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      Effects of microRNA-211 on proliferation and apoptosis of lens epithelial cells by targeting SIRT1 gene in diabetic cataract mice

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          Abstract

          Our study aimed at exploring the effects of miR-211 on the proliferation and apoptosis of lens epithelial cells in diabetic cataract mice by targetting NAD +-dependent histone deacetylase sirtulin 1 (SIRT1). Healthy male mice were assigned into normal and diabetic cataract groups. Blood glucose, lens turbidity, and apoptosis were measured. Lens epithelial cells were classified into the normal, blank, negative control (NC), miR-211 mimics, miR-211 inhibitors, siRNA-SIRT1, and miR-211 inhibitors + siRNA-SIRT1 groups. MiR-211, Bcl-2, Bax, p53, and SIRT1 expressions of each group were detected. Cell proliferation, cycle and apoptosis were tested by MTT assay and flow cytometry. MiR-211 can specifically bind to SIRT1 according to the luciferase system. SIRT1 protein concentration was strongly positive in normal mice and weakly positive in diabetic cataract mice. Apoptosis index of diabetic cataract mice was higher than the normal mice. Compared with normal mice, the expressions of miR-211, Bax, and p53 increased in diabetic cataract mice, while the Bcl-2 and SIRT1 expressions decreased. In comparison with the blank and NC groups, the expressions of miR-211, Bax, and p53 increased, while Bcl-2 and SIRT1 expressions decreased, and the proliferation decreased and apoptosis rate increased in the miR-211 mimics and siRNA-SIRT1 groups; the results were contradicting for the miR-211 inhibitor group. MiR-211 could promote apoptosis and inhibit proliferation of lens epithelial cells in diabetic cataract mice by targetting SIRT1.

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          Most cited references42

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          Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

          Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.
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            Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases.

            Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1alpha subunit. In this study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1alpha expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1alpha may play an important role in human cancer progression.
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              Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

              Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.
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                Author and article information

                Journal
                Biosci Rep
                Biosci. Rep
                ppbioscirep
                BSR
                Bioscience Reports
                Portland Press Ltd.
                0144-8463
                1573-4935
                05 July 2017
                27 July 2017
                31 August 2017
                : 37
                : 4
                : BSR20170695
                Affiliations
                Shenzhen Key Laboratory of Ophthalmology, Shenzhen Eye Hospital, Ophthalmology College of Shenzhen University, Shenzhen 518000, P.R. China
                Author notes
                Correspondence: Kun Zeng ( kunz1215@ 123456163.com )
                Article
                10.1042/BSR20170695
                5529207
                28679650
                ce8dbf5d-fb51-444f-9379-7d94c19851ce
                © 2017 The Author(s).

                This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).

                History
                : 18 April 2017
                : 14 June 2017
                : 04 July 2017
                Page count
                Pages: 14
                Categories
                Research Articles
                Research Article
                45
                13
                14

                Life sciences
                apoptosis,diabetic cataract,lens epithelial cells,microrna-211,proliferation,sirti
                Life sciences
                apoptosis, diabetic cataract, lens epithelial cells, microrna-211, proliferation, sirti

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