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      High glucose inhibits ClC-2 chloride channels and attenuates cell migration of rat keratinocytes

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          Abstract

          Background

          Accumulating evidence has demonstrated that migration of keratinocytes is critical to wound epithelialization, and defects of this function result in chronic delayed-healing wounds in diabetes mellitus patients, and the migration has been proved to be associated with volume-activated chloride channels. The aim of the study is to investigate the effects of high glucose (HG, 25 mM) on ClC-2 chloride channels and cell migration of keratinocytes.

          Methods

          Newborn Sprague Dawley rats were used to isolate and culture the keratinocyte in this study. Immunofluorescence assay, real-time polymerase chain reaction, and Western blot assay were used to examine the expression of ClC-2 protein or mRNA. Scratch wound assay was used to measure the migratory ability of keratinocytes. Transwell cell migration assay was used to measure the invasion and migration of keratinocytes. Recombinant lentivirus vectors were established and transducted to keratinocytes. Whole-cell patch clamp was used to perform the electrophysiological studies.

          Results

          We found that the expression of ClC-2 was significantly inhibited when keratinocytes were exposed to a HG (25 mM) medium, accompanied by the decline of volume-activated Cl current ( I Cl,vol), migration potential, and phosphorylated PI3K as compared to control group. When knockdown of ClC-2 by RNAi or pretreatment with wortmannin, similar results were observed, including I Cl,vol and migration keratinocytes were inhibited.

          Conclusion

          Our study proved that HG inhibited ClC-2 chloride channels and attenuated cell migration of rat keratinocytes via inhibiting PI3K signaling.

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          Most cited references 33

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          Strategies for silencing human disease using RNA interference.

          Since the first description of RNA interference (RNAi) in animals less than a decade ago, there has been rapid progress towards its use as a therapeutic modality against human diseases. Advances in our understanding of the mechanisms of RNAi and studies of RNAi in vivo indicate that RNAi-based therapies might soon provide a powerful new arsenal against pathogens and diseases for which treatment options are currently limited. Recent findings have highlighted both promise and challenges in using RNAi for therapeutic applications. Design and delivery strategies for RNAi effector molecules must be carefully considered to address safety concerns and to ensure effective, successful treatment of human diseases.
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            The molecular biology of chronic wounds and delayed healing in diabetes.

             E. Jude,  R Blakytny (2006)
            Wound healing is a complicated and integrated process. Although there is some tolerance in terms of redundancy and interrelated control mechanisms, pushing beyond such limits may contribute to delayed wound healing, and in extreme cases lead to chronic wounds/ulcers and thus potentially to lower extremity amputation. Diabetes is associated with such disruption in wound healing. Research in humans and in animal models has identified a large number of changes associated with diabetes at the molecular level in delayed wound healing and to a lesser extent in chronic diabetic ulcers. Better overall understanding of these changes and how they are interrelated would allow for specifically targeted treatment, thus ensuring improved quality of life for patients and providing savings to the high costs that are associated with all aspects of chronic diabetic ulcers. This review examines the work done at the molecular level on chronic diabetic ulcers, as well as considering changes seen in diabetes in general, both in humans and animal models, that may in turn contribute to ulcer formation.
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              Functional significance of cell volume regulatory mechanisms.

              To survive, cells have to avoid excessive alterations of cell volume that jeopardize structural integrity and constancy of intracellular milieu. The function of cellular proteins seems specifically sensitive to dilution and concentration, determining the extent of macromolecular crowding. Even at constant extracellular osmolarity, volume constancy of any mammalian cell is permanently challenged by transport of osmotically active substances across the cell membrane and formation or disappearance of cellular osmolarity by metabolism. Thus cell volume constancy requires the continued operation of cell volume regulatory mechanisms, including ion transport across the cell membrane as well as accumulation or disposal of organic osmolytes and metabolites. The various cell volume regulatory mechanisms are triggered by a multitude of intracellular signaling events including alterations of cell membrane potential and of intracellular ion composition, various second messenger cascades, phosphorylation of diverse target proteins, and altered gene expression. Hormones and mediators have been shown to exploit the volume regulatory machinery to exert their effects. Thus cell volume may be considered a second message in the transmission of hormonal signals. Accordingly, alterations of cell volume and volume regulatory mechanisms participate in a wide variety of cellular functions including epithelial transport, metabolism, excitation, hormone release, migration, cell proliferation, and cell death.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                28 August 2015
                : 9
                : 4779-4791
                Affiliations
                Department of Plastic and Reconstructive Surgery, Southwestern Hospital, Third Military Medical University, Chongqing, People’s Republic of China
                Author notes
                Correspondence: Chuan Cao; Shirong Li, Department of Plastic and Reconstructive Surgery, Southwest Hospital, Third Military Medical University, 29 Gaotanyan Main Street, Shapingba District, Chongqing 400038, People’s Republic of China, Tel/fax +86 23 6876 5551, Email ucccao@ 123456yeah.net ; lishirong_cqzx@ 123456yeah.net
                Article
                dddt-9-4779
                10.2147/DDDT.S84628
                4560522
                © 2015 Pan et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                pi3k, high glucose, cell migration, clc-2, keratinocytes

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