RESUMO
The major trials, e.g., EMPA-REG OUTCOME, CANVAS, and CREDENCE, showed the renal and cardiovascular benefit of sodium-glucose transport protein 2 (SGLT2) inhibitors. The SGLT2 inhibitors, Empagliflozin, Dapagliflozin, and Canagliflozin, have shown no significant adverse renal effects. Still, our patients with type 2 diabetes on Remogliflozin, a type of SGLT2 inhibitor approved in India for the treatment of diabetes, seems to cause acute tubular necrosis as confirmed by clinical and pathological evidence in our study. The two critical findings in our research include a consistent rise in hs-CRP and a pathologist's biopsy report, excluding other causes. Therefore, we need sizeable cardiovascular-renal outcome trials to ascertain the safety of Remogliflozin in future studies.
RESUMO
Gallic acid is claimed to possess antioxidant, antiinflammatory and cytoprotective effects. Since pancreatic islets from Type 2 diabetic patients have functional defects, it was hypothesized that glucolipotoxicity might induce apoptosis in beta-cells and gallic acid could offer protection. To test this, RINm5F beta-cells were exposed to high glucose (25 microM) or palmitate (500 microM) or a combination of both for 24 h in the presence and absence of gallic acid. Cells subjected to glucolipotoxicity in the absence and presence of gallic acid were assessed for DNA damage by comet assay. Apoptosis was inferred by caspase-3 protein expression and caspase-3 activity and changes in Bcl-2 mRNA. RT-PCR was used to analyse PDX-1, insulin and UCP-2 mRNA expression in RINm5F beta-cells and insulin levels were quantified from the cell culture supernatant. NFkappaB signal was studied by EMSA, immunofluorescence and Western blot analysis. While RINm5F beta-cells subjected to glucolipotoxicity exhibited increased DNA damage, apoptotic markers and NFkappaB signals, all these apoptotic perturbations were resisted by gallic acid. Gallic acid dose-dependently increased insulin secretion in RINm5F beta-cells and upregulated mRNA of PDX-1 and insulin. It is suggested that the insulin-secretagogue and transcriptional regulatory action of gallic acid is a newly identified mechanism in our study.
Assuntos
Apoptose/efeitos dos fármacos , Ácido Gálico/farmacologia , Células Secretoras de Insulina/efeitos dos fármacos , Insulina/metabolismo , Caspase 3/metabolismo , Linhagem Celular , Dano ao DNA , Ensaio de Desvio de Mobilidade Eletroforética , Regulação da Expressão Gênica , Glucose/efeitos adversos , Proteínas de Homeodomínio/metabolismo , Humanos , Marcação In Situ das Extremidades Cortadas , Secreção de Insulina , Canais Iônicos/metabolismo , Proteínas Mitocondriais/metabolismo , NF-kappa B/metabolismo , Ácido Palmítico/efeitos adversos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transativadores/metabolismo , Proteína Desacopladora 2RESUMO
PURPOSE: The stromal-derived factor (SDF)-1alpha and the CXC receptor (CXCR)-4 jointly regulate the trafficking of various cell types and play a pivotal role in cell migration, proliferation, and survival. The purpose of this study was to assess whether curcumin inhibits human retinal endothelial cell (HREC) migration by interfering with SDF-1alpha/CXCR4 signaling. METHODS: Primary HREC culture was established and maintained in endothelial growth medium. The viability and proliferation of HRECs were assessed by MTT and thymidine uptake assays, respectively. The effect of SDF-1alpha-induced HREC migration (chemotaxis) in the presence and absence of curcumin was determined using the Boyden chamber migration assay. Intracellular Ca(2+) concentration was measured by fluorometric analysis. Immunofluorescence and Western blot analyses were performed to quantify CXCR4, phosphorylated AKT, and PI3-kinase expression levels. RESULTS: HREC migration increased in a dose-dependent manner (1, 10, 50, and 100 ng/mL; P < 0.001) in SDF-1alpha-treated cells. In contrast, AMD3100, an inhibitor of CXCR4 effectively inhibited HREC migration dose dependently. HREC migration was decreased when the cells were exposed to EGTA, a chelator of Ca(2+). Curcumin also blocked Ca(2+) influx, an important signal for HREC migration. In addition, curcumin significantly (P < 0.001) decreased SDF-1alpha-induced HRECs migration and downregulated SDF-1alpha-induced expression of CXCR4, phospho-AKT, phospho-phosphatidylinositol-3-kinase (PI3-K), and eNOS. CONCLUSIONS: This study indicates that curcumin has an inhibitory effect on SDF-1alpha-induced HREC migration. The plausible mechanism of action could be upstream blockage of Ca(2+) influx and the downstream reduction of PI3-K/AKT signals.