Xu R

References (41)

Title : SLC25A28 Overexpression Promotes Adipogenesis by Reducing ATGL - Guan_2024_J.Diabetes.Res_2024_5511454
Author(s) : Guan H , Xiao L , Hao K , Zhang Q , Wu D , Geng Z , Duan B , Dai H , Xu R , Feng X
Ref : J Diabetes Res , 2024 :5511454 , 2024
Abstract : Adipose tissue dysfunction is seen among obese and type 2 diabetic individuals. Adipocyte proliferation and hypertrophy are the root causes of adipose tissue expansion. Solute carrier family 25 member 28 (SLC25A28) is an iron transporter in the inner mitochondrial membrane. This study is aimed at validating the involvement of SLC25A28 in adipose accumulation by tail vein injection of adenovirus (Ad)-SLC25A28 and Ad-green fluorescent protein viral particles into C57BL/6J mice. After 16 weeks, the body weight of the mice was measured. Subsequently, morphological analysis was performed to establish a high-fat diet (HFD)-induced model. SLC25A28 overexpression accelerated lipid accumulation in white and brown adipose tissue (BAT), enhanced body weight, reduced serum triglyceride (TG), and impaired serum glucose tolerance. The protein expression level of lipogenesis, lipolysis, and serum adipose secretion hormone was evaluated by western blotting. The results showed that adipose TG lipase (ATGL) protein expression was reduced significantly in white and BAT after overexpression SLC25A28 compared to the control group. Moreover, SLC25A28 overexpression inhibited the BAT formation by downregulating UCP-1 and the mitochondrial biosynthesis marker PGC-1alpha. Serum adiponectin protein expression was unregulated, which was consistent with the expression in inguinal white adipose tissue (iWAT). Remarkably, serum fibroblast growth factor (FGF21) protein expression was negatively related to the expansion of adipose tissue after administrated by Ad-SLC25A28. Data from the current study indicate that SLC25A28 overexpression promotes diet-induced obesity and accelerates lipid accumulation by regulating hormone secretion and inhibiting lipolysis in adipose tissue.
ESTHER : Guan_2024_J.Diabetes.Res_2024_5511454
PubMedSearch : Guan_2024_J.Diabetes.Res_2024_5511454
PubMedID: 38736904

Title : Computational Insights into the Allosteric Modulation of a Phthalate-Degrading Hydrolase by Distal Mutations - Xu_2023_Biomolecules_13_
Author(s) : Xu R , Bao Y , Li M , Zhang Y , Xi L , Guo J
Ref : Biomolecules , 13 : , 2023
Abstract : Phthalate esters (PAEs) are a ubiquitous kind of environmental endocrine that disrupt chemicals, causing environmental and health issues. EstJ6 is an effective phthalate-degrading hydrolase, and its mutant with a combination of three non-conservative distal mutations has an improved activity against PAEs with unknown molecular mechanisms. Herein, we attempt to fill the significant gap between distal mutations and the activity of this enzyme using computational approaches. We found that mutations resulted in a redistribution of the enzyme's preexisting conformational states and dynamic changes of key functional regions, especially the lid over the active site. The outward motion of the lid upon the mutations made it easier for substrates or products to enter or exit. Additionally, a stronger substrate binding affinity and conformational rearrangements of catalytic reaction-associated residues in the mutant, accompanied by the strengthened communication within the protein, could synergistically contribute to the elevated catalytic efficiency. Finally, an attempt was made to improve the thermostability of EstJ6 upon introducing a distal disulfide bond between residues A23 and A29, and the simulation results were as expected. Together, our work explored the allosteric effects caused by distal mutations, which could provide insights into the rational design of esterases for industrial applications in the future.
ESTHER : Xu_2023_Biomolecules_13_
PubMedSearch : Xu_2023_Biomolecules_13_
PubMedID: 36979378

Title : High Expression of ACOT2 Predicts Worse Overall Survival and Abnormal Lipid Metabolism: A Potential Target for Acute Myeloid Leukemia - Yin_2022_J.Healthc.Eng_2022_2669114
Author(s) : Yin X , Lyu C , Li Z , Wang Q , Ding Y , Wang Y , Qiu Y , Cui S , Guo D , Xu R
Ref : J Healthc Eng , 2022 :2669114 , 2022
Abstract : Acyl-CoA thioesterase (ACOT) plays a considerable role in lipid metabolism, which is closely related to the occurrence and development of cancer, nevertheless, its role has not been fully elucidated in acute myeloid leukemia (AML). To explore the role of ACOT2 in AML and to provide a potential therapeutic target for AML, the expression pattern of ACOT was investigated based on the TNMplot, Gene Expression Profiling Interactive Analysis (GEPIA), and Cancer Cell Line Encyclopedia (CCLE) database, and diagnostic value, prognostic value, and clinical phenotype of ACOT were explored based on data from The Cancer Genome Atlas (TCGA). Functional annotation and enrichment analysis of the common targets between ACOT2 coexpressed and AML-related genes were further performed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) analyses. The protein-protein interaction (PPI) network of ACOT2 coexpressed genes and functional ACOT2-related metabolites association network were constructed based on GeneMANIA and Human Metabolome Database. Among ACOTs, ACOT2 was highly expressed in AML compared to normal control subjects according to TNMplot, GEPIA, and CCLE database, which was significantly associated with poor overall survival (OS) in AML (P=0.003). Moreover, ACOT2 exhibited excellent diagnostic efficiency for AML (AUC: 1.000) and related to French-American-British (FAB) classification and cytogenetics. GO, KEGG, and GSEA analyses of 71 common targets between ACOT2 coexpressed and AML-related genes revealed that ACOT2 is closely related to ACOT1, ACOT4, enoyl-acyl carrier protein reductase, mitochondrial (MECR), puromycin-sensitive aminopeptidase (NPEPPS), SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 (SMARCB1), and long-chain fatty acid-CoA ligase 1 (ACSL1) in PPI network, and plays a significant role in lipid metabolism, that is, involved in fatty acid elongation and biosynthesis of unsaturated fatty acids. Collectively, the increase of ACOT2 may be an important characteristic of worse OS and abnormal lipid metabolism, suggesting that ACOT2 may become a potential therapeutic target for AML.
ESTHER : Yin_2022_J.Healthc.Eng_2022_2669114
PubMedSearch : Yin_2022_J.Healthc.Eng_2022_2669114
PubMedID: 36193167

Title : Identification of Differential Expression Genes between Volume and Pressure Overloaded Hearts Based on Bioinformatics Analysis - Fu_2022_Genes.(Basel)_13_
Author(s) : Fu Y , Zhao D , Zhou Y , Lu J , Kang L , Jiang X , Xu R , Ding Z , Zou Y
Ref : Genes (Basel) , 13 : , 2022
Abstract : Volume overload (VO) and pressure overload (PO) are two common pathophysiological conditions associated with cardiac disease. VO, in particular, often occurs in a number of diseases, and no clinically meaningful molecular marker has yet been established. We intend to find the main differential gene expression using bioinformatics analysis. GSE97363 and GSE52796 are the two gene expression array datasets related with VO and PO, respectively. The LIMMA algorithm was used to identify differentially expressed genes (DEGs) of VO and PO. The DEGs were divided into three groups and subjected to functional enrichment analysis, which comprised GO analysis, KEGG analysis, and the protein-protein interaction (PPI) network. To validate the sequencing data, cardiomyocytes from AR and TAC mouse models were used to extract RNA for qRT-PCR. The three genes with random absolute values of LogFC and indicators of heart failure (natriuretic peptide B, NPPB) were detected: carboxylesterase 1D (CES1D), whirlin (WHRN), and WNK lysine deficient protein kinase 2 (WNK2). The DEGs in VO and PO were determined to be 2761 and 1093, respectively, in this study. Following the intersection, 305 genes were obtained, 255 of which expressed the opposing regulation and 50 of which expressed the same regulation. According to the GO and pathway enrichment studies, DEGs with opposing regulation are mostly common in fatty acid degradation, propanoate metabolism, and other signaling pathways. Finally, we used Cytoscape's three techniques to identify six hub genes by intersecting 255 with the opposite expression and constructing a PPI network. Peroxisome proliferator-activated receptor (PPARalpha), acyl-CoA dehydrogenase medium chain (ACADM), patatin-like phospholipase domain containing 2 (PNPLA2), isocitrate dehydrogenase 3 (IDH3), heat shock protein family D member 1 (HSPD1), and dihydrolipoamide S-acetyltransferase (DLAT) were identified as six potential genes. Furthermore, we predict that the hub genes PPARalpha, ACADM, and PNPLA2 regulate VO myocardial changes via fatty acid metabolism and acyl-Coa dehydrogenase activity, and that these genes could be employed as basic biomarkers for VO diagnosis and treatment.
ESTHER : Fu_2022_Genes.(Basel)_13_
PubMedSearch : Fu_2022_Genes.(Basel)_13_
PubMedID: 35886059

Title : Novel donepezil-chalcone-rivastigmine hybrids as potential multifunctional anti-Alzheimer's agents: Design, synthesis, in vitro biological evaluation, in vivo and in silico studies - Sang_2022_Bioorg.Chem_127_106007
Author(s) : Sang Z , Bai P , Ban Y , Wang K , Wu A , Mi J , Hu J , Xu R , Zhu G , Wang J , Zhang J , Wang C , Tan Z , Tang L
Ref : Bioorg Chem , 127 :106007 , 2022
Abstract : Alzheimer's disease (AD) is a chronic, progressive brain neurodegenerative disorder. Up to now, there is no effective drug to halt or reverse the progress of AD. Given the complex pathogenesis of AD, the multi-target-directed ligands (MTDLs) strategy is considered as the promising therapy. Herein, a series of novel donepezil-chalone-rivastigmine hybrids was rationally designed and synthesized by fusing donepezil, chalone and rivastigmine. The in vitro bioactivity results displayed that compound 10c was a reversible huAChE (IC(50) = 0.87 microM) and huBuChE (IC(50) = 3.3 microM) inhibitor. It also presented significant anti-inflammation effects by suppressing the level of IL-6 and TNF-alpha production, and significantly inhibited self-mediated Abeta(1-42) aggregation (60.6%) and huAChE-mediated induced Abeta(1-40) aggregation (46.2%). In addition, 10c showed significant neuroprotective effect on Abeta(1-42)-induced PC12 cell injury and activated UPS pathway in HT22 cells to degrade tau and amyloid precursor protein (APP). Furthermore, compound 10c presented good stabilty in artificial gastrointestinal fluids and liver microsomes in vitro. The pharmacokinetic study showed that compound 10c was rapidly absorbed in rats and distributed in rat brain after intragastric administration. The PET-CT imaging demonstrated that [(11)C]10c could quickly enter the brain and washed out gradually in vivo. Further, compound 10c at a dose of 5 mg/kg improved scopolamine-induced memory impairment, deserving further investigations.
ESTHER : Sang_2022_Bioorg.Chem_127_106007
PubMedSearch : Sang_2022_Bioorg.Chem_127_106007
PubMedID: 35849893

Title : Plin5 Bidirectionally Regulates Lipid Metabolism in Oxidative Tissues - Zhang_2022_Oxid.Med.Cell.Longev_2022_4594956
Author(s) : Zhang X , Xu W , Xu R , Wang Z , Wang P , Peng K , Li M , Li J , Tan Y , Wang X , Pei H
Ref : Oxid Med Cell Longev , 2022 :4594956 , 2022
Abstract : Cytoplasmic lipid droplets (LDs) can store neutral lipids as an energy source when needed and also regulate the key metabolic processes of intracellular lipid accumulation, which is associated with several metabolic diseases. The perilipins (Plins) are a family of proteins that associate with the surface of LDs. As a member of Plins superfamily, perilipin 5 (Plin5) coats LDs in cardiomyocytes, which is significantly related to reactive oxygen species (ROS) production originated from mitochondria in the heart, consequently determining the progression of diabetic cardiomyopathy. Plin5 may play a bidirectional function in lipid metabolism which is in a state of dynamic balance. In the basic state, Plin5 inhibited the binding of comparative gene identification-58 (CGI-58) to adipose triglyceride lipase (ATGL) by binding CGI-58, thus inhibiting lipolysis. However, when the body is under stress (such as cold, fasting, exercise, and other stimuli), protein kinase A (PKA) phosphorylates and activates Plin5, which then causes Plin5 to release the binding site of CGI-58 and ATGL, prompting CGI-58 to bind to ATGL and activate ATGL activity, thus accelerating the lipolysis process, revealing the indispensable role of Plin5 in lipid turnover. Here, the purpose of this review is to summarize the present understanding of the bidirectional regulation role of Plin5 in oxidative tissues and to reveal its potential role in diabetic cardiomyopathy protection.
ESTHER : Zhang_2022_Oxid.Med.Cell.Longev_2022_4594956
PubMedSearch : Zhang_2022_Oxid.Med.Cell.Longev_2022_4594956
PubMedID: 35401929

Title : Soluble Epoxide Hydrolase Inhibition Protected against Diabetic Cardiomyopathy through Inducing Autophagy and Reducing Apoptosis Relying on Nrf2 Upregulation and Transcription Activation - Fang_2022_Oxid.Med.Cell.Longev_2022_3773415
Author(s) : Fang Q , Liu X , Ding J , Zhang Z , Chen G , Du T , Wang Y , Xu R
Ref : Oxid Med Cell Longev , 2022 :3773415 , 2022
Abstract : BACKGROUND: Many patients with diabetes die from diabetic cardiomyopathy (DCM); however, effective strategies for the prevention or treatment of DCM have not yet been clarified. METHODS: Leptin receptor-deficient (db/db) mice were treated with either the soluble epoxide hydrolase (sEH) inhibitor AUDA or vehicle alone. A virus carrying Nrf2 shRNA was used to manipulate Nrf2 expression in db/db mice. Cardiac structures and functions were analyzed using echocardiography and hemodynamic examinations. Primary cardiomyocytes cultured under high glucose and high fat (HGHF) conditions were used to conduct in vitro loss-of-function assays after culture in the presence or absence of AUDA (1 microM). Fluorescence microscopy-based detection of mCherry-GFP-LC3 was performed to assess autophagic flux. RESULTS: The sEH inhibitor AUDA significantly attenuated ventricular remodeling and ameliorated cardiac dysfunction in db/db mice. Interestingly, AUDA upregulated Nrf2 expression and promoted its nuclear translocation in db/db mice and the HGHF-treated cardiomyocytes. Additionally, AUDA increased autophagy and decreased apoptosis in db/db mice heart. Furthermore, the administration of AUDA promoted autophagic flux and elevated LC3-II protein level in the presence of bafilomycin A1. However, AUDA-induced autophagy was abolished, and the antiapoptotic effect was partially inhibited upon Nrf2 knockdown. CONCLUSION: Our findings suggest that the sEH inhibitor AUDA attenuates cardiac remodeling and dysfunction in DCM via increasing autophagy and reducing apoptosis, which is relevant to activate Nrf2 signaling pathway.
ESTHER : Fang_2022_Oxid.Med.Cell.Longev_2022_3773415
PubMedSearch : Fang_2022_Oxid.Med.Cell.Longev_2022_3773415
PubMedID: 35378826

Title : Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism - Wang_2022_Mol.Psychiatry__
Author(s) : Wang L , Mirabella VR , Dai R , Su X , Xu R , Jadali A , Bernabucci M , Singh I , Chen Y , Tian J , Jiang P , Kwan KY , Pak C , Liu C , Comoletti D , Hart RP , Chen C , Sudhof TC , Pang ZP
Ref : Mol Psychiatry , : , 2022
Abstract : Mutations in many synaptic genes are associated with autism spectrum disorders (ASD), suggesting that synaptic dysfunction is a key driver of ASD pathogenesis. Among these mutations, the R451C substitution in the NLGN3 gene that encodes the postsynaptic adhesion molecule Neuroligin-3 is noteworthy because it was the first specific mutation linked to ASDs. In mice, the corresponding Nlgn3 R451C-knockin mutation recapitulates social interaction deficits of ASD patients and produces synaptic abnormalities, but the impact of the NLGN3 R451C mutation on human neurons has not been investigated. Here, we generated human knockin neurons with the NLGN3 R451C and NLGN3 null mutations. Strikingly, analyses of NLGN3 R451C-mutant neurons revealed that the R451C mutation decreased NLGN3 protein levels but enhanced the strength of excitatory synapses without affecting inhibitory synapses; meanwhile NLGN3 knockout neurons showed reduction in excitatory synaptic strengths. Moreover, overexpression of NLGN3 R451C recapitulated the synaptic enhancement in human neurons. Notably, the augmentation of excitatory transmission was confirmed in vivo with human neurons transplanted into mouse forebrain. Using single-cell RNA-seq experiments with co-cultured excitatory and inhibitory NLGN3 R451C-mutant neurons, we identified differentially expressed genes in relatively mature human neurons corresponding to synaptic gene expression networks. Moreover, gene ontology and enrichment analyses revealed convergent gene networks associated with ASDs and other mental disorders. Our findings suggest that the NLGN3 R451C mutation induces a gain-of-function enhancement in excitatory synaptic transmission that may contribute to the pathophysiology of ASD.
ESTHER : Wang_2022_Mol.Psychiatry__
PubMedSearch : Wang_2022_Mol.Psychiatry__
PubMedID: 36280753

Title : Site-selective covalently immobilized alpha 1A adrenergic receptor for thermodynamic and extra-thermodynamic study of four ligands binding to the receptor by chromatographic methods - Yuan_2022_J.Chromatogr.A_1665_462827
Author(s) : Yuan X , Shayiranbieke A , Xu R , Jiang H , Yang Y , Zhang Y , Yin G , Zhao X
Ref : Journal of Chromatography A , 1665 :462827 , 2022
Abstract : Immobilized G protein-coupled receptor is a versatile tool to study ligand-receptor interactions. In this work, we synthesized the immobilized alpha 1A adrenergic receptor (alpha(1A)-AR), a GPCR subtype mediating smooth muscle contraction, through a site-selective covalent method that relies on the reaction between haloalkane dehalogenase tagged alpha(1A)-AR and macroporous silica gel coated with 6-chlorohexanoic acid. To investigate thermodynamic and extra-thermodynamic parameters for ligand binding, we utilized the covalently immobilized receptor as stationary phase to perform frontal analysis and injection-amount dependent analysis as well as compared with the random immobilization method. Terazosin gave the association constant of 1.48 x 10(5) M(-1) to alpha(1A)-AR, indicating that the oriented immobilization of alpha(1A)-AR enhances the ligand-binding activity by one order of magnitude in comparison with the random immobilization method (7.9 x 10(4) M(-1)). The binding of phentolamine and tamsulosin to the receptor was accompanied by a large absolute heat capacity (deltaC(p)) of 1.28 +/- 0.23 kJ mol(-1), demonstrating that the binding enthalpy and entropy appear to compensate for one another. These results indicated that the covalent immobilization of the receptor onto solid support has a profound impact on the ligand-binding activity of the receptor and the determination of ligand-receptor binding parameters. The receptor immobilized through the site-selective method will act as a benchmark for chromatographic determination of binding parameters in ligand-receptor interactions and can be used as an effective approach for rapid analysis of drug-protein interactions with high accuracy.
ESTHER : Yuan_2022_J.Chromatogr.A_1665_462827
PubMedSearch : Yuan_2022_J.Chromatogr.A_1665_462827
PubMedID: 35078002

Title : Design, synthesis, and evaluation of novel O-alkyl ferulamide derivatives as multifunctional ligands for treating Alzheimer's disease - Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
Author(s) : Zhu G , Bai P , Wang K , Mi J , Yang J , Hu J , Ban Y , Xu R , Chen R , Wang C , Tang L , Sang Z
Ref : J Enzyme Inhib Med Chem , 37 :1375 , 2022
Abstract : Herein, a series of novel O-alkyl ferulamide derivatives were designed and synthesised through the multi-target-directed ligands (MTDLs) strategy. The biological activities in vitro showed that compounds 5a, 5d, 5e, 5f, and 5h indicated significantly selective MAO-B inhibitory potency (IC(50) = 0.32, 0.56, 0.54, 0.73, and 0.86 microM, respectively) and moderate antioxidant activity. Moreover, compounds 5a, 5d, 5e, 5f, and 5h showed potent anti-inflammatory properties, remarkable effects on self-induced Abeta(1-42) aggregation, and potent neuroprotective effect on Abeta(1-42)-induced PC12 cell injury. Furthermore, compounds 5a, 5d, 5e, 5f, and 5h presented good blood-brain barrier permeation in vitro and drug-like properties. More interesting, the PET/CT images with [(11)C]5f demonstrated that [(11)C]5f could penetrate the BBB with a high brain uptake and exhibited good brain clearance kinetic property. Therefore, compound 5f would be a promising multi-functional agent for the treatment of AD.
ESTHER : Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
PubMedSearch : Zhu_2022_J.Enzyme.Inhib.Med.Chem_37_1375
PubMedID: 35549612

Title : Identification, characterization and mRNA transcript abundance profiles of the carboxylesterase (CXE5) gene in Eriocheir sinensis suggest that it may play a role in methyl farnesoate degradation - Li_2021_Comp.Biochem.Physiol.B.Biochem.Mol.Biol__110630
Author(s) : Li X , Chen T , Xu R , Huang M , Huang J , Xie Q , Liu F , Su S , Ma K
Ref : Comparative Biochemistry & Physiology B Biochem Mol Biol , :110630 , 2021
Abstract : The sesquiterpenoid methyl farnesoate (MF) is a de-epoxidized form of insect juvenile hormone (JH) III in crustaceans, and its precise titer plays important roles in regulating many critical physiological processes, including reproduction and ovarian maturation. Understanding the synthetic and degradation pathways of MF is equally important for determining how to maintain MF titers at appropriate levels and thus for potential applications in crab aquaculture. Although the synthetic pathway of MF has been well established, little is known about MF degradation. Previous research proposed that specific carboxylesterases (CXEs) that degrade MF in crustaceans are conserved from those of JH III. In this study, we identified a novel Es-CXE5 gene from Eriocheir sinensis. The Es-CXE5 protein contains some conserved motifs, including catalytic triad and oxyanion hole, which are characteristics of the biologically active CXE family. The phylogenetic analysis showed that Es-CXE5 belongs to the hormone/semiochemical processing group of the CXE family. Moreover, Tissue and stage-specific expression results suggested that Es-CXE5 expression in hepatopancreas was highest and associated with the hemolymph MF titer. Furthermore, Es-CXE5 mRNA transcripts were detected in both in vitro and in vivo experiments and ESA experiment in the hepatopancreas and ovary. The results of this study showed that Es-CXE5 mRNA abundance in the hepatopancreas was notably induced by MF addition but had no effect on the ovary. Taken together, our results suggest that Es-CXE5 may degrade MF in the hepatopancreas and may thus be involved in ovarian development in E. sinensis.
ESTHER : Li_2021_Comp.Biochem.Physiol.B.Biochem.Mol.Biol__110630
PubMedSearch : Li_2021_Comp.Biochem.Physiol.B.Biochem.Mol.Biol__110630
PubMedID: 34062270
Gene_locus related to this paper: erisi-a0a7d5ly28

Title : Development and characterization of a selective chromatographic approach to the rapid discovery of ligands binding to muscarinic-3 acetylcholine receptor - Zhao_2021_J.Chromatogr.A_1653_462443
Author(s) : Zhao X , Fu X , Yuan X , Shayiranbieke A , Xu R , Cao F , Ren J , Liang Q
Ref : Journal of Chromatography A , 1653 :462443 , 2021
Abstract : The pursuit of new ligands binding to muscarinic-3 acetylcholine receptor (M(3)R) is viewed as challenging due to the lack of screening methods with high efficiency. To address such challenges, this work developed and characterized an approach to the rapid discovery of M(3)R ligands using the immobilized receptor as the chromatographic stationary phase. We fused haloalkane dehalogenase (Halo) as a tag at the C-terminus of M(3)R. The fusion M(3)R was immobilized on 6-chlorocaproic acid-activated ammino-microspheres by the specific covalent reaction between the Halo-tag and the linker. Comprehensive characterizations of the immobilized M(3)R were performed by scanning electron microscope, X-ray photoelectron spectroscopy, and the investigation on the binding of three specific ligands to the receptor. The feasibility of the immobilized M(3)R in complex matrices was tested by screening the bioactive compounds in Zhisou oral liquid, assessing the interaction between the screened compounds and the receptor using zonal elution, and evaluating the in vivo activity of the targeted compounds. The results evidenced that the immobilized M(3)R has high specificity, good stability, and the capacity to separate M(3)R ligands from complex matrices. These allowed us to identify naringin, hesperidin, liquiritigenin, platycodin D, and glycyrrhizic acid as the potential ligands of M(3)R. The association constants of the five compounds to M(3)R were 4.44 x 10(4), 1.11 x 10(4), 7.20 x 10(4), 4.15 x 10(4), and 3.36 x 10(4) M(-1). The synergistic application of the five compounds exhibited an equivalent expectorant activity to the original formula. We reasoned that the current method is possible to provide a highly efficient strategy for the discovery of receptor ligands.
ESTHER : Zhao_2021_J.Chromatogr.A_1653_462443
PubMedSearch : Zhao_2021_J.Chromatogr.A_1653_462443
PubMedID: 34365202

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

Title : Design, synthesis and evaluation of pterostilbene beta-amino alcohol derivatives as multifunctional agents for Alzheimer's disease treatment - Zheng_2018_Bioorg.Chem_78_298
Author(s) : Zheng Y , Qiang X , Xu R , Song Q , Tian C , Liu H , Li W , Tan Z , Deng Y
Ref : Bioorg Chem , 78 :298 , 2018
Abstract : A series of pterostilbene beta-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC50=24.04muM), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. Moreover, 5f also showed self-induced Abeta1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro. These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD.
ESTHER : Zheng_2018_Bioorg.Chem_78_298
PubMedSearch : Zheng_2018_Bioorg.Chem_78_298
PubMedID: 29625269

Title : Multifunctional 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives with acetylcholinesterase, monoamine oxidases and beta-amyloid aggregation inhibitory activities as potential agents against Alzheimer's disease - Xu_2018_Bioorg.Med.Chem_26_1885
Author(s) : Xu R , Xiao G , Li Y , Liu H , Song Q , Zhang X , Yang Z , Zheng Y , Tan Z , Deng Y
Ref : Bioorganic & Medicinal Chemistry , 26 :1885 , 2018
Abstract : A series of 5,6-dimethoxybenzo[d]isothiazol-3(2H)-one-N-alkylbenzylamine derivatives were designed, synthesized and evaluated as potential multifunctional agents for the treatment of Alzheimer's disease (AD). The in vitro assays indicated that most of these derivatives were selective AChE inhibitors with good multifunctional properties. Among them, compounds 11b and 11d displayed comprehensive advantages, with good AChE (IC50=0.29+/-0.01muM and 0.46+/-0.02muM, respectively), MAO-A (IC50=8.2+/-0.08muM and 7.9+/-0.07muM, respectively) and MAO-B (IC50=20.1+/-0.16muM and 43.8+/-2.0% at 10muM, respectively) inhibitory activities, moderate self-induced Abeta1-42 aggregation inhibitory potency (35.4+/-0.42% and 48.0+/-1.53% at 25muM, respectively) and potential antioxidant activity. In addition, the two representative compounds displayed high BBB permeability in vitro. Taken together, these multifunctional properties make 11b and 11d as a promising candidate for the development of efficient drugs against AD.
ESTHER : Xu_2018_Bioorg.Med.Chem_26_1885
PubMedSearch : Xu_2018_Bioorg.Med.Chem_26_1885
PubMedID: 29500132

Title : Design, synthesis and evaluation of scutellarein-O-acetamidoalkylbenzylamines as potential multifunctional agents for the treatment of Alzheimer's disease - Sang_2017_Eur.J.Med.Chem_135_307
Author(s) : Sang Z , Qiang X , Li Y , Xu R , Cao Z , Song Q , Wang T , Zhang X , Liu H , Tan Z , Deng Y
Ref : Eur Journal of Medicinal Chemistry , 135 :307 , 2017
Abstract : A series of scutellarein-O-acetamidoalkylbenzylamines derivatives were designed based on a multitarget-directed ligands strategy for the treatment of Alzheimer's disease. Among these compounds, compound T-22 demonstrated excellent acetylcholinesterase inhibitory, moderate inhibitory effects on self-induced Abeta1-42 aggregation, Cu2+-induced Abeta1-42 aggregation, human AChE-induced Abeta1-40 aggregation and disassembled Cu2+-induced aggregation of the well-structured Abeta1-42 fibrils, and also acted as potential antioxidant and biometals chelator. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that T-22 interacted with both the catalytic active site and peripheral anionic site of AChE. Moreover, compound T-22 showed a good neuroprotective effect against H2O2-induced PC12 cell injury and low toxicity in SH-SY5Y cells. Furthermore, the step-down passive avoidance test indicated T-22 significantly reversed scopolamine-induced memory deficit in mice. Taken together, the data showed that T-22 was an interesting multifunctional lead compound worthy of further study for AD.
ESTHER : Sang_2017_Eur.J.Med.Chem_135_307
PubMedSearch : Sang_2017_Eur.J.Med.Chem_135_307
PubMedID: 28458136

Title : Multifunctional thioxanthone derivatives with acetylcholinesterase, monoamine oxidases and beta-amyloid aggregation inhibitory activities as potential agents against Alzheimer's disease - Luo_2017_Bioorg.Med.Chem_25_1997
Author(s) : Luo L , Li Y , Qiang X , Cao Z , Xu R , Yang X , Xiao G , Song Q , Tan Z , Deng Y
Ref : Bioorganic & Medicinal Chemistry , 25 :1997 , 2017
Abstract : A series of 1-hydroxyl-3-aminoalkoxy-thioxanthone derivatives were designed, synthesized and evaluated as potential multifunctional agents against Alzheimer's disease (AD). The results indicated that most of these compounds exhibited good AChE and MAOs inhibitory activities, significant inhibition of self- and Cu2+-induced Abeta1-42 aggregation, and moderate to good antioxidant activities. Specifically, compound 9e displayed high inhibitory potency toward AChE (IC50=0.59+/-0.02muM), MAO-A and MAO-B (IC50=1.01+/-0.02muM and 0.90+/-0.01muM respectively), excellent efficiency to block both self- and Cu2+-induced Abeta1-42 aggregation (74.8+/-1.2% and 87.7+/-1.9% at 25muM, respectively), good metal-chelating property and a low toxicity in SH-SY5Y cells. Furthermore, kinetic and molecular modeling studies revealed that compound 9e binds simultaneously to the catalytic active site and peripheral anionic site of AChE, and could penetrate the BBB. Collectively, these results suggested that 9e might be a potential multifunctional agent for further development in the treatment of AD.
ESTHER : Luo_2017_Bioorg.Med.Chem_25_1997
PubMedSearch : Luo_2017_Bioorg.Med.Chem_25_1997
PubMedID: 28237559

Title : Pyridoxine-resveratrol hybrids Mannich base derivatives as novel dual inhibitors of AChE and MAO-B with antioxidant and metal-chelating properties for the treatment of Alzheimer's disease - Yang_2017_Bioorg.Chem_71_305
Author(s) : Yang X , Qiang X , Li Y , Luo L , Xu R , Zheng Y , Cao Z , Tan Z , Deng Y
Ref : Bioorg Chem , 71 :305 , 2017
Abstract : A series of pyridoxine-resveratrol hybrids Mannich base derivatives as multifunctional agents have been designed, synthesized and evaluated for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activity. To further explore the multifunctional properties of the new derivatives, their antioxidant activities and metal-chelating properties were also tested. The results showed that most of these compounds could selectively inhibit acetylcholinesterase (AChE) and MAO-B. Among them, compounds 7d and 8b exhibited the highest potency for AChE inhibition with IC50 values of 2.11muM and 1.56muM, respectively, and compound 7e exhibited the highest MAO-B inhibition with an IC50 value of 2.68muM. The inhibition kinetic analysis revealed that compound 7d showed a mixed-type inhibition, binding simultaneously to the CAS and PAS of AChE. Molecular modeling study was also performed to investigate the binding mode of these hybrids with MAO-B. In addition, all target compounds displayed good antioxidant and metal-chelating properties. Taken together, these preliminary findings can be a new starting point for further development of multifunctional agents for Alzheimer's disease.
ESTHER : Yang_2017_Bioorg.Chem_71_305
PubMedSearch : Yang_2017_Bioorg.Chem_71_305
PubMedID: 28267984

Title : Design, synthesis and biological evaluation of 4'-aminochalcone-rivastigmine hybrids as multifunctional agents for the treatment of Alzheimer's disease - Xiao_2017_Bioorg.Med.Chem_25_1030
Author(s) : Xiao G , Li Y , Qiang X , Xu R , Zheng Y , Cao Z , Luo L , Yang X , Sang Z , Su F , Deng Y
Ref : Bioorganic & Medicinal Chemistry , 25 :1030 , 2017
Abstract : A series of 4'-aminochalcone-revastigmine hybrids were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease. The results showed that most of these compounds exhibited good multifunctional activities. In particular, compound 6c displayed the best inhibitory potency on acetylcholinesterase (IC50=4.91muM), and significant antioxidative activity with a value 2.83-fold of Trolox. The kinetic analysis of AChE inhibition revealed that 6c showed mixed-type inhibition, binding simultaneously to the catalytic active site and peripheral anionic site of AChE. In addition, 6c inhibited self-induced Abeta1-42 aggregation and Cu2+-induced Abeta1-42 aggregation by 89.5% and 79.7% at 25muM respectively, as well as acted as a selective monoamine oxidase B inhibitor (IC50=0.29muM) and a selective biometal chelator. Furthermore, 6c could cross the blood-brain barrier in vitro. Based on these results, Compound 6c could be considered as a very promising lead compound for Alzheimer's disease.
ESTHER : Xiao_2017_Bioorg.Med.Chem_25_1030
PubMedSearch : Xiao_2017_Bioorg.Med.Chem_25_1030
PubMedID: 28011206

Title : N-Glycolylneuraminic acid deficiency worsens cardiac and skeletal muscle pathophysiology in alpha-sarcoglycan-deficient mice - Martin_2013_Glycobiology_23_833
Author(s) : Martin PT , Camboni M , Xu R , Golden B , Chandrasekharan K , Wang CM , Varki A , Janssen PM
Ref : Glycobiology , 23 :833 , 2013
Abstract : Roughly 3 million years ago, an inactivating deletion occurred in CMAH, the human gene encoding CMP-Neu5Ac (cytidine-5'-monophospho-N-acetylneuraminic acid) hydroxylase (Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A. 1998. A mutation in human CMP-sialic acid hydroxylase occurred after the Homo-Pan divergence. Proc Natl Acad Sci USA. 95:11751-11756). This inactivating deletion is now homozygous in all humans, causing the loss of N-glycolylneuraminic acid (Neu5Gc) biosynthesis in all human cells and tissues. The CMAH enzyme is active in other mammals, including mice, where Neu5Gc is an abundant form of sialic acid on cellular membranes, including those in cardiac and skeletal muscle. We recently demonstrated that the deletion of mouse Cmah worsened the severity of pathophysiology measures related to muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy (Chandrasekharan K, Yoon JH, Xu Y, deVries S, Camboni M, Janssen PM, Varki A, Martin PT. 2010. A human-specific deletion in mouse Cmah increases disease severity in the mdx model of Duchenne muscular dystrophy. Sci Transl Med. 2:42-54). Here, we demonstrate similar changes in cardiac and skeletal muscle pathology and physiology resulting from Cmah deletion in alpha-sarcoglycan-deficient (Sgca(-/-)) mice, a model for limb girdle muscular dystrophy 2D. These experiments demonstrate that loss of mouse Cmah can worsen disease severity in more than one form of muscular dystrophy and suggest that Cmah may be a general genetic modifier of muscle disease.
ESTHER : Martin_2013_Glycobiology_23_833
PubMedSearch : Martin_2013_Glycobiology_23_833
PubMedID: 23514716

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 : Distinct contributions of Galgt1 and Galgt2 to carbohydrate expression and function at the mouse neuromuscular junction - Singhal_2012_Mol.Cell.Neurosci_51_112
Author(s) : Singhal N , Xu R , Martin PT
Ref : Molecular & Cellular Neurosciences , 51 :112 , 2012
Abstract : At the mammalian neuromuscular junction (NMJ), the CT (cytotoxic T cell) carbohydrate antigen [GalNAcbeta1,4[Neu5Ac/Gcalpha2,3]Galbeta1,4GlcNAc-] is a unique synaptic cell surface carbohydrate present in both the presynaptic and postsynaptic membranes. Here we show that Galgt1, which synthesizes the beta1,4GalNAc linkage of the CT carbohydrate on gangliosides, is required for presynaptic expression of the CT carbohydrate at the NMJ, while Galgt2, which can synthesize the beta1,4GalNAc of the CT carbohydrate on glycoproteins, is required for postsynaptic expression. Proper postsynaptic localization of the CT carbohydrate also required muscle expression of dystroglycan, a known muscle substrate for Galgt2. Transgenic overexpression of Galgt2 in skeletal myofibers altered the expression of synaptic muscle proteins and altered neuromuscular topography, which was partially NCAM-dependent, while an increase in postsynaptic AChR-rich domains was observed in both neuron- and skeletal muscle-specific Galgt2 transgenic mice. By contrast, overexpression of Galgt1 in muscle did not allow for increased expression of CT carbohydrate on the sarcolemmal membrane and instead caused muscle pathology. Loss of Galgt2 increased intracellular accumulation of acetylcholine receptors and acetylcholinesterase within skeletal myofibers, suggesting an additional role for Galgt2 in neuromuscular stability. These experiments demonstrate that Galgt1 and Galgt2 contribute in distinct ways to the expression and function of synaptic betaGalNAc-containing carbohydrates at the NMJ.
ESTHER : Singhal_2012_Mol.Cell.Neurosci_51_112
PubMedSearch : Singhal_2012_Mol.Cell.Neurosci_51_112
PubMedID: 22982027

Title : Comparative proteomic profiling of dystroglycan-associated proteins in wild type, mdx, and Galgt2 transgenic mouse skeletal muscle - Yoon_2012_J.Proteome.Res_11_4413
Author(s) : Yoon JH , Johnson E , Xu R , Martin LT , Martin PT , Montanaro F
Ref : J Proteome Res , 11 :4413 , 2012
Abstract : Dystroglycan is a major cell surface glycoprotein receptor for the extracellular matrix in skeletal muscle. Defects in dystroglycan glycosylation cause muscular dystrophy and alterations in dystroglycan glycosylation can impact extracellular matrix binding. Here we describe an immunoprecipitation technique that allows isolation of beta dystroglycan with members of the dystrophin-associated protein complex (DAPC) from detergent-solubilized skeletal muscle. Immunoprecipitation, coupled with shotgun proteomics, has allowed us to identify new dystroglycan-associated proteins and define changed associations that occur within the DAPC in dystrophic skeletal muscles. In addition, we describe changes that result from overexpression of Galgt2, a normally synaptic muscle glycosyltransferase that can modify alpha dystroglycan and inhibit the development of muscular dystrophy when it is overexpressed. These studies identify new dystroglycan-associated proteins that may participate in dystroglycan's roles, both positive and negative, in muscular dystrophy.
ESTHER : Yoon_2012_J.Proteome.Res_11_4413
PubMedSearch : Yoon_2012_J.Proteome.Res_11_4413
PubMedID: 22775139

Title : Design and synthesis of pyrimidinone and pyrimidinedione inhibitors of dipeptidyl peptidase IV - Zhang_2011_J.Med.Chem_54_510
Author(s) : Zhang Z , Wallace MB , Feng J , Stafford JA , Skene RJ , Shi L , Lee B , Aertgeerts K , Jennings A , Xu R , Kassel DB , Kaldor SW , Navre M , Webb DR , Gwaltney SL
Ref : Journal of Medicinal Chemistry , 54 :510 , 2011
Abstract : The discovery of two classes of heterocyclic dipeptidyl peptidase IV (DPP-4) inhibitors, pyrimidinones and pyrimidinediones, is described. After a single oral dose, these potent, selective, and noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and lowering of blood glucose in animal models of diabetes. Compounds 13a, 27b, and 27j were selected for development.
ESTHER : Zhang_2011_J.Med.Chem_54_510
PubMedSearch : Zhang_2011_J.Med.Chem_54_510
PubMedID: 21186796
Gene_locus related to this paper: human-DPP4

Title : Overexpression of Galgt2 in skeletal muscle prevents injury resulting from eccentric contractions in both mdx and wild-type mice - Martin_2009_Am.J.Physiol.Cell.Physiol_296_C476
Author(s) : Martin PT , Xu R , Rodino-Klapac LR , Oglesbay E , Camboni M , Montgomery CL , Shontz K , Chicoine LG , Clark KR , Sahenk Z , Mendell JR , Janssen PM
Ref : American Journal of Physiology Cell Physiol , 296 :C476 , 2009
Abstract : The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:beta1,4-N-acetylgalactosaminyltransferase that is localized to the neuromuscular synapse in adult skeletal muscle, where it creates the synaptic CT carbohydrate antigen {GalNAcbeta1,4[NeuAc(orGc)alpha2, 3]Galbeta1,4GlcNAcbeta-}. Overexpression of Galgt2 in the skeletal muscles of transgenic mice inhibits the development of muscular dystrophy in mdx mice, a model for Duchenne muscular dystrophy. Here, we provide physiological evidence as to how Galgt2 may inhibit the development of muscle pathology in mdx animals. Both Galgt2 transgenic wild-type and mdx skeletal muscles showed a marked improvement in normalized isometric force during repetitive eccentric contractions relative to nontransgenic littermates, even using a paradigm where nontransgenic muscles had force reductions of 95% or more. Muscles from Galgt2 transgenic mice, however, showed a significant decrement in normalized specific force and in hindlimb and forelimb grip strength at some ages. Overexpression of Galgt2 in muscles of young adult mdx mice, where Galgt2 has no effect on muscle size, also caused a significant decrease in force drop during eccentric contractions and increased normalized specific force. A comparison of Galgt2 and microdystrophin overexpression using a therapeutically relevant intravascular gene delivery protocol showed Galgt2 was as effective as microdystrophin at preventing loss of force during eccentric contractions. These experiments provide a mechanism to explain why Galgt2 overexpression inhibits muscular dystrophy in mdx muscles. That overexpression also prevents loss of force in nondystrophic muscles suggests that Galgt2 is a therapeutic target with broad potential applications.
ESTHER : Martin_2009_Am.J.Physiol.Cell.Physiol_296_C476
PubMedSearch : Martin_2009_Am.J.Physiol.Cell.Physiol_296_C476
PubMedID: 19109526

Title : Overexpression of Galgt2 reduces dystrophic pathology in the skeletal muscles of alpha sarcoglycan-deficient mice - Xu_2009_Am.J.Pathol_175_235
Author(s) : Xu R , deVries S , Camboni M , Martin PT
Ref : American Journal of Pathology , 175 :235 , 2009
Abstract : Recent studies have shown that a number of genes that are not mutated in various forms of muscular dystrophy may serve as surrogates to protect skeletal myofibers from injury. One such gene is Galgt2, which is also called cytotoxic T cell GalNAc transferase in mice. In this study, we show that Galgt2 overexpression reduces the development of dystrophic pathology in the skeletal muscles of mice lacking alpha sarcoglycan (Sgca), a mouse model for limb girdle muscular dystrophy 2D. Galgt2 transgenic Sgca(-/-) mice showed reduced levels of myofiber damage, as evidenced by i) normal levels of serum creatine kinase activity, ii) a lack of Evans blue dye uptake into myofibers, iii) normal levels of mouse locomotor activity, and iv) near normal percentages of myofibers with centrally located nuclei. In addition, the overexpression of Galgt2 in the early postnatal period using an adeno-associated virus gene therapy vector protected Sgca(-/-) myofibers from damage, as observed using histopathology measurements. Galgt2 transgenic Sgca(-/-) mice also had increased levels of glycosylation of alpha dystroglycan with the CT carbohydrate, but showed no up-regulation of beta, gamma, delta, or epsilon sarcoglycan. These data, coupled with results from our previous studies, show that Galgt2 has therapeutic effects in three distinct forms of muscular dystrophy and may, therefore, have a broad spectrum of therapeutic potential for the treatment of various myopathies.
ESTHER : Xu_2009_Am.J.Pathol_175_235
PubMedSearch : Xu_2009_Am.J.Pathol_175_235
PubMedID: 19498002

Title : The synaptic CT carbohydrate modulates binding and expression of extracellular matrix proteins in skeletal muscle: Partial dependence on utrophin - Yoon_2009_Mol.Cell.Neurosci_41_448
Author(s) : Yoon JH , Chandrasekharan K , Xu R , Glass M , Singhal N , Martin PT
Ref : Molecular & Cellular Neurosciences , 41 :448 , 2009
Abstract : The CT carbohydrate, Neu5Ac/Neu5Gcalpha2,3[GalNAcbeta1,4]Galbeta1,4GlcNAcbeta-, is specifically expressed at the neuromuscular junction in skeletal myofibers of adult vertebrates. When Galgt2, the glycosyltransferase that creates the synaptic beta1,4GalNAc portion of this glycan, is overexpressed in extrasynaptic regions of the myofiber membrane, alpha dystroglycan becomes glycosylated with the CT carbohydrate and this coincides with the ectopic expression of synaptic dystroglycan-binding proteins, including laminin alpha4, laminin alpha5, and utrophin. Here we show that both synaptic and extrasynaptic forms of laminin and agrin have increased binding to the CT carbohydrate compared to sialyl-N-acetyllactosamine, its extrasynaptically expressed precursor. Muscle laminins also show increased binding to CT-glycosylated muscle alpha dystroglycan relative to its non-CT-containing glycoforms. Overexpression of Galgt2 in transgenic mouse skeletal muscle increased the mRNA expression of extracellular matrix (ECM) genes, including agrin and laminin alpha5, as well as utrophin, integrin alpha7, and neuregulin. Increased expression of ECM proteins in Galgt2 transgenic skeletal muscles was partially dependent on utrophin, but utrophin was not required for Galgt2-induced changes in muscle growth or neuromuscular development. These experiments demonstrate that overexpression of a synaptic carbohydrate can increase both ECM binding to alpha dystroglycan and ECM expression in skeletal muscle, and they suggest a mechanism by which Galgt2 overexpression may inhibit muscular dystrophy and affect neuromuscular development.
ESTHER : Yoon_2009_Mol.Cell.Neurosci_41_448
PubMedSearch : Yoon_2009_Mol.Cell.Neurosci_41_448
PubMedID: 19442736

Title : Muscular dystrophy associated with alpha-dystroglycan deficiency in Sphynx and Devon Rex cats - Martin_2008_Neuromuscul.Disord_18_942
Author(s) : Martin PT , Shelton GD , Dickinson PJ , Sturges BK , Xu R , LeCouteur RA , Guo LT , Grahn RA , Lo HP , North KN , Malik R , Engvall E , Lyons LA
Ref : Neuromuscular Disorders , 18 :942 , 2008
Abstract : Recent studies have identified a number of forms of muscular dystrophy, termed dystroglycanopathies, which are associated with loss of natively glycosylated alpha-dystroglycan. Here we identify a new animal model for this class of disorders in Sphynx and Devon Rex cats. Affected cats displayed a slowly progressive myopathy with clinical and histologic hallmarks of muscular dystrophy including skeletal muscle weakness with no involvement of peripheral nerves or CNS. Skeletal muscles had myopathic features and reduced expression of alpha-dystroglycan, while beta-dystroglycan, sarcoglycans, and dystrophin were expressed at normal levels. In the Sphynx cat, analysis of laminin and lectin binding capacity demonstrated no loss in overall glycosylation or ligand binding for the alpha-dystroglycan protein, only a loss of protein expression. A reduction in laminin-alpha2 expression in the basal lamina surrounding skeletal myofibers was also observed. Sequence analysis of translated regions of the feline dystroglycan gene (DAG1) in affected cats did not identify a causative mutation, and levels of DAG1 mRNA determined by real-time QRT-PCR did not differ significantly from normal controls. Reduction in the levels of glycosylated alpha-dystroglycan by immunoblot was also identified in an affected Devon Rex cat. These data suggest that muscular dystrophy in Sphynx and Devon Rex cats results from a deficiency in alpha-dystroglycan protein expression, and as such may represent a new type of dystroglycanopathy where expression, but not glycosylation, is affected.
ESTHER : Martin_2008_Neuromuscul.Disord_18_942
PubMedSearch : Martin_2008_Neuromuscul.Disord_18_942
PubMedID: 18990577

Title : Structure-based design and synthesis of benzimidazole derivatives as dipeptidyl peptidase IV inhibitors - Wallace_2008_Bioorg.Med.Chem.Lett_18_2362
Author(s) : Wallace MB , Feng J , Zhang Z , Skene RJ , Shi L , Caster CL , Kassel DB , Xu R , Gwaltney SL, 2nd
Ref : Bioorganic & Medicinal Chemistry Lett , 18 :2362 , 2008
Abstract : A novel series of non-covalent, benzimidazole-based inhibitors of DPP-4 has been developed from a small fragment hit using structure-based drug design. A highly versatile synthetic route was created for the development of SAR, which led to the discovery of potent and selective inhibitors with excellent pharmaceutical properties.
ESTHER : Wallace_2008_Bioorg.Med.Chem.Lett_18_2362
PubMedSearch : Wallace_2008_Bioorg.Med.Chem.Lett_18_2362
PubMedID: 18346892
Gene_locus related to this paper: human-DPP4

Title : Immobilization of lipases on hydrophobilized zirconia nanoparticles: highly enantioselective and reusable biocatalysts - Chen_2008_Langmuir_24_8877
Author(s) : Chen YZ , Yang CT , Ching CB , Xu R
Ref : Langmuir , 24 :8877 , 2008
Abstract : Our study has demonstrated for the first time that zirconia nanoparticles modified by a simple carboxylic surfactant of a very long alkyl chain can significantly enhance the activity of the immobilized lipases for asymmetric synthesis in organic media. Zirconia nanoparticles of ca. 20 nm diameter were grafted with carboxylic surfactant modifiers from Tween 85 and erucic acid. The surface of nanoparticles was successfully changed from hydrophilic to hydrophobic. Lipases from Candida rugosa and Pseudomonas cepacia were immobilized on the modified zirconia nanoparticles by adsorption in aqueous solution. The immobilized lipases were used for the resolution of ( R, S)-ibuprofen and ( R, S)-1-phenylethanol through esterification and acylation, respectively, in isooctane organic solvent. When immobilized on erucic acid-modified zirconia, both lipases gave significantly higher activity and enantioselectivity compared with those from their corresponding crude lipase powders. The nanohybrid biocatalysts are stable and can be reused for eight cycles without loss in activity and selectivity. The interaction between the hydrophobic surface of zirconia support and lipases probably induces the conformational rearrangement of lipases into an active, stable form.
ESTHER : Chen_2008_Langmuir_24_8877
PubMedSearch : Chen_2008_Langmuir_24_8877
PubMedID: 18656972

Title : Inactive methyl indole-3-acetic acid ester can be hydrolyzed and activated by several esterases belonging to the AtMES esterase family of Arabidopsis - Yang_2008_Plant.Physiol_147_1034
Author(s) : Yang Y , Xu R , Ma CJ , Vlot AC , Klessig DF , Pichersky E
Ref : Plant Physiol , 147 :1034 , 2008
Abstract : The plant hormone auxin (indole-3-acetic acid [IAA]) is found both free and conjugated to a variety of carbohydrates, amino acids, and peptides. We have recently shown that IAA could be converted to its methyl ester (MeIAA) by the Arabidopsis (Arabidopsis thaliana) enzyme IAA carboxyl methyltransferase 1. However, the presence and function of MeIAA in vivo remains unclear. Recently, it has been shown that the tobacco (Nicotiana tabacum) protein SABP2 (salicylic acid binding protein 2) hydrolyzes methyl salicylate to salicylic acid. There are 20 homologs of SABP2 in the genome of Arabidopsis, which we have named AtMES (for methyl esterases). We tested 15 of the proteins encoded by these genes in biochemical assays with various substrates and identified several candidate MeIAA esterases that could hydrolyze MeIAA. MeIAA, like IAA, exerts inhibitory activity on the growth of wild-type roots when applied exogenously. However, the roots of Arabidopsis plants carrying T-DNA insertions in the putative MeIAA esterase gene AtMES17 (At3g10870) displayed significantly decreased sensitivity to MeIAA compared with wild-type roots while remaining as sensitive to free IAA as wild-type roots. Incubating seedlings in the presence of [(14)C]MeIAA for 30 min revealed that mes17 mutants hydrolyzed only 40% of the [(14)C]MeIAA taken up by plants, whereas wild-type plants hydrolyzed 100% of absorbed [(14)C]MeIAA. Roots of Arabidopsis plants overexpressing AtMES17 showed increased sensitivity to MeIAA but not to IAA. Additionally, mes17 plants have longer hypocotyls and display increased expression of the auxin-responsive DR5:beta-glucuronidase reporter gene, suggesting a perturbation in IAA homeostasis and/or transport. mes17-1/axr1-3 double mutant plants have the same phenotype as axr1-3, suggesting MES17 acts upstream of AXR1. The protein encoded by AtMES17 had a K(m) value of 13 microm and a K(cat) value of 0.18 s(-1) for MeIAA. AtMES17 was expressed at the highest levels in shoot apex, stem, and root of Arabidopsis. Our results demonstrate that MeIAA is an inactive form of IAA, and the manifestations of MeIAA in vivo activity are due to the action of free IAA that is generated from MeIAA upon hydrolysis by one or more plant esterases.
ESTHER : Yang_2008_Plant.Physiol_147_1034
PubMedSearch : Yang_2008_Plant.Physiol_147_1034
PubMedID: 18467465
Gene_locus related to this paper: arath-MES17 , arath-AT4G16690 , arath-AT4G37150 , arath-MES6 , arath-MES7 , arath-MES3 , arath-MES1 , arath-MES18 , arath-MES10 , arath-MES19

Title : Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV - Feng_2007_J.Med.Chem_50_2297
Author(s) : Feng J , Zhang Z , Wallace MB , Stafford JA , Kaldor SW , Kassel DB , Navre M , Shi L , Skene RJ , Asakawa T , Takeuchi K , Xu R , Webb DR , Gwaltney SL, 2nd
Ref : Journal of Medicinal Chemistry , 50 :2297 , 2007
Abstract : Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.
ESTHER : Feng_2007_J.Med.Chem_50_2297
PubMedSearch : Feng_2007_J.Med.Chem_50_2297
PubMedID: 17441705
Gene_locus related to this paper: human-DPP4

Title : Postnatal overexpression of the CT GalNAc transferase inhibits muscular dystrophy in mdx mice without altering muscle growth or neuromuscular development: evidence for a utrophin-independent mechanism - Xu_2007_Neuromuscul.Disord_17_209
Author(s) : Xu R , Camboni M , Martin PT
Ref : Neuromuscular Disorders , 17 :209 , 2007
Abstract : Overexpression of the cytotoxic T cell (CT) GalNAc transferase (Galgt2) in the skeletal muscles of transgenic mdx mice has been reported to inhibit the development of muscular dystrophy. The profound effect of Galgt2 on muscular dystrophy in transgenic mice, where overexpression is begins from embryonic stages, is complicated by its additional effects on muscle growth and neuromuscular structure. Here, we use adeno-associated virus (AAV) to show that overexpression of Galgt2 in skeletal myofibers in the early postnatal period is equally effective in inhibiting muscular dystrophy, but that it does so without altering muscle growth or neuromuscular structure. Unlike embryonic overexpression, postnatal overexpression of Galgt2 did not reproducibly increase the expression of utrophin, synaptic laminins, or dystrophin-associated glycoproteins along infected myofibers. Moreover, Galgt2 overexpression inhibited muscular dystrophy to the same extent in utrophin-deficient mdx muscles as it did in utrophin-expressing mdx muscles. Thus, Galgt2 is a molecular target for therapy in DMD that can be utilized in a manner that separates its clinical benefit from its effects on development, and its clinical benefit is distinct from that achieved by utrophin.
ESTHER : Xu_2007_Neuromuscul.Disord_17_209
PubMedSearch : Xu_2007_Neuromuscul.Disord_17_209
PubMedID: 17300937

Title : Overexpression of the cytotoxic T cell (CT) carbohydrate inhibits muscular dystrophy in the dyW mouse model of congenital muscular dystrophy 1A - Xu_2007_Am.J.Pathol_171_181
Author(s) : Xu R , Chandrasekharan K , Yoon JH , Camboni M , Martin PT
Ref : American Journal of Pathology , 171 :181 , 2007
Abstract : A number of recent studies have demonstrated therapeutic effects of transgenes on the development of muscle pathology in the mdx mouse model for Duchenne muscular dystrophy, but none have been shown also to be effective in mouse models for laminin alpha2-deficient congenital muscular dystrophy (MDC1A). Here, we show that overexpression of the cytotoxic T cell (CT) GalNAc transferase (Galgt2) is effective in inhibiting the development of muscle pathology in the dy(W) mouse model of MDC1A, much as we had previously shown in mdx animals. Embryonic overexpression of Galgt2 in skeletal muscles using transgenic mice or postnatal overexpression using adeno-associated virus both reduced the extent of muscle pathology in dy(W)/dy(W) skeletal muscle. As with mdx mice, embryonic overexpression of the Galgt2 transgene in dy(W)/dy(W) myofibers inhibited muscle growth, whereas postnatal overexpression did not. Both embryonic and postnatal overexpression of Galgt2 in dy(W)/dy(W) muscle increased the expression of agrin, a protein that, in recombinant form, has been shown to ameliorate disease, whereas laminin alpha1, another disease modifier, was not expressed. Galgt2 over-expression also stimulated the glycosylation of a gly-colipid with the CT carbohydrate, and glycolipids accounted for most of the CT-reactive material in postnatal overexpression experiments. These experiments demonstrate that Galgt2 overexpression is effective in altering disease progression in skeletal muscles of dy(W) mice and should be considered as a therapeutic target in MDC1A.
ESTHER : Xu_2007_Am.J.Pathol_171_181
PubMedSearch : Xu_2007_Am.J.Pathol_171_181
PubMedID: 17591965

Title : Introduction of unsaturation into the N-n-alkyl chain of the nicotinic receptor antagonists, NONI and NDNI: effect on affinity and selectivity - Sumithran_2005_AAPS.J_7_E201
Author(s) : Sumithran SP , Crooks PA , Xu R , Zhu J , Deaciuc AG , Wilkins LH , Dwoskin LP
Ref : AAPS J , 7 :E201 , 2005
Abstract : N-n-octylnicotinium iodide (NONI) and N-n-decylnicotinium iodide (NDNI) are selective nicotinic receptor (nAChR) antagonists mediating nicotine-evoked striatal dopamine (DA) release, and inhibiting [3H]nicotine binding, respectively. This study evaluated effects of introducing unsaturation into the N-n-alkyl chains of NONI and NDNI on inhibition of [3H]nicotine and [3H]methyllycaconitine binding (alpha4beta2* and alpha7* nAChRs, respectively), (86)Rb+ efflux and [3H]DA release (agonist or antagonist effects at alpha4beta2* and alpha6beta2*-containing nAChRs, respectively). In the NONI series, introduction of a C3-cis- (NONB3c), C3-trans- (NONB3t), C7-double-bond (NONB7e), or C3-triple-bond (NONB3y) afforded a 4-fold to 250-fold increased affinity for [3H]nicotine binding sites compared with NONI. NONB7e and NONB3y inhibited nicotine-evoked 86Rb+ efflux, indicating alpha4beta2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotine-evoked [3H]DA overflow compared with NONI (IC50 = 0.62 microM; Imax = 89%), with no change in Imax, except for NONB3y (Imax = 50%). In the NDNI series, introduction of a C4-cis- (NDNB4c), C4-trans-double-bond (NDNB4t), or C3-triple-bond (NDNB3y) afforded a 4-fold to 80-fold decreased affinity for [3H]nicotine binding sites compared with NDNI, whereas introduction of a C9 double-bond (NDNB9e) did not alter affinity. NDNB3y and NDNB4t inhibited nicotine-evoked 86Rb+ efflux, indicating antagonism at alpha4beta2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [3H]DA overflow (IC50 = 0.02-0.14 microM, Imax = 90%), as did NDNB4c (IC50 = 0.08 microM; Imax = 50%), whereas NDNB3y showed no inhibition. None of the analogs had significant affinity for alpha7* nAChRs. Thus, unsaturated NONI analogs had enhanced affinity at alpha4beta2*- and alpha6beta2*-containing nAChRs, however a general reduction of affinity at alpha4beta2* and an uncovering of antagonist effects at alpha6beta2*-containing nAChRs were observed with unsaturated NDNI analogs.
ESTHER : Sumithran_2005_AAPS.J_7_E201
PubMedSearch : Sumithran_2005_AAPS.J_7_E201
PubMedID: 16146341

Title : Hydroxynitrile lyase catalysis in ionic liquid-containing systems - Lou_2005_Biotechnol.Lett_27_1387
Author(s) : Lou WY , Xu R , Zong MH
Ref : Biotechnol Lett , 27 :1387 , 2005
Abstract : The cleavage of mandelonitrile catalysed by hydroxynitrile lyases (HNL) from Prunus amygdalus (PaHNL) and Manihot esculenta (MeHNL) proceeded more rapidly in monophasic aqueous media containing 1-propyl-3-methylimidazolium tetrafluoroborate [C4MIm][BF4] than in media containing acetonitrile or THF. Both HNLs were much more thermostable in [C4MIm][BF4] than in acetonitrile or THF. The addition of each of the four ionic liquids 1-butyl-, 1-pentyl- and 1-hexyl-3-methylimidazolium tetrafluoroborates at 2-6% (v/v in the aqueous phase) increased both the enzyme activity and the product e.e. in the PaHNL-catalysed transcyanation in an aqueous/DIPE biphasic system. However, MeHNL was inactivated by the ionic liquids, as indicated by the decreased reaction rate, substrate conversion and product e.e.
ESTHER : Lou_2005_Biotechnol.Lett_27_1387
PubMedSearch : Lou_2005_Biotechnol.Lett_27_1387
PubMedID: 16215854

Title : A general procedure for the enantioselective synthesis of the minor tobacco alkaloids nornicotine, anabasine, and anatabine - Ayers_2005_AAPS.J_7_E752
Author(s) : Ayers JT , Xu R , Dwoskin LP , Crooks PA
Ref : AAPS J , 7 :E752 , 2005
Abstract : The minor tobacco alkaloids nornicotine, anabasine, and anatabine from Nicotiana tobacum are known to possess nicotinic receptor agonist activity, although they are relatively less potent than S-(-)-nicotine, the principal tobacco alkaloid. Previous pharmacological investigations and structure-activity studies have been limited owing to the lack of availability of the optically pure forms of these minor alkaloids. We now report a 2-step synthetic procedure for the enantioselective synthesis of the optical isomers of nornicotine and anabasine, and a modified procedure for the synthesis of anatabine enantiomers. These procedures involve initial formation of the chiral ketimine resulting from the condensation of either 1R, 2R, 5R-(+)- or 1S, 2S, 5S-(-)-2-hydroxy-3-pinanone with 3-(aminomethyl)pyridine followed by enantioselective C-alkylation with an appropriate halogenoalkane or halogenoalkene species, N-deprotection, and base-catalyzed intramolecular ring closure, to form the appropriate, chirally pure minor tobacco alkaloid. Using this approach, the R-(+)- and S-(-)-enantiomers of the above minor tobacco alkaloids were obtained in good overall chemical yield and excellent enantomeric excess.
ESTHER : Ayers_2005_AAPS.J_7_E752
PubMedSearch : Ayers_2005_AAPS.J_7_E752
PubMedID: 16353951

Title : Enzymatic enantioselective transcyanation of silicon-containing aliphatic ketone with (S)-hydroxynitrile lyase from Manihot esculenta - Xu_2004_Appl.Microbiol.Biotechnol_66_27
Author(s) : Xu R , Zong MH , Liu YY , He J , Zhang YY , Lou WY
Ref : Applied Microbiology & Biotechnology , 66 :27 , 2004
Abstract : (S)-Hydroxynitrile lyase from Manihot esculenta (MeHNL) was shown for the first time to be able to catalyze the enantioselective transcyanation of acetyltrimethylsilane (ATMS) with acetone cyanohydrin to form (S)-2-trimethylsilyl-2-hydroxyl-propionitrile in an aqueous/organic biphasic system. To better understand the reaction, various influential variables were examined. The most suitable organic phase, optimal buffer pH, aqueous phase content, shaking rate, temperature, concentration of ATMS, acetone cyanohydrin and crude enzyme were diisopropyl ether (DIPE), 5.4, 13% (v/v), 190 rpm, 40 degrees C, 10 mM, 20 mM, and 35 U/ml, respectively, under which the initial reaction rate, substrate conversion and product enantiomeric excess (e.e.) were 19.5 mM/h, 99.0% and 93.5%, respectively. A comparative study demonstrated that silicon atoms in the substrate had a great effect on the reaction, and that ATMS was a much better substrate for MeHNL than its carbon analogue 3,3-dimethyl-2-butanone (DMBO) with respect to the initial reaction rate, substrate conversion and product e.e. MeHNL has greater affinity towards ATMS than its carbon analogue as indicated by the much lower K(m). The activation energy of MeHNL-catalyzed transcyanation of ATMS was also markedly lower than that of DMBO. The silicon effect on the reaction was rationalized on the basis of the special characteristics of silicon atoms and the catalytic mechanism of MeHNL.
ESTHER : Xu_2004_Appl.Microbiol.Biotechnol_66_27
PubMedSearch : Xu_2004_Appl.Microbiol.Biotechnol_66_27
PubMedID: 15309340

Title : Development of subtype-selective ligands as antagonists at nicotinic receptors mediating nicotine-evoked dopamine release - Crooks_2004_Bioorg.Med.Chem.Lett_14_1869
Author(s) : Crooks PA , Ayers JT , Xu R , Sumithran SP , Grinevich VP , Wilkins LH , Deaciuc AG , Allen DD , Dwoskin LP
Ref : Bioorganic & Medicinal Chemistry Lett , 14 :1869 , 2004
Abstract : N-n-Alkylation of nicotine converts it from an agonist into an antagonist at neuronal nicotinic acetylcholine receptor subtypes mediating nicotine-evoked dopamine release. Conformationally restricted analogues exhibit both high affinity and selectivity at this site, and are able to access the brain due to their ability to act as substrates for the blood-brain barrier choline transporter.
ESTHER : Crooks_2004_Bioorg.Med.Chem.Lett_14_1869
PubMedSearch : Crooks_2004_Bioorg.Med.Chem.Lett_14_1869
PubMedID: 15050618

Title : Neuronal nicotinic acetylcholine receptor binding affinities of boron-containing nicotine analogues - Xu_2001_Bioorg.Med.Chem.Lett_11_1245
Author(s) : Xu R , Dwoskin LP , Grinevich VP , Deaciuc G , Crooks PA
Ref : Bioorganic & Medicinal Chemistry Lett , 11 :1245 , 2001
Abstract : A series of boron-containing nicotine (NIC) analogues 7-9 was synthesized and evaluated for binding to alpha4beta2 and alpha7 nicotinic receptors. Compound ACME-B inhibited [3H]methyllycaconitine binding to rat brain membranes with a similar potency compared to NIC (Ki = 2.4 and 0.77 microM, respectively), but was markedly less potent in inhibiting [3H]NIC binding when compared to NIC (Ki = 0.60 microM and 1.0 nM, respectively). Thus, tethering a two-carbon bridge between the 2-pyridyl and 3'-pyrrolidino carbons of NIC or 7 affords analogues that bind to the alpha7 receptor in a manner similar to NIC, but with a dramatic loss of affinity for the alpha4beta2 receptor.
ESTHER : Xu_2001_Bioorg.Med.Chem.Lett_11_1245
PubMedSearch : Xu_2001_Bioorg.Med.Chem.Lett_11_1245
PubMedID: 11354387

Title : Degradation of acetylcholine receptors at vertebrate neuromuscular junctions -
Author(s) : Salpeter MM , Andreose J , O'Malley JP , Xu R , Fumagalli G , Lomo T
Ref : Annals of the New York Academy of Sciences , 681 :155 , 1993
PubMedID: 8357161