Shi Y

References (78)

Title : Lipoprotein-associated phospholipase A2 predicts cardiovascular death in patients on maintenance hemodialysis: a 7-year prospective cohort study - Lin_2024_Lipids.Health.Dis_23_15
Author(s) : Lin L , Teng J , Shi Y , Xie Q , Shen B , Xiang F , Cao X , Ding X , Xu X , Zhang Z
Ref : Lipids Health Dis , 23 :15 , 2024
Abstract : BACKGROUND: Cardiovascular diseases (CVD) is the leading cause of death among maintenance hemodialysis patients, with dyslipidemia being a prevalent complication. The paradoxical relationship between cardiovascular outcomes and established lipid risk markers, such as low-density lipoprotein cholesterol (LDL-C), complicates lipid management in this population. This study investigated Lipoprotein-associated phospholipase A2 (Lp-PLA2), an emerging biomarker known for its proinflammatory and proatherogenic properties, as a potential cardiovascular prognostic marker in this cohort. In this context, the association between Lp-PLA2 levels and cardiovascular outcomes was evaluated, with the aim to facilitate more accurate stratification and identification of high-risk individuals. METHODS: From August 2013 to January 2014, 361 hemodialysis patients were prospectively enrolled. Lp-PLA(2) activity and laboratory measures at baseline were quantified. Comorbidities and medications were recorded. All patients were followed until the end of April, 2022. The individual and combined effects of Lp-PLA(2) activity and LDL-C on patient outcomes were examined. The association between Lp-PLA(2) activity and all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACEs) was analyzed. RESULTS: The median Lp-PLA(2) activity was 481.2 U/L. In subjects with Lp-PLA(2) activity over 481.2 U/L, significantly higher total cholesterol (4.89 vs. 3.98 mmol/L; P < 0.001), LDL-C (3.06 vs. 2.22 mmol/L; P < 0.001), and apolipoprotein B (0.95 vs. 0.75 mmol/L; P < 0.001) were observed. Over a median follow-up of 78.1 months, 182 patients died, with 77 cases identified as cardiovascular death, 88 MACEs happened. Cardiovascular mortality and MACEs, but not all-cause mortality, were significantly increased in the high Lp-PLA2 group. Cox regression analyses showed that high Lp-PLA(2) activity was associated with cardiovascular mortality and MACE occurrence. After comprehensive adjustment, high Lp-PLA(2) activity was independently associated with cardiovascular mortality(as a dichotomous variable: HR:2.57, 95%CI:1.58,4.18, P < 0.001; as a continuous variable: HR:1.25, 95%CI:1.10,1.41, P = 0.001) and MACEs(as a dichotomous variable: HR:2.17, 95%CI:1.39,3.40, P = 0.001; as a continuous variable: HR:1.20, 95%CI:1.07,1.36, P = 0.002). When participants were grouped by median Lp-PLA2 activity and LDL-C values, those with high Lp-PLA(2) and low LDL-C had the highest CV mortality. The addition of Lp-PLA2 significantly improved reclassification (as a dichotomous variable NRI = 42.51%, 95%CI: 5.0%,61.33%; as a continuous variable, NRI = 33.32%, 95% CI: 7.47%,56.21%). CONCLUSIONS: High Lp-PLA(2) activity is an independent risk factor for cardiovascular mortality and MACEs occurrence in patients on hemodialysis. The combined measures of Lp-PLA(2) and LDL-C help to identify individuals with a higher risk of cardiovascular death.
ESTHER : Lin_2024_Lipids.Health.Dis_23_15
PubMedSearch : Lin_2024_Lipids.Health.Dis_23_15
PubMedID: 38216940

Title : Phthalate biomarkers composition in relation to fatty liver: evidence from epidemiologic and in vivo studies - Chen_2024_Sci.Total.Environ__171607
Author(s) : Chen S , Liu H , Sun Y , Li S , Shi Y , Cheng Z , Zhu H , Sun H
Ref : Sci Total Environ , :171607 , 2024
Abstract : Phthalates, classified as environmental endocrine disruptors, pose potential toxicity risks to human health. Metabolic dysfunction-associated fatty liver disease is one of the most widespread liver diseases globally. Compared to studies focusing on metabolic disorders in relation to pollutants exposure, the impact of individual factors such as fatty liver on the in vivo metabolism of pollutants is always overlooked. Therefore, this study measured concentrations and composition of phthalate monoesters (mPAEs) in human urine samples, particularly those from fatty liver patients. Furthermore, we induced fatty liver in male Wistar rats by formulating a high-fat diet for twelve weeks. After administering a single dose of DEHP at 500 mg/kg bw through gavage, we compared the levels of di-2-ethylhexyl phthalate (DEHP), its metabolites (mDEHPs) and three hepatic metabolic enzymes, namely cytochrome P450 enzymes (CYP450), UDP glucuronosyltransferase 1 (UGT1), and carboxylesterase 1 (CarE1), between the normal and fatty liver rat groups. Compared to healthy individuals (n = 75), fatty liver patients (n = 104) exhibited significantly lower urinary concentrations of mPAEs (median: 106 vs. 166 ng/mL), but with a higher proportion of mono-2-ethylhexyl phthalate in mDEHPs (25.7 % vs. 9.9 %) (p < 0.05). In the animal experiment, we found that fatty liver in rats prolonged the elimination half-life of DEHP (24.61 h vs. 18.89 h) and increased the contents of CYP450, CarE1, and UGT1, implying the common but differentiated metabolism of DEHP as excess lipid accumulation in liver cells. This study provides valuable information on how to distinguish populations in biomonitoring studies across a diverse population and in assigning exposure classifications of phthalates or similar chemicals in epidemiologic studies.
ESTHER : Chen_2024_Sci.Total.Environ__171607
PubMedSearch : Chen_2024_Sci.Total.Environ__171607
PubMedID: 38461993

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

Title : A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer's Disease - Shan_2024_ACS.Nano__
Author(s) : Shan X , Lu Y , Luo Z , Zhao X , Pang M , Yin H , Guo X , Zhou H , Zhang J , Huang J , Shi Y , Lou J , Luo L , You J
Ref : ACS Nano , : , 2024
Abstract : Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Abeta accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.
ESTHER : Shan_2024_ACS.Nano__
PubMedSearch : Shan_2024_ACS.Nano__
PubMedID: 38517764

Title : Rational Design of a Highly Sensitive Carboxylesterase Probe and Its Application in High-Throughput Screening for Uncovering Carboxylesterase Inhibitors - Wang_2024_J.Org.Chem__
Author(s) : Wang K , Wang R , Yan Z , Li Y , Shi Y , Ge JY , Bai Y , Chen Z , Zhang L
Ref : J Org Chem , : , 2024
Abstract : Tracking carboxylesterases (CESs) through noninvasive and dynamic imaging is of great significance for diagnosing and treating CES-related metabolic diseases. Herein, three BODIPY-based fluorescent probes with a pyridine unit quaternarized via an acetoxybenzyl group were designed and synthesized to detect CESs based on the photoinduced electron transfer process. Notably, among these probes, BDPN2-CES exhibited a remarkable 182-fold fluorescence enhancement for CESs within 10 min. Moreover, BDPN2-CES successfully enabled real-time imaging of endogenous CES variations in living cells. Using BDPN2-CES, a visual high-throughput screening method for CES inhibitors was established, culminating in the discovery of an efficient inhibitor, WZU-13, sourced from a chemical library. These findings suggest that BDPN2-CES could provide a new avenue for diagnosing CES-related diseases, and WZU-13 emerges as a promising therapeutic candidate for CES-overexpression pathological processes.
ESTHER : Wang_2024_J.Org.Chem__
PubMedSearch : Wang_2024_J.Org.Chem__
PubMedID: 38720168

Title : An Individualized Nomogram for Predicting Mortality Risk of Septic Shock Patients During Hospitalization: A ten Years Retrospective Analysis - Wang_2023_Infect.Drug.Resist_16_6247
Author(s) : Wang M , Shi Y , Pan X , Wang B , Lu B , Ouyang J
Ref : Infect Drug Resist , 16 :6247 , 2023
Abstract : PURPOSE: We intend to develop a nomogram for predicting the mortality risk of hospitalized septic shock patients. PATIENTS AND METHODS: Data were collected from patients hospitalized with septic shock in Affiliated Dongyang Hospital of Wenzhou Medical University in China, over 10 years between January 2013 and January 2023. The eligible study participants were divided into modeling and validation groups. Factors independently related to the mortality in the modeling group were obtained by stepwise regression analysis. A logistic regression model and a nomogram were built. The model was evaluated based on the discrimination power (the area under the curve of the receiver operating characteristic, AUC), the calibration degree and decision curve analysis. In the validation group, the discrimination powers of the logistic regression model, the sequential organ failure assessment (SOFA) scoring model and machine learning model were compared. RESULTS: A total of 1253 patients, including 878 patients in the modeling group and 375 patients in the validation group, were included in this study. Age, respiratory failure, serum cholinesterase, lactic acid, blood phosphorus, blood magnesium, total bilirubin, and pH were independent risk factors related to the mortality risk of septic shock. The AUCs of the prediction model for the modeling and validation groups were 0.881 and 0.868, respectively. The models had a good calibration degree and clinical applicability. The AUC of the SOFA model for the validation population was 0.799, significantly lower than that of our model. The AUCs of the random forest and ensemble models were 0.865 and 0.863, respectively, comparable to that of our logistical prediction model. CONCLUSION: The model established in this study can effectively predict the mortality risk in patients hospitalized with septic shock. Thus, the model could be used clinically to determine the best therapy or management for patients with septic shock.
ESTHER : Wang_2023_Infect.Drug.Resist_16_6247
PubMedSearch : Wang_2023_Infect.Drug.Resist_16_6247
PubMedID: 37750174

Title : Inulin reduces liver triacylglycerol by increasing lipid droplet lipolysis in fat-loaded mice - Chen_2023_Food.Res.Int_163_112226
Author(s) : Chen B , Shi Y , Zhang K , Chang Y , Fu P , Liu P , Zhang S
Ref : Food Res Int , 163 :112226 , 2023
Abstract : Increased consumption of high-fat low-fiber foods has been shown to contribute to the development of metabolic syndromes, such as fatty liver, obesity, diabetes, et al. Fermentable dietary fiber, such as inulin, is broadly used to mitigate host metabolic abnormalities. In this work, we studied systematically the effect of inulin on mice with metabolic disorders, induced by either short- or long-term high-fat feeding. As expected, inulin reduced the body weight of mice in both groups. However, it was found that inulin feeding could only increase energy expenditure, alleviate adiposity, and improve glucose intolerance in mice fed with high-fat diet (HFD) for 1smonth but not for 4smonths. Surprisingly, inulin supplementation could alleviate HFD-induced hepatic steatosis, mediated through increasing adipose triglyceride lipase (ATGL) on liver lipid droplets, in both groups. Gut microbiota in the short- and long-term fat-loaded mice were shown to be modulated differently, which may mediate the differential effects of inulin. These results may help in understanding the role and mechanism of fermentable fiber regulating host metabolism.
ESTHER : Chen_2023_Food.Res.Int_163_112226
PubMedSearch : Chen_2023_Food.Res.Int_163_112226
PubMedID: 36596155

Title : Efficient decolorization of melanoidin in raw molasses wastewater by thermophilic esterase in actual extreme conditions - Zhang_2023_Bioresour.Technol_382_129191
Author(s) : Zhang Z , Hu W , Xie Q , Shi Y , Zhao Y , Deng Y , He J , Wu X , Zhang Y , Zhang W , Liu P , Yang H , Wang W
Ref : Bioresour Technol , 382 :129191 , 2023
Abstract : This work was developed to explore the versatility of thermophilic esterase for decolorizing raw molasses wastewater at high temperature and acidic pH. Combining covalent crosslinking method with deep eutectic solvent, a thermophilic esterase from Pyrobaculum calidifontis was immobilized on chitosan/macroporous resin composite carrier. The application of this immobilized thermophilic esterase eliminated 92.35% of colorants in raw molasses wastewater, achieving maximal decolorization efficiency across all the enzymes tested. Strikingly, this immobilized thermophilic esterase was capable of engaging in continuous activity for a 5-day period while removing 76.23% of pigments from samples. It effectively and continuously eliminated BOD(5) and COD, effectively and directly facilitating raw molasses wastewater decolorization under extreme conditions more readily than control group. In addition, this thermophilic esterase was believed to achieve decolorization through an addition reaction that disrupted conjugated system of melanoidins. Together, these results highlight an efficient and practical means of achieving enzyme-based molasses wastewater decolorization.
ESTHER : Zhang_2023_Bioresour.Technol_382_129191
PubMedSearch : Zhang_2023_Bioresour.Technol_382_129191
PubMedID: 37196742

Title : N-terminal lid swapping contributes to the substrate specificity and activity of thermophilic lipase TrLipE - Fang_2023_Front.Microbiol_14_1193955
Author(s) : Fang Y , Liu F , Shi Y , Yang T , Xin Y , Gu Z , Shi G , Zhang L
Ref : Front Microbiol , 14 :1193955 , 2023
Abstract : TrLipE is a thermophilic lipase that has potential commercial applications because of its catalytic ability under extreme conditions. Consistent with most lipases, the lid of TrLipE is located over the catalytic pocket, controls the substrate channel to the active center, and regulates the substrate specificity, activity, and stability of the enzyme through conformational changes. TrLipE from Thermomicrobium roseum has potential industrial applications, which is hindered by its weak enzymatic activity. Here, 18 chimeras (TrL1-TrL18) were reconstructed by N-terminal lid swapping between TrLipE and structurally similar enzymes. The results showed that the chimeras had a similar pH range and optimum pH as wild TrLipE but a narrower temperature range of 40-80 degreesC, and TrL17 and the other chimeras showed lower optimum temperatures of 70 degreesC and 60 degreesC, respectively. In addition, the half-lives of the chimeras were lower than those of TrLipE under optimum temperature conditions. Molecular dynamics simulations indicated that chimeras had high RMSD, RMSF, and B-factor values. When p-nitrophenol esters with different chains were used as substrates, compared with TrLipE, most of the chimeras had a low K(m) and high k(cat) value. The chimeras TrL2, TrL3, TrL17, and TrL18 could specifically catalyze the substrate 4-nitrophenyl benzoate, with TrL17 showing the highest k(cat)/K(m) value of 363.88 +/- 15.83 L min(-1) mmol(-1). Mutants were then designed by investigating the binding free energies of TrL17 and 4-nitrophenyl benzoate. The results indicated that single, double, and triple substitution variants (M89W and I206N; E33W/I206M and M89W/I206M; and M89W/I206M/L21I and M89W/I206N/L21I, respectively) presented approximately 2- to 3-fold faster catalysis of 4-nitrophenyl benzoate than the wild TrL17. Our observations will facilitate the development of the properties and industrial applications of TrLipE.
ESTHER : Fang_2023_Front.Microbiol_14_1193955
PubMedSearch : Fang_2023_Front.Microbiol_14_1193955
PubMedID: 37434709
Gene_locus related to this paper: therp-b9l0x7

Title : MAGL inhibition relieves synovial inflammation and pain via regulating NOX4-Nrf2 redox balance in osteoarthritis - Li_2023_Free.Radic.Biol.Med_208_13
Author(s) : Li X , Tao H , Zhou J , Zhang L , Shi Y , Zhang C , Sun W , Chu M , Chen K , Gu C , Yang X , Geng D , Hao Y
Ref : Free Radic Biol Med , 208 :13 , 2023
Abstract : Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage injury, hyperplasia of bone and inflammatory lesions of synovium. Monoacylglycerol lipase (MAGL), a member of the alpha/beta hydrolase superfamily, is involved in regulation of injury protection and immune-inflammation response. Autoinflammatory response of the synovium and the release of inflammatory mediators play critical roles in occurrence of early-stage OA. Fibroblast-like synoviocytes (FLSs) are resident mesenchymal cells of the synovial tissue. Considering that MAGL inhibition regulates the inflammatory signaling cascade, it is crucial to ascertain the biological effects and specific mechanisms of MAGL in alleviating inflammatory infiltration of OA FLSs. The aim of this study was to investigate the effect of MAGL on biological function in OA FLSs. Results from in vitro experiments showed that MAGL blockade not only effectively inhibited proliferation, invasion and migration of FLSs, but also downregulated expression of inflammatory-associated proteins. Sequencing results indicated that MAGL inhibition significantly suppressed NOX4-mediated oxidative stress, thus promoting Nrf2 nuclear accumulation and inhibiting generation of intracellular reactive oxygen species (ROS). Attenuation of NOX4 further alleviated redox dysplasia and ultimately improved tumor-like phenotypes, such as abnormal proliferation, migration and migration of FLSs. In vivo results corroborated this finding, with MAGL inhibition found to modulate pain and disease progression in an OA rat model. Collectively, these results indicate that MAGL administration is an ideal therapy treating OA.
ESTHER : Li_2023_Free.Radic.Biol.Med_208_13
PubMedSearch : Li_2023_Free.Radic.Biol.Med_208_13
PubMedID: 37516370
Gene_locus related to this paper: human-MGLL

Title : Development of a Nomogram for Predicting Mortality Risk in Sepsis Patients During Hospitalization: A Retrospective Study - Lu_2023_Infect.Drug.Resist_16_2311
Author(s) : Lu B , Pan X , Wang B , Jin C , Liu C , Wang M , Shi Y
Ref : Infect Drug Resist , 16 :2311 , 2023
Abstract : PURPOSE: We attempted to establish a model for predicting the mortality risk of sepsis patients during hospitalization. PATIENTS AND METHODS: Data on patients with sepsis were collected from a clinical record mining database, who were hospitalized at the Affiliated Dongyang Hospital of Wenzhou Medical University between January 2013 and August 2022. These included patients were divided into modeling and validation groups. In the modeling group, the independent risk factors of death during hospitalization were determined using univariate and multi-variate regression analyses. After stepwise regression analysis (both directions), a nomogram was drawn. The discrimination ability of the model was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve, and the GiViTI calibration chart assessed the model calibration. The Decline Curve Analysis (DCA) was performed to evaluate the clinical effectiveness of the prediction model. Among the validation group, the logistic regression model was compared to the models established by the SOFA scoring system, random forest method, and stacking method. RESULTS: A total of 1740 subjects were included in this study, 1218 in the modeling population and 522 in the validation population. The results revealed that serum cholinesterase, total bilirubin, respiratory failure, lactic acid, creatinine, and pro-brain natriuretic peptide were the independent risk factors of death. The AUC values in the modeling group and validation group were 0.847 and 0.826. The P values of calibration charts in the two population sets were 0.838 and 0.771. The DCA curves were above the two extreme curves. Moreover, the AUC values of the models established by the SOFA scoring system, random forest method, and stacking method in the validation group were 0.777, 0.827, and 0.832, respectively. CONCLUSION: The nomogram model established by combining multiple risk factors could effectively predict the mortality risk of sepsis patients during hospitalization.
ESTHER : Lu_2023_Infect.Drug.Resist_16_2311
PubMedSearch : Lu_2023_Infect.Drug.Resist_16_2311
PubMedID: 37155474

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

Title : Identification and characterization of novel carboxyl ester lipase gene variants in patients with different subtypes of diabetes - Wu_2023_BMJ.Open.Diabetes.Res.Care_11_e003127
Author(s) : Wu H , Shu M , Liu C , Zhao W , Li Q , Song Y , Zhang T , Chen X , Shi Y , Shi P , Fang L , Wang R , Xu C
Ref : BMJ Open Diabetes Res Care , 11 : , 2023
Abstract : INTRODUCTION: Mutations of CEL gene were first reported to cause a new type of maturity-onset diabetes of the young (MODY) denoted as MODY8 and then were also found in patients with type 1 (T1D) and type 2 diabetes (T2D). However, its genotype-phenotype relationship has not been fully determined and how carboxyl ester lipase (CEL) variants result in diabetes remains unclear. The aim of our study was to identify pathogenic variants of CEL in patients with diabetes and confirm their pathogenicity. RESEARCH DESIGN AND METHODS: All five patients enrolled in our study were admitted to Shandong Provincial Hospital and diagnosed with diabetes in the past year. Whole-exome sequencing was performed to identify pathogenic variants in three patients with MODY-like diabetes, one newborn baby with T1D and one patient with atypical T2D, as well as their immediate family members. Then the consequences of the identified variants were predicted by bioinformatic analysis. Furthermore, pathogenic effects of two novel CEL variants were evaluated in HEK293 cells transfected with wild-type and mutant plasmids. Finally, we summarized all CEL gene variants recorded in Human Gene Mutation Database and analyzed the mutation distribution of CEL. RESULTS: Five novel heterozygous variants were identified in CEL gene and they were predicted to be pathogenic by bioinformatic analysis. Moreover, in vitro studies indicated that the expression of CEL(R540C) was remarkably increased, while p.G729_T739del variant did not significantly affect the expression of CEL. Both novel variants obviously abrogated the secretion of CEL. Furthermore, we summarized all reported CEL variants and found that 74.3% of missense mutations were located in exons 1, 3, 4, 10 and 11 and most missense variants clustered near catalytic triad, Arg-83 and Arg-443. CONCLUSION: Our study identified five novel CEL variants in patients with different subtypes of diabetes, expanding the gene mutation spectrum of CEL and confirmed the pathogenicity of several novel variants.
ESTHER : Wu_2023_BMJ.Open.Diabetes.Res.Care_11_e003127
PubMedSearch : Wu_2023_BMJ.Open.Diabetes.Res.Care_11_e003127
PubMedID: 36634979
Gene_locus related to this paper: human-CEL

Title : Development of novel 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives as balanced multifunctional agents against Alzheimer's disease - Shi_2022_Eur.J.Med.Chem_230_114098
Author(s) : Shi Y , Zhang H , Song Q , Yu G , Liu Z , Zhong F , Tan Z , Liu X , Deng Y
Ref : Eur Journal of Medicinal Chemistry , 230 :114098 , 2022
Abstract : Based on multitarget-directed ligands approach, through two rounds of screening, a series of 2-aminoalkyl-6-(2-hydroxyphenyl)pyridazin-3(2H)-one derivatives were designed, synthesized and evaluated as innovative multifunctional agents against Alzheimer's disease. In vitro biological assays indicated that most of the hybrids were endowed with great AChE inhibitory activity, excellent antioxidant activity and moderate Abeta(1-42) aggregation inhibition. Taken both efficacy and balance into account, 12a was identified as the optimal multifunctional ligand with significant inhibition of AChE (EeAChE, IC(50) = 0.20 microM; HuAChE, IC(50) = 37.02 nM) and anti-Abeta activity (IC(50) = 1.92 microM for self-induced Abeta(1-42) aggregation; IC(50) = 1.80 microM for disaggregation of Abeta(1-42) fibrils; IC(50) = 2.18 microM for Cu(2+)-induced Abeta(1-42) aggregation; IC(50) = 1.17 microM for disaggregation of Cu(2+)-induced Abeta(1-42) fibrils; 81.7% for HuAChE-induced Abeta(1-40) aggregation). Moreover, it was equipped with the potential to serve as antioxidant (3.03 Trolox equivalents), metals chelator and anti-neuroinflammation agent for synergetic treatment. Finally, in vivo study demonstrated that 12a, with suitable BBB permeability (log BB = -0.61), could efficaciously ameliorate cognitive dysfunction on scopolamine-treated mice by regulating cholinergic system and oxidative stress simultaneously. Altogether, these results highlight the potential of 12a as an innovative balanced multifunctional candidate for Alzheimer's disease treatment.
ESTHER : Shi_2022_Eur.J.Med.Chem_230_114098
PubMedSearch : Shi_2022_Eur.J.Med.Chem_230_114098
PubMedID: 35026532

Title : Discovery of novel 3-butyl-6-benzyloxyphthalide Mannich base derivatives as multifunctional agents against Alzheimer's disease - Liu_2022_Bioorg.Med.Chem_58_116660
Author(s) : Liu Z , Shi Y , Zhang X , Yu G , Li J , Cong S , Deng Y
Ref : Bioorganic & Medicinal Chemistry , 58 :116660 , 2022
Abstract : Based on the multitarget-directed ligands strategy, a series of 3-butyl-6-benzyloxyphthalide Mannich base derivatives were designed, synthesized and identified for Alzheimer's disease (AD). Biological activity studies demonstrated that the designed hybrids showed multitarget activities toward AD. Among them, compound 7d was the most potent agent with excellent inhibitory activities on EeAChE (IC(50) = 0.087 microM), HuAChE (IC(50) = 0.041 microM) and MAO-B (IC(50) = 0.30 microM). Furthermore, molecular docking studies were conducted to investigate the interaction mode with enzymes. Besides, 7d also possessed good effects of Cu(2+) chelation, ameliorate oxidative stress, and anti-neuroinflammation, desirable BBB permeability and eligible drug-like properties. Altogether, the multifunctional profiles of 7d prove that it deserves further investigation as a novel drug candidate for AD treatment.
ESTHER : Liu_2022_Bioorg.Med.Chem_58_116660
PubMedSearch : Liu_2022_Bioorg.Med.Chem_58_116660
PubMedID: 35183029

Title : Ancestral sequence reconstruction and spatial structure analysis guided alteration of longer-chain substrate catalysis for Thermomicrobium roseum lipase - Ma_2022_Enzyme.Microb.Technol_156_109989
Author(s) : Ma D , Xin Y , Guo Z , Shi Y , Zhang L , Li Y , Gu Z , Ding Z , Shi G
Ref : Enzyme Microb Technol , 156 :109989 , 2022
Abstract : Thermomicrobium roseum DSM 5159 lipase (TrLip) is an enzyme with marked thermostability and excellent solvent resistance. However, TrLip reveals relatively high catalytic efficiency on short-chain substrates but poor activity against mid-long or long-chain fatty acids, which would limit its industrial application. In this study, ancestral sequence reconstruction (ASR), a common engineering tool for the evolutionary history of protein families, was employed to identify the natural evolutionary trends within 5 A around the catalytic center. Two mutation libraries were constructed, one for the catalytic center and the other for the pocket flexibility. A total of 69 mutants were expressed and purified in the Escherichia coli expression system to determine the kinetic parameters, and W219G could significantly enhance the catalytic efficiency against substrates with 12-, 16- and 18-carbon side chains. In addition, the double mutant W219G/F265M could further catalyze the breakdown of the above three substrates up to 6.34-, 4.21- and 4.86-folds compared to the wild-type TrLip, while the initial pH and thermostability were maintained. Through bioinformatics analysis, the significantly enhanced catalytic efficiency against longer-side chain substrates should be associated with the reduction of steric hindrance. With the outstanding stability and the promoted activity, TrLip should be of great potential in chemical and food industry.
ESTHER : Ma_2022_Enzyme.Microb.Technol_156_109989
PubMedSearch : Ma_2022_Enzyme.Microb.Technol_156_109989
PubMedID: 35134708
Gene_locus related to this paper: therp-b9l0x7

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

Title : Contribution of multiple overexpressed carboxylesterase genes to indoxacarb resistance in Spodoptera litura - Shi_2022_Pest.Manag.Sci__
Author(s) : Shi Y , Li W , Zhou Y , Liao X , Shi L
Ref : Pest Manag Sci , : , 2022
Abstract : BACKGROUND: As an important family of detoxification enzymes, carboxylesterases (CarEs) play important roles in the development of insecticides resistance in almost all agricultural pests. Previous studies suggested that the enhancement of CarE activity was an important mechanism mediating indoxacarb resistance in Spodoptera litura, and several CarE genes were found to be overexpressed in the indoxacarb-resistant strains. However, the functions of these CarE genes in indoxacarb resistance needs to be further investigated. RESULTS: The synergist triphenyl phosphate (TPP) effectively reduced the resistance of S. litura to indoxacarb, suggesting an involvement of CarEs in indoxacarb resistance. Among seven identified S. litura CarE genes (SlituCOE hereinafter), six were overexpressed in two indoxacarb-resistant strains, but there were no significant differences in gene copy number. Knockdown of SlituCOE009 and SlituCOE050 enhanced indoxacarb sensitivity in both susceptible and resistant strains, whereas knockdown of SlituCOE090, SlituCOE093 and SlituCOE074 enhanced indoxacarb sensitivity only in the resistant strain. Knockdown of the sixth gene SlituCOE073 did not have any effect. Furthermore, knockdown of the five SlituCOE genes simultaneously had a greater effect on increasing indoxacarb sensitivity than silencing them individually. By contrast, overexpression of the five SlituCOE genes individually in Drosophila melanogaster significantly decreased the toxicity of indoxacarb to transgenic fruit flies. Furthermore, modeling and docking analysis indicated that the catalytic pockets of SlituCOE009 and SlituCOE074 were ideally shaped for indoxacarb and DCJW, but the binding affinity for DCJW was stronger than indoxacarb. CONCLUSION: This study reveals that multiple overexpressed CarE genes are involved in indoxacarb resistance in S. litura.
ESTHER : Shi_2022_Pest.Manag.Sci__
PubMedSearch : Shi_2022_Pest.Manag.Sci__
PubMedID: 35066991

Title : Identification and Characterization of Two Novel Compounds: Heterozygous Variants of Lipoprotein Lipase in Two Pedigrees With Type I Hyperlipoproteinemia - Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
Author(s) : Wang S , Cheng Y , Shi Y , Zhao W , Gao L , Fang L , Jin X , Han X , Sun Q , Li G , Zhao J , Xu C
Ref : Front Endocrinol (Lausanne) , 13 :874608 , 2022
Abstract : BACKGROUND: Type I hyperlipoproteinemia, characterized by severe hypertriglyceridemia, is caused mainly by loss-of-function mutation of the lipoprotein lipase (LPL) gene. To date, more than 200 mutations in the LPL gene have been reported, while only a limited number of mutations have been evaluated for pathogenesis. OBJECTIVE: This study aims to explore the molecular mechanisms underlying lipoprotein lipase deficiency in two pedigrees with type 1 hyperlipoproteinemia. METHODS: We conducted a systematic clinical and genetic analysis of two pedigrees with type 1 hyperlipoproteinemia. Postheparin plasma of all the members was used for the LPL activity analysis. In vitro studies were performed in HEK-293T cells that were transiently transfected with wild-type or variant LPL plasmids. Furthermore, the production and activity of LPL were analyzed in cell lysates or culture medium. RESULTS: Proband 1 developed acute pancreatitis in youth, and her serum triglycerides (TGs) continued to be at an ultrahigh level, despite the application of various lipid-lowering drugs. Proband 2 was diagnosed with type 1 hyperlipoproteinemia at 9 months of age, and his serum TG levels were mildly elevated with treatment. Two novel compound heterozygous variants of LPL (c.3G>C, p. M1? and c.835_836delCT, p. L279Vfs*3, c.188C>T, p. Ser63Phe and c.662T>C, p. Ile221Thr) were identified in the two probands. The postheparin LPL activity of probands 1 and 2 showed decreases of 72.22 +/- 9.46% (p<0.01) and 54.60 +/- 9.03% (p<0.01), respectively, compared with the control. In vitro studies showed a substantial reduction in the expression or enzyme activity of LPL in the LPL variants. CONCLUSIONS: Two novel compound heterozygous variants of LPL induced defects in the expression and function of LPL and caused type I hyperlipoproteinemia. The functional characterization of these variants was in keeping with the postulated LPL mutant activity.
ESTHER : Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
PubMedSearch : Wang_2022_Front.Endocrinol.(Lausanne)_13_874608
PubMedID: 35923617
Gene_locus related to this paper: human-LPL

Title : The Aptamer Ob2, a novel AChE inhibitor, restores cognitive deficits and alleviates amyloidogenesis in 5FAD transgenic mice - Liang_2022_Mol.Ther.Nucleic.Acids_28_114
Author(s) : Liang Z , Li X , Luo X , Luo H , Chen Y , Cai M , Zhong X , Fang Y , Guo T , Shi Y , Zhang X
Ref : Mol Ther Nucleic Acids , 28 :114 , 2022
Abstract : Loss of cerebral cholinergic neurons and decreased levels of acetylcholine (ACh) are considered to be major factors causing cognitive dysfunction in Alzheimer's disease (AD). Abnormally elevated levels of acetylcholinesterase (AChE) resulting in decreased levels of ACh are common in AD patients; thus, AChE inhibitors (AChEIs) are widely used for the treatment of AD. In our previous work, we acquired DNA aptamers Ob1, Ob2, and Ob3 against human brain AChE from systematic evolution of ligands by exponential enrichment (SELEX). In this study, we investigated the effect of these aptamers on learning and memory abilities, as well as the underlying mechanism in a 5xFAD transgenic AD mouse model. Here, we showed that only aptamer Ob2 exhibits a good inhibitory effect on both mouse and human AChE activity. In addition, chronic treatment with aptamer Ob2 significantly improved cognitive ability of 5xFAD mice in the Morris water maze. Moreover, the mechanism of aptamer Ob2 in 5xFAD mice may be associated with its inhibition of AChE activity, alleviation of the levels of Abeta by lowering the expression of beta-secretase (BACE1), and activation of astrocytes in the brains of 5xFAD mice. These results indicate that aptamer Ob2 exhibits potential as an effective AChEI for the treatment of AD.
ESTHER : Liang_2022_Mol.Ther.Nucleic.Acids_28_114
PubMedSearch : Liang_2022_Mol.Ther.Nucleic.Acids_28_114
PubMedID: 35402070

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 : Effect of antiamyloid-beta drugs on Alzheimer's disease: study protocol for a systematic review and meta-analysis - Lyu_2021_BMJ.Open_11_e048453
Author(s) : Lyu D , Shi Y , Lyu X
Ref : BMJ Open , 11 :e048453 , 2021
Abstract : INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disease with a complex aetiology involving multiple targets and pathways. With the continuous growth of the ageing population, the burden of AD is increasing year by year. However, there has not been new drug approved for over a decade. In addition, the efficacy of memantine and cholinesterase inhibitors is not satisfactory. As amyloid-beta (Abeta) is regarded as the core pathological change and the trigger mechanism of AD, anti-Abeta therapy may be an effective therapy. In recent years, a lot of clinical trials have been carried out in this field, but the results have not been well summarised and analysed. METHODS AND ANALYSIS: In this study, we will study the effect of anti-Abeta antibodies versus placebo on the clinical efficacy, biomarkers, neuroimaging and safety in different stages of AD, as well as the factors that may affect the efficacy. Drugs that only target the existing Abeta are regarded as anti-Abeta antibodies. Following electronic databases will be searched from inception to April 2021: Medline-Ovid, EMBase-Ovid, Cochrane Central and clinical trial registration platform After identifying eligible studies through screening title, abstract and read full text of each retrieved literature, we will contact the correspondence authors for additional information and grey literatures. To get more reliable results, random effect model will be conducted for meta-analysis and analysis of subgroups or subsets. Funnel plot, Egger's test and sensitivity analysis will be conducted to explore potential heterogeneity. Meta-regression will be conducted to identify the factors that may affect clinical efficacy. Evidence quality assessment and trial sequential analysis will be conducted to assess the quality of evidence and confirm the reliability of the results in this study. ETHICS AND DISCUSSION: This study does not require formal ethical approval. The findings will be submitted to a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42020202370.
ESTHER : Lyu_2021_BMJ.Open_11_e048453
PubMedSearch : Lyu_2021_BMJ.Open_11_e048453
PubMedID: 34006557

Title : Clinical Features and Prognosis in Chinese Patients With Dipeptidyl-Peptidase-Like Protein 6 Antibody-Associated Encephalitis - Miao_2021_Front.Neurol_12_817896
Author(s) : Miao A , Shi Y , Wang X , Ge J , Yu C
Ref : Front Neurol , 12 :817896 , 2021
Abstract : OBJECTIVES: Anti-dipeptidyl-peptidase-like protein 6 (anti-DPPX) encephalitis an extremely rare type of immune-mediated encephalitis. This study aimed to analyze the electroclinical characteristics and prognosis of anti-DPPX encephalitis. METHODS: Five patients (all male) with anti-DPPX encephalitis in East China from January 2016 to October 2021 was retrospective analyzed. Electroclinical features and outcomes were reviewed. RESULTS: All five patients were male. The media age at disease onset was 32 years old with a range of 14-56 years. The main symptoms included psychiatric disturbances (2/5), amnesia (4/5), confusion (3/5), and seizures (3/5). Migrating myoclonus were identified in patient 4 with positive DPPX and contactin-associated protein-like 2 antibodies in blood. All of the patients had positive DPPX antibodies in serum. Only one of them had positive antibody in the cerebrospinal fluid. EEG showed diffuse slowing in two patients, but no epileptiform discharges were observed. Eighty percent (4/5) of the patients showed normal brain magnetic resonance imaging. After immunotherapy, improvement of neuropsychiatric symptoms from all of the patients was observed. Over a mean follow-up of 30.8 weeks, all of the patients had marked improvement in the modified Rankin Scale. To date, no tumors were not observed in any patients. CONCLUSIONS: Anti-DPPX encephalitis mainly presents as neuropsychiatric symptoms. Cooperation of DPPX antibodies and CASPR2 antibodies might have contributed to the migration of myoclonus in the patient 4. Prompt immunotherapy often results in improvement.
ESTHER : Miao_2021_Front.Neurol_12_817896
PubMedSearch : Miao_2021_Front.Neurol_12_817896
PubMedID: 35095748
Gene_locus related to this paper: human-DPP6

Title : Network Pharmacology-Based Study of the Underlying Mechanisms of Huangqi Sijunzi Decoction for Alzheimer's Disease - Zhang_2021_Evid.Based.Complement.Alternat.Med_2021_6480381
Author(s) : Zhang W , Lv M , Shi Y , Mu Y , Yao Z , Yang Z
Ref : Evid Based Complement Alternat Med , 2021 :6480381 , 2021
Abstract : BACKGROUND: Huangqi Sijunzi decoction (HQSJZD) is a commonly used conventional Chinese herbal medicine prescription for invigorating Qi, tonifying Yang, and removing dampness. Modern pharmacology and clinical applications of HQSJZD have shown that it has a certain curative effect on Alzheimer's disease (AD). METHODS: The active components and targets of HQSJZD were searched in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The genes corresponding to the targets were retrieved using UniProt and GeneCard database. The herb-compound-target network and protein-protein interaction (PPI) network were constructed by Cytoscape. The core targets of HQSJZD were analysed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The main active compounds of HQSJZD were docked with acetylcholinesterase (AChE). In vitro experiments were conducted to detect the inhibitory and neuroprotective effects of AChE. RESULTS: Compound-target network mainly contained 132 compounds and 255 corresponding targets. The main compounds contained quercetin, kaempferol, formononetin, isorhamnetin, hederagenin, and calycosin. Key targets contained AChE, PTGS2, PPARG, IL-1B, GSK3B, etc. There were 1708 GO items in GO enrichment analysis and 310 signalling pathways in KEGG, mainly including the cAMP signalling pathway, the vascular endothelial growth factor (VEGF) signalling pathway, serotonergic synapses, the calcium signalling pathway, type II diabetes mellitus, arginine and proline metabolism, and the longevity regulating pathway. Molecular docking showed that hederagenin and formononetin were the top 2 compounds of HQSJZD, which had a high affinity with AChE. And formononetin has a good neuroprotective effect, which can improve the oxidative damage of nerve cells. CONCLUSION: HQSJZD was found to have the potential to treat AD by targeting multiple AD-related targets. Formononetin and hederagenin in HQSJZD may regulate multiple signalling pathways through AChE, which might play a therapeutic role in AD.
ESTHER : Zhang_2021_Evid.Based.Complement.Alternat.Med_2021_6480381
PubMedSearch : Zhang_2021_Evid.Based.Complement.Alternat.Med_2021_6480381
PubMedID: 34650613

Title : Design, synthesis, and in vitro evaluation of 4-aminoalkyl-1(2H)-phthalazinones as potential multifunctional anti-Alzheimer's disease agents - Ye_2021_Bioorg.Chem_111_104895
Author(s) : Ye C , Xu R , Cao Z , Song Q , Yu G , Shi Y , Liu Z , Liu X , Deng Y
Ref : Bioorg Chem , 111 :104895 , 2021
Abstract : A series of 4-aminoalkyl-1(2H)-phthalazinone derivatives was designed and synthesized as potential multifunctional agents for Alzheimer's disease (AD) treatment. In vitro biological assay results demonstrated that most synthesized compounds exhibited significant AChE inhibition, moderate to high MAOs inhibitory potencies and good anti-platelet aggregation abilities. Among them, compound 15b exhibited the highest inhibitory potencies towards MAO-B and MAO-A (IC(50) = 0.7 microM and 6.4 microM respectively), moderate inhibition towards AChE (IC(50) = 8.2 microM), and good activities against self- and Cu(2+)-induced Abeta(1-42) aggregation and platelet aggregation. Moreover, 15b also displayed antioxidant capacity, neuroprotective potency, anti-neuroinflammation and BBB permeability. These excellent results indicated that compound 15b could be worthy of further studies to be considered as a promising multifunctional candidate for the treatment of AD.
ESTHER : Ye_2021_Bioorg.Chem_111_104895
PubMedSearch : Ye_2021_Bioorg.Chem_111_104895
PubMedID: 33887586

Title : Lipase Inhibitors for Obesity: A Review - Liu_2020_Biomed.Pharmacother_128_110314
Author(s) : Liu TT , Liu XT , Chen QX , Shi Y
Ref : Biomed Pharmacother , 128 :110314 , 2020
Abstract : With the rapid increase in the population of obese individuals, obesity has become a global problem. Many kinds of chronic metabolic diseases easily caused by obesity have received increasing attention from researchers. People are also striving to find various safe and effective treatment methods as well as anti-obesity medicines. Pancreatic lipase (PL) inhibitors have received substantial attention from researchers in recent years, and PL inhibitors from natural products have attracted much attention due to their structural diversity, low toxicity and wide range of sources. They have been used in the intestinal tract, blood, and the central nervous system with no side effects, and these advantages could lead to a new generation of diet pills or health care products with great development potential. This article is mainly aimed at discussing the research of obesity drug treatment with PL inhibitors and offers a brief review of related properties and the use of PL inhibitors in the field of weight loss.
ESTHER : Liu_2020_Biomed.Pharmacother_128_110314
PubMedSearch : Liu_2020_Biomed.Pharmacother_128_110314
PubMedID: 32485574

Title : Characterization of XtjR8: A novel esterase with phthalate-hydrolyzing activity from a metagenomic library of lotus pond sludge - Qiu_2020_Int.J.Biol.Macromol_164_1510
Author(s) : Qiu J , Yang H , Yan Z , Shi Y , Zou D , Ding L , Shao Y , Li L , Khan U , Sun S , Xin Z
Ref : Int J Biol Macromol , 164 :1510 , 2020
Abstract : A fosmid metagenomic library containing 9.7 x 10(4) clones was constructed. A novel esterase, XtjR8, was isolated through functional screening. XtjR8 shared the maximum amino acid identity (44%) with acetyl-hydrolase from Streptomyces hygroscopicus, and was classified into family IV esterase. XtjR8 exhibited the highest hydrolytic activity for p-nitrophenyl acetate at 40 degreesC and pH 8.0, and presented more than 40% activity from 20 degreesC to 80 degreesC. More importantly, XtjR8 displayed the ability to hydrolyze both phthalate monoesters and diesters, this feature is extremely rare among previously reported esterases. Site-directed mutagenesis experiments revealed that the catalytic triad residues were Ser152, Glu246, and His276. Among them, Ser152 formed a hydrogen bond with dibutyl phthalate (DBP) by molecular docking, Gly84, Gly85, and Leu248 of conserved motifs formed hydrophobic interactions with DBP, respectively, which were important for the catalytic activity. Considering its wide range of temperature and hydrolytic potential toward phthalate esters, XtjR8 will be served as an interesting candidate for biodegradation and industrial applications.
ESTHER : Qiu_2020_Int.J.Biol.Macromol_164_1510
PubMedSearch : Qiu_2020_Int.J.Biol.Macromol_164_1510
PubMedID: 32755708
Gene_locus related to this paper: 9zzzz-XtjR8

Title : Sanger's Reagent Sensitized Photocleavage of Amide Bond for Constructing Photocages and Regulation of Biological Functions - Wei_2020_J.Am.Chem.Soc__
Author(s) : Wei T , Lu S , Sun J , Xu Z , Yang X , Wang F , Ma Y , Shi Y , Chen X
Ref : Journal of the American Chemical Society , : , 2020
Abstract : Photolabile groups offer promising tools to study biological processes with highly spatial and temporal control. In the investigation, we designed and prepared several new glycine amide derivatives of Sanger's reagent and demonstrated that they serve as a new class of photocages for Zn2+ and an acetylcholinesterase (AChE) inhibitor. We showed that the mechanism for photocleavage of these substances involves initial light-driven cyclization between the 2,4-dinitrophenyl and glycine methylene groups to form acyl benzimidazole N-oxides, which undergo secondary photoinduced decarboxylation in association with rupture of an amide bond. The cleavage reactions proceed with modest to high quantum yields. We demonstrated that these derivatives can be used in targeted intracellular delivery of Zn2+, fluorescent imaging by light-triggered Zn2+ release, and regulation of biological processes including the enzymatic activity of carbonic anhydrase (CA), negative regulation of N-methyl-D-aspartate receptors (NMDARs) and pulse rate of cardiomyocytes. The successful proof-of-concept examples described above open a new avenue for using Sanger's reagent-based glycine amides as photocages for the exploration of complex cellular functions and signaling pathways.
ESTHER : Wei_2020_J.Am.Chem.Soc__
PubMedSearch : Wei_2020_J.Am.Chem.Soc__
PubMedID: 32023409

Title : Identification and characterization of a novel phthalate-degrading hydrolase from a soil metagenomic library - Qiu_2020_Ecotoxicol.Environ.Saf_190_110148
Author(s) : Qiu J , Zhang Y , Shi Y , Jiang J , Wu S , Li L , Shao Y , Xin Z
Ref : Ecotoxicology & Environmental Safety , 190 :110148 , 2020
Abstract : Phthalate esters have raised public concerns owing to their effects on the environment and human health. We identified a novel phthalate-degrading hydrolase, EstJ6, from a metagenomic library using function-driven screening. Phylogenetic analysis indicated that EstJ6 is a member of family IV esterases. EstJ6 hydrolyzed various dialkyl and monoalkyl phthalate esters, and exhibited high hydrolytic activity (128 U/mg) toward dibutyl phthalate at 40 degrees C and pH 7.5. EstJ6 hydrolyzed not only common phthalate esters with simple side chains but also diethylhexyl phthalate and monoethylhexyl phthalate, which have complex and long side chains. Site-directed mutagenesis indicated that the catalytic triad residues of EstJ6 consists of Ser146, Glu240, and His270. EstJ6 is therefore a promising biodegradation enzyme, and our study illustrates the advantages of a metagenomic approach in identifying enzyme-coding genes for agricultural, food, and biotechnological applications.
ESTHER : Qiu_2020_Ecotoxicol.Environ.Saf_190_110148
PubMedSearch : Qiu_2020_Ecotoxicol.Environ.Saf_190_110148
PubMedID: 31911388
Gene_locus related to this paper: 9zzzz-EstJ6

Title : Glucoconjugated Monoterpene Indole Alkaloids from Uncaria rhynchophylla - Guo_2019_J.Nat.Prod_82_3288
Author(s) : Guo Q , Si X , Shi Y , Yang H , Liu X , Liang H , Tu P , Zhang Q
Ref : Journal of Natural Products , 82 :3288 , 2019
Abstract : Twenty-six glucoconjugated monoterpene indole alkaloids, including 12 new compounds, rhynchophyllosides A-L (1-12), and 14 known ones, 13-26, were obtained from the hook-bearing stems of Uncaria rhynchophylla (Miq.) Miq. ex Havil. Their structures were unambiguously elucidated by analyses of UV, MS, NMR, ECD, and single-crystal X-ray diffraction data. The ESI-MS(n) behavior of the new glucoalkaloids was also elucidated. Although comprising the same glucosyl moiety, the aglycone skeletons and glucosidic numbers and linkage varied greatly, implying the diversity in biosynthetic pathways. This is the first report of such structurally diverse glucoconjugated monoterpene indole alkaloids from U. rhynchophylla. Compound 1 represents a new subtype of oxindole alkaloid with a seven-membered D-ring, 10 is a rare monoterpene indole alkaloid with the glucosyl moiety located at C-9, 4 and 5 are the first two oxindole alkaloid diglycosides, and 11 and 12 represent the first two examples of alkaloids with a quinolone nucleus from the genus Uncaria. Compound 10 exhibited moderate acetylcholinesterase (AChE) inhibitory activity with an IC50 value of 10.5 muM. Molecular docking was performed to explore the binding mode of inhibitor 10 at the active site of AChE.
ESTHER : Guo_2019_J.Nat.Prod_82_3288
PubMedSearch : Guo_2019_J.Nat.Prod_82_3288
PubMedID: 31804070

Title : Effects of BIS-MEP on Reversing Amyloid Plaque Deposition and Spatial Learning and Memory Impairments in a Mouse Model of beta-Amyloid Peptide- and Ibotenic Acid-Induced Alzheimer's Disease - Wang_2019_Front.Aging.Neurosci_11_3
Author(s) : Wang Y , Xia J , Shen M , Zhou Y , Wu Z , Shi Y , Xu J , Hou L , Zhang R , Qiu Z , Xie Q , Chen H , Zhang Y , Wang H
Ref : Front Aging Neurosci , 11 :3 , 2019
Abstract : Alzheimer's disease (AD) is the main type of dementia and is characterized by progressive memory loss and a notable decrease in cholinergic neuron activity. As classic drugs currently used in the clinic, acetylcholinesterase inhibitors (AChEIs) restore acetylcholine levels and relieve the symptoms of AD, but are insufficient at delaying the onset of AD. Based on the multi-target-directed ligand (MTDL) strategy, bis-(-)-nor-meptazinol (BIS-MEP) was developed as a multi-target AChEI that mainly targets AChE catalysis and the beta-amyloid (Abeta) aggregation process. In this study, we bilaterally injected Abeta oligomers and ibotenic acid (IBO) into the hippocampus of ICR mice and then subcutaneously injected mice with BIS-MEP to investigate its therapeutic effects and underlying mechanisms. According to the results from the Morris water maze test, BIS-MEP significantly improved the spatial learning and memory impairments in AD model mice. Compared with the vehicle control, the BIS-MEP treatment obviously inhibited the AChE activity in the mouse brain, consistent with the findings from the behavioral tests. The BIS-MEP treatment also significantly reduced the Abeta plaque area in both the hippocampus and cortex, suggesting that BIS-MEP represents a direct intervention for AD pathology. Additionally, the immunohistochemistry and ELISA results revealed that microglia (ionized calcium-binding adapter molecule 1, IBA1) and astrocyte (Glial fibrillary acidic protein, GFAP) activation and the secretion of relevant inflammatory factors (TNFalpha and IL-6) induced by Abeta were decreased by the BIS-MEP treatment. Furthermore, BIS-MEP showed more advantages than donepezil (an approved AChEI) as an Abeta intervention. Based on our findings, BIS-MEP improved spatial learning and memory deficits in AD mice by regulating acetylcholinesterase activity, Abeta deposition and the inflammatory response in the brain.
ESTHER : Wang_2019_Front.Aging.Neurosci_11_3
PubMedSearch : Wang_2019_Front.Aging.Neurosci_11_3
PubMedID: 30723404

Title : Jia-Wei-Kai-Xin-San, an Herbal Medicine Formula, Ameliorates Cognitive Deficits via Modulating Metabolism of Beta Amyloid Protein and Neurotrophic Factors in Hippocampus of Abeta1-42 Induced Cognitive Deficit Mice - Zhu_2019_Front.Pharmacol_10_258
Author(s) : Zhu Y , Shi Y , Cao C , Han Z , Liu M , Qi M , Huang R , Zhu Z , Qian D , Duan JA
Ref : Front Pharmacol , 10 :258 , 2019
Abstract : Jia-Wei-Kai-Xin-San (JWKXS) is a Chinese medicine formula applied for treating morbid forgetfulness in ancient China. Today, this formula is frequently applied for Alzheimer's disease and vascular dementia (VD) in clinic. Here, we developed it as granules and aimed to evaluate its anti-AD effect on beta amyloid protein 1-42 (Abeta1-42) induced cognitive deficit mice and reveal the possible molecular mechanisms. Firstly, daily intra-gastric administration of chemically standardized of JWKXS granules for 7 days significantly ameliorated the cognitive deficit symptoms and inhibited cell apoptosis in hippocampus on Abeta1-42 injection mice. JWKXS granules significantly decreased Abeta level, increased superoxide dismutase activity and decreased malondialdehyde level in hippocampus of model mice. It also restored acetylcholine amounts, inhibited acetylcholinesterase activities and increased choline acetyltransferase activities. In addition, JWKXS granules enabled the transformation of precursors of NGF and BDNF into mature forms. Furthermore, JWKXS granules could regulate gene expressions related to Abeta production, transportation, degradation and neurotrophic factor transformation, which led to down-regulation of Abeta and up-regulation of NGF and BDNF. These findings suggested that JWKXS granules ameliorated cognitive deficit via decreasing Abeta levels, protecting neuron from oxidation damages and nourishing neuron, which could serve as alternative medicine for patients suffering from AD.
ESTHER : Zhu_2019_Front.Pharmacol_10_258
PubMedSearch : Zhu_2019_Front.Pharmacol_10_258
PubMedID: 30941041

Title : A systemic study of indoxacarb resistance in Spodoptera litura revealed complex expression profiles and regulatory mechanism - Shi_2019_Sci.Rep_9_14997
Author(s) : Shi L , Shi Y , Zhang Y , Liao X
Ref : Sci Rep , 9 :14997 , 2019
Abstract : The tobacco cutworm, Spodoptera litura, is an important pest of crop and vegetable plants worldwide, and its resistance to insecticides have quickly developed. However, the resistance mechanisms of this pest are still unclear. In this study, the change in mRNA and miRNA profiles in the susceptible, indoxacarb-resistant and field indoxacarb-resistant strains of S. litura were characterized. Nine hundred and ten co-up-regulated and 737 co-down-regulated genes were identified in the resistant strains. Further analysis showed that 126 co-differentially expressed genes (co-DEGs) (cytochrome P450, carboxy/cholinesterase, glutathione S-transferase, ATP-binding cassette transporter, UDP-glucuronosyl transferase, aminopeptidase N, sialin, serine protease and cuticle protein) may play important roles in indoxacarb resistance in S. litura. In addition, a total of 91 known and 52 novel miRNAs were identified, and 10 miRNAs were co-differentially expressed in the resistant strains of S. litura. Furthermore, 10 co-differentially expressed miRNAs (co-DEmiRNAs) had predicted co-DEGs according to the expected miRNA-mRNA negative regulation pattern and 37 indoxacarb resistance-related co-DEGs were predicted to be the target genes. These results not only broadened our understanding of molecular mechanisms of insecticide resistance by revealing complicated profiles, but also provide important clues for further study on the mechanisms of miRNAs involved in indoxacarb resistance in S. litura.
ESTHER : Shi_2019_Sci.Rep_9_14997
PubMedSearch : Shi_2019_Sci.Rep_9_14997
PubMedID: 31628365

Title : Laboratory and field evaluation of the aphidicidal activity of moso bamboo (Phyllostachys pubescens) leaf extract and identification of the active components - Gao_2019_Pest.Manag.Sci_75_3167
Author(s) : Gao Q , Shi Y , Liao M , Xiao J , Li X , Zhou L , Liu C , Liu P , Cao H
Ref : Pest Manag Sci , 75 :3167 , 2019
Abstract : BACKGROUND: Botanical pesticides increasingly play important roles in the control of agricultural pests. In this study, the aphidicidal effect of moso bamboo (Phyllostachys pubescens) extract against mustard aphid was confirmed, the main active compounds identified, and aphidicidal mechanism of the most active compound established. RESULTS: When the treatment concentration was 10.0 g L(-1) , the corrected mortality of bamboo leaf extract (BE) was 53.22 +/- 5.20% and the petroleum ether component of bamboo leaf extract (PE) reached 82.76 +/- 4.50%, which also showed a synergistic effect with imidacloprid. Four flavonoids were identified as the main active components in the BE via activity tracking and phytochemical method. Isoorientin had an LC50 of 313.22 mg L(-1) , and affected the activities of acetylcholinesterase and peroxidase significantly, revealing the possible aphidicidal mechanism. When the treatment of 11.1% PE.imidacloprid was 200 mL, the control effect was 99.07%, which was better than that observed with 10% of imidacloprid or 0.5% of matrine. CONCLUSIONS: These data provide a better understanding of the aphidicidal activity and aphidicidal mechanism of moso bamboo leaf extract and the most active compound, isoorientin. This will help in developing a more effective botanical aphicide. (c) 2019 Society of Chemical Industry.
ESTHER : Gao_2019_Pest.Manag.Sci_75_3167
PubMedSearch : Gao_2019_Pest.Manag.Sci_75_3167
PubMedID: 30941856

Title : Bis(9)-(-)-Meptazinol, a novel dual-binding AChE inhibitor, rescues cognitive deficits and pathological changes in APP\/PS1 transgenic mice - Shi_2018_Transl.Neurodegener_7_21
Author(s) : Shi Y , Huang W , Wang Y , Zhang R , Hou L , Xu J , Qiu Z , Xie Q , Chen H , Zhang Y , Wang H
Ref : Transl Neurodegener , 7 :21 , 2018
Abstract : Background: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative brain disorder, which is the most common form of dementia. Intensive efforts have been made to find effective and safe treatment against AD. Acetylcholinesterase inhibitors (AChEIs) have been widely used for the treatment of mild to moderate AD. In this study, we investigated the effect of Bis(9)-(-)-Meptazinol (B9M), a novel potential dual-binding acetylcholinesterase (AChE) inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Methods: B9M (0.1 mug/kg, 0.3 mug/kg, and 1 mug/kg) was administered by subcutaneous injection into eight-month-old APP/PS1 transgenic mice for four weeks. Morris water maze, nest-building and novel object recognition were used to examine learning and memory ability. Abeta levels and Abeta plaque were evaluated by ELISA and immunochemistry. Results: Our results showed that chronic treatment with B9M significantly improved the cognitive function of APP/PS1 transgenic mice in the Morris water maze test, nest-building test and novel object recognition test. Moreover, B9M improved cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of the AChE activity, Abeta plaque burden, levels of Abeta and the consequent activation of astrocytes and microglia in the brain of APP/PS1 transgenic mice. Most of important, the most effective dose of B9M in the present study is 1 mug/kg, which is one thousand of the dosage of Donepezil acted as the control treatment. Furthermore, B9M reduced Abeta plaque burden better than Donepezil. Conclusion: These results indicate that B9M appears to have potential as an effective AChE inhibitor for the treatment of AD with symptom-relieving and disease-modifying properties.
ESTHER : Shi_2018_Transl.Neurodegener_7_21
PubMedSearch : Shi_2018_Transl.Neurodegener_7_21
PubMedID: 30237878

Title : The role of ursodeoxycholic acid on cholestatic hepatic fibrosis in infant rats - Tang_2018_Mol.Med.Rep_17_3837
Author(s) : Tang N , Zhang Y , Liang Q , Liu Z , Shi Y
Ref : Mol Med Rep , 17 :3837 , 2018
Abstract : The aim of the present study was to identify the impact of ursodeoxycholic acid (UDCA) on liver function and fibrosis markers in infant rats by establishing a cholestaticinduced hepatic fibrosis model. alphanaphthylisothiocyanate (ANIT) was administrated by gavage to induce cholestatic hepatic fibrosis in infant rats. UCDA treatment was performed to assess its impact on biochemical indicators of liver function, four serum biomarkers of hepatic fibrosis, hepatic fibrosis indices in liver tissues and the pathology of liver tissues. Colorimetric assays and biochemical assays based on the initial rate method were performed to determine the levels of liver function markers in the serum, whereas the serum biomarkers of hepatic fibrosis were measured via radioimmunoassay. Sections of liver tissue were harvested and stained with hematoxylineosin or picric acidSirius red, and subjected to immunohistochemical staining to analyze liver pathology. All indicators of liver function, except for cholinesterase, were significantly higher in the ANIT model than in the control group (P<0.01). gammaglutamyl transpeptidase and total bile acids of the UDCA treatment group were significantly lower than the ANIT model (P<0.05); whereas no significant differences were observed in alanine aminotransferase, aspartate aminotransferase, total bilirubin, direct bilirubin and indirect bilirubin between the two groups. Serum laminin protein (LN) and typeIV collagen (cIV) in the UDCA treatment group were significantly lower than in the ANIT model (P<0.01); whereas no significant differences were observed in hyaluronic acid and typeIII procollagen between the two groups. Liver LN and cIV in the UDCA treatment group were significantly lower than in the ANIT model (P<0.01). The degree of hepatic fibrosis in the UDCA treatment group was significantly lower than in the ANIT model (P<0.01). The results of the present study demonstrated that UDCA is able to reduce LN and cIV in serum and protect liver tissues against hepatic fibrosis.
ESTHER : Tang_2018_Mol.Med.Rep_17_3837
PubMedSearch : Tang_2018_Mol.Med.Rep_17_3837
PubMedID: 29257337

Title : Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan: In vitro and in vivo insights from quantitative ultra-performance liquid chromatography-mass spectrometry analysis - Qin_2018_Biomed.Chromatogr__e4320
Author(s) : Qin Y , Kang A , Zhou G , Wang H , Wei W , Cao Y , Chen Y , Wang J , Shi Y , Tang Y , Jiang J
Ref : Biomedical Chromatography , :e4320 , 2018
Abstract : Carboxylesterase and UDP-glucuronosyltransferases mediated metabolism of irinotecan (CPT-11) has long been proposed to be responsible for its anti-tumor activity and toxicity, like delayed-onset diarrhea. However, recent studies failed to gain more comprehensive in vivo and in vitro pharmacokinetic profiles of irinotecan. Herein, we choose rat plasma, human liver microsomes and immortalized HepG2 cell as experimental subjects to describes an sensitive and versatile UHPLC-MS/MS method for simultaneously quantify CPT-11 and its metabolites, including SN-38 and SN-38G. Meanwhile, we have adopted the method to investigate the pharmacokinetic or metabolism behavior of CPT-11 in the above biological samples. Calibration curves for all bio-matrices showed desirable linearity (r(2) >0.99). The intra-day and inter-day precision (RSD, %) were within 15 % and the excellent accuracy (RE, %) was between 2.96% and 14.12%. In addition, the specificity, matrix effect and extraction recovery were all meet the requirements of biological sample analysis. We have successfully applied this method to investigating pharmacokinetic of irinotecan in different biological samples, which mediated by carboxylesterase and UDP-glucuronosyltransferases. And this method could be emplyed in monitoring the metabolic status and clinical efficacy of irinotecan in the future.
ESTHER : Qin_2018_Biomed.Chromatogr__e4320
PubMedSearch : Qin_2018_Biomed.Chromatogr__e4320
PubMedID: 29920713

Title : Fluorescein as a Visible-Light-Induced Oxidase Mimic for Signal-Amplified Colorimetric Assay of Carboxylesterase by an Enzymatic Cascade Reaction - Liu_2018_Chemistry_24_6148
Author(s) : Liu L , Sun C , Yang J , Shi Y , Long Y , Zheng H
Ref : Chemistry , 24 :6148 , 2018
Abstract : We have found that fluorescein possesses high visible-light-induced oxidase mimetic activity and could transform colorless 3,3',5,5'-tetramethylbenzidine (TMB) into blue oxidized TMB (oxTMB) without unstable and destructive H2 O2 under visible-light illumination. Instead, fluorescein uses oxygen as a mild and green electron acceptor, and its activity can be easily controlled by the switching "on/off" of visible light. In addition, the visible-light-induced catalytic mechanism was elucidated in detail and, as the main reactive species h(+) and O2(.-) accounted for TMB oxidation. Based on the fact that fluorescein diacetate (FDA) possessed no activity and generated active fluorescein in situ in the presence of carboxylesterase (CaE), a signal-amplified sensing platform through a cascade reaction for CaE detection was constructed. Our proposed sensing system displayed excellent analytical performance for the detection of CaE in a wide linear range from 0.040 to 20 U L(-1) with a low detection limit of 0.013 U L(-1) . This work not only changes the conventional concept that fluorescein is generally considered to be photocatalytically inert, but also provides a novel sensing strategy by tailoring the enzyme mimetic activity of fluorescein derivatives with analyte.
ESTHER : Liu_2018_Chemistry_24_6148
PubMedSearch : Liu_2018_Chemistry_24_6148
PubMedID: 29493016

Title : Transfection of neurotrophin-3 into neural stem cells using ultrasound with microbubbles to treat denervated muscle atrophy - Gong_2018_Exp.Ther.Med_15_620
Author(s) : Gong L , Jiang C , Liu L , Wan S , Tan W , Ma S , Jia X , Wang M , Hu A , Shi Y , Zhang Y , Shen Y , Wang F , Chen Y
Ref : Exp Ther Med , 15 :620 , 2018
Abstract : Neurotrophin-3 (NT-3) has potential as a therapeutic agent for the treatment of patients with denervated muscle atrophy. However, the endogenous secretion of NT-3 is low and exogenous NT-3 lacks sufficient time to accumulate due to its short half-life. The transfection of NT-3 has been demonstrated to have a beneficial effect on denervated muscle and motor endplates. Neural stem cells (NSCs) differentiate into neurons and form motor endplate nerve-muscle connections. It has been previously demonstrated that local and noninvasive transfection can be performed using ultrasound with microbubbles (MBs). In the current study, hematoxylin and eosin, acetylcholinesterase and gold chloride staining, as well as transmission electron microscopy, were performed to verify the effects of this treatment strategy. The results demonstrated that using ultrasound with MBs for the transfection of NT-3 into NSCs, and their subsequent transplantation in vivo, attenuated the atrophy of denervated muscle and reduced motor endplate degeneration. This noninvasive, efficient and targeted treatment strategy may therefore be a potential treatment for patients with denervated muscle atrophy.
ESTHER : Gong_2018_Exp.Ther.Med_15_620
PubMedSearch : Gong_2018_Exp.Ther.Med_15_620
PubMedID: 29403547

Title : Effect of food matrices on the in vitro bioavailability and oxidative damage in PC12 cells of lead - Xia_2018_Food.Chem_266_397
Author(s) : Xia J , Fang Y , Shi Y , Shen X , Wu J , Xie M , Li P , Pei F , Hu Q
Ref : Food Chem , 266 :397 , 2018
Abstract : The bioavailability and oxidative damage toxicity of lead (Pb) in seven food matrices, including rice, milk, tomato, garlic, apple, kelp and pork, were determined using an in vitro digestion/Caco-2 cell model and a rat pheochromocytoma (PC12) oxidative damage model. Results showed that Pb bioaccessibility and bioavailability in the apple and kelp groups were significantly lower than other food matrix groups, with corresponding values of 11.05-28.31% and 1.57-8.81%, respectively. Oxidative damage assays showed that digestion products of apple polyphenol extract, which was selected from seven food matrices, could increase the oxidation resistance and the levels of glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and acetyl cholinesterase (AChE) by 32.23%, 39.02%, 27.14% and 30.90%, respectively. Additionally, malondialdehyde (MDA) and reactive oxygen species (ROS) levels could be decreased by 59.66% and 40.21%, respectively. In conclusion, phenolics were an important food matrix that could decrease the bioavailability and oxidative damage of Pb.
ESTHER : Xia_2018_Food.Chem_266_397
PubMedSearch : Xia_2018_Food.Chem_266_397
PubMedID: 30381204

Title : Sublethal or not? Responses of multiple biomarkers in Daphnia magna to single and joint effects of BDE-47 and BDE-209 - Xiong_2018_Ecotoxicol.Environ.Saf_164_164
Author(s) : Xiong Q , Shi Y , Lu Y , Pan K , Dakhil MA , Zhang L , Xiao Y
Ref : Ecotoxicology & Environmental Safety , 164 :164 , 2018
Abstract : Polybrominated diphenyl ethers (PBDEs) are extremely incessant anthropogenic contaminants found in the environment, with dreadful risk to aquatic ecosystems. However, there is a limited amount of data concerning their impacts on freshwater organisms. 2,2',3,3',4,4',5,5',6,6'-decabromodiphenyl ether (BDE-209) and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) are significant components of total PBDEs in water. The sublethal effects of BDE-47, BDE-209 and their binary mixtures on the aquatic organism Daphnia magna were investigated in acute and chronic exposure experiments. Immobilization and heartbeat were studied in daphnids after 48h of exposure. Mortality rate, breed number, Cholinesterase (ChE), Glutathione S-transferases (GST) and Catalase (CAT) activities were evaluated after 21 days of exposure. The results showed that at 100 and 200mug/L concentration of BDE-47, immobilization rate of daphnids were inhibited by 44.0+/-16.7% and 88.0+/-10.9%, respectively. The binary mixture of BDE-47 and BDE-209 had uncongenial effects on immobilization of D. magna under acute toxicity test. BDE-209 significantly increased the heartbeat rate of daphnids, which increased even further when combined with BDE-47. After 21 days of exposure, daphnids exposed to single BDE-47 were physiologically altered. The combination of BDE-47 with BDE-209 significantly decreased the mortality rate of daphnids. Irrespective of the concentration, higher numbers of offsprings were produced in the mixtures compared to BDE-47 treatment alone. ChE activities significantly (p<0.05) decreased at concentrations of 2 and 4mug/L in single BDE-47 treatment, while GST activity significantly (p<0.05) decreased at 0.5mug/L. CAT activities significantly increased with BDE-47 treatments in all the tested concentrations (p<0.05). The mixtures significantly affect ChE (p<0.05), GST (p<0.05) and CAT activities (p<0.05). The results illustrated that the toxicity of the mixture of PBDE congeners exposed to aquatic organisms may have antagonistic effects. The 21 days chronic test in this study suggests that acute toxicity tests, i.e. 48-h tests, using Daphnia may lead to underestimation of risks associated with PBDEs, especially, BDE-209. Hence, there is a necessity to re-examine PBDE congeners' environmental risk in aquatic organisms.
ESTHER : Xiong_2018_Ecotoxicol.Environ.Saf_164_164
PubMedSearch : Xiong_2018_Ecotoxicol.Environ.Saf_164_164
PubMedID: 30107326

Title : A novel variant associated with HDL-C levels by modifying DAGLB expression levels: An annotation-based genome-wide association study - Zhou_2018_Eur.J.Hum.Genet_26_838
Author(s) : Zhou D , Zhang D , Sun X , Li Z , Ni Y , Shan Z , Li H , Liu C , Zhang S , Liu Y , Zheng R , Pan F , Zhu Y , Shi Y , Lai M
Ref : Eur J Hum Genet , 26 :838 , 2018
Abstract : Although numbers of genome-wide association studies (GWAS) have been performed for serum lipid levels, limited heritability has been explained. Studies showed that combining data from GWAS and expression quantitative trait loci (eQTLs) signals can both enhance the discovery of trait-associated SNPs and gain a better understanding of the mechanism. We performed an annotation-based, multistage genome-wide screening for serum-lipid-level-associated loci in totally 6863 Han Chinese. A serum high-density lipoprotein cholesterol (HDL-C) associated variant rs1880118 (hg19 chr7:g. 6435220G>C) was replicated (Pcombined = 1.4E-10). rs1880118 was associated with DAGLB (diacylglycerol lipase, beta) expression levels in subcutaneous adipose tissue (P = 5.9E-42) and explained 47.7% of the expression variance. After the replication, an active segment covering variants tagged by rs1880118 near 5' of DAGLB was annotated using histone modification and transcription factor binding signals. The luciferase report assay revealed that the segment containing the minor alleles showed increased transcriptional activity compared with segment contains the major alleles, which was consistent with the eQTL analyses. The expression-trait association tests indicated the association between the DAGLB and serum HDL-C levels using gene-based approaches called "TWAS" (P = 3.0E-8), "SMR" (P = 1.1E-4), and "Sherlock" (P = 1.6E-6). To summarize, we identified a novel HDL-C-associated variant which explained nearly half of the expression variance of DAGLB. Integrated analyses established a genotype-gene-phenotype three-way association and expanded our knowledge of DAGLB in lipid metabolism.
ESTHER : Zhou_2018_Eur.J.Hum.Genet_26_838
PubMedSearch : Zhou_2018_Eur.J.Hum.Genet_26_838
PubMedID: 29476167

Title : Neonatal isolation modulates glucocorticoid-receptor function and synaptic plasticity of hippocampal and amygdala neurons in a rat model of single prolonged stress - Cheng_2018_J.Affect.Disord_246_682
Author(s) : Cheng W , Han F , Shi Y
Ref : J Affect Disord , 246 :682 , 2018
Abstract : BACKGROUND: Early life and stressful experiences affect hippocampal and amygdala structure and function. They also increase the incidence of mental and nervous system disorders in adults. However, prospective studies have yet to show if early-life experiences affect the risk/severity of post-traumatic stress disorder (PTSD). METHODS: We applied neonatal isolation (NI) alone, single prolonged stress (SPS) alone and NI+SPS to rats. We evaluated anxiety-like behavior and spatial memory of behavior using open field, elevated plus maze, and Morris water maze tests. Then, we measured expression of glucocorticoid receptors (GRs) and synaptic-related proteins by immunofluorescence, immunohistochemistry and western blotting in the hippocampus and amygdala. RESULTS: NI+SPS exacerbated the increased anxiety levels and impaired spatial memory induced by NI alone or SPS alone. NI alone or SPS alone induced varying degrees of change in expression of GRs and synaptic proteins (synapsin I and postsynaptic density protein-95) in the hippocampus and amygdala. There were opposite changes in GR expression in the hippocampal dentate gyrus and basolateral amygdala. The degree of such change was exacerbated considerably by NI+SPS. In addition, neuroligin (NLG)-1 and NLG-2 were distributed in postsynaptic sites of excitatory and inhibitory synapses, respectively. NI, SPS, and NI+SPS altered the patterns of NLG-1 and NLG-2 colocalization as well as their intensity. NI+SPS strengthened the increased ratio of NLG-1/NLG-2 in the hippocampus, but decreased this ratio in the amygdala. CONCLUSIONS: NI and SPS together induced greater degrees of change in anxiety and spatial memory, as well as GR and synaptic protein levels, in the hippocampus and amygdala than the changes induced by NI alone or SPS alone.
ESTHER : Cheng_2018_J.Affect.Disord_246_682
PubMedSearch : Cheng_2018_J.Affect.Disord_246_682
PubMedID: 30611912

Title : Increased Expression of NDRG3 in Mouse Uterus During Embryo Implantation and in Mouse Endometrial Stromal Cells During In Vitro Decidualization - Yang_2017_Reprod.Sci__1933719117737843
Author(s) : Yang Q , Zhang X , Shi Y , He YP , Sun ZG , Shi HJ , Wang J
Ref : Reprod Sci , :1933719117737843 , 2017
Abstract : Decidualization is an indispensable event in the embryo implantation process, but its underlying molecular mechanisms remain elusive. In this study, we showed that in mice, the uterine expression of N-myc downstream-regulated gene 3 (NDRG3), a member of the alpha/beta hydrolase superfamily, was induced by estradiol and progesterone. During the embryo implantation process, uterine Ndrg3 expression was remarkably upregulated, and its expression level at implantation sites (IS) was significantly higher than that at inter-IS. Increased uterine expression of Ndrg3 was associated with artificial decidualization and the activation of delayed implantation. The in vitro decidualization of mouse endometrial stromal cells (ESCs) induced by estradiol and progesterone was also accompanied by increased Ndrg3 expression, and downregulated Ndrg3 expression in ESCs effectively inhibited decidualization. miR-290b-5p was identified as an upstream regulator of Ndrg3, and the uterine expression level of miR-290b-5p was decreased during the implantation process. Furthermore, overexpression of miR-290b-5p in mouse ESCs inhibited their in vitro decidualization. Taken together, these data suggested that Ndrg3 might play an important role in embryo implantation by regulating decidualization potentially via the estrogen/progesterone/miR-290b-5p pathway.
ESTHER : Yang_2017_Reprod.Sci__1933719117737843
PubMedSearch : Yang_2017_Reprod.Sci__1933719117737843
PubMedID: 29096585
Gene_locus related to this paper: human-NDRG3 , mouse-ndr3

Title : Hypoxic postconditioning attenuates apoptosis via inactivation of adenosine A2a receptor through NDRG3-Raf-ERK pathway - Cui_2017_Biochem.Biophys.Res.Commun_491_277
Author(s) : Cui C , Lin H , Shi Y , Pan R
Ref : Biochemical & Biophysical Research Communications , 491 :277 , 2017
Abstract : BACKGROUND: In recent years, many studies have demonstrated that endogenous adenosine induced by ischemia postconditioning reduces apoptosis in animal and cell models, but no study has clearly elucidated the effects of hypoxia postconditioning (HPC) in human dermal microvascular endothelial cells (HDMECs) of flaps, and the subtype of adenosine receptors involved remains unknown. In our study, we sought to identify the roles of adenosine A2a receptor, NDRG3 (N-myc downstream-regulated gene 3) and Raf-ERK pathway in the anti-apoptotic effects of hypoxia postconditioning. METHODS: Human dermal microvascular endothelial cells were put into a hypoxic incubator (94% N2 + 5% CO2 + 1% O2) for 8 h (hypoxia), and followed 24 h of normoxic culture with 95% air and 5% CO2 (reoxygenation). Hypoxia postconditioning model of HDMECs was achieved as follows: Before HDMECs were put into a normoxic incubator, HDMECs were treated by three cycles of 5 min of brief reoxygenation and 5 min of re-hypoxia. Opening level of mitochondrial permeability transition pore and change of mitochondrial membrane potential were detected with related Kit. The protein expressions of mitochondrion apoptosis, adenosine A2a receptor and NDRG3-Raf-ERK pathway were measured by western blot. RESULT: Hypoxia/reoxygenation (H/R) resulted in injury in HDMRCs as evidenced by an increase in apoptosis percentage, mitochondrial membrane permeability and an increase in expression of pro-apoptosis proteins (Bax, c-caspase-3 and cytochrom C), meanwhile, hypoxia/reoxygenation increased expression of A2a receptor, NDRG3, p-c-Raf, p-ERK, which was significantly attenuated by hypoxia postconditioning treatment. Moreover, Hypoxia/reoxygenation (H/R) resulted in a decrease in expression of anti-apoptotic protein (Bcl-2). However, the protective effect of hypoxia postconditioning treatment could be inhibited by adding CGS21680, a selective adenosine A2a receptor agonist (all P values < 0.05).
ESTHER : Cui_2017_Biochem.Biophys.Res.Commun_491_277
PubMedSearch : Cui_2017_Biochem.Biophys.Res.Commun_491_277
PubMedID: 28743501

Title : Shengjiang Xiexin Decoction Alters Pharmacokinetics of Irinotecan by Regulating Metabolic Enzymes and Transporters: A Multi-Target Therapy for Alleviating the Gastrointestinal Toxicity - Guan_2017_Front.Pharmacol_8_769
Author(s) : Guan HY , Li PF , Wang XM , Yue JJ , He Y , Luo XM , Su MF , Liao SG , Shi Y
Ref : Front Pharmacol , 8 :769 , 2017
Abstract : Shengjiang Xiexin decoction (SXD), a classic traditional Chinese medical formula chronicled in Shang Han Lun, is used in modern clinical practice to decrease gastrointestinal toxicity induced by the chemotherapeutic drug irinotecan (CPT-11). In this study, the effect of SXD on the pharmacokinetics of CPT-11 and its active metabolites (SN-38 and SN-38G), and the underlying mechanisms were further examined. An ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was developed and validated for the simultaneous quantification of CPT-11, SN-38, and SN-38G in the plasma, bile, liver, intestine, and intestinal contents of control and SXD-pre-treated rats after intravenous administration of CPT-11. SXD pretreatment increased the area under the curve (AUC) and the initial plasma concentration (C0) of CPT-11 but decreased the plasma clearance (CL). The AUC and the maximum plasma concentration (Cmax) of SN-38 decreased, whereas the Cmax of SN-38G increased. Compared with that of the control group, the biliary excretion of CPT-11, SN-38, and SN-38G was inhibited. The CPT-11, SN-38, and SN-38G concentrations in the liver, intestine, and intestinal contents were different between the two groups. Furthermore, the hepatic expression of multidrug resistance-associated protein-2 (Mrp-2), P-glycoprotein (P-gp), and carboxylesterase 2 (CES2) was significantly down-regulated by SXD, while the hepatic and jejunal uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1) expression was elevated. The hydrolysis of CPT-11 to SN-38 by CES and the glucuronidation of SN-38 to SN-38G by UGT were affected by liver and jejunum S9 fractions from rats pre-treated with SXD. Therefore, this study demonstrated for the first time that SXD could alter the pharmacokinetics of CPT-11 and its metabolites to alleviate CPT-11-induced diarrhea. And the underlying mechanism of drug interaction between CPT-11 and SXD involves decreasing hepatic Mrp-2 and P-gp expression and altering the activities of CES and UGT.
ESTHER : Guan_2017_Front.Pharmacol_8_769
PubMedSearch : Guan_2017_Front.Pharmacol_8_769
PubMedID: 29163158

Title : Di(2-ethylhexyl) phthalate induces apoptosis through mitochondrial pathway in GC-2spd cells - Fu_2017_Environ.Toxicol_32_1055
Author(s) : Fu G , Dai J , Zhang D , Zhu L , Tang X , Zhang L , Zhou T , Duan P , Quan C , Zhang Z , Song S , Shi Y
Ref : Environ Toxicol , 32 :1055 , 2017
Abstract : Di(2-ethylhexyl) phthalate (DEHP), a plasticizer of synthetic polymers, is a well-known endocrine disrupting chemical (EDC) and reproductive toxicant. Addressing the unclear mechanism of DEHP-induced reproductive dysfunction, this study used GC-2spd cells to investigate the molecular mechanism involved in the DEHP-induced toxicity in the male reproductive system. The results indicated that the apoptotic cell death was significantly induced by DEHP exposure over 100 muM. Furthermore, DEHP treatment could induce oxidative stress in GC-2spd cells involving in the decrease of superoxide dismutase (SOD) activity (200 muM) and glutathione peroxidase (GSH-Px) activity (50 and 100 muM). In addition, DEHP induction also caused the elevated ratios of Bax/Bcl-2, release of cytochrome c and decomposition of procaspase-3 and procaspase-9 in GC-2spd cells. Taken together, our work provided the evidence that DEHP exposure might induce apoptosis of GC-2spd cells via mitochondria pathway mediated by oxidative stress.
ESTHER : Fu_2017_Environ.Toxicol_32_1055
PubMedSearch : Fu_2017_Environ.Toxicol_32_1055
PubMedID: 27416487

Title : Structure of the S1 subunit C-terminal domain from bat-derived coronavirus HKU5 spike protein - Han_2017_Virology_507_101
Author(s) : Han X , Qi J , Song H , Wang Q , Zhang Y , Wu Y , Lu G , Yuen KY , Shi Y , Gao GF
Ref : Virology , 507 :101 , 2017
Abstract : Accumulating evidence indicates that MERS-CoV originated from bat coronaviruses (BatCoVs). Previously, we demonstrated that both MERS-CoV and BatCoV HKU4 use CD26 as a receptor, but how the BatCoVs evolved to bind CD26 is an intriguing question. Here, we solved the crystal structure of the S1 subunit C-terminal domain of HKU5 (HKU5-CTD), another BatCoV that is phylogenetically related to MERS-CoV but cannot bind to CD26. We observed that the conserved core subdomain and those of other betacoronaviruses (betaCoVs) have a similar topology of the external subdomain, indicating the same ancestor of lineage C betaCoVs. However, two deletions in two respective loops located in HKU5-CTD result in conformational variations in CD26-binding interface and are responsible for the non-binding of HKU5-CTD to CD26. Combined with sequence variation in the HKU5-CTD receptor binding interface, we propose the necessity for surveilling the mutation in BatCoV HKU5 spike protein in case of bat-to-human interspecies transmission.
ESTHER : Han_2017_Virology_507_101
PubMedSearch : Han_2017_Virology_507_101
PubMedID: 28432925

Title : The Dendrobium catenatum Lindl. genome sequence provides insights into polysaccharide synthase, floral development and adaptive evolution - Zhang_2016_Sci.Rep_6_19029
Author(s) : Zhang GQ , Xu Q , Bian C , Tsai WC , Yeh CM , Liu KW , Yoshida K , Zhang LS , Chang SB , Chen F , Shi Y , Su YY , Zhang YQ , Chen LJ , Yin Y , Lin M , Huang H , Deng H , Wang ZW , Zhu SL , Zhao X , Deng C , Niu SC , Huang J , Wang M , Liu GH , Yang HJ , Xiao XJ , Hsiao YY , Wu WL , Chen YY , Mitsuda N , Ohme-Takagi M , Luo YB , Van de Peer Y , Liu ZJ
Ref : Sci Rep , 6 :19029 , 2016
Abstract : Orchids make up about 10% of all seed plant species, have great economical value, and are of specific scientific interest because of their renowned flowers and ecological adaptations. Here, we report the first draft genome sequence of a lithophytic orchid, Dendrobium catenatum. We predict 28,910 protein-coding genes, and find evidence of a whole genome duplication shared with Phalaenopsis. We observed the expansion of many resistance-related genes, suggesting a powerful immune system responsible for adaptation to a wide range of ecological niches. We also discovered extensive duplication of genes involved in glucomannan synthase activities, likely related to the synthesis of medicinal polysaccharides. Expansion of MADS-box gene clades ANR1, StMADS11, and MIKC(*), involved in the regulation of development and growth, suggests that these expansions are associated with the astonishing diversity of plant architecture in the genus Dendrobium. On the contrary, members of the type I MADS box gene family are missing, which might explain the loss of the endospermous seed. The findings reported here will be important for future studies into polysaccharide synthesis, adaptations to diverse environments and flower architecture of Orchidaceae.
ESTHER : Zhang_2016_Sci.Rep_6_19029
PubMedSearch : Zhang_2016_Sci.Rep_6_19029
PubMedID: 26754549
Gene_locus related to this paper: 9aspa-a0a2i0w093 , 9aspa-a0a2i0vyy1 , 9aspa-a0a2i0x5j6 , 9aspa-a0a2i0win6 , 9aspa-a0a2i0vg82

Title : alpha\/beta-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors - Wei_2016_Proc.Natl.Acad.Sci.U.S.A_113_E2695
Author(s) : Wei M , Zhang J , Jia M , Yang C , Pan Y , Li S , Luo Y , Zheng J , Ji J , Chen J , Hu X , Xiong J , Shi Y , Zhang C
Ref : Proc Natl Acad Sci U S A , 113 :E2695 , 2016
Abstract : In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. alpha/beta-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.
ESTHER : Wei_2016_Proc.Natl.Acad.Sci.U.S.A_113_E2695
PubMedSearch : Wei_2016_Proc.Natl.Acad.Sci.U.S.A_113_E2695
PubMedID: 27114538
Gene_locus related to this paper: human-ABHD6

Title : Design, synthesis and evaluation of scutellarein-O-alkylamines as multifunctional agents for the treatment of Alzheimer's disease - Sang_2015_Eur.J.Med.Chem_94_348
Author(s) : Sang Z , Qiang X , Li Y , Yuan W , Liu Q , Shi Y , Ang W , Luo Y , Tan Z , Deng Y
Ref : Eur Journal of Medicinal Chemistry , 94 :348 , 2015
Abstract : A series of scutellarein-O-alkylamine derivatives were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good multifunctional activities. Among them, compound 16d demonstrated significant metal chelating properties, moderate acetylcholinesterase (AChE) inhibitory and anti-oxidative activity, and excellent inhibitory effects on self-induced Abeta1-42 aggregation, Cu2+-induced Abeta1-42 aggregation, human AChE-induced Abeta1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Abeta1-42 fibrils. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that 16d binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Moreover, compound 16d showed a good protective effect against H2O2-induced PC12 cell injury, with low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. Thus, 16d was shown to be an interesting multifunctional lead compound worthy of further study.
ESTHER : Sang_2015_Eur.J.Med.Chem_94_348
PubMedSearch : Sang_2015_Eur.J.Med.Chem_94_348
PubMedID: 25778991

Title : Draft Genome Sequence of Norvancomycin-Producing Strain Amycolatopsis orientalis CPCC200066 - Lei_2015_Genome.Announc_3_
Author(s) : Lei X , Yuan F , Shi Y , Li X , Wang L , Hong B
Ref : Genome Announc , 3 : , 2015
Abstract : Amycolatopsis orientalis CPCC200066 is an actinomycete that can produce the glycopeptide antibiotic norvancomycin, which has significant inhibitory activity against Gram-positive cocci and bacilli. Here, we report the draft genome sequence of A. orientalis CPCC200066 and identified the genes involved in norvancomycin biosynthesis.
ESTHER : Lei_2015_Genome.Announc_3_
PubMedSearch : Lei_2015_Genome.Announc_3_
PubMedID: 25977416
Gene_locus related to this paper: amyor-a0a193bq04 , amyor-a0a193bty5 , amyor-a0a193bvz8 , amyor-a0a193byg1 , amyor-a0a193by54 , amyor-a0a193c2b2 , amyor-a0a193bzy5 , amyor-a0a193cbs3

Title : Intervention effect of traditional Chinese medicine Yi Tang Kang on metabolic syndrome of spleen deficiency - Liu_2015_Asian.Pac.J.Trop.Med_8_162
Author(s) : Liu XX , Shi Y
Ref : Asian Pac J Trop Med , 8 :162 , 2015
Abstract : OBJECTIVE: To investigate effects of herbal compound Yi Tang Kang on the spleen deficiency metabolic syndrome.
METHODS: Forty male Wistar rats were randomly divided into two groups: the normal control group and the MS spleen deficiency syndrome group. The control group rats were fed with standard diet and water, while MS spleen deficiency syndrome group with high fat diet and low dose intraperitoneal injection of streptozocin, which swam to the endurance limit. After 12 weeks, the MS spleen deficiency syndrome group was randomly divided into two groups, with 13 rats in each group. Rats in model group were fed with high fat diet and continuouly administered with daily saline, and rats in intervention group with high fat diet were trated with traditional Chinese medicines Yi Tang Kang by gavage, 2 mL/200 g at the same time every day. 10 weeks later, the expression of serum proteomics was investigated through abdominal aortic puncture and separation of serum, using isotope labeling technique, high performance liquid chromatography and four bar-Orbitrap mass spectrometer.
RESULTS: After treatment with traditional Chinese medicine yitangkang, in the model group, important carboxylesterase and retinal guanylate cyclase 2 precursor were upregulated. As for intervention group, these indesxes were raised, but immunoglobulin IgG, carnitine acetyltransferase, tubulin beta -5, and Gan Lu sugar binding protein C were down-regulated. At the same time, some new biological active substances, such as protein tyrosine kinase, beta glucosidase were also found.
CONCLUSIONS: Traditional Chinese medicines Yi Tang Kang could regulate glucose and lipid metabolism in rats with spleen deficiency syndrome.
ESTHER : Liu_2015_Asian.Pac.J.Trop.Med_8_162
PubMedSearch : Liu_2015_Asian.Pac.J.Trop.Med_8_162
PubMedID: 25902033

Title : Preparation and characterization of a novel thermostable lipase from Thermomicrobium roseum - Fang_2021_Catal.Sci.Technol_11_7386
Author(s) : Fang Y , Zhou Y , Xin Y , Shi Y , Guo Z , Li Y , Gu Z , Ding Z , Shi G , Zhang L
Ref : Catal Sci Technol , 11 :7386 , 2015
Abstract : In this study, a hypothetical lipase gene from Thermomicrobium roseum DSM 5159 (GenBank: ACM04789.1) was recombinantly expressed and characterized. The TrLIP gene was inserted into two different plasmids (pTIG and pMA5 constructed by our laboratory) and further expressed in E. coli BL21 and B. subtilis W600 (TrLIPB/E), respectively. After purification, TrLipE/B showed a single band at approx. 38 kDa on 10% reducing SDS-PAGE gels. The successful expression of TrLipE/B was further confirmed by peptide map fingerprinting (PMF) analysis. For both expression systems, the target enzyme revealed marked stability over a wide temperature and pH range. In E. coli BL21, the optimal temperature and pH were 85 C and 8.5, while these were 90 C and 9 in B. subtilis W600. Additionally, the studied TrLipE/B was found to show remarkable tolerance in mixed systems constituted by water and organic solvents. Depending on the different expression systems, TrLipB has better enzymatic properties, in particular, thermostability and organic solvent tolerance. Based on the circular dichroism (CD) analysis, the corresponding helix, beta-sheet, beta-turn and random coil compositions were slightly different between TrLipE (34.8%, 11.2%, 23.4% and 30.6%) and TrLipB (35.9%, 11.1%, 23.3% and 29.7%). The thermostability of TrLipE/B was further verified with nano-DSC analysis. The melting temperature (Tm) and denaturation enthalpy (deltaH) of TrLipE were 97.51 C and 1637 KJ mol-1, 98.53 C and 1463 kJ mol-1 for TrLipB. The substrate specificity and enzymatic kinetics were analyzed as well. The studied TrLipE/B's capability to catalyze p-nitrophenol esters with different carbon chain lengths was verified. Enzymatic transesterification of immobilized TrLipB was confirmed, with a molar conversion rate of 23.32%. This research therefore provides a candidate that could be applied for biocleanser production and organic synthesis, especially under environments requiring high temperature.
ESTHER : Fang_2021_Catal.Sci.Technol_11_7386
PubMedSearch : Fang_2021_Catal.Sci.Technol_11_7386

Title : Design, synthesis and evaluation of genistein-O-alkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease - Qiang_2014_Eur.J.Med.Chem_76_314
Author(s) : Qiang X , Sang Z , Yuan W , Li Y , Liu Q , Bai P , Shi Y , Ang W , Tan Z , Deng Y
Ref : Eur Journal of Medicinal Chemistry , 76C :314 , 2014
Abstract : A series of genistein derivatives with carbon spacer-linked alkylbenzylamines were designed, synthesized and tested as multifunctional agents for the treatment of Alzheimer's disease (AD). The results showed that most of these compounds exhibited good acetylcholinesterase (AChE) inhibitory activity, with moderate-to-good anti-oxidative activity. Specifically, compounds 10b, 19d and 25d exhibited significant inhibition of beta-amyloid (Abeta) aggregation and exhibited metal chelating properties. In particular, 25d inhibited: self-induced Abeta1-42 aggregation, Cu2+-induced Abeta1-42 aggregation, and human AChE-induced Abeta1-40 aggregation by 35%, 77.8%, and 36.2%, respectively. Moreover, both kinetic analysis of AChE inhibition and the molecular modeling study suggested that 25d binds simultaneously to catalytic active site and peripheral anionic site of AChE. More importantly, compound 25d disassembled the well-structured Abeta fibrils generated by Cu2+-induced Abeta aggregation by 72.1%. Furthermore, the step-down passive avoidance test showed this compound significantly reversed scopolamine-induced memory deficit in mice. These results suggest that 25d may be a promising multifunctional agent for AD treatment.
ESTHER : Qiang_2014_Eur.J.Med.Chem_76_314
PubMedSearch : Qiang_2014_Eur.J.Med.Chem_76_314
PubMedID: 24589487

Title : Physiological effects of Paichongding applied to rice on the Nilaparvata lugens (Sta L), the brown planthopper - Qin_2014_Arch.Insect.Biochem.Physiol_87_72
Author(s) : Qin X , Zhang R , Zhang J , Shi Y
Ref : Archives of Insect Biochemistry & Physiology , 87 :72 , 2014
Abstract : Nilaparvata lugens (Stal) is a major rice pest in Asia. Paichongding is a novel neonicotinoid insecticide developed in 2008. The effects of this insecticide on the activity of detoxification enzymes of N. lugens and on rice resistance to the pest were examined in the laboratory. The results showed that paichongding could significantly decrease the acetylcholinesterase and GSHs transferase activities of N. lugens. The variation tendency of mixed function oxidase (MFO) activity was similar with that of the esterase. After 12 h treatment, there was no significance between the treatment and control. However, the activities of MFO and esterase increased after 24 and 48 h treatment, which suggested that MFO and esterase may play an important role in the detoxification of paichongding for N. lugens. Our results also demonstrated that treated with paichongding, damage levels of rice plants were significantly lower than those of control plants except 15 days after treatment. Compared with the control, injury indices decreased 70.22, 49.12, 34.44, and 23.23% at 3 , 6 , 9, and 12 days after paichongding treatment, respectively. The laboratory results suggested that paichongding may be effective for the control of brown planthopper.
ESTHER : Qin_2014_Arch.Insect.Biochem.Physiol_87_72
PubMedSearch : Qin_2014_Arch.Insect.Biochem.Physiol_87_72
PubMedID: 25042427

Title : Effect of darapladib treatment on endarterectomy carotid plaque lipoprotein-associated phospholipase A2 activity: a randomized, controlled trial - Johnson_2014_PLoS.One_9_e89034
Author(s) : Johnson JL , Shi Y , Snipes R , Janmohamed S , Rolfe TE , Davis B , Postle A , Macphee CH
Ref : PLoS ONE , 9 :e89034 , 2014
Abstract : BACKGROUND: The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A2 inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A2 activity. METHODS: Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication. RESULTS: Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A2 activity by 52% and 81%, respectively, versus placebo (both P<0.001). Significant reductions in plaque lipoprotein-associated phospholipase A2 activity were also observed compared with placebo (P<0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg (P = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 (P<0.001) and caspase-8 (P<0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study. CONCLUSIONS: Short-term treatment (14 +/- 4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A2 activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A2 activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.
ESTHER : Johnson_2014_PLoS.One_9_e89034
PubMedSearch : Johnson_2014_PLoS.One_9_e89034
PubMedID: 24586490

Title : Comparative gene identification-58 (CGI-58) promotes autophagy as a putative lysophosphatidylglycerol acyltransferase - Zhang_2014_J.Biol.Chem_289_33044
Author(s) : Zhang J , Xu D , Nie J , Han R , Zhai Y , Shi Y
Ref : Journal of Biological Chemistry , 289 :33044 , 2014
Abstract : CGI-58 is a lipid droplet-associated protein that, when mutated, causes Chanarin-Dorfman syndrome in humans, which is characterized by excessive storage of triglyceride in various tissues. However, the molecular mechanisms underlying the defect remain elusive. CGI-58 was previously reported to catalyze the resynthesis of phosphatidic acid as a lysophosphatidic acid acyltransferase. In addition to triglyceride, phosphatidic acid is also used a substrate for the synthesis of various mitochondrial phospholipids. In this report, we investigated the propensity of CGI-58 in the remodeling of various phospholipids. We found that the recombinant CGI-58 overexpressed in mammalian cells or purified from Sf9 insect cells catalyzed efficiently the reacylation of lysophosphatidylglycerol to phosphatidylglycerol (PG), which requires acyl-CoA as the acyl donor. In contrast, the recombinant CGI-58 was devoid of acyltransferase activity toward other lysophospholipids. Accordingly, overexpression and knockdown of CGI-58 adversely affected the endogenous PG level in C2C12 cells. PG is a substrate for the synthesis of cardiolipin, which is required for mitochondrial oxidative phosphorylation and mitophagy. Consequently, overexpression and knockdown of CGI-58 adversely affected autophagy and mitophagy in C2C12 cells. In support for a key role of CGI-58 in mitophagy, overexpression of CGI-58 significantly stimulated mitochondrial fission and translocation of PINK1 to mitochondria, key steps involved in mitophagy. Furthermore, overexpression of CGI-58 promoted mitophagic initiation through activation of 5'-AMP-activated protein kinase and inhibition of mTORC1 mammalian target of rapamycin complex 1 signaling, the positive and negative regulators of autophagy, respectively. Together, these findings identified novel molecular mechanisms by which CGI-58 regulates lipid homeostasis, because defective autophagy is implicated in dyslipidemia and fatty liver diseases.
ESTHER : Zhang_2014_J.Biol.Chem_289_33044
PubMedSearch : Zhang_2014_J.Biol.Chem_289_33044
PubMedID: 25315780
Gene_locus related to this paper: human-ABHD5

Title : Molecular basis of binding between novel human coronavirus MERS-CoV and its receptor CD26 - Lu_2013_Nature_500_227
Author(s) : Lu G , Hu Y , Wang Q , Qi J , Gao F , Li Y , Zhang Y , Zhang W , Yuan Y , Bao J , Zhang B , Shi Y , Yan J , Gao GF
Ref : Nature , 500 :227 , 2013
Abstract : The newly emergent Middle East respiratory syndrome coronavirus (MERS-CoV) can cause severe pulmonary disease in humans, representing the second example of a highly pathogenic coronavirus, the first being SARS-CoV. CD26 (also known as dipeptidyl peptidase 4, DPP4) was recently identified as the cellular receptor for MERS-CoV. The engagement of the MERS-CoV spike protein with CD26 mediates viral attachment to host cells and virus-cell fusion, thereby initiating infection. Here we delineate the molecular basis of this specific interaction by presenting the first crystal structures of both the free receptor binding domain (RBD) of the MERS-CoV spike protein and its complex with CD26. Furthermore, binding between the RBD and CD26 is measured using real-time surface plasmon resonance with a dissociation constant of 16.7 nM. The viral RBD is composed of a core subdomain homologous to that of the SARS-CoV spike protein, and a unique strand-dominated external receptor binding motif that recognizes blades IV and V of the CD26 beta-propeller. The atomic details at the interface between the two binding entities reveal a surprising protein-protein contact mediated mainly by hydrophilic residues. Sequence alignment indicates, among betacoronaviruses, a possible structural conservation for the region homologous to the MERS-CoV RBD core, but a high variation in the external receptor binding motif region for virus-specific pathogenesis such as receptor recognition.
ESTHER : Lu_2013_Nature_500_227
PubMedSearch : Lu_2013_Nature_500_227
PubMedID: 23831647
Gene_locus related to this paper: human-DPP4

Title : Molecular cloning and characterization of a newly isolated pyrethroid-degrading esterase gene from a genomic library of Ochrobactrum anthropi YZ-1 - Ruan_2013_PLoS.One_8_e77329
Author(s) : Ruan Z , Zhai Y , Song J , Shi Y , Li K , Zhao B , Yan Y
Ref : PLoS ONE , 8 :e77329 , 2013
Abstract : A novel pyrethroid-degrading esterase gene pytY was isolated from the genomic library of Ochrobactrum anthropi YZ-1. It possesses an open reading frame (ORF) of 897 bp. Blast search showed that its deduced amino acid sequence shares moderate identities (30% to 46%) with most homologous esterases. Phylogenetic analysis revealed that PytY is a member of the esterase VI family. pytY showed very low sequence similarity compared with reported pyrethroid-degrading genes. PytY was expressed, purified, and characterized. Enzyme assay revealed that PytY is a broad-spectrum degrading enzyme that can degrade various pyrethroids. It is a new pyrethroid-degrading gene and enriches genetic resource. Kinetic constants of Km and Vmax were 2.34 mmol.L(-1) and 56.33 nmol min(-1), respectively, with lambda-cyhalothrin as substrate. PytY displayed good degrading ability and stability over a broad range of temperature and pH. The optimal temperature and pH were of 35 degrees C and 7.5. No cofactors were required for enzyme activity. The results highlighted the potential use of PytY in the elimination of pyrethroid residuals from contaminated environments.
ESTHER : Ruan_2013_PLoS.One_8_e77329
PubMedSearch : Ruan_2013_PLoS.One_8_e77329
PubMedID: 24155944
Gene_locus related to this paper: 9rhiz-c4wm13

Title : Isolation, characterization and acetylcholinesterase inhibitory activity of alkaloids from roots of Stemona sessilifolia - Lai_2013_Fitoterapia_89_257
Author(s) : Lai DH , Yang ZD , Xue WW , Sheng J , Shi Y , Yao XJ
Ref : Fitoterapia , 89 :257 , 2013
Abstract : Two new alkaloids, named stenine A (1) and stenine B (2), along with the known compounds neostenine (3), stenine (4) and neotuberostemonine (5), were isolated from the roots of Stemona sessilifolia. Their structures were elucidated by 1D- and 2D-NMR spectra and X-ray single-crystal diffraction experiment. Anti-acetylcholinesterase (AChE) activity of compounds 1-5 were also tested. Compounds 2 and 4 showed significant anti-acetylcholinesterase activities, with IC50 values of 2.1+/-0.2muM and 19.8+/-2.5muM, resp. The mode of AChE inhibition by Compound 2 (the most potential AChE inhibitor) was reversible and competitive. In addition, molecular modeling was performed to explore the binding mode of compound 2 with AChE.
ESTHER : Lai_2013_Fitoterapia_89_257
PubMedSearch : Lai_2013_Fitoterapia_89_257
PubMedID: 23831460

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

Title : Genome sequences of wild and domestic bactrian camels - Jirimutu_2012_Nat.Commun_3_1202
Author(s) : Jirimutu , Wang Z , Ding G , Chen G , Sun Y , Sun Z , Zhang H , Wang L , Hasi S , Zhang Y , Li J , Shi Y , Xu Z , He C , Yu S , Li S , Zhang W , Batmunkh M , Ts B , Narenbatu , Unierhu , Bat-Ireedui S , Gao H , Baysgalan B , Li Q , Jia Z , Turigenbayila , Subudenggerile , Narenmanduhu , Wang J , Pan L , Chen Y , Ganerdene Y , Dabxilt , Erdemt , Altansha , Altansukh , Liu T , Cao M , Aruuntsever , Bayart , Hosblig , He F , Zha-ti A , Zheng G , Qiu F , Zhao L , Zhao W , Liu B , Li C , Tang X , Guo C , Liu W , Ming L , Temuulen , Cui A , Li Y , Gao J , Wurentaodi , Niu S , Sun T , Zhai Z , Zhang M , Chen C , Baldan T , Bayaer T , Meng H
Ref : Nat Commun , 3 :1202 , 2012
Abstract : Bactrian camels serve as an important means of transportation in the cold desert regions of China and Mongolia. Here we present a 2.01 Gb draft genome sequence from both a wild and a domestic bactrian camel. We estimate the camel genome to be 2.38 Gb, containing 20,821 protein-coding genes. Our phylogenomics analysis reveals that camels shared common ancestors with other even-toed ungulates about 55-60 million years ago. Rapidly evolving genes in the camel lineage are significantly enriched in metabolic pathways, and these changes may underlie the insulin resistance typically observed in these animals. We estimate the genome-wide heterozygosity rates in both wild and domestic camels to be 1.0 x 10(-3). However, genomic regions with significantly lower heterozygosity are found in the domestic camel, and olfactory receptors are enriched in these regions. Our comparative genomics analyses may also shed light on the genetic basis of the camel's remarkable salt tolerance and unusual immune system.
ESTHER : Jirimutu_2012_Nat.Commun_3_1202
PubMedSearch : Jirimutu_2012_Nat.Commun_3_1202
PubMedID: 23149746
Gene_locus related to this paper: 9ceta-s9yik4 , 9ceta-s9yb99 , 9ceta-s9x0n3 , 9ceta-s9xqa3 , 9ceta-s9xi02 , camfr-s9wiw9 , camfr-s9x3r3 , camfr-s9xce1 , camfr-s9xcr2 , camfr-s9yuz0 , camfr-s9xlc8 , camfr-s9w5f6 , camfr-s9xmm4

Title : Molecular cloning, purification and biochemical characterization of a novel pyrethroid-hydrolyzing carboxylesterase gene from Ochrobactrum anthropi YZ-1 - Zhai_2012_J.Hazard.Mater_221-222_206
Author(s) : Zhai Y , Li K , Song J , Shi Y , Yan Y
Ref : J Hazard Mater , 221-222 :206 , 2012
Abstract : Strain YZ-1 was isolated from activated sludge and identified as Ochrobactrum anthropi. This strain was capable of degrading pyrethroids pesticides, suggesting the presence of degrading enzymes. In the present study, a novel esterase gene pytZ was cloned from the genomic library of YZ-1 successfully. The pytZ contained an open reading frame of 606bp encoding a pyrethroid-hydrolyzing carboxylesterase. Deduced amino acid sequence showed moderate identities (39-59%) with most homologous carboxylesterase, except a putative carboxylesterase from O. anthropi ATCC 49188 with the highest identity of 85%. Phylogenetic analysis revealed that PytZ belonged to esterase VI family. The gene pytZ showed no any sequence similarity with reported pyrethroid-hydrolyzing genes and was a new pyrethroid-degrading gene. PytZ was expressed in Escherichia coli BL21 (DE3) and purified using Ni-NTA Fast Start. PytZ was able to degrade various pyrethroids. The optimal temperature and pH were 35 degrees C and 7.5. This enzyme was very stable over a wide range of temperature and pH. No cofactors were required for enzyme activity. Broad substrate specificity, high enzyme activity, and the favorable stability make the PytZ a potential candidate for the detoxification of pyrethroid residues in biotechnological application.
ESTHER : Zhai_2012_J.Hazard.Mater_221-222_206
PubMedSearch : Zhai_2012_J.Hazard.Mater_221-222_206
PubMedID: 22579404
Gene_locus related to this paper: 9hyph-h2esq9

Title : Time-series analyses of Monterey Bay coastal microbial picoplankton using a 'genome proxy' microarray - Rich_2011_Environ.Microbiol_13_116
Author(s) : Rich VI , Pham VD , Eppley J , Shi Y , DeLong EF
Ref : Environ Microbiol , 13 :116 , 2011
Abstract : To investigate the temporal, spatial and phylogenetic resolution of marine microbial community structure and variability, we designed and expanded a genome proxy array (an oligonucleotide microarray targeting marine microbial genome fragments and genomes), evaluated it against metagenomic sequencing, and applied it to time-series samples from the Monterey Bay. The expanded array targeted 268 microbial genotypes across much of the known diversity of cultured and uncultured marine microbes. The target abundances measured by the array were highly correlated to pyrosequence-based abundances (linear regression R(2) = 0.85-0.91, P < 0.0001). Fifty-seven samples from approximately 4 years in Monterey Bay were examined with the array, spanning the photic zone (0 m), the base of the surface mixed layer (30 m) and the subphotic zone (200 m). A significant portion of the expanded genome proxy array's targets showed signal (95 out of 268 targets present in >/= 1 sample). The multi-year community survey showed the consistent presence of a core group of common and abundant targeted taxa at each depth in Monterey Bay, higher variability among shallow than deep samples, and episodic occurrences of more transient marine genotypes. The abundance of the most dominant genotypes peaked after strong episodic upwelling events. The genome-proxy array's ability to track populations of closely related genotypes indicated population shifts within several abundant target taxa, with specific populations in some cases clustering by depth or oceanographic season. Although 51 cultivated organisms were targeted (representing 19% of the array) the majority of targets detected and of total target signal (85% and approximately 92% respectively) were from uncultivated genotypes, often those derived from Monterey Bay. The array provided a relatively cost-effective approach ( approximately 15 dollars per array) for surveying the natural history of uncultivated lineages.
ESTHER : Rich_2011_Environ.Microbiol_13_116
PubMedSearch : Rich_2011_Environ.Microbiol_13_116
PubMedID: 20695878

Title : Searching for the Multi-Target-Directed Ligands against Alzheimer's disease: discovery of quinoxaline-based hybrid compounds with AChE, H(3)R and BACE 1 inhibitory activities - Huang_2011_Bioorg.Med.Chem_19_7158
Author(s) : Huang W , Tang L , Shi Y , Huang S , Xu L , Sheng R , Wu P , Li J , Zhou N , Hu Y
Ref : Bioorganic & Medicinal Chemistry , 19 :7158 , 2011
Abstract : A novel series of quinoxaline derivatives, as Multi-Target-Directed Ligands (MTDLs) for AD treatment, were designed by lending the core structural elements required for H(3)R antagonists and hybridizing BACE 1 inhibitor 1 with AChE inhibitor BYYT-25. A virtual database consisting of quinoxaline derivatives was first screened on a pharmacophore model of BACE 1 inhibitors, and then filtered by a molecular docking model of AChE. Seventeen quinoxaline derivatives with high score values were picked out, synthesized and evaluated for their biological activities. Compound 11a, the most effective MTDL, showed the potent activity to H(3)R/AChE/BACE 1 (H(3)R antagonism, IC(50)=280.0 +/- 98.0 nM; H(3)R inverse agonism, IC(50)=189.3 +/- 95.7 nM; AChE, IC(50)=483 +/- 5 nM; BACE 1, 46.64+/-2.55% inhibitory rate at 20 muM) and high selectivity over H(1)R/H(2)R/H(4)R. Furthermore, the protein binding patterns between 11a and AChE/BACE 1 showed that it makes several essential interactions with the enzymes.
ESTHER : Huang_2011_Bioorg.Med.Chem_19_7158
PubMedSearch : Huang_2011_Bioorg.Med.Chem_19_7158
PubMedID: 22019465

Title : The MDGA1 gene confers risk to schizophrenia and bipolar disorder - Li_2011_Schizophr.Res_125_194
Author(s) : Li J , Liu J , Feng G , Li T , Zhao Q , Li Y , Hu Z , Zheng L , Zeng Z , He L , Wang T , Shi Y
Ref : Schizophr Res , 125 :194 , 2011
Abstract : OBJECTIVE: The structural, cytoarchitectural and functional brain abnormalities reported in patients with mental disorders may be due to aberrant neuronal migration influenced by cell adhesion molecules. MDGA1, like Ig-containing cell adhesion molecules, has several cell adhesion molecule-like domains. Moreover, Kahler et al. (2008) reported that the MDGA1 gene was a schizophrenia susceptibility gene in Scandinavian population. To further investigate whether the MDGA1 gene is a shared risk factor of schizophrenia, bipolar disorder and major depressive disorder in Chinese Han population, we conducted this study.
METHODS: We recruited 1135 unrelated schizophrenia patients, 1135 unrelated bipolar disorder patients, 1135 unrelated major depressive disorder patients and 1135 unrelated controls of Chinese Han origin. A total of eleven common SNPs were genotyped using TaqMan(R) technology.
RESULTS: The genotype frequency of rs11759115 differed significantly between schizophrenia patients and controls. The C-C haplotype of rs11759115-rs7769372 was also positively associated with schizophrenia (permutated p=0.046). Rs1883901 was found to be positively associated with bipolar disorder (allele: permutated p=0.0085; genotype: permutated p=0.0009; OR=1.31 [95%CI=1.12-1.52]). The A-G-G haplotype of rs1883901-rs10807187-rs9462343 was also positively associated with bipolar disorder with a global p value of 0.0391 after permutations. No individual SNP or haplotype was associated with major depressive disorder after permutations. CONCLUSION: The MDGA1 gene may confer risk to schizophrenia and bipolar disorder in Chinese Han population.
ESTHER : Li_2011_Schizophr.Res_125_194
PubMedSearch : Li_2011_Schizophr.Res_125_194
PubMedID: 21146959

Title : Biallelic p.R2223H mutation in the thyroglobulin gene causes thyroglobulin retention and severe hypothyroidism with subsequent development of thyroid carcinoma - Raef_2010_J.Clin.Endocrinol.Metab_95_1000
Author(s) : Raef H , Al-Rijjal R , Al-Shehri S , Zou M , Al-Mana H , Baitei EY , Parhar RS , Al-Mohanna FA , Shi Y
Ref : J Clinical Endocrinology Metab , 95 :1000 , 2010
Abstract : CONTEXT: Dyshormonogenesis due to genetic defect in thyroglobulin (Tg) synthesis and secretion can lead to congenital hypothyroidism. OBJECTIVES: The aim of the study was to analyze the TG gene for the presence of mutations and to study the underlying mechanisms leading to dyshormonogenesis. CASES: Two siblings aged 25 and 31 yr presented with recurrent goitrous hypothyroidism with undetectable serum Tg. The older sibling was diagnosed with follicular variant of papillary thyroid carcinoma (FVPTC) at age 21 and metastatic FVPTC 8 yr later.
METHODS: The entire coding region of TG gene was sequenced. BRAF, RAS, and P53 mutations or PAX8/PPAR-gamma rearrangement were screened in the FVPTC. Tg expression was studied by immunohistochemistry.
RESULTS: Biallelic c.6725G>A (p.R2223H) and c.6396C>T (p.S2113L) sequence variations were detected in both patients and monoallelic variations in their family members. The c.6396C>T (p.S2113L) sequence variation was found in 14% of 100 population controls, whereas c.6725G>A variation was not present in the controls. Two previously reported polymorphisms (c.2200T>G and c.3082A>G) were present in all the family members. Strong cytoplasmic immunostaining of Tg was observed in the hyperplastic thyroid epithelial cells and weak or no staining in the follicular lumen. Cytoplasmic staining was localized in the endoplasmic reticulum. Reduced staining was found in the FVPTC. Neither RAS, BRAF, or P53 gene mutation nor a PAX8/PPAR-gamma rearrangement was detected in the tumor tissue.
CONCLUSIONS: Biallelic c.6725G>A (p.R2223H) mutation causes Tg retention in the endoplasmic reticulum, resulting in dyshormonogenesis. Prolonged TSH stimulation may promote malignant transformation and development of thyroid cancer. The c.6396C>T (p.S2113L) is a novel polymorphism.
ESTHER : Raef_2010_J.Clin.Endocrinol.Metab_95_1000
PubMedSearch : Raef_2010_J.Clin.Endocrinol.Metab_95_1000
PubMedID: 20089614
Gene_locus related to this paper: human-TG

Title : AChE deficiency or inhibition decreases apoptosis and p53 expression and protects renal function after ischemia\/reperfusion - Ye_2010_Apoptosis_15_474
Author(s) : Ye W , Gong X , Xie J , Wu J , Zhang X , Ouyang Q , Zhao X , Shi Y
Ref : Apoptosis , 15 :474 , 2010
Abstract : We recently reported that the expression of the synaptic form of acetylcholinesterase (AChE) is induced during apoptosis in various cell types in vitro. Here, we provide evidence to confirm that AChE is expressed during ischemia-reperfusion (I/R)-induced apoptosis in vivo. Renal I/R is a major cause of acute renal failure (ARF), resulting in injury and the eventual death of renal cells due to a combination of apoptosis and necrosis. Using AChE-deficient mice and AChE inhibitors, we investigated whether AChE deficiency or inhibition can protect against apoptosis caused by I/R in a murine kidney model. Unilateral clamping of renal pedicles for 90 min followed by reperfusion for 24 h caused significant renal dysfunction and injury. Both genetic AChE deficiency and chemical inhibition of AChE (provided by huperzine A, tacrine and donepezil) significantly reduced the biochemical and histological evidence of renal dysfunction following I/R. Activation of caspases-8, -9, -12, and -3 in vivo were prevented and associated with reduced levels of cell apoptosis and cell death. A further investigation also confirmed that AChE deficiency down-regulated p53 induction and phosphorylation at serine-15, and decreased the Bax/Bcl-2 ratio during I/R. In conclusion, our study demonstrates that AChE may be a pro-apoptotic factor and the inhibition of AChE reduces renal I/R injury. These findings suggest that AChE inhibitors may represent a therapeutic strategy for protection against ischemic acute renal failure.
ESTHER : Ye_2010_Apoptosis_15_474
PubMedSearch : Ye_2010_Apoptosis_15_474
PubMedID: 20054652

Title : The sequence and de novo assembly of the giant panda genome - Li_2010_Nature_463_311
Author(s) : Li R , Fan W , Tian G , Zhu H , He L , Cai J , Huang Q , Cai Q , Li B , Bai Y , Zhang Z , Zhang Y , Wang W , Li J , Wei F , Li H , Jian M , Nielsen R , Li D , Gu W , Yang Z , Xuan Z , Ryder OA , Leung FC , Zhou Y , Cao J , Sun X , Fu Y , Fang X , Guo X , Wang B , Hou R , Shen F , Mu B , Ni P , Lin R , Qian W , Wang G , Yu C , Nie W , Wang J , Wu Z , Liang H , Min J , Wu Q , Cheng S , Ruan J , Wang M , Shi Z , Wen M , Liu B , Ren X , Zheng H , Dong D , Cook K , Shan G , Zhang H , Kosiol C , Xie X , Lu Z , Li Y , Steiner CC , Lam TT , Lin S , Zhang Q , Li G , Tian J , Gong T , Liu H , Zhang D , Fang L , Ye C , Zhang J , Hu W , Xu A , Ren Y , Zhang G , Bruford MW , Li Q , Ma L , Guo Y , An N , Hu Y , Zheng Y , Shi Y , Li Z , Liu Q , Chen Y , Zhao J , Qu N , Zhao S , Tian F , Wang X , Wang H , Xu L , Liu X , Vinar T , Wang Y , Lam TW , Yiu SM , Liu S , Huang Y , Yang G , Jiang Z , Qin N , Li L , Bolund L , Kristiansen K , Wong GK , Olson M , Zhang X , Li S , Yang H
Ref : Nature , 463 :311 , 2010
Abstract : Using next-generation sequencing technology alone, we have successfully generated and assembled a draft sequence of the giant panda genome. The assembled contigs (2.25 gigabases (Gb)) cover approximately 94% of the whole genome, and the remaining gaps (0.05 Gb) seem to contain carnivore-specific repeats and tandem repeats. Comparisons with the dog and human showed that the panda genome has a lower divergence rate. The assessment of panda genes potentially underlying some of its unique traits indicated that its bamboo diet might be more dependent on its gut microbiome than its own genetic composition. We also identified more than 2.7 million heterozygous single nucleotide polymorphisms in the diploid genome. Our data and analyses provide a foundation for promoting mammalian genetic research, and demonstrate the feasibility for using next-generation sequencing technologies for accurate, cost-effective and rapid de novo assembly of large eukaryotic genomes.
ESTHER : Li_2010_Nature_463_311
PubMedSearch : Li_2010_Nature_463_311
PubMedID: 20010809
Gene_locus related to this paper: ailme-ABH15 , ailme-ACHE , ailme-BCHE , ailme-d2gtv3 , ailme-d2gty9 , ailme-d2gu87 , ailme-d2gu97 , ailme-d2gve7 , ailme-d2gwu1 , ailme-d2gx08 , ailme-d2gyt0 , ailme-d2gz36 , ailme-d2gz37 , ailme-d2gz38 , ailme-d2gz39 , ailme-d2gz40 , ailme-d2h5r9 , ailme-d2h7b7 , ailme-d2h9c9 , ailme-d2h794 , ailme-d2hau7 , ailme-d2hau8 , ailme-d2hcd9 , ailme-d2hdi6 , ailme-d2heu6 , ailme-d2hga4 , ailme-d2hqw5 , ailme-d2hs98 , ailme-d2hsx4 , ailme-d2hti6 , ailme-d2htv3 , ailme-d2htz6 , ailme-d2huc7 , ailme-d2hwj8 , ailme-d2hwy7 , ailme-d2hxm1 , ailme-d2hyc8 , ailme-d2hyv2 , ailme-d2hz11 , ailme-d2hza3 , ailme-d2hzr4 , ailme-d2i1l4 , ailme-d2i2g8 , ailme-g1l7m3 , ailme-g1lu36 , ailme-g1m769 , ailme-g1mc29 , ailme-g1mdj8 , ailme-g1mdr5 , ailme-g1mfp4 , ailme-g1mfx5 , ailme-g1lj41 , ailme-g1lm28 , ailme-g1l3u1 , ailme-g1l7l1 , ailme-g1m5i3 , ailme-g1l2f6 , ailme-g1lji5 , ailme-g1lqk3 , ailme-g1l8s9 , ailme-d2h717 , ailme-d2h718 , ailme-d2h719 , ailme-d2h720 , ailme-g1m5v0 , ailme-g1m5y7 , ailme-g1lkt7 , ailme-g1l2a1 , ailme-g1lsc8 , ailme-g1lrp4 , ailme-d2gv02 , ailme-g1mik5 , ailme-g1ljr1 , ailme-g1lxw7 , ailme-d2h8b5 , ailme-d2h2r2 , ailme-d2h9w7 , ailme-g1meh3 , ailme-g1m719

Title : A novel cold-adapted phospholipase A(1) from Serratia sp. xjF1: Gene cloning, expression and characterization - Fu_2008_Enzyme.Microb.Technol_42_187
Author(s) : Fu J , Huang H , Meng K , Yuan T , Yao B , Shi Y , Ouyang P
Ref : Enzyme Microb Technol , 42 :187 , 2008
Abstract : The gene encoding a cold-adapted phospholipase A(1) (PLA(1)) from a psychrotrophic, glacier soil bacterium Serratia sp. xjF1 was cloned by two-step PCR (general PCR and TAIL-PCR). The full-length fragment comprised two open reading frames plA and plS. The gene product of plA encoding 320 amino acids with a molecular weight of 33.8kDa was identified as a phospholipase A(1). Its amino acid sequence exhibited the highest homology to PLA(1) of Serratia marcescens (71%). plS encoded a protein of 251 amino acids, which showed no enzymatic activity. The result of plA expression in Escherichia coli indicated that plS might improve the efficient expression of PLA(1) in E. coli. Furthermore, PLA(1) was functionally expressed in Pichia pastoris, yielding 41.8U/mL in a 3.7L fermentor. The purified recombinant phospholipase A(1) (rPLA(1)) had features typical of cold-adapted enzymes with a temperature optimum of 35 degrees C and a maximum activity of 70% at 10 degrees C. The rate of catalysis was optimal at pH 9.0 and the enzyme could be slightly activated by Ca(2+). This is the first report on gene isolation and expression of cold-adapted PLA(1).
ESTHER : Fu_2008_Enzyme.Microb.Technol_42_187
PubMedSearch : Fu_2008_Enzyme.Microb.Technol_42_187
PubMedID: 22578870
Gene_locus related to this paper: 9entr-a9x3m0

Title : Structural mechanism of demethylation and inactivation of protein phosphatase 2A - Xing_2008_Cell_133_154
Author(s) : Xing Y , Li Z , Chen Y , Stock JB , Jeffrey PD , Shi Y
Ref : Cell , 133 :154 , 2008
Abstract : Protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that plays a role in many biological processes. Reversible carboxyl methylation of the PP2A catalytic subunit is an essential regulatory mechanism for its function. Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. However, the underlying mechanism of PME-1 function remains enigmatic. Here we report the crystal structures of PME-1 by itself and in complex with a PP2A heterodimeric core enzyme. The structures reveal that PME-1 directly binds to the active site of PP2A and that this interaction results in the activation of PME-1 by rearranging the catalytic triad into an active conformation. Strikingly, these interactions also lead to inactivation of PP2A by evicting the manganese ions that are required for the phosphatase activity of PP2A. These observations identify a dual role of PME-1 that regulates PP2A activation, methylation, and holoenzyme assembly in cells.
ESTHER : Xing_2008_Cell_133_154
PubMedSearch : Xing_2008_Cell_133_154
PubMedID: 18394995
Gene_locus related to this paper: human-PPME1

Title : Polymorphisms of the lipoprotein lipase gene are associated with atherosclerotic cerebral infarction in the Chinese - Xu_2008_Neurosci_155_403
Author(s) : Xu E , Li W , Zhan L , Guan G , Wang X , Chen S , Shi Y
Ref : Neuroscience , 155 :403 , 2008
Abstract : BACKGROUND: Lipoprotein lipase (LPL), which plays an essential role in plasma lipoprotein metabolism and transportation, appears to be a risk factor for ischemic vascular diseases. Several studies have recently reported the presence of relationship between HindIII, PvuII, Ser447Ter (C-->G) polymorphisms of LPL and ischemic vascular diseases. PURPOSE: We first studied the relationship between LPL polymorphisms and the risk of atherosclerotic cerebral infarction (CI) by detecting the frequencies of LPL HindIII, PvuII and Ser447Ter genotypes and combined genotypes in the Chinese. METHODS: We recruited 185 CI patients, confirmed by cranial computed tomography or magnetic resonance imaging/angiography, or both, and 186 control subjects. Polymerase chain reaction-restriction fragment length polymorphisms technique was used to detect HindIII, PvuII and Ser447Ter polymorphisms of the LPL gene. RESULTS: The frequencies of the H+H+ genotype and H+ allele did not differ between CI and control groups. The frequencies of the P+P+ genotype and P+ allele gene were significantly higher in the CI group (P=0.040, P=0.015). The frequencies of CG+GG genotype and G allele were lower in the CI group (P<0.001, P<0.001). In the CI group, the individuals with P+P+ genotype had a significantly higher level of plasma triglyceride (TG) and a lower level of plasma high density lipoprotein cholesterol (HDL-c). CG+GG genotypes were correlated with significantly higher levels of plasma total cholesterol (TC), HDL-c and low density lipoprotein cholesterol (LDL-c) in the CI group. The frequencies of H+/C and P+/C combined genotypes were higher in the CI group than in controls (P<0.001, P<0.001). The frequency of H+/P+/C combined genotype was significantly higher in the CI group than in controls (P<0.001). CONCLUSIONS: Our study suggests that PvuII and Ser447Ter polymorphisms are associated with lipid profile and CI.
ESTHER : Xu_2008_Neurosci_155_403
PubMedSearch : Xu_2008_Neurosci_155_403
PubMedID: 18590804

Title : Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development - Wilensky_2008_Nat.Med_14_1059
Author(s) : Wilensky RL , Shi Y , Mohler ER, 3rd , Hamamdzic D , Burgert ME , Li J , Postle A , Fenning RS , Bollinger JG , Hoffman BE , Pelchovitz DJ , Yang J , Mirabile RC , Webb CL , Zhang L , Zhang P , Gelb MH , Walker MC , Zalewski A , Macphee CH
Ref : Nat Med , 14 :1059 , 2008
Abstract : Increased lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity is associated with increased risk of cardiac events, but it is not known whether Lp-PLA(2) is a causative agent. Here we show that selective inhibition of Lp-PLA(2) with darapladib reduced development of advanced coronary atherosclerosis in diabetic and hypercholesterolemic swine. Darapladib markedly inhibited plasma and lesion Lp-PLA(2) activity and reduced lesion lysophosphatidylcholine content. Analysis of coronary gene expression showed that darapladib exerted a general anti-inflammatory action, substantially reducing the expression of 24 genes associated with macrophage and T lymphocyte functioning. Darapladib treatment resulted in a considerable decrease in plaque area and, notably, a markedly reduced necrotic core area and reduced medial destruction, resulting in fewer lesions with an unstable phenotype. These data show that selective inhibition of Lp-PLA(2) inhibits progression to advanced coronary atherosclerotic lesions and confirms a crucial role of vascular inflammation independent from hypercholesterolemia in the development of lesions implicated in the pathogenesis of myocardial infarction and stroke.
ESTHER : Wilensky_2008_Nat.Med_14_1059
PubMedSearch : Wilensky_2008_Nat.Med_14_1059
PubMedID: 18806801
Gene_locus related to this paper: human-PLA2G7

Title : Study on dual-site inhibitors of acetylcholinesterase: Highly potent derivatives of bis- and bifunctional huperzine B - He_2007_Bioorg.Med.Chem_15_1394
Author(s) : He XC , Feng S , Wang ZF , Shi Y , Zheng S , Xia Y , Jiang H , Tang XC , Bai D
Ref : Bioorganic & Medicinal Chemistry , 15 :1394 , 2007
Abstract : Natural (-)-huperzine B (HupB), isolated from Chinese medicinal herb, displayed moderate inhibitory activity of acetylcholinesterase (AChE). Based on the active dual-site of AChE, a series of novel derivatives of bis- and bifunctional HupB were designed and synthesized. The AChE inhibition potency of most derivatives of HupB was enhanced about 2-3 orders of magnitude as compared with the parental HupB. Among bis-HupB derivatives, 12h exhibited the most potent in the AChE inhibition and has been evaluated for its pharmacological actions in vivo on ChE inhibition, cognitive enhancement, and neuroprotection. The docking study on the bis-HupB derivatives 12 series with TcAChE has demonstrated that the ligands bound to the dual-site of the enzyme in different level.
ESTHER : He_2007_Bioorg.Med.Chem_15_1394
PubMedSearch : He_2007_Bioorg.Med.Chem_15_1394
PubMedID: 17126020

Title : Effect of antioxidant capacity on blood lipid metabolism and lipoprotein lipase activity of rats fed a high-fat diet - Yang_2006_Nutrition_22_1185
Author(s) : Yang R , Le G , Li A , Zheng J , Shi Y
Ref : Nutrition , 22 :1185 , 2006
Abstract : OBJECTIVE: The present study explored the effect of antioxidant capacity on blood lipid metabolism and lipoprotein lipase (LPL) activity of rats fed with a high-fat diet (HFD). Furthermore, the relation of the atherosclerotic index (AI) and LPL activity to total antioxidant capacity (TAC) was studied.
METHODS: Thirty-two Sprague-Dawley rats were randomly assigned to one of four groups (n = 8). The control group consumed an ordinary diet (5.1% fat, w/w). The other three experimental groups were fed with an HFD (14.1% fat, w/w), an HFD plus 0.1% lipoic acid (LA), or an HFD plus 0.1% N-acetylcysteine (NAC). After 4 wk, serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol and LPL activity were examined. To evaluate rats' antioxidant status, TAC and superoxide dismutase activities and malondialdehyde level were measured.
RESULTS: The HFD induced abnormal increases in lipid peroxidation, serum concentrations of total cholesterol, triacylglycerol, and low-density lipoprotein cholesterol, and a decrease in high-density lipoprotein cholesterol concentration. Decreased activity of LPL, accompanied by a depressed antioxidant defense system, was observed in HFD-fed rats. These changes were partially restored in the NAC- and LA-treated groups. There was a negative correlation between AI and TAC (r = -0.969, P < 0.05). In addition, a significant positive correlation between LPL activity and TAC was found (r = 0.979, P < 0.05). CONCLUSION: Oxidative injury and lipid abnormalities were induced by an HFD. Administration of LA and NAC can improve the antioxidant capacity and activity of LPL and reduce blood lipid significantly. Antioxidant capacity is correlated with AI and LPL activity.
ESTHER : Yang_2006_Nutrition_22_1185
PubMedSearch : Yang_2006_Nutrition_22_1185
PubMedID: 17095404

Title : Solution structure of GOPC PDZ domain and its interaction with the C-terminal motif of neuroligin - Li_2006_Protein.Sci_15_2149
Author(s) : Li X , Zhang J , Cao Z , Wu J , Shi Y
Ref : Protein Science , 15 :2149 , 2006
Abstract : GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein) represents a PDZ domain-containing protein associated with the Golgi apparatus, which plays important roles in vesicular trafficking in secretory and endocytic pathways. GOPC interacts with many other proteins, such as the Wnt receptors Frizzled 8 and neuroligin via its PDZ domain. Neuroligin is a neural cell-adhesion molecule of the post-synapse, which binds to the presynapse molecule neurexin to form a heterotypic intercellular junction. Here we report the solution structure of the GOPC PDZ domain by NMR. Our results show that it is a canonical class I PDZ domain, which contains two alpha-helices and six beta-strands. Using chemical shift perturbation experiments, we further studied the binding properties of the GOPC PDZ domain with the C-terminal motif of neuroligin. The observations showed that the ensemble of the interaction belongs to fast exchange with low affinity. The 3D model of the GOPC PDZ domain/neuroligin C-terminal peptide complex was constructed with the aid of the molecular dynamics simulation method. Our discoveries provide insight into the specific interaction of the GOPC PDZ domain with the C-terminal peptide of Nlg and also provide a general insight about the possible binding mode of the interaction of Nlg with other PDZ domain-containing proteins.
ESTHER : Li_2006_Protein.Sci_15_2149
PubMedSearch : Li_2006_Protein.Sci_15_2149
PubMedID: 16882988
Gene_locus related to this paper: human-NLGN1

Title : Clinical case seminar: metastatic follicular thyroid carcinoma arising from congenital goiter as a result of a novel splice donor site mutation in the thyroglobulin gene - Alzahrani_2006_J.Clin.Endocrinol.Metab_91_740
Author(s) : Alzahrani AS , Baitei EY , Zou M , Shi Y
Ref : J Clinical Endocrinology Metab , 91 :740 , 2006
Abstract : CONTEXT: Defects in thyroglobulin (Tg) synthesis are one of the causes of thyroid dyshormonogenesis. Only a few mutations in the Tg gene have been described. OBJECTIVES: We describe a novel Tg gene mutation and discuss the mechanisms by which it causes dyshormonogenesis with subsequent malignant transformation. CASES: Two siblings aged 21 and 19 yr presented with recurrent goiters for which they had undergone multiple thyroid surgeries since early childhood. The older sibling was diagnosed with metastatic follicular thyroid carcinoma at age 15 yr.
METHODS: The entire coding region and intron-exon boundaries of the Tg gene were amplified and sequenced from the patients. We also sequenced the boundaries of exon 5 and intron 5 from both parents. RT-PCR amplification of a cDNA fragment encompassing exons 4-6 was also performed.
RESULTS: A homozygous G to A point mutation at position +1 of the splice donor site of intron 5 (g.IVS5+1G-->A) was detected in both patients, whereas a monoallelic mutation was found in their parents. RT-PCR amplification of a cDNA fragment covering exons 4-6 revealed a 191-bp fragment in the patients and 351- and 191-bp fragments in the parents. Sequence analysis of these two fragments confirmed deletion of exon 5 in the 191-bp fragment.
CONCLUSIONS: Aberrant splicing occurred as a result of the g.IVS5+1G-->A mutation, which caused fusion of exons 4 and 6, resulting in the frame shift at codon position 141 and a premature stop codon at position 147 (FS141-->147X). The malignant transformation is likely a result of prolonged TSH stimulation.
ESTHER : Alzahrani_2006_J.Clin.Endocrinol.Metab_91_740
PubMedSearch : Alzahrani_2006_J.Clin.Endocrinol.Metab_91_740
PubMedID: 16403815
Gene_locus related to this paper: human-TG