Shen J

References (50)

Title : Glimepiride, a novel soluble epoxide hydrolase inhibitor, protects against heart failure via increasing epoxyeicosatrienoic acids - Zhao_2023_J.Mol.Cell.Cardiol_185_13
Author(s) : Zhao C , Jiang X , Peng L , Zhang Y , Li H , Zhang Q , Wang Y , Yang F , Wu J , Wen Z , He Z , Shen J , Chen C , Wang DW
Ref : Journal of Molecular & Cellular Cardiology , 185 :13 , 2023
Abstract : BACKGROUND: Epoxyeicosatrienoic acids (EETs), which exert multiple endogenous protective effects, are hydrolyzed into less active dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH). However, commercial drugs related to EETs or sEH are not yet in clinical use. METHODS: Firstly, the plasma concentration of EETs and DHETs of 316 patients with heart failure (HF) were detected and quantitated by liquid chromatography-tandem mass spectrometry. Then, transverse aortic constriction (TAC)-induced HF was introduced in cardiomyocyte-specific Ephx2(-/-) mice. Moreover, Western blot, real-time PCR, luciferase reporter, ChIP assays were employed to explore the underlying mechanism. Finally, multiple sEH inhibitors were designed, synthesized, and validated in vitro and in vivo. RESULTS: The ratios of DHETs/EETs were increased in the plasma from patients with HF. Meanwhile, the expression of sEH was upregulated in the heart of patients and mice with HF, especially in cardiomyocytes. Cardiomyocyte-specific Ephx2(-/-) mice ameliorated cardiac dysfunction induced by TAC. Consistently, Ephx2 knockdown protected Angiotensin II (AngII)-treated cardiomyocytes via increasing EETs in vitro. Mechanistically, AngII could enhance the expression of transcript factor Krppel-like factor 15 (KLF15), which in turn upregulated sEH. Importantly, glimepiride was identified as a novel sEH inhibitor, which benefited from the elevated EETs during HF. CONCLUSIONS: Glimepiride attenuates HF in mice in part by increasing EETs. CLINICAL TRIAL IDENTIFIER: NCT03461107 (https://clinicaltrials.gov).
ESTHER : Zhao_2023_J.Mol.Cell.Cardiol_185_13
PubMedSearch : Zhao_2023_J.Mol.Cell.Cardiol_185_13
PubMedID: 37871528

Title : Xanthophyll esterases in association with fibrillins control the stable storage of carotenoids in yellow flowers of rapeseed (Brassica juncea) - Li_2023_New.Phytol__
Author(s) : Li R , Zeng Q , Zhang X , Jing J , Ge X , Zhao L , Yi B , Tu J , Fu T , Wen J , Shen J
Ref : New Phytol , : , 2023
Abstract : Biosynthesis, stabilization, and storage of carotenoids are vital processes in plants that collectively contribute to the vibrant colors observed in flowers and fruits. Despite its importance, the carotenoid storage pathway remains poorly understood and lacks thorough characterization. We identified two homologous genes, BjA02.PC1 and BjB04.PC2, belonging to the esterase/lipase/thioesterase (ELT) family of acyltransferases. We showed that BjPCs in association with fibrillin gene BjFBN1b control the stable storage of carotenoids in yellow flowers of Brassica juncea. Through genetic, high-resolution mass spectrometry and transmission electron microscopy analyses, we demonstrated that both BjA02.PC1 and BjB04.PC2 can promote the accumulation of esterified xanthophylls, facilitating the formation of carotenoid-enriched plastoglobules (PGs) and ultimately producing yellow pigments in flowers. The elimination of BjPCs led to the redirection of metabolic flux from xanthophyll ester biosynthesis to lipid biosynthesis, resulting in white flowers for B. juncea. Moreover, we genetically verified the function of two fibrillin genes, BjA01.FBN1b and BjB05.FBN1b, in mediating PG formation and demonstrated that xanthophyll esters must be deposited in PGs for stable storage. These findings identified a previously unknown carotenoid storage pathway that is regulated by BjPCs and BjFBN1b, while offering unique opportunities for improving the stability, deposition, and bioavailability of carotenoids.
ESTHER : Li_2023_New.Phytol__
PubMedSearch : Li_2023_New.Phytol__
PubMedID: 37194444

Title : Polyphenols: Natural food grade biomolecules for treating neurodegenerative diseases from a multi-target perspective - Li_2023_Front.Nutr_10_1139558
Author(s) : Li Z , Zhao T , Shi M , Wei Y , Huang X , Shen J , Zhang X , Xie Z , Huang P , Yuan K , Li N , Qin D
Ref : Front Nutr , 10 :1139558 , 2023
Abstract : As natural functional bioactive ingredients found in foods and plants, polyphenols play various antioxidant and anti-inflammatory roles to prevent the development of disease and restore human health. The multi-target modulation of polyphenols provides a novel practical therapeutic strategy for neurodegenerative diseases that are difficult to treat with traditional drugs like glutathione and cholinesterase inhibitors. This review mainly focuses on the efficacy of polyphenols on ischemic stroke, Parkinson's disease and Alzheimer's disease, including in vivo and in vitro experimental studies. It is further emphasized that polyphenols exert neuroprotective effects primarily through inhibiting production of oxidative stress and inflammatory cytokines, which may be the underlying mechanism. However, polyphenols are still rarely used as medicines to treat neurodegenerative diseases. Due to the lack of clinical trials, the mechanism of polyphenols is still in the stage of insufficient exploration. Future large-scale multi-center randomized controlled trials and in-depth mechanism studies are still needed to fully assess the safety, efficacy and side effects of polyphenols.
ESTHER : Li_2023_Front.Nutr_10_1139558
PubMedSearch : Li_2023_Front.Nutr_10_1139558
PubMedID: 36925964

Title : Increased Soluble Epoxide Hydrolase Activity Positively Correlates with Mortality in Heart Failure Patients with Preserved Ejection Fraction: Evidence from Metabolomics - Peng_2023_Phenomics_3_34
Author(s) : Peng L , Song Z , Zhao C , Abuduwufuer K , Wang Y , Wen Z , Ni L , Li C , Yu Y , Zhu Y , Jiang H , Shen J , Jiang X , Chen C , Zhang X , Wang DW
Ref : Phenomics , 3 :34 , 2023
Abstract : Epoxyeicosatrienoic acids (EETs) have pleiotropic endogenous cardiovascular protective effects and can be hydrolyzed to the corresponding dihydroxyeicosatrienoic acids by soluble epoxide hydrolase (sEH). Heart failure with preserved ejection fraction (HFpEF) has shown an increased prevalence and worse prognosis over the decades. However, the role of sEH activity in HFpEF remains unclear. We enrolled 500 patients with HFpEF and 500 healthy controls between February 2010 and March 2016. Eight types of sEH-related eicosanoids were measured according to target metabolomics, and their correlation with clinical endpoints was also analyzed. The primary endpoint was cardiac mortality, and the secondary endpoint was a composite of cardiac events, including heart failure (HF) readmission, cardiogenic hospitalization, and all-cause mortality. Furthermore, the effect of sEH inhibitors on cardiac diastolic function in HFpEF was investigated in vivo and in vitro. Patients with HFpEF showed significantly enhanced EET degradation by the sEH enzyme compared with healthy controls. More importantly, sEH activity was positively correlated with cardiac mortality in patients with HFpEF, especially in older patients with arrhythmia. A consistent result was obtained in the multiple adjusted models. Decreased sEH activity by the sEH inhibitor showed a significant effective effect on the improvement of cardiac diastolic function by ameliorating lipid disorders in cardiomyocytes of HFpEF mouse model. This study demonstrated that increased sEH activity was associated with cardiac mortality in patients with HFpEF and suggested that sEH inhibition could be a promising therapeutic strategy to improve diastolic cardiac function. Clinical trial identifier: NCT03461107 (https://clinicaltrials.gov). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43657-022-00069-8.
ESTHER : Peng_2023_Phenomics_3_34
PubMedSearch : Peng_2023_Phenomics_3_34
PubMedID: 36939801

Title : Glimepiride Use is Associated with Reduced Cardiovascular Mortality in Patients with Type 2 Diabetes and Chronic Heart Failure: A Prospective Cohort Study - He_2022_Eur.J.Prev.Cardiol__
Author(s) : He W , Yuan G , Han Y , Yan Y , Li G , Zhao C , Shen J , Jiang X , Chen C , Ni L , Wang DW
Ref : Eur J Prev Cardiol , : , 2022
Abstract : BACKGROUND: Glimepiride has good cardiovascular safety. However, whether glimepiride benefits clinical cardiovascular outcomes is unclear. METHODS: A total of 21,451 inpatients with type 2 diabetes (T2D) and chronic heart failure (CHF) were analyzed, including 638 who received glimepiride treatment and 20,813 who did not. Propensity score matching yielded 509 pairs (glimepiride and non-glimepiride groups), and both groups were followed up. Kaplan-Meier and Cox regression analyses were used to compare all-cause mortality, cardiovascular mortality, hospitalizations and emergency visits for heart failure, and hospitalizations for acute myocardial infarction or stroke. RESULTS: During follow-up, the all-cause mortality (adjusted hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.35-0.63; P < 0.001), cardiovascular mortality (adjusted HR, 0.34; 95% CI, 0.24-0.48; P < 0.001), and number of hospitalizations and emergency visits for heart failure (adjusted HR, 0.42; 95% CI, 0.36-0.50; P < 0.001) and hospitalizations for acute myocardial infarction or stroke (adjusted HR, 0.53; 95% CI, 0.38-0.73; P < 0.001) were significantly lower in the glimepiride group; the conclusion remained similar in all subgroups. Furthermore, high-dose glimepiride use (2-4mg/day) was associated with lower cardiovascular mortality than low-dose (1mg/day) (adjusted HR, 0.55; 95% CI, 0.31-0.99; P = 0.047). Glimepiride exhibited good molecular docking with soluble epoxide hydrolase (sEH) and increased the level epoxyeicosatrienoic acid (EET). CONCLUSIONS: Long-term continuous glimepiride use is associated with better survival, fewer hospitalizations and emergency visits for heart failure, and fewer hospitalizations for acute myocardial infarction or stroke in patients with T2D and CHF. High-dose glimepiride has greater cardiovascular protective advantages than low-dose glimepiride. The cardiovascular protective effect of glimepiride may be related to the EET level increase through sEH inhibition.
ESTHER : He_2022_Eur.J.Prev.Cardiol__
PubMedSearch : He_2022_Eur.J.Prev.Cardiol__
PubMedID: 36573717

Title : A Proof-of-Concept Inhibitor of Endothelial Lipase Suppresses Triple-Negative Breast Cancer Cells by Hijacking the Mitochondrial Function - Yang_2022_Cancers.(Basel)_14_3763
Author(s) : Yang R , Han S , Clayton J , Haghighatian M , Tsai CC , Yao Y , Li P , Shen J , Zhou Q
Ref : Cancers (Basel) , 14 :3763 , 2022
Abstract : Triple-negative breast cancer (TNBC) cells reprogram their metabolism to provide metabolic flexibility for tumor cell growth and survival in the tumor microenvironment. While our previous findings indicated that endothelial lipase (EL/LIPG) is a hallmark of TNBC, the precise mechanism through which LIPG instigates TNBC metabolism remains undefined. Here, we report that the expression of LIPG is associated with long non-coding RNA DANCR and positively correlates with gene signatures of mitochondrial metabolism-oxidative phosphorylation (OXPHOS). DANCR binds to LIPG, enabling tumor cells to maintain LIPG protein stability and OXPHOS. As one mechanism of LIPG in the regulation of tumor cell oxidative metabolism, LIPG mediates histone deacetylase 6 (HDAC6) and histone acetylation, which contribute to changes in IL-6 and fatty acid synthesis gene expression. Finally, aided by a relaxed docking approach, we discovered a new LIPG inhibitor, cynaroside, that effectively suppressed the enzyme activity and DANCR in TNBC cells. Treatment with cynaroside inhibited the OXPHOS phenotype of TNBC cells, which severely impaired tumor formation. Taken together, our study provides mechanistic insights into the LIPG modulation of mitochondrial metabolism in TNBC and a proof-of-concept that targeting LIPG is a promising new therapeutic strategy for the treatment of TNBC.
ESTHER : Yang_2022_Cancers.(Basel)_14_3763
PubMedSearch : Yang_2022_Cancers.(Basel)_14_3763
PubMedID: 35954428
Gene_locus related to this paper: human-LIPG

Title : Simultaneous CSM-TACE with CalliSpheres() and partial splenic embolization using 8spheres() for hepatocellular carcinoma with hypersplenism: Early prospective multicenter clinical outcome - Zhou_2022_Front.Oncol_12_998500
Author(s) : Zhou J , Feng Z , Liu S , Li X , Liu Y , Gao F , Shen J , Zhang YW , Zhao GS , Zhang M
Ref : Front Oncol , 12 :998500 , 2022
Abstract : BACKGROUND: Primary hepatocellular carcinoma is often complicated with hepatitis and liver cirrhosis. Some patients develop different degrees of splenomegaly, hypersplenism and hypohepatia due to the aggravation of liver cirrhosis, which to some extent interfere with the treatment of tumors and even affect the prognosis of patients. In this study, we prospectively evaluate the efficacy and safety of simultaneous CalliSpheres((a)) microspheres transcatheter arterial chemoembolization (CSM-TACE) and partial splenic embolization (PSE) using 8spheres((a)) for hepatocellular carcinoma (HCC) with hypersplenism. METHODS: Ninety consecutive HCC patients with hypersplenism who underwent CSM-TACE were selected: 32 patients in CSM-TACE+PSE group, and 58 patients in CSM-TACE group. The peripheral blood cell counts (leukocyte, platelet (PLT), liver function and red blood cell (RBC)), CSM-TACE and/or PSE related complications, and the tumor control rate at 1 month after CSM-TACE were compared. The survival time and prognostic factors were also observed. RESULTS: Before CSM-TACE, there were no significant differences in sex, age, Child-Pugh grade, tumor size, and alpha-fetoprotein (AFP) between the two groups. After CSM-TACE, the PLT and white blood cell (WBC) counts in CSM-TACE+PSE group were significantly higher than those in the CSM-TACE group (P<0.05). There were no significant differences in RBC before and after treatment (P > 0.05). In the CSM-TACE group, there were no significant differences in WBC, PLT, and RBC before and after treatment (P > 0.05). There was no significant difference in liver function at 1 month after treatment between the two groups. The cholinesterase (CHE) level in the CSM-TACE+PSE group after CSM-TACE+PSE was obviously higher than that before CSM-TACE+PSE and higher than that in the CSM-TACE group (P<0.05). However, the level of CHE returned to the preoperative level 1 month after CSM-TACE in the CSM-TACE group. The objective response rate (ORR) and median overall survival (OS) in the CSM-TACE+PSE group were higher than those in the CSM-TACE group (P<0.05). The adverse reactions of the two groups were fever, abdominal pain, stomach discomfort, nausea, and vomiting, and no serious complications occurred. The degree of abdominal pain and fever in the experimental group was lower than that in the control group (P > 0.05). CONCLUSIONS: Simultaneous CSM-TACE and PSE using domestic embolization particles for HCC with hypersplenism have good safety and efficacy and has a low incidence of PSE-related adverse events, it is conducive to improving liver function reserve, and can further improve the median OS.
ESTHER : Zhou_2022_Front.Oncol_12_998500
PubMedSearch : Zhou_2022_Front.Oncol_12_998500
PubMedID: 36530976

Title : MicroRNA-199a-3p regulates proliferation and milk fat synthesis of ovine mammary epithelial cells by targeting VLDLR - Wang_2022_Front.Vet.Sci_9_948873
Author(s) : Wang J , Hao Z , Hu L , Qiao L , Luo Y , Hu J , Liu X , Li S , Zhao F , Shen J , Li M , Zhao Z
Ref : Front Vet Sci , 9 :948873 , 2022
Abstract : In our previous study, microRNA (miR)-199a-3p was found to be the most upregulated miRNA in mammary gland tissue during the non-lactation period compared with the peak-lactation period. However, there have been no reports describing the function of miR-199a-3p in ovine mammary epithelial cells (OMECs) and the biological mechanisms by which the miRNA affects cell proliferation and milk fat synthesis in sheep. In this study, the effect of miR-199a-3p on viability, proliferation, and milk fat synthesis of OMECs was investigated, and the target relationship of the miRNA with very low-density lipoprotein receptor (VLDLR) was also verified. Transfection with a miR-199a-3p mimic increased the viability of OMECs and the number of Edu-labeled positive OMECs. In contrast, a miR-199-3p inhibitor had the opposite effect with the miR-199a-3p mimic. The expression levels of three marker genes were also regulated by both the miR-199a-3p mimic and miR-199-3p inhibitor in OMECs. Together, these results suggest that miR-199a-3p promotes the viability and proliferation of OMECs. A dual luciferase assay confirmed that miR-199a-3p can target VLDLR by binding to the 3'-untranslated regions (3'UTR) of the gene. Further studies found a negative correlation in the expression of miR-199a-3p with VLDLR. The miR-199a-3p mimic decreased the content of triglycerides, as well as the expression levels of six milk fat synthesis marker genes in OMECs, namely, lipoprotein lipase gene (LPL), acetyl-CoA carboxylase alpha gene (ACACA), fatty acid binding protein 3 gene (FABP3), CD36, stearoyl-CoA desaturase gene (SCD), and fatty acid synthase gene (FASN). The inhibition of miR-199a-3p increased the level of triglycerides and the expression of LPL, ACACA, FABP3, SCD, and FASN in OMECs. These findings suggest that miR-199a-3p inhibited milk fat synthesis of OMECs. This is the first study to reveal the molecular mechanisms by which miR-199a-3p regulates the proliferation and milk fat synthesis of OMECs in sheep.
ESTHER : Wang_2022_Front.Vet.Sci_9_948873
PubMedSearch : Wang_2022_Front.Vet.Sci_9_948873
PubMedID: 35990270

Title : Intact aleurone cells limit the hydrolysis of endogenous lipids in wheat bran during storage - Chen_2022_Food.Res.Int_161_111799
Author(s) : Chen Z , Shen J , Yang Y , Wang H , Xu B
Ref : Food Res Int , 161 :111799 , 2022
Abstract : This work aimed to elucidate the effect of aleurone cell integrity on the hydrolysis of endogenous lipids in wheat bran and flour. The distribution of lipases in the bran dissected layers (aleurone layer, outer pericarp and intermediate layer) and the lipid hydrolysis in the bran fractions and flour containing the aleurone cells with different integrity were investigated. The results indicated that 80% of the lipase activities in bran layers were associated with the aleurone layer. After centrifugal impact milling, the aleurone layer in commercial bran could be detached into the monolayer cell clusters with decreasing integrities as the particle size decreased. In the oil phase, intact aleurone cells did not limit the lipase activities in the bran fractions because the oil could penetrate into aleurone cells. During storage, the hydrolysis rates of endogenous lipids in the bran fractions and their mixed flour increased as the integrity of aleurone cells decreased; while after the aleurone cells were broken, the hydrolysis rates of endogenous lipids increased to be in line with the lipase activities in bran fractions, indicating the limitation of intact aleurone cells on lipid hydrolysis. These results gave a new understanding of the effect of aleurone cell structure on the interaction between lipases and lipids in wheat bran, and will facilitate the production of stable wheat bran and whole wheat flour.
ESTHER : Chen_2022_Food.Res.Int_161_111799
PubMedSearch : Chen_2022_Food.Res.Int_161_111799
PubMedID: 36192945

Title : Stilbenoids isolated from the roots of Rheum lhasaense under the guidance of the acetylcholinesterase inhibition activity - Liu_2021_J.Nat.Med__
Author(s) : Liu Q , Shen J , Li P , Li Y , He C , Xiao P
Ref : J Nat Med , : , 2021
Abstract : Four unknown stilbenoids, including one dimer, namely 4'-methoxy-scirpusin A (5) and three monomeric stilbene glycosides, namely piceatannol-3'-O-[2''-(3,5-dihydroxy-4-methoxybenzoyl)]-beta-D-glucopyranoside (13), piceatannol-3'-O-(2''-galloyl)-beta-D-glucopyranoside (14) and piceatannol-3'-O-(6''-p-coumaroyl)-beta-D-glucopyranoside (16) together with 15 described compounds, were isolated from the ethyl acetate fraction of the ethanol extract of roots of Rheum lhasaense based on the guidance of the inhibitory effect on acetylcholinesterase. The structures of the unknown compounds were established by combined spectroscopic analysis and comparing their spectral data with compounds with similar structures. Some selected components were also investigated for their inhibitory abilities on acetylcholinesterase (AChE), indicating that compound 13 may be responsible for higher inhibitory activity of the ethyl acetate fraction on AChE.
ESTHER : Liu_2021_J.Nat.Med__
PubMedSearch : Liu_2021_J.Nat.Med__
PubMedID: 33411157

Title : Toxicologic effect and transcriptome analysis for short-term orally dosed enrofloxacin combined with two veterinary antimicrobials on rat liver - Luan_2021_Ecotoxicol.Environ.Saf_220_112398
Author(s) : Luan Y , Zhao J , Han H , Shen J , Tang S , Cheng L
Ref : Ecotoxicology & Environmental Safety , 220 :112398 , 2021
Abstract : Presently, toxicological assessment of multiple veterinary antimicrobials has not been performed on mammals. In this study, we assessed the short-term toxicity of enrofloxacin (E) combined with colistin (C) and quinocetone (Q). Young male rats were orally dosed drug mixtures and single drugs in 14 consecutive days, each at the dose of 20, 80, and 400 mg/(kg.BW) for environmental toxicologic study. The results showed that at the high dose treatment, the combination of E + C+Q significantly decreased body intake, lymphocytes count on rats; significantly increased the values of Alanine aminotransferase (ALT), Glutamic oxaloacetic transaminase (AST) and, cholinesterase (CHE); it also got the severest histopathological changes, where sinusoidal congestion and a large number of black particles in sinusoids were observed. This means E + C+Q in the high dose groups was able to cause significant damage to the liver. Other combinations or doses did not induce significant liver damage. Transcriptome analysis was then performed on rats in high dose group for further research. For E + C and E + Q, an amount of 375 and 480 differently expressed genes were filtered out, revealing their possible underlying effect on genomes. For E + C+Q, a weighted gene co-expression network analysis was performed and 96 hub genes were identified to reveal the specific effect induced by this combination. This study indicates that joint toxicity should be taken into consideration when involving the risk assessment of these antimicrobials.
ESTHER : Luan_2021_Ecotoxicol.Environ.Saf_220_112398
PubMedSearch : Luan_2021_Ecotoxicol.Environ.Saf_220_112398
PubMedID: 34116333

Title : Detection of organophosphorus pesticides by nanogold\/mercaptomethamidophos multi-residue electrochemical biosensor - Zhao_2021_Food.Chem_354_129511
Author(s) : Zhao G , Zhou B , Wang X , Shen J , Zhao B
Ref : Food Chem , 354 :129511 , 2021
Abstract : Based on the successful synthesis of mercaptomethamidophos as a substrate, a novel nanogold/mercaptomethamidophos multi-residue electrochemical biosensor was designed and fabricated by combining nanoscale effect, strong Au-S bonds as well as interaction between acetylcholinesterase (AChE) and mercaptomethamidophos, which can simultaneously detect 11 kinds of organophosphorus pesticides (OPPs) and total amount of OPPs using indirect competitive method. Electrochemical behavior of the modified electrode was characterized by differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). The AChE concentration and incubation time were optimized at 37.4 degreesC to achieve the best detection effect. This biosensor exhibits excellent electrochemical properties with a wider linear range of 0.1 ~ 1500 ng.mL(-1), lower detection limit of 0.019 ~ 0.077 ng.mL(-1), better stability and repeatability, which realizes the rapid detection of total amount of OPPs, and can simultaneously detect a large class of OPPs rather than one kind of OPP. Two OPPs (trichlorfon, dichlorvos) were detected in actual samples of apple and cabbage and achieved satisfactory test results.
ESTHER : Zhao_2021_Food.Chem_354_129511
PubMedSearch : Zhao_2021_Food.Chem_354_129511
PubMedID: 33735695

Title : Serum Cholinesterases, a Novel Marker of Clinical Activity in Inflammatory Bowel Disease: A Retrospective Case-Control Study - Shao_2020_Mediators.Inflamm_2020_4694090
Author(s) : Shao X , Yang L , Hu K , Shen R , Ye Q , Yuan X , Zhao Q , Shen J
Ref : Mediators Inflamm , 2020 :4694090 , 2020
Abstract : BACKGROUND: The aim of our study was to investigate whether serum cholinesterase (ChE) levels were associated with inflammatory bowel disease (IBD). MATERIALS AND METHODS: We conducted a retrospective case-control study to clarify the relationship between serum ChE levels and IBD that included 142 patients with ulcerative colitis (UC), 60 patients with Crohn's disease (CD), and 264 healthy controls (HCs). We used ROC curves to evaluate the diagnostic value of serum ChE levels for IBD. RESULTS: Substantially lower serum ChE levels were detected in patients with UC than in HCs (6376 U/L versus 8418 U/L, P < 0.001) and in patients with CD than in HCs (5181 U/L versus 8418 U/L, P < 0.001). Additionally, patients with CD displayed significantly lower serum ChE levels than patients with UC (5181 U/L versus 6376 U/L, P < 0.01). We also found that there was a negative association between serum ChE levels and the Crohn's Disease Activity Index (CDAI) score of patients with CD (P = 0.011) and the Simple Clinical Colitis Activity Index (SCCAI) score of patients with UC (P = 0.018). The area under the curve (AUC) for serum ChE for the diagnosis of IBD was 0.826, and the AUCs of serum ChE for the diagnosis of CD and UC were 0.890 and 0.800, respectively. CONCLUSIONS: Serum ChE levels have important clinical significance in the diagnosis and assessment of clinical activity in patients with IBD, and the cholinergic anti-inflammatory pathway may provide new ideas for targeted treatment of IBD.
ESTHER : Shao_2020_Mediators.Inflamm_2020_4694090
PubMedSearch : Shao_2020_Mediators.Inflamm_2020_4694090
PubMedID: 32733165

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 : Inhibition of soluble epoxide hydrolase attenuates airway remodeling in a chronic asthma model - Jiang_2020_Eur.J.Pharmacol_868_172874
Author(s) : Jiang JX , Guan Y , Shen HJ , Jia YL , Shen J , Zhang LH , Liu Q , Zhu YL , Xie QM
Ref : European Journal of Pharmacology , 868 :172874 , 2020
Abstract : Airway remodeling in asthma is difficult to treat because of its complex pathophysiology that involves proinflammatory cytokines, as well as the arachidonic acid cytochrome P-450 (CYP) pathway; however, it has received little attention. In this study, we assessed the efficacy of a soluble epoxide hydrolase (sEH) on airway remodeling in a mouse model of chronic asthma. The expression of sEH and CYP2J2 and the level of 14,15-epoxyeicosatrienoic acid (14,15-EET), airway remodeling and hyperresponsiveness (AHR) were analyzed to determine the level of sEH inhibition. AUDA, a sEH inhibitor, was given daily for 9 weeks orally, which significantly increased the level of 14,15-EET by inhibiting the expression of sEH and increasing the expression of CYP2J2 in lung tissues. The inhibition of sEH reduced the expression of remodeling-related molecular markers, such as interleukin (IL)-13, IL-17, matrix metalloproteinase 9, N-cadherin, alpha-smooth muscle actin (alpha-SMA), S100A4, Twist, epithelial goblet cell metaplasia, and collagen deposition in bronchoalveolar lavage fluid (BAL fluid) and lung tissues. Moreover, remodeling-related eosinophil accumulation in the BAL fluid and infiltration into the lung tissue were improved by AUDA. Finally, AUDA alleviated AHR, which is a functional indicator of airway remodeling. The effect of AUDA on airway remodeling was related to the downregulation of extracellular-regulated protein kinases (Erk1/2), c-Jun N-terminal kinases (JNK) and signal transducer and activator of transcription 3 (STAT3). To our knowledge, this is the first report to demonstrate that inhibition of sEH exerts significant protective effects on airway remodeling in asthma.
ESTHER : Jiang_2020_Eur.J.Pharmacol_868_172874
PubMedSearch : Jiang_2020_Eur.J.Pharmacol_868_172874
PubMedID: 31866410

Title : Biochemical Mechanisms, Cross-resistance and Stability of Resistance to Metaflumizone in Plutella xylostella - Shen_2020_Insects_11_
Author(s) : Shen J , Li Z , Li D , Wang R , Zhang S , You H , Li J
Ref : Insects , 11 : , 2020
Abstract : The diamondback moth, Plutella xylostella (L.) is an important pest of cruciferous crops worldwide. It has developed resistance to many conventional and novel insecticide classes. Metaflumizone belongs to the new chemical class of semicarbazone insecticides. To delay the development of metaflumizone resistance in P. xylostella and to guide insecticide use in the field, the biochemical mechanisms, cross-resistance spectrum, and stability of resistance to metaflumizone were studied in a laboratory-selected resistant strain (metaflu-SEL). Synergism tests with the carboxylesterase inhibitor triphenyl phosphate (TPP), the glutathione S-transferase depletor diethyl maleate (DEM), and the P450 inhibitor piperonyl butoxide(PBO) had no obvious effect on metaflumizone in the metaflu-SEL strain and the susceptible strain (SS) of P. xylostella, with synergism ratios that ranged from 1.02 to 1.86. Biochemical studies revealed that the cytochrome P450-dependent monooxygenase increased only 1.13-fold in the metaflu-SEL strain compared with the UNSEL stain; meanwhile, carboxylesterase and glutathione S-transferase activity showed no difference. These results suggest that these detoxification enzymes may be not actively involved in metaflumizone resistance. Furthermore, the metaflu-SEL population showed a moderate level of cross-resistance to indoxacarb (11.63-fold), but only very low cross-resistance to spinosad (1.75-fold), spinetoram (3.52-fold), abamectin (2.81-fold), beta-cypermethrin (0.71-fold), diafenthiuron (0.79-fold), chlorantraniliprole (2.16-fold), BT (WG-001) (3.34-fold), chlorfenapyr (0.49-fold), and chlorfluazuron (0.97-fold). Moreover, metaflumizone resistance decreased from 1087.85- to 1.23-fold in the metaflu-SEL strain after 12 generations without exposure to metaflumizone. These results are useful for formulating insecticide resistance management strategies to control P. xylostella and to delay the development of metaflumizone resistance in the field.
ESTHER : Shen_2020_Insects_11_
PubMedSearch : Shen_2020_Insects_11_
PubMedID: 32429053

Title : Lipoprotein-associated phospholipase A2: The story continues - Huang_2020_Med.Res.Rev_40_79
Author(s) : Huang F , Wang K , Shen J
Ref : Med Res Rev , 40 :79 , 2020
Abstract : Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein-associated phospholipase A2 (Lp-PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation-related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp-PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp-PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp-PLA2 have been reported recently, while novel inhibitors were identified through a fragment-based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp-PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp-PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp-PLA2, identify more potent and selective Lp-PLA2 inhibitors, and discover the potential indications of Lp-PLA2 inhibitors.
ESTHER : Huang_2020_Med.Res.Rev_40_79
PubMedSearch : Huang_2020_Med.Res.Rev_40_79
PubMedID: 31140638
Gene_locus related to this paper: human-PLA2G7

Title : Structural optimization of pyrazolo[1,5-a]pyrimidine derivatives as potent and highly selective DPP-4 inhibitors - Shen_2020_Eur.J.Med.Chem_208_112850
Author(s) : Shen J , Deng X , Sun R , Tavallaie MS , Wang J , Cai Q , Lam C , Lei S , Fu L , Jiang F
Ref : Eur Journal of Medicinal Chemistry , 208 :112850 , 2020
Abstract : Our previous discovery of pyrazolo [1,5-a]pyrimidin-7(4H)-one scaffold-based DPP-4 inhibitors yielded two potent compounds b2 (IC(50) = 79 nM) and d1 (IC(50) = 49 nM) but characterized by cytotoxicity. Herein, with scaffold hopping and fragment-based drug design strategies, highly potent and selective pyrazolo [1,5-a]pyrimidine DPP-4 inhibitors were found featured by reduced or diminished cytotoxicity. Specifically, c24 (IC(50) = 2 nM) exhibits a 25 to 40-fold increase of inhibitory activity respect to those of b2 and d1, respectively, 2-fold from Alogliptin (IC(50) = 4 nM), and remarkable selectivity over DPP-8 and DPP-9 (>2000 fold). Further docking studies confirmed that the pyrazolo [1,5-a]pyrimidine core interacts with the S1 pocket whereas its substituted aromatic ring interacts with the sub-S1 pocket. The interactive mode in this case resembles that of Alogliptin and Trelagliptin. Further in vivo IPGTT assays in diabetic mice demonstrated that c24 effectively reduces glucose excursion by 48% at the dose of 10 mg/kg, suggesting that c24 is worthy of further development as a potent anti-diabetes agent.
ESTHER : Shen_2020_Eur.J.Med.Chem_208_112850
PubMedSearch : Shen_2020_Eur.J.Med.Chem_208_112850
PubMedID: 32987315

Title : Identification and molecular docking study of fish roe-derived peptides as potent BACE 1, AChE, and BChE inhibitors - Yu_2020_Food.Funct_11_6643
Author(s) : Yu Z , Ji H , Shen J , Kan R , Zhao W , Li J , Ding L , Liu J
Ref : Food Funct , 11 :6643 , 2020
Abstract : Acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and beta-secretase 1 (BACE 1) play vital roles in the development and progression of Alzheimer's disease (AD). The objective of the present study was to identify fish roe-derived anti-AD peptides with activities against AChE, BChE, and BACE 1. Fish roe proteins were cleaved in silico by gastrointestinal proteases, and the released peptides were collected. Subsequently, the toxicity, solubility, and biological properties of these novel di- and tri-peptides were predicted and validated. Finally, potential anti-AD peptides were docked to targets, i.e., AChE, BChE, and BACE 1. A novel anti-AD tripeptide WIR with potent inhibition of AChE and BACE 1 was identified, with IC(50) values of 43.32 +/- 1.22 microM and 2.27 +/- 0.35 mM, respectively. In addition, the inhibition rate of WIR (at a concentration of 1.06 +/- 0.87 microM) against BChE was 33.5%, and the peptide WIR was able to simultaneously interact with AChE, BChE, and BACE 1. Residues Ser286 of AChE, Asp70 of BChE, and Thr231, Arg235 of BACE 1 played key roles in the interaction with peptide WIR. In summary, peptide WIR exhibits the potential to be an effective treatment for AD.
ESTHER : Yu_2020_Food.Funct_11_6643
PubMedSearch : Yu_2020_Food.Funct_11_6643
PubMedID: 32656560

Title : Identification of ovalbumin-derived peptides as multi-target inhibitors of AChE, BChE and BACE1 - Yu_2020_J.Sci.Food.Agric__
Author(s) : Yu Z , Dong W , Wu S , Shen J , Zhao W , Ding L , Liu J , Zheng F
Ref : J Sci Food Agric , : , 2020
Abstract : BACKGROUND: Alzheimer's disease (AD) is a kind of progressive neurodegenerative disease that occurs to the elderly. But there is no ideal treatment for AD. Thus, the purpose of this study is to identify anti-AD peptides from ovalbumin. RESULTS: The potential tripeptides IEK, LYR and CIK were selected for molecular docking. The '-CDOCKER_Energy' value of the best docking position of the tripeptide IEK, LYR and CIK interacting with acetylcholinesterase (AChE) were - 93.8119, -86.9556 and - 73.6370 kcal/mol, respectively. The '-CDOCKER_Energy' values for interaction with butyrylcholinesterase (BChE) were - 96.6386, -80.8392 and - 87.4341 kcal/mol, respectively. Most importantly, the '-CDOCKER_Energy' values for interaction with beta-site amyloid precursor protein cleavage enzyme1 (BACE1) were - 85.5903, -71.3342 and - 68.4290 kcal/mol, respectively. Overall, in vitro assays results demonstrated that peptide CIK exhibited impressive inhibitory activities against AChE, BChE, and BACE1, with the IC50 value of 6.76, 7.72, and 34.48 muM, respectively. Especially, CIK can be contacted with some peripheral anion sites (PAS) and catalytic sites on AChE, BChE and BACE1. CONCLUSION: Tripeptide CIK can effectively inhibit the activities of AChE, BChE and BACE1. Therefore, tripeptide CIK has the potential to effectively treat AD. This article is protected by copyright. All rights reserved.
ESTHER : Yu_2020_J.Sci.Food.Agric__
PubMedSearch : Yu_2020_J.Sci.Food.Agric__
PubMedID: 31997357

Title : Multilevel ecotoxicity assessment of environmentally relevant bisphenol F concentrations in Daphnia magna - Liu_2020_Chemosphere_240_124917
Author(s) : Liu J , Shen J , Lu G , Xu X , Yang H , Yan Z , Chen W
Ref : Chemosphere , 240 :124917 , 2020
Abstract : With the pressure to ban or limit the use of Bisphenol A (BPA), substitutes such as bisphenol F (BPF) are applied to various commodities and generally detected in aquatic systems worldwide. To understand the potential ecological risk of BPF, the acute toxicity as well as behavioural, physiological and biochemical parameters of the water flea Daphnia magna were assessed. Following BPF exposure at concentrations ranging from 0.1mugL(-1) to 100mugL(-1), phenotypic traits including growth development, fecundity and swimming activity were significantly inhibited in response to exposure to sublethal concentrations (1-100mugL(-1)) of BPF, which had a positive relationship with the activity of antioxidant enzymes. Moreover, the acetylcholinesterase (AChE) activity, which was strictly associated with the behavioural changes, was clearly inhibited, which was also obviously related to the heart rate and thoracic limb activity. Compared to the toxicity of BPA, BPF induces similar toxic effects, and the health concerns regarding the use of these alternatives should be highlighted.
ESTHER : Liu_2020_Chemosphere_240_124917
PubMedSearch : Liu_2020_Chemosphere_240_124917
PubMedID: 31726617

Title : SNHG20\/miR-140-5p\/NDRG3 axis contributes to 5-fluorouracil resistance in gastric cancer - Yu_2019_Oncol.Lett_18_1337
Author(s) : Yu J , Shen J , Qiao X , Cao L , Yang Z , Ye H , Xi C , Zhou Q , Wang P , Gong Z
Ref : Oncol Lett , 18 :1337 , 2019
Abstract : 5-fluorouracil (5-FU)-based chemotherapy is the first line treatment for advanced gastric cancer. However, the effectiveness of 5-FU is limited by drug resistance. The N-myc downstream-regulated gene, family member 3 (NDRG3) is a member of the NDRG family and has been implicated in numerous types of cancer. However, the role of NDRG3 in gastric cancer remains unclear. In the present study, NDRG3 mRNA expression in gastric cancer and adjacent normal tissues was analyzed using the Gene Expression Profiling Interactive Analysis web tool. NDRG3 expression was silenced using short hairpin RNAs to examine the effect of NDRG3 on the growth of gastric cancer cells. Potential regulators of NDRG3 were identified using the TargetScan and MicroRNA tools and verified by a luciferase assay and reverse transcription-quantitative PCR analysis. The current study demonstrated that NDRG3 was upregulated in gastric cancer specimens and promoted cell proliferation in gastric cancer cell lines. Furthermore, the present study revealed that the small nucleolar RNA host gene 20 (SNHG20)/microRNA (miR)-140-5p signaling pathway may regulate the expression of NDRG3. SNHG20 was revealed to be involved in mediating resistance to 5-FU in gastric cancer cell lines via NDRG3. In conclusion, the results of the present study suggest that the SNHG20/miR-140-5p/NDRG3 axis may be involved in mediating resistance to 5-FU in gastric cancer.
ESTHER : Yu_2019_Oncol.Lett_18_1337
PubMedSearch : Yu_2019_Oncol.Lett_18_1337
PubMedID: 31423195
Gene_locus related to this paper: human-NDRG3

Title : Screening of acetylcholinesterase inhibitors and characterizing of phytochemical constituents from Dichocarpum auriculatum (Franch.) W.T. Wang & P. K. Hsiao through UPLC-MS combined with an acetylcholinesterase inhibition assay in vitro - Li_2019_J.Ethnopharmacol_245_112185
Author(s) : Li P , Liu S , Liu Q , Shen J , Yang R , Jiang B , He C , Xiao P
Ref : J Ethnopharmacol , 245 :112185 , 2019
Abstract : ETHNOPHARMACOLOGICAL RELEVANCE: The genus Dichocarpum is endemic to East Asia, and many of them are traditionally used folk medicine in China. Dichocarpum auriculatum (Franch.) W. T. Wang et P. K. Hsiao has the effect of clearing away heat, removing toxicity, and relieving swelling in southwestern China. Intriguingly, its root and whole herb also used as remedy for the neurological disease epilepsy. However, there are not any scientific reports on the phytochemistry and pharmacological activities of D. auriculatum. AIM OF STUDY: Traditional and folk medicinal knowledge would be useful for finding new pharmaceutical resources. There are many evidences over the years reported that an interaction probably exists between epilepsy and Alzheimer's disease (AD). The aim of the study was to investigate the potential AChE inhibitors and the phytochemical profiles of the specie D. auriculatum. MATERIALS AND METHODS: The AChE inhibitory activity of plant extracts of D. auriculatum and other 6 species from different regions of the genus Dichocarpum were evaluated in vitro assays and the UPLC-Q-TOF-MS technique was used to analyze the chemical constituents. Moreover, UPLC-ESI-MS/MS was used to determine the distribution of 12 standard compounds in samples. RESULTS: As a preferred source of potential acetylcholinesterase inhibitors of the genus Dichocarpum, D. auriculatum has been further investigated. The screening results show that the ability of root extracts from D. auriculatum (IC50=0.15mg.mL(-)(1)) to inhibit AChE was better than other samples, it is consistent with traditional medicinal records. The phytochemical constituents of D. auriculatum was surveyed firstly by UPLC-Q-TOF-MS analysis, and 36 compounds, including 14 alkaloids, 16 flavonoids, 6 others, were identified tentatively. Further experiments showed that five compounds (columbamine, palmatine, dauricine, jatrorrhizine and berberine) from D. auriculatum were confirmed the potential inhibition of AChE activity in vitro (IC50: 0.24-6.37muM) and UPLC-ESI-MS/MS results showed that the content of most active compounds in roots was much higher than in aerial parts. Palmatine (IC50=0.34muM) and columbamine (IC50=0.24muM) showed prominent AChE inhibitory activity among the tested compounds. CONCLUSIONS: This is the first report about the evaluation of AChE inhibitory activity and phytochemical profiles of D. auriculatum, led to the identification of 36 compounds including alkaloids and flavonoids, and five alkaloids exhibited a significant AChE inhibitory activity and had the potential as AChE inhibitors. This study provided scientific experimental basis for the traditional efficacy of neurological disease of the plant.
ESTHER : Li_2019_J.Ethnopharmacol_245_112185
PubMedSearch : Li_2019_J.Ethnopharmacol_245_112185
PubMedID: 31446073

Title : Donepezil decreases heart rate in elderly patients with Alzheimer's disease - Pu_2019_Int.J.Clin.Pharmacol.Ther_57_94
Author(s) : Pu Z , Xu W , Lin Y , Shen J , Sun Y
Ref : Int J Clinical Pharmacology & Therapeutics , 57 :94 , 2019
Abstract : OBJECTIVE: Donepezil is an acetylcholinesterase inhibitor (AChI) that improves cognitive function in Alzheimer's disease (AD) patients. However, AChIs are usually associated with peripheral adverse reactions. Here, we investigated the cardiac outcomes in elderly AD patients treated with donepezil. MATERIALS AND METHODS: A total of 82 AD patients (age, 75.47 +/- 6.53 years) received 5 mg or 10 mg donepezil (n = 41/group) once daily for 12 weeks. Next, we examined the heart rate (HR), cardiac rhythm, and PR, QRS, and QTc intervals. RESULTS: Compared to the 5-mg donepezil-treated group, the HR was slower in the 10-mg donepezil-treated group at the 4(th), 8(th), and 12(th) weeks of treatment (p = 0.041, 0.026, 0.008, respectively). The PR interval was longer in the 10-mg donepezil-treated group at the 12(th) week of treatment (p = 0.022). Compared to the pretreatment values, the post-treatment HR and PR interval in the 10-mg donepezil-treated group were significantly slower and longer, respectively (p = 0.002, p = 0.005). Further, the HR was significantly correlated to the donepezil dosage (p = 0.014). Similarly, donepezil dosage and treatment interval were significantly correlated (p = 0.048). CONCLUSION: Taken together, our findings suggest that 10 mg donepezil decreased the HR of elderly AD patients without inducing severe cardiac outcomes. Therefore, AD patients receiving donepezil should undergo regular cardiovascular monitoring..
ESTHER : Pu_2019_Int.J.Clin.Pharmacol.Ther_57_94
PubMedSearch : Pu_2019_Int.J.Clin.Pharmacol.Ther_57_94
PubMedID: 30378536

Title : Parental transfer of ethylhexyl methoxy cinnamate and induced biochemical responses in zebra fi sh - Zhou_2018_Aquat.Toxicol_206_24
Author(s) : Zhou R , Lu G , Yan Z , Jiang R , Shen J , Bao X
Ref : Aquat Toxicol , 206 :24 , 2018
Abstract : Ethylhexyl methoxy cinnamate (EHMC) is one of the major organic ultraviolet (UV) filter pollutants in the environment. The purpose of this study was to investigate the parental transfer of EHMC and induced biochemical responses in zebra fi sh (Danio rerio). Zebrafish embryos were exposed to EHMC solution (1, 10, and 100 mug/L) for 4 months until sexual maturation. Then male and female parents were paired to lay eggs. F1 generations were divided into 2 categories: with and without continued EHMC exposure. EHMC was detected in both F0 parents and F1 eggs, indicating that EHMC can accumulate in zebrafish and transfer to offspring through reproduction. The hatching rate decreased and malformation rate increased significantly among parents and progeny embryos in the high concentration exposure group. For 40 dpf (days post-fertilisation) F0 generations, estradiol hormone and vitellogenin (Vtg) contents, the expression levels of Vtg1, P450 aromatase (Cyp19a and Cyp19b), 17beta-hydroxysteroid dehydrogenase (Hsd17b1, Hsd17b3), estrogen receptor-alpha and progesterone receptor in all concentration groups decreased significantly, while androgen receptor increased significantly in 10 and 100 mug/L exposure groups compared with the corresponding control group, showing anti-estrogen and androgen effects. For 120 dpf F0 generations, acetylcholinesterase activity was significantly decreased and glutathione and malondialdehyde levels, superoxide dismutase, catalase and glutathione reductase activities were significantly increased in all treatment groups compared with the corresponding control group. In addition, F1 offspring with or without continued exposure to EHMC suffered similar or stronger oxidative stress compared with their parents. DNA breakage and apoptosis also occurred in 120 dpf parental liver cells in all treatment groups as a result of oxidative damage. Results suggested that EHMC have transfer effects between parents and offspring, which may cause negative effects on growth and development of zebrafish and induce biochemical responses in both parents and offspring.
ESTHER : Zhou_2018_Aquat.Toxicol_206_24
PubMedSearch : Zhou_2018_Aquat.Toxicol_206_24
PubMedID: 30419393

Title : Surrogating and redirection of pyrazolo[1,5-a]pyrimidin-7(4H)-one core, a novel class of potent and selective DPP-4 inhibitors - Deng_2018_Bioorg.Med.Chem_26_903
Author(s) : Deng X , Shen J , Zhu H , Xiao J , Sun R , Xie F , Lam C , Wang J , Qiao Y , Tavallaie MS , Hu Y , Du Y , Li J , Fu L , Jiang F
Ref : Bioorganic & Medicinal Chemistry , 26 :903 , 2018
Abstract : The initial focus on characterizing novel pyrazolo[1,5-a]pyrimidin-7(4H)-one derivatives as DPP-4 inhibitors, led to a potent and selective inhibitor compound b2. This ligand exhibits potent in vitro DPP-4 inhibitory activity (IC(50): 80 nM), while maintaining other key cellular parameters such as high selectivity, low cytotoxicity and good cell viability. Subsequent optimization of b2 based on docking analysis and structure-based drug design knowledge resulted in d1. Compound d1 has nearly 2-fold increase of inhibitory activity (IC(50): 49 nM) and over 1000-fold selectivity against DPP-8 and DPP-9. Further in vivo IPGTT assays showed that compound b2 effectively reduce glucose excursion by 34% at the dose of 10 mg/kg in diabetic mice. Herein we report the optimization and design of a potent and highly selective series of pyrazolo[1,5-a]pyrimidin-7(4H)-one DPP-4 inhibitors.
ESTHER : Deng_2018_Bioorg.Med.Chem_26_903
PubMedSearch : Deng_2018_Bioorg.Med.Chem_26_903
PubMedID: 29373269

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 : Soluble epoxide hydrolase inhibitor AUDA decreases bleomycin-induced pulmonary toxicity in mice by inhibiting the p38\/Smad3 pathways - Dong_2017_Toxicology_389_31
Author(s) : Dong XW , Jia YL , Ge LT , Jiang B , Jiang JX , Shen J , Jin YC , Guan Y , Sun Y , Xie QM
Ref : Toxicology , 389 :31 , 2017
Abstract : Bleomycin (BLM) has potent tumor cell-killing properties that have given it an important place in cancer chemotherapy, but pulmonary toxicity is its major adverse effect. Soluble epoxide hydrolase (sEH) inhibitors have been reported to have protective effects in fibrosis models, but the effects of AUDA, an sEH inhibitor of BLM-induced pulmonary toxicity and fibrosis, remain to be researched. In this study, we assessed the effects of AUDA on the BLM-induced pulmonary fibrosis in a mouse model, and transforming growth factor (TGF)-beta1-induced epithelial proliferation and epithelial-mesenchymal transition (EMT) in vitro by monitoring changes in pulmonary function, inflammatory response, fibrotic remodeling, and signaling pathways. AUDA was administered by intragastric administration (i.g) daily for three weeks, starting at seven days after intratracheal instillation of BLM. All examinations were performed 24h after the last i.g. In vivo, AUDA significantly improved BLM-induced decline in lung function and body weight, and inhibited inflammatory cell accumulation and the mRNA and protein expression of interleukin (IL)-1beta, TGF-beta1, and matrix metalloproteinase 9 (MMP-9) in lung tissue. Moreover, AUDA attenuated BLM-induced deposition of collagen fibers, destruction of alveolar structures, and pulmonary parenchyma. Additionally, AUDA regulated the expression of alpha-smooth muscle actin (alpha-SMA) and E-cadherin by inhibiting the Smad3/p38 signaling pathway. In vitro, AUDA significantly inhibited TGF-beta1-induced epithelial cells and fibroblast proliferation, reduced sEH expression and alpha-SMA expression, and increased epoxyeicosatrienoic acid (EET) levels and E-cadherin expression in epithelial cells. These effects were blocked by AUDA by downregulating the Smad3 and p38 signaling pathways. Taken together, these data indicate that treatment with sEH inhibitors may improve BLM-induced pulmonary toxicity.
ESTHER : Dong_2017_Toxicology_389_31
PubMedSearch : Dong_2017_Toxicology_389_31
PubMedID: 28694203

Title : Discovery of Potent and Orally Active Lipoprotein-Associated Phospholipase A2 (Lp-PLA2) Inhibitors as a Potential Therapy for Diabetic Macular Edema - Chen_2016_J.Med.Chem_59_2674
Author(s) : Chen X , Wang K , Xu W , Ma Q , Chen M , Du L , Mo M , Wang Y , Shen J
Ref : Journal of Medicinal Chemistry , 59 :2674 , 2016
Abstract : Lipoprotein-associated phospholipase A2 (Lp-PLA2) is considered to be a promising therapeutic target for several inflammation-associated diseases. Herein, we describe the discovery of a series of pyrimidone derivatives as Lp-PLA2 inhibitors. Systematic structural modifications led to the identification of several pyrimidone compounds with promising in vitro inhibitory potency and pharmacokinetic properties. Compound 14c, selected for in vivo evaluation, demonstrated decent pharmacokinetic profiles and robust inhibitory potency against Lp-PLA2 in Sprague-Dawley (SD) rats. Furthermore, 14c significantly inhibited retinal thickening in STZ-induced diabetic SD rats as a model of diabetic macular edema (DME) after oral dosing for 4 weeks. Taken together, these results suggested that 14c can serve as a valuable lead in the search for new Lp-PLA2 inhibitors for prevention and/or treatment of DME.
ESTHER : Chen_2016_J.Med.Chem_59_2674
PubMedSearch : Chen_2016_J.Med.Chem_59_2674
PubMedID: 26927682
Gene_locus related to this paper: human-PLA2G7

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 : Neuroprotective effects of polygalacic acid on scopolamine-induced memory deficits in mice - Guo_2016_Phytomedicine_23_149
Author(s) : Guo C , Shen J , Meng Z , Yang X , Li F
Ref : Phytomedicine , 23 :149 , 2016
Abstract : BACKGROUND: Polygala tenuifolia Willd is a Traditional Chinese Medicine used for the treatment of learning and memory deficits. Triterpenoid saponins, the main bioactive compounds of Polygala tenuifolia Willd, are easily hydrolyzed to polygalacic acid (PA). PURPOSE: The present study was undertaken to investigate the neuroprotective effects of PA on scopolamine-induced cognitive dysfunction and to elucidate its underlying mechanisms of action.
METHODS: PA (3, 6, and 12 mg/kg) was administered orally to mice for fourteen days, and scopolamine (1 mg/kg) was injected intraperitoneally for fourteen days to induce memory impairment. Memory-related behaviors were evaluated using the Morris water maze. Cholinergic and neuroinflammatory activities were measured in brain tissue. Superoxide dismutase activities, malondialdehyde and reduced glutathione contents were also measured in the brains.
RESULTS: Treatment with scopolamine significantly increased the escape latency time, decreased the number of crossings, and shortened the time spent in the target quadrant, while PA reversed these scopolamine-induced effects. PA significantly improved cholinergic system reactivity, as indicated by decreased acetylcholinesterase (AChE) activity, increased choline acetyltransferase (ChAT) activity, and elevated levels of acetylcholine (ACh) in the hippocampus and frontal cortex. PA also significantly ameliorated neuroinflammation and oxidative stress in mice. CONCLUSION: These results suggest that PA might exert a significant neuroprotective effect on cognitive impairment, driven in part by the modulation of cholinergic activity and neuroinflammation.
ESTHER : Guo_2016_Phytomedicine_23_149
PubMedSearch : Guo_2016_Phytomedicine_23_149
PubMedID: 26926176

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 : Relaxant action of plumula nelumbinis extract on mouse airway smooth muscle - Tan_2015_Evid.Based.Complement.Alternat.Med_2015_523640
Author(s) : Tan L , Chen W , Wei MY , Shen J , Yu MF , Yang G , Guo D , Qin G , Ji G , Liu QH
Ref : Evid Based Complement Alternat Med , 2015 :523640 , 2015
Abstract : The traditional herb Plumula Nelumbinis is widely used in the world because it has many biological activities, such as anti-inflammation, antioxidant, antihypertension, and butyrylcholinesterase inhibition. However, the action of Plumula Nelumbinis on airway smooth muscle (ASM) relaxation has not been investigated. A chloroform extract of Plumula Nelumbinis (CEPN) was prepared, which completely inhibited precontraction induced by high K(+) in a concentration-dependent manner in mouse tracheal rings, but it had no effect on resting tension. CEPN also blocked voltage-dependent L-type Ca(2+) channel- (VDCC-) mediated currents. In addition, ACh-induced precontraction was also completely blocked by CEPN and partially inhibited by nifedipine or pyrazole 3. Besides, CEPN partially reduced ACh-activated nonselective cation channel (NSCC) currents. Taken together, our data demonstrate that CEPN blocked VDCC and NSCC to inhibit Ca(2+) influx, resulting in relaxation of precontracted ASM. This finding indicates that CEPN would be a candidate of new potent bronchodilators.
ESTHER : Tan_2015_Evid.Based.Complement.Alternat.Med_2015_523640
PubMedSearch : Tan_2015_Evid.Based.Complement.Alternat.Med_2015_523640
PubMedID: 25763092

Title : Associations of ABHD2 Genetic Variations with Risks for Chronic Obstructive Pulmonary Disease in a Chinese Han Population - Liu_2015_PLoS.One_10_e0123929
Author(s) : Liu L , Li X , Yuan R , Zhang H , Qiang L , Shen J , Jin S
Ref : PLoS ONE , 10 :e0123929 , 2015
Abstract : The human alpha/beta hydrolase domain-containing protein 2 gene (ABHD2) plays a critical role in pulmonary emphysema, a major subset of the clinical entity known as chronic obstructive pulmonary disease (COPD). Here, we evaluated genetic variation in the ABHD2 gene in a Chinese Han population of 286 COPD patients and 326 control subjects. The rs12442260 CT/CC genotype was associated with COPD (P < 0.001) under a dominant model. In the former-smoker group, the rs12442260 TT genotype was associated with a decreased risk of developing COPD after adjusting for age, gender and pack-years (P = 0.012). Rs12442260 was also associated with pre-FEV1 (the predicted bronchodilator forced expiratory volume in the first second) in controls (P = 0.027), but with FEV1/ forced vital capacity (FVC) ratios only in COPD patients (P = 0.012) under a dominant model. Results from the current study suggest that ABHD2 gene polymorphisms contribute to COPD susceptibility in the Chinese Han population.
ESTHER : Liu_2015_PLoS.One_10_e0123929
PubMedSearch : Liu_2015_PLoS.One_10_e0123929
PubMedID: 25880496
Gene_locus related to this paper: human-ABHD2

Title : Acetylcholinesterase overexpression mediated by oncolytic adenovirus exhibited potent anti-tumor effect - Xu_2014_BMC.Cancer_14_668
Author(s) : Xu H , Shen Z , Xiao J , Yang Y , Huang W , Zhou Z , Shen J , Zhu Y , Liu XY , Chu L
Ref : BMC Cancer , 14 :668 , 2014
Abstract : BACKGROUND: Acetylcholinesterase (AChE) mainly functions as an efficient terminator for acetylcholine signaling transmission. Here, we reported the effect of AChE on gastric cancer therapy.
METHODS: The expression of AChE in gastric cancerous tissues and adjacent non-cancerous tissues was examined by immunohistochemistry. Gastric cancer cells were treated with AChE delivered by replication-deficient adenoviral vector (Ad.AChE) or oncolytic adenoviral vector (ZD55-AChE), respectively, followed by measurement of cell viability and apoptosis by MTT assay and apoptosis detection assays. In vivo, the tumor growth of gastric cancer xenografts in mice treated with Ad.AChE or ZD55-AChE (1 x 109 PFU) were measured. In addition, the cell viability of gastric cancer stem cells treated with Ad.AChE or ZD55-AChE were evaluated by MTT assay.
RESULTS: A positive correlation was found between higher level of AChE expression in gastric cancer patient samples and longer survival time of the patients. Ad.AChE and ZD55-AChE inhibited gastric cancer cell growth, and low dose of ZD55-AChE induced mitochondrial pathway of apoptosis in cells. ZD55-AChE repressed tumor growth in vivo, and the anti-tumor efficacy is greater than Ad.AChE. Moreover, ZD55-AChE suppressed the growth of gastric cancer stem cells. CONCLUSION: ZD55-AChE represented potential therapeutic effect for human gastric cancer.
ESTHER : Xu_2014_BMC.Cancer_14_668
PubMedSearch : Xu_2014_BMC.Cancer_14_668
PubMedID: 25220382

Title : Plant genetics. Early allopolyploid evolution in the post-Neolithic Brassica napus oilseed genome - Chalhoub_2014_Science_345_950
Author(s) : Chalhoub B , Denoeud F , Liu S , Parkin IA , Tang H , Wang X , Chiquet J , Belcram H , Tong C , Samans B , Correa M , Da Silva C , Just J , Falentin C , Koh CS , Le Clainche I , Bernard M , Bento P , Noel B , Labadie K , Alberti A , Charles M , Arnaud D , Guo H , Daviaud C , Alamery S , Jabbari K , Zhao M , Edger PP , Chelaifa H , Tack D , Lassalle G , Mestiri I , Schnel N , Le Paslier MC , Fan G , Renault V , Bayer PE , Golicz AA , Manoli S , Lee TH , Thi VH , Chalabi S , Hu Q , Fan C , Tollenaere R , Lu Y , Battail C , Shen J , Sidebottom CH , Canaguier A , Chauveau A , Berard A , Deniot G , Guan M , Liu Z , Sun F , Lim YP , Lyons E , Town CD , Bancroft I , Meng J , Ma J , Pires JC , King GJ , Brunel D , Delourme R , Renard M , Aury JM , Adams KL , Batley J , Snowdon RJ , Tost J , Edwards D , Zhou Y , Hua W , Sharpe AG , Paterson AH , Guan C , Wincker P
Ref : Science , 345 :950 , 2014
Abstract : Oilseed rape (Brassica napus L.) was formed ~7500 years ago by hybridization between B. rapa and B. oleracea, followed by chromosome doubling, a process known as allopolyploidy. Together with more ancient polyploidizations, this conferred an aggregate 72x genome multiplication since the origin of angiosperms and high gene content. We examined the B. napus genome and the consequences of its recent duplication. The constituent An and Cn subgenomes are engaged in subtle structural, functional, and epigenetic cross-talk, with abundant homeologous exchanges. Incipient gene loss and expression divergence have begun. Selection in B. napus oilseed types has accelerated the loss of glucosinolate genes, while preserving expansion of oil biosynthesis genes. These processes provide insights into allopolyploid evolution and its relationship with crop domestication and improvement.
ESTHER : Chalhoub_2014_Science_345_950
PubMedSearch : Chalhoub_2014_Science_345_950
PubMedID: 25146293
Gene_locus related to this paper: braol-Q8GTM3 , braol-Q8GTM4 , brana-a0a078j4a9 , brana-a0a078e1m0 , brana-a0a078cd75 , brana-a0a078evd3 , brana-a0a078j4f0 , brana-a0a078cta5 , brana-a0a078cus4 , brana-a0a078f8c2 , brana-a0a078jql1 , brana-a0a078dgj3 , brana-a0a078hw50 , brana-a0a078cuu0 , brana-a0a078iyl8 , brana-a0a078dfa9 , brana-a0a078ic91 , brana-a0a078cnf7 , brana-a0a078fh41 , brana-a0a078ca65 , brana-a0a078ctc8 , brana-a0a078h021 , brana-a0a078h0h8 , brana-a0a078jx23 , brana-a0a078ci96 , brana-a0a078cqd7 , brana-a0a078dh94 , brana-a0a078h612 , brana-a0a078ild2 , brana-a0a078j2t3 , braol-a0a0d3dpb2 , braol-a0a0d3dx76 , brana-a0a078jxa8 , brana-a0a078i2k3 , braol-a0a0d3ef55 , brarp-m4dcj8 , brana-a0a078fw53 , brana-a0a078itf3 , brana-a0a078jsn1 , brana-a0a078jrt9 , brana-a0a078i6d2 , brana-a0a078jku0 , brana-a0a078fss7 , brana-a0a078i1l0 , brana-a0a078i402

Title : Design and synthesis of 4-(2,4,5-trifluorophenyl)butane-1,3-diamines as dipeptidyl peptidase IV inhibitors - Zhu_2013_ChemMedChem_8_1104
Author(s) : Zhu L , Li Y , Qiu L , Su M , Wang X , Xia C , Qu Y , Li J , Xiong B , Shen J
Ref : ChemMedChem , 8 :1104 , 2013
Abstract : The worldwide prevalence of diabetes has spurred numerous studies on the development of new antidiabetic medicines. As a result, dipeptidyl peptidase IV (DPP4) has been recognized as a validated target. In our efforts to discover new DPP4 inhibitors, we analyzed the complexed structures of DPP4 available in Protein Data Bank and designed a series of triazole compounds. After enzyme activity assays and crystallographic verification of the binding interaction patterns, we found that the triazole compounds can inhibit DPP4 with micromolar IC50 values. Liver microsome stability and cytochrome P450 metabolic tests were performed on this series, revealing undesirable pharmacokinetic profiles for the triazole compounds. To overcome this liability, we substituted the triazole ring with an amide or urea group to produce a new series of DPP4 inhibitors. Based on its enzyme activity, metabolic stability, and selectivity over DPP8 and DPP9, we selected compound 21 r for further study of its in vivo effects in mice using an oral glucose tolerance test (OGTT). The results show that 21 r has efficacy similar to that of sitagliptin at a dose of 3 mg kg(-1) . The crystal structure of 21 r bound to DPP4 also reveals that the trifluoromethyl group is directed toward a subpocket different from the subsite bound by sitagliptin, providing clues for the design of new DPP4 inhibitors.
ESTHER : Zhu_2013_ChemMedChem_8_1104
PubMedSearch : Zhu_2013_ChemMedChem_8_1104
PubMedID: 23671024
Gene_locus related to this paper: human-DPP4

Title : Functional alpha7beta2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid beta peptides - Liu_2012_BMC.Neurosci_13_155
Author(s) : Liu Q , Huang Y , Shen J , Steffensen S , Wu J
Ref : BMC Neurosci , 13 :155 , 2012
Abstract : BACKGROUND: beta-amyloid (Abeta) accumulation is described as a hallmark of Alzheimer's disease (AD). Abeta perturbs a number of synaptic components including nicotinic acetylcholine receptors containing alpha7 subunits (alpha7-nAChRs), which are abundantly expressed in the hippocampus and found on GABAergic interneurons. We have previously demonstrated the existence of a novel, heteromeric alpha7beta2-nAChR in basal forebrain cholinergic neurons that exhibits high sensitivity to acute Abeta exposure. To extend our previous work, we evaluated the expression and pharmacology of alpha7beta2-nAChRs in hippocampal interneurons and their sensitivity to Abeta.
RESULTS: GABAergic interneurons in the CA1 subregion of the hippocampus expressed functional alpha7beta2-nAChRs, which were characterized by relatively slow whole-cell current kinetics, pharmacological sensitivity to dihydro-beta-erythroidine (DHbetaE), a nAChR beta2* subunit selective blocker, and alpha7 and beta2 subunit interaction using immunoprecipitation assay. In addition, alpha7beta2-nAChRs were sensitive to 1 nM oligomeric Abeta. Similar effects were observed in identified hippocampal interneurons prepared from GFP-GAD mice. CONCLUSION: These findings suggest that Abeta modulation of cholinergic signaling in hippocampal GABAergic interneurons via alpha7beta2-nAChRs could be an early and critical event in Abeta-induced functional abnormalities of hippocampal function, which may be relevant to learning and memory deficits in AD.
ESTHER : Liu_2012_BMC.Neurosci_13_155
PubMedSearch : Liu_2012_BMC.Neurosci_13_155
PubMedID: 23272676

Title : Lipopolysaccharide down-regulates carbolesterases 1 and 2 and reduces hydrolysis activity in vitro and in vivo via p38MAPK-NF-kappaB pathway - Mao_2011_Toxicol.Lett_201_213
Author(s) : Mao Z , Li Y , Peng Y , Luan X , Gui H , Feng X , Hu G , Shen J , Yan B , Yang J
Ref : Toxicol Lett , 201 :213 , 2011
Abstract : Carboxylesterases constitute a class of enzymes that hydrolyze drugs containing such functional groups as carboxylic acid ester, amide, and thioester. Hydrolysis of many drugs is reduced in liver diseases such as hepatitis and cirrhosis. In this study, we have demonstrated, in vitro and in vivo, treatment with LPS decreased the expression of HCE1 and HCE2 and the capacity of hydrolytic activity. In HepG2 cells, the decreased expression by LPS occurred at both mRNA and protein levels. Both HCE1 and HCE2 promoters were significantly repressed by LPS, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting the transrepression is responsible for suppressed expression. Further study showed that both PDTC, a NF-B inhibitor, and SB203580, a p38MAPK inhibitor, could abolish the repression of HCE1 and HCE2 mediated by LPS, but U0126, a selective ERK1/2 inhibitor, could not do so, suggesting the repression of HCE1 and HCE2 by LPS through the p38MAPK-NF-B pathway. In addition, being pretreated with LPS, HepG2 cells altered the cellular responsiveness to ester therapeutic agents, including clopidogrel (hydrolyzed by HCE1) and irinotecan (hydrolyzed by HCE2). The altered cellular responsiveness occurred at low micromolar concentrations, suggesting that suppressed expression of carboxylesterases by LPS has profound pharmacological and toxicological consequences, particularly with those that are hydrolyzed in an isoform-specific manner. This study provides new insight into the understanding of the pharmacological and toxicological effects and the mechanisms for repressing drug metabolism enzymes in inflammation.
ESTHER : Mao_2011_Toxicol.Lett_201_213
PubMedSearch : Mao_2011_Toxicol.Lett_201_213
PubMedID: 21237253

Title : Possible ligand release pathway of dipeptidyl peptidase IV investigated by molecular dynamics simulations - Li_2011_Proteins_79_1800
Author(s) : Li C , Shen J , Li W , Lu C , Liu G , Tang Y
Ref : Proteins , 79 :1800 , 2011
Abstract : Dipeptidyl peptidase IV (DPP4) is an important target for the treatment of Type II diabetes mellitus. The crystal structure of DPP4 demonstrates that there are two possible pathways to the active site, a side opening and a beta propeller opening. However, it still lacks quantitative evidence to illustrate which pathway is more favorable for inhibitor to enter into or release from the active site. In this study, conventional and steered molecular dynamics simulations were performed to explore the details of inhibitor Q448 release from the active site of DPP4 via the two potential pathways. The comparisons of force and work together with potentials of mean force results suggested that the side opening might be more favorable for the inhibitor to pass through. Moreover, Glu205-Glu206 and Phe357 were recognized as two "key residues" in the active site for inhibitor binding. Accordingly, suggestions for further inhibitor design were provided.
ESTHER : Li_2011_Proteins_79_1800
PubMedSearch : Li_2011_Proteins_79_1800
PubMedID: 21465558

Title : The anticonvulsive drug lamotrigine blocks neuronal {alpha}4{beta}2 nicotinic acetylcholine receptors - Zheng_2010_J.Pharmacol.Exp.Ther_335_401
Author(s) : Zheng C , Yang K , Liu Q , Wang MY , Shen J , Valles AS , Lukas RJ , Barrantes FJ , Wu J
Ref : Journal of Pharmacology & Experimental Therapeutics , 335 :401 , 2010
Abstract : Lamotrigine (LTG), an anticonvulsive drug, is often used for the treatment of a variety of epilepsies. In addition to block of sodium channels, LTG may act on other targets to exert its antiepileptic effect. In the present study, we evaluated the effects of LTG on neuronal nicotinic acetylcholine receptors (nAChRs) using the patch-clamp technique on human alpha4beta2-nAChRs heterologously expressed in the SH-EP1 cell line and on native alpha4beta2-nAChRs in dopaminergic (DA) neurons in rat ventral tegmental area (VTA). In SH-EP1 cells, LTG diminished the peak and steady-state components of the inward alpha4beta2-nAChR-mediated currents. This effect exhibited concentration-, voltage- and use-dependent behavior. Nicotine dose-response curves showed that in the presence of LTG, the nicotine-induced maximal current was reduced, suggesting a noncompetitive inhibition. These findings suggest that LTG inhibits human neuronal alpha4beta2-nAChR function through an open-channel blocking mechanism. LTG-induced inhibition in alpha4beta2-nAChRs was more profound when preceded by a 2-min pretreatment, after which the nicotine-induced current was reduced even without coapplication of LTG, suggesting that LTG is also able to inhibit alpha4beta2-nAChRs without channel activation. In freshly dissociated VTA DA neurons, LTG inhibited alpha4beta2-nAChR-mediated currents but did not affect glutamate- or GABA-induced currents, indicating that LTG selectively inhibits nAChR function. Collectively, our data suggest that the neuronal alpha4beta2-nAChR is likely an important target for mediating the anticonvulsive effect of LTG and the blockade of alpha4beta2-nAChR possibly underlying the mechanism through which LTG effectively controls some types of epilepsy, such as autosomal dominant nocturnal frontal lobe epilepsy or juvenile myoclonic epilepsy.
ESTHER : Zheng_2010_J.Pharmacol.Exp.Ther_335_401
PubMedSearch : Zheng_2010_J.Pharmacol.Exp.Ther_335_401
PubMedID: 20688974

Title : Physical inactivity interacts with an endothelial lipase polymorphism to modulate high density lipoprotein cholesterol in the GOLDN study - Smith_2009_Atherosclerosis_206_500
Author(s) : Smith CE , Arnett DK , Tsai MY , Lai CQ , Parnell LD , Shen J , Laclaustra M , Junyent M , Ordovas JM
Ref : Atherosclerosis , 206 :500 , 2009
Abstract : BACKGROUND: Plasma high density lipoprotein (HDL) cholesterol (HDL-C) concentration is highly heritable but is also modifiable by environmental factors including physical activity. HDL-C response to exercise varies among individuals, and this variability may be associated with genetic polymorphisms in the key regulators of HDL metabolism including endothelial lipase (LIPG).
METHODS: We examined associations between variants LIPG T111I (rs2000813) and LIPG i24582 (rs6507931), HDL and television viewing/computer use ("screen time") as a marker for physical inactivity in a population with high prevalence of metabolic syndrome. Subjects consisted of 539 White men and 584 women (mean+/-S.D., 49+/-16 years) participating in the GOLDN study.
RESULTS: We did not observe an association with either LIPG SNP or HDL independently of screen time. In multi-adjusted linear regression models, HDL interacted significantly with screen time as a continuous variable in LIPG i24582 subjects with TT genotype (P<0.05). By dichotomizing screen time into high and low levels, we found significant genotype-associated differences in HDL in women but not men. When screen time was >or=2.6h/day, the concentrations of total HDL-C, large HDL, large low density lipoprotein (LDL) were lower, the concentration of small LDL was higher and HDL and LDL particle sizes were smaller in subjects with LIPG i24582 TT compared to CT and CC subjects (P<0.05).
CONCLUSIONS: We found a significant gene-physical inactivity interaction for HDL and some LDL measures for the LIPG i24582 polymorphism. Higher levels of physical activity may be protective for HDL-C concentrations and low activity detrimental in LIPG i24582 TT individuals, especially in women.
ESTHER : Smith_2009_Atherosclerosis_206_500
PubMedSearch : Smith_2009_Atherosclerosis_206_500
PubMedID: 19380136
Gene_locus related to this paper: human-LIPG

Title : Design, synthesis and biological evaluation of novel dual inhibitors of acetylcholinesterase and beta-secretase - Zhu_2009_Bioorg.Med.Chem_17_1600
Author(s) : Zhu Y , Xiao K , Ma L , Xiong B , Fu Y , Yu H , Wang W , Wang X , Hu D , Peng H , Li J , Gong Q , Chai Q , Tang X , Zhang H , Shen J
Ref : Bioorganic & Medicinal Chemistry , 17 :1600 , 2009
Abstract : To explore novel effective drugs for the treatment of Alzheimer's disease (AD), a series of dual inhibitors of acetylcholineterase (AChE) and beta-secretase (BACE-1) were designed based on the multi-target-directed ligands strategy. Among them, inhibitor 28 exhibited good dual potency in enzyme inhibitory potency assay (BACE-1: IC(50)=0.567 microM; AChE: IC(50)=1.83 microM), and also showed excellent inhibitory effects on Abeta production of APP transfected HEK293 cells (IC(50)=98.7 nM) and mild protective effect against hydrogen peroxide (H(2)O(2))-induced PC12 cell injury. Encouragingly, intracerebroventricular injection of 28 into amyloid precursor protein (APP) transgenic mice caused a 29% reduction of Abeta(1-40) production. Therefore, 28 was demonstrated as a good lead compound for the further study and more importantly, the strategy of AChE and BACE-1 dual inhibitors might be a promising direction for developing novel drugs for AD patients.
ESTHER : Zhu_2009_Bioorg.Med.Chem_17_1600
PubMedSearch : Zhu_2009_Bioorg.Med.Chem_17_1600
PubMedID: 19162488

Title : Age-related pulmonary emphysema in mice lacking alpha\/beta hydrolase domain containing 2 gene - Jin_2009_Biochem.Biophys.Res.Commun_380_419
Author(s) : Jin S , Zhao G , Li Z , Nishimoto Y , Isohama Y , Shen J , Ito T , Takeya M , Araki K , He P , Yamamura K
Ref : Biochemical & Biophysical Research Communications , 380 :419 , 2009
Abstract : The alpha/beta hydrolase family genes have been identified as down-regulated genes in human emphysematous lungs. Although proteins in the alpha/beta hydrolase family generally act as enzymes, such as lipases, the specific functions of the Abhd2 protein are unknown. To examine the role of Abhd2 in the lung, we analyzed Abhd2 deficient mice obtained by gene trap mutagenesis. Abhd2 was expressed in the alveolar type II cells. Abhd2 deficiency resulted in a decreased level of phosphatidylcholine in the bronchoalveolar lavage. These mice developed spontaneous gradual progression of emphysema, due to increased macrophage infiltration, increased inflammatory cytokines, a protease/anti-protease imbalance and enhanced apoptosis. This phenotype is more akin to the pace of emphysema that develops in humans. Our findings suggest that derangement in alveolar phospholipid metabolism can induce emphysema, and that Abhd2 plays a critical role in maintaining lung structural integrity.
ESTHER : Jin_2009_Biochem.Biophys.Res.Commun_380_419
PubMedSearch : Jin_2009_Biochem.Biophys.Res.Commun_380_419
PubMedID: 19250629
Gene_locus related to this paper: human-ABHD2 , mouse-ABHD2

Title : A novel enantioselective epoxide hydrolase for (R)-phenyl glycidyl ether to generate (R)-3-phenoxy-1,2-propanediol - Wu_2007_Appl.Microbiol.Biotechnol_76_1281
Author(s) : Wu S , Shen J , Zhou X , Chen J
Ref : Applied Microbiology & Biotechnology , 76 :1281 , 2007
Abstract : Bacillus sp. Z018, a novel strain producing epoxide hydrolase, was isolated from soil. The epoxide hydrolase catalyzed the stereospecific hydrolysis of (R)-phenyl glycidyl ether to generate (R)-3-phenoxy-1,2-propanediol. Epoxide hydrolase from Bacillus sp. Z018 was inducible, and (R)-phenyl glycidyl ether was able to act as an inducer. The fermentation conditions for epoxide hydrolase were 35 degrees C, pH 7.5 with glucose and NH(4)Cl as the best carbon and nitrogen source, respectively. Under optimized conditions, the biotransformation yield of 45.8% and the enantiomeric excess of 96.3% were obtained for the product (R)-3-phenoxy-1,2-propanediol.
ESTHER : Wu_2007_Appl.Microbiol.Biotechnol_76_1281
PubMedSearch : Wu_2007_Appl.Microbiol.Biotechnol_76_1281
PubMedID: 17710393
Gene_locus related to this paper: tsupd-d5us69

Title : Dynamic mechanism of E2020 binding to acetylcholinesterase: a steered molecular dynamics simulation - Niu_2005_J.Phys.Chem.B_109_23730
Author(s) : Niu C , Xu Y , Luo X , Duan W , Silman I , Sussman JL , Zhu W , Chen K , Shen J , Jiang H
Ref : J Phys Chem B , 109 :23730 , 2005
Abstract : The unbinding process of E2020 ((R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine) leaving from the long active site gorge of Torpedo californica acetylcholinesterase (TcAChE) was studied by using steered molecular dynamics (SMD) simulations on a nanosecond scale with different velocities, and unbinding force profiles were obtained. Different from the unbinding of other AChE inhibitors, such as Huperzine A that undergoes the greatest barrier located at the bottleneck of the gorge, the major resistance preventing E2020 from leaving the gorge is from the peripheral anionic site where E2020 interacts intensively with several aromatic residues (e.g., Tyr70, Tyr121, and Trp279) through its benzene ring and forms a strong direct hydrogen bond and a water bridge with Ser286 via its O24. These interactions cause the largest rupture force, approximately 550 pN. It was found that the rotatable bonds of the piperidine ring to the benzene ring and dimethoxyindanone facilitate E2020 to pass the bottleneck through continuous conformation change by rotating those bonds to avoid serious conflict with Tyr121 and Phe330. The aromatic residues lining the gorge wall are the major components contributing to hydrophobic interactions between E2020 and TcAChE. Remarkably, these aromatic residues, acting in three groups as "sender" and "receiver", compose a "conveyer belt" for E2020 entering and leaving the TcAChE gorge.
ESTHER : Niu_2005_J.Phys.Chem.B_109_23730
PubMedSearch : Niu_2005_J.Phys.Chem.B_109_23730
PubMedID: 16375354

Title : How does huperzine A enter and leave the binding gorge of acetylcholinesterase? Steered molecular dynamics simulations - Xu_2003_J.Am.Chem.Soc_125_11340
Author(s) : Xu Y , Shen J , Luo X , Silman I , Sussman JL , Chen K , Jiang H
Ref : Journal of the American Chemical Society , 125 :11340 , 2003
Abstract : The entering and leaving processes of Huperzine A (HupA) binding with the long active-site gorge of Torpedo californica acetylcholinesterase (TcAChE) have been investigated by using steered molecular dynamics simulations. The analysis of the force required along the pathway shows that it is easier for HupA to bind to the active site of AChE than to disassociate from it, which for the first time interprets at the atomic level the previous experimental result that unbinding process of HupA is much slower than its binding process to AChE. The direct hydrogen bonds, water bridges, and hydrophobic interactions were analyzed during two steered molecular dynamics (SMD) simulations. Break of the direct hydrogen bond needs a great pulling force. The steric hindrance of bottleneck might be the most important factor to produce the maximal rupture force for HupA to leave the binding site but it has a little effect on the binding process of HupA with AChE. Residue Asp72 forms a lot of water bridges with HupA leaving and entering the AChE binding gorge, acting as a clamp to take out HupA from or put HupA into the active site. The flip of the peptide bond between Gly117 and Gly118 has been detected during both the conventional MD and SMD simulations. The simulation results indicate that this flip phenomenon could be an intrinsic property of AChE and the Gly117-Gly118 peptide bond in both HupA bound and unbound AChE structures tends to adopt the native enzyme structure. At last, in a vacuum the rupture force is increased up to 1500 pN while in water solution the greatest rupture force is about 800 pN, which means water molecules in the binding gorge act as lubricant to facilitate HupA entering or leaving the binding gorge.
ESTHER : Xu_2003_J.Am.Chem.Soc_125_11340
PubMedSearch : Xu_2003_J.Am.Chem.Soc_125_11340
PubMedID: 16220957

Title : APP processing and synaptic plasticity in presenilin-1 conditional knockout mice - Yu_2001_Neuron_31_713
Author(s) : Yu H , Saura CA , Choi SY , Sun LD , Yang X , Handler M , Kawarabayashi T , Younkin L , Fedeles B , Wilson MA , Younkin S , Kandel ER , Kirkwood A , Shen J
Ref : Neuron , 31 :713 , 2001
Abstract : We have developed a presenilin-1 (PS1) conditional knockout mouse (cKO), in which PS1 inactivation is restricted to the postnatal forebrain. The PS1 cKO mouse is viable and exhibits no gross abnormalities. The carboxy-terminal fragments of the amyloid precursor protein differentially accumulate in the cerebral cortex of cKO mice, while generation of beta-amyloid peptides is reduced. Expression of Notch downstream effector genes, Hes1, Hes5, and Dll1, is unaffected in the cKO cortex. Although basal synaptic transmission, long-term potentiation, and long-term depression at hippocampal area CA1 synapses are normal, the PS1 cKO mice exhibit subtle but significant deficits in long-term spatial memory. These results demonstrate that inactivation of PS1 function in the adult cerebral cortex leads to reduced Abeta generation and subtle cognitive deficits without affecting expression of Notch downstream genes.
ESTHER : Yu_2001_Neuron_31_713
PubMedSearch : Yu_2001_Neuron_31_713
PubMedID: 11567612

Title : [A gene analysis of familial lipoprotein lipase deficiency in China] - Shen_1999_Zhonghua.Yi.Xue.Yi.Chuan.Xue.Za.Zhi_16_233
Author(s) : Shen J , Chen R , Hu W , Bingshen KE , Li L , Du Y , Liu Y
Ref : Zhonghua Yi Xue Yi Chuan Xue Za Zhi , 16 :233 , 1999
Abstract : OBJECTIVE: To investigate the gene mutation of lipoprotein lipase(LPL) of familial LPL deficiency in China.
METHODS: The DNA sequencing of LPL gene of the patients was performed with the dideoxy method based on the polymerase chain reaction amplification using the genomic DNA as a template.
RESULTS: It was identified that a missense mutation in exon 6 of LPL gene (6G(979)-->A) resulted in the substitution of Glu(242) by Lys in a heterozygous state. CONCLUSION: The missense mutation of LPL may play a key role in the decrease of LPL activity. This is the first report about the gene mutation of LPL at this site in familial LPL deficiency. Moreover, it contributes to the elucidation of the pathophysiological mechanisms of atherosclerosis and some metabolic diseases.
ESTHER : Shen_1999_Zhonghua.Yi.Xue.Yi.Chuan.Xue.Za.Zhi_16_233
PubMedSearch : Shen_1999_Zhonghua.Yi.Xue.Yi.Chuan.Xue.Za.Zhi_16_233
PubMedID: 10431049

Title : Studies on the comprehensive control of babesiasis in cattle and buffaloes - Zhou_1997_Trop.Anim.Health.Prod_29_66S
Author(s) : Zhou J , Shen J , He G , Wang Q
Ref : Trop Anim Health Prod , 29 :66S , 1997
Abstract : To obtain a highly effective method for controlling babesiosis in cattle and buffalo, an epidemiological survey was carried out at Zuiyun village in Hubai Province. On the grounds of the epidemiological data, control measures which included preventive drugs and killing the vectors were devised. After two years of control no clinical cases of bovine babesiosis were found. The average number of ticks on cattle or buffalo decreased from 9-282 to 0-11.3. Good results were obtained in another epidemic area using this control method. These results indicated that this technique of controlling babesiosis is highly effective.
ESTHER : Zhou_1997_Trop.Anim.Health.Prod_29_66S
PubMedSearch : Zhou_1997_Trop.Anim.Health.Prod_29_66S
PubMedID: 9512748