25 results on '"Zhou, Mingyan"'
Search Results
2. Integrating network pharmacology, bioinformatics, and experimental validation to unveil the molecular targets and mechanisms of galangin for treating hepatocellular carcinoma
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Li, Xiaoliang, Zhou, Mingyan, Chen, Weijia, Sun, Jiangbo, Zhao, Yihang, Wang, Gaoan, Wang, Bingshu, Pan, Yipeng, Zhang, Junqing, and Xu, Jian
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- 2024
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3. Physicochemical Characterization, Antioxidant and Anticancer Activity Evaluation of an Acidic Polysaccharide from Alpinia officinarum Hance.
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Wen, Huan, Kuang, Yangjun, Lian, Xiuxia, Li, Hailong, Zhou, Mingyan, Tan, Yinfeng, Zhang, Xuguang, Pan, Yipeng, Zhang, Junqing, and Xu, Jian
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MONOSACCHARIDES ,ALPINIA ,POLYSACCHARIDES ,FOURIER transform infrared spectroscopy ,ANTINEOPLASTIC agents ,GEL permeation chromatography ,NUCLEAR magnetic resonance ,NUCLEAR magnetic resonance spectroscopy ,POLYMER liquid crystals - Abstract
AHP-3a, a triple-helix acidic polysaccharide isolated from Alpinia officinarum Hance, was evaluated for its anticancer and antioxidant activities. The physicochemical properties and structure of AHP-3a were investigated through gel permeation chromatography, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. The weight-average molecular weight of AHP-3a was 484 kDa, with the molar percentages of GalA, Gal, Ara, Xyl, Rha, Glc, GlcA, and Fuc being 35.4%, 21.4%, 16.9%, 11.8%, 8.9%, 3.1%, 2.0%, and 0.5%, respectively. Based on the results of the monosaccharide composition analysis, methylation analysis, and NMR spectroscopy, the main chain of AHP-3a was presumed to consist of (1→4)-α-D-GalpA and (1→2)-α-L-Rhap residues, which is a pectic polysaccharide with homogalacturonan (HG) and rhamnogalacturonan-I (RG-I) structural domains containing side chains. In addition, the results of the antioxidant activity assay revealed that the ability of AHP-3a to scavenge DPPH, ABTS, and OH free radicals increased with an increase in its concentration. Moreover, according to the results from the EdU, wound healing, and Transwell assays, AHP-3a can control the proliferation, migration, and invasion of HepG2 and Huh7 hepatocellular carcinoma cells without causing any damage to healthy cells. Thus, AHP-3a may be a natural antioxidant and anticancer component. [ABSTRACT FROM AUTHOR]
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- 2024
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4. A Benchmark Comparison of Imitation Learning-based Control Policies for Autonomous Racing
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Sun, Xiatao, Zhou, Mingyan, Zhuang, Zhijun, Yang, Shuo, Betz, Johannes, and Mangharam, Rahul
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FOS: Computer and information sciences ,Computer Science - Robotics ,Robotics (cs.RO) - Abstract
Autonomous racing with scaled race cars has gained increasing attention as an effective approach for developing perception, planning and control algorithms for safe autonomous driving at the limits of the vehicle's handling. To train agile control policies for autonomous racing, learning-based approaches largely utilize reinforcement learning, albeit with mixed results. In this study, we benchmark a variety of imitation learning policies for racing vehicles that are applied directly or for bootstrapping reinforcement learning both in simulation and on scaled real-world environments. We show that interactive imitation learning techniques outperform traditional imitation learning methods and can greatly improve the performance of reinforcement learning policies by bootstrapping thanks to its better sample efficiency. Our benchmarks provide a foundation for future research on autonomous racing using Imitation Learning and Reinforcement Learning.
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- 2022
5. Investigation of the Potential Mechanism of Alpinia officinarum Hance in Improving Type 2 Diabetes Mellitus Based on Network Pharmacology and Molecular Docking.
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Zhang, Xuguang, Li, Xiangyi, Li, Hailong, Zhou, Mingyan, Zhang, Yuxin, Lai, Weiyong, Zheng, Xiuwen, Bai, Feihu, and Zhang, Junqing
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PROTEINS ,MEDICINAL plants ,GENETICS ,TYPE 2 diabetes ,CELLULAR signal transduction ,GENOMICS ,TUMOR necrosis factors ,MESSENGER RNA ,DESCRIPTIVE statistics ,RESEARCH funding ,PLANT extracts ,PHARMACEUTICAL chemistry ,COMPUTER-assisted molecular modeling - Abstract
Objective. We used network pharmacology, molecular docking, and cellular analysis to explore the pharmacodynamic components and action mechanism of Alpinia officinarum Hance (A. officinarum) in improving type 2 diabetes mellitus (T2DM). Methods. The protein-protein interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to predict the potential targets and mechanism of A. officinarum toward improving T2DM. The first 9 core targets and potential active compounds were docked using Discovery Studio 2019. Finally, IR-HepG2 cells and qPCR were applied to determine the mRNA expression of the top 6 core targets of the PPI network. Results. A total of 29 active ingredients and 607 targets of A. officinarum were obtained. T2DM-related targets overlapped with 176 targets. The core targets of the PPI network were identified as AKT serine/threonine kinase 1 (AKT1), an activator of transcription 3 (STAT3), tumor necrosis factor (TNF), tumor protein p53 (TP53), SRC proto-oncogene, nonreceptor tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), albumin (ALB), mitogen-activated protein kinase 1 (MAPK1), and peroxisome proliferator-activated receptor gamma (PPARG). A. officinarum performs an antidiabetic role via the AGE-RAGE signaling pathway, the HIF-1 signaling pathway, the PI3K-AKT signaling pathway, and others, according to GO and KEGG enrichment analyses. Molecular docking revealed that the binding ability of diarylheptanoid active components in A. officinarum to core target protein was higher than that of flavonoids. The cell experiments confirmed that the A. officinarum extracts improved the glucose uptake of IR-HepG2 cells and AKT expression while inhibiting the STAT3, TNF, TP53, SRC, and EGFR mRNA expression. Conclusion. A. officinarum Hance improves T2DM by acting on numerous components, multiple targets, and several pathways. Our results lay the groundwork for the subsequent research and broaden the clinical application of A. officinarum Hance. [ABSTRACT FROM AUTHOR]
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- 2023
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6. DPHC From Alpinia officinarum Ameliorates Oxidative Stress and Insulin Resistance via Activation of Nrf2/ARE Pathway in db/db Mice and High Glucose-Treated HepG2 Cells
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Zhang, Xuguang, Zhang, Yuxin, Zhou, Mingyan, Xie, Yiqiang, Dong, Xiujuan, Bai, Feihu, and Zhang, Junqing
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Pharmacology ,DPHC ,insulin resistance ,Nrf2/are ,T2DM ,oxidative stress ,Pharmacology (medical) ,Therapeutics. Pharmacology ,RM1-950 ,Alpinia officinarum ,Original Research - Abstract
(R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC) from the natural plant Alpinia officinarum has been reported to have antioxidation and antidiabetic effects. In this study, the therapeutic effect and molecular mechanism of DPHC on type 2 diabetes mellitus (T2DM) were investigated based on the regulation of oxidative stress and insulin resistance (IR) in vivo and in vitro. In vivo, the fasting blood glucose (FBG) level of db/db mice was significantly reduced with improved glucose tolerance and insulin sensitivity after 8 weeks of treatment with DPHC. In vitro, DPHC ameliorated IR because of its increasing glucose consumption and glucose uptake of IR-HepG2 cells induced by high glucose. In addition, in vitro and in vivo experiments showed that DPHC could regulate the antioxidant enzyme levels including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), thereby reducing the occurrence of oxidative stress and improving insulin resistance. Western blotting and polymerase chain reaction results showed that DPHC could promote the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), the heme oxygenase-1 (HO-1), protein kinase B (AKT), and glucose transporter type 4 (GLUT4), and reduced the phosphorylation levels of c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 (IRS-1) on Ser307 both in vivo and in vitro. These findings verified that DPHC has the potential to relieve oxidative stress and IR to cure T2DM by activating Nrf2/ARE signaling pathway in db/db mice and IR-HepG2 cells.
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- 2022
7. Lipocalin-2 Deficiency Attenuates Insulin Resistance Associated With Aging and Obesity
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Law, Ivy K.M., Xu, Aimin, Lam, Karen S.L., Berger, Thorsten, Mak, Tak W., Vanhoutte, Paul M., Liu, Jacky T.C., Sweeney, Gary, Zhou, Mingyan, Yang, Bo, and Wang, Yu
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- 2010
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8. Overexpression of Angiopoietin-Like Protein 4 Alters Mitochondria Activities and Modulates Methionine Metabolic Cycle in the Liver Tissues of db/db Diabetic Mice
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Wang, Yu, Lam, Karen S. L., Lam, Janice B. B., Lam, Michael C., Leung, Priscilla T. Y., Zhou, Mingyan, and Xu, Aimin
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- 2007
9. Identification and Characterization of a Novel Monoamine Transporter in the Human Brain
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Engel, Karen, Zhou, Mingyan, and Wang, Joanne
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- 2004
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10. Modeling organic molecule transport through nanofiltration membranes
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Zhou, Mingyan, Wu, Ke, Kilduff, James E., Belfort, Georges, Rensselaer Polytechnic Institute, and Universität Leipzig
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diffusion, transport ,ddc:530 - Published
- 2011
11. Metabolic activation of the phenothiazine antipsychotics chlorpromazine and thioridazine to electrophilic iminoquinone species in human liver microsomes and recombinant P450s
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Wen, Bo and Zhou, Mingyan
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ANTIPSYCHOTIC agents , *DRUG activation , *CYTOCHROME P-450 , *PHENOTHIAZINE , *CHLORPROMAZINE , *THIORIDAZINE , *ELECTROPHILES , *HEPATOTOXICOLOGY , *TANDEM mass spectrometry - Abstract
Abstract: The phenothiazine-derived antipsychotics, namely chlorpromazine and thioridazine, have been associated with very rare but severe incidences of hepatotoxicity in patients. While the mechanism of idiosyncratic hepatotoxicity remains unknown, it is possible that metabolic activation and subsequent covalently binding of reactive metabolites to cellular proteins play a causative role. Studies were initiated to determine whether chlorpromazine and thioridazine undergo cytochrome P450 (P450)-mediated bioactivation in human liver microsomes to electrophilic intermediates. LC/MS/MS analysis of incubations containing chlorpromazine or thioridazine in the presence of NADPH and glutathione (GSH) revealed the formation of GSH conjugates derived from the addition of the sulfydryl nucleophile to monohydroxy metabolites of chlorpromazine and thioridazine, respectively. Formation of reactive intermediates of chlorpromazine and thioridazine was primarily mediated by heterologously expressed recombinant CYP2D6, and to a less extent, CYP1A2. The 7-hydroxyl metabolites of chlorpromazine and thioridazine were also detected by tandem mass spectrometry. A tentative pathway states that after initial 7-hydroxylation, a bioactivation sequence involves P450-catalyzed oxidation of the phenothiazine core to an electrophilic quinone imine intermediate, which is subsequently attacked by glutathione yielding the sulfydryl conjugates. The results from the current investigation constitute the first report on the cytochrome P450-catalyzed bioactivation of the phenothiazine antipsychotics chlorpromazine and thioridazine. [Copyright &y& Elsevier]
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- 2009
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12. Podocyte-specific expression of organic cation transporter PMAT: implication in puromycin aminonucleoside nephrotoxicity.
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Xia, Li, Zhou, Mingyan, Kalhorn, Thomas F., Ho, Horace T. B., and Wang, Joanne
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CELL membranes , *PUROMYCIN , *NEPHROTOXICOLOGY , *MONOAMINE oxidase , *CATIONS , *NUCLEOSIDES , *AMINO acid sequence - Abstract
Plasma membrane monoamine transporter (PMAT) is a novel polyspecific organic cation transporter that transports organic cations and the purine nucleoside, adenosine. PMAT is expressed in the kidney, but the specific localization and function of this transporter in renal cells are unclear. In this study, we developed a polyclonal antibody toward a 14-amino acid sequence in the last intracellular loop of PMAT and determined the precise cellular localization of PMAT in human and rat kidneys. Surprisingly, we found that the PMAT protein was predominantly expressed in the glomerulus with minimal expression in tubular cells. Within the glomerulus, dual-color immunofluorescence labeling showed that the PMAT protein was specifically localized to the visceral glomerular epithelial cells, i.e., podocytes. There was no significant PMAT immunoreactivity in mesangial or glomerular endothelial cells. We further showed that puromycin aminonucleoside (PAN), a classic podocyte toxin that induces massive proteinuria and severe glomerulopathy, is transported by PMAT. Expression of PMAT in Madin-Darby canine kidney cells significantly increased cell sensitivity to PAN. Decynium 22, a potent PMAT inhibitor, abolished PAN toxicity in PMAT-expressing cells. Together, our data suggest that PMAT is specifically expressed in podocytes and may play an important role in PAN-induced kidney injury. [ABSTRACT FROM AUTHOR]
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- 2009
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13. Facilitated mitochondrial import of antiviral and anticancer nucleoside drugs by human equilibrative nucleoside transporter-3.
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Govindarajan, Rajgopal, Leung, George P. H., Zhou, Mingyan, Tse, Chung-Ming, Wang, Joanne, and Unadkat, Jashvant D.
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NUCLEOSIDES ,HIV ,MITOCHONDRIA ,IMMUNOFLUORESCENCE ,CELL membranes ,LIVER cells ,LYSOSOMES - Abstract
Human equilibrative nucleoside transporter-3 (hENT3) was recently reported as a pH- dependent, intracellular (lysosomal) transporter capable of transporting anti-human immunodeficiency virus (HIV) dideoxynucleosides (ddNs). Because most anti-HIV ddNs (e.g., zidovudine, AZT) exhibit clinical mitochondrial toxicity, we investigated whether hENT3 facilitates transport of anti-HIV ddNs into the mitochondria. Cellular fractionation and immunofluorescence microscopy studies in several human cell lines identified a substantial presence of hENT3 in the mitochondria, with additional presence at the cell surface of two placental cell lines (JAR, JEG3). Mitochondrial or cell surface hENT3 expression was confirmed in human hepatocytes and placental tissues, respectively. Unlike endogenous hENT3, yellow fluorescent protein (YFP)-tagged hENT3 was partially directed to the lysosomes. Xenopus oocytes expressing NH
2 -terminal-deleted hENT3 (expressed at the cell surface) showed pH-dependent interaction with several classes of nucleosides (anti-HTV ddNs, gemcitabine, fialuridine, ribavirin) that produce mitochondrial toxicity. Transport studies in hENT3 gene-silenced JAR cells showed significant reduction in mitochondrial transport of nucleosides and nucleoside drugs. Our data suggest that cellular localization of hENT3 is cell type dependent and the native transporter is substantially expressed in mitochondria and/or cell surface. hENT3-mediated mitochondrial transport may play an important role in mediating clinically observed mitochondrial toxicity of nucleoside drugs. In addition, our finding that hENT3 is a mitochondrial transporter is consistent with the recent finding that mutations in the hENT3 gene cause an autosomal recessive disorder in humans called the H syndrome. [ABSTRACT FROM AUTHOR]- Published
- 2009
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14. Deficiency of ZnT8 Promotes Adiposity and Metabolic Dysfunction by Increasing Peripheral Serotonin Production.
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Mao, Zhuo, Lin, Hui, Su, Wen, Li, Jinghui, Zhou, Minsi, Li, Zhuoran, Zhou, Beibei, Yang, Qing, Zhou, Mingyan, Pan, Ke, He, Jinhan, and Zhang, Weizhen
- Abstract
ZnT8 is a zinc transporter enriched in pancreatic β-cells, and its polymorphism is associated with increased susceptibility to type 2 diabetes. However, the exact role of ZnT8 in systemic energy metabolism remains elusive. In this study, we found that ZnT8 knockout mice displayed increased adiposity without obvious weight gain. We also observed that the intestinal tract morphology, motility, and gut microbiota were changed in ZnT8 knockout mice. Further study demonstrated that ZnT8 was expressed in enteroendocrine cells, especially in 5-hydroxytryptamine (5-HT)-positive enterochromaffin cells. Lack of ZnT8 resulted in an elevated circulating 5-HT level owing to enhanced expression of tryptophan hydroxylase 1. Blocking 5-HT synthesis in ZnT8-deficient mice restored adiposity, high-fat diet-induced obesity, and glucose intolerance. Moreover, overexpression of human ZnT8 diabetes high-risk allele R325W increased 5-HT levels relative to the low-risk allele in RIN14B cells. Our study revealed an unexpected role of ZnT8 in regulating peripheral 5-HT biogenesis and intestinal microenvironment, which might contribute to the increased risk of obesity and type 2 diabetes. [ABSTRACT FROM AUTHOR]
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- 2019
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15. Genome-wide Analyses of Chromatin State in Human Mast Cells Reveal Molecular Drivers and Mediators of Allergic and Inflammatory Diseases.
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Cildir, Gökhan, Toubia, John, Yip, Kwok Ho, Zhou, Mingyan, Pant, Harshita, Hissaria, Pravin, Zhang, Jingxian, Hong, Wanjin, Robinson, Nirmal, Grimbaldeston, Michele A., Lopez, Angel F., and Tergaonkar, Vinay
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MAST cells , *HUMAN chromatin , *INFLAMMATORY mediators , *ALLERGIES , *CELL physiology - Abstract
Mast cells (MCs) are versatile immune cells capable of rapidly responding to a diverse range of extracellular cues. Here, we mapped the genomic and transcriptomic changes in human MCs upon diverse stimuli. Our analyses revealed broad H3K4me3 domains and enhancers associated with activation. Notably, the rise of intracellular calcium concentration upon immunoglobulin E (IgE)-mediated crosslinking of the high-affinity IgE receptor (FcεRI) resulted in genome-wide reorganization of the chromatin landscape and was associated with a specific chromatin signature, which we term Ca2+-dependent open chromatin (COC) domains. Examination of differentially expressed genes revealed potential effectors of MC function, and we provide evidence for fibrinogen-like protein 2 (FGL2) as an MC mediator with potential relevance in chronic spontaneous urticaria. Disease-associated single-nucleotide polymorphisms mapped onto cis -regulatory regions of human MCs suggest that MC function may impact a broad range of pathologies. The datasets presented here constitute a resource for the further study of MC function. • Enhancers and broad H3K4me3 domains are enriched in genes regulating MC functions • Intracellular calcium levels govern the chromatin landscape upon FcεRI crosslinking • Disease-associated SNPs are enriched in regulatory chromatin regions of human MCs Cildir et al. map the genomic and transcriptomic changes in human mast cells upon diverse stimuli, defining chromatin changes associated with activation and Ca2+ flux and revealing potential effectors of mast cell function. Disease-associated SNPs mapped onto cis -regulatory regions of mast cells suggest that mast cell function may impact a broad range of pathologies. [ABSTRACT FROM AUTHOR]
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- 2019
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16. Risk Factors of Venous Thromboembolism in Inpatients With Colorectal Cancer in China.
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Chen F, Sun Y, Zhang C, Li L, Du Y, Zhou M, and Cheng W
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- Humans, Inpatients, Risk Factors, Retrospective Studies, Venous Thromboembolism epidemiology, Venous Thromboembolism etiology, Thrombosis complications, Colorectal Neoplasms complications, Anemia complications
- Abstract
To explore the risk factors for venous thromboembolism (VTE) in inpatients with colorectal cancer. The demographic factors, comorbidities, and hematological indices of patients with colorectal cancer treated in our hospital from 2016 to 2021 were collected and recorded. Venous thromboembolism events, including deep venous thrombosis and/or pulmonary embolism, were recorded and the patients were divided into the VTE group and the non-VTE group. We compared clinical data between the two groups and explored risk factors for VTE. Comparing the clinical data of 293 cases of non-VTE group and 235 cases of VTE group, we found significant differences in age, smoking, temperature, amount of blood loss, differentiation degree, peripherally inserted central catheter (PICC), radiotherapy, anemia, infection, white blood cell count, prothrombin time (PT), PT%, prothrombin ratio, international normalized ratio, thrombin time, CA199 and CEA between the two groups ( P < 0.05). Logistic regression analysis showed that age ( P = 0.0444), temperature ( P = 0.0317), amount of blood loss ( P = 0.0067), PICC ( P < 0.0001), chemotherapy ( P = 0.0459), anemia ( P = 0.0007), international normalized ratio ( P = 0.003) and CA199 ( p = 0.0234) were independent risk factors for VTE. Receiver operating characteristic curve analysis showed that the amount of blood loss predicted thrombosis better (AUC = 0.778, P < 0.001), when the cutoff value was 20 mL, the sensitivity was 76.17%, and the specificity was 79.18%, respectively. And PICC predicted thrombosis better (AUC = 0.808, P < 0.001), the sensitivity was 70.21%, and the specificity was 91.47%, respectively. Clinical parameters are associated with VTE in inpatients with colorectal cancer, which will help to guide clinicians to take effective measures to improve the patients' prognosis., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2023
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17. Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria.
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Qian M, Liu Z, Peng L, Tang X, Meng F, Ao Y, Zhou M, Wang M, Cao X, Qin B, Wang Z, Zhou Z, Wang G, Gao Z, Xu J, and Liu B
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- Animals, Ataxia Telangiectasia Mutated Proteins deficiency, Ataxia Telangiectasia Mutated Proteins metabolism, Caenorhabditis elegans, DNA Repair, Longevity, Mice, Mice, Knockout, Motor Activity, Phosphorylation, Protein Processing, Post-Translational, Proteolysis, Proto-Oncogene Proteins c-mdm2 metabolism, Chloroquine administration & dosage, Progeria drug therapy, Sirtuins metabolism
- Abstract
DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans , but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases., Competing Interests: MQ, ZL, LP, XT, FM, YA, MZ, MW, XC, BQ, ZW, ZZ, GW, ZG, JX, BL No competing interests declared, (© 2018, Qian et al.)
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- 2018
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18. SIRT7 antagonizes TGF-β signaling and inhibits breast cancer metastasis.
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Tang X, Shi L, Xie N, Liu Z, Qian M, Meng F, Xu Q, Zhou M, Cao X, Zhu WG, and Liu B
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- Animals, Breast Neoplasms genetics, Breast Neoplasms pathology, Cell Line, Cell Line, Tumor, Down-Regulation, Epithelial-Mesenchymal Transition drug effects, Epithelial-Mesenchymal Transition genetics, Gene Expression Regulation, Neoplastic, HEK293 Cells, Humans, Lung Neoplasms genetics, Lung Neoplasms secondary, Mice, Inbred BALB C, Mice, Nude, Mice, Transgenic, RNA Interference, Signal Transduction, Sirtuins genetics, Smad4 Protein metabolism, Transforming Growth Factor beta pharmacology, Transplantation, Heterologous, Breast Neoplasms metabolism, Lung Neoplasms metabolism, Sirtuins metabolism, Transforming Growth Factor beta metabolism
- Abstract
Distant metastasis is the main cause of breast cancer-related death; however, effective therapeutic strategies targeting metastasis are still scarce. This is largely attributable to the spatiotemporal intratumor heterogeneity during metastasis. Here we show that protein deacetylase SIRT7 is significantly downregulated in breast cancer lung metastases in human and mice, and predicts metastasis-free survival. SIRT7 deficiency promotes breast cancer cell metastasis, while temporal expression of Sirt7 inhibits metastasis in polyomavirus middle T antigen breast cancer model. Mechanistically, SIRT7 deacetylates and promotes SMAD4 degradation mediated by β-TrCP1, and SIRT7 deficiency activates transforming growth factor-β signaling and enhances epithelial-to-mesenchymal transition. Significantly, resveratrol activates SIRT7 deacetylase activity, inhibits breast cancer lung metastases, and increases survival. Our data highlight SIRT7 as a modulator of transforming growth factor-β signaling and suppressor of breast cancer metastasis, meanwhile providing an effective anti-metastatic therapeutic strategy.Metastatic disease is the major reason for breast cancer-related deaths; therefore, a better understanding of this process and its players is needed. Here the authors report the role of SIRT7 in inhibiting SMAD4-mediated breast cancer metastasis providing a possible therapeutic avenue.
- Published
- 2017
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19. Histone Deacetylase HDAC8 Promotes Insulin Resistance and β-Catenin Activation in NAFLD-Associated Hepatocellular Carcinoma.
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Tian Y, Wong VW, Wong GL, Yang W, Sun H, Shen J, Tong JH, Go MY, Cheung YS, Lai PB, Zhou M, Xu G, Huang TH, Yu J, To KF, Cheng AS, and Chan HL
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- Animals, Blotting, Western, Carcinogenesis metabolism, Carcinoma, Hepatocellular etiology, Cell Line, Chromatin Immunoprecipitation, Disease Models, Animal, Flow Cytometry, Humans, Immunohistochemistry, Insulin Resistance physiology, Liver Neoplasms etiology, Mice, Mice, Inbred C57BL, Reverse Transcriptase Polymerase Chain Reaction, Transcriptome, Up-Regulation, beta Catenin metabolism, Carcinoma, Hepatocellular enzymology, Histone Deacetylases biosynthesis, Liver Neoplasms enzymology, Non-alcoholic Fatty Liver Disease complications, Obesity complications, Repressor Proteins biosynthesis
- Abstract
The growing epidemic of obesity, which causes nonalcoholic fatty liver disease (NAFLD) and the more severe phenotype nonalcoholic steatohepatitis (NASH), has paralleled the increasing incidence of hepatocellular carcinoma (HCC). Accumulating evidence demonstrates that overnutrition and metabolic pathways can trigger modifications of DNA and histones via deregulation of chromatin modifiers, resulting in aberrant transcriptional activity. However, the epigenetic regulation of HCC development in NAFLD remains obscure. Here, we uncover key epigenetic regulators using both dietary and genetic obesity-promoted HCC models through quantitative expression profiling and characterize the oncogenic activities of histone deacetylase HDAC8 in NAFLD-associated hepatocarcinogenesis. HDAC8 is directly upregulated by the lipogenic transcription factor SREBP-1 where they are coexpressed in dietary obesity models of NASH and HCC. Lentiviral-mediated HDAC8 attenuation in vivo reversed insulin resistance and reduced NAFLD-associated tumorigenicity. HDAC8 modulation by genetic and pharmacologic approaches inhibited p53/p21-mediated apoptosis and G2-M phase cell-cycle arrest and stimulated β-catenin-dependent cell proliferation. Mechanistically, HDAC8 physically interacted with the chromatin modifier EZH2 to concordantly repress Wnt antagonists via histone H4 deacetylation and H3 lysine 27 trimethylation. In human NAFLD-associated HCC, levels of SREBP-1, HDAC8, EZH2, H4 deacetylation, H3K27me3, and active β-catenin were all correlated positively in tumors compared with nontumor tissues. Overall, our findings show how HDAC8 drives NAFLD-associated hepatocarcinogenesis, offering a novel epigenetic target to prevent or treat HCC in obese patients., (©2015 American Association for Cancer Research.)
- Published
- 2015
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20. Selective inhibition of spleen tyrosine kinase (SYK) with a novel orally bioavailable small molecule inhibitor, RO9021, impinges on various innate and adaptive immune responses: implications for SYK inhibitors in autoimmune disease therapy.
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Liao C, Hsu J, Kim Y, Hu DQ, Xu D, Zhang J, Pashine A, Menke J, Whittard T, Romero N, Truitt T, Slade M, Lukacs C, Hermann J, Zhou M, Lucas M, Narula S, DeMartino J, and Tan SL
- Subjects
- Administration, Oral, Aminopyridines chemistry, Aminopyridines pharmacology, Animals, Arthritis, Experimental metabolism, Arthritis, Experimental prevention & control, Autoimmune Diseases drug therapy, Autoimmune Diseases metabolism, B-Lymphocytes drug effects, B-Lymphocytes immunology, B-Lymphocytes metabolism, Cell Line, Tumor, Cells, Cultured, Flow Cytometry, Humans, Intracellular Signaling Peptides and Proteins chemistry, Intracellular Signaling Peptides and Proteins metabolism, Jurkat Cells, Macrophages cytology, Macrophages drug effects, Macrophages metabolism, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Models, Molecular, Molecular Structure, Osteoclasts cytology, Osteoclasts drug effects, Osteoclasts metabolism, Protein Binding, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Protein Structure, Tertiary, Protein-Tyrosine Kinases chemistry, Protein-Tyrosine Kinases metabolism, Pyridazines chemistry, Pyridazines pharmacology, Signal Transduction drug effects, Small Molecule Libraries administration & dosage, Small Molecule Libraries chemistry, Syk Kinase, Adaptive Immunity drug effects, Immunity, Innate drug effects, Intracellular Signaling Peptides and Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Protein-Tyrosine Kinases antagonists & inhibitors, Small Molecule Libraries pharmacology
- Abstract
Introduction: Spleen tyrosine kinase (SYK) is a key integrator of intracellular signals triggered by activated immunoreceptors, including Bcell receptors (BCR) and Fc receptors, which are important for the development and function of lymphoid cells. Given the clinical efficacy of Bcell depletion in the treatment of rheumatoid arthritis and multiple sclerosis, pharmacological modulation of Bcells using orally active small molecules that selectively target SYK presents an attractive alternative therapeutic strategy., Methods: A SYK inhibitor was developed and assayed in various in vitro systems and in the mouse model of collagen-induced arthritis (mCIA)., Results: A novel ATP-competitive inhibitor of SYK, 6-[(1R,2S)-2-Amino-cyclohexylamino]-4-(5,6-dimethyl-pyridin-2-ylamino)-pyridazine-3-carboxylic acid amide, designated RO9021, with an adequate kinase selectivity profile and oral bioavailability, was developed. In addition to suppression of BCR signaling in human peripheral blood mononuclear cells (PBMC) and whole blood, FcγR signaling in human monocytes, and FcϵR signaling in human mast cells, RO9021 blocked osteoclastogenesis from mouse bone marrow macrophages in vitro. Interestingly, Toll-like Receptor (TLR) 9 signaling in human Bcells was inhibited by RO9021, resulting in decreased levels of plasmablasts, immunoglobulin (Ig) M and IgG upon B-cell differentiation. RO9021 also potently inhibited type I interferon production by human plasmacytoid dendritic cells (pDC) upon TLR9 activation. This effect is specific to TLR9 as RO9021 did not inhibit TLR4- or JAK-STAT-mediated signaling. Finally, oral administration of RO9021 inhibited arthritis progression in the mCIA model, with observable pharmacokinetics (PK)-pharmacodynamic (PD) correlation., Conclusions: Inhibition of SYK kinase activity impinges on various innate and adaptive immune responses. RO9021 could serve as a starting point for the development of selective SYK inhibitors for the treatment of inflammation-related and autoimmune-related disorders.
- Published
- 2013
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21. The mechanism of effective electroacupuncture on T cell response in rats with experimental autoimmune encephalomyelitis.
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Liu Y, Wang H, Wang X, Mu L, Kong Q, Wang D, Wang J, Zhang Y, Yang J, Zhou M, Wang G, Sun B, and Li H
- Subjects
- Animals, Apoptosis drug effects, Apoptosis immunology, Cell Proliferation drug effects, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Humans, Multiple Sclerosis pathology, Multiple Sclerosis therapy, Naloxone pharmacology, Rats, Rats, Inbred Lew, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, Th1-Th2 Balance drug effects, Th17 Cells cytology, Th17 Cells drug effects, Th17 Cells immunology, beta-Endorphin pharmacology, Electroacupuncture, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental therapy, Multiple Sclerosis immunology
- Abstract
Previously, we demonstrated that electroacupuncture (EA) decreased lymphocyte infiltration into the spinal cords of rats presenting with experimental autoimmune encephalomyelitis (EAE), a disease model used in the study of multiple sclerosis (MS). The aim of this study was to characterize the effects of EA on the EAE. Female Lewis rats were divided into either CFA, EAE, EA, or injection with naloxone after electroacupuncture (NAL) groups. Electroacupuncture was administered every day for 21 days. To evaluate proliferation and apoptosis, lymphocytes from rats presenting with EAE were collected and cultured with β-endorphin. Immunohistochemisty, flow cytometry and radio-immunity methods were applied to detect the expression of β-endorphin. Results presented in this report demonstrate that the beneficial anti-inflammatory effects of EA on EAE were related to β-endorphin production that balances the Thl/Th2 and Th17/Treg responses. These results suggest that β-endorphin could be an important component in the development of EA-based therapies used for the treatment of EAE.
- Published
- 2013
- Full Text
- View/download PDF
22. Upregulation of UCP2 by adiponectin: the involvement of mitochondrial superoxide and hnRNP K.
- Author
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Zhou M, Xu A, Tam PK, Lam KS, Huang B, Liang Y, Lee IK, Wu D, and Wang Y
- Subjects
- Animals, Endothelial Cells metabolism, Liver cytology, Mice, Mice, Knockout, RNA, Messenger analysis, Uncoupling Protein 2, Up-Regulation, Adiponectin physiology, Heterogeneous-Nuclear Ribonucleoprotein K metabolism, Ion Channels biosynthesis, Mitochondria, Liver metabolism, Mitochondrial Proteins biosynthesis, Superoxides metabolism
- Abstract
Background: The adipocyte-derived hormone adiponectin elicits protective functions against fatty liver diseases and hepatic injuries at least in part by stimulating the expression of a mitochondrial inner membrane transporter, uncoupling protein 2 (UCP2). The present study was designed to investigate the cellular and molecular mechanisms underlying adiponectin-induced UCP2 expression., Methodology/principal Findings: Mice were treated with adiponectin and/or different drug inhibitors. Parenchymal (PCs) and nonparenchymal (NPCs) cells were fractionated from the liver tissues for mitochondria isolation, Western blotting and quantitative PCR analysis. Mitochondrial superoxide production was monitored by MitoSOX staining and flow cytometry analysis. Compared to control mice, the expression of UCP2 was significantly lower in NPCs, but not PCs of adiponectin knockout mice (AKO). Both chronic and acute treatment with adiponectin selectively increased the mRNA and protein abundance of UCP2 in NPCs, especially in the enriched endothelial cell fractions. The transcription inhibitor actinomycin D could not block adiponectin-induced UCP2 expression, whereas the protein synthesis inhibitor cycloheximide inhibited the elevation of UCP2 protein but not its mRNA levels. Mitochondrial content of heterogeneous nuclear ribonucleoprotein K (hnRNP K), a nucleic acid binding protein involved in regulating mRNA transportation and stabilization, was significantly enhanced by adiponectin, which also evoked a transient elevation of mitochondrial superoxide. Rotenone, an inhibitor of mitochondrial respiratory complex I, abolished adiponectin-induced superoxide production, hnRNP K recruitment and UCP2 expression., Conclusions/significance: Mitochondrial superoxide production stimulated by adiponectin serves as a trigger to initiate the translocation of hnRNP K, which in turn promotes UCP2 expressions in liver.
- Published
- 2012
- Full Text
- View/download PDF
23. Adipose tissue-specific inhibition of hypoxia-inducible factor 1{alpha} induces obesity and glucose intolerance by impeding energy expenditure in mice.
- Author
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Zhang X, Lam KSL, Ye H, Chung SK, Zhou M, Wang Y, and Xu A
- Subjects
- Adipocytes metabolism, Animals, Diet adverse effects, Dietary Fats administration & dosage, Dietary Fats adverse effects, Gene Expression Regulation genetics, Glucose Intolerance genetics, Humans, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Mice, Mice, Transgenic, Mitochondria genetics, Mitochondria metabolism, Neovascularization, Pathologic genetics, Obesity genetics, Organ Specificity, Thermogenesis genetics, Adipose Tissue, Brown metabolism, Energy Metabolism, Glucose Intolerance metabolism, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Obesity metabolism
- Abstract
Hypoxia in adipose tissue has been postulated as a possible contributor to obesity-related chronic inflammation, insulin resistance, and metabolic dysfunction. HIF1α (hypoxia-inducible factor 1α), a master signal mediator of hypoxia response, is elevated in obese adipose tissue. However, the role of HIF1α in obesity-related pathologies remains to be determined. Here we show that transgenic mice with adipose tissue-selective expression of a dominant negative version of HIF1α developed more severe obesity and were more susceptible to high fat diet-induced glucose intolerance and insulin resistance compared with their wild type littermates. Obesity in the transgenic mice was attributed to impaired energy expenditure and reduced thermogenesis. Histological examination of interscapular brown adipose tissue (BAT) in the transgenic mice demonstrated a markedly increased size of lipid droplets and decreased mitochondrial density in adipocytes, a phenotype similar to that in white adipose tissue. These changes in BAT of the transgenic mice were accompanied by decreased mitochondrial biogenesis and reduced expression of key thermogenic genes. In the transgenic mice, angiogenesis in BAT was decreased but was little affected in white adipose tissue. These findings support an indispensable role of HIF1α in maintaining the thermogenic functions of BAT, possibly through promoting angiogenesis and mitochondrial biogenesis in this tissue.
- Published
- 2010
- Full Text
- View/download PDF
24. Molecular determinants of substrate selectivity of a novel organic cation transporter (PMAT) in the SLC29 family.
- Author
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Zhou M, Xia L, Engel K, and Wang J
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, Cations metabolism, Cell Line, Dogs, Equilibrative Nucleoside Transport Proteins, Humans, Kidney, Kinetics, Mammals, Models, Molecular, Molecular Sequence Data, Nerve Tissue Proteins chemistry, Organic Cation Transport Proteins chemistry, Protein Conformation, Protein Structure, Secondary, Recombinant Proteins chemistry, Recombinant Proteins metabolism, Substrate Specificity, Transfection, Nerve Tissue Proteins metabolism, Organic Cation Transport Proteins metabolism
- Abstract
Plasma membrane monoamine transporter (PMAT or ENT4) is a newly cloned transporter assigned to the equilibrative nucleoside transporter (ENT) family (SLC29). Unlike ENT1-3, PMAT mainly functions as a polyspecific organic cation transporter. In this study, we investigated the molecular mechanisms underlying the unique substrate selectivity of PMAT. By constructing chimeras between human PMAT and ENT1, we showed that a chimera consisting of transmembrane domains (TM) 1-6 of PMAT and TM7-11 of hENT1 behaved like PMAT, transporting 1-methyl-4-phenylpyridinium (MPP+, an organic cation) but not uridine (a nucleoside), suggesting that TM1-6 contains critical domains responsible for substrate recognition. To identify residues important for the cation selectivity of PMAT, 10 negatively charged residues were chosen and substituted with alanine. Five of the alanine mutants retained PMAT activity, and four were non-functional due to impaired targeting to the plasma membrane. However, alanine substitution at Glu(206) in TM5 abolished PMAT activity without affecting cell surface expression. Eliminating the charge at Glu(206) (E206Q) resulted in loss of organic cation transport activity, whereas conserving the negative charge (E206D) restored transporter function. Interestingly, mutant E206Q, which possesses the equivalent residue in ENT1, gained uridine transport activity. Thr(220), another residue in TM5, also showed an effect on PMAT activity. Helical wheel analysis of TM5 revealed a distinct amphipathic pattern with Glu(206) and Thr(220) clustered in the center of the hydrophilic face. In summary, our results suggest that Glu(206) functions as a critical charge sensor for cationic substrates and TM5 forms part of the substrate permeation pathway in PMAT.
- Published
- 2007
- Full Text
- View/download PDF
25. Membrane localization and pH-dependent transport of a newly cloned organic cation transporter (PMAT) in kidney cells.
- Author
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Xia L, Engel K, Zhou M, and Wang J
- Subjects
- 1-Methyl-4-phenylpyridinium metabolism, Adenosine pharmacology, Animals, Antibody Formation, Cells, Cultured, Cladribine pharmacology, Dogs, Equilibrative Nucleoside Transport Proteins, Histamine metabolism, Humans, Kidney cytology, Nerve Tissue Proteins immunology, Organic Cation Transport Proteins immunology, Tubercidin analogs & derivatives, Tubercidin pharmacology, Cell Membrane chemistry, Kidney chemistry, Nerve Tissue Proteins metabolism, Organic Cation Transport Proteins metabolism
- Abstract
Plasma membrane monoamine transporter (PMAT) is a novel membrane transporter recently cloned and characterized in our laboratory. We previously demonstrated that PMAT functions as a polyspecific organic cation transporter and efficiently transports many organic cations such as monoamine neurotransmitters and 1-methyl-4-phenylpyridinium (MPP(+)). In this study, we explored the role of PMAT in the renal handling of organic cations. Using a polyclonal antibody generated toward the NH(2)-terminal 66 amino acid residues of human PMAT, we showed that the PMAT protein (approximately 55 kDa) is expressed in the human kidney and is primarily targeted to the apical membranes when expressed in polarized Madin-Darby canine kidney (MDCK) cells. Using MDCK cells stably expressing human PMAT, we showed that PMAT-mediated MPP(+) uptake is strongly dependent on extracellular pH. Lowering extracellular pH from 7.4 to 6.6 greatly stimulated PMAT-mediated MPP(+) uptake, whereas elevating extracellular pH to 8.2 abolished transporter activity. Kinetic analysis revealed that the apparent V(max) at pH 6.6 is about fourfold higher than that at pH 7.4, whereas the apparent K(m) values were not statistically different at these two conditions. Under acidic conditions (pH 6.6), the proton ionophore, carbonyl cyanide p-trifluormethoxyphenylhydrazone, drastically reduced PMAT-mediated MPP(+) uptake, suggesting that the stimulatory effect of proton may be due to transporter coupling with a proton gradient. Taken together, our data suggest that PMAT is expressed on the apical membranes of renal epithelial cells and may use luminal proton gradient to drive organic cation reabsorption in the kidney.
- Published
- 2007
- Full Text
- View/download PDF
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