Dapagliflozin Ameliorates STZ-Induced Cardiac Hypertrophy in Type 2 Diabetic Rats by Inhibiting the Calpain-1 Expression and Nuclear Transfer of NF-κB.

OBJECTIVE: To investigate the effect of dapagliflozin (DAPA) on cardiac hypertrophy induced by type 2 diabetes mellitus (T2DM) and its mechanism. METHODS: SD rats with T2DM were divided into a T2DM group (n = 6) and DAPA group (n = 6). They were, respectively, fed with the same amount of normal saline and 1 mg/kg DAPA. The control group (n = 6) was also fed with normal saline. The hearts were tested by the application of echocardiography and hemodynamics. Subsequently, fasting blood glucose (FBG), serum total cholesterol (TC), and triglyceride (TG) as well as interleukin- (IL-) 10, IL-6, and tumor necrosis factor (TNF)-α in serum were tested. H&E and Masson staining was performed to observe the degree of cardiac tissue lesions, and expression of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), calpain-1, p-IκBα, and p65 in myocardial tissue was tested by qRT-PCR and Western blot. RESULTS: Compared with the control group, rats in the T2DM group exhibited significant diabetic symptoms: FBG was significantly elevated, and the levels of TC, TG, IL-6, and TNF-α were significantly increased, while the levels of IL-10 and the calpain activity were evidently decreased. However, DAPA treatment could improve the above changes. At the same time, the damage and fibrosis of the heart tissue in the DAPA group were markedly improved. Additionally, the mRNA expression of ANP and BNP in myocardial tissue of the DAPA group was markedly increased. And DAPA could inhibit the expression of p-IκBα/IκBα in the cytoplasm and p65 in the nucleus as well as the expression of calpain-1 in myocardial tissue. CONCLUSION: DAPA treatment ameliorates the cardiac hypertrophy caused by T2DM by decreasing body blood glucose, while reducing the expression of calpain-1 in cardiomyocytes and inhibiting the nuclear translocation of NF-κB.

GDF11 protects against glucotoxicity-induced mice retinal microvascular endothelial cell dysfunction and diabetic retinopathy disease.

Growth differentiation factor 11 (GDF11) has been implicated in the regulation of embryonic development and age-related dysfunction, including the regulation of retinal progenitor cells. However, little is known about the functions of GDF11 in diabetic retinopathy. In this study, we demonstrated that GDF11 treatment improved diabetes-induced retinal cell death, capillary degeneration, pericyte loss, inflammation, and blood-retinal barrier breakdown in mice. Treatment of isolated mouse retinal microvascular endothelial cells with recombinant GDF11 in vitro attenuated glucotoxicity-induced retinal endothelial apoptosis and the inflammatory response. The protective mechanisms exerted are associated with TGF-ß/Smad2, PI3k-Akt-FoxO1 activation，and NF-κB pathway inhibition. This study indicated that GDF11 is a novel therapeutic target for diabetic retinopathy.

Reprogramming of mice primary hepatocytes into insulin-producing cells by transfection with multicistronic vectors.

The neogenesis of insulin-producing cells (IPCs) from non-beta-cells has emerged as a potential method for treating diabetes mellitus (DM). Many groups have documented that activation of pancreatic transcription factor(s) in hepatocytes can improve the hyperglycemia in diabetic mice. In the present study, we explored a novel protocol that reprogrammed primary hepatocytes into functional IPCs by using multicistronic vectors carrying pancreatic and duodenal homeobox-1 (Pdx1), neurogenin 3 (Ngn3), and v-musculoaponeurotic fibrosarcoma oncogene homolog A (MafA). These triple-transfected cells activated multiple beta-cell genes, synthesized and stored considerable amounts of insulin, and released the hormone in a glucose-regulated manner in vitro. Furthermore, when transplanted into streptozotocin-induced diabetic mice, the cells markedly ameliorated glucose tolerance. Our results indicated that ectopic expression of Pdx1, Ngn3, and MafA facilitated hepatocytes-to-IPCs reprogramming. This approach may offer opportunities for treatment of DM.

[Role of TRB3 in the inhibitory effect of fenofibrate against high glucose-induced proliferation of glomerular mesangial cells].

OBJECTIVE: To investigate the role of TRB3 in the inhibitory effect of fenofibrate against the proliferation of glomerular mesangial cell induced by high glucose. METHODS: Rat glomerular mesangial cells (MCs) were cultured in the presence of 5.5 mmol/L glucose (normal control), 25 mmol/L glucose (high glucose group), or high glucose along with 10, 50, or 100 µmol/L fenofibrate. Cell counting kit-8 (CCK-8) assay was used to evaluate cell proliferation, and Hoechst 33258 staining was employed to determine chromatin distribution in the MCs. Flow cytometry was performed to analyze the cell cycle changes in different groups. The expressions of TRB3 and P-AKT in different groups were detected using immunocytochemistry and Western blotting. RESULTS: High glucose induced obvious proliferation of the MCs (P<0.001), which was significantly inhibited by fenofibrate in a concentration-dependent manner (P<0.001). The MCs exposed to fenofibrate presented with typical apoptotic morphologies and cell cycle arrest at G1/S phase. Low levels of TRB3 expression was detected in the normal control and high glucose groups, whereas in the 3 fenofibrate groups, TRB3 expression increased and P-AKT expression decreased as fenofibrate concentration increased. CONCLUSION: Fenofibrate can promote TRB3 expression in rat MCs. TRB3 causes cell cycle arrest at G1/S phase by inhibiting AKT phosphorylation to result in suppressed proliferation of the MCs.