Type 2 diabetes mellitus (T2DM) is a widespread metabolic disease characterized by chronic hyperglycemia. Human microbiota, which is regarded as a "hidden organ", plays an important role in the initiation and development of T2DM. In addition, antihyperglycemic agents and traditional Chinese medicine may affect the composition of gut microbiota and consequently improve glucose metabolism. However, the relationship between gut microbiota, T2DM and anti-hyperglycemic agents or traditional Chinese medicine is poorly understood. In this review, we summarized pre-clinical and clinical studies to elucidate the possible underlying mechanism. Some anti-hyperglycemic agents and traditional Chinese medicine may partly exert hypoglycemic effects by altering the gut microbiota composition in ways that reduce metabolic endotoxemia, maintain the integrity of intestinal mucosal barrier, promote the production of short-chain fatty acids (SCFAs), decrease trimethylamine-N-oxide (TMAO) and regulate bile acid metabolism. In conclusion, gut microbiota may provide some new therapeutic targets for treatment of patients with diabetes mellitus.
To explore the underlying mechanism of lncRNA MALAT1 in the pathogenesis of diabetic cardiomyopathy (DCM). DCM models were confirmed in db/db mice. MiRNAs in myocardium were detected by miRNA sequencing. The interactions of miR‐185‐5p with MALAT1 and RhoA were validated by dual‐luciferase reporter assays. Primary neonatal cardiomyocytes were cultured with 5.5 or 30 mmol/L D‐glucose (HG) in the presence or absence of MALAT1‐shRNA and fasudil, a ROCK inhibitor. MALAT1 and miR‐185‐5p expression were determined by real‐time quantitative PCR. The apoptotic cardiomyocytes were evaluated using flow cytometry and TUNEL staining. SOD activity and MDA contents were measured. The ROCK activity, phosphorylation of Drp1S616, mitofusin 2 and apoptosis‐related proteins were analysed by Western blotting. Mitochondrial membrane potential was examined by JC‐1. MALAT1 was significantly up‐regulated while miR‐185‐5p was down‐regulated in myocardium of db/db mice and HG‐induced cardiomyocytes. MALAT1 regulated RhoA/ROCK pathway via sponging miR‐185‐5p in cardiomyocytes in HG. Knockdown of MALAT1 and fasudil all inhibited HG‐induced oxidative stress, and alleviated imbalance of mitochondrial dynamics and mitochondrial dysfunction, accompanied by reduced cardiomyocyte apoptosis. MALAT1 activated the RhoA/ROCK pathway via sponging miR‐185‐5p and mediated HG‐induced oxidative stress, mitochondrial damage and apoptosis of cardiomyocytes in mice.
Objectives
Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes and the main cause of end-stage kidney disease. Podocyte injury or apoptosis exerts a crucial role in the pathogenesis of DN. Recently, long noncoding RNAs (lncRNAs) have been gradually identified to be functional in a variety of different mechanisms associating with DN. However, the relationship between lncRNAs and podocyte apoptosis in DN is still in its infancy. This study aimed to investigate whether lncRNA Glis2 could regulate podocyte injury via miR-328-5p in DN and uncover the underlying mechanism.
Methods
Normal-glucose or high-glucose cultured podocytes and diabetic db/db mice were used to investigate the exact role and regulatory mechanism of lncRNA Glis2 on podocyte apoptosis in DN. Apoptosis rate of podocyte was detected by flow cytometry. Cell viability was measured using the Cell Counting Kit-8 colorimetric assay (CCK-8). The expressions of lncRNA Glis2 and miR-328-5p were measured by qRT-PCR. The relationship between lncRNA Glis2 and miR-328-5p was examined by dual luciferase reporter assay. Mitochondrial membrane potential (ΔΨM) was measured using JC-1 staining. Mitochondrial morphology was detected by MitoTracker Deep Red staining. Then, the histopathological and ultrastructure changes of renal tissues in diabetic mice were observed using periodic acid-Schiff (PAS) staining and transmission electron microscopy. Finally, the effect of lncRNA Glis2 on podocyte mitochondrial dysfunction and apoptosis through miR-328-5p/Sirt1 was detected by western blot.
Results
We found that lncRNA Glis2 was significantly downregulated in high-glucose cultured podocytes and renal tissues of db/db mice. Furthermore, lncRNA Glis2 overexpression or knockdown was found to regulate podocyte mitochondrial dysfunction and apoptosis. The direct interaction between lncRNA Glis2 and miR-328-5p was confirmed by dual luciferase reporter assay. LncRNA Glis2 overexpression alleviated podocyte mitochondrial dysfunction and apoptosis via miR-328-5p/Sirt1 pathway in podocytes and diabetic mice.
Conclusion
Taken together, this study demonstrated that lncRNA Glis2, acting as a competing endogenous RNA (ceRNA) of miRNA-328-5p, regulated Sirt1 mediated mitochondrial dysfunction and podocyte apoptosis in DN.
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