Project description:We found canagliflozin shows elimination of senescent cells from organs in age-related pathology mouse model including diabetes. To clarify detailed change by canagliflozin treatement, we conducted RNA-seq analysis in gonadal white adipose tissue(gWAT).
Project description:We assessed the change in hepatic transciptional pattern after treatment with SGLT-2 inhibitors canagliflozin in a mice model of diet-induced obesity.
Project description:We show the proximal tubular specific pathway analysis demonstrating the downregulation of oxidative phosphorylation in dapagliflozin treated db/db mice, a type 2 diabetic model. After 8-week treatment of dapagliflozin for db/db mice having proximal tubule specific tdTomato reporter, tdTomato-positive cells were isolated by FACS. Pathway analysis of RNA sequence of isolated tubular epithelia revealed that oxidative phosphorylation was downregulated in dapagliflozin-treated mice. However, depletion of renal tissue ATP content in db/db mice was ameliorated by dapagliflozin administration. Pimonidazole staining demonstrated that renal cortical tissue hypoxia was noted in db/db mice, which was improved by dapagliflozin administration. These findings suggest that dapagliflozin can ameliorated the excessive oxygen and ATP consumption and subsequent tissue hypoxia in diabetic kidney, which may explain, in part, the responsible mechanisms of renoprotecitive effect by dapagliflozin.
Project description:Radiotherapy (RT) is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve RT response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, is approved for use in diabetes and heart failure, but is also shown to inhibit PC growth. However, whether canagliflozin can improve RT response in PC remains unknown. Here, we show that well-tolerated doses of canagliflozin suppress proliferation and survival of androgen-sensitive and insensitive human PC cells and tumors and sensitize them to RT. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK and mTOR-p70S6k/4EBP1 pathways, activates cell cycle checkpoints, and inhibits proliferation in part through HIF-1 suppression. Canagliflozin mediates transcriptional reprogramming of several metabolic and survival pathways known to be regulated by ETS and E2F family transcription factors. Genes downregulated by canagliflozin are associated with poor PC prognosis. This study lays the groundwork for clinical investigation of canagliflozin in PC prevention and treatment in combination with RT.
Project description:Augmented T-cell function leading to host damage in autoimmunity is supported by metabolic dysregulation. Targeting immunometabolism for the treatment of autoimmunity by repurposing clinically approved metabolic modulators, such as those used to treat people with type 2 diabetes (T2D), is therefore an attractive avenue. Canagliflozin, a class of the newest type of T2D drug – sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including mitochondrial glutamate dehydrogenase (GDH) and complex I inhibition. To date, the effects of SGLT2 inhibitors on human T-cell function are extremely limited. Here, we analysed 748 genes using the Nanostring nCounter® Metabolic Pathways Panel and discovered 38 genes that were differentially regulated between canagliflozin-treated (cana, C; n = 6) and DMSO vehicle control (V; n = 6) T-cells. Of these genes, 24 were downregulated, whilst 14 were upregulated. Notably, 17 of the 24 genes that were downregulated following canagliflozin treatment were associated with the cell cycle, whilst SMAD3 was the only cell cycle-associated gene upregulated by canagliflozin. These analyses allowed a greater understanding of the global changes in T-cell metabolism that occur in response to treatment with SGLT2 inhibitors.
Project description:We investigated the gene expression profiles of RNA isolated from kidney glomeruli from aged, 25 week old type-2 diabetic (db/db) and non-diabetic mice. In order to investigate the consequences of hyperglycemia on the pathogenesis and progression of diabetic nephropathy Kidney glomeruli from 3 diabetic and 3 non-diabetic, control mice were isolated and RNA purified for RNA-Seq analysis on the Illumina HiSeq 2000. The goal of the project was to generate comprehensive list of noncoding RNA genes differentially regulated between the two conditions in order to identify novel targets for further study.
Project description:In an effort to reduce hepatic glucose production and lower plasma glucose levels that are characteristics of diabetes, we have devised a treatment whereby we enhance glycolysis in the liver of a type 2 diabetic mouse model (KK/H1J). We achieve this by raising the levels of a potent regulator of glucose metabolism, fructose-2,6-bisphosphate (F26BP). Treating the mice in this way, we have demonstrated amelioration of the diabetic phenotype in terms of lowering plasma glucose and insulin levels. These treated mice also display reduced weight gain, reduced adiposity, and normalized plasma and hepatic lipid levels. These latter metabolic changes brought about by raising F26BP levels are counterintuitive. A concurrent increase in glycolysis and lipogenesis is expected, however, we observe an increase in glycolysis with a concurrent decrease in lipogenesis. Preliminary analysis of gene expression in these mice has revealed alterations in gene expression of several genes that support the therapeutic effect of raising F26BP levels. To further profile F26BP effects on hepatic gene expression, we have applied a comprehensive approach to identify sets of genes and thereby biological pathways that are differentially regulated when hepatic glycolysis is accelerated in diabetic mice. Comparing diabetic and treated animals, we hope to further clarify the molecular and genetic signature of type 2 diabetes and obesity and elucidate how this signature is affected by raising F26BP levels. Our study examining gene array as well as the hepatic proteome has identified multiple gene and protein expression changes. Of particular relevance, we note that fatty acid metabolism and cholesterol metabolism pathways are significantly down-regulated in diabetic mice treated with a PFK-2 mutant engineered to raise F26BP levels, which underlie the changes we see in the metabolic parameters.
Project description:Augmented T-cell function leading to host damage in autoimmunity is supported by metabolic dysregulation. Targeting immunometabolism for the treatment of autoimmunity by repurposing clinically approved metabolic modulators, such as those used to treat people with type 2 diabetes (T2D), is therefore an attractive avenue. Canagliflozin, a class of the newest type of T2D drug – sodium glucose co-transporter 2 (SGLT2) inhibitors – has known off-target effects including mitochondrial glutamate dehydrogenase (GDH) and complex I inhibition. To date, the effects of SGLT2 inhibitors on human T-cell function are extremely limited. Here, we analysed 784 genes using the Nanostring nCounter® Autoimmune Profiling Panel and discovered 42 genes that were differentially regulated between canagliflozin-treated (cana, C; n = 6) and DMSO vehicle control (V; n = 6) T-cells. Of these genes, 39 were downregulated, including IL2, CSF2 and CCL20; whilst 3 were upregulated, including SELL. Dapagliflozin was used as another control, as this SGLT2 inhibitor does not exhibit any known off-target effects like canagliflozin. Here, there were no differentially expressed genes between dapagliflozin-treated (dapa, D; n = 4) and DMSO vehicle control (V; n = 4) T-cells. These analyses allowed a greater understanding of the global changes in T-cell function that occur in response to treatment with SGLT2 inhibitors.