Lu W

References (35)

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

Title : Enzymatic Preparation, In-Depth Molecular Analysis, and In Vitro Digestion Simulation of Palmitoleic Acid (-7)-Enriched Fish Oil Triacylglycerols - Ge_2024_J.Agric.Food.Chem__
Author(s) : Ge L , Cheng K , Lu W , Cui Y , Yin X , Jiang J , Li Y , Yao H , Liao J , Xue J , Shen Q
Ref : Journal of Agricultural and Food Chemistry , : , 2024
Abstract : In this study, an enzymatic reaction was developed for synthesizing pure triacylglycerols (TAG) with a high content of palmitoleic acid (POA) using fish byproduct oil. The characteristics of synthesized structural TAGs rich in POA (POA-TAG) were analyzed in detail through ultrahigh-performance liquid chromatography Q Exactive orbitrap mass spectrometry. Optimal conditions were thoroughly investigated and determined for reaction systems, including the use of Lipozyme TL IM and Novozym 435, 15 wt % lipase loading, substrate mass ratio of 1:3, and water content of 2.5 and 0.5 wt %, respectively, resulting in yields of 67.50 and 67.45% for POA-TAG, respectively. Multivariate statistical analysis revealed that TAG 16:1/16:1/20:4, TAG 16:1/16:1/16:1, TAG 16:1/16:1/18:1, and TAG 16:0/16:1/18:1 were the main variables in Lipozyme TL IM and Novozym 435 enzyme-catalyzed products under different water content conditions. Finally, the fate of POA-TAG across the gastrointestinal tract was simulated using an in vitro digestion model. The results showed that the maximum release of free fatty acids and apparent rate constants were 71.44% and 0.0347 s(-1), respectively, for POA-TAG lipids, and the physical and structural characteristics during digestion depended on their microenvironments. These findings provide a theoretical basis for studying the rational design of POA-structural lipids and exploring the nutritional and functional benefits of POA products.
ESTHER : Ge_2024_J.Agric.Food.Chem__
PubMedSearch : Ge_2024_J.Agric.Food.Chem__
PubMedID: 38564481

Title : Regulation of NLGN3 and the synaptic Rho-GEF signaling pathway by CDK5 - Jeong_2023_J.Neurosci__
Author(s) : Jeong J , Han W , Hong E , Pandey S , Li Y , Lu W , Roche KW
Ref : Journal of Neuroscience , : , 2023
Abstract : Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that are involved in synapse assembly and function. The NLGN gene family consists of 5 genes (NLGN1-3, 4X, and 4Y). NLGN3 forms heterodimers with other NLGNs and is expressed at both excitatory and inhibitory synapses, although the distinct role at different synapses is not fully understood. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase that targets various neuronal substrates to impact neuronal migration, neurite outgrowth, synaptic transmission, and plasticity. Both NLGNs and their presynaptic binding partners neurexins are highly associated with neurodevelopmental disorders. The NLGN3 gene is on the X chromosome and variants in NLGN3 have been linked to the pathophysiology in neurodevelopmental disorders. To better understand the endogenous modulation of NLGN3, we generated an HA-tagged knock-in (KI) mouse. We found that Cdk5 associates with NLGN3 in vivo and phosphorylates NLGN3 on serine 725 (S725) in the KI mouse of either sex. The phosphorylation affects the NLGN3 association with Kalirin-7, a postsynaptic guanine nucleotide exchange factors (GEFs) for Rho GTPase family proteins. We further observed that the phosphorylation modulates NLGN3 surface expression and NLGN3-mediated synaptic currents in cultured rat neurons. Thus, we characterized NLGN3 as a novel Cdk5 substrate and revealed the functional consequences of NLGN3 S725 phosphorylation in neurons. Our study provides a novel molecular mechanism underlying Cdk5-mediated regulation of postsynaptic cell adhesion molecules.Significance StatementNLGN3 is involved in synapse assembly and function at both excitatory and inhibitory synapses and has been associated with the pathophysiology of neurodevelopmental disorders. Cdk5 has a brain-specific activity and involved in neuronal transmission, synapse function and plasticity. Here, we characterize NLGN3 as a Cdk5 substrate for the first time and show Cdk5-mediated phosphorylation regulates NLGN3 function. We demonstrate NLGN3 S725 is a Cdk5 phosphorylation site and reveal the site is important for NLGN3 association with Kalirin-7, NLGN3 surface expression, and NLGN3-mediated synaptic transmission.
ESTHER : Jeong_2023_J.Neurosci__
PubMedSearch : Jeong_2023_J.Neurosci__
PubMedID: 37699715

Title : Preparation, structural properties, and in vitro and in vivo activities of peptides against dipeptidyl peptidase IV (DPP-IV) and alpha-glucosidase: a general review - Mu_2023_Crit.Rev.Food.Sci.Nutr__1
Author(s) : Mu X , Wang R , Cheng C , Ma Y , Zhang Y , Lu W
Ref : Crit Rev Food Sci Nutr , :1 , 2023
Abstract : Diabetes is one of the fastest-growing and most widespread diseases worldwide. Approximately 90% of diabetic patients have type 2 diabetes. In 2019, there were about 463 million diabetic patients worldwide. Inhibiting the dipeptidyl peptidase IV (DPP-IV) and alpha-glucosidase activity is an effective strategy for the treatment of type 2 diabetes. Currently, various anti-diabetic bioactive peptides have been isolated and identified. This review summarizes the preparation methods, structure-effect relationships, molecular binding sites, and effectiveness validation of DPP-IV and alpha-glucosidase inhibitory peptides in cellular and animal models. The analysis of peptides shows that the DPP-IV inhibitory peptides, containing 2-8 amino acids and having proline, leucine, and valine at their N-terminal and C-terminal, are the highly active peptides. The more active alpha-glucosidase inhibitory peptides contain 2-9 amino acids and have valine, isoleucine, and proline at the N-terminal and proline, alanine, and serine at the C-terminal.
ESTHER : Mu_2023_Crit.Rev.Food.Sci.Nutr__1
PubMedSearch : Mu_2023_Crit.Rev.Food.Sci.Nutr__1
PubMedID: 37310013

Title : Molecular mechanisms by which targeted muscle reinnervation improves the microenvironment of spinal cord motor neurons and target muscles - Lu_2022_Neurosci.Lett_789_136879
Author(s) : Lu W , Jiang Z , Tang C , Wang P , Yang L
Ref : Neuroscience Letters , 789 :136879 , 2022
Abstract : Targeted muscle reinnervation is a clinically valuable nerve transfers technology used to reconstruct the information sources reconstruct the motor nerve information sources lost because of nerve injury. This study aimed to investigate the effects and underlying molecular mechanisms of hind limb TMR on motor neurons and target muscles in rats after tibial nerve transection (TNT). Immunohistochemistry was performed to detect acetylcholinesterase expression in the target muscles and myelin basic protein, neuregulin-1 (NRG1), and ErbB2 expression in the tibial nerve of rats. Masson's trichrome staining was performed to observe fibrillar collagen expression in the target muscles. Western blot analysis was used to detect the protein expression of NRG1 and its receptor, ErbB2, in the target muscles. TMR significantly enhanced NRG1, ErbB2, and myelin basic protein expression in nerve fibers compared with those in the TNT group and exerted a protective effect on the maintenance of a large number of nerve fibers and myelin sheath thickness. The above results indicated that TMR can regulate NRG1 and ErbB2 expression in residual nerve fibers and protect the integrity of the myelin sheath, thus improving the functional status of the target muscles, which is beneficial for restoring hind limb motor function after TNT.
ESTHER : Lu_2022_Neurosci.Lett_789_136879
PubMedSearch : Lu_2022_Neurosci.Lett_789_136879
PubMedID: 36152746

Title : Pathogenicity of Beauveria bassiana PfBb and Immune Responses of a Non-Target Host, Spodoptera frugiperda (Lepidoptera: Noctuidae) - Gao_2022_Insects_13_
Author(s) : Gao YP , Luo M , Wang XY , He XZ , Lu W , Zheng XL
Ref : Insects , 13 : , 2022
Abstract : Exploring the pathogenicity of a new fungus strain to non-target host pests can provide essential information on a large scale for potential application in pest control. In this study, we tested the pathogenicity of Beauveria bassiana PfBb on the important agricultural pest Spodoptera frugiperda (Lepidoptera: Noctuidae) by determining the relative activities of protective enzymes and detoxifying enzymes in different larval instars. Our results show that the B. bassiana PfBb strain could infect all six larval instars of S. frugiperda, and its virulence to S. frugiperda larvae gradually increased with an increase in spore concentration. Seven days after inoculation, the LC(50) of B. bassiana PfBb was 7.7 x 10(5), 5.5 x 10(6), 2.2 x 10(7), 3.1 x 10(8), 9.6 x 10(8), and 2.5 x 10(11) spores/mL for first to sixth instars of S. frugiperda, respectively, and the LC(50) and LC(90) of B. bassiana PfBb for each S. frugiperda instar decreased with infection time, indicating a significant dose effect. Furthermore, the virulence of B. bassiana PfBb to S. frugiperda larvae gradually decreased with an increase in larval instar. The activities of protective enzymes (i.e., catalase, peroxidase, and superoxide dismutase) and detoxifying enzymes (i.e., glutathione S-transferases, carboxylesterase, and cytochrome P450) in S. frugiperda larvae of the first three instars infected with B. bassiana PfBb changed significantly with infection time, but such variations were not obvious in the fifth and sixth instars. Additionally, after being infected with B. bassiana PfBb, the activities of protective enzymes and detoxification enzymes in S. frugiperda larvae usually lasted from 12 to 48 h, which was significantly longer than the control. These results indicate that the pathogenicity of B. bassiana PfBb on the non-target host S. frugiperda was significant but depended on the instar stage. Therefore, the findings of this study suggest that B. bassiana PfBb can be used as a bio-insecticide to control young larvae of S. frugiperda in an integrated pest management program.
ESTHER : Gao_2022_Insects_13_
PubMedSearch : Gao_2022_Insects_13_
PubMedID: 36292862

Title : Highly Potent and Selective Butyrylcholinesterase Inhibitors for Cognitive Improvement and Neuroprotection - Li_2021_J.Med.Chem__
Author(s) : Li Q , Chen Y , Xing S , Liao Q , Xiong B , Wang Y , Lu W , He S , Feng F , Liu W , Sun H
Ref : Journal of Medicinal Chemistry , : , 2021
Abstract : Butyrylcholinesterase (BChE) has been considered as a potential therapeutic target for Alzheimer's disease (AD) because of its compensation capacity to hydrolyze acetylcholine (ACh) and its close association with Abeta deposit. Here, we identified S06-1011 (hBChE IC(50) = 16 nM) and S06-1031 (hBChE IC(50) = 25 nM) as highly effective and selective BChE inhibitors, which were proved to be safe and long-acting. Candidate compounds exhibited neuroprotective effects and the ability to improve cognition in scopolamine- and Abeta(1-42) peptide-induced cognitive deficit models. The best candidate S06-1011 increased the level of ghrelin, a substrate of BChE, which can function as improving the mental mood appetite. The weight gain of the S06-1011-treated group remarkably increased. Hence, BChE inhibition not only plays a protective role against dementia but also exerts a great effect on treating and nursing care.
ESTHER : Li_2021_J.Med.Chem__
PubMedSearch : Li_2021_J.Med.Chem__
PubMedID: 33973470

Title : Synthesis and bio-evaluation of a novel selective butyrylcholinesterase inhibitor discovered through structure-based virtual screening - Xing_2021_Int.J.Biol.Macromol_166_1352
Author(s) : Xing S , Chen Y , Xiong B , Lu W , Li Q , Wang Y , Jiao M , Feng F , Liu W , Sun H
Ref : Int J Biol Macromol , 166 :1352 , 2021
Abstract : In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using Schrodinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513-4169 displayed the highest inhibitory activity and selectivity against BChE (eeAChE IC(50) > 10 microM, eqBChE IC(50) = 3.73 +/- 1.90 microM). Molecular dynamic (MD) simulation validated the binding pattern of 2513-4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513-4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513-4169 against toxic Abeta(1)(-)(42). In vivo behavioral study further confirmed the great efficacy of 2513-4169 on reversing Abeta(1)(-)(42)-induced cognitive impairment of mice and clearing the toxic Abeta(1)(-)(42) in brains. Moreover, 2513-4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513-4169 is a promising lead compound for future optimization to discover anti-AD treating agents.
ESTHER : Xing_2021_Int.J.Biol.Macromol_166_1352
PubMedSearch : Xing_2021_Int.J.Biol.Macromol_166_1352
PubMedID: 33161083

Title : Structural Insights into Notum Covalent Inhibition - Zhao_2021_J.Med.Chem_64_11354
Author(s) : Zhao Y , Svensson F , Steadman D , Frew S , Monaghan A , Bictash M , Moreira T , Chalk R , Lu W , Fish PV , Jones EY
Ref : Journal of Medicinal Chemistry , 64 :11354 , 2021
Abstract : The carboxylesterase Notum hydrolyzes a palmitoleate moiety from Wingless/Integrated(Wnt) ligands and deactivates Wnt signaling. Notum inhibitors can restore Wnt signaling which may be of therapeutic benefit for pathologies such as osteoporosis and Alzheimer's disease. We report the identification of a novel class of covalent Notum inhibitors, 4-(indolin-1-yl)-4-oxobutanoate esters. High-resolution crystal structures of the Notum inhibitor complexes reveal a common covalent adduct formed between the nucleophile serine-232 and hydrolyzed butyric esters. The covalent interaction in solution was confirmed by mass spectrometry analysis. Inhibitory potencies vary depending on the warheads used. Mechanistically, the resulting acyl-enzyme intermediate carbonyl atom is positioned at an unfavorable angle for the approach of the active site water, which, combined with strong hydrophobic interactions with the enzyme pocket residues, hinders the intermediate from being further processed and results in covalent inhibition. These insights into Notum catalytic inhibition may guide development of more potent Notum inhibitors.
ESTHER : Zhao_2021_J.Med.Chem_64_11354
PubMedSearch : Zhao_2021_J.Med.Chem_64_11354
PubMedID: 34292747
Gene_locus related to this paper: human-NOTUM

Title : A Cluster of Autism-Associated Variants on X-Linked NLGN4X Functionally Resemble NLGN4Y - Nguyen_2020_Neuron_106_759
Author(s) : Nguyen TA , Wu K , Pandey S , Lehr AW , Li Y , Bemben MA , Badger JD, 2nd , Lauzon JL , Wang T , Zaghloul KA , Thurm A , Jain M , Lu W , Roche KW
Ref : Neuron , 106 :759 , 2020
Abstract : Autism spectrum disorder (ASD) is more prevalent in males; however, the etiology for this sex bias is not well understood. Many mutations on X-linked cell adhesion molecule NLGN4X result in ASD or intellectual disability. NLGN4X is part of an X-Y pair, with NLGN4Y sharing approximately 97% sequence homology. Using biochemistry, electrophysiology, and imaging, we show that NLGN4Y displays severe deficits in maturation, surface expression, and synaptogenesis regulated by one amino acid difference with NLGN4X. Furthermore, we identify a cluster of ASD-associated mutations surrounding the critical amino acid in NLGN4X, and these mutations phenocopy NLGN4Y. We show that NLGN4Y cannot compensate for the functional deficits observed in ASD-associated NLGN4X mutations. Altogether, our data reveal a potential pathogenic mechanism for male bias in NLGN4X-associated ASD.
ESTHER : Nguyen_2020_Neuron_106_759
PubMedSearch : Nguyen_2020_Neuron_106_759
PubMedID: 32243781
Gene_locus related to this paper: human-NLGN4X

Title : Identification, characterization and expression analyses of cholinesterases genes in Yesso scallop (Patinopecten yessoensis) reveal molecular function allocation in responses to ocean acidification - Xing_2020_Aquat.Toxicol_231_105736
Author(s) : Xing Q , Liao H , Peng C , Zheng G , Yang Z , Wang J , Lu W , Huang X , Bao Z
Ref : Aquat Toxicol , 231 :105736 , 2020
Abstract : Cholinesterases are key enzymes in central and peripheral cholinergic nerve system functioning on nerve impulse transmission in animals. Though cholinesterases have been identified in most vertebrates, the knowledge about the variable numbers and multiple functions of the genes is still quite meagre in invertebrates, especially in scallops. In this study, the complete cholinesterase (ChE) family members have been systematically characterized in Yesso scallop (Patinopecten yessoensis) via whole-genome scanning through in silico analysis. Ten ChE family members in the genome of Yesso scallop (designated PyChEs) were identified and potentially acted to be the largest number of ChE in the reported species to date. Phylogenetic and protein structural analyses were performed to determine the identities and evolutionary relationships of these genes. The expression profiles of PyChEs were determined in all developmental stages, in healthy adult tissues, and in mantles under low pH stress (pH 6.5 and 7.5). Spatiotemporal expression suggested the ubiquitous functional roles of PyChEs in all stages of development, as well as general and tissue-specific functions in scallop tissues. Regulation expressions revealed diverse up- and down-regulated expression patterns at most time points, suggesting different functional specialization of gene superfamily members in response to ocean acidification (OA). Evidences in gene number, phylogenetic relationships and expression patterns of PyChEs revealed that functional innovations and differentiations after gene duplication may result in altered functional constraints among PyChEs gene clusters. Collectively, our results provide the potential clues that the selection pressures coming from the environment were the potential inducement leading to function allocation of ChE family members in scallop.
ESTHER : Xing_2020_Aquat.Toxicol_231_105736
PubMedSearch : Xing_2020_Aquat.Toxicol_231_105736
PubMedID: 33422860
Gene_locus related to this paper: mizye-a0a210qls6 , mizye-a0a210qis3 , mizye-a0a210qg00 , mizye-a0a210r5n9 , mizye-a0a210qbv2 , mizye-a0a210pu25 , mizye-a0a210ptr6 , mizye-a0a210ptv1 , mizye-a0a210ptq0 , mizye-P021348901.2

Title : Discovery and Biological Evaluation of a Novel Highly Potent Selective Butyrylcholinsterase Inhibitor - Li_2020_J.Med.Chem_63_10030
Author(s) : Li Q , Xing S , Chen Y , Liao Q , Xiong B , He S , Lu W , Liu Y , Yang H , Feng F , Liu W , Sun H
Ref : Journal of Medicinal Chemistry , 63 :10030 , 2020
Abstract : To discover novel BChE inhibitors, a hierarchical virtual screening protocol followed by biochemical evaluation was applied. The most potent compound 8012-9656 (eqBChE IC(50) = 0.18 +/- 0.03 M, hBChE IC(50) = 0.32 +/- 0.07 M) was purchased and synthesized. It inhibited BChE in a noncompetitive manner and could occupy the binding pocket forming diverse interactions with the target. 8012-9656 was proven to be safe in vivo and in vitro and showed comparable performance in ameliorating the scopolamine-induced cognition impairment to tacrine. Additionally, treatment with 8012-9656 could almost entirely recover the Abeta(1-42) (icv)-impaired cognitive function to the normal level and showed better behavioral performance than donepezil. The evaluation of the Abeta(1-42) total amount confirmed its anti-amyloidogenic profile. Moreover, 8012-9656 possessed blood-brain barrier (BBB) penetrating ability, a long T(1/2), and low intrinsic clearance. Hence, the novel potential BChE inhibitor 8012-9656 can be considered as a promising lead compound for further investigation of anti-AD agents.
ESTHER : Li_2020_J.Med.Chem_63_10030
PubMedSearch : Li_2020_J.Med.Chem_63_10030
PubMedID: 32787113

Title : Caffeine inhibits Notum activity by binding at the catalytic pocket - Zhao_2020_Commun.Biol_3_555
Author(s) : Zhao Y , Ren J , Hillier J , Lu W , Jones EY
Ref : Commun Biol , 3 :555 , 2020
Abstract : Notum inhibits Wnt signalling via enzymatic delipidation of Wnt ligands. Restoration of Wnt signalling by small molecule inhibition of Notum may be of therapeutic benefit in a number of pathologies including Alzheimer's disease. Here we report Notum activity can be inhibited by caffeine (IC(50) 19 microM), but not by demethylated caffeine metabolites: paraxanthine, theobromine and theophylline. Cellular luciferase assays show Notum-suppressed Wnt3a function can be restored by caffeine with an EC(50) of 46 microM. The dissociation constant (K(d)) between Notum and caffeine is 85 microM as measured by surface plasmon resonance. High-resolution crystal structures of Notum complexes with caffeine and its minor metabolite theophylline show both compounds bind at the centre of the enzymatic pocket, overlapping the position of the natural substrate palmitoleic lipid, but using different binding modes. The structural information reported here may be of relevance for the design of more potent brain-accessible Notum inhibitors.
ESTHER : Zhao_2020_Commun.Biol_3_555
PubMedSearch : Zhao_2020_Commun.Biol_3_555
PubMedID: 33033363
Gene_locus related to this paper: human-NOTUM

Title : Gamma-glutamyl transpeptidase to cholinesterase and platelet ratio in predicting significant liver fibrosis and cirrhosis of chronic hepatitis B - Liu_2019_Clin.Microbiol.Infect_25_514 e1
Author(s) : Liu D , Li J , Lu W , Wang Y , Zhou X , Huang D , Li X , Ding R , Zhang Z
Ref : Clin Microbiol Infect , 25 :514 e1 , 2019
Abstract : OBJECTIVES: To evaluate the performance of a new mathematical model gamma-glutamyl transpeptidase to cholinesterase and platelet ratio (GCPR) versus gamma-glutamyl transpeptidase to platelet ratio (GPR) in predicting significant fibrosis and cirrhosis of chronic hepatitis B. METHODS: A complete cohort of 2343 patients was divided into early and late cohort depending on the time of liver biopsy. With reference to the Scheuer standard, liver pathologic stage 2 or higher and stage 4 or higher were defined as significant fibrosis and cirrhosis, respectively. Receiver operating characteristic (ROC) curve was used to evaluate the performance of investigated models. RESULTS: In the early cohort, the areas under ROC curves (AUROCs) of GCPR in predicting significant fibrosis of hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients (0.782 and 0.775) were both significantly greater than those of GPR (0.748 and 0.747) (Z = 8.198 and Z = 6.023, both p <0.0001); the AUROCs of GCPR in predicting cirrhosis of HBeAg-positive and HBeAg-negative patients (0.842 and 0.861) were both significantly greater than those of GPR (0.802 and 0.823) (Z = 6.686 and Z = 6.116, both p <0.0001). In early, late and complete cohorts, using a single cutoff of GCPR > 0.080, the specificities of GCPR in predicting significant fibrosis of HBeAg-positive patients were 83.3%, 88.2% and 85.0% and of HBeAg-negative patients were 87.6%, 87.4% and 87.6%, respectively; and the sensitivities of GCPR in predicting cirrhosis of HBeAg-positive patients were 81.9%, 88.7% and 84.2% and of HBeAg-negative patients were 83.1%, 82.1% and 82.7%, respectively. CONCLUSIONS: GCPR has higher performance than GPR in predicting significant fibrosis and cirrhosis of chronic hepatitis B.
ESTHER : Liu_2019_Clin.Microbiol.Infect_25_514 e1
PubMedSearch : Liu_2019_Clin.Microbiol.Infect_25_514 e1
PubMedID: 29906588

Title : Structural characterisation of melatonin as an inhibitor of the Wnt deacylase Notum - Zhao_2019_J.Pineal.Res__e12630
Author(s) : Zhao Y , Ren J , Hillier J , Jones M , Lu W , Jones EY
Ref : J Pineal Res , :e12630 , 2019
Abstract : The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/beta-catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N-[2-(5-fluoro-1H-indol-3-yl)ethyl]acetamide that is structurally similar to melatonin, came to our attention. We then soaked melatonin and its precursor N-acetylserotonin into Notum crystals and obtained high resolution structures (<= 1.5 A) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme's catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid; and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 microM), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer's disease, in which up-regulation of Wnt signalling may be beneficial.
ESTHER : Zhao_2019_J.Pineal.Res__e12630
PubMedSearch : Zhao_2019_J.Pineal.Res__e12630
PubMedID: 31876313
Gene_locus related to this paper: human-NOTUM

Title : A Conserved Tyrosine Residue in Slitrk3 Carboxyl-Terminus Is Critical for GABAergic Synapse Development - Li_2019_Front.Mol.Neurosci_12_213
Author(s) : Li J , Han W , Wu K , Li YD , Liu Q , Lu W
Ref : Front Mol Neurosci , 12 :213 , 2019
Abstract : Single-passing transmembrane protein, Slitrk3 (Slit and Trk-like family member 3, ST3), is a synaptic cell adhesion molecule highly expressed at inhibitory synapses. Recent studies have shown that ST3, through its extracellular domain, selectively regulates inhibitory synapse development via the trans-synaptic interaction with presynaptic cell adhesion molecule, receptor protein tyrosine phosphatase delta (PTPdelta) and the cis-interaction with postsynaptic cell adhesion molecule, Neuroligin 2 (NL2). However, little is known about the physiological function of ST3 intracellular, carboxyl (C)-terminal region. Here we report that in heterologous cells, ST3 C-terminus is not required for ST3 homo-dimerization and trafficking to the cell surface. In contrast, in hippocampal neurons, ST3 C-terminus, more specifically, the conserved tyrosine Y969 (in mice), is critical for GABAergic synapse development. Indeed, overexpression of ST3 Y969A mutant markedly reduced the gephyrin puncta density and GABAergic transmission in hippocampal neurons. In addition, single-cell genetic deletion of ST3 strongly impaired GABAergic transmission. Importantly, wild-type (WT) ST3, but not the ST3 Y969A mutant, could fully rescue GABAergic transmission deficits in neurons lacking endogenous ST3, confirming a critical role of Y969 in the regulation of inhibitory synapses. Taken together, our data identify a single critical residue in ST3 C-terminus that is important for GABAergic synapse development and function.
ESTHER : Li_2019_Front.Mol.Neurosci_12_213
PubMedSearch : Li_2019_Front.Mol.Neurosci_12_213
PubMedID: 31551708

Title : De novo transcriptomic analysis of the alimentary tract of the tephritid gall fly, Procecidochares utilis - Li_2018_PLoS.One_13_e0201679
Author(s) : Li L , Lan M , Lu W , Li Z , Xia T , Zhu J , Ye M , Gao X , Wu G
Ref : PLoS ONE , 13 :e0201679 , 2018
Abstract : The tephritid gall fly, Procecidochares utilis, is an important obligate parasitic insect of the malignant weed Eupatorium adenophorum which biosynthesizes toxic secondary metabolites. Insect alimentary tracts secrete several enzymes that are used for detoxification, including cytochrome P450s, glutathione S-transferases, and carboxylesterases. To explore the adaptation of P. utilis to its toxic host plant, E. adenophorum at molecular level, we sequenced the transcriptome of the alimentary tract of P. utilis using Illumina sequencing. Sequencing and de novo assembly yielded 62,443 high-quality contigs with an average length of 604 bp that were further assembled into 45,985 unigenes with an average length of 674 bp and an N50 of 983 bp. Among the unigenes, 30,430 (66.17%) were annotated by alignment against the NCBI non-redundant protein (Nr) database, while 16,700 (36.32%), 16,267 (35.37%), and 11,530 (25.07%) were assigned functions using the Clusters of Orthologous Groups (COG), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Ontology (GO) databases, respectively. Using the comprehensive transcriptome data set, we manually identified several important gene families likely to be involved in the detoxification of toxic compounds including 21 unigenes within the glutathione S-transferase (GST) family, 22 unigenes within the cytochrome P450 (P450) family, and 16 unigenes within the carboxylesterase (CarE) family. Quantitative PCR was used to verify eight, six, and two genes of GSTs, P450s, and CarEs, respectively, in different P. utilis tissues and at different developmental stages. The detoxification enzyme genes were mainly expressed in the foregut and midgut. Moreover, the unigenes were higher expressed in the larvae, pupae, and 3-day adults, while they were expressed at lower levels in eggs. These transcriptomic data provide a valuable molecular resource for better understanding the function of the P. utilis alimentary canal. These identified genes could be pinpoints to address the molecular mechanisms of P. utilis interacting with toxic plant host.
ESTHER : Li_2018_PLoS.One_13_e0201679
PubMedSearch : Li_2018_PLoS.One_13_e0201679
PubMedID: 30138350

Title : Scallop genome provides insights into evolution of bilaterian karyotype and development - Wang_2017_Nat.Ecol.Evol_1_120
Author(s) : Wang S , Zhang J , Jiao W , Li J , Xun X , Sun Y , Guo X , Huan P , Dong B , Zhang L , Hu X , Sun X , Wang J , Zhao C , Wang Y , Wang D , Huang X , Wang R , Lv J , Li Y , Zhang Z , Liu B , Lu W , Hui Y , Liang J , Zhou Z , Hou R , Li X , Liu Y , Li H , Ning X , Lin Y , Zhao L , Xing Q , Dou J , Mao J , Guo H , Dou H , Li T , Mu C , Jiang W , Fu Q , Fu X , Miao Y , Liu J , Yu Q , Li R , Liao H , Kong Y , Jiang Z , Chourrout D , Bao Z
Ref : Nat Ecol Evol , 1 :120 , 2017
Abstract : Reconstructing the genomes of bilaterian ancestors is central to our understanding of animal evolution, where knowledge from ancient and/or slow-evolving bilaterian lineages is critical. Here we report a high-quality, chromosome-anchored reference genome for the scallop Patinopecten yessoensis, a bivalve mollusc that has a slow-evolving genome with many ancestral features. Chromosome-based macrosynteny analysis reveals a striking correspondence between the 19 scallop chromosomes and the 17 presumed ancestral bilaterian linkage groups at a level of conservation previously unseen, suggesting that the scallop may have a karyotype close to that of the bilaterian ancestor. Scallop Hox gene expression follows a new mode of subcluster temporal co-linearity that is possibly ancestral and may provide great potential in supporting diverse bilaterian body plans. Transcriptome analysis of scallop mantle eyes finds unexpected diversity in phototransduction cascades and a potentially ancient Pax2/5/8-dependent pathway for noncephalic eyes. The outstanding preservation of ancestral karyotype and developmental control makes the scallop genome a valuable resource for understanding early bilaterian evolution and biology.
ESTHER : Wang_2017_Nat.Ecol.Evol_1_120
PubMedSearch : Wang_2017_Nat.Ecol.Evol_1_120
PubMedID: 28812685
Gene_locus related to this paper: mizye-a0a210qls6 , mizye-a0a210qis3 , mizye-a0a210qg00 , mizye-a0a210ped6 , mizye-a0a210q4h5 , mizye-a0a210q4h9 , mizye-a0a210q4j1 , mizye-a0a210qf86 , mizye-a0a210q332 , mizye-a0a210pqn0 , mizye-a0a210q7t5 , mizye-a0a210pij5 , mizye-a0a210qyk8 , mizye-a0a210pwl7 , mizye-a0a210q8u5 , mizye-a0a210r5n9 , mizye-a0a210qbv2 , mizye-a0a210pu25 , mizye-a0a210pek1 , mizye-a0a210pul3 , mizye-a0a210pum3 , mizye-a0a210ptr6 , mizye-a0a210ptq5 , mizye-a0a210ptc4.1 , mizye-a0a210ptc4.2 , mizye-a0a210ptv1 , mizye-a0a210ptv7 , mizye-a0a210qgl6 , mizye-a0a210qg90 , mizye-a0a210ptq0 , mizye-a0a210qg72 , mizye-a0a210ptb1 , mizye-a0a210pjd3 , mizye-a0a210qg92 , mizye-a0a210q8v2 , mizye-a0a210qg93 , mizye-a0a210q160.1 , mizye-a0a210q160.2 , mizye-a0a210qes4 , mizye-a0a210pk25 , mizye-a0a210q1b8 , mizye-a0a210q110 , mizye-a0a210r503 , mizye-P021348901.1 , mizye-P021348901.2

Title : Molecular Dissection of Neuroligin 2 and Slitrk3 Reveals an Essential Framework for GABAergic Synapse Development - Li_2017_Neuron_96_808
Author(s) : Li J , Han W , Pelkey KA , Duan J , Mao X , Wang YX , Craig MT , Dong L , Petralia RS , McBain CJ , Lu W
Ref : Neuron , 96 :808 , 2017
Abstract : In the brain, many types of interneurons make functionally diverse inhibitory synapses onto principal neurons. Although numerous molecules have been identified to function in inhibitory synapse development, it remains unknown whether there is a unifying mechanism for development of diverse inhibitory synapses. Here we report a general molecular mechanism underlying hippocampal inhibitory synapse development. In developing neurons, the establishment of GABAergic transmission depends on Neuroligin 2 (NL2), a synaptic cell adhesion molecule (CAM). During maturation, inhibitory synapse development requires both NL2 and Slitrk3 (ST3), another CAM. Importantly, NL2 and ST3 interact with nanomolar affinity through their extracellular domains to synergistically promote synapse development. Selective perturbation of the NL2-ST3 interaction impairs inhibitory synapse development with consequent disruptions in hippocampal network activity and increased seizure susceptibility. Our findings reveal how unique postsynaptic CAMs work in concert to control synaptogenesis and establish a general framework for GABAergic synapse development.
ESTHER : Li_2017_Neuron_96_808
PubMedSearch : Li_2017_Neuron_96_808
PubMedID: 29107521

Title : Downregulated expression of microRNA-124 in pediatric intestinal failure patients modulates macrophages activation by inhibiting STAT3 and AChE - Xiao_2016_Cell.Death.Dis_7_e2521
Author(s) : Xiao YT , Wang J , Lu W , Cao Y , Cai W
Ref : Cell Death Dis , 7 :e2521 , 2016
Abstract : Intestinal inflammation plays a critical role in the pathogenesis of intestinal failure (IF). The macrophages are essential to maintain the intestinal homeostasis. However, the underlying mechanisms of intestinal macrophages activation remain poorly understood. Since microRNAs (miRNAs) have pivotal roles in regulation of immune responses, here we aimed to investigate the role of miR-124 in the activation of intestinal macrophages. In this study, we showed that the intestinal macrophages increased in pediatric IF patients and resulted in the induction of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). The miRNA fluorescence in situ hybridization analysis showed that the expression of miR-124 significantly reduced in intestinal macrophages in IF patients. Overexpression of miR-124 was sufficient to inhibit intestinal macrophages activation by attenuating production of IL-6 and TNF-alpha. Further studies showed that miR-124 could directly target the 3'-untranslated region of both signal transducer and activator of transcription 3 (STAT3) and acetylcholinesterase (AChE) mRNAs, and suppress their protein expressions. The AChE potentially negates the cholinergic anti-inflammatory signal by hydrolyzing the acetylcholine. We here showed that intestinal macrophages increasingly expressed the AChE and STAT3 in IF patients when compared with controls. The inhibitors against to STAT3 and AChE significantly suppressed the lipopolysaccharides-induced IL-6 and TNF-alpha production in macrophages. Taken together, these findings highlight an important role for miR-124 in the regulation of intestinal macrophages activation, and suggest a potential application of miR-124 in pediatric IF treatment regarding as suppressing intestinal inflammation.
ESTHER : Xiao_2016_Cell.Death.Dis_7_e2521
PubMedSearch : Xiao_2016_Cell.Death.Dis_7_e2521
PubMedID: 27977009

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

Title : Functionalized photonic crystal for the sensing of Sarin agents - Yan_2016_Talanta_159_412
Author(s) : Yan C , Qi F , Li S , Xu J , Liu C , Meng Z , Qiu L , Xue M , Lu W , Yan Z
Ref : Talanta , 159 :412 , 2016
Abstract : The indiscriminate use of nerve agents by terrorist groups has attracted attention of the scientific communities toward the development of novel sensor technique for these deadly chemicals. A photonic crystal (PhC) hydrogel immobilized with butyrylcholinesterase (BuChE) was firstly prepared for the sensing of Sarin agents. Periodic polystyrene colloidal (240nm) array was embedded inside an acrylamide hydrogel, and then BuChE was immobilized inside the hydrogel matrix via condensation with 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3h)-one (DEPBT). It indicated that a total of 3.7 units of BuChE were immobilized onto the PhC hydrogel. The functionalized hydrogel recognized the Sarin agent and then shrunk, thus the diffraction of PhC hydrogel blue shifted significantly, and a limit of detection (LOD) of 10(-15)molL(-1) was achieved.
ESTHER : Yan_2016_Talanta_159_412
PubMedSearch : Yan_2016_Talanta_159_412
PubMedID: 27474325

Title : Detoxification of Organophosphate Poisoning Using Nanoparticle Bioscavengers - Pang_2015_ACS.Nano_9_6450
Author(s) : Pang Z , Hu CM , Fang RH , Luk BT , Gao W , Wang F , Chuluun E , Angsantikul P , Thamphiwatana S , Lu W , Jiang X , Zhang L
Ref : ACS Nano , 9 :6450 , 2015
Abstract : Organophosphate poisoning is highly lethal as organophosphates, which are commonly found in insecticides and nerve agents, cause irreversible phosphorylation and inactivation of acetylcholinesterase (AChE), leading to neuromuscular disorders via accumulation of acetylcholine in the body. Direct interception of organophosphates in the systemic circulation thus provides a desirable strategy in treatment of the condition. Inspired by the presence of AChE on red blood cell (RBC) membranes, we explored a biomimetic nanoparticle consisting of a polymeric core surrounded by RBC membranes to serve as an anti-organophosphate agent. Through in vitro studies, we demonstrated that the biomimetic nanoparticles retain the enzymatic activity of membrane-bound AChE and are able to bind to a model organophosphate, dichlorvos, precluding its inhibitory effect on other enzymatic substrates. In a mouse model of organophosphate poisoning, the nanoparticles were shown to improve the AChE activity in the blood and markedly improved the survival of dichlorvos-challenged mice.
ESTHER : Pang_2015_ACS.Nano_9_6450
PubMedSearch : Pang_2015_ACS.Nano_9_6450
PubMedID: 26053868

Title : Gender specific effect of LIPC C-514T polymorphism on obesity and relationship with plasma lipid levels in Chinese children - Wang_2015_J.Cell.Mol.Med_19_2296
Author(s) : Wang H , Zhang D , Ling J , Lu W , Zhang S , Zhu Y , Lai M
Ref : J Cell Mol Med , 19 :2296 , 2015
Abstract : Hepatic lipase (LIPC) is a key rate-limiting enzyme in lipoprotein catabolism pathways involved in the development of obesity. The C-514T polymorphism in the promoter region is associated with decreased LIPC activity. We performed a case-controlled study (850 obese children and 2119 controls) and evaluated the association between LIPC C-514T polymorphism, obesity and plasma lipid profile in Chinese children and adolescents. Additionally, we conducted a meta-analysis of all results from published studies as well as our own data. A significant association between the polymorphism and obesity is observed in boys (P = 0.042), but not in girls. And we observed a significant relationship of the polymorphism with total cholesterol (TC) and high density lipoprotein cholesterol (HDL-C) independent of obesity in boys. The T allele carriers have higher levels of low density lipoprotein cholesterol (LDL-C) in obese boys, and triglyceride (TG), TC and LDL-C in non-obese girls (all P < 0.05). In the meta-analysis, under dominant model the T allele increased body mass index (BMI) level in boys, while it decreased BMI in girls, and increased the levels of TC both in the overall and subgroups, TG and HDL-C in the overall and boys, and LDL-C in the overall (all P < 0.05). Our results suggest that the T allele might carry an increased risk of obesity in Chinese boys. The meta-analysis suggests that T allele acts as a risk allele for higher BMI levels in male childhood, while it is a protective allele in female childhood. And the polymorphism is associated with the levels of plasma lipids, which may be modulated by obesity and gender.
ESTHER : Wang_2015_J.Cell.Mol.Med_19_2296
PubMedSearch : Wang_2015_J.Cell.Mol.Med_19_2296
PubMedID: 26282880

Title : Preoperative risk factors for prolonged postoperative ventilation following thymectomy in myasthenia gravis - Lu_2015_Int.J.Clin.Exp.Med_8_13990
Author(s) : Lu W , Yu T , Longhini F , Jiang X , Qin X , Jin X
Ref : Int J Clin Exp Med , 8 :13990 , 2015
Abstract : Adequate preoperative evaluation and preparation for surgery are required to prevent prolonged mechanical ventilation after thymectomy, and facilitate the recovery of patients with myasthenia gravis (MG). The objective of this study was to identify the preoperative risk factors for extubation failure after thymectomy in patients with MG.
METHODS: A retrospective study was conducted on 61 patients with MG who underwent extended thymectomy. Several factors were evaluated including patients' demographic data, preoperative medical therapies, medical history, and comorbidities. Multivariate logistic regression analysis was used to identify the predictors of late extubation after thymectomy for MG.
RESULTS: Fourteen patients (22.95%) required breathing support after anesthesia or endotracheal re-intubation within 48 h. Univariate analysis illustrated that the quantitative MG (QMG) grade (odds ratio [OR] = 1.368, P = 0.000), preoperative muscle strength (OR = 0.279, P = 0.000), use of pyridostigmine (OR = 1.011, P = 0.024) and prednisone (OR = 1.059, P = 0.022), preoperative lung function (OR = 4.875, P = 0.016), low preoperative cholinesterase levels (OR = 0.999, P = 0.014), impaired preoperative swallowing muscle activity (OR = 7.619, P = 0.003), and positivity for acetylcholine receptor antibodies (OR = 14.143, P = 0.001) were significant predictors of prolonged postoperative intubation. Multivariate logistic regression analysis revealed that the QMG score (OR = 3.408, P = 0.000) and Myasthenia Gravis Foundation of America (MGFA) classification (OR = 28.683, P = 0.002) were independent risk factors for prolonged postoperative intubation. CONCLUSION: The preoperative MGFA clinical classification and QMG score were independent risk factors for prolonged postoperative intubation in patients with MG.
ESTHER : Lu_2015_Int.J.Clin.Exp.Med_8_13990
PubMedSearch : Lu_2015_Int.J.Clin.Exp.Med_8_13990
PubMedID: 26550357

Title : Arterial baroreflex dysfunction impairs ischemia-induced angiogenesis - Hao_2014_J.Am.Heart.Assoc_3_e000804
Author(s) : Hao C , Huang ZH , Song SW , Shi YQ , Cheng XW , Murohara T , Lu W , Su DF , Duan JL
Ref : J Am Heart Assoc , 3 :e000804 , 2014
Abstract : BACKGROUND: Endothelium-derived acetylcholine (eACh) plays an important role in the regulation of vascular actions in response to hypoxia, whereas arterial baroreflex (ABR) dysfunction impairs the eACh system. We investigated the effects of ABR dysfunction on ischemia-induced angiogenesis in animal models of hindlimb ischemia with a special focus on eACh/nicotinic ACh receptor (nAChR) signaling activation. METHODS AND
RESULTS: Male Sprague-Dawley rats were randomly assigned to 1 of 3 groups that received (1) sham operation (control group), (2) sinoaortic denervation (SAD)-induced ABR dysfunction (SAD group), or (3) SAD rats on diet with an acetylcholinesterase inhibitor pyridostigmine (30 mg/kg per day, SAD+Pyr group). After 4 weeks of the SAD intervention, unilateral limb ischemia was surgically induced in all animals. At postoperative day 14, SAD rats exhibited impaired angiogenic action (skin temperature and capillary density) and decreased angiogenic factor expressions (vascular endothelial growth factor [VEGF] and hypoxic inducible factor [HIF]-1alpha) in ischemic muscles. These changes were restored by acetylcholinesterase inhibition. Rats with ABR dysfunction had lower eACh levels than did control rats, and this effect was recovered in SAD+Pyr rats. In alpha7-nAChR knockout mice, pyridostigmine improved ischemia-induced angiogenic responses and increased the levels of VEGF and HIF-1alpha. Moreover, nicotinic receptor blocker inhibited VEGF expression and VEGF receptor 2 phosphorylation (p-VEGFR2) induced by ACh analog.
CONCLUSIONS: Thus, ABR dysfunction appears to impair ischemia-induced angiogenesis through the reduction of eACh/alpha7-nAChR-dependent and -independent HIF-1alpha/VEGF-VEGFR2 signaling activation.
ESTHER : Hao_2014_J.Am.Heart.Assoc_3_e000804
PubMedSearch : Hao_2014_J.Am.Heart.Assoc_3_e000804
PubMedID: 24820655

Title : Regulation of carboxylesterase-2 expression by p53 family proteins and enhanced anti-cancer activities among 5-fluorouracil, irinotecan and doxazolidine prodrug - Xiao_2013_Br.J.Pharmacol_168_1989
Author(s) : Xiao D , Yang D , Guo L , Lu W , Charpentier M , Yan B
Ref : British Journal of Pharmacology , 168 :1989 , 2013
Abstract : BACKGROUND AND PURPOSE: For four decades, 5-fluorouracil (5-FU) has been a major anti-cancer medicine. This drug is increasingly used with other anti-cancer agents such as irinotecan. Irinotecan and many others such as PPD (pentyl carbamate of p-aminobenzyl carbamate of doxazolidine) require activation by carboxylesterase-2 (CES2). 5-FU, on the other hand, reportedly induces CES2 in colorectal tumour lines. The aims of this study were to determine the molecular basis for the induction and to ascertain interactive cell-killing activity between 5-FU and ester prodrugs. EXPERIMENTAL APPROACH: Colorectal and non-colorectal lines and xenografts were treated with 5-FU and the expression of CES2 was determined. Cell-killing activity of irinotecan and PPD were determined in the presence or absence of CES2 inhibitor. Several molecular experiments were used to determine the molecular basis for the induction. KEY
RESULTS: Without exceptions, robust induction was detected in cell lines expressing functional p53. High-level induction was also detected in xenografts. 5-FU pretreatment significantly increased cell-killing activity of irinotecan and PPD. Molecular experiments established that the induction was achieved by both transactivation and increased mRNA stability through p53. Either p63 or p73, functionally related to p53, did not support the transactivation. CONCLUSIONS AND IMPLICATIONS: The results in this study suggest that FOLFIRI, a common regimen combining irinotecan and 5-FU, should switch the dosing sequence, namely from 5-FU to irinotecan, to enhance hydrolytic activation of irinotecan. This modified order likely reduces the dose of anti-cancer agents, thus minimizing overall toxicity. The results also conclude that p53 family members act differently in regulating gene expression.
ESTHER : Xiao_2013_Br.J.Pharmacol_168_1989
PubMedSearch : Xiao_2013_Br.J.Pharmacol_168_1989
PubMedID: 23373735

Title : The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells - Shi_2013_Hum.Mol.Genet_22_3749
Author(s) : Shi L , Chang X , Zhang P , Coba MP , Lu W , Wang K
Ref : Hum Mol Genet , 22 :3749 , 2013
Abstract : Genetic mutations in NLGN4X (neuroligin 4), including point mutations and copy number variants (CNVs), have been associated with susceptibility to autism spectrum disorders (ASDs). However, it is unclear how mutations in NLGN4X result in neurodevelopmental defects. Here, we used neural stem cells (NSCs) as in vitro models to explore the impacts of NLGN4X knockdown on neurodevelopment. Using two shRNAmir-based vectors targeting NLGN4X and one control shRNAmir vector, we modulated NLGN4X expression and differentiated these NSCs into mature neurons. We monitored the neurodevelopmental process at Weeks 0, 0.5, 1, 2, 4 and 6, based on morphological analysis and whole-genome gene expression profiling. At the cellular level, in NSCs with NLGN4X knockdown, we observed increasingly delayed neuronal development and compromised neurite formation, starting from Week 2 through Week 6 post differentiation. At the molecular level, we identified multiple pathways, such as neurogenesis, neuron differentiation and muscle development, which are increasingly disturbed in cells with NLGN4X knockdown. Notably, several postsynaptic genes, including DLG4, NLGN1 and NLGN3, also have decreased expression. Based on in vitro models, NLGN4X knockdown directly impacts neurodevelopmental process during the formation of neurons and their connections. Our functional genomics study highlights the utility of NSCs models in understanding the functional roles of CNVs in affecting neurodevelopment and conferring susceptibility to neurodevelopmental diseases.
ESTHER : Shi_2013_Hum.Mol.Genet_22_3749
PubMedSearch : Shi_2013_Hum.Mol.Genet_22_3749
PubMedID: 23710042

Title : Synthesis, structure-activity relationship, and pharmacophore modeling studies of pyrazole-3-carbohydrazone derivatives as dipeptidyl peptidase IV inhibitors - Wu_2012_Chem.Biol.Drug.Des_79_897
Author(s) : Wu D , Jin F , Lu W , Zhu J , Li C , Wang W , Tang Y , Jiang H , Huang J , Liu G , Li J
Ref : Chemical Biology Drug Des , 79 :897 , 2012
Abstract : Type 2 diabetes mellitus (T2DM) is a metabolic disease and a major challenge to healthcare systems around the world. Dipeptidyl peptidase IV (DPP-4), a serine protease, has been rapidly emerging as an effective therapeutic target for the treatment for T2DM. In this study, a series of novel DPP-4 inhibitors, featuring the pyrazole-3-carbohydrazone scaffold, have been discovered using an integrated approach of structure-based virtual screening, chemical synthesis, and bioassay. Virtual screening of SPECS Database, followed by enzymatic activity assay, resulted in five micromolar or low-to-mid-micromolar inhibitory level compounds (1-5) with different scaffold. Compound 1 was selected for the further structure modifications in considering inhibitory activity, structural variability, and synthetic accessibility. Seventeen new compounds were synthesized and tested with biological assays. Nine compounds (6e, 6g, 6k-l, and 7a-e) were found to show inhibitory effects against DPP-4. Molecular docking models give rational explanation about structure-activity relationships. Based on eight DPP-4 inhibitors (1-5, 6e, 6k, and 7d), the best pharmacophore model hypo1 was obtained, consisting of one hydrogen bond donor (HBD), one hydrogen bond acceptor (HBA), and two hydrophobic (HY) features. Both docking models and pharmacophore mapping results are in agreement with pharmacological results. The present studies give some guiding information for further structural optimization and are helpful for future DPP-4 inhibitors design.
ESTHER : Wu_2012_Chem.Biol.Drug.Des_79_897
PubMedSearch : Wu_2012_Chem.Biol.Drug.Des_79_897
PubMedID: 22381062

Title : Genome sequence and transcriptome analysis of the radioresistant bacterium Deinococcus gobiensis: insights into the extreme environmental adaptations - Yuan_2012_PLoS.One_7_e34458
Author(s) : Yuan M , Chen M , Zhang W , Lu W , Wang J , Yang M , Zhao P , Tang R , Li X , Hao Y , Zhou Z , Zhan Y , Yu H , Teng C , Yan Y , Ping S , Wang Y , Lin M
Ref : PLoS ONE , 7 :e34458 , 2012
Abstract : The desert is an excellent model for studying evolution under extreme environments. We present here the complete genome and ultraviolet (UV) radiation-induced transcriptome of Deinococcus gobiensis I-0, which was isolated from the cold Gobi desert and shows higher tolerance to gamma radiation and UV light than all other known microorganisms. Nearly half of the genes in the genome encode proteins of unknown function, suggesting that the extreme resistance phenotype may be attributed to unknown genes and pathways. D. gobiensis also contains a surprisingly large number of horizontally acquired genes and predicted mobile elements of different classes, which is indicative of adaptation to extreme environments through genomic plasticity. High-resolution RNA-Seq transcriptome analyses indicated that 30 regulatory proteins, including several well-known regulators and uncharacterized protein kinases, and 13 noncoding RNAs were induced immediately after UV irradiation. Particularly interesting is the UV irradiation induction of the phrB and recB genes involved in photoreactivation and recombinational repair, respectively. These proteins likely include key players in the immediate global transcriptional response to UV irradiation. Our results help to explain the exceptional ability of D. gobiensis to withstand environmental extremes of the Gobi desert, and highlight the metabolic features of this organism that have biotechnological potential.
ESTHER : Yuan_2012_PLoS.One_7_e34458
PubMedSearch : Yuan_2012_PLoS.One_7_e34458
PubMedID: 22470573
Gene_locus related to this paper: deigi-h8gtt4 , deigi-h8h0j9

Title : Genome sequence of Acinetobacter calcoaceticus PHEA-2, isolated from industry wastewater - Zhan_2011_J.Bacteriol_193_2672
Author(s) : Zhan Y , Yan Y , Zhang W , Yu H , Chen M , Lu W , Ping S , Peng Z , Yuan M , Zhou Z , Elmerich C , Lin M
Ref : Journal of Bacteriology , 193 :2672 , 2011
Abstract : Genome analysis of Acinetobacter calcoaceticus PHEA-2 was undertaken because of the importance of this bacterium for bioremediation of phenol-polluted water and because of the close phylogenetic relationship of this species with the human pathogen Acinetobacter baumannii. To our knowledge, this is the first strain of A. calcoaceticus whose genome has been sequenced.
ESTHER : Zhan_2011_J.Bacteriol_193_2672
PubMedSearch : Zhan_2011_J.Bacteriol_193_2672
PubMedID: 21441526
Gene_locus related to this paper: aciad-q6fc40 , aciba-d0c992 , aciba-q76hj1 , acibt-a3m5r6 , acibt-a3m5t3 , acibt-a3m5x2 , acica-d0ryi9 , acica-d0ryx6 , acicp-f0kgu1 , acicp-f0kh68 , acicp-f0khy0 , acicp-f0kj61 , aciba-w3svn7 , aciba-a0a009wzt4

Title : Complete genome sequence of the nitrogen-fixing and rhizosphere-associated bacterium Pseudomonas stutzeri strain DSM4166 - Yu_2011_J.Bacteriol_193_3422
Author(s) : Yu H , Yuan M , Lu W , Yang J , Dai S , Li Q , Yang Z , Dong J , Sun L , Deng Z , Zhang W , Chen M , Ping S , Han Y , Zhan Y , Yan Y , Jin Q , Lin M
Ref : Journal of Bacteriology , 193 :3422 , 2011
Abstract : We present here the analysis of the whole-genome sequence of Pseudomonas stutzeri strain DSM4166, a diazotrophic isolate from the rhizosphere of a Sorghum nutans cultivar. To our knowledge, this is the second genome to be sequenced for P. stutzeri. The availability and analysis of the genome provide insight into the evolution of the nitrogen fixation property and identification of rhizosphere competence traits required in interactions with host plants.
ESTHER : Yu_2011_J.Bacteriol_193_3422
PubMedSearch : Yu_2011_J.Bacteriol_193_3422
PubMedID: 21515765
Gene_locus related to this paper: pseu5-a4vfn0 , pseu5-a4vj02 , pseu5-a4vrl9 , pseut-f8h720 , pseu5-a4vkl7 , pseu5-a4vgd4 , pseu5-a4vr33

Title : Development of a sensitive high-performance liquid chromatographic method with simple extraction for simultaneous determination of huperzine A and huperzine B in the species containing lycopodium alkaloids - Zhang_2009_J.AOAC.Int_92_1060
Author(s) : Zhang Y , Xie J , Chen WQ , Zhou TY , Lu W
Ref : Journal of AOAC International , 92 :1060 , 2009
Abstract : A sensitive HPLC method with simple extraction was developed for simultaneous determination of huperzine A (HupA) and huperzine B (HupB) in Huperzia serrata, H. crispata, H. miyoshiana, and Lycopodiastrum casuarinoides. In order to avoid conventional multiple-step and time-consuming sample preparation methods, direct reflux extraction with alkaline chloroform was adopted. The quantitative determination was conducted by reversed-phase HPLC with a photodiode array detector set at 308 nm. Separation was performed on a Luna C18 column (250 x 4.6 mm id, 5 microm) with methanol-0.2% aqueous acetic acid (18 + 82, v/v) mobile phase. The method was validated for accuracy, reproducibility, precision, and limits of detection and quantification. Quantification of the two active compounds in the samples was performed by this newly developed method, and the content of HupA and HupB varied substantially among four different species. The satisfactory results indicated that the developed method can readily be utilized for quality control of the species of Huperziaceae and Lycopodiaceae containing the two compounds.
ESTHER : Zhang_2009_J.AOAC.Int_92_1060
PubMedSearch : Zhang_2009_J.AOAC.Int_92_1060
PubMedID: 19714972

Title : Cutinase-catalyzed hydrolysis of poly(ethylene terephthalate) - Ronkvist_2009_Macromolecules_42_4632
Author(s) : Ronkvist AM , Xie W , Lu W , Gross RA
Ref : Macromolecules , 42 :5128 , 2009
Abstract : A detailed study and comparison was made on the catalytic activities of cutinases from Humilica insolens (HiC), Pseudomonas mendocina (PmC), and Fusarium solani (FsC) using low-crystallinity (lc) and biaxially oriented (bo) poly(ethylene terephthalate) (PET) films as model substrates. Cutinase activity for PET hydrolysis was assayed using a pH-stat to measure NaOH consumption versus time, where initial activity was expressed as units of micromoles of NaOH added per hour and per milliliter of reaction volume. HiC was found to have good thermostability with maximum initial activity from 70 to 80 degC, whereas PmC and FsC performed best at 50 degC. Assays by pH-stat showed that the cutinases had about 10-fold higher activity for the lcPET (7% crystallinity) than for the boPET (35% crystallinity). Under optimal reaction conditions, initial activities of cutinases were successfully fit by a heterogeneous kinetic model. The hydrolysis rate constant k2 was 7-fold higher for HiC at 70 degC (0.62 mol/cm2/h) relative to PmC and FsC at 50 and 40 degC, respectively. With respect to PET affinity, PmC had the highest affinity, while FsC had the lowest value. In a 96 h degradation study using lcPET films, incubation with PmC and FsC both resulted in a 5% film weight loss at 50 and 40 degC, respectively. In contrast, HiC-catalyzed lcPET film hydrolysis at 70 degC resulted in a 97 3% weight loss in 96 h, corresponding to a loss in film thickness of 30 m per day. As degradation of lcPET progressed, crystallinity of the remaining film increased to 27% due to preferential degradation of amorphous regions. Furthermore, for all three cutinases, analysis of aqueous soluble degradation products showed that they consist exclusively of terephthalic acid and ethylene glycol.
ESTHER : Ronkvist_2009_Macromolecules_42_4632
PubMedSearch : Ronkvist_2009_Macromolecules_42_4632
PubMedID:
Gene_locus related to this paper: humin-cut , fusso-cutas , psemy-a4y035

Title : Genome sequence of Shigella flexneri 2a: insights into pathogenicity through comparison with genomes of Escherichia coli K12 and O157 - Jin_2002_Nucleic.Acids.Res_30_4432
Author(s) : Jin Q , Yuan Z , Xu J , Wang Y , Shen Y , Lu W , Wang J , Liu H , Yang J , Yang F , Zhang X , Zhang J , Yang G , Wu H , Qu D , Dong J , Sun L , Xue Y , Zhao A , Gao Y , Zhu J , Kan B , Ding K , Chen S , Cheng H , Yao Z , He B , Chen R , Ma D , Qiang B , Wen Y , Hou Y , Yu J
Ref : Nucleic Acids Research , 30 :4432 , 2002
Abstract : We have sequenced the genome of Shigella flexneri serotype 2a, the most prevalent species and serotype that causes bacillary dysentery or shigellosis in man. The whole genome is composed of a 4 607 203 bp chromosome and a 221 618 bp virulence plasmid, designated pCP301. While the plasmid shows minor divergence from that sequenced in serotype 5a, striking characteristics of the chromosome have been revealed. The S.flexneri chromosome has, astonishingly, 314 IS elements, more than 7-fold over those possessed by its close relatives, the non-pathogenic K12 strain and enterohemorrhagic O157:H7 strain of Escherichia coli. There are 13 translocations and inversions compared with the E.coli sequences, all involve a segment larger than 5 kb, and most are associated with deletions or acquired DNA sequences, of which several are likely to be bacteriophage-transmitted pathogenicity islands. Furthermore, S.flexneri, resembling another human-restricted enteric pathogen, Salmonella typhi, also has hundreds of pseudogenes compared with the E.coli strains. All of these could be subjected to investigations towards novel preventative and treatment strategies against shigellosis.
ESTHER : Jin_2002_Nucleic.Acids.Res_30_4432
PubMedSearch : Jin_2002_Nucleic.Acids.Res_30_4432
PubMedID: 12384590
Gene_locus related to this paper: ecoli-Aes , ecoli-yafa , ecoli-ycfp , ecoli-yqia , ecoli-YfhR , shifl-AES , shifl-BIOH , shifl-entf , shifl-FES , shifl-PLDB , shifl-PTRB , shifl-SF1334 , shifl-SF1808 , shifl-SF3046 , shifl-SF3908 , shifl-yafa , shifl-YBFF , shifl-YCDJ , shifl-YCJY , shifl-YFBB , shifl-YHET , shifl-YIEL , shifl-YJFP , shifl-YPFH