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      Zinc inhibits high glucose-induced NLRP3 inflammasome activation in human peritoneal mesothelial cells

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          Abstract

          Zinc (Zn) deficiency is important for inducing nucleotide-binding domain and leucine-rich repeat-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in macrophages. However, its function in the NLRP3 inflammasome activation of peritoneal mesothelial cells (PMCs) remains to be elucidated. In the present study, the human PMC (HPMC) line HMrSV5 was co-treated with high glucose and either ZnSO4 or a Zn chelator. The activity of the NLRP3/caspase-1 inflammasome was assessed via western blot analysis, immunofluorescence, reverse transcription-quantitative polymerase chain reaction and ELISA. In addition, the activity of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway was detected using western blotting, and the level of reactive oxygen species (ROS) was assessed by 2,7-dichlorofluorescein fluorescence and flow cytometry. It was found that Zn supplementation inhibited HG-induced NLRP3 inflammasome activation in the HPMCs by attenuating ROS production. Further experiments revealed that Zn supplementation inhibited the HG-induced production of ROS through activation of the Nrf2 antioxidant pathway. These results indicated that Zn inhibited NLRP3 inflammasome activation in the HG-treated HPMCs by activating the Nrf2 antioxidant pathway and reducing the production of ROS.

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          Most cited references24

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution.

            The Keap1–Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3–Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1–Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy.
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              Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells.

              During continuous ambulatory peritoneal dialysis, the peritoneum is exposed to bioincompatible dialysis fluids that cause denudation of mesothelial cells and, ultimately, tissue fibrosis and failure of ultrafiltration. However, the mechanism of this process has yet to be elucidated. Mesothelial cells isolated from effluents in dialysis fluid from patients undergoing continuous ambulatory peritoneal dialysis were phenotypically characterized by flow cytometry, confocal immunofluorescence, Western blotting, and reverse-transcriptase polymerase chain reaction. These cells were compared with mesothelial cells from omentum and treated with various stimuli in vitro to mimic the transdifferentiation observed during continuous ambulatory peritoneal dialysis. Results were confirmed in vivo by immunohistochemical analysis performed on peritoneal-biopsy specimens. Soon after dialysis is initiated, peritoneal mesothelial cells undergo a transition from an epithelial phenotype to a mesenchymal phenotype with a progressive loss of epithelial morphology and a decrease in the expression of cytokeratins and E-cadherin through an induction of the transcriptional repressor snail. Mesothelial cells also acquire a migratory phenotype with the up-regulation of expression of alpha2 integrin. In vitro analyses point to wound repair and profibrotic and inflammatory cytokines as factors that initiate mesothelial transdifferentiation. Immunohistochemical studies of peritoneal-biopsy specimens from patients undergoing continuous ambulatory peritoneal dialysis demonstrate the expression of the mesothelial markers intercellular adhesion molecule 1 and cytokeratins in fibroblast-like cells entrapped in the stroma, suggesting that these cells stemmed from local conversion of mesothelial cells. Our results suggest that mesothelial cells have an active role in the structural and functional alteration of the peritoneum during peritoneal dialysis. The findings suggest potential targets for the design of new dialysis solutions and markers for the monitoring of patients. Copyright 2003 Massachusetts Medical Society
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                Author and article information

                Journal
                Mol Med Rep
                Mol Med Rep
                Molecular Medicine Reports
                D.A. Spandidos
                1791-2997
                1791-3004
                October 2017
                11 August 2017
                11 August 2017
                : 16
                : 4
                : 5195-5202
                Affiliations
                Department of Nephrology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning 110001, P.R. China
                Author notes
                Correspondence to: Dr Jianfei Ma, Department of Nephrology, The First Affiliated Hospital, China Medical University, 155th Nanjing North Street, Shenyang, Liaoning 110001, P.R. China, E-mail: majianfei56@ 123456sohu.com
                Article
                mmr-16-04-5195
                10.3892/mmr.2017.7236
                5647055
                28849014
                599994a4-6cf5-451b-a90c-808ecca537c4
                Copyright: © Fan et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 17 September 2016
                : 01 June 2017
                Categories
                Articles

                human peritoneal mesothelial cells,zinc,high glucose,nucleotide-binding domain and leucine-rich repeat-containing family,pyrin domain-containing-3,inflammasome activation

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