
PubMedSearch : Ai_2016_Cancer.Biol.Ther_17_943
PubMedID: 27414086

Title : Structural basis of unique ligand specificity of KAI2-like protein from parasitic weed Striga hermonthica - Xu_2016_Sci.Rep_6_31386
Author(s) : Xu Y , Miyakawa T , Nakamura H , Nakamura A , Imamura Y , Asami T , Tanokura M
Ref : Sci Rep , 6 :31386 , 2016
Abstract : The perception of two plant germination inducers, karrikins and strigolactones, are mediated by the proteins KAI2 and D14. Recently, KAI2-type proteins from parasitic weeds, which are possibly related to seed germination induced by strigolactone, have been classified into three clades characterized by different responses to karrikin/strigolactone. Here we characterized a karrikin-binding protein in Striga (ShKAI2iB) that belongs to intermediate-evolving KAI2 and provided the structural bases for its karrikin-binding specificity. Binding assays showed that ShKAI2iB bound karrikins but not strigolactone, differing from other KAI2 and D14. The crystal structures of ShKAI2iB and ShKAI2iB-karrikin complex revealed obvious structural differences in a helix located at the entry of its ligand-binding cavity. This results in a smaller closed pocket, which is also the major cause of ShKAI2iB's specificity of binding karrikin. Our structural study also revealed that a few non-conserved amino acids led to the distinct ligand-binding profile of ShKAI2iB, suggesting that the evolution of KAI2 resulted in its diverse functions.
ESTHER : Xu_2016_Sci.Rep_6_31386
PubMedSearch : Xu_2016_Sci.Rep_6_31386
PubMedID: 27507097
Gene_locus related to this paper: strhe-ShHTL3

Title : Structural and Thermodynamic Characterization of Protein-Ligand Interactions Formed between Lipoprotein-Associated Phospholipase A2 and Inhibitors - Liu_2016_J.Med.Chem_59_5115
Author(s) : Liu Q , Chen X , Chen W , Yuan X , Su H , Shen J , Xu Y
Ref : Journal of Medicinal Chemistry , 59 :5115 , 2016
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) represents a promising therapeutic target for atherosclerosis and Alzheimer's disease. Here we reported the first crystal structures of Lp-PLA2 bound with reversible inhibitors and the thermodynamic characterization of complexes. High rigidity of Lp-PLA2 structure and similar binding modes of inhibitors with completely different scaffolds are revealed. It not only provides the molecular basis for inhibitory activity but also sheds light on the essential features of Lp-PLA2 recognition with reversible inhibitors.
ESTHER : Liu_2016_J.Med.Chem_59_5115
PubMedSearch : Liu_2016_J.Med.Chem_59_5115
PubMedID: 27078579
Gene_locus related to this paper: human-PLA2G7

Title : Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes - Li_2016_J.Med.Chem_59_6772
Author(s) : Li S , Xu H , Cui S , Wu F , Zhang Y , Su M , Gong Y , Qiu S , Jiao Q , Qin C , Shan J , Zhang M , Wang J , Yin Q , Xu M , Liu X , Wang R , Zhu L , Li J , Xu Y , Jiang H , Zhao Z , Li H
Ref : Journal of Medicinal Chemistry , 59 :6772 , 2016
Abstract : Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 approximately 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.
ESTHER : Li_2016_J.Med.Chem_59_6772
PubMedSearch : Li_2016_J.Med.Chem_59_6772
PubMedID: 27396490
Gene_locus related to this paper: human-DPP4

Title : The Impact of Crystallization Conditions on Structure-Based Drug Design: A Case Study on the Methylene Blue\/Acetylcholinesterase Complex - Dym_2016_Protein.Sci_25_1096
Author(s) : Dym O , Song W , Felder CE , Roth E , Shnyrov V , Ashani Y , Xu Y , Joosten RP , Weiner L , Sussman JL , Silman I
Ref : Protein Science , 25 :1096 , 2016
Abstract : Structure-based drug design utilizes apo-protein or complex structures retrieved from the PDB. >57% of crystallographic PDB entries were obtained with polyethyleneglycols (PEGs) as precipitant and/or as cryoprotectant, but >6% of these report presence of individual ethyleneglycol oligomers. We report a case in which ethyleneglycol oligomers' presence in a crystal structure markedly affected the bound ligand's position. Specifically, we compared the positions of methylene blue and decamethonium in acetylcholinesterase complexes obtained using isomorphous crystals precipitated with PEG200 or ammonium sulfate. The ligands' positions within the active-site gorge in complexes obtained using PEG200 are influenced by presence of ethyleneglycol oligomers in both cases bound to W84 at the gorge's bottom, preventing interaction of the ligand's proximal quaternary group with its indole. Consequently, both ligands are approximately 3.0A further up the gorge than in complexes obtained using crystals precipitated with ammonium sulfate, in which the quaternary groups make direct pi-cation interactions with the indole. These findings have implications for structure-based drug design, since data for ligand-protein complexes with polyethyleneglycol as precipitant may not reflect the ligand's position in its absence, and could result in selecting incorrect drug discovery leads. Docking methylene blue into the structure obtained with PEG200, but omitting the ethyleneglycols, yields results agreeing poorly with the crystal structure; excellent agreement is obtained if they are included. Many proteins display features in which precipitants might lodge. It will be important to investigate presence of precipitants in published crystal structures, and whether it has resulted in misinterpreting electron density maps, adversely affecting drug design. This article is protected by copyright. All rights reserved.
ESTHER : Dym_2016_Protein.Sci_25_1096
PubMedSearch : Dym_2016_Protein.Sci_25_1096
PubMedID: 26990888
Gene_locus related to this paper: torca-ACHE

Title : Computational analysis and enzyme assay of inhibitor response to disease single nucleotide polymorphisms (SNPs) in lipoprotein lipase - He_2016_J.Bioinform.Comput.Biol__1650028
Author(s) : He D , Huang L , Xu Y , Pan X , Liu L
Ref : J Bioinform Comput Biol , :1650028 , 2016
Abstract : Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of the triglyceride (TG) core of circulating TG-rich lipoproteins, chylomicrons, and very low-density lipoproteins. The enzyme has been established as an efficacious and safe therapeutic target for the management of obesity. Here, a systematic profile of the lipase inhibitor response of three anti-obesity agents (Orlistat, Lipstatin, and Cetilistat) to clinical LPL missense mutations arising from disease single nucleotide polymorphisms (SNPs) was established by integrating complex structure modeling, virtual mutagenesis, molecular dynamics (MD) simulations, binding energy analysis, and radiolabeled TG hydrolysis assays. The profile was then used to characterize the resistance and sensitivity of systematic mutation-inhibitor pairs. It is suggested that the Orlistat and Lipstatin have a similar response profile to the investigated mutations due to their homologous chemical structures, but exhibit a distinct profile to that of Cetilistat. Most mutations were predicted to have a modest or moderate effect on inhibitor binding; they are located far away from the enzyme active site and thus can only influence the binding limitedly. A number of mutations were found to sensitize or cause resistance for lipase inhibitors by directly interacting with the inhibitor ligands or by indirectly addressing allosteric effect on enzyme active site. Long-term MD simulations revealed a different noncovalent interaction network at the complex interfaces of Orlistat with wild-type LPL as well as its sensitized mutant H163R and resistant mutant I221T.
ESTHER : He_2016_J.Bioinform.Comput.Biol__1650028
PubMedSearch : He_2016_J.Bioinform.Comput.Biol__1650028
PubMedID: 27427383

Title : Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4alpha and Protects Against Alcohol- and MCD diet-induced Liver Injury - Xu_2016_Sci.Rep_6_24277
Author(s) : Xu J , Xu Y , Li Y , Jadhav K , You M , Yin L , Zhang Y
Ref : Sci Rep , 6 :24277 , 2016
Abstract : The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4alpha (HNF4alpha) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4alpha and CES1 expression in primary hepatocytes. HNF4alpha regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.
ESTHER : Xu_2016_Sci.Rep_6_24277
PubMedSearch : Xu_2016_Sci.Rep_6_24277
PubMedID: 27075303
Gene_locus related to this paper: human-CES1

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 : Inhibition of protein methylesterase 1 decreased cancerous phenotypes in endometrial adenocarcinoma cell lines and xenograft tumor models - Pusey_2016_Tumour.Biol_37_11835
Author(s) : Pusey M , Bail S , Xu Y , Buiakova O , Nestor M , Yang JJ , Rice LM
Ref : Tumour Biol , 37 :11835 , 2016
Abstract : Protein methylesterase 1 (PME-1) promotes cancerous phenotypes through the demethylation and inactivation of protein phosphatase 2A. We previously demonstrated that PME-1 overexpression promotes Akt, ERK, and may promote Wnt signaling and increases tumor burden in a xenograft model of endometrial cancer. Here, we show that covalent PME-1 inhibitors decrease cell proliferation and invasive growth in vitro but have no effect in vivo at the concentrations tested; however, depletion of PME-1 with shRNA in an endometrial cancer xenograft model significantly reduced tumor growth. Thus, discovery of more potent PME-1 inhibitors may be beneficial for the treatment of endometrial cancer.
ESTHER : Pusey_2016_Tumour.Biol_37_11835
PubMedSearch : Pusey_2016_Tumour.Biol_37_11835
PubMedID: 27048286
Gene_locus related to this paper: human-PPME1

Title : Efficient production of (2)H, (13)C, (15)N-enriched industrial enzyme Rhizopus chinensis lipase with native disulfide bonds - Zhang_2016_Microb.Cell.Fact_15_123
Author(s) : Zhang M , Yu XW , Swapna GV , Xiao R , Zheng H , Sha C , Xu Y , Montelione GT
Ref : Microb Cell Fact , 15 :123 , 2016
Abstract : BACKGROUND: In order to use most modern methods of NMR spectroscopy to study protein structure and dynamics, isotope-enriched protein samples are essential. Especially for larger proteins (>20 kDa), perdeuterated and Ile (delta1), Leu, and Val methyl-protonated protein samples are required for suppressing nuclear relaxation to provide improved spectral quality, allowing key backbone and side chain resonance assignments needed for protein structure and dynamics studies. Escherichia coli and Pichia pastoris are two of the most popular expression systems for producing isotope-enriched, recombinant protein samples for NMR investigations. The P. pastoris system can be used to produce (13)C, (15)N-enriched and even (2)H,(13)C, (15)N-enriched protein samples, but efficient methods for producing perdeuterated proteins with Ile (delta1), Leu and Val methyl-protonated groups in P. pastoris are still unavailable. Glycosylation heterogeneity also provides challenges to NMR studies. E. coli expression systems are efficient for overexpressing perdeuterated and Ile (delta1), Leu, Val methyl-protonated protein samples, but are generally not successful for producing secreted eukaryotic proteins with native disulfide bonds.
RESULTS: The 33 kDa protein-Rhizopus chinensis lipase (RCL), an important industrial enzyme, was produced using both P. pastoris and E. coli BL21 trxB (DE3) systems. Samples produced from both systems exhibit identical native disulfide bond formation and similar 2D NMR spectra, indicating similar native protein folding. The yield of (13)C, (15)N-enriched r27RCL produced using P. pastoris was 1.7 times higher that obtained using E. coli, while the isotope-labeling efficiency was ~15 % lower. Protein samples produced in P. pastoris exhibit O-glycosylation, while the protein samples produced in E. coli were not glycosylated. The specific activity of r27RCL from P. pastoris was ~1.4 times higher than that produced in E. coli.
CONCLUSIONS: These data demonstrate efficient production of (2)H, (13)C, (15)N-enriched, Ile (delta1), Leu, Val methyl-protonated eukaryotic protein r27RCL with native disulfides using the E. coli BL21 trxB (DE3) system. For certain NMR studies, particularly efforts for resonance assignments, structural studies, and dynamic studies, E. coli provides a cost-effective system for producing isotope-enriched RCL. It should also be potential for producing other (2)H, (13)C, (15)N-enriched, Ile (delta1), Leu, Val methyl-protonated eukaryotic proteins with native disulfide bonds.
ESTHER : Zhang_2016_Microb.Cell.Fact_15_123
PubMedSearch : Zhang_2016_Microb.Cell.Fact_15_123
PubMedID: 27411547

Title : Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice - Li_2016_Hepatology_63_1860
Author(s) : Li Y , Zalzala M , Jadhav K , Xu Y , Kasumov T , Yin L , Zhang Y
Ref : Hepatology , 63 :1860 , 2016
Abstract : Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). So far, the underlying mechanism remains poorly understood. Here, we show that hepatic carboxylesterase 2 (CES2) is markedly reduced in NASH patients, diabetic db/db mice, and high-fat diet (HFD)-fed mice. Restoration of hepatic CES2 expression in db/db or HFD-fed mice markedly ameliorates liver steatosis and insulin resistance. In contrast, knockdown of hepatic CES2 causes liver steatosis and damage in chow- or Western diet-fed C57BL/6 mice. Mechanistically, we demonstrate that CES2 has triglyceride hydrolase activity. As a result, gain of hepatic CES2 function increases fatty acid oxidation and inhibits lipogenesis, whereas loss of hepatic CES2 stimulates lipogenesis by inducing endoplasmic reticulum stress. We further show that loss of hepatic CES2 stimulates lipogenesis in a sterol regulatory element-binding protein 1 (SREBP-1)-dependent manner. Finally, we show that hepatocyte nuclear factor 4 alpha (HNF-4alpha) plays a key role in controlling hepatic CES2 expression in diabetes, obesity, or NASH. CONCLUSION: CES2 plays a protective role in development of NAFLD. Targeting the HNF-4alpha/CES2 pathway may be useful for treatment of NAFLD. (Hepatology 2016;63:1860-1874).
ESTHER : Li_2016_Hepatology_63_1860
PubMedSearch : Li_2016_Hepatology_63_1860
PubMedID: 26806650

Title : Insights into Adaptations to a Near-Obligate Nematode Endoparasitic Lifestyle from the Finished Genome of Drechmeria coniospora - Zhang_2016_Sci.Rep_6_23122
Author(s) : Zhang L , Zhou Z , Guo Q , Fokkens L , Miskei M , Pocsi I , Zhang W , Chen M , Wang L , Sun Y , Donzelli BG , Gibson DM , Nelson DR , Luo JG , Rep M , Liu H , Yang S , Wang J , Krasnoff SB , Xu Y , Molnar I , Lin M
Ref : Sci Rep , 6 :23122 , 2016
Abstract : Nematophagous fungi employ three distinct predatory strategies: nematode trapping, parasitism of females and eggs, and endoparasitism. While endoparasites play key roles in controlling nematode populations in nature, their application for integrated pest management is hindered by the limited understanding of their biology. We present a comparative analysis of a high quality finished genome assembly of Drechmeria coniospora, a model endoparasitic nematophagous fungus, integrated with a transcriptomic study. Adaptation of D. coniospora to its almost completely obligate endoparasitic lifestyle led to the simplification of many orthologous gene families involved in the saprophytic trophic mode, while maintaining orthologs of most known fungal pathogen-host interaction proteins, stress response circuits and putative effectors of the small secreted protein type. The need to adhere to and penetrate the host cuticle led to a selective radiation of surface proteins and hydrolytic enzymes. Although the endoparasite has a simplified secondary metabolome, it produces a novel peptaibiotic family that shows antibacterial, antifungal and nematicidal activities. Our analyses emphasize the basic malleability of the D. coniospora genome: loss of genes advantageous for the saprophytic lifestyle; modulation of elements that its cohort species utilize for entomopathogenesis; and expansion of protein families necessary for the nematode endoparasitic lifestyle.
ESTHER : Zhang_2016_Sci.Rep_6_23122
PubMedSearch : Zhang_2016_Sci.Rep_6_23122
PubMedID: 26975455
Gene_locus related to this paper: 9hypo-a0a151ga75 , 9hypo-a0a151gbh5 , 9hypo-a0a151gd50 , 9hypo-a0a151ggb9 , 9hypo-a0a151gjd5 , 9hypo-a0a151gtv2 , 9hypo-a0a151gxh2 , 9hypo-a0a151gaw8 , 9hypo-a0a151gia2

Title : Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys - Warren_2016_Nature_531_381
Author(s) : Warren TK , Jordan R , Lo MK , Ray AS , Mackman RL , Soloveva V , Siegel D , Perron M , Bannister R , Hui HC , Larson N , Strickley R , Wells J , Stuthman KS , Van Tongeren SA , Garza NL , Donnelly G , Shurtleff AC , Retterer CJ , Gharaibeh D , Zamani R , Kenny T , Eaton BP , Grimes E , Welch LS , Gomba L , Wilhelmsen CL , Nichols DK , Nuss JE , Nagle ER , Kugelman JR , Palacios G , Doerffler E , Neville S , Carra E , Clarke MO , Zhang L , Lew W , Ross B , Wang Q , Chun K , Wolfe L , Babusis D , Park Y , Stray KM , Trancheva I , Feng JY , Barauskas O , Xu Y , Wong P , Braun MR , Flint M , McMullan LK , Chen SS , Fearns R , Swaminathan S , Mayers DL , Spiropoulou CF , Lee WA , Nichol ST , Cihlar T , Bavari S
Ref : Nature , 531 :381 , 2016
Abstract : The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.
ESTHER : Warren_2016_Nature_531_381
PubMedSearch : Warren_2016_Nature_531_381
PubMedID: 26934220

Title : Regulations of Xenobiotics and Endobiotics on Carboxylesterases: A Comprehensive Review - Xu_2016_Eur.J.Drug.Metab.Pharmacokinet_41_321
Author(s) : Xu Y , Zhang C , He W , Liu D
Ref : Eur J Drug Metab Pharmacokinet , 41 :321 , 2016
Abstract : Carboxylesterases (CESs) play major roles in catalyzing the hydrolysis of a wide range of ester- and amide-containing compounds. CESs dominate both the biotransformation of numerous therapeutic drugs and the detoxification of environmental toxicants, and the activity alteration of CESs may be a determinant reason for modification of the resultant pharmacokinetic/pharmacodynamic profile when two or more drugs are concurrently used. Herein, we provide a comprehensive review of the current literature involving of induction and inhibition on CESs by both exogenous and endogenous compounds. In particular, the inhibition constant and inhibition pattern of inhibitors on CESs in studies using animal microsomes or human recombinant CESs are summarized. Further studies are needed to clarify the underlying regulation mechanism, and alterations in CESs activity should be taken into consideration for safe clinical therapy.
ESTHER : Xu_2016_Eur.J.Drug.Metab.Pharmacokinet_41_321
PubMedSearch : Xu_2016_Eur.J.Drug.Metab.Pharmacokinet_41_321
PubMedID: 26914100

Title : [Effects of methomyl on acetylcholinesterase in erythrocyte membrane and various brain areas] - Zhao_2015_Zhonghua.Lao.Dong.Wei.Sheng.Zhi.Ye.Bing.Za.Zhi_33_417
Author(s) : Zhao F , Li T , Zhang C , Xu Y , Xu H , Shi N
Ref : Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi , 33 :417 , 2015
Abstract : OBJECTIVE: To study the toxicity of methomyl to acetylcholinesterase (AChE) in different regions.
METHODS: The optimal temperature and time for measurement of AChE activity were determined in vitro. The dose- and time-response relationships of methomyl with AChE activity in human erythrocyte membrane, rat erythrocyte membrane, cortical synapses, cerebellar synapses, hippocampal synapses, and striatal synapses were evaluated. The half maximal inhibitory concentration (IC50) and bimolecular rate constant (Ki) of methomyl for AChE activity in different regions were calculated, and the type of inhibition of AChE activity by methomyl was determined.
RESULTS: AChE achieved the maximum activity at 37 degrees C, and the optimal time to determine initial reaction velocity was 0~17 min. There were dose- and time-response relationships between methomyl and AChE activity in the erythrocyte membrane and various brain areas. The IC50 value of methomyl for AChE activity in human erythrocyte membrane was higher than that in rat erythrocyte membrane, while the Ki value of methomyl for AChE activity in rat erythrocyte membrane was higher than that in human erythrocyte membrane. Among synapses in various brain areas, the striatum had the highest IC50 value, followed by the cerebellum, cerebral cortex, and hippocampus, while the cerebral cortex had the highest Ki value, followed by the hippocampus, striatum, and cerebellum. Lineweaver-Burk diagram demonstrated that with increasing concentration of methomyl, the maximum reaction velocity (Vmax) of AChE decreased, and the Michaelis constant (Km) remained the same. CONCLUSION: Methomyl is a reversible non-competitive inhibitor of AChE. AChE of rat erythrocyte membrane is more sensitive to methomyl than that of human erythrocyte membrane; the cerebral cortical synapses have the most sensitive AChE to methomyl among synapses in various brain areas.
ESTHER : Zhao_2015_Zhonghua.Lao.Dong.Wei.Sheng.Zhi.Ye.Bing.Za.Zhi_33_417
PubMedSearch : Zhao_2015_Zhonghua.Lao.Dong.Wei.Sheng.Zhi.Ye.Bing.Za.Zhi_33_417
PubMedID: 26653373

Title : Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis - Wang_2015_Hepatology_61_870
Author(s) : Wang C , Zhao Y , Gao X , Li L , Yuan Y , Liu F , Zhang L , Wu J , Hu P , Zhang X , Gu Y , Xu Y , Wang Z , Li Z , Zhang H , Ye J
Ref : Hepatology , 61 :870 , 2015
Abstract : Abnormal metabolism of nonesterified fatty acids (NEFAs) and their derivatives has been reported to be the main cause of intracellular lipotoxic injury. Normally, NEFAs are stored in lipid droplets (LDs) in the form of triglyceride (TG), which could reduce the lipotoxicity of cytosolic NEFAs. Previous studies have implicated that Perilipin 5 (Plin5), an LD-binding protein, regulates the storage and hydrolysis of TG in LD. However, its roles and underlying mechanisms in the liver remain unknown. Here we found that Plin5 expression was increased in steatotic livers. Using Plin5 knockout mice, we found that Plin5 deficiency resulted in reduced hepatic lipid content and smaller-sized LDs, which was due to the elevated lipolysis rate and fatty acid utilization. Plin5-deficient hepatocytes showed increased mitochondria proliferation, which could be explained by the increased expression and activity of PPARalpha stimulated by the increased NEFA levels. Meanwhile, Plin5-deficient livers also exhibited enhanced mitochondrial oxidative capacity. We also found that Plin5 deficiency induces lipotoxic injury in hepatocytes, attributed to lipid peroxidation. Mechanistically, we found that Plin5 blocks adipose triglyceride lipase (ATGL)-mediated lipolysis by competitively binding to comparative gene identification-58 (CGI-58) and disrupting the interaction between CGI-58 and ATGL. CONCLUSION: Plin5 is an important protective factor against hepatic lipotoxicity induced by NEFAs generated from lipolysis. This provides an important new insight into the regulation of hepatic lipid storage and relation between lipid storage and lipotoxicity.
ESTHER : Wang_2015_Hepatology_61_870
PubMedSearch : Wang_2015_Hepatology_61_870
PubMedID: 25179419

Title : The resurrection genome of Boea hygrometrica: A blueprint for survival of dehydration - Xiao_2015_Proc.Natl.Acad.Sci.U.S.A_112_5833
Author(s) : Xiao L , Yang G , Zhang L , Yang X , Zhao S , Ji Z , Zhou Q , Hu M , Wang Y , Chen M , Xu Y , Jin H , Xiao X , Hu G , Bao F , Hu Y , Wan P , Li L , Deng X , Kuang T , Xiang C , Zhu JK , Oliver MJ , He Y
Ref : Proc Natl Acad Sci U S A , 112 :5833 , 2015
Abstract : "Drying without dying" is an essential trait in land plant evolution. Unraveling how a unique group of angiosperms, the Resurrection Plants, survive desiccation of their leaves and roots has been hampered by the lack of a foundational genome perspective. Here we report the approximately 1,691-Mb sequenced genome of Boea hygrometrica, an important resurrection plant model. The sequence revealed evidence for two historical genome-wide duplication events, a compliment of 49,374 protein-coding genes, 29.15% of which are unique (orphan) to Boea and 20% of which (9,888) significantly respond to desiccation at the transcript level. Expansion of early light-inducible protein (ELIP) and 5S rRNA genes highlights the importance of the protection of the photosynthetic apparatus during drying and the rapid resumption of protein synthesis in the resurrection capability of Boea. Transcriptome analysis reveals extensive alternative splicing of transcripts and a focus on cellular protection strategies. The lack of desiccation tolerance-specific genome organizational features suggests the resurrection phenotype evolved mainly by an alteration in the control of dehydration response genes.
ESTHER : Xiao_2015_Proc.Natl.Acad.Sci.U.S.A_112_5833
PubMedSearch : Xiao_2015_Proc.Natl.Acad.Sci.U.S.A_112_5833
PubMedID: 25902549
Gene_locus related to this paper: 9lami-a0a2z7c6k4 , 9lami-a0a2z7bgj4

Title : Discovery of a Novel Series of Imidazo[1,2-a]pyrimidine Derivatives as Potent and Orally Bioavailable Lipoprotein-Associated Phospholipase A2 Inhibitors - Chen_2015_J.Med.Chem_58_8529
Author(s) : Chen X , Xu W , Wang K , Mo M , Zhang W , Du L , Yuan X , Xu Y , Wang Y , Shen J
Ref : Journal of Medicinal Chemistry , 58 :8529 , 2015
Abstract : Inhibition of lipoprotein-associated phospholipase A2 (Lp-PLA2) has been suggested to be a promising therapeutic strategy for several inflammation-associated diseases, including atherosclerosis, Alzheimer's disease, and diabetic macular edema. Herein, we report the discovery of a novel series of Lp-PLA2 inhibitors constructed on an imidazo[1,2-a]pyrimidine scaffold through a conformational restriction strategy. Structure-activity relationship (SAR) analysis resulted in the identification of several compounds with high potency in vitro and good metabolic stability in liver S9 fractions. Compounds 7c and 14b selected for further exploration in vivo demonstrated excellent pharmacokinetic profiles and exhibited significant inhibitory efficacy in SD rats upon oral dosing.
ESTHER : Chen_2015_J.Med.Chem_58_8529
PubMedSearch : Chen_2015_J.Med.Chem_58_8529
PubMedID: 26479945
Gene_locus related to this paper: human-PLA2G7

Title : Genome-wide transcriptomic analysis of a superior biomass-degrading strain of A. fumigatus revealed active lignocellulose-degrading genes - Miao_2015_BMC.Genomics_16_459
Author(s) : Miao Y , Liu D , Li G , Li P , Xu Y , Shen Q , Zhang R
Ref : BMC Genomics , 16 :459 , 2015
Abstract : BACKGROUND: Various saprotrophic microorganisms, especially filamentous fungi, can efficiently degrade lignocellulose that is one of the most abundant natural materials on earth. It consists of complex carbohydrates and aromatic polymers found in the plant cell wall and thus in plant debris. Aspergillus fumigatus Z5 was isolated from compost heaps and showed highly efficient plant biomass-degradation capability. RESULTS: The 29-million base-pair genome of Z5 was sequenced and 9540 protein-coding genes were predicted and annotated. Genome analysis revealed an impressive array of genes encoding cellulases, hemicellulases and pectinases involved in lignocellulosic biomass degradation. Transcriptional responses of A. fumigatus Z5 induced by sucrose, oat spelt xylan, Avicel PH-101 and rice straw were compared. There were 444, 1711 and 1386 significantly differently expressed genes in xylan, cellulose and rice straw, respectively, when compared to sucrose as a control condition. CONCLUSIONS: Combined analysis of the genomic and transcriptomic data provides a comprehensive understanding of the responding mechanisms to the most abundant natural polysaccharides in A. fumigatus. This study provides a basis for further analysis of genes shown to be highly induced in the presence of polysaccharide substrates and also the information which could prove useful for biomass degradation and heterologous protein expression.
ESTHER : Miao_2015_BMC.Genomics_16_459
PubMedSearch : Miao_2015_BMC.Genomics_16_459
PubMedID: 26076650
Gene_locus related to this paper: neofi-a1d0b8

Title : Baicalein alters PI3K\/Akt\/GSK3beta signaling pathway in rats with diabetes-associated cognitive deficits - Qi_2015_Int.J.Clin.Exp.Med_8_1993
Author(s) : Qi Z , Xu Y , Liang Z , Li S , Wang J , Wei Y , Dong B
Ref : Int J Clin Exp Med , 8 :1993 , 2015
Abstract : Our present investigation focused on assessing the neuroprotective potential of baicalein (BAC) against diabetes-associated cognitive deficit (DACD) using a diabetic model and further figure out the potential molecular mechanisms. Diabetic rat model was established by streptozotocin (STZ). Vehicle or BAC by the doses of 2 and 4 mg/kg was intraperitoneally injected once a day for seven consecutive weeks. Memory function was evaluated by Morris water maze test and avoidance passive test. The activities of acetylcholinesterase (AChE), choline acetylase (ChAT), caspase-9 and caspase-3 in STZ-induced diabetic rats' hippocampus were detected via responsive commercial kits. Western blot assay were used to determine the protein levels of phospho-phosphatidylinositol 3-kinase (p-PI3K), phospho-Akt (p-Akt), and phospho-glycogen synthase kinase-3beta (p-GSK3beta). Our results showed that BAC remarkably increased body weight and ChAT activity, decreased blood glucose level and AChE activity as well as improved cognitive deficits in diabetic rats. Additionally, it was also found that treatment with BAC to diabetes obviously stimulated the p-PI3K and p-Akt and inhibited the level of p-GSK3beta. Furthermore, the neuronal apoptosis was also prevented after BAC treatment by decreasing caspase-9 and caspase-3 activities in diabetic rats' hippocampus. It is concluded that BAC exerted beneficial effects against DACD in rats and its neuroprotection might be linked with activating PI3K and Akt phosphorylation accompanied with suppressing the phosphorylated level of GSK3beta. These results hint that BAC is likely to be served as an adjuvant therapy to conventional anti-hyperglycemic regimens as well as DACD.
ESTHER : Qi_2015_Int.J.Clin.Exp.Med_8_1993
PubMedSearch : Qi_2015_Int.J.Clin.Exp.Med_8_1993
PubMedID: 25932128

Title : Effect of Marine Collagen Peptides on Physiological and Neurobehavioral Development of Male Rats with Perinatal Asphyxia - Xu_2015_Mar.Drugs_13_3653
Author(s) : Xu L , Dong W , Zhao J , Xu Y
Ref : Mar Drugs , 13 :3653 , 2015
Abstract : Asphyxia during delivery produces long-term deficits in brain development. We investigated the neuroprotective effects of marine collagen peptides (MCPs), isolated from Chum Salmon skin by enzymatic hydrolysis, on male rats with perinatal asphyxia (PA). PA was performed by immersing rat fetuses with uterine horns removed from ready-to-deliver rats into a water bath for 15 min. Caesarean-delivered pups were used as controls. PA rats were intragastrically administered with 0.33 g/kg, 1.0 g/kg and 3.0 g/kg body weight MCPs from postnatal day 0 (PND 0) till the age of 90-days. Behavioral tests were carried out at PND21, PND 28 and PND 90. The results indicated that MCPs facilitated early body weight gain of the PA pups, however had little effects on early physiological development. Behavioral tests revealed that MCPs facilitated long-term learning and memory of the pups with PA through reducing oxidative damage and acetylcholinesterase (AChE) activity in the brain, and increasing hippocampus phosphorylated cAMP-response element binding protein (p-CREB) and brain derived neurotrophic factor (BDNF) expression.
ESTHER : Xu_2015_Mar.Drugs_13_3653
PubMedSearch : Xu_2015_Mar.Drugs_13_3653
PubMedID: 26058015

Title : Down-regulation of carboxylesterases 1 and 2 plays an important role in prodrug metabolism in immunological liver injury rats - Zhang_2015_Int.Immunopharmacol_24_153
Author(s) : Zhang C , Xu Y , Gao P , Lu J , Li X , Liu D
Ref : Int Immunopharmacol , 24 :153 , 2015
Abstract : Liver plays a central role in xenobiotics metabolism, thus affecting the in vivo disposition and therapeutic effects of drugs. Carboxylesterases (CESs), with the main isoforms CES1 and CES2, are important in the metabolism of ester-type prodrugs. However, influences of immunological liver injury on the activity of CES remain undefined. In the present study, we demonstrated treatment with lipopolysaccharide (LPS) suppressed the activities of CES1 and CES2. The decreased activities of CES1 and CES2 were preliminarily assessed by the hydrolysis assay for their common substrate p-nitrophenyl acetate (PNPA) with rat hepatic microsomal enzyme. Subsequently, RT-PCR results showed that the levels of CES1 mRNA and mRNA of CES2 (AB010635) and CES2 (AY034877) in the model group were significantly lower than those of the normal control group (P<0.05). Western blot results showed that the expressions of CES1 and CES2 proteins were decreased (P<0.05). To further clarify the effects of LPS on the metabolic activities of CESs, pharmacokinetic studies were performed in rats by utilizing imidapril and irinotecan (CPT-11) as the specific substrates for CES1 and CES2, respectively. After treatment with LPS, AUC0-inf and Cmax of imidaprilat were decreased from 2084.86+/-340.66ng.h(-1).mL(-1) and 234.66+/-68.85ng.mL(-1) to 983.87+/-315.34ng.h(-1).mL(-1) and 113.1+/-19.69ng.mL(-1) (P<0.05), respectively. Moreover, AUC0-inf and Cmax of SN-38 were decreased from 8100+/-918.6ng.h(-1).mL(-1) and 144.67+/-20.28ng.mL(-1) to 3270+/-500.5ng.h(-1).mL(-1) and 56.19+/-10.38ng.mL(-1) (P<0.05), respectively. In summary, immunological liver injury remarkably attenuated the expressions and metabolic activities of CES1 and CES2, which may be associated with the regulatory effects of cytokines under inflammation.
ESTHER : Zhang_2015_Int.Immunopharmacol_24_153
PubMedSearch : Zhang_2015_Int.Immunopharmacol_24_153
PubMedID: 25499727

Title : Complete genome sequences for 59 burkholderia isolates, both pathogenic and near neighbor - Johnson_2015_Genome.Announc_3_
Author(s) : Johnson SL , Bishop-Lilly KA , Ladner JT , Daligault HE , Davenport KW , Jaissle J , Frey KG , Koroleva GI , Bruce DC , Coyne SR , Broomall SM , Li PE , Teshima H , Gibbons HS , Palacios GF , Rosenzweig CN , Redden CL , Xu Y , Minogue TD , Chain PS
Ref : Genome Announc , 3 : , 2015
Abstract : The genus Burkholderia encompasses both pathogenic (including Burkholderia mallei and Burkholderia pseudomallei, U.S. Centers for Disease Control and Prevention Category B listed), and nonpathogenic Gram-negative bacilli. Here we present full genome sequences for a panel of 59 Burkholderia strains, selected to aid in detection assay development.
ESTHER : Johnson_2015_Genome.Announc_3_
PubMedSearch : Johnson_2015_Genome.Announc_3_
PubMedID: 25931592

Title : Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels - Xu_2014_PLoS.One_9_e109663
Author(s) : Xu J , Yin L , Xu Y , Li Y , Zalzala M , Cheng G , Zhang Y
Ref : PLoS ONE , 9 :e109663 , 2014
Abstract : Metabolic syndrome, characterized by obesity, hyperglycemia, dyslipidemia and hypertension, increases the risks for cardiovascular disease, diabetes and stroke. Carboxylesterase 1 (CES1) is an enzyme that hydrolyzes triglycerides and cholesterol esters, and is important for lipid metabolism. Our previous data show that over-expression of mouse hepatic CES1 lowers plasma glucose levels and improves insulin sensitivity in diabetic ob/ob mice. In the present study, we determined the physiological role of hepatic CES1 in glucose homeostasis. Hepatic CES1 expression was reduced by fasting but increased in diabetic mice. Treatment of mice with glucose induced hepatic CES1 expression. Consistent with the in vivo study, glucose stimulated CES1 promoter activity and increased acetylation of histone 3 and histone 4 in the CES1 chromatin. Knockdown of ATP-citrate lyase (ACL), an enzyme that regulates histone acetylation, abolished glucose-mediated histone acetylation in the CES1 chromatin and glucose-induced hepatic CES1 expression. Finally, knockdown of hepatic CES1 significantly increased postprandial blood glucose levels. In conclusion, the present study uncovers a novel glucose-CES1-glucose pathway which may play an important role in regulating postprandial blood glucose levels.
ESTHER : Xu_2014_PLoS.One_9_e109663
PubMedSearch : Xu_2014_PLoS.One_9_e109663
PubMedID: 25285996
Gene_locus related to this paper: mouse-Ces1c

Title : Improvement of the activation of lipase from Candida rugosa following physical and chemical immobilization on modified mesoporous silica - Wang_2014_Mater.Sci.Eng.C.Mater.Biol.Appl_45_261
Author(s) : Wang C , Li Y , Zhou G , Jiang X , Xu Y , Bu Z
Ref : Mater Sci Eng C Mater Biol Appl , 45 :261 , 2014
Abstract : Lipase from Candida rugosa (CRL) was chemically and physically immobilized onto four types of rod-shaped mesoporous silica (RSMS). RSMS prepared using surfactant P123 and poly(ethylene glycol) as co-templates was functionalized with (3-aminopropyl)triethoxysilane (APTES) to obtain P-RSMS by post-synthesis grafting. Tetraethoxysilane was hydrothermally co-condensed with APTES to obtain C-RSMS. A two-step process using APTES and glutaraldehyde was also performed to obtain G-RSMS. The effects of modification methods (including post-synthesis grafting and co-condensation) and glutaraldehyde on the mesoscopic order, interplanar spacing d100, cell parameter a0, mesoporous structure, and wall thickness of RSMS were studied in detail. Results showed that all samples were mesoporous materials with 2D mesostructures (p6mm). Pore size and d100 decreased, whereas the wall thickness increased after different modifications. CRL was used as a model enzyme to determine the effect of physical and chemical adsorption on loading amount and enzymatic activity. The possible mechanism of CRL immobilization on G-RSMS by chemical adsorption was systematically investigated. The chemical immobilization of CRL on G-RSMS increased the loading amount, hydrolytic activity, thermal stability, and reusability. Moreover, immobilized CRL was employed to catalyze the resolution of 2-octanol by esterification with caprylic acid. The enantiomeric excess of 2-octanol was 45.8% when the reaction was catalyzed by G-RSMS-CRL and decreased to about 38%-39% using the physically immobilized CRL, after 48h of reaction in hexane.
ESTHER : Wang_2014_Mater.Sci.Eng.C.Mater.Biol.Appl_45_261
PubMedSearch : Wang_2014_Mater.Sci.Eng.C.Mater.Biol.Appl_45_261
PubMedID: 25491828

Title : NMR structures of the human alpha7 nAChR transmembrane domain and associated anesthetic binding sites - Bondarenko_2014_Biochim.Biophys.Acta_1838_1389
Author(s) : Bondarenko V , Mowrey DD , Tillman TS , Seyoum E , Xu Y , Tang P
Ref : Biochimica & Biophysica Acta , 1838 :1389 , 2014
Abstract : The alpha7 nicotinic acetylcholine receptor (nAChR), assembled as homomeric pentameric ligand-gated ion channels, is one of the most abundant nAChR subtypes in the brain. Despite its importance in memory, learning and cognition, no structure has been determined for the alpha7 nAChR TM domain, a target for allosteric modulators. Using solution state NMR, we determined the structure of the human alpha7 nAChR TM domain (PDB ID: 2MAW) and demonstrated that the alpha7 TM domain formed functional channels in Xenopus oocytes. We identified the associated binding sites for the anesthetics halothane and ketamine; the former cannot sensitively inhibit alpha7 function, but the latter can. The alpha7 TM domain folds into the expected four-helical bundle motif, but the intra-subunit cavity at the extracellular end of the alpha7 TM domain is smaller than the equivalent cavity in the alpha4beta2 nAChRs (PDB IDs: 2LLY; 2LM2). Neither drug binds to the extracellular end of the alpha7 TM domain, but two halothane molecules or one ketamine molecule binds to the intracellular end of the alpha7 TM domain. Halothane and ketamine binding sites are partially overlapped. Ketamine, but not halothane, perturbed the alpha7 channel-gate residue L9'. Furthermore, halothane did not induce profound dynamics changes in the alpha7 channel as observed in alpha4beta2. The study offers a novel high-resolution structure for the human alpha7 nAChR TM domain that is invaluable for developing alpha7-specific therapeutics. It also provides evidence to support the hypothesis: only when anesthetic binding perturbs the channel pore or alters the channel motion, can binding generate functional consequences.
ESTHER : Bondarenko_2014_Biochim.Biophys.Acta_1838_1389
PubMedSearch : Bondarenko_2014_Biochim.Biophys.Acta_1838_1389
PubMedID: 24384062

Title : In Vitro Evaluation of the Inhibitory Potential of Pharmaceutical Excipients on Human Carboxylesterase 1A and 2 - Zhang_2014_PLoS.One_9_e93819
Author(s) : Zhang C , Xu Y , Zhong Q , Li X , Gao P , Feng C , Chu Q , Chen Y , Liu D
Ref : PLoS ONE , 9 :e93819 , 2014
Abstract : Two major forms of human carboxylesterase (CES), CES1A and CES2, dominate the pharmacokinetics of most prodrugs such as imidapril and irinotecan (CPT-11). Excipients, largely used as insert vehicles in formulation, have been recently reported to affect drug enzyme activity. The influence of excipients on the activity of CES remains undefined. In this study, the inhibitory effects of 25 excipients on the activities of CES1A1 and CES2 were evaluated. Imidapril and CPT-11 were used as substrates and cultured with liver microsomes in vitro. Imidapril hydrolase activities of recombinant CES1A1 and human liver microsomes (HLM) were strongly inhibited by sodium lauryl sulphate (SLS) and polyoxyl 40 hydrogenated castor oil (RH40) [Inhibition constant (Ki) = 0.04+/-0.01 mug/ml and 0.20+/-0.09 mug/ml for CES1A1, and 0.12+/-0.03 mug/ml and 0.76+/-0.33 mug/ml, respectively, for HLM]. The enzyme hydrolase activity of recombinant CES2 was substantially inhibited by Tween 20 and polyoxyl 35 castor oil (EL35) (Ki = 0.93+/-0.36 mug/ml and 4.4+/-1.24 mug/ml, respectively). Thus, these results demonstrate that surfactants such as SLS, RH40, Tween 20 and EL35 may attenuate the CES activity; such inhibition should be taken into consideration during drug administration.
ESTHER : Zhang_2014_PLoS.One_9_e93819
PubMedSearch : Zhang_2014_PLoS.One_9_e93819
PubMedID: 24699684

Title : Genome sequence of Anopheles sinensis provides insight into genetics basis of mosquito competence for malaria parasites - Zhou_2014_BMC.Genomics_15_42
Author(s) : Zhou D , Zhang D , Ding G , Shi L , Hou Q , Ye Y , Xu Y , Zhou H , Xiong C , Li S , Yu J , Hong S , Yu X , Zou P , Chen C , Chang X , Wang W , Lv Y , Sun Y , Ma L , Shen B , Zhu C
Ref : BMC Genomics , 15 :42 , 2014
Abstract : BACKGROUND: Anopheles sinensis is an important mosquito vector of Plasmodium vivax, which is the most frequent and widely distributed cause of recurring malaria throughout Asia, and particularly in China, Korea, and Japan.
RESULTS: We performed 454 next-generation sequencing and obtained a draft sequence of A. sinensis assembled into scaffolds spanning 220.8 million base pairs. Analysis of this genome sequence, we observed expansion and contraction of several immune-related gene families in anopheline relative to culicine mosquito species. These differences suggest that species-specific immune responses to Plasmodium invasion underpin the biological differences in susceptibility to Plasmodium infection that characterize these two mosquito subfamilies.
CONCLUSIONS: The A. sinensis genome produced in this study, provides an important resource for analyzing the genetic basis of susceptibility and resistance of mosquitoes to Plasmodium parasites research which will ultimately facilitate the design of urgently needed interventions against this debilitating mosquito-borne disease.
ESTHER : Zhou_2014_BMC.Genomics_15_42
PubMedSearch : Zhou_2014_BMC.Genomics_15_42
PubMedID: 24438588
Gene_locus related to this paper: anoga-Q7PVF9 , 9dipt-a0a084vlt1 , 9dipt-a0a084vdq2 , 9dipt-sime3xf.a , 9dipt-sime3xf.b , 9dipt-a0a084vbj8 , 9dipt-a0a084wan7 , 9dipt-a0a084wik4 , 9dipt-a0a084wk64 , 9dipt-a0a084wez8 , 9dipt-a0a084vji7 , 9dipt-a0a084vlc2 , 9dipt-a0a084vsa5 , 9dipt-a0a084wlk0 , 9dipt-a0a084wah8 , 9dipt-a0a084wln4 , 9dipt-a0a084we78 , 9dipt-a0a084wjm6 , 9dipt-a0a084wjm7 , 9dipt-a0a084we77 , 9dipt-a0a084wlk1 , 9dipt-a0a084we80 , 9dipt-a0a084wjm4 , 9dipt-a0a084w1n7 , 9dipt-a0a084we79 , 9dipt-a0a084wev9 , 9dipt-a0a084vlc3 , 9dipt-a0a084vdq4 , 9dipt-a0a084vdq5 , 9dipt-a0a084vdq1 , 9dipt-a0a084wah9 , 9dipt-a0a084wan6 , 9dipt-a0a084wlj8 , 9dipt-a0a084wk45 , 9dipt-a0a084wk46 , 9dipt-a0a084wlj9 , 9dipt-a0a084vsa4 , 9dipt-a0a084vs93 , 9dipt-a0a084wl93 , anosi-a0a0f7kyf5 , anosi-a0a0f7l1f2 , anosi-a0a084wum0 , anost-a0a182xxz0 , anosi-a0a084vn28 , anosi-a0a084vpt0 , anoga-q7q887

Title : Conversion of a Rhizopus chinensis lipase into an esterase by lid swapping - Yu_2014_J.Lipid.Res_55_1044
Author(s) : Yu XW , Zhu SS , Xiao R , Xu Y
Ref : J Lipid Res , 55 :1044 , 2014
Abstract : In an effort to explore the feasibility of converting a lipase into an esterase by modifying the lid region, we designed and characterized two novel Rhizopus chinensis lipase variants by lid swapping. The substrate specificity of an R. chinensis lipase was successfully modified toward water-soluble substrates, that is, turned into an esterase, by replacing the hydrophobic lid with a hydrophilic lid from ferulic acid esterase from Aspergillus niger. Meanwhile, as a comparison, the lid of R. chinensis lipase was replaced by a hydrophobic lid from Rhizomucor miehei lipase, which did not alter its substrate specificity but led to a 5.4-fold higher catalytic efficiency (k*cat/K*m) toward p-nitrophenyl laurate. Based on the analysis of structure-function relationships, it suggests that the amphipathic nature of the lid is very important for the substrate specificity. This study provides new insight into the structural basis of lipase specificities and a way to tune the substrate preference of lipases.
ESTHER : Yu_2014_J.Lipid.Res_55_1044
PubMedSearch : Yu_2014_J.Lipid.Res_55_1044
PubMedID: 24670990

Title : Maternal supplementation of nucleotides improves the behavioral development of prenatal ethanol-exposed mice - Dong_2014_Cogn.Affect.Behav.Neurosci_14_879
Author(s) : Dong W , Wu Z , Xu L , Fang Y , Xu Y
Ref : Cogn Affect Behavioral Neuroscience , 14 :879 , 2014
Abstract : Maternal ethanol consumption during pregnancy can induce learning deficits in the offspring. The objective of this study was to assess whether supplementation of exogenous nucleotides during pregnancy and lactation would ameliorate prenatal ethanol-induced learning and memory deficits in the offspring of mice, and to explore the possible mechanisms. In the present study, pregnant C57BL/6J mice were exposed to ethanol (5 g/kg body weight) intragastrically from gestational day (GD) 6 to GD15. The dams in exogenous nucleotide intervention groups were fed with feed containing 0.01 %, 0.04 %, or 0.16 % nucleotide powder, with control and ethanol groups receiving normal feed. The dams were allowed to deliver naturally and to breast feed their offspring. After weaning, behavioral tests were carried out in the offspring of each group. Serum oxidation indexes were analyzed, and the hippocampus of each offspring was collected and detected for acetyl cholinesterase (AChE) activity and the expression of p-CREB, CREB, and BDNF. The results showed that maternal supplementation with exogenous nucleotides during pregnancy could ameliorate prenatal ethanol-induced learning and memory deficits in the offspring of mice, through improving their antioxidant capacity, reversing hippocampus AChE levels, and allowing the expression of some proteins related to learning and memory. However, different sensitivities were found between the two sexes.
ESTHER : Dong_2014_Cogn.Affect.Behav.Neurosci_14_879
PubMedSearch : Dong_2014_Cogn.Affect.Behav.Neurosci_14_879
PubMedID: 24146316

Title : Platelet aggregation unchanged by lipoprotein-associated phospholipase A inhibition: results from an in vitro study and two randomized phase I trials - Shaddinger_2014_PLoS.One_9_e83094
Author(s) : Shaddinger BC , Xu Y , Roger JH , Macphee CH , Handel M , Baidoo CA , Magee M , Lepore JJ , Sprecher DL
Ref : PLoS ONE , 9 :e83094 , 2014
Abstract : BACKGROUND: We explored the theorized upregulation of platelet-activating factor (PAF)- mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials. METHODS AND RESULTS: Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA2 inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n=26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n=58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0-10 microg/ml) for characterizing EC50 values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC50 values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA2 inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9-27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC50 examination. CONCLUSIONS: Lp-PLA2 inhibition does not enhance platelet aggregation. TRIAL REGISTRATION: 1) Study 1: ClinicalTrials.gov NCT01745458 2) Study 2: ClinicalTrials.gov NCT00387257.
ESTHER : Shaddinger_2014_PLoS.One_9_e83094
PubMedSearch : Shaddinger_2014_PLoS.One_9_e83094
PubMedID: 24475026

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 : Dynamics of fecal microbial communities in children with diarrhea of unknown etiology and genomic analysis of associated Streptococcus lutetiensis - Jin_2013_BMC.Microbiol_13_141
Author(s) : Jin D , Chen C , Li L , Lu S , Li Z , Zhou Z , Jing H , Xu Y , Du P , Wang H , Xiong Y , Zheng H , Bai X , Sun H , Wang L , Ye C , Gottschalk M , Xu J
Ref : BMC Microbiol , 13 :141 , 2013
Abstract : BACKGROUND: The sequences of the 16S rRNA genes extracted from fecal samples provide insights into the dynamics of fecal microflora. This potentially gives valuable etiological information for patients whose conditions have been ascribed to unknown pathogens, which cannot be accomplished using routine culture methods. We studied 33 children with diarrhea who were admitted to the Children's Hospital in Shanxi Province during 2006.
RESULTS: Nineteen of 33 children with diarrhea could not be etiologically diagnosed by routine culture and polymerase chain reaction methods. Eleven of 19 children with diarrhea of unknown etiology had Streptococcus as the most dominant fecal bacterial genus at admission. Eight of nine children whom three consecutive fecal samples were collected had Streptococcus as the dominant fecal bacterial genus, including three in the Streptococcus bovis group and three Streptococcus sp., which was reduced during and after recovery. We isolated strains that were possibly from the S. bovis group from feces sampled at admission, which were then identified as Streptococcus lutetiensis from one child and Streptococcus gallolyticus subsp. pasteurianus from two children. We sequenced the genome of S. lutetiensis and identified five antibiotic islands, two pathogenicity islands, and five unique genomic islands. The identified virulence genes included hemolytic toxin cylZ of Streptococcus agalactiae and sortase associated with colonization of pathogenic streptococci.
CONCLUSIONS: We identified S. lutetiensis and S. gallolyticus subsp. pasteurianus from children with diarrhea of unknown etiology, and found pathogenic islands and virulence genes in the genome of S. lutetiensis.
ESTHER : Jin_2013_BMC.Microbiol_13_141
PubMedSearch : Jin_2013_BMC.Microbiol_13_141
PubMedID: 23782707

Title : Crystal structures of two phytohormone signal-transducing alpha\/beta hydrolases: karrikin-signaling KAI2 and strigolactonesignaling DWARF14 -
Author(s) : Zhao LH , Zhou XE , Wu ZS , Yi W , Xu Y , Li S , Xu TH , Liu Y , Chen RZ , Kovach A , Kang Y , Hou L , He Y , Xie C , Song W , Zhong D , Wang Y , Li J , Zhang C , Melcher K , Xu HE
Ref : Cell Res , 23 :436 , 2013
PubMedID: 23381136
Gene_locus related to this paper: orysj-Q10QA5

Title : Poster: Structures of alpha7 and alpha4beta2 nAChR transmenbrane domains and associated binding sites for allosteric modulators -
Author(s) : Bondarenko V , Mowrey D , Xu Y , Tang P
Ref : Biochemical Pharmacology , 86 :1227 , 2013
PubMedID:

Title : High-level expression and characterization of a chimeric lipase from Rhizopus oryzae for biodiesel production - Yu_2013_Biotechnol.Biofuels_6_29
Author(s) : Yu XW , Sha C , Guo YL , Xiao R , Xu Y
Ref : Biotechnol Biofuels , 6 :29 , 2013
Abstract : ABSTRACT: BACKGROUND: Production of biodiesel from non-edible oils is receiving increasing attention. Tung oil, called "China wood oil" is one kind of promising non-edible biodiesel oil in China. To our knowledge, tung oil has not been used to produce biodiesel by enzymatic method. The enzymatic production of biodiesel has been investigated extensively by using Rhizopus oryzae lipase as catalyst. However, the high cost of R. oryzae lipase remains a barrier for its industrial applications. Through different heterologous expression strategies and fermentation techniques, the highest expression level of the lipase from R. oryzae reached 1334 U/mL in Pichia pastoris, which is still not optimistic for industry applications.
RESULTS: The prosequence of lipases from Rhizopus sp. is very important for the folding and secretion of an active lipase. A chimeric lipase from R. oryzae was constructed by replacing the prosequence with that from the R. chinensis lipase and expressed in P. pastoris. The maximum activity of the chimera reached 4050 U/mL, which was 11 fold higher than that of the parent. The properties of the chimera were studied. The immobilized chimera was used successfully for biodiesel production from tung oil, which achieved higher FAME yield compared with the free chimeric lipase, non-chimeric lipase and mature lipase. By response surface methodology, three variables, water content, methanol to tung oil molar ratio and enzyme dosage were proved to be crucial parameters for biosynthesis of FAME and the FAME yield reached 91.9+/-2.5 % at the optimized conditions by adding 5.66 wt.% of the initial water based on oil weight, 3.88 of methanol to tung oil molar ratio and 13.24 wt.% of enzyme concentration based on oil weight at 40 [degree sign]C.
CONCLUSIONS: This is the first report on improving the expression level of the lipase from R. oryzae by replacing prosequences. The immobilized chimera was used successfully for biodiesel production from tung oil. Using tung oil as non-edible raw material and a chimeric lipase from R. oryzae as an economic catalyst make this study a promising one for biodiesel applications.
ESTHER : Yu_2013_Biotechnol.Biofuels_6_29
PubMedSearch : Yu_2013_Biotechnol.Biofuels_6_29
PubMedID: 23432946

Title : Effects of puerarin on cholinergic enzymes in the brain of ovariectomized guinea pigs - Zhang_2013_Int.J.Neurosci_123_783
Author(s) : Zhang Y , Chen Y , Shan Y , Wang D , Zhu C , Xu Y
Ref : International Journal of Neuroscience , 123 :783 , 2013
Abstract : Estrogen has beneficial effects on neurodegenerative disorders and cognitive function of postmenopausal women. Puerarin, isolated from Pueraria lobota, has been classified as a phytoestrogen, which can be highly effective against cerebrovascular diseases. In this study, the effects of puerarin on neural cholinergic system in the brain of ovariectomized guinea pigs were studied. The puerarin at the doses used (15 mg/kg body weight (bw)/day and 30 mg/kg bw/day) for 10 days had the estrogenic activity indicated by the attenuation of the reduction of uterine weight induced by ovariectomy. In brain, puerarin treatment increased choline acetyltransferase (ChAT) activity and expression in hippocampus, and increased ChAT immnuopositive signals in septal diagonal region. Puerarin treatment could suppress the increase of acetylcholinesterase expression and activity to the levels of the intact group, although they were not significantly different from those of the ovariectomized animals. Moreover, puerarin decreased the beta-amyloid immunopositive staining in hippocampus. In brief, the present study suggests that puerarin prevents the dysfunction of the neuronal cholinergic system and ameliorates the increase of beta-amyloid caused by estrogen deficiency.
ESTHER : Zhang_2013_Int.J.Neurosci_123_783
PubMedSearch : Zhang_2013_Int.J.Neurosci_123_783
PubMedID: 23668913

Title : Characterization of CpdC, a large-ring lactone-hydrolyzing enzyme from Pseudomonas sp. strain HI-70, and its use as a fusion tag facilitating overproduction of proteins in Escherichia coli - Xu_2013_Appl.Environ.Microbiol_79_7091
Author(s) : Xu Y , Grosse S , Iwaki H , Hasegawa Y , Lau PC
Ref : Applied Environmental Microbiology , 79 :7091 , 2013
Abstract : There are few entries of carbon-carbon bond hydrolases (EC 3.7.1.-) in the ExPASy database. In microbes, these enzymes play an essential role in the metabolism of alicyclic or aromatic compounds as part of the global carbon cycle. CpdC is a omega-pentadecalactone hydrolase derived from the degradation pathway of cyclopentadecanol or cyclopentadecanone by Pseudomonas sp. strain HI-70. CpdC was purified to homogeneity and characterized. It is active as a dimer of 56,000 Da with a subunit molecular mass of 33,349. Although CpdC has the highest activity and reaction rate (kcat) toward omega-pentadecalactone, its catalytic efficiency favors lauryl lactone as a substrate. The melting temperature (Tm) of CpdC was estimated to be 50.9 +/- 0.1 degrees C. The half-life of CpdC at 35 degrees C is several days. By virtue of its high level of expression in Escherichia coli, the intact CpdC-encoding gene and progressive 3'-end deletions were employed in the construction of a series of fusion plasmid system. Although we found them in inclusion bodies, proof-of-concept of overproduction of three microbial cutinases of which the genes were otherwise expressed poorly or not at all in E. coli was demonstrated. On the other hand, two antigenic proteins, azurin and MPT63, were readily produced in soluble form.
ESTHER : Xu_2013_Appl.Environ.Microbiol_79_7091
PubMedSearch : Xu_2013_Appl.Environ.Microbiol_79_7091
PubMedID: 24038681

Title : Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis - Xu_2013_Hepatology__1
Author(s) : Xu J , Li Y , Chen WD , Xu Y , Yin L , Ge X , Jadhav K , Adorini L , Zhang Y
Ref : Hepatology , :1 , 2013
Abstract : Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. Conclusion: Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis. (Hepatology 2014).
ESTHER : Xu_2013_Hepatology__1
PubMedSearch : Xu_2013_Hepatology__1
PubMedID: 24038130
Gene_locus related to this paper: mouse-Ces1g

Title : Poster: Functional chimera of the human alpha7 acetylcholine receptor for mechanistic investigations of allosteric modulation -
Author(s) : Tillman TS , Seyoum E , Xu Y , Tang P
Ref : Biochemical Pharmacology , 86 :1226 , 2013
PubMedID:

Title : Characterization of the biosynthetic genes for 10,11-dehydrocurvularin, a heat shock response-modulating anticancer fungal polyketide from Aspergillus terreus - Xu_2013_Appl.Environ.Microbiol_79_2038
Author(s) : Xu Y , Espinosa-Artiles P , Schubert V , Xu YM , Zhang W , Lin M , Gunatilaka AA , Sussmuth R , Molnar I
Ref : Applied Environmental Microbiology , 79 :2038 , 2013
Abstract : 10,11-Dehydrocurvularin is a prevalent fungal phytotoxin with heat shock response and immune-modulatory activities. It features a dihydroxyphenylacetic acid lactone polyketide framework with structural similarities to resorcylic acid lactones like radicicol or zearalenone. A genomic locus was identified from the dehydrocurvularin producer strain Aspergillus terreus AH-02-30-F7 to reveal genes encoding a pair of iterative polyketide synthases (A. terreus CURS1 [AtCURS1] and AtCURS2) that are predicted to collaborate in the biosynthesis of 10,11-dehydrocurvularin. Additional genes in this locus encode putative proteins that may be involved in the export of the compound from the cell and in the transcriptional regulation of the cluster. 10,11-Dehydrocurvularin biosynthesis was reconstituted in Saccharomyces cerevisiae by heterologous expression of the polyketide synthases. Bioinformatic analysis of the highly reducing polyketide synthase AtCURS1 and the nonreducing polyketide synthase AtCURS2 highlights crucial biosynthetic programming differences compared to similar synthases involved in resorcylic acid lactone biosynthesis. These differences lead to the synthesis of a predicted tetraketide starter unit that forms part of the 12-membered lactone ring of dehydrocurvularin, as opposed to the penta- or hexaketide starters in the 14-membered rings of resorcylic acid lactones. Tetraketide N-acetylcysteamine thioester analogues of the starter unit were shown to support the biosynthesis of dehydrocurvularin and its analogues, with yeast expressing AtCURS2 alone. Differential programming of the product template domain of the nonreducing polyketide synthase AtCURS2 results in an aldol condensation with a different regiospecificity than that of resorcylic acid lactones, yielding the dihydroxyphenylacetic acid scaffold characterized by an S-type cyclization pattern atypical for fungal polyketides.
ESTHER : Xu_2013_Appl.Environ.Microbiol_79_2038
PubMedSearch : Xu_2013_Appl.Environ.Microbiol_79_2038
PubMedID: 23335766
Gene_locus related to this paper: aspte-curs2

Title : Rational reprogramming of fungal polyketide first-ring cyclization - Xu_2013_Proc.Natl.Acad.Sci.U.S.A_110_5398
Author(s) : Xu Y , Zhou T , Zhou Z , Su S , Roberts SA , Montfort WR , Zeng J , Chen M , Zhang W , Lin M , Zhan J , Molnar I
Ref : Proc Natl Acad Sci U S A , 110 :5398 , 2013
Abstract : Resorcylic acid lactones and dihydroxyphenylacetic acid lactones represent important pharmacophores with heat shock response and immune system modulatory activities. The biosynthesis of these fungal polyketides involves a pair of collaborating iterative polyketide synthases (iPKSs): a highly reducing iPKS with product that is further elaborated by a nonreducing iPKS (nrPKS) to yield a 1,3-benzenediol moiety bridged by a macrolactone. Biosynthesis of unreduced polyketides requires the sequestration and programmed cyclization of highly reactive poly-beta-ketoacyl intermediates to channel these uncommitted, pluripotent substrates to defined subsets of the polyketide structural space. Catalyzed by product template (PT) domains of the fungal nrPKSs and discrete aromatase/cyclase enzymes in bacteria, regiospecific first-ring aldol cyclizations result in characteristically different polyketide folding modes. However, a few fungal polyketides, including the dihydroxyphenylacetic acid lactone dehydrocurvularin, derive from a folding event that is analogous to the bacterial folding mode. The structural basis of such a drastic difference in the way a PT domain acts has not been investigated until now. We report here that the fungal vs. bacterial folding mode difference is portable on creating hybrid enzymes, and we structurally characterize the resulting unnatural products. Using structure-guided active site engineering, we unravel structural contributions to regiospecific aldol condensations and show that reshaping the cyclization chamber of a PT domain by only three selected point mutations is sufficient to reprogram the dehydrocurvularin nrPKS to produce polyketides with a fungal fold. Such rational control of first-ring cyclizations will facilitate efforts to the engineered biosynthesis of novel chemical diversity from natural unreduced polyketides.
ESTHER : Xu_2013_Proc.Natl.Acad.Sci.U.S.A_110_5398
PubMedSearch : Xu_2013_Proc.Natl.Acad.Sci.U.S.A_110_5398
PubMedID: 23509261
Gene_locus related to this paper: aspte-curs2 , floch-rads2

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 : Thioesterase domains of fungal nonreducing polyketide synthases act as decision gates during combinatorial biosynthesis - Xu_2013_J.Am.Chem.Soc_135_10783
Author(s) : Xu Y , Zhou T , Zhang S , Xuan LJ , Zhan J , Molnar I
Ref : Journal of the American Chemical Society , 135 :10783 , 2013
Abstract : A crucial step during the programmed biosynthesis of fungal polyketide natural products is the release of the final polyketide intermediate from the iterative polyketide synthases (iPKSs), most frequently by a thioesterase (TE) domain. Realization of combinatorial biosynthesis with iPKSs requires TE domains that can accept altered polyketide intermediates generated by hybrid synthase enzymes and successfully release "unnatural products" with the desired structure. Achieving precise control over product release is of paramount importance with O-C bond-forming TE domains capable of macrocyclization, hydrolysis, transesterification, and pyrone formation that channel reactive, pluripotent polyketide intermediates to defined structural classes of bioactive secondary metabolites. By exploiting chimeric iPKS enzymes to offer substrates with controlled structural variety to two orthologous O-C bond-forming TE domains in situ, we show that these enzymes act as nonequivalent decision gates, determining context-dependent release mechanisms and overall product flux. Inappropriate choice of a TE could eradicate product formation in an otherwise highly productive chassis. Conversely, a judicious choice of a TE may allow the production of a desired hybrid metabolite. Finally, a serendipitous choice of a TE may reveal the unexpected productivity of some chassis. The ultimate decision gating role of TE domains influences the observable outcome of combinatorial domain swaps, emphasizing that the deduced programming rules are context dependent. These factors may complicate engineering the biosynthesis of a desired "unnatural product" but may also open additional avenues to create biosynthetic novelty based on fungal nonreduced polyketides.
ESTHER : Xu_2013_J.Am.Chem.Soc_135_10783
PubMedSearch : Xu_2013_J.Am.Chem.Soc_135_10783
PubMedID: 23822773
Gene_locus related to this paper: aspte-curs2 , floch-rads2

Title : [Enhanced thermostability of Rhizopus chinensis lipase by error-prone PCR] - Wang_2013_Sheng.Wu.Gong.Cheng.Xue.Bao_29_1753
Author(s) : Wang R , Yu X , Xu Y
Ref : Sheng Wu Gong Cheng Xue Bao , 29 :1753 , 2013
Abstract : Directed evolution was conducted to improve the thermostability of lipase from Rhizopus chinensis CCTCC M201021. Mutations were introduced by two rounds of error-prone PCR and mutant lipase was selected by fast-blue RR top agar screening. Two positive variants were selected in the first-round and four in the second-round screening process. Ep2-4 was proved as the most thermostable lipase and its DNA sequencing revealed three amino acid substitutions: A129S, P168L and V329A. Compared with the parent, its half-life at 60 degrees C was 5.4- times longer and T50 was 7.8 degrees higher. Purified lipase of Ep2-4 was characterized and the result shows that its thermostability improved without compromising enzyme activity. According to the mimicked protein structure, mutation A129S formed a hydrogen bond with Gln133 and improved the thermostability by increasing the hydrophilicity and polarity of protein; mutation P168L by forming a hydrophobic bond with the nearby Leu164.
ESTHER : Wang_2013_Sheng.Wu.Gong.Cheng.Xue.Bao_29_1753
PubMedSearch : Wang_2013_Sheng.Wu.Gong.Cheng.Xue.Bao_29_1753
PubMedID: 24660623

Title : Free energy landscape for the binding process of Huperzine A to acetylcholinesterase - Bai_2013_Proc.Natl.Acad.Sci.U.S.A_110_4273
Author(s) : Bai F , Xu Y , Chen J , Liu Q , Gu J , Wang X , Ma J , Li H , Onuchic JN , Jiang H
Ref : Proc Natl Acad Sci U S A , 110 :4273 , 2013
Abstract : Drug-target residence time (t = 1/k(off), where k(off) is the dissociation rate constant) has become an important index in discovering better- or best-in-class drugs. However, little effort has been dedicated to developing computational methods that can accurately predict this kinetic parameter or related parameters, k(off) and activation free energy of dissociation (DeltaG(off) not equal). In this paper, energy landscape theory that has been developed to understand protein folding and function is extended to develop a generally applicable computational framework that is able to construct a complete ligand-target binding free energy landscape. This enables both the binding affinity and the binding kinetics to be accurately estimated. We applied this method to simulate the binding event of the anti-Alzheimer's disease drug (-)-Huperzine A to its target acetylcholinesterase (AChE). The computational results are in excellent agreement with our concurrent experimental measurements. All of the predicted values of binding free energy and activation free energies of association and dissociation deviate from the experimental data only by less than 1 kcal/mol. The method also provides atomic resolution information for the (-)-Huperzine A binding pathway, which may be useful in designing more potent AChE inhibitors. We expect this methodology to be widely applicable to drug discovery and development.
ESTHER : Bai_2013_Proc.Natl.Acad.Sci.U.S.A_110_4273
PubMedSearch : Bai_2013_Proc.Natl.Acad.Sci.U.S.A_110_4273
PubMedID: 23440190

Title : The interaction between OsMADS57 and OsTB1 modulates rice tillering via DWARF14 - Guo_2013_Nat.Commun_4_1566
Author(s) : Guo S , Xu Y , Liu H , Mao Z , Zhang C , Ma Y , Zhang Q , Meng Z , Chong K
Ref : Nat Commun , 4 :1566 , 2013
Abstract : Rice tillering is a multigenic trait that influences grain yield, but its regulation molecular module is poorly understood. Here we report that OsMADS57 interacts with OsTB1 (TEOSINTE BRANCHED1) and targets D14 (Dwarf14) to control the outgrowth of axillary buds in rice. An activation-tagged mutant osmads57-1 and OsMADS57-overexpression lines showed increased tillers, whereas OsMADS57 antisense lines had fewer tillers. OsMIR444a-overexpressing lines exhibited suppressed OsMADS57 expression and tillering. Furthermore, osmads57-1 was insensitive to strigolactone treatment to inhibit axillary bud outgrowth, and OsMADS57's function in tillering was dependent on D14. D14 expression was downregulated in osmads57-1, but upregulated in antisense and OsMIR444a-overexpressing lines. OsMADS57 bound to the CArG motif [C(A/T)TTAAAAAG] in the promoter and directly suppressed D14 expression. Interaction of OsMADS57 with OsTB1 reduced OsMADS57 inhibition of D14 transcription. Therefore, OsMIR444a-regulated OsMADS57, together with OsTB1, target D14 to control tillering. This regulation mechanism could have important application in rice molecular breeding programs focused on high grain yield.
ESTHER : Guo_2013_Nat.Commun_4_1566
PubMedSearch : Guo_2013_Nat.Commun_4_1566
PubMedID: 23463009

Title : Highly sensitive detection of organophosphorus pesticides by acetylcholinesterase-coated thin film bulk acoustic resonator mass-loading sensor - Chen_2013_Biosens.Bioelectron_41_163
Author(s) : Chen D , Wang J , Xu Y , Li D , Zhang L , Li Z
Ref : Biosensors & Bioelectronics , 41 :163 , 2013
Abstract : An acetylcholinesterase-coated thin film bulk acoustic resonator has been developed for the detection of organophosphorus pesticides. The thin film bulk acoustic resonator acts as a robust mass-sensitive transducer for bio-sensing. This device works in thickness shear mode with a resonance at 1.97GHz. The detection is based on the inhibitory effects of organophosphorus compounds on the enzymatic activity of the acetylcholinesterase immobilized on one of the faces of the acoustic resonator. The enzyme reaction in the substrate solution and the inhibitory effect is observed are real time by measuring the frequency shift. The presence of organophosphorus pesticides can be detected from the diminution of the frequency shift compared with the levels found in their absence. The device exhibits linear responses, good reproducibility, simple operation, portability and a low detection limit of 5.3x10(-11)M for paraoxon. The detection results of organophosphorus pesticide residues in practical samples show that the proposed sensor has the feasibility and sensing accuracy comparable to gas chromatography.
ESTHER : Chen_2013_Biosens.Bioelectron_41_163
PubMedSearch : Chen_2013_Biosens.Bioelectron_41_163
PubMedID: 23017678

Title : Genome sequence of the Leisingera aquimarina type strain (DSM 24565(T)), a member of the marine Roseobacter clade rich in extrachromosomal elements - Riedel_2013_Stand.Genomic.Sci_8_389
Author(s) : Riedel T , Teshima H , Petersen J , Fiebig A , Davenport K , Daligault H , Erkkila T , Gu W , Munk C , Xu Y , Chen A , Pati A , Ivanova N , Goodwin LA , Chain P , Detter JC , Rohde M , Gronow S , Kyrpides NC , Woyke T , Goker M , Brinkhoff T , Klenk HP
Ref : Stand Genomic Sci , 8 :389 , 2013
Abstract : Leisingera aquimarina Vandecandelaere et al. 2008 is a member of the genomically well characterized Roseobacter clade within the family Rhodobacteraceae. Representatives of the marine Roseobacter clade are metabolically versatile and involved in carbon fixation and biogeochemical processes. They form a physiologically heterogeneous group, found predominantly in coastal or polar waters, especially in symbiosis with algae, in microbial mats, in sediments or associated with invertebrates. Here we describe the features of L. aquimarina DSM 24565(T) together with the permanent-draft genome sequence and annotation. The 5,344,253 bp long genome consists of one chromosome and an unusually high number of seven extrachromosomal elements and contains 5,129 protein-coding and 89 RNA genes. It was sequenced as part of the DOE Joint Genome Institute Community Sequencing Program 2010 and of the activities of the Transregional Collaborative Research Centre 51 funded by the German Research Foundation (DFG).
ESTHER : Riedel_2013_Stand.Genomic.Sci_8_389
PubMedSearch : Riedel_2013_Stand.Genomic.Sci_8_389
PubMedID: 24501625

Title : Role of Met93 and Thr96 in the Lid Hinge Region of Rhizopus chinensis Lipase - Zhu_2013_Appl.Biochem.Biotechnol_170_436
Author(s) : Zhu SS , Li M , Yu X , Xu Y
Ref : Appl Biochem Biotechnol , 170 :436 , 2013
Abstract : We engineered Rhizopus chinensis lipase to study its critical amino acid role in catalytic properties. Based on the amino acid sequence and three-dimensional model of the lipase, residues located in its lid hinge region (Met93 and Thr96) were replaced with corresponding amino acid residues (Ile93 and Asn96) found in the lid hinge region of Rhizopus oryzae lipase. The substitutions in the lid hinge region affected not only substrate specificity but also the thermostability of the lipase. Both lipases preferred p-nitrophenyl laurate and glyceryl trilaurate (C12). However, the variant S4-3O showed a slight decline in activity toward long-chain fatty acid (C16-C18). When enzymes activities decreased by half, the temperature of the variant (45 degrees C) was 22 degrees C lower than the parent (67 degrees C), probably substantially destabilized the structure of the lid region. The interfacial kinetic analysis of S4-3O suggested that the lower catalytic efficiency was due to a higher K m* value. According to the lipase structure investigated, Ile93Met played a role of narrowing the size of the hydrophobic patch, which affected the substrate binding affinity, and Asn96Thr destabilized the structure of the lipase by disrupting the H-bond interaction in the lid region.
ESTHER : Zhu_2013_Appl.Biochem.Biotechnol_170_436
PubMedSearch : Zhu_2013_Appl.Biochem.Biotechnol_170_436
PubMedID: 23546870
Gene_locus related to this paper: rhich-a3fm73

Title : The specific interaction of the photosensitizer methylene blue with acetylcholinesterase provides a model system for studying the molecular consequences of photodynamic therapy - Silman_2013_Chem.Biol.Interact_203_63
Author(s) : Silman I , Roth E , Paz A , Triquigneaux MM , Ehrenshaft M , Xu Y , Shnyrov VL , Sussman JL , Deterding LJ , Ashani Y , Mason RP , Weiner L
Ref : Chemico-Biological Interactions , 203 :63 , 2013
Abstract : The photosensitizer, methylene blue (MB), generates singlet oxygen ((1)O2) that irreversibly inhibits Torpedo californica acetylcholinesterase (TcAChE). In the dark MB inhibits reversibly, binding being accompanied by a bathochromic shift that can be used to show its displacement by other reversible inhibitors binding to the catalytic 'anionic' subsite (CAS), the peripheral 'anionic' subsite (PAS), or bridging them. Data concerning both reversible and irreversible inhibition are here reviewed. MB protects TcAChE from thermal denaturation, and differential scanning calorimetry reveals a approximately 8 degrees C increase in the denaturation temperature. The crystal structure of the MB/TcAChE complex reveals a single MB stacked against W279 in the PAS, pointing down the gorge towards the CAS. The intrinsic fluorescence of the irreversibly inhibited enzyme displays new emission bands that can be ascribed to N'-formylkynurenine (NFK); this was indeed confirmed using anti-NFK antibodies. Mass spectroscopy revealed that two Trp residues, Trp84 in the CAS, and Trp279 in the PAS, were the only Trp residues, out of a total of 14, significantly modified by photo-oxidation, both being converted to NFK. In the presence of competitive inhibitors that displace MB from the gorge, their modification is completely prevented. Thus, photo-oxidative damage caused by MB involves targeted release of (1)O2 by the bound photosensitizer within the aqueous milieu of the active-site gorge.
ESTHER : Silman_2013_Chem.Biol.Interact_203_63
PubMedSearch : Silman_2013_Chem.Biol.Interact_203_63
PubMedID: 23159732

Title : Enhancement of lipase r27RCL production in Pichia pastoris by regulating gene dosage and co-expression with chaperone protein disulfide isomerase - Sha_2013_Enzyme.Microb.Technol_53_438
Author(s) : Sha C , Yu XW , Lin NX , Zhang M , Xu Y
Ref : Enzyme Microb Technol , 53 :438 , 2013
Abstract : Pichia pastoris has been successfully used in the production of many secreted and intracellular recombinant proteins, but there is still a large room of improvement for this expression system. Two factors drastically influence the lipase r27RCL production from Rhizopus chinensis CCTCC M201021, which are gene dosage and protein folding in the endoplasmic reticulum (ER). Regarding the effect of gene dosage, the enzyme activity for recombinant strain with three copies lipase gene was 1.95-fold higher than that for recombinant strain with only one copy lipase gene. In addition, the lipase production was further improved by co-expression with chaperone PDI involved in the disulfide bond formation in the ER. Overall, the maximum enzyme activity reached 355U/mL by the recombinant strain with one copy chaperone gene PDI plus five copies lipase gene proRCL in shaking flasks, which was 2.74-fold higher than that for the control strain with only one copy lipase gene. Overall, co-expression with PDI vastly increased the capacity for processing proteins of ER in P. pastoris.
ESTHER : Sha_2013_Enzyme.Microb.Technol_53_438
PubMedSearch : Sha_2013_Enzyme.Microb.Technol_53_438
PubMedID: 24315648
Gene_locus related to this paper: rhich-a3fm73

Title : Enzymatic synthesis of extremely pure triacylglycerols enriched in conjugated linoleic acids - Cao_2013_Molecules_18_9704
Author(s) : Cao Y , Wang W , Xu Y , Yang B , Wang Y
Ref : Molecules , 18 :9704 , 2013
Abstract : This work was objectively targeted to synthesize extremely pure triacylglycerols (TAG) enriched in conjugated linoleic acids (CLAs) for medical and dietetic purposes. Extremely pure CLA-enriched TAG was successfully synthesized by using the multi-step process: TAG was primarily synthesized by lipase-catalyzed esterification of CLA and glycerol and then the lower glycerides [monoacylglycerol (MAG) and diacylglycerol (DAG)] in the esterification mixtures was hydrolyzed to free fatty acids (FFAs) by a mono- and di-acylglycerol lipase (lipase SMG1), finally, the FFAs were further separated from TAG by low temperature (150 degreesC) molecular distillation. The operation parameters for the lipase SMG1-catalyzed hydrolysis were optimized using response surface methodology based on the central composite rotatable design (CCRD). The operation parameters included water content, pH and reaction temperature and all of these three parameters showed significant effects on the hydrolysis of lower glycerides. The optimal conditions were obtained with a water content of 66.4% (w/w, with respect to oil mass), pH at 5.7 and 1 h of reaction time at 19.6 degreesC. Under these conditions, the content of lower glycerides in the reaction mixture decreased from 45.2% to 0.3% and the purity of CLA-enriched TAG reached 99.7%. Further purification of TAG was accomplished by molecular distillation and the final CLA-enriched TAG product yielded 99.8% of TAG. These extremely pure CLA-enriched TAG would be used for in vivo studies in animals and humans in order to get specic information concerning CLA metabolism.
ESTHER : Cao_2013_Molecules_18_9704
PubMedSearch : Cao_2013_Molecules_18_9704
PubMedID: 23945644

Title : Efficient secretion of lipase r27RCL in Pichia pastoris by enhancing the disulfide bond formation pathway in the endoplasmic reticulum - Sha_2013_J.Ind.Microbiol.Biotechnol_40_1241
Author(s) : Sha C , Yu XW , Zhang M , Xu Y
Ref : J Ind Microbiol Biotechnol , 40 :1241 , 2013
Abstract : The lipase r27RCL from Rhizopus chinensis CCTCC M201021 was heterologously expressed in Pichia pastoris GS115 by simultaneous co-expression with two secretion factors ERO1p and PDI involved in the endoplasmic reticulum (ER). Compared to the expression of the lipase alone (12,500 U/ml), co-expression with these two proteins resulted in the production of larger total quantities of enzymes. The largest increase was seen when the combined ERO1p/PDI system was co-expressed, resulting in approximately 30 % higher enzyme yields (16,200 U/ml) than in the absence of co-expressed secretion factors. The extracellular protein concentration of the recombinant strain Co XY RCL-5 reached 9.39 g/l in the 7-l fermentor. Simultaneously, the fermentation time was also shortened by about 8 h compared to that of the control. The substrate-specific consumption rate (Qs) and the product-specific production rate (Qp) were both investigated in this research. In conclusion, the space-time yield was improved by co-expression with ERO1p and PDI. This is a potential strategy for high level expression of other heterologous proteins in P. pastoris.
ESTHER : Sha_2013_J.Ind.Microbiol.Biotechnol_40_1241
PubMedSearch : Sha_2013_J.Ind.Microbiol.Biotechnol_40_1241
PubMedID: 23990169
Gene_locus related to this paper: rhich-a3fm73

Title : A thin film electro-acoustic enzyme biosensor allowing the detection of trace organophosphorus pesticides - Chen_2012_Anal.Biochem_429_42
Author(s) : Chen D , Wang J , Xu Y , Zhang L
Ref : Analytical Biochemistry , 429 :42 , 2012
Abstract : We report an analytical method using a thin film electro-acoustic resonator for the detection of organophosphorus pesticides The acetylcholinesterase AChE enzyme was immobilized on the surface of the resonator In the presence of organophosphorus compounds the degree of inhibitory effect of organophosphorus compounds on the AChE activity and the concentration of pesticides were detected in real time by measuring the frequency shift of the resonator The proposed device has a remarkably low detection limit of 1.8x10(-11)M and obvious advantages such as small size simple operation and integrated circuit compatibility providing a promising tool for pesticide analysis.
ESTHER : Chen_2012_Anal.Biochem_429_42
PubMedSearch : Chen_2012_Anal.Biochem_429_42
PubMedID: 22796536

Title : Engineering a Disulfide Bond in the Lid Hinge Region of Rhizopus chinensis Lipase: Increased Thermostability and Altered Acyl Chain Length Specificity - Yu_2012_PLoS.One_7_e46388
Author(s) : Yu XW , Tan NJ , Xiao R , Xu Y
Ref : PLoS ONE , 7 :e46388 , 2012
Abstract : The key to enzyme function is the maintenance of an appropriate balance between molecular stability and structural flexibility. The lid domain which is very important for interfacial activation is the most flexible part in the lipase structure In this work rational design was applied to explore the relationship between lid rigidity and lipase activity by introducing a disulfide bond in the hinge region of the lid in the hope of improving the thermostability of R chinensis lipase through stabilization of the lid domain without interfering with its catalytic performance. A disulfide bridge between F95C and F214C was introduced into the lipase from R chinensis in the hinge region of the lid according to the prediction of the Disulfide by Design algorithm. The disulfide variant showed substantially improved thermostability with an eleven-fold increase in the t(1/2 value at 60 degrees C and a 7 degrees C increase of T(m compared with the parent enzyme probably contributed by the stabilization of the geometric structure of the lid region. The additional disulfide bond did not interfere with the catalytic rate k(cat and the catalytic efficiency towards the short-chain fatty acid substrate however the catalytic efficiency of the disulfide variant towards pNPP decreased by 1.5-fold probably due to the block of the hydrophobic substrate channel by the disulfide bond. Furthermore in the synthesis of fatty acid methyl esters the maximum conversion rate by RCLCYS reached 95 which was 9 higher than that by RCL This is the first report on improving the thermostability of the lipase from R chinensis by introduction of a disulfide bond in the lid hinge region without compromising the catalytic rate.
ESTHER : Yu_2012_PLoS.One_7_e46388
PubMedSearch : Yu_2012_PLoS.One_7_e46388
PubMedID: 23056295

Title : A two-stage enzymatic ethanol-based biodiesel production in a packed bed reactor - Xu_2012_J.Biotechnol_162_407
Author(s) : Xu Y , Nordblad M , Woodley JM
Ref : J Biotechnol , 162 :407 , 2012
Abstract : A two-stage enzymatic process for producing fatty acid ethyl ester (FAEE) in a packed bed reactor is reported. The process uses an experimental immobilized lipase (NS 88001) and Novozym 435 to catalyze transesterification (first stage) and esterification (second stage), respectively. Both stages were conducted in a simulated series of reactors by repeatedly passing the reaction mixture through a single reactor, with separation of the by-product glycerol and water between passes in the first and second stages, respectively. The second stage brought the major components of biodiesel to 'in-spec' levels according to the European biodiesel specifications for methanol-based biodiesel. The highest overall productivity achieved in the first stage was 2.52 kg FAEE(kg catalyst)- h- at a superficial velocity of 7.6 cm min-, close to the efficiency of a stirred tank reactor under similar conditions. The overall productivity of the proposed two-stage process was 1.56 kg FAEE(kg catalyst)- h-. Based on this process model, the challenges of scale-up have been addressed and potential continuous process options have been proposed.
ESTHER : Xu_2012_J.Biotechnol_162_407
PubMedSearch : Xu_2012_J.Biotechnol_162_407
PubMedID: 22728395

Title : Structural and functional characterization of the interaction of the photosensitizing probe methylene blue with Torpedo californica acetylcholinesterase - Paz_2012_Protein.Sci_21_1138
Author(s) : Paz A , Roth E , Ashani Y , Xu Y , Shnyrov VL , Sussman JL , Silman I , Weiner L
Ref : Protein Science , 21 :1138 , 2012
Abstract : The photosensitizer methylene blue MB generates singlet oxygen that irreversibly inhibits Torpedo californica acetylcholinesterase TcAChE In the dark it inhibits reversibly Binding is accompanied by a bathochromic absorption shift used to demonstrate displacement by other acetylcholinesterase inhibitors interacting with the catalytic anionic subsite CAS the peripheral anionic subsite PAS or bridging them MB is a noncompetitive inhibitor of TcAChE competing with reversible inhibitors directed at both anionic subsites but a single site is involved in inhibition MB also quenches TcAChE's intrinsic fluorescence It binds to TcAChE covalently inhibited by a small organophosphate OP but not an OP containing a bulky pyrene Differential scanning calorimetry shows an 8 degrees increase in the denaturation temperature of the MB/TcAChE complex relative to native TcAChE and a less than twofold increase in cooperativity of the transition The crystal structure reveals a single MB stacked against Trp279 in the PAS oriented down the gorge toward the CAS it is plausible that irreversible inhibition is associated with photooxidation of this residue and others within the active-site gorge The kinetic and spectroscopic data showing that inhibitors binding at the CAS can impede binding of MB are reconciled by docking studies showing that the conformation adopted by Phe330 midway down the gorge in the MB/TcAChE crystal structure precludes simultaneous binding of a second MB at the CAS Conversely binding of ligands at the CAS dislodges MB from its preferred locus at the PAS The data presented demonstrate that TcAChE is a valuable model for understanding the molecular basis of local photooxidative damage.
ESTHER : Paz_2012_Protein.Sci_21_1138
PubMedSearch : Paz_2012_Protein.Sci_21_1138
PubMedID: 22674800
Gene_locus related to this paper: torca-ACHE

Title : Efficient production of biodiesel from waste grease: one-pot esterification and transesterification with tandem lipases - Yan_2012_Bioresour.Technol_123_332
Author(s) : Yan J , Li A , Xu Y , Ngo TP , Phua S , Li Z
Ref : Bioresour Technol , 123 :332 , 2012
Abstract : A novel concept and efficient method for producing biodiesel (FAME) from grease (15-40wt% free fatty acid, FFA) were developed by using tandem lipases for one-pot esterification of FFA and transesterification of triglyceride with methanol in a solvent-free system. Combining immobilized Candida antarctica lipase B (CALB) (Novozyme 435) favoring the esterification and immobilized Thermomyces lanuginosus lipase (TLL) (Lipozyme TLIM) preferring the transesterification at 2:8 (wt/wt) gave FAME in 80% yield, being better than that with Novozyme 435 or Lipozyme TLIM. Recombinant Escherichia coli (Calb/Tll) co-expressing CALB and TLL was engineered as a more efficient tandem-lipases system. Using wet or dry cells (4wt%) gave FAME in 87% or 95% yield, which is much better than that with E. coli cells expressing either CALB or TLL alone. Cells of E. coli (Calb/Tll) were recycled for five times and retained 75% productivity, thus being practical for producing biodiesel from grease.
ESTHER : Yan_2012_Bioresour.Technol_123_332
PubMedSearch : Yan_2012_Bioresour.Technol_123_332
PubMedID: 22940338

Title : Examining the interactome of huperzine A by magnetic biopanning - Guo_2012_PLoS.One_7_e37098
Author(s) : Guo W , Liu S , Peng J , Wei X , Sun Y , Qiu Y , Gao G , Wang P , Xu Y
Ref : PLoS ONE , 7 :e37098 , 2012
Abstract : Huperzine A is a bioactive compound derived from traditional Chinese medicine plant Qian Ceng Ta (Huperzia serrata), and was found to have multiple neuroprotective effects. In addition to being a potent acetylcholinesterase inhibitor, it was thought to act through other mechanisms such as antioxidation, antiapoptosis, etc. However, the molecular targets involved with these mechanisms were not identified. In this study, we attempted to exam the interactome of Huperzine A using a cDNA phage display library and also mammalian brain tissue extracts. The drugs were chemically linked on the surface of magnetic particles and the interactive phages or proteins were collected and analyzed. Among the various cDNA expressing phages selected, one was identified to encode the mitochondria NADH dehydrogenase subunit 1. Specific bindings between the drug and the target phages and target proteins were confirmed. Another enriched phage clone was identified as mitochondria ATP synthase, which was also panned out from the proteome of mouse brain tissue lysate. These data indicated the possible involvement of mitochondrial respiratory chain matrix enzymes in Huperzine A's pharmacological effects. Such involvement had been suggested by previous studies based on enzyme activity changes. Our data supported the new mechanism. Overall we demonstrated the feasibility of using magnetic biopanning as a simple and viable method for investigating the complex molecular mechanisms of bioactive molecules.
ESTHER : Guo_2012_PLoS.One_7_e37098
PubMedSearch : Guo_2012_PLoS.One_7_e37098
PubMedID: 22615909

Title : Dexamethasone regulates differential expression of carboxylesterase 1 and carboxylesterase 2 through activation of nuclear receptors - Zhang_2012_J.Huazhong.Univ.Sci.Technolog.Med.Sci_32_798
Author(s) : Zhang C , Gao P , Yin W , Xu Y , Xiang D , Liu D
Ref : J Huazhong Univ Sci Technolog Med Sci , 32 :798 , 2012
Abstract : Carboxylesterases (CESs) play important roles in the metabolism of endogenous and foreign compounds in physiological and pharmacological responses. The aim of this study was to investigate the effect of dexamethasone at different doses on the expression of CES1 and CES2. Imidapril and irinotecan hydrochloride (CPT-11) were used as special substrates for CES1 and CES2, respectively. Rat hepatocytes were cultured and treated with different concentrations of dexamethasone. The hydrolytic activity of CES1 and CES2 was tested by incubation experiment and their expression was quantitated by real-time PCR. A pharmacokinetic study was conducted in SD rats to further evaluate the effect of dexamethasone on CESs activity in vivo. Western blotting was performed to investigate the regulatory mechanism related to pregnane X receptor (PXR) and glucocorticoid receptor (GR). The results showed that exposure of cultured rat hepatocytes to nanomolar dexamethasone inhibited the imidapril hydrolase activity, which was slightly elevated by micromolar dexamethasone. For CES2, CPT-11 hydrolase activity was induced only when dexamethasone reached micromolar levels. The real-time PCR demonstrated that CES1 mRNA was markedly decreased by nanomolar dexamethasone and increased by micromolar dexamethasone, whereas CES2 mRNA was significantly increased by micromolar dexamethasone. The results of a complementary animal study showed that the concurrent administration of dexamethasone significantly increased the plasma concentration of the metabolite of imidapril while the ratio of CPT-11 to its metabolite SN-38 was significantly decreased. PXR protein was gradually increased by serial concentrations of dexamethasone. However, only nanomolar dexamethasone elevated the level of GR protein. The different concentrations of dexamethasone required suggested that suppression of CES1 may be mediated by GR whereas the induction of CES2 may result from the role of PXR. It was concluded that dexamethasone at different concentrations can differentially regulate CES1 and CES2.
ESTHER : Zhang_2012_J.Huazhong.Univ.Sci.Technolog.Med.Sci_32_798
PubMedSearch : Zhang_2012_J.Huazhong.Univ.Sci.Technolog.Med.Sci_32_798
PubMedID: 23271276

Title : Bacterial biosynthesis and maturation of the didemnin anti-cancer agents - Xu_2012_J.Am.Chem.Soc_134_8625
Author(s) : Xu Y , Kersten RD , Nam SJ , Lu L , Al-Suwailem AM , Zheng H , Fenical W , Dorrestein PC , Moore BS , Qian PY
Ref : Journal of the American Chemical Society , 134 :8625 , 2012
Abstract : The anti-neoplastic agent didemnin B from the Caribbean tunicate Trididemnum solidum was the first marine drug to be clinically tested in humans. Because of its limited supply and its complex cyclic depsipeptide structure, considerable challenges were encountered during didemnin B's development that continue to limit aplidine (dehydrodidemnin B), which is currently being evaluated in numerous clinical trials. Herein we show that the didemnins are bacterial products produced by the marine alpha-proteobacteria Tistrella mobilis and Tistrella bauzanensis via a unique post-assembly line maturation process. Complete genome sequence analysis of the 6,513,401 bp T. mobilis strain KA081020-065 with its five circular replicons revealed the putative didemnin biosynthetic gene cluster (did) on the 1,126,962 bp megaplasmid pTM3. The did locus encodes a 13-module hybrid non-ribosomal peptide synthetase-polyketide synthase enzyme complex organized in a collinear arrangement for the synthesis of the fatty acylglutamine ester derivatives didemnins X and Y rather than didemnin B as first anticipated. Imaging mass spectrometry of T. mobilis bacterial colonies captured the time-dependent extracellular conversion of the didemnin X and Y precursors to didemnin B, in support of an unusual post-synthetase activation mechanism. Significantly, the discovery of the didemnin biosynthetic gene cluster may provide a long-term solution to the supply problem that presently hinders this group of marine natural products and pave the way for the genetic engineering of new didemnin congeners.
ESTHER : Xu_2012_J.Am.Chem.Soc_134_8625
PubMedSearch : Xu_2012_J.Am.Chem.Soc_134_8625
PubMedID: 22458477

Title : Antibacterial bisabolane-type sesquiterpenoids from the sponge-derived fungus Aspergillus sp - Li_2012_Mar.Drugs_10_234
Author(s) : Li D , Xu Y , Shao CL , Yang RY , Zheng CJ , Chen YY , Fu XM , Qian PY , She ZG , de Voogd NJ , Wang CY
Ref : Mar Drugs , 10 :234 , 2012
Abstract : Four new bisabolane-type sesquiterpenoids, aspergiterpenoid A (1), (-)-sydonol (2), (-)-sydonic acid (3), and (-)-5-(hydroxymethyl)-2-(2',6',6'-trimethyltetrahydro-2H- pyran-2-yl)phenol (4) together with one known fungal metabolite (5) were isolated from the fermentation broth of a marine-derived fungus Aspergillus sp., which was isolated from the sponge Xestospongia testudinaria collected from the South China Sea. Four of them (1-4) are optically active compounds. Their structures and absolute configurations were elucidated by using NMR spectroscopic techniques and mass spectrometric analysis, and by comparing their optical rotations with those related known analogues. Compounds 1-5 showed selective antibacterial activity against eight bacterial strains with the MIC (minimum inhibiting concentrations) values between 1.25 and 20.0 microM. The cytotoxic, antifouling, and acetylcholinesterase inhibitory activities of these compounds were also examined.
ESTHER : Li_2012_Mar.Drugs_10_234
PubMedSearch : Li_2012_Mar.Drugs_10_234
PubMedID: 22363233

Title : Genome sequence of Enterobacter cloacae subsp. dissolvens SDM, an efficient biomass-utilizing producer of platform chemical 2,3-butanediol - Xu_2012_J.Bacteriol_194_897
Author(s) : Xu Y , Wang A , Tao F , Su F , Tang H , Ma C , Xu P
Ref : Journal of Bacteriology , 194 :897 , 2012
Abstract : Enterobacter cloacae subsp. dissolvens SDM has an extraordinary characteristic of biomass utilization for 2,3-butanediol production. Here we present a 4.9-Mb assembly of its genome. The key genes for regulation and metabolism of 2,3-butanediol production were annotated, which could provide further insights into the molecular mechanism of high-yield production of 2,3-butanediol.
ESTHER : Xu_2012_J.Bacteriol_194_897
PubMedSearch : Xu_2012_J.Bacteriol_194_897
PubMedID: 22275097
Gene_locus related to this paper: entcl-i6s5g2 , entcl-y1bd05 , entcl-g8lek8

Title : Enhanced thermostability of a Rhizopus chinensis lipase by in vivo recombination in Pichia pastoris - Yu_2012_Microb.Cell.Fact_11_102
Author(s) : Yu XW , Wang R , Zhang M , Xu Y , Xiao R
Ref : Microb Cell Fact , 11 :102 , 2012
Abstract : BACKGROUND: Lipase from Rhizopus chinensis is a versatile biocatalyst for various bioconversions and has been expressed at high-level in Pichia pastoris. However, the use of R. chinensis lipase in industrial applications is restricted by its low thermostability. Directed evolution has been proven to be a powerful and efficient protein engineering tool for improvement of biocatalysts. The present work describes improvement of the thermostability of R. chinensis lipase by directed evolution using P. pastoris as the host. RESULTS: An efficient, fast and highly simplified method was developed to create a mutant gene library in P. pastoris based on in vivo recombination, whose recombination efficiency could reach 2.3 x 10/microg DNA. The thermostability of r27RCL was improved significantly by two rounds of error-prone PCR and two rounds of DNA shuffling in P. pastoris. The S4-3 variant was found to be the most thermostable lipase, under the conditions tested. Compared with the parent, the optimum temperature of S4-3 was two degrees higher, Tm was 22 degrees higher and half-lives at 60 degreesC and 65 degreesC were 46- and 23- times longer. Moreover, the catalytic efficiency kcat/Km of S4-3 was comparable to the parent. Stabilizing mutations probably increased thermostability by increasing the hydrophilicity and polarity of the protein surface and creating hydrophobic contacts inside the protein. CONCLUSIONS: P. pastoris was shown to be a valuable cell factory to improve thermostability of enzymes by directed evolution and it also could be used for improving other properties of enzymes. In this study, by using P. pastoris as a host to build mutant pool, we succeeded in obtaining a thermostable variant S4-3 without compromising enzyme activity and making it a highly promising candidate for future applications at high temperatures.
ESTHER : Yu_2012_Microb.Cell.Fact_11_102
PubMedSearch : Yu_2012_Microb.Cell.Fact_11_102
PubMedID: 22866667
Gene_locus related to this paper: rhich-a3fm73

Title : [Clinical application of the transjugular intrahepatic portosystemic stent-shunt in the emergency treatment of esophagogastric varices bleeding due to cirrhosis] - You_2011_Zhonghua.Gan.Zang.Bing.Za.Zhi_19_490
Author(s) : You LY , Li YC , Yan D , Xu Y , Yang J , Yang LH , Cheng F , Yang JH
Ref : Zhonghua Gan Zang Bing Za Zhi , 19 :490 , 2011
Abstract : OBJECTIVE: To investigate the effects of transjugular intrahepatic portosystemic stent-shunt (TIPS) in emergency treatment of esophagogastric varices bleeding for the cirrhosis patients. METHODS: 39 cases with esophageal and gastric varices bleeding due to liver cirrhosis received TIPS and were followed-up for 1 to 12 months, the short-term effects including 24 hours haemostasis rates post TIPS, pressure gradient between portal vein and systemic circulation, average pressure of portal vein were observed. The levels of albumin, cholinesterase, total bilirubin and prothrombin time post TIPS were also evaluated were observed and evaluated. RESULTS: 37 cases received TIPS successfully among the 39 patients, with a total effective rate of 94.87% (37/39) and the rate of hemostasis in 24 hours was 100%. PSG dropped from (30.44+/-7.68) cm H2O to (18.78+/-4.71) cm H2O, mean portal pressure declined from (38.22+/-7.40) cm H2O to (27.00+/-5.38) cm H2O (P is less than 0.01). No significant differences existed at the level of albumin(A) and cholinesterase (CHE) before and after operation (P is more than 0.05). The relapse rate of frame stenosis was 5.71% (2/35). The incidence rate of hepatic encephalopathy was 13.51% (5/37). The relapse rate of rehaemorrhagia was 2.86% (1/35). The incidence rate of hepatic failure was 2.70% (1/37). The death rate was 5.71% (2/35). CONCLUSION: The effect of TIPS in treating portal hypertension caused by liver cirrhosis is prominent and safe, and is worthy of clinical application.
ESTHER : You_2011_Zhonghua.Gan.Zang.Bing.Za.Zhi_19_490
PubMedSearch : You_2011_Zhonghua.Gan.Zang.Bing.Za.Zhi_19_490
PubMedID: 22152237

Title : Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations - Sanson_2011_Protein.Sci_20_1114
Author(s) : Sanson B , Colletier JP , Xu Y , Lang PT , Jiang H , Silman I , Sussman JL , Weik M
Ref : Protein Science , 20 :1114 , 2011
Abstract : The transient opening of a backdoor in the active-site wall of acetylcholinesterase, one of nature's most rapid enzymes, has been suggested to contribute to the efficient traffic of substrates and products. A crystal structure of Torpedo californica acetylcholinesterase in complex with the peripheral-site inhibitor aflatoxin is now presented, in which a tyrosine at the bottom of the active-site gorge rotates to create a 3.4-A wide exit channel. Molecular dynamics simulations show that the opening can be further enlarged by movement of Trp84. The crystallographic and molecular dynamics simulation data thus point to the interface between Tyr442 and Trp84 as the key element of a backdoor, whose opening permits rapid clearance of catalysis products from the active site. Furthermore, the crystal structure presented provides a novel template for rational design of inhibitors and reactivators, including anti-Alzheimer drugs and antidotes against organophosphate poisoning.
ESTHER : Sanson_2011_Protein.Sci_20_1114
PubMedSearch : Sanson_2011_Protein.Sci_20_1114
PubMedID: 21594947
Gene_locus related to this paper: torca-ACHE

Title : Complete genome sequence of Bordetella pertussis CS, a Chinese pertussis vaccine strain - Zhang_2011_J.Bacteriol_193_4017
Author(s) : Zhang S , Xu Y , Zhou Z , Wang S , Yang R , Wang J , Wang L
Ref : Journal of Bacteriology , 193 :4017 , 2011
Abstract : Bordetella pertussis is the causative agent of pertussis. Here, we report the genome sequence of Bordetella pertussis strain CS, isolated from an infant patient in Beijing and widely used as a vaccine strain for production of an acellular pertussis vaccine in China.
ESTHER : Zhang_2011_J.Bacteriol_193_4017
PubMedSearch : Zhang_2011_J.Bacteriol_193_4017
PubMedID: 21622744
Gene_locus related to this paper: borpe-CATD2

Title : Genomic analysis and temperature-dependent transcriptome profiles of the rhizosphere originating strain Pseudomonas aeruginosa M18 - Wu_2011_BMC.Genomics_12_438
Author(s) : Wu DQ , Ye J , Ou HY , Wei X , Huang X , He YW , Xu Y
Ref : BMC Genomics , 12 :438 , 2011
Abstract : BACKGROUND: Our previously published reports have described an effective biocontrol agent named Pseudomonas sp. M18 as its 16S rDNA sequence and several regulator genes share homologous sequences with those of P. aeruginosa, but there are several unusual phenotypic features. This study aims to explore its strain specific genomic features and gene expression patterns at different temperatures.
RESULTS: The complete M18 genome is composed of a single chromosome of 6,327,754 base pairs containing 5684 open reading frames. Seven genomic islands, including two novel prophages and five specific non-phage islands were identified besides the conserved P. aeruginosa core genome. Each prophage contains a putative chitinase coding gene, and the prophage II contains a capB gene encoding a putative cold stress protein. The non-phage genomic islands contain genes responsible for pyoluteorin biosynthesis, environmental substance degradation and type I and III restriction-modification systems. Compared with other P. aeruginosa strains, the fewest number (3) of insertion sequences and the most number (3) of clustered regularly interspaced short palindromic repeats in M18 genome may contribute to the relative genome stability. Although the M18 genome is most closely related to that of P. aeruginosa strain LESB58, the strain M18 is more susceptible to several antimicrobial agents and easier to be erased in a mouse acute lung infection model than the strain LESB58. The whole M18 transcriptomic analysis indicated that 10.6% of the expressed genes are temperature-dependent, with 22 genes up-regulated at 28 degrees C in three non-phage genomic islands and one prophage but none at 37 degrees C.
CONCLUSIONS: The P. aeruginosa strain M18 has evolved its specific genomic structures and temperature dependent expression patterns to meet the requirement of its fitness and competitiveness under selective pressures imposed on the strain in rhizosphere niche.
ESTHER : Wu_2011_BMC.Genomics_12_438
PubMedSearch : Wu_2011_BMC.Genomics_12_438
PubMedID: 21884571
Gene_locus related to this paper: pseae-PA1558 , pseae-PA2927 , pseae-PA2949 , pseae-PA3695 , pseae-PA5080 , pseae-q9i252

Title : Identification of carboxylesterases expressed in rat intestine and effects of their hydrolyzing activity in predicting first-pass metabolism of ester prodrugs - Liu_2011_Pharmazie_66_888
Author(s) : Liu D , Gao J , Zhang C , Ren X , Liu Y , Xu Y
Ref : Pharmazie , 66 :888 , 2011
Abstract : Carboxylesterases (CESs) located in the intestine play an unique role in the absorption of many drugs especially ester prodrugs. In order to determine the expression and hydrolyzing activity of CESs isozymes (CES1 and CES2) located in rat intestine, the activities of CES1 and CES2 were evaluated by the intestinal S9 incubation with imidapril and irinotecan (CPT-11), the substrates of CES1 and CES2, respectively. The distribution characteristics of CES1, CES2, Pregnane X Receptor (PXR) and Constitutive Androstane Receptor were analyzed by real-time polymerase chain reaction (RT-PCR) or Western blot. Imidaprilat metabolized from imidapril by CES1 was too low to be detected in rat intestinal S9 fractions, while there was little and even no expression of CES1 mRNA in intestinal segments. In contrast, Vmax values for CPT-11 diminished gradually from proximal to distal segments within the rat intestine which was consistent with the mRNA expression level of CES2. These results indicated that CES2 represents the major CESs isoform in the rat complete intestine and decreased from duodenum to colon, whereas the expression of CES1 was too low to influence the metabolism of ester prodrugs. The expression of PXR and CAR decreased slightly along the entire intestine on both mRNA and protein levels which indicated that PXR and CAR may be one of the major factors which contribute to the expression of CES1 and CES2. Thus, the knowledge about the characteristic and site-specific expression of CES1 and CES2 in rat intestine will help to predict the oral bioavailability of ester prodrugs.
ESTHER : Liu_2011_Pharmazie_66_888
PubMedSearch : Liu_2011_Pharmazie_66_888
PubMedID: 22204136

Title : [Selective isolation and diversity of cold-adapted lipase-producing strains from permafrost soil at the terminus of a glacier in the Tianshan Mountains] - Xu_2011_Wei.Sheng.Wu.Xue.Bao_51_233
Author(s) : Xu Y , Wang D , Shi X , Zheng X , Zhou H , Liu Y , Ni Y
Ref : Wei Sheng Wu Xue Bao , 51 :233 , 2011
Abstract : OBJECTIVE: The diversity of culturable lipase-producing bacterial strains from permafrost soils at the terminus of a glacier in the Tianshan Mountains was investigated. Isolation and molecular phylogenetic analysis were performed to expand our knowledge on diversity of psychrotrophic and psychrophilic bacteria. In addition, efforts were made focusing on screening for cold active lipases. METHODS: Lipase-producing bacterial strains were detected on tween 80 and olive oil plates, respectively. Identity and genetic diversity of strains isolated were determined by spatial 16S rRNA gene sequences and rep-PCR fingerprint. The physiological tests were carried out to determine the phonotypic differences between strains showing high similarity of 16S rRNA gene sequences. RESULTS: Of the total 17 bacterial stains exhibiting cold-adapted lipase activity, we found that only 8 stains were able to hydrolyze olive oil. Based on 16S rRNA gene sequences, the lipase-producing bacterial isolates fell in five phylogenetic groups: subclasses (, ( and ( of Proteobacteria, Actinobacteria, and the Cytophaga-Flexibacter-Bacteroides (CFB) phylum. Nearly 59% of the isolates were affiliated with the genus Pseudomonas. CONCLUSION: The results enrich our knowledge on the psychrotrophic bacterial diversity and biogeographic distribution of cold active lipases-producing bacteria in cold environments.
ESTHER : Xu_2011_Wei.Sheng.Wu.Xue.Bao_51_233
PubMedSearch : Xu_2011_Wei.Sheng.Wu.Xue.Bao_51_233
PubMedID: 21574385

Title : Functional characterization of a gene cluster involved in gentisate catabolism in Rhodococcus sp. strain NCIMB 12038 - Liu_2011_Appl.Microbiol.Biotechnol_90_671
Author(s) : Liu TT , Xu Y , Liu H , Luo S , Yin YJ , Liu SJ , Zhou NY
Ref : Applied Microbiology & Biotechnology , 90 :671 , 2011
Abstract : Rhodococcus sp. strain NCIMB 12038 utilizes naphthalene as a sole source of carbon and energy, and degrades naphthalene via salicylate and gentisate. To identify the genes involved in this pathway, we cloned and sequenced a 12-kb DNA fragment containing a gentisate catabolic gene cluster. Among the 13 complete open reading frames deduced from this fragment, three (narIKL) have been shown to encode the enzymes involved in the reactions of gentisate catabolism. NarI is gentisate 1,2-dioxygenase which converts gentisate to maleylpyruvate, NarL is a mycothiol-dependent maleylpyruvate isomerase which catalyzes the isomerization of maleylpyruvate to fumarylpyruvate, and NarK is a fumarylpyruvate hydrolase which hydrolyzes fumarylpyruvate to fumarate and pyruvate. The narX gene, which is divergently transcribed with narIKL, has been shown to encode a functional 3-hydroxybenzoate 6-monooxygenase. This led us to discover that this strain is also capable of utilizing 3-hydroxybenzoate as its sole source of carbon and energy. Both NarL and NarX were purified to homogeneity as His-tagged proteins, and they were determined by gel filtration to exist as a trimer and a monomer, respectively. Our study suggested that the gentisate degradation pathway was shared by both naphthalene and 3-hydroxybenzoate catabolism in this strain.
ESTHER : Liu_2011_Appl.Microbiol.Biotechnol_90_671
PubMedSearch : Liu_2011_Appl.Microbiol.Biotechnol_90_671
PubMedID: 21181154

Title : A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy - Chandrasekharan_2010_Sci.Transl.Med_2_42ra54
Author(s) : Chandrasekharan K , Yoon JH , Xu Y , deVries S , Camboni M , Janssen PM , Varki A , Martin PT
Ref : Sci Transl Med , 2 :42ra54 , 2010
Abstract : During the evolution of humans, an inactivating deletion was introduced in the CMAH (cytidine monophosphate-sialic acid hydroxylase) gene, which eliminated biosynthesis of the common mammalian sialic acid N-glycolylneuraminic acid from all human cells. We found that this human-specific change in sialylation capacity contributes to the marked discrepancy in phenotype between the mdx mouse model for Duchenne muscular dystrophy (DMD) and the human disease. When compared to human patients with DMD, mdx mice show reduced severity or slower development of clinically relevant disease phenotypes, despite lacking dystrophin protein in almost all muscle cells. This is especially true for the loss of ambulation, cardiac and respiratory muscle weakness, and decreased life span, all of which are major phenotypes contributing to DMD morbidity and mortality. These phenotypes occur at an earlier age or to a greater degree in mdx mice that also carry a human-like mutation in the mouse Cmah gene, possibly as a result of reduced strength and expression of the dystrophin-associated glycoprotein complex and increased activation of complement. Cmah-deficient mdx mice are a small-animal model for DMD that better approximates the human glycome and its contributions to muscular dystrophy.
ESTHER : Chandrasekharan_2010_Sci.Transl.Med_2_42ra54
PubMedSearch : Chandrasekharan_2010_Sci.Transl.Med_2_42ra54
PubMedID: 20668298

Title : Transcriptome sequencing and comparative analysis of cucumber flowers with different sex types - Guo_2010_BMC.Genomics_11_384
Author(s) : Guo S , Zheng Y , Joung JG , Liu S , Zhang Z , Crasta OR , Sobral BW , Xu Y , Huang S , Fei Z
Ref : BMC Genomics , 11 :384 , 2010
Abstract : BACKGROUND: Cucumber, Cucumis sativus L., is an economically and nutritionally important crop of the Cucurbitaceae family and has long served as a primary model system for sex determination studies. Recently, the sequencing of its whole genome has been completed. However, transcriptome information of this species is still scarce, with a total of around 8,000 Expressed Sequence Tag (EST) and mRNA sequences currently available in GenBank. In order to gain more insights into molecular mechanisms of plant sex determination and provide the community a functional genomics resource that will facilitate cucurbit research and breeding, we performed transcriptome sequencing of cucumber flower buds of two near-isogenic lines, WI1983G, a gynoecious plant which bears only pistillate flowers, and WI1983H, a hermaphroditic plant which bears only bisexual flowers. RESULT: Using Roche-454 massive parallel pyrosequencing technology, we generated a total of 353,941 high quality EST sequences with an average length of 175bp, among which 188,255 were from gynoecious flowers and 165,686 from hermaphroditic flowers. These EST sequences, together with approximately 5,600 high quality cucumber EST and mRNA sequences available in GenBank, were clustered and assembled into 81,401 unigenes, of which 28,452 were contigs and 52,949 were singletons. The unigenes and ESTs were further mapped to the cucumber genome and more than 500 alternative splicing events were identified in 443 cucumber genes. The unigenes were further functionally annotated by comparing their sequences to different protein and functional domain databases and assigned with Gene Ontology (GO) terms. A biochemical pathway database containing 343 predicted pathways was also created based on the annotations of the unigenes. Digital expression analysis identified approximately 200 differentially expressed genes between flowers of WI1983G and WI1983H and provided novel insights into molecular mechanisms of plant sex determination process. Furthermore, a set of SSR motifs and high confidence SNPs between WI1983G and WI1983H were identified from the ESTs, which provided the material basis for future genetic linkage and QTL analysis. CONCLUSION: A large set of EST sequences were generated from cucumber flower buds of two different sex types. Differentially expressed genes between these two different sex-type flowers, as well as putative SSR and SNP markers, were identified. These EST sequences provide valuable information to further understand molecular mechanisms of plant sex determination process and forms a rich resource for future functional genomics analysis, marker development and cucumber breeding.
ESTHER : Guo_2010_BMC.Genomics_11_384
PubMedSearch : Guo_2010_BMC.Genomics_11_384
PubMedID: 20565788
Gene_locus related to this paper: cucsa-a0a0a0ktw5 , cucsa-a0a0a0lnt6 , cucsa-a0a0a0kpn7 , cucsa-a0a0a0lvt9 , cucsa-a0a0a0kdx8 , cucsa-a0a0a0m228 , cucsa-a0a0a0kz31 , cucsa-a0a0a0k5t5 , cucsa-a0a0a0kfs7 , cucsa-a0a0a0kjj7 , cucsa-a0a0a0kzs7 , cucsa-a0a0a0l0a6 , cucsa-a0a0a0l4w4 , cucsa-a0a0a0lpz0

Title : Omega-3 and omega-6 fatty acids suppress ER- and oxidative stress in cultured neurons and neuronal progenitor cells from mice lacking PPT1 - Kim_2010_Neurosci.Lett_479_292
Author(s) : Kim SJ , Zhang Z , Saha A , Sarkar C , Zhao Z , Xu Y , Mukherjee AB
Ref : Neuroscience Letters , 479 :292 , 2010
Abstract : Reactive oxygen species (ROS) damage brain lipids, carbohydrates, proteins, as well as DNA and may contribute to neurodegeneration. We previously reported that ER- and oxidative stress cause neuronal apoptosis in infantile neuronal ceroid lipofuscinosis (INCL), a lethal neurodegenerative storage disease, caused by palmitoyl-protein thioesterase-1 (PPT1) deficiency. Polyunsaturated fatty acids (PUFA) are essential components of cell membrane phospholipids in the brain and excessive ROS may cause oxidative damage of PUFA leading to neuronal death. Using cultured neurons and neuroprogenitor cells from mice lacking Ppt1, which mimic INCL, we demonstrate that Ppt1-deficient neurons and neuroprogenitor cells contain high levels of ROS, which may cause peroxidation of PUFA and render them incapable of providing protection against oxidative stress. We tested whether treatment of these cells with omega-3 or omega-6 PUFA protects the neurons and neuroprogenitor cells from oxidative stress and suppress apoptosis. We report here that both omega-3 and omega-6 fatty acids protect the Ppt1-deficient cells from ER- as well as oxidative stress and suppress apoptosis. Our results suggest that PUFA supplementation may have neuroprotective effects in INCL.
ESTHER : Kim_2010_Neurosci.Lett_479_292
PubMedSearch : Kim_2010_Neurosci.Lett_479_292
PubMedID: 20561933
Gene_locus related to this paper: mouse-ppt

Title : Long route or shortcut? A molecular dynamics study of traffic of thiocholine within the active-site gorge of acetylcholinesterase - Xu_2010_Biophys.J_99_4003
Author(s) : Xu Y , Colletier JP , Weik M , Qin G , Jiang H , Silman I , Sussman JL
Ref : Biophysical Journal , 99 :4003 , 2010
Abstract : The principal role of acetylcholinesterase is termination of nerve impulse transmission at cholinergic synapses, by rapid hydrolysis of the neurotransmitter acetylcholine to acetate and choline. Its active site is buried at the bottom of a deep and narrow gorge, at the rim of which is found a second anionic site, the peripheral anionic site. The fact that the active site is so deeply buried has raised cogent questions as to how rapid traffic of substrate and products occurs in such a confined environment. Various theoretical and experimental approaches have been used to solve this problem. Here, multiple conventional molecular dynamics simulations have been performed to investigate the clearance of the product, thiocholine, from the active-site gorge of acetylcholinesterase. Our results indicate that thiocholine is released from the peripheral anionic site via random pathways, while three exit routes appear to be favored for its release from the active site, namely, along the axis of the active-site gorge, and through putative back- and side-doors. The back-door pathway is that via which thiocholine exits most frequently. Our results are in good agreement with kinetic and kinetic-crystallography studies. We propose the use of multiple molecular dynamics simulations as a fast yet accurate complementary tool in structural studies of enzymatic trafficking.
ESTHER : Xu_2010_Biophys.J_99_4003
PubMedSearch : Xu_2010_Biophys.J_99_4003
PubMedID: 21156143

Title : Identification of resistance-responsive proteins in larvae of Bactrocera dorsalis (Hendel), for pyrethroid toxicity by a proteomic approach - Jin_2010_Pestic.Biochem.Physiol_96_1
Author(s) : Jin T , Zeng L , Lu Y , Xu Y , Liang G
Ref : Pesticide Biochemistry and Physiology , 96 :1 , 2010
Abstract : Insect resistance to the pyrethroid toxins has been examined previously using a number of traditional biochemical and molecular techniques. In this study, a proteomic approach involving two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) and tandem mass spectrometry (MS/MS) were applied to examine changes in resistant stains larvae of Bactracera dorsalis Hendel induced by pyrethroid treatment over a 3 h, 6 h and 12 h time period, and a number of proteins changes were observed to change in the level of regulation. Out of total 15 proteins, 9 proteins were observed only after pyrethroid treatment; 6 proteins showed different expression. After MALDI-TOF analyses and peptide mapping method, the data was compared with those of the known proteins available in public databases. Sequence analyses revealed that resistance response correlates with up-regulation (glycerol-3-phosphate dehydrogenase) and down-regulation (ATP-ADP antiporter) of energy-related proteins. It indicated that increased metabolism and energy-indeed as a resistance response to pyrethroid toxins. The regulation of cytoskeleton proteins were possibly a B. dorsalis tissue repair response or in cell division. Up-regulation of protein synthesis would results in substantial bioenergetic enhancement, suggesting a trade-off insect resistance to pyrethroid. Down regulation of neural protein indicated that neural system was physically injured after pyrethroid stress. Some remaining proteins were not identifiable, suggesting these may be novel proteins. Oriental fruit fly proteomes of pesticide induced provide an integrative basis for consolidating our knowledge of insect resistance. The results pave the way for future investigation of the alteration of the insect resistance to chemical pesticides.
ESTHER : Jin_2010_Pestic.Biochem.Physiol_96_1
PubMedSearch : Jin_2010_Pestic.Biochem.Physiol_96_1
PubMedID:

Title : Novel minor lipase from Rhizopus chinensis during solid-state fermentation: biochemical characterization and its esterification potential for ester synthesis - Sun_2009_Bioresour.Technol_100_2607
Author(s) : Sun SY , Xu Y , Wang D
Ref : Bioresour Technol , 100 :2607 , 2009
Abstract : Rhizopus chinensis produces two lipases that catalyze ester synthesis when cultured under solid-state fermentation. The Lip2 was purified to homogeneity by ammonium sulphate precipitation, hydrophobic interaction chromatography and gel filtration chromatography. It has an apparent molecular weight of 33 kDa estimated from SDS-PAGE and 32 kDa calculated from analytical gel permeation, with synthetic activity and purification fold of 96.8 U/mg and 138.3, respectively. Maximum hydrolytic activity was obtained at pH 8.0-8.5 and 40 degrees C using pNPP as substrate. Slight activation of the enzyme was observed when Mn(2+) is present. The enzyme was most active on p-nitrophenyl laurate (C12). The purified lipase exhibited maximum synthetic activity at pH memory of 6.0 and 30 degrees C. Most of ethyl esters synthesized by lyophilized enzyme achieved good yields (>90%), and caprylic acid served as the best acyl donor. The enzyme presented a particular affinity for ethanol, n-propanol and n-hexanol, with conversion of 92%, 93% and 92%, respectively, after 20 h incubation.
ESTHER : Sun_2009_Bioresour.Technol_100_2607
PubMedSearch : Sun_2009_Bioresour.Technol_100_2607
PubMedID: 19157870

Title : Genetic and biochemical analyses of chlorobenzene degradation gene clusters in Pandoraea sp. strain MCB032 - Jiang_2009_Arch.Microbiol_191_485
Author(s) : Jiang XW , Liu H , Xu Y , Wang SJ , Leak DJ , Zhou NY
Ref : Arch Microbiol , 191 :485 , 2009
Abstract : Pandoraea sp. strain MCB032 was isolated as an emerging chlorobenzene degrader from a functionally stable bioreactor where species succession had occurred. In this study, two gene clusters encoding chlorobenzene metabolic functions have been cloned. Within the cbs gene cluster, CbsA and CbsB are similar to the chlorobenzene dioxygenase and the cis-chlorobenzene dihydrodiol dehydrogenase in Ralstonia sp. JS705 and shown to transform chlorobenzene to 3-chlorocatechol. The clc gene cluster shows strong similarity to the clc genes of Ralstonia sp. JS705 and encodes chlorocatechol 1,2-dioxygenase (ClcA) and other enzymes, which catalyze the conversion of chlorocatechol to 3-oxoadipate. The Michaelis constants (K (m)) values of ClcA for catechol, 3-methylcatechol and 3-chlorocatechol were determined as 10.0, 8.9 and 3.4 muM, respectively. CbsX, a putative transport protein present in the cbs cluster of strain MCB032 but not in those of other chlorobenzene degraders, shows 76 and 53% identities to two previously identified transport proteins involved in toluene degradation, TbuX from Ralstonia pickettii PKO1 and TodX from Pseudomonas putida F1. The presence of the transport protein in strain MCB032 likely provides a mechanistic explanation for its higher chlorobenzene affinity and may well be the basis for the competitive advantage of this strain in the bioreactor.
ESTHER : Jiang_2009_Arch.Microbiol_191_485
PubMedSearch : Jiang_2009_Arch.Microbiol_191_485
PubMedID: 19365620
Gene_locus related to this paper: 9burk-a7kx00

Title : Donepezil treatment in severe Alzheimer's disease: a pooled analysis of three clinical trials - Winblad_2009_Curr.Med.Res.Opin_25_2577
Author(s) : Winblad B , Black SE , Homma A , Schwam EM , Moline M , Xu Y , Perdomo CA , Swartz J , Albert K
Ref : Curr Med Res Opin , 25 :2577 , 2009
Abstract : OBJECTIVE: Individual clinical trials have demonstrated benefits of donepezil in patients with severe Alzheimer's disease (AD). Data were pooled from three randomized, placebo-controlled trials of donepezil for severe AD to further evaluate treatment effects and overall tolerability/safety. METHODS: Total scores and sub-scores were analyzed for measures of cognition, global function, function, and behavior. Additional analyses were performed to investigate (1) relationships between cognitive, functional, and behavioral changes, and (2) patterns of combined domain response. RESULTS: Using pooled total scores, significant treatment differences at endpoint in favor of donepezil were observed for cognition, global function (both p < 0.0001), and function (p = 0.03), with an effect size (Cohen's d) of 0.51, 0.26, and 0.17, respectively. There was no significant treatment difference for behavior. However, donepezil-treated patients with stabilized/improved cognition tended to show significant improvements in function and behavior over placebo-treated patients. Patients treated with donepezil were 2-3 times more likely to achieve a combined domain response than placebo-treated patients (p < 0.0001). Adverse events were as expected for cholinergic therapy, and mortality rates were similar between the treatment groups. CONCLUSIONS: These findings suggest measurable donepezil-mediated symptomatic benefits in cognition, global function, and daily living activities in patients with severe AD. The treatment effects support the importance of cholinesterase inhibition as a clinically relevant therapeutic option across the spectrum of AD.
ESTHER : Winblad_2009_Curr.Med.Res.Opin_25_2577
PubMedSearch : Winblad_2009_Curr.Med.Res.Opin_25_2577
PubMedID: 19735164

Title : Biosynthesis of the cyclooligomer depsipeptide bassianolide, an insecticidal virulence factor of Beauveria bassiana - Xu_2009_Fungal.Genet.Biol_46_353
Author(s) : Xu Y , Orozco R , Wijeratne EMK , Espinosa-Artiles P , Gunatilaka AA , Patricia Stock S , Molnar I
Ref : Fungal Genet Biol , 46 :353 , 2009
Abstract : Beauveria bassiana is a facultative entomopathogen with an extremely broad host range that is used as a commercial biopesticide for the control of insects of agricultural, veterinary and medical significance. B. bassiana produces bassianolide, a cyclooligomer depsipeptide secondary metabolite. We have cloned the bbBsls gene of B. bassiana encoding a nonribosomal peptide synthetase (NRPS). Targeted inactivation of the B. bassiana genomic copy of bbBsls abolished bassianolide production, but did not affect the biosynthesis of beauvericin, another cyclodepsipeptide produced by the strain. Comparative sequence analysis of the BbBSLS bassianolide synthetase revealed enzymatic domains for the iterative synthesis of an enzyme-bound dipeptidol monomer intermediate from d-2-hydroxyisovalerate and l-leucine. Further BbBSLS domains are predicted to catalyze the formation of the cyclic tetrameric ester bassianolide by recursive condensations of this monomer. Comparative infection assays against three selected insect hosts established bassianolide as a highly significant virulence factor of B. bassiana.
ESTHER : Xu_2009_Fungal.Genet.Biol_46_353
PubMedSearch : Xu_2009_Fungal.Genet.Biol_46_353
PubMedID: 19285149

Title : The genome of the cucumber, Cucumis sativus L - Huang_2009_Nat.Genet_41_1275
Author(s) : Huang S , Li R , Zhang Z , Li L , Gu X , Fan W , Lucas WJ , Wang X , Xie B , Ni P , Ren Y , Zhu H , Li J , Lin K , Jin W , Fei Z , Li G , Staub J , Kilian A , van der Vossen EA , Wu Y , Guo J , He J , Jia Z , Tian G , Lu Y , Ruan J , Qian W , Wang M , Huang Q , Li B , Xuan Z , Cao J , Asan , Wu Z , Zhang J , Cai Q , Bai Y , Zhao B , Han Y , Li Y , Li X , Wang S , Shi Q , Liu S , Cho WK , Kim JY , Xu Y , Heller-Uszynska K , Miao H , Cheng Z , Zhang S , Wu J , Yang Y , Kang H , Li M , Liang H , Ren X , Shi Z , Wen M , Jian M , Yang H , Zhang G , Yang Z , Chen R , Ma L , Liu H , Zhou Y , Zhao J , Fang X , Fang L , Liu D , Zheng H , Zhang Y , Qin N , Li Z , Yang G , Yang S , Bolund L , Kristiansen K , Li S , Zhang X , Wang J , Sun R , Zhang B , Jiang S , Du Y
Ref : Nat Genet , 41 :1275 , 2009
Abstract : Cucumber is an economically important crop as well as a model system for sex determination studies and plant vascular biology. Here we report the draft genome sequence of Cucumis sativus var. sativus L., assembled using a novel combination of traditional Sanger and next-generation Illumina GA sequencing technologies to obtain 72.2-fold genome coverage. The absence of recent whole-genome duplication, along with the presence of few tandem duplications, explains the small number of genes in the cucumber. Our study establishes that five of the cucumber's seven chromosomes arose from fusions of ten ancestral chromosomes after divergence from Cucumis melo. The sequenced cucumber genome affords insight into traits such as its sex expression, disease resistance, biosynthesis of cucurbitacin and 'fresh green' odor. We also identify 686 gene clusters related to phloem function. The cucumber genome provides a valuable resource for developing elite cultivars and for studying the evolution and function of the plant vascular system.
ESTHER : Huang_2009_Nat.Genet_41_1275
PubMedSearch : Huang_2009_Nat.Genet_41_1275
PubMedID: 19881527
Gene_locus related to this paper: cucsa-a0a0a0ktw5 , cucsa-a0a0a0lnt6 , cucsa-a0a0a0kpn7 , cucsa-a0a0a0lvt9 , cucsa-a0a0a0kdx8 , cucsa-a0a0a0m228 , cucsa-a0a0a0kz31 , cucsa-a0a0a0k5t5 , cucsa-a0a0a0kfs7 , cucsa-a0a0a0kjj7 , cucsa-a0a0a0kzs7 , cucsa-a0a0a0l0a6 , cucsa-a0a0a0l4w4 , cucsa-a0a0a0lpz0 , cucsa-a0a0a0ls66

Title : Integrated production for biodiesel and 1,3-propanediol with lipase-catalyzed transesterification and fermentation - Xu_2009_Biotechnol.Lett_31_1335
Author(s) : Xu Y , Liu H , Du W , Sun Y , Ou X , Liu D
Ref : Biotechnol Lett , 31 :1335 , 2009
Abstract : Biodiesel, a renewable alternative to fossil energy, has shown great prospects for global proliferation in the past decade. Lipase catalyzed transesterification for biodiesel production, as a biological process with many advantages has drawn increasing attention. As a by-product, glycerol accounts for about 10% w/w of biodiesel during the process of biodiesel production. As a result, the conversion of glycerol has become a common problem which has to be resolved if considering large amount of biodiesel production. Glycerol can be fermented into 1,3-propanediol, a high value added chemical with a promising future in the polymers, for example, polytrimethylene terephthalate, and also fermentation approaches for 1,3-propanediol production which have drawn more and more attention due to advantages such as relatively low investment, mild reaction conditions and using renewable sources as the starting materials. Based on the latest technology advancements in lipase-mediated transformation for biodiesel production, the aerobic fermentation technology and genetic engineering for 1,3-propanediol production, and the integrated production of 1,3-propanediol from crude glycerol could be a promising way to improve the profit of the whole process during biodiesel production.
ESTHER : Xu_2009_Biotechnol.Lett_31_1335
PubMedSearch : Xu_2009_Biotechnol.Lett_31_1335
PubMedID: 19466559

Title : Donepezil treatment of patients with MCI: a 48-week randomized, placebo-controlled trial - Doody_2009_Neurology_72_1555
Author(s) : Doody RS , Ferris SH , Salloway S , Sun Y , Goldman R , Watkins WE , Xu Y , Murthy AK
Ref : Neurology , 72 :1555 , 2009
Abstract : BACKGROUND: Treatment of mild cognitive impairment (MCI) with cholinesterase inhibitors may improve symptoms. METHODS: In this multicenter, randomized, placebo-controlled trial, subjects with MCI entered a 3-week placebo run-in period followed by 48 weeks of double-blind donepezil (5 mg/day for 6 weeks, then 10 mg/day for 42 weeks) or placebo treatment. Primary efficacy variables included change from baseline in the modified Alzheimer Disease Assessment Scale-cognitive subscale (ADAS-Cog) and Clinical Dementia Rating Scale-sum of boxes (CDR-SB) after 48 weeks of treatment (modified intention-to-treat analysis). Secondary efficacy measures evaluated cognition, behavior, and function. RESULTS: The dual primary efficacy endpoint was not reached. We noted a small, but significant, decrease in modified ADAS-Cog scores in favor of donepezil at study endpoint. Little change from baseline in CDR-SB and secondary variables was observed for either group. Patient Global Assessment scores favored donepezil at all time points except week 12 (p < or = 0.05). Perceived Deficits Questionnaire scores favored donepezil at week 24 (p = 0.05). Clinical Global Impression of Change-MCI scores favored donepezil only at week 6 (p = 0.04). Adverse events were generally mild or moderate. More donepezil-treated subjects (18.4%) discontinued treatment due to adverse events than placebo-treated subjects (8.3%). CONCLUSIONS: Donepezil demonstrated small but significant improvement on the primary measure of cognition but there was no change on the primary measure of global function. Most other measures of global impairment, cognition, and function were not improved, possibly because these measures are insensitive to change in MCI. Responses on subjective measures suggest subjects perceived benefits with donepezil treatment.
ESTHER : Doody_2009_Neurology_72_1555
PubMedSearch : Doody_2009_Neurology_72_1555
PubMedID: 19176895

Title : Changes in morphology of Rhizopus chinensis in submerged fermentation and their effect on production of mycelium-bound lipase - Teng_2009_Bioprocess.Biosyst.Eng_32_397
Author(s) : Teng Y , Xu Y , Wang D
Ref : Bioprocess Biosyst Eng , 32 :397 , 2009
Abstract : In order to control suitable mycelium morphology to obtain high lipase productivity by Rhizopus chinensis in submerged fermentation, the effects of fungal morphology on the lipase production by this strain both in shake flask and fermentor were investigated. Different inoculum level and shear stress were used to develop distinctive morphologies. Analyses and investigations both on micromorphology and macromorphology were performed. Study of micromorphology reveals that micromorphologies for dispersed mycelia and aggregated mycelia are different in cell shape, biosynthetic activity. Macromorphology and broth rheology study in fermentor indicate that pellet formation results in low broth viscosity. Under this condition, the oil can disperse sufficiently in broth which is very important for lipase production. These results indicate that morphology changes affected the lipase production significantly for R. chinensis and the aggregated mycelia were suggested to achieve high lipase production.
ESTHER : Teng_2009_Bioprocess.Biosyst.Eng_32_397
PubMedSearch : Teng_2009_Bioprocess.Biosyst.Eng_32_397
PubMedID: 18779980

Title : [Prostaglandin E(2) and omeprazole in treating poisoning related acute mucosal lesion] - Fan_2009_Zhong.Nan.Da.Xue.Xue.Bao.Yi.Xue.Ban_34_1036
Author(s) : Fan X , Xu Y , Zhang H
Ref : Zhong Nan Da Xue Xue Bao Yi Xue Ban , 34 :1036 , 2009
Abstract : OBJECTIVE: To determine the effects of prostaglandin E(2) alone and the combination with omeprazole for poisoning related acute mucosal lesion. METHODS: Forty-two healthy SD rats were randomly divided into 7 groups: control group (control) , methamidophos poisoning model group (intox), 10 mg/kg omeprazole group (ome1), 50 mg/kg omeprazole group (ome2), 10 microg/kg prostaglandin E(2) group (PG1), 50 microg/kg prostaglandin E(2) group (PG2), 10 microg/kg prostaglandin E(2) combined with 10 mg/kg omeprazole group (union). The gastric ulcer index was counted and the content of serum cholinesterase, endothelin, and tumor necrosis factor were measured, and dependability was analyzed. RESULTS: There was no obvious difference between the prostaglandin group and the poisoning model group in gastric ulcer index, endothelin, and tumor necrosis factor. The omeprazole alone and the combination treatment could improve the acute gastric mucosa lesion induced by methamidophos poisoning. CONCLUSION: Prostaglandin E(2) alone can not obviously improve the acute gastric mucosa lesion by methamidophos poisoning. The combination with omeprazole may be a promising treatment.
ESTHER : Fan_2009_Zhong.Nan.Da.Xue.Xue.Bao.Yi.Xue.Ban_34_1036
PubMedSearch : Fan_2009_Zhong.Nan.Da.Xue.Xue.Bao.Yi.Xue.Ban_34_1036
PubMedID: 19893258

Title : Functional characterization of the biosynthesis of radicicol, an Hsp90 inhibitor resorcylic acid lactone from Chaetomium chiversii - Wang_2008_Chem.Biol_15_1328
Author(s) : Wang S , Xu Y , Maine EA , Wijeratne EM , Espinosa-Artiles P , Gunatilaka AA , Molnar I
Ref : Chemical Biology , 15 :1328 , 2008
Abstract : Fungal polyketides with the resorcylic acid lactone (RAL) scaffold are of interest for growth stimulation, the treatment of cancer, and neurodegenerative diseases. The RAL radicicol is a nanomolar inhibitor of the chaperone Hsp90, whose repression leads to a combinatorial blockade of cancer-causing pathways. Clustered genes for radicicol biosynthesis were identified and functionally characterized from the endophytic fungus Chaetomium chiversii, and compared to recently described RAL biosynthetic gene clusters. Radicicol production is abolished upon targeted inactivation of a putative cluster-specific regulator, or either of the two polyketide synthases that are predicted to collectively synthesize the radicicol polyketide core. Genomic evidence supports the existence of flavin-dependent halogenases in fungi: inactivation of such a putative halogenase from the C. chiversii radicicol locus yields dechloro-radicicol (monocillin I). Inactivation of a cytochrome P450 epoxidase furnishes pochonin D, a deepoxy-dihydro radicicol analog.
ESTHER : Wang_2008_Chem.Biol_15_1328
PubMedSearch : Wang_2008_Chem.Biol_15_1328
PubMedID: 19101477
Gene_locus related to this paper: floch-rads2

Title : Culture condition improvement for whole-cell lipase production in submerged fermentation by Rhizopus chinensis using statistical method - Teng_2008_Bioresour.Technol_99_3900
Author(s) : Teng Y , Xu Y
Ref : Bioresour Technol , 99 :3900 , 2008
Abstract : Rhizopus chinensis CCTCC M201021 was a versatile strain capable of producing whole-cell lipase with synthetic activity in submerged fermentation. In order to improve the production of whole-cell lipase and study the culture conditions systematically, the combination of taguchi method and response surface methodology was performed. Taguchi method was used for the initial optimization, and eight factors viz., maltose, olive oil, peptone, K2HPO4, agitation, inoculum size, fermentation volume and pH were selected for this study. The whole-cell lipase activity yield was two times higher than the control experiment under initial optimal conditions, and four significant factors (inoculum, olive oil, fermentation volume and peptone) were selected to test the effect on the lipase production using response surface methodology. The optimal fermentation parameters for enhanced whole-cell lipase yield were found to be: inoculum 4.25 x 10(8) spores/L, olive oil 2.367% (w/v), fermentation volume 18 mL/250 mL flask, peptone 4.06% (w/v). Subsequent experimental trails confirmed the validity of the model. These optimal culture conditions in the shake flask led to a lipase yield of 13875 U/L, which 120% increased compare with the non-optimized conditions.
ESTHER : Teng_2008_Bioresour.Technol_99_3900
PubMedSearch : Teng_2008_Bioresour.Technol_99_3900
PubMedID: 17888652

Title : Novel inhibitor for prolyl tripeptidyl aminopeptidase from Porphyromonas gingivalis and details of substrate-recognition mechanism - Xu_2008_J.Mol.Biol_375_708
Author(s) : Xu Y , Nakajima Y , Ito K , Zheng H , Oyama H , Heiser U , Hoffmann T , Gartner UT , Demuth HU , Yoshimoto T
Ref : Journal of Molecular Biology , 375 :708 , 2008
Abstract : A new inhibitor, H-Ala-Ile-pyrrolidin-2-yl boronic acid, was developed as an inhibitor against prolyl tripeptidyl aminopeptidase with a K(i) value of 88.1 nM. The structure of the prolyl tripeptidyl aminopeptidase complexed with the inhibitor (enzyme-inhibitor complex) was determined at 2.2 A resolution. The inhibitor was bound to the active site through a covalent bond between Ser603 and the boron atom of the inhibitor. This structure should closely mimic the structure of the reaction intermediate between the enzyme and substrate. We previously proposed that two glutamate residues, Glu205 and Glu636, are involved in the recognition of substrates. In order to clarify the function of these glutamate residues in substrate recognition, three mutant enzymes, E205A, E205Q, and E636A were generated by site-directed mutagenesis. The E205A mutant was expressed as an inclusion body. The E205Q mutant was expressed in soluble form, but no activity was detected. Here, the structures of the E636A mutant and its complex with the inhibitor were determined. The inhibitor was located at almost the same position as in the wild-type enzyme-inhibitor complex. The amino group of the inhibitor interacted with Glu205 and the main-chain carbonyl group of Gln203. In addition, a water molecule in the place of Glu636 of the wild-type enzyme interacted with the amino group of the inhibitor. This water molecule was located near the position of Glu636 in the wild-type and formed a hydrogen bond with Gln203. The k(cat)/K(M) values of the E636A mutant toward the two substrates used were smaller than those of the wild-type by two orders of magnitude. The K(i) value of our inhibitor for the E636A mutant was 48.8 microM, which was 554-fold higher than that against the wild-type enzyme. Consequently, it was concluded that Glu205 and Glu636 are significant residues for the N-terminal recognition of a substrate.
ESTHER : Xu_2008_J.Mol.Biol_375_708
PubMedSearch : Xu_2008_J.Mol.Biol_375_708
PubMedID: 18042490
Gene_locus related to this paper: porgi-q7muw6

Title : Induced-fit or preexisting equilibrium dynamics? Lessons from protein crystallography and MD simulations on acetylcholinesterase and implications for structure-based drug design - Xu_2008_Protein.Sci_17_601
Author(s) : Xu Y , Colletier JP , Jiang H , Silman I , Sussman JL , Weik M
Ref : Protein Science , 17 :601 , 2008
Abstract : Crystal structures of acetylcholinesterase complexed with ligands are compared with side-chain conformations accessed by native acetylcholinesterase in molecular dynamics (MD) simulations. Several crystallographic conformations of a key residue in a specific binding site are accessed in a simulation of native acetylcholinesterase, although not seen in rotomer plots. Conformational changes upon ligand binding thus involve preexisting equilibrium dynamics. Consequently, rational drug design could benefit significantly from conformations monitored by MD simulations of native targets.
ESTHER : Xu_2008_Protein.Sci_17_601
PubMedSearch : Xu_2008_Protein.Sci_17_601
PubMedID: 18359854

Title : Flexibility of aromatic residues in the active-site gorge of acetylcholinesterase: X-ray versus molecular dynamics - Xu_2008_Biophys.J_95_2500
Author(s) : Xu Y , Colletier JP , Weik M , Jiang H , Moult J , Silman I , Sussman JL
Ref : Biophysical Journal , 95 :2500 , 2008
Abstract : The high aromatic content of the deep and narrow active-site gorge of acetylcholinesterase (AChE) is a remarkable feature of this enzyme. Here, we analyze conformational flexibility of the side chains of the 14 conserved aromatic residues in the active-site gorge of Torpedo californica AChE based on the 47 three-dimensional crystal structures available for the native enzyme, and for its complexes and conjugates, and on a 20-ns molecular dynamics (MD) trajectory of the native enzyme. The degree of flexibility of these 14 aromatic side chains is diverse. Although the side-chain conformations of F330 and W279 are both very flexible, the side-chain conformations of F120, W233, W432, Y70, Y121, F288, F290 and F331 appear to be fixed. Residues located on, or adjacent to, the Omega-loop (C67-C94), namely W84, Y130, Y442, and Y334, display different flexibilities in the MD simulations and in the crystal structures. An important outcome of our study is that the majority of the side-chain conformations observed in the 47 Torpedo californica AChE crystal structures are faithfully reproduced by the MD simulation on the native enzyme. Thus, the protein can assume these conformations even in the absence of the ligand that permitted their experimental detection. These observations are pertinent to structure-based drug design.
ESTHER : Xu_2008_Biophys.J_95_2500
PubMedSearch : Xu_2008_Biophys.J_95_2500
PubMedID: 18502801

Title : Effect of folding factors in rescuing unstable heterologous lipase B to enhance its overexpression in the periplasm of Escherichia coli - Xu_2008_Appl.Microbiol.Biotechnol_79_1035
Author(s) : Xu Y , Lewis D , Chou CP
Ref : Applied Microbiology & Biotechnology , 79 :1035 , 2008
Abstract : Functional expression of recombinant Pseudozyma antarctica lipase B (PalB) in Escherichia coli was explored. While PalB was stably expressed in the cytoplasm, most of the expressed gene product aggregated in cells as inactive inclusion bodies. In contrast, PalB was extremely unstable when expressed in the periplasm, also leading to poor expression performance. Such unstable PalB can be rescued by coexpression of several periplasmic folding factors, such as DegP, FkpA, DsbA, and DsbC but not cytoplasmic ones. As a result, the performance for functional PalB expression in the periplasm was significantly improved. To our knowledge, this is the first report demonstrating the use of folding factors to rescue the extremely unstable gene product that is otherwise completely degradable.
ESTHER : Xu_2008_Appl.Microbiol.Biotechnol_79_1035
PubMedSearch : Xu_2008_Appl.Microbiol.Biotechnol_79_1035
PubMedID: 18496685

Title : Heterologous expression of lipase in Escherichia coli is limited by folding and disulfide bond formation - Xu_2008_Appl.Microbiol.Biotechnol_81_79
Author(s) : Xu Y , Yasin A , Tang R , Scharer JM , Moo-Young M , Chou CP
Ref : Applied Microbiology & Biotechnology , 81 :79 , 2008
Abstract : Functional expression of lipase B from Pseudozyma antarctica (PalB) in the cytoplasm of Escherichia coli BL21(DE3) and its mutant derivative Origami B(DE3) was explored. Coexpression of DsbA was found to be effective in enhancing PalB expression. The improvement was particularly pronounced with Origami B(DE3) as a host, suggesting that both folding and disulfide bond formation may be major factors limiting PalB expression. Fusion tag technique was also explored by constructing several PalB fusions for the evaluation of their expression performance. While the solubility was enhanced for most PalB fusions, only the DsbA tag was effective in boosting PalB activity, possibly by both enhanced solubility and correct disulfide bond formation. Our results suggest that PalB activity is closely associated with correct disulfide bond formation, and increased solubilization by PalB fusions does not necessarily result in activity enhancement.
ESTHER : Xu_2008_Appl.Microbiol.Biotechnol_81_79
PubMedSearch : Xu_2008_Appl.Microbiol.Biotechnol_81_79
PubMedID: 18758768

Title : Production of a novel recombinant Drosophila melanogaster acetylcholinesterase for detection of organophosphate and carbamate insecticide residues - Xu_2007_Biomol.Eng_24_253
Author(s) : Xu S , Wu A , Chen H , Xie Y , Xu Y , Zhang L , Li J , Zhang D
Ref : Biomol Eng , 24 :253 , 2007
Abstract : A novel recombinant Drosophila melanogaster acetylcholinesterase (R-DmAChE) produced in Pichia pastoris was first reported in this study. We cloned the DmAChE cDNA by reverse transcription PCR with removal of the signal for glycosylphosphatidylinositol (GPI) anchor attachment and the endogenous signal peptide coding sequence, and inserted it into P. pastoris vector pPIC9K under control of the alcohol oxidase gene AOX1 promoter (5'AOX1). The expression cassette of AChE cDNA was then introduced into methylotrophic yeast GS115 and several recombinant strains expressing R-DmAChE were obtained. The secreted R-DmAChE showed high stability in neutral phosphate buffer at 4 degrees C, and its kinetic parameters were identical to those of the native DmAChE. The bimolecular rate constants of R-DmAChE to dichlorvos, aldicarb and carbaryl were ranging from three to six times higher than of native DmAChE. Within six insecticides, the R-DmAChE was more sensitive than EeAChE, NbAChE and HuAChE. For 10 widely used insecticides, the IC50 values to the R-DmAChE were much lower than those to AChEs commonly used in China. With the R-DmAChE-based assay, samples spiked with three concentrations of pesticides caused enzymatic activity inhibition with R.S.D. of 0-13.7%. These results suggest that the R-DmAChE can be useful for detection of organophosphate and carbamate insecticide residues.
ESTHER : Xu_2007_Biomol.Eng_24_253
PubMedSearch : Xu_2007_Biomol.Eng_24_253
PubMedID: 17222583

Title : Production of lysophosphatidylcholine by cPLA2 in the brain of mice lacking PPT1 is a signal for phagocyte infiltration - Zhang_2007_Hum.Mol.Genet_16_837
Author(s) : Zhang Z , Lee YC , Kim SJ , Choi MS , Tsai PC , Saha A , Wei H , Xu Y , Xiao YJ , Zhang P , Heffer A , Mukherjee AB
Ref : Hum Mol Genet , 16 :837 , 2007
Abstract : In the majority of neurodegenerative storage disorders, neuronal death in the brain is followed by infiltration of phagocytic cells (e.g. activated microglia, astroglia and macrophages) for the efficient removal of cell corpses. However, it is increasingly evident that these phagocytes may also cause death of adjoining viable neurons contributing to rapid progression of neurodegeneration. Infantile neuronal ceroid lipofuscinosis (INCL) is a devastating, neurodegenerative, lysosomal storage disorder caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. PPT1 catalyzes the cleavage of thioester linkages in S-acylated (palmitoylated) proteins and its deficiency leads to abnormal accumulation of thioesterified polypeptides (ceroid) in lysosomes causing INCL pathogenesis. PPT1-knockout (PPT1-KO) mice mimic the clinical and pathological features of human INCL including rapid neuronal death by apoptosis and phagocyte infiltration. We previously reported that in PPT1-KO mice, the neurons undergo endoplasmic reticulum stress activating unfolded protein response, which mediates caspase-12 activation and apoptosis. However, the molecular mechanism(s) by which the phagocytic cells are recruited in the PPT1-KO mouse brain remains poorly understood. We report here that increased production of lysophosphatidylcholine (LPC), catalyzed by the activation of cytosolic phospholipase A(2) (cPLA(2)) in the PPT1-KO mouse brain, is a 'lipid signal' for phagocyte recruitment. We also report that an age-dependent increase in LPC levels in the PPT1-KO mouse brain positively correlates with elevated expression of the genes characteristically associated with phagocytes. We propose that increased cPLA(2)-catalyzed LPC production in the brain is at least one of the mechanisms that mediate phagocyte infiltration contributing to INCL neuropathology.
ESTHER : Zhang_2007_Hum.Mol.Genet_16_837
PubMedSearch : Zhang_2007_Hum.Mol.Genet_16_837
PubMedID: 17341491
Gene_locus related to this paper: mouse-ppt

Title : Synthetic activity enhancement of membrane-bound lipase from Rhizopus chinensis by pretreatment with isooctane - Wang_2007_Bioprocess.Biosyst.Eng_30_147
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