Lin H

References (49)

Title : Donepezil promotes skin flap survival through activation of the HIF-1alpha\/VEGF signalling pathway - Lin_2024_Wound.Repair.Regen__
Author(s) : Lin H , Wang K , Yang J , Wang A , Deng J , Lin D
Ref : Wound Repair Regen , : , 2024
Abstract : Flaps are mainly used to repair wounds in the clinical setting but can sometimes experience ischaemic necrosis postoperatively. This study investigated whether donepezil, an acetylcholinesterase inhibitor, can enhance the survival rate of flaps. We randomly allocated 36 rats into control, low-dose (3 mg/kg/day), and high-dose (5 mg/kg/day) groups. On Postoperative day 7, we assessed flap viability and calculated the mean area of viable flap. After euthanizing the rats, we employed immunological and molecular biology techniques to examine the changes in flap tissue vascularization, apoptosis, autophagy, and inflammation. Donepezil enhanced the expression of hypoxia-inducible factor and vascular endothelial growth factor to facilitate angiogenesis. In addition, it elevated the expression of LC3B, p62, and beclin to stimulate autophagy. Furthermore, it increased the expression of Bcl-2 while reducing the expression of Bax, thus inhibiting apoptosis. Finally, it had anti-inflammatory effects by reducing the levels of IL-1beta, IL-6, and TNF-alpha. The results suggest that donepezil can enhance the viability of randomly generated skin flaps by upregulating HIF-1alpha/VEGF signalling pathway, facilitating vascularization, inducing autophagy, suppressing cell apoptosis, and mitigating inflammation within the flap tissue.
ESTHER : Lin_2024_Wound.Repair.Regen__
PubMedSearch : Lin_2024_Wound.Repair.Regen__
PubMedID: 38551210

Title : Sequence-based design and construction of synthetic nanobody library - Liu_2024_Biotechnol.Bioeng__
Author(s) : Liu C , Li Y , He Q , Fu J , Wei Q , Lin H , Luo Y , Tu Z
Ref : Biotechnol Bioeng , : , 2024
Abstract : Nanobody (Nb), the smallest antibody fragments known to bind antigens, is now widely applied to various studies, including protein structure analysis, bioassay, diagnosis, and biomedicine. The traditional approach to generating specific nanobodies involves animal immunization which is time-consuming and expensive. As the understanding of the antibody repertoire accumulation, the synthetic library, which is devoid of animals, has attracted attention widely in recent years. Here, we describe a synthetic phage display library (S-Library), designed based on the systematic analysis of the next-generation sequencing (NGS) of nanobody repertoire. The library consists of a single highly conserved scaffold (IGHV3S65*01-IGHJ4*01) and complementary determining regions of constrained diversity. The S-Library containing 2.19 x 10(8) independent clones was constructed by the one-step assembly and rapid electro-transformation. The S-Library was screened against various targets (Nb G8, fusion protein of Nb G8 and green fluorescent protein, bovine serum albumin, ovalbumin, and acetylcholinesterase). In comparison, a naive library (N-Library) from the source of 13 healthy animals was constructed and screened against the same targets as the S-Library. Binders were isolated from both S-Library and N-Library. The dynamic affinity was evaluated by the biolayer interferometry. The data confirms that the feature of the Nb repertoire is conducive to reducing the complexity of library design, thus allowing the S-Library to be built on conventional reagents and primers.
ESTHER : Liu_2024_Biotechnol.Bioeng__
PubMedSearch : Liu_2024_Biotechnol.Bioeng__
PubMedID: 38548653

Title : Effects of Lipid Metabolism-Related Genes PTGIS and HRASLS on Phenotype, Prognosis, and Tumor Immunity in Lung Squamous Cell Carcinoma - Lei_2023_Oxid.Med.Cell.Longev_2023_6811625
Author(s) : Lei K , Liang R , Tan B , Li L , Lyu Y , Wang K , Wang W , Hu X , Wu D , Lin H , Wang M
Ref : Oxid Med Cell Longev , 2023 :6811625 , 2023
Abstract : BACKGROUND: Lipid metabolism reprogramming played an important role in cancer occurrence, development, and immune regulation. The aim of this study was to identify and validate lipid metabolism-related genes (LMRGs) associated with the phenotype, prognosis, and immunological characteristics of lung squamous cell carcinoma (LUSC). METHODS: In the TCGA cohort, bioinformatics and survival analysis were used to identify lipid metabolism-related differentially expressed genes (DEGs) associated with the prognosis of LUSC. PTGIS/HRASLS knockdown and overexpression effects on the LUSC phenotype were analyzed in vitro experiments. Based on the expression distribution of PTGIS/HRASLS, LUSC patients were divided into two clusters by consensus clustering. Clinical information, prognosis, immune infiltration, expression of immune checkpoints, and tumor mutation burden (TMB) level were compared between the TCGA and GSE4573 cohorts. The genes related to clustering and tumor immunity were screened by weighted gene coexpression network analysis (WGCNA), and the target module genes were analyzed by functional enrichment analysis, protein-protein interaction (PPI) analysis, and immune correlation analysis. RESULTS: 191 lipid metabolism-related DEGs were identified, of which 5 genes were independent prognostic genes of LUSC. PTGIS/HRASLS were most closely related to LUSC prognosis and immunity. RT-qPCR, western blot (WB) analysis, and immunohistochemistry (IHC) showed that the expression of PTGIS was low in LUSC, while HRASLS was high. Functionally, PTGIS promoted LUSC proliferation, migration, and invasion, while HRASLS inhibited LUSC proliferation, migration, and invasion. The two clusters' expression and distribution of PTGIS/HRASLS had the opposite trend. Cluster 1 was associated with lower pathological staging (pT, pN, and pTNM stages), better prognosis, stronger immune infiltration, higher expression of immune checkpoints, and higher TMB level than cluster 2. WGCNA found that 28 genes including CD4 and IL10RA were related to the expression of PTGIS/HRASLS and tumor immune infiltration. PTGIS/HRASLS in the GSE4573 cohort had the same effect on LUSC prognosis and tumor immunity as the TCGA cohort. CONCLUSIONS: PTGIS and HRASLS can be used as new therapeutic targets for LUSC as well as biomarkers for prognosis and tumor immunity, which has positive significance for guiding the immunotherapy of LUSC.
ESTHER : Lei_2023_Oxid.Med.Cell.Longev_2023_6811625
PubMedSearch : Lei_2023_Oxid.Med.Cell.Longev_2023_6811625
PubMedID: 36703911

Title : Biodegradation of Fumonisins by the Consecutive Action of a Fusion Enzyme - Li_2022_Toxins.(Basel)_14_
Author(s) : Li K , Yu S , Yu D , Lin H , Liu N , Wu A
Ref : Toxins (Basel) , 14 : , 2022
Abstract : Fumonisins (FBs) are toxic mycotoxins that commonly exist in food and feed. FBs can induce many aspects of toxicity, leading to adverse effects on human and animal health; therefore, investigating methods to reduce fumonisin contamination is necessary. In our study, we generated a recombinant fusion enzyme called FUMDI by linking the carboxylesterase gene (fumD) and the aminotransferase gene (fumI) by overlapping polymerase chain reaction (PCR). The fusion enzyme FUMDI was successfully, secretively expressed in the host Pichia pastoris (P. pastoris) GS115, and its expression was optimized. Our results demonstrated that the fusion enzyme FUMDI had high biodegradation activity of fumonisin B1 (FB1) and other common FBs, such as fumonisin B2 (FB2) and fumonisin B3 (FB3), and almost completely degraded 5 microg/mL of each toxin within 24 h. We also found that FUMDI enzyme and its reaction products had no negative effect on cell viability and did not induce cell apoptosis, oxidative stress, or endoplasmic reticulum (ER) stress in a human gastric epithelial cell line (GES-1). The results indicated that these FBs degradation products cannot have adverse effects in a cell model. In conclusion, a safe and efficient fumonisin-degrading enzyme was discovered, which could be a new a technical method for hazard control of FBs in the future.
ESTHER : Li_2022_Toxins.(Basel)_14_
PubMedSearch : Li_2022_Toxins.(Basel)_14_
PubMedID: 35448875
Gene_locus related to this paper: sphmc-FumD

Title : Design, synthesis and evaluation of fused hybrids with acetylcholinesterase inhibiting and Nrf2 activating functions for Alzheimer's disease - Wang_2022_Eur.J.Med.Chem_244_114806
Author(s) : Wang Y , Xiong B , Lin H , Li Q , Yang H , Qiao Y , Xu Z , Lyu W , Qu W , Liu W , Chen Y , Feng F , Sun H
Ref : Eur Journal of Medicinal Chemistry , 244 :114806 , 2022
Abstract : Designing of multiple-target directed ligands (MTDLs) has emerged as an attractive strategy for Alzheimer's disease (AD). Fusing the benzylpiperidine motif from AChE inhibitor donepezil and the 1,2,4-oxadiazole core from the Nrf2 activator 25 that was previously reported, we designed and synthesized a series of multifunctional anti-AD hybrids. The optimal hybrid 15a exhibited excellent AChE inhibitory (eeAChE IC(50) = 0.07 +/- 0.01 microM; hAChE IC(50) = 0.38 +/- 0.04 microM) and significant Nrf2 inductivity. It upregulated the protein and transcription level of Nrf2 and its downstream proteins HO-1, NQO1, and GCLM and promoted Nrf2 translocation from cytoplasm into nuclei. Additionally, 15a exhibited important neuroprotective function in protecting the cells from being damaged by H(2)O(2) and Abeta(1-42) aggregation and exerted antioxidant stress and anti-inflammatory activities in reducing the production of ROS and pro-inflammatory cytokines. Moreover, 15a effectively shortened the latency time and escape distance to the target, increased the arrival times, and simplified the tracks in Morris water maze test induced by scopolamine and Abeta(1-42). At the same time, it significantly reduced the levels of proinflammatory factors in the mice model brains. These effects of 15a in improving cognition and alleviating inflammation were even better than the combination of AChE inhibitor and Nrf2 activator, suggesting a remarkable benefit for AD treatment. 15a could serve as a novel hit compound with Nrf2 inductive activity and AChE inhibitory activity for further research.
ESTHER : Wang_2022_Eur.J.Med.Chem_244_114806
PubMedSearch : Wang_2022_Eur.J.Med.Chem_244_114806
PubMedID: 36223681

Title : Toxic effects of waterborne benzylparaben on the growth, antioxidant capacity and lipid metabolism of Nile tilapia (Oreochromis niloticus) - Lin_2022_Aquat.Toxicol_248_106197
Author(s) : Lin H , Jia Y , Han F , Xia C , Zhao Q , Zhang J , Li E
Ref : Aquat Toxicol , 248 :106197 , 2022
Abstract : Benzylparaben (BzP) is a potential endocrine disruptor; however, its antioxidant defense, lipotoxicity and underlying mechanism of BzP in aquatic organisms are unknown. This study investigated the impacts of waterborne low-, environmental-related and high-level benzylparaben on the growth, antioxidant capacity, lipid metabolism and lipidomic response of Nile tilapia (Oreochromis niloticus). Juvenile tilapia (0.60 +/- 0.11 g) were exposed to 0, 5, 50, 500 and 5000 ng/L benzylparaben for 8 weeks in quadruplicate for each group. Benzylparaben increased the body crude fat content but decreased brain acetylcholinesterase activity in O. niloticus. Benzylparaben caused oxidative stress, leading to hepatic morphology damage and lipid metabolism disorders in fish. Lipidomic analysis identified 13 lipid classes in fish liver. Benzylparaben exposure induced metabolic disorders of glycerol phospholipids, glycerolipids and sphingomyelins in fish liver. These findings indicate that environmentally related benzylparaben levels (5 to 50 ng/L) could induce an antioxidant response, result in triglyceride accumulation, and increase adipocyte formation and fatty acid intake in tilapia. However, high benzylparaben concentrations inhibit lipid deposition, presumably due to the effects of the antioxidant system, and induce tissue inflammation. Therefore, this study provides new insights into the toxic effects and potential mechanism of benzylparaben in fish, especially from the aspect of lipid metabolism.
ESTHER : Lin_2022_Aquat.Toxicol_248_106197
PubMedSearch : Lin_2022_Aquat.Toxicol_248_106197
PubMedID: 35623196

Title : Explainable machine learning model for predicting spontaneous bacterial peritonitis in cirrhotic patients with ascites - Hu_2021_Sci.Rep_11_21639
Author(s) : Hu Y , Chen R , Gao H , Lin H , Wang J , Wang X , Liu J , Zeng Y
Ref : Sci Rep , 11 :21639 , 2021
Abstract : Spontaneous bacterial peritonitis (SBP) is a life-threatening complication in patients with cirrhosis. We aimed to develop an explainable machine learning model to achieve the early prediction and outcome interpretation of SBP. We used CatBoost algorithm to construct MODEL-1 with 46 variables. After dimensionality reduction, we constructed MODEL-2. We calculated and compared the sensitivity and negative predictive value (NPV) of MODEL-1 and MODEL-2. Finally, we used the SHAP (SHapley Additive exPlanations) method to provide insights into the model's outcome or prediction. MODEL-2 (AUROC: 0.822; 95% confidence interval [CI] 0.783-0.856), liked MODEL-1 (AUROC: 0.822; 95% CI 0.784-0.856), could well predict the risk of SBP in cirrhotic ascites patients. The 6 most influential predictive variables were total protein, C-reactive protein, prothrombin activity, cholinesterase, lymphocyte ratio and apolipoprotein A1. For binary classifier, the sensitivity and NPV of MODEL-1 were 0.894 and 0.885, respectively, while for MODEL-2 they were 0.927 and 0.904, respectively. We applied CatBoost algorithm to establish a practical and explainable prediction model for risk of SBP in cirrhotic patients with ascites. We also identified 6 important variables closely related to the occurrence of SBP.
ESTHER : Hu_2021_Sci.Rep_11_21639
PubMedSearch : Hu_2021_Sci.Rep_11_21639
PubMedID: 34737270

Title : Synthesis, Biological Activity, Molecular Docking Studies of a Novel Series of 3-Aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one Derivatives as the Acetylcholinesterase Inhibitors - Jin_2020_J.Biomol.Struct.Dyn__1
Author(s) : Jin Z , Zhang C , Liu M , Jiao S , Zhao J , Liu X , Lin H , Wan DC , Hu C
Ref : J Biomol Struct Dyn , :1 , 2020
Abstract : The acetylcholinesterase inhibitors play a critical role in the drug therapy for Alzheimer's disease. In this study, twenty-nine novel 3-aryl-7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives were synthesized and assayed for their human acetylcholinesterase (hAChE) inhibitory activities. Inhibitory ratio values of seventeen compounds were above 55% with 4c having the highest value as 77.19%. The compounds with the halogen atoms in the aromatic ring, and N,N-diethylamino or N,N-dimethylamino groups in the side chains at C-3 positions exhibited good inhibitory activity. SAR study was carried out by means of molecular docking technique. According to molecular docking results, the common interacting site for all compounds were found to be peripheral anionic site whereas highly active compounds were interacting with the catalytic active site too.
ESTHER : Jin_2020_J.Biomol.Struct.Dyn__1
PubMedSearch : Jin_2020_J.Biomol.Struct.Dyn__1
PubMedID: 32266865

Title : Design, synthesis, in vitro and in vivo evaluation of benzylpiperidine-linked 1,3-dimethylbenzimidazolinones as cholinesterase inhibitors against Alzheimer's disease - Mo_2020_J.Enzyme.Inhib.Med.Chem_35_330
Author(s) : Mo J , Chen T , Yang H , Guo Y , Li Q , Qiao Y , Lin H , Feng F , Liu W , Chen Y , Liu Z , Sun H
Ref : J Enzyme Inhib Med Chem , 35 :330 , 2020
Abstract : Cholinesterase inhibitor plays an important role in the treatment of patients with Alzheimer's disease (AD). Herein, we report the medicinal chemistry efforts leading to a new series of 1,3-dimethylbenzimidazolinone derivatives. Among the synthesised compounds, 15b and 15j showed submicromolar IC50 values (15b, eeAChE IC50 = 0.39 +/- 0.11 microM; 15j, eqBChE IC50 = 0.16 +/- 0.04 microM) towards acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Kinetic and molecular modelling studies revealed that 15b and 15j act in a competitive manner. 15b and 15j showed neuroprotective effect against H2O2-induced oxidative damage on PC12 cells. This effect was further supported by their antioxidant activity determined in a DPPH assay in vitro. Morris water maze test confirmed the memory amelioration effect of the two compounds in a scopolamine-induced mouse model. Moreover, the hepatotoxicity of 15b and 15j was lower than tacrine. In summary, these data suggest 15b and 15j are promising multifunctional agents against AD.
ESTHER : Mo_2020_J.Enzyme.Inhib.Med.Chem_35_330
PubMedSearch : Mo_2020_J.Enzyme.Inhib.Med.Chem_35_330
PubMedID: 31856607

Title : Design, Synthesis, and Evaluation of a Series of Novel Super Long-Acting DPP-4 Inhibitors for the Treatment of Type 2 Diabetes - Zhang_2020_J.Med.Chem_63_7108
Author(s) : Zhang C , Ye F , Wang J , He P , Lei M , Huang L , Huang A , Tang P , Lin H , Liao Y , Liang Y , Ni J , Yan P
Ref : Journal of Medicinal Chemistry , 63 :7108 , 2020
Abstract : In the present work, a novel series of trifluoromethyl-substituted tetrahydropyran derivatives were rationally designed and synthesized as potent DPP-4 inhibitors with significantly improved duration time of action over current commercially available DPP-4 inhibitors. The incorporation of the trifluoromethyl group on the 6-position of the tetrahydropyran ring of omarigliptin with the configuration of (2R,3S,5R,6S) not only significantly improves the overall pharmacokinetic profiles in mice but also maintains comparable DPP-4 inhibition activities. Further preclinical development of compound 2 exhibited its extraordinary efficacy in vivo and good safety profile. Clinical studies of compound 2 (Haisco HSK7653) are now ongoing in China, which revealed that inhibitor 2 could serve as an efficient candidate with a once-biweekly therapeutic regimen.
ESTHER : Zhang_2020_J.Med.Chem_63_7108
PubMedSearch : Zhang_2020_J.Med.Chem_63_7108
PubMedID: 32452679

Title : Design, synthesis, biological evaluation, and molecular modeling studies of quinoline-ferulic acid hybrids as cholinesterase inhibitors - Mo_2019_Bioorg.Chem_93_103310
Author(s) : Mo J , Yang H , Chen T , Li Q , Lin H , Feng F , Liu W , Qu W , Guo Q , Chi H , Chen Y , Sun H
Ref : Bioorg Chem , 93 :103310 , 2019
Abstract : A series of quinoline-ferulic acid hybrids has been designed, synthesized, and evaluated as cholinesterase inhibitors. Most of the compounds showed good inhibitory activities toward both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Among them, 10f was found to be the most potent inhibitor against AChE (IC50=0.62+/-0.17mum), and 14 was the most potent inhibitor against BChE (IC50=0.10+/-0.01mum). Representative compounds, such as 10f and 12g, act in a competitive manner when they inhibit AChE or BChE. Molecular docking and dynamic simulation revealed that the synthesized compounds bind to the target by simultaneously interacting with the catalytic active site (CAS) and the peripheral anionic site (PAS) of both AChE and BChE. The U-shaped confirmation was preferred when 12g bound to BChE, which was different from the linear conformation of 10f bound to AChE. Cell-based assays have confirmed the moderate neuroprotective effects of compounds 10f and 12g against H2O2-induced oxidative damage towards PC12 cells. Moreover, the hepatotoxicity of 12g was lower than that of tacrine, indicating its potential safety as an anti-Alzheimer's agent. In summary, we report a new chemotype of multifunctional hybrid, which may be further modified to develop new anti-Alzheimer's agents.
ESTHER : Mo_2019_Bioorg.Chem_93_103310
PubMedSearch : Mo_2019_Bioorg.Chem_93_103310
PubMedID: 31586704

Title : Selenepezil, a Selenium-Containing Compound, Exerts Neuroprotective Effect via Modulation of the Keap1-Nrf2-ARE Pathway and Attenuates Abeta-Induced Cognitive Impairment in Vivo - Yan_2019_ACS.Chem.Neurosci_10_2903
Author(s) : Yan J , Pang Y , Zhuang J , Lin H , Zhang Q , Han L , Ke P , Huang X
Ref : ACS Chem Neurosci , 10 :2903 , 2019
Abstract : Oxidative stress is a major risk factor for neurodegenerative disease. The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2)-antioxidant response element (ARE) pathway is one of the most potent defensive systems against oxidative stress. Selenepezil, a selenium-based compound, was previously found to exhibit excellent acetylcholinesterase (AChE) inhibition, to mimic endogenous glutathione peroxidase (GPx) activity, and to exhibit scavenging activity for hydrogen peroxide in vitro. However, none of these activities have been evaluated in a cellular model, and detailed molecular mechanisms are not elucidated. Moreover, whether selenepezil ameliorates memory deficits in vivo remains unknown. This study validated the cytoprotective effect of selenepezil against 6-hydroxydopamine (6-OHDA)- or H2O2-induced SH-SY5Y cell damage via alleviation or neutralization of intracellular microtubule disorder, reactive oxygen species (ROS) accumulation, mitochondrial dysfunction, and cell apoptosis. Our study clearly demonstrated that selenepezil pretreatment exhibited remarkable cytoprotective effect in a Nrf2-dependent manner via activating the Keap1-Nrf2-ARE pathway and stimulating the transcription of Nrf2-ARE-regulated cytoprotective genes. Moreover, selenepezil.HCl exerts neuroprotective effect via attenuating Abeta-induced cognitive impairment in Alzheimer's disease (AD) rat and was more active than the reference drug donepezil. In summary, selenepezil deserves further consideration for AD therapy.
ESTHER : Yan_2019_ACS.Chem.Neurosci_10_2903
PubMedSearch : Yan_2019_ACS.Chem.Neurosci_10_2903
PubMedID: 31035749

Title : Insecticide Resistance Status and Mechanisms of Anopheles sinensis (Diptera: Culicidae) in Wenzhou, an Important Coastal Port City in China - Chen_2019_J.Med.Entomol_56_803
Author(s) : Chen S , Qin Q , Zhong D , Fang X , He H , Wang L , Dong L , Lin H , Zhang M , Cui L , Yan G
Ref : Journal of Medical Entomology , 56 :803 , 2019
Abstract : Although scaled-up interventions and effective control efforts have drastically reduced malaria morbidity and mortality, malaria remains a serious threat to public health worldwide. Anopheles sinensis Wiedemann 1828 is a historically important vector of Plasmodium vivax (Haemosporida: Plasmodiidae) malaria in China. Insecticide resistance has become a major obstacle to vector-borne disease control. However, little is known about the insecticide resistance of An. sinensis in Wenzhou, an important coastal port city in Zhejiang province, China. The aim of this study was to examine insecticide resistance and mechanisms in An. sinensis field mosquito populations. Evidence of multiple insecticide resistance was found in An. sinensis adult female populations. Medium to high frequencies of target site kdr together with fixed ace-1 mutations was detected in both the Ruian and Yongjia populations. Both populations showed an association between kdr L1014 mutation and resistance phenotype when tested against deltamethrin and DDT. Significantly different metabolic enzyme activities were found between the susceptible laboratory strain and field-collected mosquitoes from both Ruian and Yongjia. Both field collected An. sinensis populations exhibited significantly higher P450 enzyme activity compared with the laboratory strain, while the field-collected resistant mosquitoes exhibited various GST and COE enzyme activities. These results indicate multiple resistance mechanisms in An. sinensis field populations. Effective implementation of insecticide resistance management strategies is urgently needed. The data collected in this study will be valuable for modeling insecticide resistance spread and vector-control interventions.
ESTHER : Chen_2019_J.Med.Entomol_56_803
PubMedSearch : Chen_2019_J.Med.Entomol_56_803
PubMedID: 30715428

Title : P8 nuclear receptor responds to acaricides exposure and regulates transcription of P450 enzyme in the two-spotted spider mite, Tetranychus urticae - Jia_2019_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_224_108561
Author(s) : Jia H , Peiling L , Yuan H , Wencai L , Zhifeng X , Lin H
Ref : Comparative Biochemistry & Physiology C Toxicol Pharmacol , 224 :108561 , 2019
Abstract : Spider mites are destructive arthropod pests on many crops and they have developed resistance to nearly all acaricides. In recent years, along with the application of high throughput sequencing, the molecular mechanisms of mite resistance had made a series of progress. But, the response in molecular level of mite exposure to acaricides, as well as the original mechanism of resistance development was still unclear. To disclose the deeply mechanisms, we used RNA sequencing to analyze the responses of mite exposure to a sublethal concentration (LC30) treatment of the three different action mode acaricides (Abamectin, Fenpropathrin, and Tebufenpyrad). A high number of differentially expressed genes may well be involved in detoxification and regulatory, with extensive overlap in differentially expressed genes between the three insecticide treatments. Two cytochrome P450 genes were co-up-regulated and one glutathione S-transferase genes were co-down-regulated in all the treatments, while carboxylesterase genes only had a response to abamectin. This interesting phenomenon revealed that P450 enzymes play an important role in the early stage of mite exposure to acaricide. Moreover, a P8 nuclear receptor gene was in response to stress caused by exposure to acaricides and RNA interference (RNAi) experiment indicated P8 nuclear receptor regulates the P450 enzyme activity and susceptibility of mites to acaricide. The differential response information of gene expression based on a large-scale sequence would provide some useful clues for studying the molecular mechanisms of mite resistance formation and development.
ESTHER : Jia_2019_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_224_108561
PubMedSearch : Jia_2019_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_224_108561
PubMedID: 31254664

Title : Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2,3-dioxygenase 1 (IDO1) inhibition: The design, synthesis of miconazole analogues targeting Alzheimer's disease - Lu_2018_Bioorg.Med.Chem_26_1665
Author(s) : Lu X , He SY , Li Q , Yang H , Jiang X , Lin H , Chen Y , Qu W , Feng F , Bian Y , Zhou Y , Sun H
Ref : Bioorganic & Medicinal Chemistry , 26 :1665 , 2018
Abstract : In our endeavor towards the development of potent multi-target ligands for the treatment of Alzheimer's disease, miconazole was identified to show BuChE-IDO1 dual-target inhibitory effects. Morris water maze test indicated that miconazole obviously ameliorated the cognitive function impaired by scopolamine. Furthermore, it showed good safety in primary hepatotoxicity evaluation. Based on these results, we designed, synthesized, and evaluated a series of miconazole derivatives as BuChE-IDO1 dual-target inhibitors. Out of the 12 compounds, 5i and 5j exhibited the best potency in enzymatic evaluation, thus were selected for subsequent behavioral study, in which the two compounds exerted much improved effect than tacrine. Meanwhile, 5i and 5j displayed no apparent hepatotoxicity. The results suggest that miconazole analogue offers an attractive starting point for further development of new BuChE-IDO1 dual-target inhibitors against Alzheimer's disease.
ESTHER : Lu_2018_Bioorg.Med.Chem_26_1665
PubMedSearch : Lu_2018_Bioorg.Med.Chem_26_1665
PubMedID: 29475581

Title : Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity - Turcot_2018_Nat.Genet_50_26
Author(s) : Turcot V , Lu Y , Highland HM , Schurmann C , Justice AE , Fine RS , Bradfield JP , Esko T , Giri A , Graff M , Guo X , Hendricks AE , Karaderi T , Lempradl A , Locke AE , Mahajan A , Marouli E , Sivapalaratnam S , Young KL , Alfred T , Feitosa MF , Masca NGD , Manning AK , Medina-Gomez C , Mudgal P , Ng MCY , Reiner AP , Vedantam S , Willems SM , Winkler TW , Abecasis G , Aben KK , Alam DS , Alharthi SE , Allison M , Amouyel P , Asselbergs FW , Auer PL , Balkau B , Bang LE , Barroso I , Bastarache L , Benn M , Bergmann S , Bielak LF , Bluher M , Boehnke M , Boeing H , Boerwinkle E , Boger CA , Bork-Jensen J , Bots ML , Bottinger EP , Bowden DW , Brandslund I , Breen G , Brilliant MH , Broer L , Brumat M , Burt AA , Butterworth AS , Campbell PT , Cappellani S , Carey DJ , Catamo E , Caulfield MJ , Chambers JC , Chasman DI , Chen YI , Chowdhury R , Christensen C , Chu AY , Cocca M , Collins FS , Cook JP , Corley J , Corominas Galbany J , Cox AJ , Crosslin DS , Cuellar-Partida G , D'Eustacchio A , Danesh J , Davies G , Bakker PIW , Groot MCH , Mutsert R , Deary IJ , Dedoussis G , Demerath EW , Heijer M , Hollander AI , Ruijter HM , Dennis JG , Denny JC , Angelantonio E , Drenos F , Du M , Dube MP , Dunning AM , Easton DF , Edwards TL , Ellinghaus D , Ellinor PT , Elliott P , Evangelou E , Farmaki AE , Farooqi IS , Faul JD , Fauser S , Feng S , Ferrannini E , Ferrieres J , Florez JC , Ford I , Fornage M , Franco OH , Franke A , Franks PW , Friedrich N , Frikke-Schmidt R , Galesloot TE , Gan W , Gandin I , Gasparini P , Gibson J , Giedraitis V , Gjesing AP , Gordon-Larsen P , Gorski M , Grabe HJ , Grant SFA , Grarup N , Griffiths HL , Grove ML , Gudnason V , Gustafsson S , Haessler J , Hakonarson H , Hammerschlag AR , Hansen T , Harris KM , Harris TB , Hattersley AT , Have CT , Hayward C , He L , Heard-Costa NL , Heath AC , Heid IM , Helgeland O , Hernesniemi J , Hewitt AW , Holmen OL , Hovingh GK , Howson JMM , Hu Y , Huang PL , Huffman JE , Ikram MA , Ingelsson E , Jackson AU , Jansson JH , Jarvik GP , Jensen GB , Jia Y , Johansson S , Jorgensen ME , Jorgensen T , Jukema JW , Kahali B , Kahn RS , Kahonen M , Kamstrup PR , Kanoni S , Kaprio J , Karaleftheri M , Kardia SLR , Karpe F , Kathiresan S , Kee F , Kiemeney LA , Kim E , Kitajima H , Komulainen P , Kooner JS , Kooperberg C , Korhonen T , Kovacs P , Kuivaniemi H , Kutalik Z , Kuulasmaa K , Kuusisto J , Laakso M , Lakka TA , Lamparter D , Lange EM , Lange LA , Langenberg C , Larson EB , Lee NR , Lehtimaki T , Lewis CE , Li H , Li J , Li-Gao R , Lin H , Lin KH , Lin LA , Lin X , Lind L , Lindstrom J , Linneberg A , Liu CT , Liu DJ , Liu Y , Lo KS , Lophatananon A , Lotery AJ , Loukola A , Luan J , Lubitz SA , Lyytikainen LP , Mannisto S , Marenne G , Mazul AL , McCarthy MI , McKean-Cowdin R , Medland SE , Meidtner K , Milani L , Mistry V , Mitchell P , Mohlke KL , Moilanen L , Moitry M , Montgomery GW , Mook-Kanamori DO , Moore C , Mori TA , Morris AD , Morris AP , Muller-Nurasyid M , Munroe PB , Nalls MA , Narisu N , Nelson CP , Neville M , Nielsen SF , Nikus K , Njolstad PR , Nordestgaard BG , Nyholt DR , O'Connel JR , O'Donoghue ML , Olde Loohuis LM , Ophoff RA , Owen KR , Packard CJ , Padmanabhan S , Palmer CNA , Palmer ND , Pasterkamp G , Patel AP , Pattie A , Pedersen O , Peissig PL , Peloso GM , Pennell CE , Perola M , Perry JA , Perry JRB , Pers TH , Person TN , Peters A , Petersen ERB , Peyser PA , Pirie A , Polasek O , Polderman TJ , Puolijoki H , Raitakari OT , Rasheed A , Rauramaa R , Reilly DF , Renstrom F , Rheinberger M , Ridker PM , Rioux JD , Rivas MA , Roberts DJ , Robertson NR , Robino A , Rolandsson O , Rudan I , Ruth KS , Saleheen D , Salomaa V , Samani NJ , Sapkota Y , Sattar N , Schoen RE , Schreiner PJ , Schulze MB , Scott RA , Segura-Lepe MP , Shah SH , Sheu WH , Sim X , Slater AJ , Small KS , Smith AV , Southam L , Spector TD , Speliotes EK , Starr JM , Stefansson K , Steinthorsdottir V , Stirrups KE , Strauch K , Stringham HM , Stumvoll M , Sun L , Surendran P , Swift AJ , Tada H , Tansey KE , Tardif JC , Taylor KD , Teumer A , Thompson DJ , Thorleifsson G , Thorsteinsdottir U , Thuesen BH , Tonjes A , Tromp G , Trompet S , Tsafantakis E , Tuomilehto J , Tybjaerg-Hansen A , Tyrer JP , Uher R , Uitterlinden AG , Uusitupa M , Laan SW , Duijn CM , Leeuwen N , van Setten J , Vanhala M , Varbo A , Varga TV , Varma R , Velez Edwards DR , Vermeulen SH , Veronesi G , Vestergaard H , Vitart V , Vogt TF , Volker U , Vuckovic D , Wagenknecht LE , Walker M , Wallentin L , Wang F , Wang CA , Wang S , Wang Y , Ware EB , Wareham NJ , Warren HR , Waterworth DM , Wessel J , White HD , Willer CJ , Wilson JG , Witte DR , Wood AR , Wu Y , Yaghootkar H , Yao J , Yao P , Yerges-Armstrong LM , Young R , Zeggini E , Zhan X , Zhang W , Zhao JH , Zhao W , Zhou W , Zondervan KT , Rotter JI , Pospisilik JA , Rivadeneira F , Borecki IB , Deloukas P , Frayling TM , Lettre G , North KE , Lindgren CM , Hirschhorn JN , Loos RJF
Ref : Nat Genet , 50 :26 , 2018
Abstract : Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
ESTHER : Turcot_2018_Nat.Genet_50_26
PubMedSearch : Turcot_2018_Nat.Genet_50_26
PubMedID: 29273807

Title : Synthesis, pharmacology and molecular docking on multifunctional tacrine-ferulic acid hybrids as cholinesterase inhibitors against Alzheimer's disease - Zhu_2018_J.Enzyme.Inhib.Med.Chem_33_496
Author(s) : Zhu J , Yang H , Chen Y , Lin H , Li Q , Mo J , Bian Y , Pei Y , Sun H
Ref : J Enzyme Inhib Med Chem , 33 :496 , 2018
Abstract : The cholinergic hypothesis has long been a "polar star" in drug discovery for Alzheimer's disease (AD), resulting in many small molecules and biological drug candidates. Most of the drugs marketed for AD are cholinergic. Herein, we report our efforts in the discovery of cholinesterases inhibitors (ChEIs) as multi-target-directed ligands. A series of tacrine-ferulic acid hybrids have been designed and synthesised. All these compounds showed potent acetyl-(AChE) and butyryl cholinesterase(BuChE) inhibition. Among them, the optimal compound 10g, was the most potent inhibitor against AChE (electrophorus electricus (eeAChE) half maximal inhibitory concentration (IC50) = 37.02 nM), it was also a strong inhibitor against BuChE (equine serum (eqBuChE) IC50 = 101.40 nM). Besides, it inhibited amyloid beta-protein self-aggregation by 65.49% at 25 muM. In subsequent in vivo scopolamine-induced AD models, compound 10g obviously ameliorated the cognition impairment and showed preliminary safety in hepatotoxicity evaluation. These data suggest compound 10g as a promising multifunctional agent in the drug discovery process against AD.
ESTHER : Zhu_2018_J.Enzyme.Inhib.Med.Chem_33_496
PubMedSearch : Zhu_2018_J.Enzyme.Inhib.Med.Chem_33_496
PubMedID: 29405075

Title : Repellent action and contact toxicity mechanisms of the essential oil extracted from Chinese chive against Plutella xylostella larvae - Gao_2018_Arch.Insect.Biochem.Physiol__e21509
Author(s) : Gao Q , Song L , Sun J , Cao HQ , Wang L , Lin H , Tang F
Ref : Archives of Insect Biochemistry & Physiology , :e21509 , 2018
Abstract : Botanical pesticides play increasingly important roles in the control of agricultural pests. In this study, the insecticidal effects, specifically the repellent action and contact toxicity, of the essential oil extracted from Chinese chive (EOC) against Plutella xylostella larvae were confirmed. The mechanisms of repellent's action were studied using electroantennograms (EAGs), and the effects on glutathione S-transferase (GST), carboxylesterase (CarE), and acetyl cholinesterase were investigated after EOC treatments. The EOC affected the EAG results and inhibited the activities of GST and CarE in treated P. xylostella larvae, which could explain its insecticidal effects. And, four pyrazines showed greater repellent activities than that of the EOC, which was confirmed as the main active compounds of EOC.
ESTHER : Gao_2018_Arch.Insect.Biochem.Physiol__e21509
PubMedSearch : Gao_2018_Arch.Insect.Biochem.Physiol__e21509
PubMedID: 30390324

Title : Synthesis and bioevaluation of new tacrine-cinnamic acid hybrids as cholinesterase inhibitors against Alzheimer's disease - Chen_2018_J.Enzyme.Inhib.Med.Chem_33_290
Author(s) : Chen Y , Zhu J , Mo J , Yang H , Jiang X , Lin H , Gu K , Pei Y , Wu L , Tan R , Hou J , Chen J , Lv Y , Bian Y , Sun H
Ref : J Enzyme Inhib Med Chem , 33 :290 , 2018
Abstract : Small molecule cholinesterases inhibitor (ChEI) provides an effective therapeutic strategy to treat Alzheimer's disease (AD). Currently, the discovery of new ChEI with multi-target effect is still of great importance. Herein, we report the synthesis, structure-activity relationship study and biological evaluation of a series of tacrine-cinnamic acid hybrids as new ChEIs. All target compounds are evaluated for their in vitro cholinesterase inhibitory activities. The representatives which show potent activity on cholinesterase, are evaluated for the amyloid beta-protein self-aggregation inhibition and in vivo assays. The optimal compound 19, 27, and 30 (human AChE IC50 = 10.2 +/- 1.2, 16.5 +/- 1.7, and 15.3 +/- 1.8 nM, respectively) show good performance in ameliorating the scopolamine-induced cognition impairment and preliminary safety in hepatotoxicity evaluation. These compounds deserve further evaluation for the development of new therapeutic agents against AD.
ESTHER : Chen_2018_J.Enzyme.Inhib.Med.Chem_33_290
PubMedSearch : Chen_2018_J.Enzyme.Inhib.Med.Chem_33_290
PubMedID: 29278947

Title : Genetic invalidation of Lp-PLA(2) as a therapeutic target: Large-scale study of five functional Lp-PLA(2)-lowering alleles - Gregson_2017_Eur.J.Prev.Cardiol_24_492
Author(s) : Gregson JM , Freitag DF , Surendran P , Stitziel NO , Chowdhury R , Burgess S , Kaptoge S , Gao P , Staley JR , Willeit P , Nielsen SF , Caslake M , Trompet S , Polfus LM , Kuulasmaa K , Kontto J , Perola M , Blankenberg S , Veronesi G , Gianfagna F , Mannisto S , Kimura A , Lin H , Reilly DF , Gorski M , Mijatovic V , Munroe PB , Ehret GB , Thompson A , Uria-Nickelsen M , Malarstig A , Dehghan A , Vogt TF , Sasaoka T , Takeuchi F , Kato N , Yamada Y , Kee F , Muller-Nurasyid M , Ferrieres J , Arveiler D , Amouyel P , Salomaa V , Boerwinkle E , Thompson SG , Ford I , Wouter Jukema J , Sattar N , Packard CJ , Shafi Majumder AA , Alam DS , Deloukas P , Schunkert H , Samani NJ , Kathiresan S , Nordestgaard BG , Saleheen D , Howson JM , Di Angelantonio E , Butterworth AS , Danesh J
Ref : Eur J Prev Cardiol , 24 :492 , 2017
Abstract : Aims Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA(2) enzyme activity is causally relevant to coronary heart disease. Methods In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA(2). We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA(2) activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA(2)-lowering alleles. Results Lp-PLA(2) activity was decreased by 64% ( p = 2.4 x 10(-25)) with carriage of any of the four loss-of-function variants, by 45% ( p < 10(-300)) for every allele inherited at Val279Phe, and by 2.7% ( p = 1.9 x 10(-12)) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA(2) activity by 65% ( p < 10(-300)). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA(2) activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. Conclusions In a large-scale human genetic study, none of a series of Lp-PLA(2)-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA(2) is unlikely to be a causal risk factor.
ESTHER : Gregson_2017_Eur.J.Prev.Cardiol_24_492
PubMedSearch : Gregson_2017_Eur.J.Prev.Cardiol_24_492
PubMedID: 27940953
Gene_locus related to this paper: human-PLA2G7

Title : Therapeutic Agents in Alzheimer's Disease Through a Multi-targetdirected Ligands Strategy: Recent Progress Based on Tacrine Core - Lin_2017_Curr.Top.Med.Chem_17_3000
Author(s) : Lin H , Li Q , Gu K , Zhu J , Jiang X , Chen Y , Sun H
Ref : Curr Top Med Chem , 17 :3000 , 2017
Abstract : Alzheimer's Disease (AD) is one of the most common forms of dementia in elderly people. To date, efficacious therapeutic agent for the treatment of AD is still very limited, so it has long been a challenging and attractive task to discover new anti-AD drugs. Considering the multifactorial nature of AD, recently, the concept of Multi-Target-Directed Ligands (MTDLs) has emerged as a new strategy for designing therapeutic agents on AD. MTDLs are believed to exert their effects through simultaneously affecting multiple targets which contribute to etiology of AD. Therefore, MTDLs are considered to be more efficacious than mono-target agents. Tacrine is the first drug approved by Food and Drug Administration (FDA). Although the clinical use of tacrine is restricted because of its hepatotoxicity, the high Ligand Efficiency (LE) of this compound makes it an ideal component for designing MTDLs. This article provides an update review of the advances on the development of MTDLs based on tacrine. Case studies are carefully selected to show the detailed strategy on medicinal modification of Tacrine-Based MTDLs. Finally, several concerns and opinions on designing new MTDLs are discussed as well.
ESTHER : Lin_2017_Curr.Top.Med.Chem_17_3000
PubMedSearch : Lin_2017_Curr.Top.Med.Chem_17_3000
PubMedID: 28714419

Title : Disease spectrum of alcoholic liver disease in Beijing 302 Hospital from 2002 to 2013: A large tertiary referral hospital experience from 7422 patients - Huang_2017_Medicine.(Baltimore)_96_e6163
Author(s) : Huang A , Chang B , Sun Y , Lin H , Li B , Teng G , Zou ZS
Ref : Medicine (Baltimore) , 96 :e6163 , 2017
Abstract : Alcohol consumption in China has substantially increased over the last 3 decades and the number of patients with alcoholic liver disease (ALD) is rising at an alarming rate. However, accurate and representative data on time trends in its hospitalization rates are not available. The aim of this study is to assess the current status and burden of ALD in China by analyzing the data from a large tertiary referral hospital, Beijing 302 Hospital.Data were retrospectively recorded from patients diagnosed as ALD in Beijing 302 Hospital from 2002 to 2013. The disease spectrum and biochemical parameters of each patient were collected.The patients with ALD accounted for 3.93% (7422) of all patients (188,902) with liver diseases between 2002 and 2013. The number of patients hospitalized with ALD increased from 110 in 2002 to 1672 in 2013. The ratio of patients hospitalized with ALD to all patients hospitalized with liver diseases was rising almost continuously and increased from 1.68% in 2002 to 4.59% in 2013. Most patients with ALD were male. Age distribution of ALD hospitalization showed that the highest rate was in 40- to 49-year-old group in subjects. Notably, the annual proportion of severe alcoholic hepatitis (SAH) increased 2.43 times from 2002 to 2013. We found the highest levels of mean corpuscular volume, the aspartate aminotransferase/alanine aminotransferase ratio, total bilirubin, international normalized ratio, and alkaline phosphatase in SAH patients, while serum levels of hemoglobin, albumin, and cholinesterase were significantly decreased in SAH group. Among these ALD, the SAH patient population has the worst prognosis. Alcoholic cirrhosis (ALC) is the most common ALD, and annual admissions for ALC increased significantly during the analyzed period.The number of hospitalized patients with ALD and the annual hospitalization rate of ALD were increasing continuously in Beijing 302 Hospital from 2002 to 2013. More attention should be paid to develop population-based effective strategy to control ALD.
ESTHER : Huang_2017_Medicine.(Baltimore)_96_e6163
PubMedSearch : Huang_2017_Medicine.(Baltimore)_96_e6163
PubMedID: 28207552

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 : Transcriptional activity of acetylcholinesterase gene is regulated by DNA methylation during C2C12 myogenesis - Lau_2016_Brain.Res_1642_114
Author(s) : Lau KM , Gong AG , Xu ML , Lam CT , Zhang LM , Bi CWC , Cui D , Cheng AW , Dong TTX , Tsim KWK , Lin H
Ref : Brain Research , 1642 :114 , 2016
Abstract : The expression of acetylcholinesterase (AChE), an enzyme hydrolyzes neurotransmitter acetylcholine at vertebrate neuromuscular junction, is regulated during myogenesis, indicating the significance of muscle intrinsic factors in controlling the enzyme expression. DNA methylation is essential for temporal control of myogenic gene expression during myogenesis; however, its role in AChE regulation is not known. The promoter of vertebrate ACHE gene carries highly conserved CG-rich regions, implying its likeliness to be methylated for epigenetic regulation. A DNA methyltransferase inhibitor, 5-azacytidine (5-Aza), was applied onto C2C12 cells throughout the myotube formation. When DNA methylation was inhibited, the promoter activity, transcript expression and enzymatic activity of AChE were markedly increased after day 3 of differentiation, which indicated the putative role of DNA methylation. By bisulfite pyrosequencing, the overall methylation rate was found to peak at day 3 during C2C12 cell differentiation; a SP1 site located at -1826bp upstream of mouse ACHE gene was revealed to be heavily methylated. The involvement of transcriptional factor SP1 in epigenetic regulation of AChE was illustrated here: (i) the SP1-driven transcriptional activity was increased in 5-Aza-treated C2C12 culture; (ii) the binding of SP1 onto the SP1 site of ACHE gene was fully blocked by the DNA methylation; and (iii) the sequence flanking SP1 sites of ACHE gene was precipitated by chromatin immuno-precipitation assay. The findings suggested the role of DNA methylation on AChE transcriptional regulation and provided insight in elucidating the DNA methylation-mediated regulatory mechanism on AChE expression during muscle differentiation.
ESTHER : Lau_2016_Brain.Res_1642_114
PubMedSearch : Lau_2016_Brain.Res_1642_114
PubMedID: 27021952

Title : Cell-bound lipases from Burkholderia sp. ZYB002: gene sequence analysis, expression, enzymatic characterization, and 3D structural model - Shu_2016_BMC.Biotechnol_16_38
Author(s) : Shu Z , Lin H , Shi S , Mu X , Liu Y , Huang J
Ref : BMC Biotechnol , 16 :38 , 2016
Abstract : BACKGROUND: The whole-cell lipase from Burkholderia cepacia has been used as a biocatalyst in organic synthesis. However, there is no report in the literature on the component or the gene sequence of the cell-bound lipase from this species. Qualitative analysis of the cell-bound lipase would help to illuminate the regulation mechanism of gene expression and further improve the yield of the cell-bound lipase by gene engineering.
RESULTS: Three predictive cell-bound lipases, lipA, lipC21 and lipC24, from Burkholderia sp. ZYB002 were cloned and expressed in E. coli. Both LipA and LipC24 displayed the lipase activity. LipC24 was a novel mesophilic enzyme and displayed preference for medium-chain-length acyl groups (C10-C14). The 3D structural model of LipC24 revealed the open Y-type active site. LipA displayed 96 % amino acid sequence identity with the known extracellular lipase. lipA-inactivation and lipC24-inactivation decreased the total cell-bound lipase activity of Burkholderia sp. ZYB002 by 42 % and 14 %, respectively.
CONCLUSIONS: The cell-bound lipase activity from Burkholderia sp. ZYB002 originated from a multi-enzyme mixture with LipA as the main component. LipC24 was a novel lipase and displayed different enzymatic characteristics and structural model with LipA. Besides LipA and LipC24, other type of the cell-bound lipases (or esterases) should exist.
ESTHER : Shu_2016_BMC.Biotechnol_16_38
PubMedSearch : Shu_2016_BMC.Biotechnol_16_38
PubMedID: 27142276
Gene_locus related to this paper: burce-lipaa

Title : [Safety and efficacy of human umbilical cord derived-mesenchymal stem cell transplantation for treating patients with HBV-related decompensated cirrhosis] - Yu_2016_Zhonghua.Gan.Zang.Bing.Za.Zhi_24_51
Author(s) : Yu SJ , Chen LM , Lyu S , Li YY , Yang B , Geng H , Lin H , Wang SY , Xu RN , Wang LF , Shi M , Wang FS
Ref : Zhonghua Gan Zang Bing Za Zhi , 24 :51 , 2016
Abstract : OBJECTIVE: To retrospectively investigate the efficacy of human umbilical cord-derived mesenchymal stem cells (UC-MSC) as clinical treatment for HBV-related decompensated liver cirrhosis (HBV-DLC)*D.
METHODS: Sixty patients with HBV-DLC were given standard medical treatment combined with a 3-month regimen of UC-MSC at a dose of 0.5-1.0x10(6) cells/kg/month. Another group of patients with HBV-DLC (n=120; control group) that was matched (2:1) to the case group by age, sex, diagnosis, and follow-up period was given the standard medical treatment only. We reviewed all patients' data of biochemical tests, imaging examinations, Child-Pugh scores, and adverse reactions. Comparisons of continuous data between the two groups were made by independent-sample t-test, and comparisons of categorical data were made by chi-square test.
RESULTS: Compared with the control group, the group that received the combination UC-MSC treatment showed a significant rise in cholinesterase, globulin and alkaline phosphatase, and reduced Child-Pugh scores during the follow-up period. However, there was no significant difference between the groups of patients for levels of alanine transaminase, total bilirubin, albumin, total cholesterol, or prothrombin activity.
CONCLUSIONS: Addition of the UC-MSC treatment to the standard therapy could help to improve liver function in patients with HBV-DLC.
ESTHER : Yu_2016_Zhonghua.Gan.Zang.Bing.Za.Zhi_24_51
PubMedSearch : Yu_2016_Zhonghua.Gan.Zang.Bing.Za.Zhi_24_51
PubMedID: 26983390

Title : VvMJE1 of the grapevine (Vitis vinifera) VvMES methylesterase family encodes for methyl jasmonate esterase and has a role in stress response - Zhao_2016_Plant.Physiol.Biochem_102_125
Author(s) : Zhao N , Lin H , Lan S , Jia Q , Chen X , Guo H , Chen F
Ref : Plant Physiol Biochem , 102 :125 , 2016
Abstract : The known members of plant methyl esterase (MES) family catalyze the hydrolysis of a C-O ester linkage of methyl esters of several phytohormones including indole-3-acetic acid, salicylic acid and jasmonic acid. The genome of grapevine (Vitis vinifera) was found to contain 15 MES genes, designated VvMES1-15. In this report, VvMES5 was selected for molecular, biochemical and structural studies. VvMES5 is most similar to tomato methyl jasmonate esterase. E. coli-expressed recombinant VvMES5 displayed methyl jasmonate (MeJA) esterase activity, it was renamed VvMJE1. Under steady-state conditions, VvMJE1 exhibited an apparent Km value of 92.9 muM with MeJA. VvMJE1 was also shown to have lower activity with methyl salicylate (MeSA), another known substrate of the MES family, and only at high concentrations of the substrate. To understand the structural basis of VvMJE1 in discriminating MeJA and MeSA, a homolog model of VvMJE1 was made using the X-ray structure of tobacco SABP2, which encodes for methyl salicylate esterase, as a template. Interestingly, two bulky residues at the binding site and near the surface of tobacco SABP2 are replaced by relatively small residues in VvMJE1. Such a change enables the accommodation of a larger substrate MeJA in VvMJE1. The expression of VvMJE1 was compared in control grape plants and grape plants treated with one of the three stresses: heat, cold and UV-B. While the expression of VvMJE1 was not affected by heat treatment, its expression was significantly up-regulated by cold treatment and UV-B treatment. This result suggests that VvMJE1 has a role in response of grape plants to these two abiotic stresses.
ESTHER : Zhao_2016_Plant.Physiol.Biochem_102_125
PubMedSearch : Zhao_2016_Plant.Physiol.Biochem_102_125
PubMedID: 26934101
Gene_locus related to this paper: vitvi-d7ssd8

Title : Three N-Glycosylation Sites of Human Acetylcholinesterase Shares Similar Glycan Composition - Xu_2015_J.Mol.Neurosci_57_486
Author(s) : Xu ML , Luk WK , Lau KM , Bi CWC , Cheng AW , Gong AG , Lin H , Tsim KWK
Ref : Journal of Molecular Neuroscience , 57 :486 , 2015
Abstract : Acetylcholinesterase (AChE; EC is a glycoprotein possessing three conserved N-linked glycosylation sites in mammalian species, locating at 296, 381, and 495 residues of the human sequence. Several lines of evidence demonstrated that N-glycosylation of AChE affected the enzymatic activity, as well as its biosynthesis. In order to determine the role of three N-glycosylation sites in AChE activity and glycan composition, the site-directed mutagenesis of N-glycosylation sites in wild-type human AChET sequence was employed to generate the single-site mutants (i.e., AChET (N296Q), AChET (N381Q), and AChET (N495Q)) and all site mutant (i.e., AChET (3N-->3Q)). The mutation did not affect AChE protein expression in the transfected cells. The mutants, AChET (3N-->3Q) and AChET (N381Q), showed very minimal enzymatic activity, while the other mutants showed reduced activity. By binding to lectins, Con A, and SNA, the glycosylation profile was revealed in those mutated AChE. The binding affinity with lectins showed no significant difference between various N-glycosylation mutants, which suggested that similar glycan composition should be resulted from different N-glycosylation sites. Although the three glycosylation sites within AChE sequence have different extent in affecting the enzymatic activity, their glycan compositions are very similar.
ESTHER : Xu_2015_J.Mol.Neurosci_57_486
PubMedSearch : Xu_2015_J.Mol.Neurosci_57_486
PubMedID: 26231935

Title : Colorimetric sensor array for detection and identification of organophosphorus and carbamate pesticides - Qian_2015_Anal.Chem_87_5395
Author(s) : Qian S , Lin H
Ref : Analytical Chemistry , 87 :5395 , 2015
Abstract : Due to relatively low persistence and high effectiveness for insect and pest eradication, organophosphates (OPs) and carbamates are the two major classes of pesticides that broadly used in agriculture. Hence, the sensitive and selective detection of OPs and carbamates is highly significant. In this current study, a colorimetric sensor array comprising five inexpensive and commercially available thiocholine and H2O2 sensitive indicators for the simultaneous detection and identification of OPs and carbamates is developed. The sensing mechanism of this array is based on the irreversible inhibition capability of OPs and carbamates to the activity of acetylcholinesterase (AChE), preventing production of thiocholine and H2O2 from S-acetylthiocholine and acetylcholine and thus resulting in decreased or no color reactions to thiocholine and H2O2 sensitive indicators. Through recognition patterns and standard statistical methods (i.e., hierarchical clustering analysis and principal component analysis), the as-developed array demonstrates not only discrimination of OPs and carbamates from other kinds of pesticides but, more interestingly, identification of them exactly from each other. Moreover, this array is experimentally confirmed to have high selectivity and sensitivity, good anti-interference capability, and potential applications in real samples for OPs and carbamates.
ESTHER : Qian_2015_Anal.Chem_87_5395
PubMedSearch : Qian_2015_Anal.Chem_87_5395
PubMedID: 25913282

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

Title : Evidences for B6C3-Tg (APPswe\/PSEN1dE9) Double-Transgenic Mice Between 3 and 10 Months as an Age-Related Alzheimer's Disease Model - Zhong_2014_J.Mol.Neurosci_53_370
Author(s) : Zhong Z , Yang L , Wu X , Huang W , Yan J , Liu S , Sun X , Liu K , Lin H , Kuang S , Tang X
Ref : Journal of Molecular Neuroscience , 53 :370 , 2014
Abstract : Transgenic mouse has shown great advantages in the study of Alzheimer's disease (AD) and drug screening as AD develops rapidly resent years, while more detail information of these transgenic mice and experience of application are needed. To obtain the basic background information of the B6C3-Tg (APPswe/PSEN1dE9) double-transgenic mouse, which was reported with early onset AD, three- to ten-month-old B6C3-Tg AD mice and normal C57BL/6 mice were selected randomly to test the ability of learning memory by Morris water maze, the brain acetylcholinesterase (AChE) activity by AChE kit, and beta amyloid protein level by immunohistochemistry staining. Compared with the control group, the escape latency time of B6C3-Tg AD mice at 9 and 10 months of age is significantly longer (P < 0.05) in Morris maze test, and the activity of brain AChE is higher. beta-Amyloid plaques were observed at 3 months of age and developed rapidly. Statistical analysis showed a positive correlation between the area of these plaques and the ages of B6C3-Tg AD mouse (y = 0.0355e(0.5557x), R = 0.9557). The model's behavior is conformed to simulate behaviors of human Alzheimer's disease at the early stage and may provide detail background information a new choice when transgenic mice are needed in the research of AD.
ESTHER : Zhong_2014_J.Mol.Neurosci_53_370
PubMedSearch : Zhong_2014_J.Mol.Neurosci_53_370
PubMedID: 24362678

Title : Synthesis and biological evaluation of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives as dual binding site acetylcholinesterase inhibitors - Liu_2014_Eur.J.Med.Chem_81C_237
Author(s) : Liu S , Shang R , Shi L , Wan DC , Lin H
Ref : Eur Journal of Medicinal Chemistry , 81C :237 , 2014
Abstract : A series of 7H-thiazolo[3,2-b]-1,2,4-triazin-7-one derivatives 7a-i were synthesized and evaluated as novel acetylcholinesterase (AChE) inhibitors. All target compounds were evaluated in vitro for the inhibitory activities against AChE via Ellman colorimetric assay. Compound 7c showed an excellent (89.82%) inhibitory activity. The molecular docking studies revealed that 7c, 7d and 7g, with the lateral chain in the para position of the phenyl ring, possessed an optimal docking pose and can perfectly fit into the catalytic active site (CAS) and peripheral anionic site (PAS), simultaneously, and, consequently, exhibited higher inhibitory potency than 7b that bears the same lateral chain as 7g, but in the ortho position of the phenyl ring.
ESTHER : Liu_2014_Eur.J.Med.Chem_81C_237
PubMedSearch : Liu_2014_Eur.J.Med.Chem_81C_237
PubMedID: 24844448

Title : Uncovering divergent evolution of alpha\/beta-hydrolases: a surprising residue substitution needed to convert hydroxynitrile lyase into an esterase - Nedrud_2014_Chem.Sci_5_4265
Author(s) : Nedrud DM , Lin H , Lopez G , Padhi SK , Legatt GA , Kazlauskas RJ
Ref : Chem Sci , 5 :4265 , 2014
Abstract : Hevea brasiliensis hydroxynitrile lyase (HbHNL) and salicylic acid binding protein 2 (SABP2, an esterase) share 45% amino acid sequence identity, the same protein fold, and even the same catalytic triad of Ser-His-Asp. However, they catalyze different reactions: cleavage of hydroxynitriles and hydrolysis of esters, respectively. To understand how other active site differences in the two enzymes enable the same catalytic triad to catalyze different reactions, we substituted amino acid residues in HbHNL with the corresponding residues from SABP2, expecting hydroxynitrile lyase activity to decrease and esterase activity to increase. Previous mechanistic studies and x-ray crystallography suggested that esterase activity requires removal of an active site lysine and threonine from the hydroxynitrile lyase. The Thr11Gly Lys236Gly substitutions in HbHNL reduced hydroxynitrile lyase activity for cleavage of mandelonitrile 100-fold, but increased esterase activity only threefold to kcat ~ 0.1 min-1 for hydrolysis of p-nitrophenyl acetate. Adding a third substitution - Glu79His - increased esterase activity more than tenfold to kcat ~ 1.6 min-1. The specificity constant (kcat/KM) for this triple substitution variant versus wild type HbHNL shifted more than one million-fold from hydroxynitrile lyase activity (acetone cyanohydrin substrate) to esterase activity (p-nitrophenyl acetate substrate). The contribution of Glu79His to esterase activity was surprising since esterases and lipases contain many different amino acids at this position, including glutamate. Saturation mutagenesis at position 79 showed that 13 of 19 possible amino acid substitutions increased esterase activity, suggesting that removal of glutamate, not addition of histidine, increased esterase activity. Molecular modeling indicates that Glu79 disrupts esterase activity in HbHNL when its negatively charged side chain distorts the orientation of the catalytic histidine. Naturally occurring glutamate at the corresponding location of Candida lipases is uncharged due to other active site differences and does not cause the same distortion. This example of the fine tuning of the same catalytic triad for different types of catalysis by subtle interactions with other active site residues shows how difficult it is to design new catalytic reactions of enzymes.
ESTHER : Nedrud_2014_Chem.Sci_5_4265
PubMedSearch : Nedrud_2014_Chem.Sci_5_4265
PubMedID: 25346843
Gene_locus related to this paper: hevbr-hnl , nicta-SABP2

Title : Cortical synaptic NMDA receptor deficits in alpha7 nicotinic acetylcholine receptor gene deletion models: Implications for neuropsychiatric diseases - Lin_2014_Neurobiol.Dis_63_129
Author(s) : Lin H , Hsu FC , Baumann BH , Coulter DA , Lynch DR
Ref : Neurobiol Dis , 63 :129 , 2014
Abstract : Microdeletion of the human CHRNA7 gene (alpha7 nicotinic acetylcholine receptor, nAChR) as well as dysfunction in N-methyl-d-aspartate receptors (NMDARs) have been associated with cortical dysfunction in a broad spectrum of neurodevelopmental and neuropsychiatric disorders including schizophrenia. However, the pathophysiological roles of synaptic vs. extrasynaptic NMDARs and their interactions with alpha7 nAChRs in cortical dysfunction remain largely uncharacterized. Using a combination of in vivo and in vitro models, we demonstrate that alpha7 nAChR gene deletion leads to specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in mouse cortex. alpha7 nAChR null mice had decreased cortical NMDAR expression and glutamatergic synapse formation during postnatal development. Similar reductions in NMDAR expression and glutamatergic synapse formation were revealed in cortical cultures lacking alpha7 nAChRs. Interestingly, synaptic, but not extrasynaptic, NMDAR currents were specifically diminished in cultured cortical pyramidal neurons as well as in acute prefrontal cortical slices of alpha7 nAChR null mice. Moreover, d-serine responsive synaptic NMDAR-mediated currents and levels of the d-serine synthetic enzyme serine racemase were both reduced in alpha7 nAChR null cortical pyramidal neurons. Our findings thus identify specific loss of synaptic NMDARs and their coagonist, d-serine, as well as glutamatergic synaptic deficits in alpha7 nAChR gene deletion models of cortical dysfunction, thereby implicating alpha7 nAChR-mediated control of synaptic NMDARs and serine racemase/d-serine pathways in cortical dysfunction underlying many neuropsychiatric and neurodevelopmental disorders, particularly those associated with deletion of human CHRNA7.
ESTHER : Lin_2014_Neurobiol.Dis_63_129
PubMedSearch : Lin_2014_Neurobiol.Dis_63_129
PubMedID: 24326163

Title : Improvement of the Oryza sativa Nipponbare reference genome using next generation sequence and optical map data - Kawahara_2013_Rice.(N.Y)_6_4
Author(s) : Kawahara Y , de la Bastide M , Hamilton JP , Kanamori H , McCombie WR , Ouyang S , Schwartz DC , Tanaka T , Wu J , Zhou S , Childs KL , Davidson RM , Lin H , Quesada-Ocampo L , Vaillancourt B , Sakai H , Lee SS , Kim J , Numa H , Itoh T , Buell CR , Matsumoto T
Ref : Rice (N Y) , 6 :4 , 2013
Abstract : BACKGROUND: Rice research has been enabled by access to the high quality reference genome sequence generated in 2005 by the International Rice Genome Sequencing Project (IRGSP). To further facilitate genomic-enabled research, we have updated and validated the genome assembly and sequence for the Nipponbare cultivar of Oryza sativa (japonica group). RESULTS: The Nipponbare genome assembly was updated by revising and validating the minimal tiling path of clones with the optical map for rice. Sequencing errors in the revised genome assembly were identified by re-sequencing the genome of two different Nipponbare individuals using the Illumina Genome Analyzer II/IIx platform. A total of 4,886 sequencing errors were identified in 321 Mb of the assembled genome indicating an error rate in the original IRGSP assembly of only 0.15 per 10,000 nucleotides. A small number (five) of insertions/deletions were identified using longer reads generated using the Roche 454 pyrosequencing platform. As the re-sequencing data were generated from two different individuals, we were able to identify a number of allelic differences between the original individual used in the IRGSP effort and the two individuals used in the re-sequencing effort. The revised assembly, termed Os-Nipponbare-Reference-IRGSP-1.0, is now being used in updated releases of the Rice Annotation Project and the Michigan State University Rice Genome Annotation Project, thereby providing a unified set of pseudomolecules for the rice community. CONCLUSIONS: A revised, error-corrected, and validated assembly of the Nipponbare cultivar of rice was generated using optical map data, re-sequencing data, and manual curation that will facilitate on-going and future research in rice. Detection of polymorphisms between three different Nipponbare individuals highlights that allelic differences between individuals should be considered in diversity studies.
ESTHER : Kawahara_2013_Rice.(N.Y)_6_4
PubMedSearch : Kawahara_2013_Rice.(N.Y)_6_4
PubMedID: 24280374
Gene_locus related to this paper: orysa-Q0JK71 , orysj-q6yse8 , orysa-q6yzk1 , orysa-q7xej4 , orysa-q7xem8 , orysa-q7xr64 , orysj-a0a0p0y6l9 , orysj-pla4 , orysj-pla1 , orysj-q2r2z8

Title : 6-acetyl-5H-thiazolo[3,2-a]pyrimidine derivatives as the novel acetylcholinesterase inhibitors: design, synthesis, and biological activity - Zhi_2013_Med.Chem_9_703
Author(s) : Zhi H , Zhang C , Cheng Z , Jin Z , Huang E , Li S , Lin H , Wan DC , Hu C
Ref : Med Chem , 9 :703 , 2013
Abstract : Acetylcholinesterase inhibitors are the most frequently prescribed anti-Alzheimer's drugs. A series of 6-acetyl- 5H-thiazolo[3,2-a]pyrimidine derivatives as the novel acetylcholinesterase inhibitors were designed based on virtual screening methods. The target compounds which are not reported in the literature were synthesized with Biginelli reaction and Hantzsch-type condensation of dihydropyrimidines with substituted phenacyl chlorides, and were characterized with elemental analysis, IR, MS, 1H-NMR and 13C-NMR. The biological evaluation against human acetylcholinesterase in vitro showed most of the target compounds exhibited varying inhibition at 10 microM using the Ellman method. The results provide a starting point for the development of novel drugs to treat Alzheimer's disease, and a foundation in search for improved acetylcholinesterase inhibitors with the novel scaffolds. The preliminary structure-activity relationships were the 2-hydroxyethoxy group at the phenyl ring at C4 position of the parent nucleus played significant roles in the AChE inhibitory activity of the target compounds.
ESTHER : Zhi_2013_Med.Chem_9_703
PubMedSearch : Zhi_2013_Med.Chem_9_703
PubMedID: 23270368

Title : Toxicogenomic studies of human neural cells following exposure to organophosphorus chemical warfare nerve agent VX - Gao_2013_Neurochem.Res_38_916
Author(s) : Gao X , Lin H , Ray R , Ray P
Ref : Neurochem Res , 38 :916 , 2013
Abstract : Organophosphorus (OP) compounds represent an important group of chemical warfare nerve agents that remains a significant and constant military and civilian threat. OP compounds are considered acting primarily via cholinergic pathways by binding irreversibly to acetylcholinesterase, an important regulator of the neurotransmitter acetylcholine. Many studies over the past years have suggested that other mechanisms of OP toxicity exist, which need to be unraveled by a comprehensive and systematic approach such as genome-wide gene expression analysis. Here we performed a microarray study in which cultured human neural cells were exposed to 0.1 or 10 muM of VX for 1 h. Global gene expression changes were analyzed 6, 24, and 72 h post exposure. Functional annotation and pathway analysis of the differentially expressed genes has revealed many genes, networks and canonical pathways that are related to nervous system development and function, or to neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, and Parkinson's disease. In particular, the neuregulin pathway impacted by VX exposure has important implications in many nervous system diseases including schizophrenia. These results provide useful information valuable in developing suitable antidotes for more effective prevention and treatment of, as well as in developing biomarkers for, VX-induced chronic neurotoxicity.
ESTHER : Gao_2013_Neurochem.Res_38_916
PubMedSearch : Gao_2013_Neurochem.Res_38_916
PubMedID: 23440544

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

Title : Skeletal muscle IP3R1 receptors amplify physiological and pathological synaptic calcium signals - Zhu_2011_J.Neurosci_31_15269
Author(s) : Zhu H , Bhattacharyya BJ , Lin H , Gomez CM
Ref : Journal of Neuroscience , 31 :15269 , 2011
Abstract : Ca(2+) release from internal stores is critical for mediating both normal and pathological intracellular Ca(2+) signaling. Recent studies suggest that the inositol 1,4,5-triphosphate (IP(3)) receptor mediates Ca(2+) release from internal stores upon cholinergic activation of the neuromuscular junction (NMJ) in both physiological and pathological conditions. Here, we report that the type I IP(3) receptor (IP(3)R(1))-mediated Ca(2+) release plays a crucial role in synaptic gene expression, development, and neuromuscular transmission, as well as mediating degeneration during excessive cholinergic activation. We found that IP(3)R(1)-mediated Ca(2+) release plays a key role in early development of the NMJ, homeostatic regulation of neuromuscular transmission, and synaptic gene expression. Reducing IP(3)R(1)-mediated Ca(2+) release via siRNA knockdown or IP(3)R blockers in C2C12 cells decreased calpain activity and prevented agonist-induced acetylcholine receptor (AChR) cluster dispersal. In fully developed NMJ in adult muscle, IP(3)R(1) knockdown or blockade effectively increased synaptic strength at presynaptic and postsynaptic sites by increasing both quantal release and expression of AChR subunits and other NMJ-specific genes in a pattern resembling muscle denervation. Moreover, in two mouse models of cholinergic overactivity and NMJ Ca(2+) overload, anti-cholinesterase toxicity and the slow-channel myasthenic syndrome (SCS), IP(3)R(1) knockdown eliminated NMJ Ca(2+) overload, pathological activation of calpain and caspase proteases, and markers of DNA damage at subsynaptic nuclei, and improved both neuromuscular transmission and clinical measures of motor function. Thus, blockade or genetic silencing of muscle IP(3)R(1) may be an effective and well tolerated therapeutic strategy in SCS and other conditions of excitotoxicity or Ca(2+) overload.
ESTHER : Zhu_2011_J.Neurosci_31_15269
PubMedSearch : Zhu_2011_J.Neurosci_31_15269
PubMedID: 22031873

Title : Diversity and plasticity of the intracellular plant pathogen and insect symbiont Candidatus Liberibacter asiaticus as revealed by hypervariable prophage genes with intragenic tandem repeats - Zhou_2011_Appl.Environ.Microbiol_77_6663
Author(s) : Zhou L , Powell CA , Hoffman MT , Li W , Fan G , Liu B , Lin H , Duan Y
Ref : Applied Environmental Microbiology , 77 :6663 , 2011
Abstract : "Candidatus Liberibacter asiaticus" is a psyllid-transmitted, phloem-limited alphaproteobacterium and the most prevalent species of "Ca. Liberibacter" associated with a devastating worldwide citrus disease known as huanglongbing (HLB). Two related and hypervariable genes (hyv(I) and hyv(II)) were identified in the prophage regions of the Psy62 "Ca. Liberibacter asiaticus" genome. Sequence analyses of the hyv(I) and hyv(II) genes in 35 "Ca. Liberibacter asiaticus" DNA isolates collected globally revealed that the hyv(I) gene contains up to 12 nearly identical tandem repeats (NITRs, 132 bp) and 4 partial repeats, while hyv(II) contains up to 2 NITRs and 4 partial repeats and shares homology with hyv(I). Frequent deletions or insertions of these repeats within the hyv(I) and hyv(II) genes were observed, none of which disrupted the open reading frames. Sequence conservation within the individual repeats but an extensive variation in repeat numbers, rearrangement, and the sequences flanking the repeat region indicate the diversity and plasticity of "Ca. Liberibacter asiaticus" bacterial populations in the world. These differences were found not only in samples of distinct geographical origins but also in samples from a single origin and even from a single "Ca. Liberibacter asiaticus"-infected sample. This is the first evidence of different "Ca. Liberibacter asiaticus" populations coexisting in a single HLB-affected sample. The Florida "Ca. Liberibacter asiaticus" isolates contain both hyv(I) and hyv(II), while all other global "Ca. Liberibacter asiaticus" isolates contain either one or the other. Interclade assignments of the putative Hyv(I) and Hyv(II) proteins from Florida isolates with other global isolates in phylogenetic trees imply multiple "Ca. Liberibacter asiaticus" populations in the world and a multisource introduction of the "Ca. Liberibacter asiaticus" bacterium into Florida.
ESTHER : Zhou_2011_Appl.Environ.Microbiol_77_6663
PubMedSearch : Zhou_2011_Appl.Environ.Microbiol_77_6663
PubMedID: 21784907
Gene_locus related to this paper: libap-c6xgr3

Title : Enhanced performance of lipase-catalyzed kinetic resolution of secondary alcohols in monoether-functionalized ionic liquids - Zhou_2011_Bioresour.Technol_102_5562
Author(s) : Zhou H , Chen J , Ye L , Lin H , Yuan Y
Ref : Bioresour Technol , 102 :5562 , 2011
Abstract : Several cationic monoether-functionalized ionic liquids (MEF-ILs) with different substituents were synthesized and used as media for kinetic resolution of secondary alcohols catalyzed by several lipases. The results indicate that Novozym 435 (an immobilized Candida antarctica Lipase B) had higher efficiency compared to other lipases in deracemization. The alkyl substituents at the 2- and 3-positions in the imidazolium ring of MEF-ILs were found to contribute to the increased enantioselectivity and enhancement of the reaction rate, respectively, while the higher stereo-hindrance of ether bonds decreased the activity. An enantioselectivity higher than 99% with 50% conversion of rac-1-phenylethanol was achieved using the catalyst system comprised of Novozym 435 and the MEF-IL 1-(3-ethoxypropyl)-2,3-dimethylimidazolium bis(trifluoromethylsulfonyl)imide. The catalytic system could be separated and reused without considerable activity loss. MEF-ILs can be a new class of enzyme-benign media suitable for lipase-catalyzed kinetic resolution of secondary alcohols.
ESTHER : Zhou_2011_Bioresour.Technol_102_5562
PubMedSearch : Zhou_2011_Bioresour.Technol_102_5562
PubMedID: 21388804

Title : Genome sequence and analysis of the tuber crop potato - Xu_2011_Nature_475_189
Author(s) : Xu X , Pan S , Cheng S , Zhang B , Mu D , Ni P , Zhang G , Yang S , Li R , Wang J , Orjeda G , Guzman F , Torres M , Lozano R , Ponce O , Martinez D , De la Cruz G , Chakrabarti SK , Patil VU , Skryabin KG , Kuznetsov BB , Ravin NV , Kolganova TV , Beletsky AV , Mardanov AV , Di Genova A , Bolser DM , Martin DM , Li G , Yang Y , Kuang H , Hu Q , Xiong X , Bishop GJ , Sagredo B , Mejia N , Zagorski W , Gromadka R , Gawor J , Szczesny P , Huang S , Zhang Z , Liang C , He J , Li Y , He Y , Xu J , Zhang Y , Xie B , Du Y , Qu D , Bonierbale M , Ghislain M , Herrera Mdel R , Giuliano G , Pietrella M , Perrotta G , Facella P , O'Brien K , Feingold SE , Barreiro LE , Massa GA , Diambra L , Whitty BR , Vaillancourt B , Lin H , Massa AN , Geoffroy M , Lundback S , DellaPenna D , Buell CR , Sharma SK , Marshall DF , Waugh R , Bryan GJ , Destefanis M , Nagy I , Milbourne D , Thomson SJ , Fiers M , Jacobs JM , Nielsen KL , Sonderkaer M , Iovene M , Torres GA , Jiang J , Veilleux RE , Bachem CW , De Boer J , Borm T , Kloosterman B , van Eck H , Datema E , Hekkert B , Goverse A , van Ham RC , Visser RG
Ref : Nature , 475 :189 , 2011
Abstract : Potato (Solanum tuberosum L.) is the world's most important non-grain food crop and is central to global food security. It is clonally propagated, highly heterozygous, autotetraploid, and suffers acute inbreeding depression. Here we use a homozygous doubled-monoploid potato clone to sequence and assemble 86% of the 844-megabase genome. We predict 39,031 protein-coding genes and present evidence for at least two genome duplication events indicative of a palaeopolyploid origin. As the first genome sequence of an asterid, the potato genome reveals 2,642 genes specific to this large angiosperm clade. We also sequenced a heterozygous diploid clone and show that gene presence/absence variants and other potentially deleterious mutations occur frequently and are a likely cause of inbreeding depression. Gene family expansion, tissue-specific expression and recruitment of genes to new pathways contributed to the evolution of tuber development. The potato genome sequence provides a platform for genetic improvement of this vital crop.
ESTHER : Xu_2011_Nature_475_189
PubMedSearch : Xu_2011_Nature_475_189
PubMedID: 21743474
Gene_locus related to this paper: soltu-q2tqv0 , soltu-q4h433 , soltu-m0zl00 , soltu-m1aw23 , soltu-m0zxh5 , soltu-m1d3q4 , soltu-m1bz14 , soltu-m1d3q6 , sollc-k4b1g3 , soltu-m0zzn8 , soltu-m1ba60 , sollc-k4bf33 , soltu-m1c8d8 , soltu-m1ced9 , soltu-m1a385 , soltu-m1bz15 , soltu-m1a7s9 , soltu-m1bc84 , soltu-m1bpd1 , sollc-k4bm34 , soltu-m1a487 , soltu-m1a5u0 , soltu-m1cjx7 , soltu-m1bvq8 , soltu-m1baq1 , soltu-m1cfh4 , soltu-m1azl4 , soltu-m0ztj0 , soltu-m1d6d0 , soltu-m1cap1 , soltu-m1a7m1 , soltu-m1d3s6

Title : Dexamethasone facilitates lipid accumulation and mild feed restriction improves fatty acids oxidation in skeletal muscle of broiler chicks (Gallus gallus domesticus) - Wang_2010_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_151_447
Author(s) : Wang X , Lin H , Song Z , Jiao H
Ref : Comparative Biochemistry & Physiology C Toxicol Pharmacol , 151 :447 , 2010
Abstract : Effects of dexamethasone (DEX) and mild feed restriction on the uptake and utilization of fatty acids in skeletal muscle of broiler chicks (Gallus gallus domesticus) were investigated. Male Arbor Acres chicks (7-days old, n=30) were injected with DEX or saline for 3days, and a feed restriction group was included. DEX enhanced circulating very low density lipoprotein (VLDL) level and the lipid accumulation in both adipose and skeletal muscle tissues. Compared with the control, liver-carnitine palmitoyltransferase 1 (L-CPT1) and AMP-activated protein kinase (AMPK) alpha2 mRNA level of M. biceps femoris (BF) were down-regulated significantly by DEX, while mRNA expression of lipoprotein lipase (LPL), fatty acid transport protein 1 (FATP1), heart-fatty acid binding protein (H-FABP), long-chain acyl-CoA dehydrogenase (LCAD), activities of LPL and AMPK in both skeletal muscles were not obviously affected. Feed restriction increased the mRNA expression of LPL, L-CPT1 and LCAD of M. pectoralis major (PM), and FATP1, H-FABP, L-CPT1 and LCAD of BF. In conclusion, DEX retards the growth of body mass but facilitates lipid accumulation in both adipose and skeletal muscle tissues. In contrast to the favorable effect of mild feed restriction, DEX did not alter the uptake of fatty acids in the skeletal muscle. The result suggests that DEX may promote intramyocellular lipid accumulation by suppressed fatty acid oxidation while mild feed restriction improved fatty acid oxidation in skeletal muscle, especially in red muscle. Glucocorticoids (GCs) regulated muscle fatty acid metabolism in a different way from energy deficit caused by mild feed restriction.
ESTHER : Wang_2010_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_151_447
PubMedSearch : Wang_2010_Comp.Biochem.Physiol.C.Toxicol.Pharmacol_151_447
PubMedID: 20138241

Title : DWARF27, an iron-containing protein required for the biosynthesis of strigolactones, regulates rice tiller bud outgrowth - Lin_2009_Plant.Cell_21_1512
Author(s) : Lin H , Wang R , Qian Q , Yan M , Meng X , Fu Z , Yan C , Jiang B , Su Z , Li J , Wang Y
Ref : Plant Cell , 21 :1512 , 2009
Abstract : Tillering in rice (Oryza sativa) is one of the most important agronomic traits that determine grain yields. Previous studies on rice tillering mutants have shown that the outgrowth of tiller buds in rice is regulated by a carotenoid-derived MAX/RMS/D (more axillary branching) pathway, which may be conserved in higher plants. Strigolactones, a group of terpenoid lactones, have been recently identified as products of the MAX/RMS/D pathway that inhibits axillary bud outgrowth. We report here the molecular genetic characterization of d27, a classic rice mutant exhibiting increased tillers and reduced plant height. D27 encodes a novel iron-containing protein that localizes in chloroplasts and is expressed mainly in vascular cells of shoots and roots. The phenotype of d27 is correlated with enhanced polar auxin transport. The phenotypes of the d27 d10 double mutant are similar to those of d10, a mutant defective in the ortholog of MAX4/RMS1 in rice. In addition, 2'-epi-5-deoxystrigol, an identified strigolactone in root exudates of rice seedlings, was undetectable in d27, and the phenotypes of d27 could be rescued by supplementation with GR24, a synthetic strigolactone analog. Our results demonstrate that D27 is involved in the MAX/RMS/D pathway, in which D27 acts as a new member participating in the biosynthesis of strigolactones.
ESTHER : Lin_2009_Plant.Cell_21_1512
PubMedSearch : Lin_2009_Plant.Cell_21_1512
PubMedID: 19470589

Title : Complete genome sequence of citrus huanglongbing bacterium, 'Candidatus Liberibacter asiaticus' obtained through metagenomics - Duan_2009_Mol.Plant.Microbe.Interact_22_1011
Author(s) : Duan Y , Zhou L , Hall DG , Li W , Doddapaneni H , Lin H , Liu L , Vahling CM , Gabriel DW , Williams KP , Dickerman A , Sun Y , Gottwald T
Ref : Mol Plant Microbe Interact , 22 :1011 , 2009
Abstract : Citrus huanglongbing is the most destructive disease of citrus worldwide. It is spread by citrus psyllids and is associated with a low-titer, phloem-limited infection by any of three uncultured species of alpha-Proteobacteria, 'Candidatus Liberibacter asiaticus', 'Ca. L. americanus', and 'Ca. L. africanus'. A complete circular 'Ca. L. asiaticus' genome has been obtained by metagenomics, using the DNA extracted from a single 'Ca. L. asiaticus'-infected psyllid. The 1.23-Mb genome has an average 36.5% GC content. Annotation revealed a high percentage of genes involved in both cell motility (4.5%) and active transport in general (8.0%), which may contribute to its virulence. 'Ca. L. asiaticus' appears to have a limited ability for aerobic respiration and is likely auxotrophic for at least five amino acids. Consistent with its intracellular nature, 'Ca. L. asiaticus' lacks type III and type IV secretion systems as well as typical free-living or plant-colonizing extracellular degradative enzymes. 'Ca. L. asiaticus' appears to have all type I secretion system genes needed for both multidrug efflux and toxin effector secretion. Multi-protein phylogenetic analysis confirmed 'Ca. L. asiaticus' as an early-branching and highly divergent member of the family Rhizobiaceae. This is the first genome sequence of an uncultured alpha-proteobacteria that is both an intracellular plant pathogen and insect symbiont.
ESTHER : Duan_2009_Mol.Plant.Microbe.Interact_22_1011
PubMedSearch : Duan_2009_Mol.Plant.Microbe.Interact_22_1011
PubMedID: 19589076
Gene_locus related to this paper: libap-c6xhk4 , libap-c6xgr3

Title : Resistance selection and biochemical mechanism of resistance to two Acaricides in Tetranychus cinnabarinus (Boiduval) - Lin_2009_Pestic.Biochem.Physiol_93_47
Author(s) : Lin H , Chuan-hua X , Jin-jun W , Ming L , Wen-cai L , Zhi-mo Z
Ref : Pesticide Biochemistry and Physiology , 93 :47 , 2009
Abstract : A Tetranychus cinnabarinus strain was collected from Chongqing, China. After 42 generations of selection with abamectin and 20 generations of selection with fenpropathrin in the laboratory, this T. cinnabarinus strain developed 8.7- and 28.7-fold resistance, respectively. Resistance to abamectin in AbR (abamectin resistant strain) and to fenpropathrin in FeR (fenpropathrin resistant strain) was partially suppressed by piperonyl butoxide (PBO), diethyl maleate (DEM) and triphenyl phosphate (TPP), inhibitors of mixed function oxidase (MFO), glutathione S-transferases (GST), and hydrolases, respectively, suggesting that these three enzyme families are important in conferring abamectin and fenpropathrin resistance in T. cinnabarinus. The major resistant mechanism to abamectin was the increasing activities of carboxylesterases (CarE), glutathione-S-transferase (GST) and mixed function oxidase (MFO), and the activity in resistant strain developed 2.7-, 3.4- and 1.4-fold contrasted to that in susceptible strain, respectively. The activity of glutathione-S-transferase (GST) in the FeR strain developed 2.8-fold when compared with the susceptible strain, which meant the resistance to fenpropathrin was related with the activity increase of glutathione-S-transferase (GST) in T. cinnabarinus. The result of the kinetic mensuration of carboxylesterases (CarE) showed that the structure of CarE in the AbR has been changed.
ESTHER : Lin_2009_Pestic.Biochem.Physiol_93_47
PubMedSearch : Lin_2009_Pestic.Biochem.Physiol_93_47

Title : Enzyme inhibitor screening by electrospray mass spectrometry with immobilized enzyme on magnetic silica microspheres - Hu_2008_J.Am.Soc.Mass.Spectrom_19_865
Author(s) : Hu F , Zhang H , Lin H , Deng C , Zhang X
Ref : J Am Soc Mass Spectrom , 19 :865 , 2008
Abstract : In this study, a novel technique for screening inhibitors by electrospray mass spectrometry (ESI-MS) with immobilized enzyme on magnetic microspheres has been demonstrated. First, the model enzyme acetylcholinesterase (AChE) is immobilized onto the 3-glycidoxypropyltrimethoxysilane (GLYMO)-modified magnetic silica microspheres. AChE activity was monitored by biochemical assay that is based on mixing of AChE immobilized microspheres and model substrate acetylcholine, separating and detecting the product through ESI-MS. Stability of the enzyme-immobilized microspheres was investigated. No apparent loss of enzyme activity was observed after fivefold reuse of AChE-immobilized microspheres. The enzyme-immobilized bioassay was used to effectively identify AChE inhibitors among two standard samples, huperzine A and huperzine B, and their source herbal Huperzia serrata, all of which were spiked into the substrate. The inhibition was determined by measuring a decrease of product formation using ESI-MS.
ESTHER : Hu_2008_J.Am.Soc.Mass.Spectrom_19_865
PubMedSearch : Hu_2008_J.Am.Soc.Mass.Spectrom_19_865
PubMedID: 18396060

Title : Structural characterization of enterobactin hydrolase IroE - Larsen_2006_Biochemistry_45_10184
Author(s) : Larsen NA , Lin H , Wei R , Fischbach MA , Walsh CT
Ref : Biochemistry , 45 :10184 , 2006
Abstract : The proliferation of many pathogenic bacteria is limited by the scarcity of soluble iron in their environment. Many of these bacteria scavenge iron by synthesizing and exporting small molecule siderophores that chelate iron. Iron-bound siderophores are subsequently imported for metabolic processing. Three related serine hydrolases have been characterized biochemically in this pathway: Fes, IroD, and IroE. Here, we report the crystal structure of IroE from uropathogenic Escherichia coli CFT073. The native structure and a complex with diisopropyl fluorophosphonate (DFP, a potent serine hydrolase inhibitor) were determined at 2.3 and 1.4 A resolution, respectively. IroE has the typical alpha/beta-hydrolase fold with an atypical catalytic dyad composed of Ser 189 and His 287. Mutation of either residue was detrimental to catalysis. In addition, rather than the typical oxyanion hole composed of backbone amides, IroE employs the atypical guanidinium moiety of Arg 130. Asp 90 anchors Arg 130 in the active site, and mutation of either residue was likewise detrimental to catalysis. We also compare the structure of IroE to the structure of Fes from Shigella flexneri (PDB entry 2B20). Both enzymes have similar active sites, but Fes has an additional amino-terminal lid domain. These lid domains are proposed to confer specificity to these related hydrolases.
ESTHER : Larsen_2006_Biochemistry_45_10184
PubMedSearch : Larsen_2006_Biochemistry_45_10184
PubMedID: 16922493
Gene_locus related to this paper: ecoli-IROE

Title : In vitro characterization of salmochelin and enterobactin trilactone hydrolases IroD, IroE, and Fes - Lin_2005_J.Am.Chem.Soc_127_11075
Author(s) : Lin H , Fischbach MA , Liu DR , Walsh CT
Ref : Journal of the American Chemical Society , 127 :11075 , 2005
Abstract : The iroA locus encodes five genes (iroB, iroC, iroD, iroE, iroN) that are found in pathogenic Salmonella and Escherichia coli strains. We recently reported that IroB is an enterobactin (Ent) C-glucosyltransferase, converting the siderophore into mono-, di-, and triglucosyl enterobactins (MGE, DGE, and TGE, respectively). Here, we report the characterization of IroD and IroE as esterases for the apo and Fe(3+)-bound forms of Ent, MGE, DGE, and TGE, and we compare their activities with those of Fes, the previously characterized enterobactin esterase. IroD hydrolyzes both apo and Fe(3+)-bound siderophores distributively to generate DHB-Ser and/or Glc-DHB-Ser, with higher catalytic efficiencies (k(cat)/K(m)) on Fe(3+)-bound forms, suggesting that IroD is the ferric MGE/DGE esterase responsible for cytoplasmic iron release. Similarly, Fes hydrolyzes ferric Ent more efficiently than apo Ent, confirming Fes is the ferric Ent esterase responsible for Fe(3+) release from ferric Ent. Although each enzyme exhibits lower k(cat)'s processing ferric siderophores, dramatic decreases in K(m)'s for ferric siderophores result in increased catalytic efficiencies. The inability of Fes to efficiently hydrolyze ferric MGE, ferric DGE, or ferric TGE explains the requirement for IroD in the iroA cluster. IroE, in contrast, prefers apo siderophores as substrates and tends to hydrolyze the trilactone just once to produce linearized trimers. These data and the periplasmic location of IroE suggest that it hydrolyzes apo enterobactins while they are being exported. IroD hydrolyzes apo MGE (and DGE) regioselectively to give a single linear trimer product and a single linear dimer product as determined by NMR.
ESTHER : Lin_2005_J.Am.Chem.Soc_127_11075
PubMedSearch : Lin_2005_J.Am.Chem.Soc_127_11075
PubMedID: 16076215
Gene_locus related to this paper: ecoli-fes , ecoli-IROD , ecoli-IROE