Notoginsenoside R1 Protects Against High Glucose-Induced Cell Injury Through AMPK/Nrf2 and Downstream HO-1 Signaling

Notoginsenoside R1 (NGR1), the primary bioactive compound found in Panax notoginseng, is believed to have antihypertrophic and antiapoptotic properties, and has long been used to prevent and treat cardiovascular diseases. However, its potential role in prevention of diabetic cardiomyopathy remains unclear. The present study aimed to investigate the mechanism of NGR1 action in high glucose-induced cell injury. H9c2 cardiomyocytes were cultured in a high-glucose medium as an in-vitro model, and apoptotic cells were visualized using TUNEL staining. Expression of Nrf2 and HO-1 was measured using Western blotting or reverse transcription-quantitative PCR (RT-qPCR). The Nrf2 small interfering (si) RNA was transfected into cardiomyocytes using Opti-MEM containing Lipofectamine® RNAiMAX. NGR1 protected H9c2 cardiomyocytes from cell death, apoptosis and hypertrophy induced by high glucose concentration. Expression of auricular natriuretic peptide and brain natriuretic peptide was remarkably reduced in NGR1-treated H9C2 cells. Western blot analysis showed that high glucose concentration markedly inhibited AMPK, Nrf2 and HO-1, and this could be reversed by NGR1 treatment. However, the cardioprotective effect of NGR1 was attenuated by compound C, which reverses Nrf2 and HO-1 expression levels, suggesting that AMPK upregulates Nrf2 and HO-1 gene expression, protein synthesis and secretion. Transfection of H9C2 cells with Nrf2 siRNA markedly reduced the cardioprotective effect of NGR1 via reduced expression of HO-1. These results indicated that NGR1 attenuated high glucose-induced cell injury via AMPK/Nrf2 signaling and its downstream target, the HO-1 pathway. We conclude that the cardioprotective effects of NGR1 result from upregulation of AMPK/Nrf2 signaling and HO-1 expression in cardiomyocytes. Our findings suggest that NGR1 treatment might provide a novel therapy for diabetic cardiomyopathy.

Hydrogel-based flexible materials for diabetes diagnosis, treatment, and management

Diabetes is a chronic metabolic disease characterized by high glucose concentration in blood. Conventional management of diabetes requires skin pricking and subcutaneous injection, causing physical pain and physiological issues to diabetic individuals. Hydrogels possess unique advantages such as lightweight, stretchability, biocompatibility, and biodegradability, offering the opportunities to be integrated as flexible devices for diabetes management. This review highlights the development of hydrogels as flexible materials for diabetes applications in glucose monitoring, insulin delivery, wound care, and cell transplantation in recent years. Challenges and prospects in the development of hydrogel-based flexible devices for personalized management of diabetes are discussed as well.

Sulodexide reduces glucose induced senescence in human retinal endothelial cells

Chronic exposure of retinal endothelium cells to hyperglycemia is the leading cause of diabetic retinopathy. We evaluated the effect of high glucose concentration on senescence in human retinal endothelial cells (HREC) and modulation of that effect by Sulodexide. Experiments were performed on HREC undergoing in vitro replicative senescence in standard medium or medium supplemented with glucose 20 mmol/L (GLU) or mannitol 20 mnol/L (MAN). Effect of Sulodexide 0.5 LRU/mL (SUL) on the process of HREC senescence was studied. Glucose 20 mmol/L accelerates senescence of HREC: population doubling time (+ 58%, p < 0.001) β-galactosidase activity (+ 60%, p < 0.002) intracellular oxidative stress (+ 65%, p < 0.01), expression of p53 gene (+ 118%, p < 0.001). Senescent HREC had also reduced transendothelial electrical resistance (TEER) (− 30%, p < 0.001). Mannitol 20 mmol/L used in the same scenario as glucose did not induce HREC senescence. In HREC exposed to GLU and SUL, the senescent changes were smaller. HREC, which became senescent in the presence of GLU, demonstrated higher expression of genes regulating the synthesis of Il6 and VEGF-A, which was reflected by increased secretion of these cytokines (IL6 + 125%, p < 0.001 vs control and VEGF-A + 124% p < 0.001 vs control). These effects were smaller in the presence of SUL, and additionally, an increase of TEER in the senescent HREC was observed. Chronic exposure of HREC to high glucose concentration in medium accelerates their senescence, and that process is reduced when the cells are simultaneously exposed to Sulodexide. Additionally, Sulodexide decreases the secretion of IL6 and VEGF-A from senescent HREC and increases their TEER.

Glycolytic overload-driven dysfunction of periodontal ligament fibroblasts in high glucose concentration, corrected by glyoxalase 1 inducer

IntroductionPatients with diabetes have increased risk of periodontal disease, with increased risk of weakening of periodontal ligament and tooth loss. Periodontal ligament is produced and maintained by periodontal ligament fibroblasts (PDLFs). We hypothesized that metabolic dysfunction of PDLFs in hyperglycemia produces an accumulation of the reactive glycating agent, methylglyoxal (MG), leading to increased formation of the major advanced glycation endproduct, MG-H1 and PDLF dysfunction. The aim of this study was to assess if there is dicarbonyl stress and functional impairment of human PDLFs in primary culture in high glucose concentration—a model of hyperglycemia, to characterize the metabolic drivers of it and explore remedial intervention by the glyoxalase 1 inducer dietary supplement, trans-resveratrol and hesperetin combination (tRES-HESP).Research design and methodsHuman PDLFs were incubated in low and high glucose concentration in vitro. Metabolic and enzymatic markers of MG and glucose control were quantified and related changes in the cytoplasmic proteome and cell function—binding to collagen-I, assessed. Reversal of PDLF dysfunction by tRES-HESP was explored.ResultsIn high glucose concentration cultures, there was a ca. twofold increase in cellular MG, cellular protein MG-H1 content and decreased attachment of PDLFs to collagen-I. This was driven by increased hexokinase-2 linked glucose metabolism and related increased MG formation. Proteomics analysis revealed increased abundance of chaperonins, heat shock proteins (HSPs), Golgi-to-endoplasmic reticulum transport and ubiquitin E3 ligases involved in misfolded protein degradation in high glucose concentration, consistent with activation of the unfolded protein response by increased misfolded MG-modified proteins. PDLF dysfunction was corrected by tRES-HESP.ConclusionsIncreased hexokinase-2 linked glucose metabolism produces dicarbonyl stress, increased MG-modified protein, activation of the unfolded protein response and functional impairment of PDLFs in high glucose concentration. tRES-HESP resolves this at source by correcting increased glucose metabolism and may be of benefit in prevention of diabetic periodontal disease.