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Glucose toxicity become serious risk factor of type 2 diabetes mellitus. Multiple complication can be caused of the abnormal condition of glucose level in blood. Thus, managing the plasma glucose is one of the strategy to minimize the negative effects of type 2 diabetes mellitus. In this present study, we aimed to virtually evaluate the bioactive compounds from Alpinia galanga as inhibitor agent against alpha-glucosidase, which was known as carbohydrate catabolic enzyme. The 2D structure of ligands were retrieved from PubChem database (pubchem.ncbi.nlm.nih.gov/) and were evaluated based on Lipinski rule of five for ensured the druglike-ness standard, while the sequence and 3D structure of target protein, alpha-glucosidase, was retrieved from UniProt database (https://www.uniprot.org/) and was modelled through SWISS-MODEL (swissmodel.expasy.org/). All ligands used in this study then underwent optimization prior to molecular docking and analyzing procedures. According to our prediction results, we found that galangin and 1's-1'-acetoxychavicol acetate which known as bioactive compounds found in A. galanga have significant potency as inhibitor agents against the alphaglucosidase due to its binding affinity scores and other physicochemical properties compared to the anti-diabetic drug, mignitol. Thus, from this finding, we have recent starting point to expand the potency of these bioactive compounds, especially for inhibiting the alphaglucosidase as the novel strategy to reduce the poor prognosis of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

In organisms, high glucose can cause several aspects of toxicity, including the lifespan reduction. Paeoniflorin is the major component of Paeoniaceae plants. Nevertheless, the possible effect of paeoniflorin to suppress high glucose toxicity in reducing lifespan and underlyingmechanism are largely unclear. Thus, in this study, we examined the possible effect of paeoniflorin in suppressing high glucose (50mM)-induced lifespan reduction and the underlying mechanism in Caenorhabditis elegans. Administration with 16-64 mg/L paeoniflorin could prolong the lifespan in glucose treated nematodes. Accompanied with this beneficial effect, in glucose treated nematodes, expressions of daf-2 encoding insulin receptor and its downstream kinase genes (age-1, akt-1, and akt-2) were decreased and expression of daf-16 encoding FOXO transcriptional factor was increased by 16-64 mg/L paeoniflorin administration. Meanwhile, the effect of paeoniflorin in extending lifespan in glucose treated nematodes was enhanced by RNAi of daf-2, age-1, akt-1, and akt-2 and inhibited by RNAi of daf-16. In glucose treated nematodes followed by paeoniflorin administration, the increased lifespan caused by daf-2 RNAi could be suppressed by RNAi of daf-16, suggesting that DAF-2 acted upstream of DAF-16 to regulate pharmacological effect of paeoniflorin. Moreover, in glucose treated nematodes followed by paeoniflorin administration, expression of sod-3 encoding mitochondrial Mn-SOD was inhibited by daf-16 RNAi, and the effect of paeoniflorin in extending lifespan in glucose treated nematodes could be suppressed by sod-3 RNAi. Molecular docking analysis indicated the binding potential of paeoniflorin with DAF-2, AGE-1, AKT-1, and AKT-2. Therefore, our results demonstrated the beneficial effect of paeoniflorin administration in inhibiting glucose-induced lifespan reduction by suppressing signaling cascade of DAF-2-AGE-1-AKT-1/2-DAF-16-SOD-3 in insulin signaling pathway. [ABSTRACT FROM AUTHOR]

The abnormal intermediate glucose metabolic pathways induced by elevated intracellular glucose levels during hyperglycemia often establish the metabolic abnormality that leads to cellular and structural changes in development and to progression of diabetic pathologies. Glucose toxicity generally refers to the hyperglycemia-induced irreversible cellular dysfunctions over time. These irreversible cellular dysfunctions in diabetic nephropathy include: (1) inflammatory responses, (2) mesangial expansion, and (3) podocyte dysfunction. Using these three cellular events in diabetic nephropathy as examples of glucose toxicity in the diabetic complications, this review focuses on: (1) the molecular and cellular mechanisms associated with the hexosamine biosynthetic pathway that underly glucose toxicity; and (2) the potential therapeutic tools to inhibit hyperglycemia induced pathologies. We propose novel therapeutic strategies that directly shunts intracellular glucose buildup under hyperglycemia by taking advantage of intracellular glucose metabolic pathways to dampen it by normal synthesis and secretion of hyaluronan, and/or by intracellular chondroitin sulfate synthesis and secretion. This could be a useful way to detoxify the glucose toxicity in hyperglycemic dividing cells, which could mitigate the hyperglycemia induced pathologies in diabetes.

Abstract Aims/Introduction Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) might be less effective in patients with severe hyperglycemia, because hyperglycemia downregulated the GLP‐1 receptor in an animal study. To examine this hypothesis clinically, we compared the glucose‐lowering effects of GLP‐1 receptor agonist liraglutide with and without prior glycemic control. Materials and Methods In an open‐label, parallel trial, participants with poorly controlled type 2 diabetes were recruited and randomized to receive once‐daily insulin therapy, degludec (Insulin–GLP‐1 RA relay group, mean 16.8 ± 11.4 IU/day), for 12 weeks and then liraglutide for 12 weeks or subcutaneous injections of GLP‐1 RA, liraglutide (GLP‐1 RA first group, 0.9 mg), for 24 weeks. The primary efficacy end‐points consisted of changes in the levels of fasting plasma glucose and glycated hemoglobin (HbA1c). Results The median fasting plasma glucose and HbA1c before the study were 210.0 mg/dL and 9.8%, respectively. The levels of fasting plasma glucose and HbA1c significantly decreased in the Insulin–GLP‐1 RA relay group (P

Objective: To investigate the role of Mirabilis jalapa root extracts in restoration of glucose homeostasis in alloxan-induced hyperglycemic Wistar albino rats. Methods: Experimental hyperglycemic rats were treated daily with 200 and 400 mg/kg of Mirabilis jalapa extracts after initial fasting for 6 h. Two-hour postprandial glucose and changes in body weight were monitored during treatment. After 14 d, the rats were sacrificed and blood was collected for biochemical assessment of serum glucose and insulin levels, lipid profile, and oxidative stress markers. Histopathological examinations of harvested pancreas were also carried out. Results: Mirabilis jalapa root extracts at 200 and 400 mg/kg increased the body weight of hyperglycemic rats. Postprandial glucose levels of the extract-treated hyperglycemic groups progressively declined during treatment compared with the untreated hyperglycemic control group (P

Mitochondrial dysfunction is associated with hyperglycemic conditions and insulin resistance leading to cellular damage and apoptosis of cardiomyocytes in diabetic cardiomyopathy. The dysregulation of glucagon-like peptide-1 (GLP-1) receptor and mammalian target of rapamycin (mTOR) is linked to cardiomyopathies and myocardial dysfunctions mediated by hyperglycemia. However, the involvements of mTOR for GLP-1 receptor-mediated cardioprotection against high glucose (HG)-induced mitochondrial disturbances are not clearly identified. The present study demonstrated that HG-induced cellular stress and mitochondrial damage resulted in impaired ATP production and oxidative defense markers such as catalase and SOD2, along with a reduction in survival markers such as Bcl-2 and p-Akt, while an increased expression of pro-apoptotic marker Bax was observed in H9c2 cardiomyoblasts. In addition, the autophagic marker LC3-II was considerably reduced, together with the disruption of autophagy regulators (p-mTOR and p-AMPKα) under the hyperglycemic state. Furthermore, there was a dysregulated expression of several indicators related to mitochondrial homeostasis, including MFN2, p-DRP1, FIS1, MCU, UCP3, and Parkin. Remarkably, treatment with either exendin-4 (GLP-1 receptor agonist) or rapamycin (mTOR inhibitor) significantly inhibited HG-induced mitochondrial damage while co-treatment of exendin-4 and rapamycin completely reversed all mitochondrial abnormalities. Antagonism of GLP-1 receptors using exendin-(9-39) abolished these cardioprotective effects of exendin-4 and rapamycin under HG conditions. In addition, exendin-4 attenuated HG-induced phosphorylation of mTOR, and this inhibitory effect was antagonized by exendin-(9-39), indicating the regulation of mTOR by GLP-1 receptor. Therefore, improvement of mitochondrial dysfunction by stimulating the GLP-1 receptor/AMPK/Akt pathway and inhibiting mTOR signaling could ameliorate cardiac abnormalities caused by hyperglycemic conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Diabetic cataract (DC) is a major cause of blindness worldwide. Prion protein (PRNP) was proved to be up-regulated and hypomethylated in DC samples. Here, we investigated whether PRNP was involved in DC progression in N6-methyladenosine (m6A)-dependent manner, and its potential mechanisms., Methods: Levels of genes and proteins were assayed using qRT-PCR and western blotting. Cell proliferation and apoptosis were determined using Cell Counting Kit-8 assay, 5-thynyl-2'-deoxyuridine (EdU) assay, and flow cytometry, respectively. Oxidative stress was analyzed by measuring the production of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), and malondialdehyde (MDA). The m6A modification was determined by RNA immunoprecipitation (Me-RIP) assay. The interaction between RBM15 (RNA binding motif protein 15) and PRNP was probed using RIP assay., Results: PRNP was highly expressed in DC patients and HG-induced HLECs. Functionally, PRNP deficiency reversed HG-induced apoptosis and oxidative stress in HLECs. Mechanistically, RBM15 induced PRNP m6A modification and directly bound to PRNP. Knockdown of RBM15 abolished HG-induced apoptotic and oxidative injury in HLECs, while these effects were rescued after PRNP overexpression., Conclusion: RBM15 silencing suppressed HG-induced lens epithelial cell injury by regulating PRNP in an m6A-mediated manner, hinting a novel therapeutic strategy for DC patients.

Background and Purpose: Diabetic retinopathy (DR) is a prevalent complication of diabetes, with a rising global incidence, and can result in significant vision impairment and potential blindness in adults. Corilagin (COR) has been shown to regulate several pathological processes. However, the specific protective role and mechanism of action of COR in DR remain unknown., Experimental Approach: The protective effects and mechanisms of COR in DR were examined using the ARPE-19 cell line and C57BL/6 mice. Intraretinal tissue damage and molecular markers were evaluated to investigate the impact of COR on oxidative stress and cell death pathways., Key Results: In vitro, COR significantly reduced the cytotoxic effects of high glucose (HG) on ARPE-19 cells. Furthermore, COR also effectively decreased HG-induced lipid peroxidation, iron deposition, and ferroptosis and reduced damage to retinal tight junction proteins. Similarly, an in vivo study of streptozotocin (STZ)-induced DM mice showed that the daily gavage of COR for eight weeks notably alleviated DR. Mechanistically, COR activated the Nrf2 antioxidant signaling pathway both in vivo and in vitro, preventing HG-induced alterations in morphological and biochemical parameters. Notably, our study demonstrated that compared with controls, Nrf2 knockout mice and siNrf2-treated cells were more vulnerable to ferroptosis under HG conditions, and the protective effect of COR on DR was substantially diminished in these models., Conclusion and Implications: These data indicate that COR has a protective effect against HG-induced retinal injury via a mechanism associated with the Nrf2-dependent antioxidant pathway and ferroptosis regulation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Trigonelline (TRIG) is a natural compound in an alkaloid family found in diverse plants. This compound exerts anti-inflammatory, anti-allergic, anti-oxidative and anti-fibrotic activities in several disease models. However, its beneficial role in endothelial injury, especially induced by diabetes, is unclear. We, therefore, evaluated the effects of TRIG on the cellular proteome of human endothelial (EA.hy926) cells followed by functional validation in high-glucose (HG)-induced endothelial deteriorations. Label-free quantification using nanoLC-ESI-Qq-TOF MS/MS revealed 40 downregulated and 29 upregulated proteins induced by TRIG. Functional enrichment analysis using DAVID and REVIGO tools suggested the involvement of these altered proteins in several biological processes and molecular functions, particularly cell-cell adhesion, ATP metabolic process, cell redox homeostasis, cadherin binding, and ATP hydrolysis activity. Experimental validation showed that HG triggered endothelial-to-mesenchymal transition (EndMT) (as demonstrated by increased spindle index and mesenchymal markers, i.e., fibronectin and vimentin, and decreased endothelial markers, i.e., PECAM-1 and VE-cadherin), increased oxidized proteins, and reduced intracellular ATP, active mitochondria, endothelial tube/mesh formation and VEGF secretion. However, TRIG successfully abolished all these defects induced by HG. These data indicate that TRIG prevents HG-induced EndMT, oxidative stress, mitochondrial dysfunction, and impaired angiogenic activity in human endothelial cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

As one of the most commonly used antidiabetic medications clinically, liraglutide is involved in the protection of vascular endothelium, and whether it can relieve high glucose-induced vascular endothelial damage was unknown. This study aims to address the response of liraglutide (LIRA) on human umbilical vein endothelial cells, as well as to elucidate its possible underlying mechanism. We established a vascular endothelial cell injury model by exposing human umbilical vein endothelial cells (HUVECs) to high glucose, and used LIRA pretreatment before HG treatment to address the endothelial protective effect of LIRA. Our results suggest that LIRA prevented HG-induced HUVEC apoptosis, oxidative stress, inflammasome activation, and pyroptosis. Furthermore, silencing of tribbles homolog 3 (TRIB3) could markedly reduce HG-induced HUVEC apoptosis, ROS level, the expressions of TXNIP, cleaved caspase3, NLRP3, and caspase1, indicating TRIB3 inhibition protected HUVECs against HG-induced vascular endothelial injury. In addition, LIRA restrained NF-κB/IκB-α signaling pathway activation in HUVECs. Thus, LIRA appears to mitigate HG-induced apoptosis, oxidative stress, inflammasome activation, and pyroptosis in HUVECs via regulating the TRIB3/NF-κB/IκB-α signaling pathway. Our study provides new insight into the mechanisms underlying the protective activity of LIRA against the vascular endothelial injury in diabetic vascular complication., (© 2024. The Society for In Vitro Biology.)

Background: Diabetic nephropathy (DN) is a common complication of diabetes mellitus, and Prolyl 4-Hydroxylase Subunit Beta (P4HB) expression is increased in high glucose (HG)-induced renal tubular epithelial cells (TECs). But it's role in HG-induced TECs remains to be elucidated., Methods: The HK-2 cells were induced using HG and transfected with SiRNA-P4HB. DCFH-DA staining was utilized for the detection of cellular levels of ROS. WB and immunofluorescence were utilized to detect the expression of P4HB, epithelial-mesenchymal transition (EMT), fibrosis, and TGFβ/SMAD3-related proteins in HK-2 cells. Online databases were utilized for predicting the interaction target of P4HB, and immunoprecipitation (IP) experiments were employed to validate the binding of P4HB with the target. SiRNA and overexpression vectors of target gene were used to verify the mechanism of action of P4HB., Results: HG induced an increase in the expression of P4HB and TGFβ, p-SMAD3, and ROS in HK-2 cells. Furthermore, HG downregulated the expression of E-cadherin and upregulated the expression of N-cadherin, Vimentin, α-SMA, Fibronectin, Collagen IV, SNAIL, and SLUG in HK-2 cells. Interfering with P4HB significantly reversed the expression of these proteins. Database predictions and IP experiments showed that P4HB interacts with PRMT1, and the expression of PRMT1 was increased in HG-induced HK-2 cells. Interfering with PRMT1 inhibited the changes in expression of EMT and fibrosis related proteins induced by HG. However, overexpression of PRMT1 weakened the regulatory effect of P4HB interference on the EMT, fibrosis, and TGFβ/SMAD3-related proteins in HK-2 cells., Conclusion: P4HB regulated the TGFβ/SMAD3 signaling pathway through PRMT1 and thus participates in HG-induced EMT and fibrosis in HK-2 cells., (© 2024. The Author(s).)

Growing clinical evidence shows that sulfonylurea therapy for patients with type 2 diabetic mellitus (T2DM) contributes to progressive worsening of their liver. The present study presents hepatotoxicity induced by gliclazide, a second-generation sulfonylurea, and alpha-lipoic acid (ALA) as a novel and promising drug for T2DM treatment. Normal human liver cells (HL-7702) were incubated with high-glucose DMEM in the presence or absence of gliclazide and ALA for 72 h, and cell viability and death were measured by flow cytometry. Next, Sprague-Dawley rats were subjected to 12 h of fasting, and fasting blood glucose was measured. The rats were randomized into four groups: HC (healthy control; n = 7), T2DM (diabetic rats without treatment; n = 9), GLC (diabetic rats with 15 mg/kg gliclazide treatment; n = 7) and GLC+ALA (diabetic rats with gliclazide and 60 mg/kg ALA treatment; n = 7). T2DM was induced by a bolus administration of 110 mg/kg nicotinamide and 55 mg/kg streptozotocin intraperitoneally. The experimental protocol lasted for 6 weeks after which the animals were sacrificed and pancreas, liver and blood samples were collected for biochemical, histological and molecular analyses. Compared to healthy control (HC) group, exposure of HL-7702 cells to high glucose induced significant cell death by 19 % (p < 0.001), which was exacerbated with gliclazide treatment by 29 % (p < 0.0001) but markedly reduced by 6 % to near HC value following ALA treatment. In vivo, GLC-treated rats had severe liver damage characterized by increased hepatocellular vacuolation, and significant expression of ED-1, iNOS and caspase-3 as well as markedly high levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase compared to T2DM rats. Interestingly, ALA administration prevented these pathological changes and protected the diabetic liver to levels comparable to HC rats. ALA showed hepatoprotective effect against gliclazide-induced hepatotoxicity by suppressing inflammation and apoptosis while activating antioxidant pathway in the diabetic liver. Abbreviations: ALA, Alpha-lipoic acid; ALT, Alanine aminotransferase; ALP, Alkaline phosphatase; AMPK, Adenosine monophosphate-activated protein kinase; AST, Aspartate aminotransferase; ATP, Adenosine triphosphate; DMEM, Dulbecco's Modified Eagle Medium; EDTA, ethylenediaminetetraacetic acid; FBG, Fasting blood glucose; FBS, Fetal bovine serum; GLC, Gliclazide; GLUT4, Glucose transporter type 4; GSH, Glutathione; H&E, Hematoxylin/Eosin; HbA1c, Glycosylated haemoglobin A1c; HC, Healthy control; HG, Hyperglycemic group; HOMA-β, Homeostasis model assessment of β-cell function; IL-1β, Interleukin-1β; IL-6, Interleukin-6; iNOS, Inducible nitric oxide synthase; K ATP , ATP-dependent potassium channels; MDA, Malondialdehyde; MPTP, Mitochondrial permeability transition pore; NO, Nitric oxide; P/S, Penicillin/streptomycin; PAS, Periodic acid-Schiff; RIA, Radioimmunoassay; ROS, Reactive oxygen species; SOD, Superoxide dismutase; T2DM, Type 2 diabetes mellitus; TBARS, Thiobarbituric acid reactive substances; TNF-α, Tumor necrosis factor-alpha., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To investigate the role of Mirabilis jalapa root extracts in restoration of glucose homeostasis in alloxan-induced hyperglycemic Wistar albino rats. Methods: Experimental hyperglycemic rats were treated daily with 200 and 400 mg/kg of Mirabilis jalapa extracts after initial fasting for 6 h. Two-hour postprandial glucose and changes in body weight were monitored during treatment. After 14 d, the rats were sacrificed and blood was collected for biochemical assessment of serum glucose and insulin levels, lipid profile, and oxidative stress markers. Histopathological examinations of harvested pancreas were also carried out. Results: Mirabilis jalapa root extracts at 200 and 400 mg/kg increased the body weight of hyperglycemic rats. Postprandial glucose levels of the extract-treated hyperglycemic groups progressively declined during treatment compared with the untreated hyperglycemic control group (P<0.05). The lipid profile indices of the untreated negative control group were significantly elevated (P<0.05), which were reversed by treatment with Mirabilis jalapa extracts. The remarkable increases in antioxidant enzyme activities and a significant decrease in malondialdehyde levels were observed in the hyperglycemic group treated with Mirabilis jalapa extracts. Mirabilis jalapa extracts also significantly increased serum insulin levels (P<0.05). In addition, histopathological examinations of the pancreas revealed a significant cell population within the islet nests of the extract-treated hyperglycemic groups. Conclusions: Mirabilis jalapa extract can restore glucose homeostasis and show hypoglycemic and hypolipidemic effects in hyperglycemic rats. Further studies are needed to verify the active components of the plant and the underlying mechanism of action in the future. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) might be less effective in patients with severe hyperglycemia, because hyperglycemia downregulated the GLP‐1 receptor in an animal study. To examine this hypothesis clinically, we compared the glucose‐lowering effects of GLP‐1 receptor agonist liraglutide with and without prior glycemic control. Materials and Methods: In an open‐label, parallel trial, participants with poorly controlled type 2 diabetes were recruited and randomized to receive once‐daily insulin therapy, degludec (Insulin–GLP‐1 RA relay group, mean 16.8 ± 11.4 IU/day), for 12 weeks and then liraglutide for 12 weeks or subcutaneous injections of GLP‐1 RA, liraglutide (GLP‐1 RA first group, 0.9 mg), for 24 weeks. The primary efficacy end‐points consisted of changes in the levels of fasting plasma glucose and glycated hemoglobin (HbA1c). Results: The median fasting plasma glucose and HbA1c before the study were 210.0 mg/dL and 9.8%, respectively. The levels of fasting plasma glucose and HbA1c significantly decreased in the Insulin–GLP‐1 RA relay group (P < 0.001) and GLP‐1 RA first group (P < 0.001) by week 24, although no intergroup differences were observed. The reduction of HbA1c in the Insulin–GLP‐1 RA relay group tended to be larger than that in the GLP‐1 RA first group in the lowest CPR (C‐peptide immunoreactivity) quartile (P = 0.072). The adverse events consisted of gastrointestinal problems, followed by hypoglycemia. Conclusions: The GLP‐1 receptor agonist is overall effective without prior glycemic control with insulin in participants with poorly controlled type 2 diabetes. However, in participants with insulinopenic type 2 diabetes, prior glycemic control with insulin might overcome glucose toxicity‐induced GLP‐1 resistance. [ABSTRACT FROM AUTHOR]

Introduction: Previous studies have suggested that high glucose (HG) condition shortens the lifespan of worms by increasing glycolytic flux followed by accelerating reactive oxygen species (ROS) production, termed glucose toxicity. This study was designed to investigate the protective effects of the leaves of black bamboo (Phyllostachys nigra var. henosis) on the HG-induced toxicity using Caenorhabditis elegans model system. Methods: To determine the effect of black bamboo leaf extract (BLE) against HG-induced toxicity, lifespan assay was carried out with wild-type and daf-16 null mutant worms under 2% glucose condition. The involvement of DAF-16 was further confirmed by observing fluorescence signal of transgenic mutant carrying DAF-16::GFP transgene. ROS levels and glucose concentration of worms were analyzed using fluorescent probe H2DCF-DA and glucose meter, respectively. Nile-red staining was carried out to evaluate the lipid storage of worms. Intercellular lipid accumulation was measured using Oil-Red O staining method. Results: BLE strongly extended the lifespan of worms under not only normal culture condition but also HG condition. Our additional studies suggested that DAF-16 activation was responsible for BLE-mediated longevity and protective action against glucose toxicity. In addition, HG-fed worms showed increased ROS generation, and it was completely normalized by BLE treatment. Moreover, BLE reduced body glucose concentration and lipid accumulation in HG-fed worms. We further confirmed the inhibitory effect of BLE on lipid storage under HG condition using 3T3-L1 adipocytes. Conclusion: These therapeutic values of BLE on glucose toxicity raise the possibility that BLE might have beneficial effects on the pathogenesis of diabetes mellitus.

The crosstalk between energy metabolism and calorie uptake by any human is considered as the epicenter for a myriad of metabolic emergency. The systemic and mechanistic link between the availability of excessive release of glucose and its subsequent storage as fat within adipose tissue leads unwanted factors for initiating the malfunctioning of organ system. This paradigm shift reorganizes the homeostatic metabolism, which finally end up with metabolic complications. Glucose toxicity is a term which defines a metabolic condition, which can start or vice-versa stop the initiation of metabolic emergency. In fact, human awareness towards healthy low-sugar diet, hale and hearty exercise, good habits of saying "NO" to alcohol and abusive drugs can render beneficial effects without any medicine. The homeostatic control of mTOR signaling pathway can prevent the deposition of fats, which can systematically prevent an individual from cardiovascular attacks, obesity, diabetes and its associated complications of chronic nephropathy, acute retinopathy, limb amputation, imbalanced gut microbiota and pre-mature aging. Although, sexual mood, potency and fertility are also related with glucose toxicity. The present article articulates the epitome of type II diabetes and its associated complications with critical autopsy of mTOR signaling metabolic cascade. [Display omitted] [ABSTRACT FROM AUTHOR]

Glucolipotoxicity (GLT) has emerged as established mechanism in the progression of diabetes. Identifying compounds that mitigate GLT-induced deleterious effect on β-cells are considered important strategy to overcome diabetes. Hence, in the present study, astaxanthin-s-allyl cysteine (AST-SAC) diester was studied against GLT in β-cells. Mus musculus pancreatic β-cell line (βTC-tet) was treated with high glucose (25 mM; HG) and 95 μM palmitate (PA) for 24 h to induce GLT. AST-SAC at various concentrations (5, 10, and 15 μg/ml) were treated to understand the protective effect against HG + PA exposure in β-cells. Under HG + PA exposure conditions oxidative stress, deregulation of mTOR pathway and endoplasmic reticulum (ER) stress are witnessed. AST-SAC treatment eased oxidative stress, mitochondrial depolarization, DNA damage, calcium overload and accumulation of autophagosome against HG + PA exposure conditions thereby protected the cell viability of β-cells. AST-SAC maintained the level of proteins involved in mTOR pathway under HG + PA exposure conditions. Also, AST-SAC treatment has mitigated the increased expression of genes and proteins such as IRE1 and PERK involved in ER stress-mediated unfolded protein response (UPR) signaling pathways. In correspondence to it, the expression of genes involved in insulin secretion was preserved by AST-SAC. Due to these protective effects of AST-SAC the insulin secretion was well-maintained in β-cells under HG + PA exposure conditions. AST-SAC through normalizing antioxidant status and mTOR axis as well as preventing the harmful effect of ER-stress mediated UPR pathway has promoted the β-cell survival and insulin secretion against GLT. Simultaneously targeting oxidative stress/mTOR axis/ER stress is required to efficiently overcome GLT in β-cells., (© 2024 Wiley Periodicals LLC.)

Type 2 diabetes mellitus (T2DM) is a chronic, progressive disease characterized by a steady decline in beta-cell function and insulin resistance. As a result, most patients with T2DM may require treatment with insulin after 15-20 years of diagnosis. Various pathophysiological defects were identified leading to hyperglycemia, including reduced insulin secretion due to beta-cell failure. They reduced beta-cell mass and a defect in insulin secretion, which leads to a relative insulin deficiency in these patients requiring insulin treatment. Most international guidelines recommend starting insulin treatment in patients with poor glucose control, mainly if the glycated hemoglobin (HbA1c) is above 9% with the presence of symptoms, especially in relatively newly diagnosed patients with T2DM. We present a 45-year-old patient with T2DM of 5 years duration who attended our center with severe hyperglycemia with evidence of insulin deficiency both clinically and biochemically, who responded well to oral antidiabetic agents achieving adequate glycemic control. [ABSTRACT FROM AUTHOR]

Voacangine, a naturally occurring alkaloid, has been testified to display beneficial effects on a variety of human diseases, but its role in ischemic stroke is unclear. The impacts of voacangine on oxygen-glucose deprivation/reoxygenation (OGD/R)-tempted hippocampal neuronal cells are investigated. The bioinformatics analysis found that voacangine is a bioactive ingredient that may have good effects on ischemic stroke. KEGG pathways analysis found that voacangine may regulate ischemic stroke through modulating the PI3K-Akt-FoxO signaling pathway. Voacangine could mitigate OGD/R-tempted cytotoxicity in HT22 cells. Voacangine mitigated OGD/R-tempted oxidative stress in HT22 cells by diminishing reactive oxygen species level and enhancing superoxide dismutase level. Voacangine mitigated OGD/R-tempted ferroptosis in HT22 cells. Voacangine promoted activation of the PI3K-Akt-FoxO signaling in OGD/R-induced HT22 cells. Inactivation of the PI3K-Akt-FoxO signaling pathway reversed the protective effects of voacangine against OGD/R-tempted oxidative stress, cytotoxicity, and ferroptosis in HT22 cells. In conclusion, voacangine protects hippocampal neuronal cells against OGD/R-caused oxidative stress and ferroptosis by activating the PI3K-Akt-FoxO signaling., (© 2024 John Wiley & Sons Ltd.)

Bitter taste receptors (TAS2Rs) Tas2r108 gene possesses a high abundance in mouse kidney; however, the biological functions of Tas2r108 encoded receptor TAS2Rs member 4 (TAS2R4) are still unknown. In the present study, we found that mouse TAS2R4 (mTAS2R4) signaling was inactivated in chronic high glucose-stimulated mouse podocyte cell line MPC, evidenced by the decreased protein expressions of mTAS2R4 and phospholipase C β2 (PLCβ2), a key downstream molecule of mTAS2R4 signaling. Nonetheless, agonism of mTAS2R4 by quinine recovered mTAS2R4 and PLCβ2 levels, and increased podocyte cell viability as well as protein expressions of ZO-1 and nephrin, biomarkers of podocyte slit diaphragm, in high glucose-cultured MPC cells. However, blockage of mTAS2R4 signaling with mTAS2R4 blockers γ-aminobutyric acid and abscisic acid, a Gβγ inhibitor Gallein, or a PLCβ2 inhibitor U73122 all abolished the effects of quinine on NLRP3 inflammasome and p-NF-κB p65 as well as the functional podocyte proteins in MPC cells in a high glucose condition. Furthermore, knockdown of mTAS2R4 with lentivirus-carrying Tas2r108 shRNA also ablated the effect of quinine on the key molecules of the above inflammatory signalings and podocyte functions in high glucose-cultured MPC cells. In summary, we demonstrated that activation of TAS2R4 signaling alleviated the podocyte injury caused by chronic high glucose, and inhibition of NF-κB p65 and NLRP3 inflammasome mediated the protective effects of TAS2R4 activation on podocytes. Moreover, activation of TAS2R4 signaling could be an important strategy for prevention and treatment of diabetic kidney disease., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Background: Diabetic nephropathy (DN) is a complication of diabetes that is the leading cause of death in diabetic patients. Circular RNA (circRNA) is a hot topic in the research of human diseases. However, the role of circ&#95;Supt3 in DN remains unclear. Methods: High glucose (HG) treatment of mouse podocyte (MPC5) cells to mimic DN cell injury. Quantitative real-time polymerase chain reaction was performed to detect the expression of circ&#95;Supt3, microRNA-185-5p (miR-185-5p), and GTPase-activating protein-binding protein 2 (G3bp2). 5-Ethynyl-2'-deoxyuridine (EdU) and 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium Bromide (MTT) assays were used to examine cell proliferation, and flow cytometry was used to detect cell apoptosis. Western blot was used to assess the levels of relative proteins. Enzyme-linked immunosorbent assay detected the inflammation cytokines. Dual-luciferase reporter and RNA pull-down assays were used to confirm the interaction of miR-185-5p and circ&#95;Supt3 or G3bp2. Results: Circ&#95;Supt3 and G3bp2 were highly expressed and miR-185-5p expression was diminished in DN mice. HG treatment inhibited cell proliferation and accelerated cell apoptosis and inflammation response, and the knockdown of circ&#95;Supt3 reversed these effects. Bioinformatics predicted that circ&#95;Supt3 contained a binding site for miR-185-5p, and G3bp2 was a direct target of miR-185-5p. Circ&#95;Supt3 regulated G3bp2 expression by miR-185-5p. Moreover, the circ&#95;Supt3/miR-185-5p/G3bp2 axis regulated the cell behavior of HG-induced MPC5 cells. Conclusion: Our findings suggest that the knockdown of circ&#95;Supt3 protects mouse MPC5 cells against HG-induced cell injury via the miR-185-5p/G3bp2 axis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Epidemiological studies have suggested a correlation between bisphenol A (BPA) and type 2 diabetes (T2DM). The effects of BPA on β-cell dysfunction may reveal the risks from an in vitro perspective. We used the rat insulinoma (INS-1) cell lines (a type of β-cells) to set up normal or damaged models (DM), which were exposed to various concentrations of BPA (0.001, 0.01, 0.1, 1, 10 and 100 μM). An increase in reactive oxygen species (ROS) and apoptosis, and a decrease in cell viability were observed in INS-1 cells exposed to high doses of BPA for 48 h. Interestingly, exposure to lower doses of BPA for 24 h resulted in increased ROS levels and apoptosis rates in INS-1 in the DM group, along with decreased cell viability, suggesting that BPA exerts toxicity to INS-1 cells, particularly to the DM group. Insulin levels and Glut2 expression, glucose consumption, intracellular Ca 2+ and insulin secretion were increased in INS-1 cells after 48 h exposure to high dose of BPA. Stronger effects were observed in the DM group, even those exposed to low doses of BPA for 24 h. Moreover, BPA inhibited high glucose-stimulated insulin secretion in these cells. Our research suggests that low doses of BPA exacerbate the dysfunction caused by glucolipotoxicity, implying environmental BPA exposure poses a risk for individuals with prediabetes or T2DM., Competing Interests: Declaration of competing interest The authors declare no known financial or personal relationships that could be perceived as potential conflicts of interest, and there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The incidence of diabetes is increasing annually, and the disease is uncurable due to its complex pathogenesis. Therefore, understanding diabetes pathogenesis and developing new treatments are crucial. This study showed that the NO donor SNP (8 µM) significantly alleviated high glucose-induced developmental toxicity in zebrafish larvae. High glucose levels caused hyperglycemia, leading to oxidative stress and mitochondrial damage from excessive ROS accumulation. This promoted mitochondrial-dependent apoptosis and lipid peroxidation (LPO)-induced ferroptosis, along with immune inflammatory reactions that decreased mitochondrial function and altered intracellular grid morphology, causing imbalanced kinetics and autophagy. After SNP treatment, zebrafish larvae showed improved developmental toxicity and glucose utilization, reduced ROS accumulation, and increased antioxidant activity. The NO-sGC-cGMP signaling pathway, inhibited by high glucose, was significantly activated by SNP, improving mitochondrial homeostasis, increasing mitochondrial count, and enhancing mitochondrial function. It's worth noting that apoptosis, ferroptosis and immune inflammation were effectively alleviated. In summary, SNP improved high glucose-induced developmental toxicity by activating the NO-sGC-cGMP signaling pathway to reduce toxic effects such as apoptosis, ferroptosis and inflammation resulting from mitochondrial homeostasis imbalance., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Skeletal muscle handles about 80% of insulin-stimulated glucose uptake and become the major organ occurring insulin resistance (IR). Many studies have confirmed the interactions between macrophages and skeletal muscle regulated the inflammation and regeneration of skeletal muscle. However, despite of the decades of research, whether macrophages infiltration and polarization in skeletal muscle under high glucose (HG) milieus results in the development of IR is yet to be elucidated. C2C12 myoblasts are well-established and excellent model to study myogenic regulation and its responses to stimulation. Further exploration of macrophages' role in myoblasts IR and the dynamics of their infiltration and polarization is warranted., Aim: To evaluate interactions between myoblasts and macrophages under HG, and its effects on inflammation and IR in skeletal muscle., Methods: We detected the polarization status of macrophages infiltrated to skeletal muscles of IR mice by hematoxylin and eosin and immunohistochemical staining. Then, we developed an in vitro co-culture system to study the interactions between myoblasts and macrophages under HG milieus. The effects of myoblasts on macrophages were explored through morphological observation, CCK-8 assay, Flow Cytometry, and enzyme-linked immunosorbent assay. The mediation of macrophages to myogenesis and insulin sensitivity were detected by morphological observation, CCK-8 assay, Immunofluorescence, and 2-NBDG assay., Results: The F4/80 and co-localization of F4/80 and CD86 increased, and the myofiber size decreased in IR group ( P < 0.01, g = 6.26). Compared to Mc group, F4/80+CD86+CD206- cells, tumor necrosis factor-α (TNFα), inerleukin-1β (IL-1β) and IL-6 decreased, and IL-10 increased in McM group ( P < 0.01, g > 0.8). In McM + HG group, F4/80+CD86+CD206- cells, monocyte chemoattractant protein 1, TNFα, IL-1β and IL-6 were increased, and F4/80+CD206+CD86- cells and IL-10 were decreased compared with Mc + HG group and McM group ( P < 0.01, g > 0.8). Compered to M group, myotube area, myotube number and E-MHC were increased in MMc group ( P < 0.01, g > 0.8). In MMc + HG group, myotube area, myotube number, E-MHC, GLUT4 and glucose uptake were decreased compared with M + HG group and MMc group ( P < 0.01, g > 0.8)., Conclusion: Interactions between myoblasts and macrophages under HG milieus results in inflammation and IR, which support that the macrophage may serve as a promising therapeutic target for skeletal muscle atrophy and IR., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Epithelial mesenchymal transition (EMT) is a critical process implicated in the pathogenesis of retinal fibrosis and the exacerbation of diabetic retinopathy (DR) within retinal pigment epithelium (RPE) cells. Apigenin (AP), a potential dietary supplement for managing diabetes and its associated complications, has demonstrated inhibitory effects on EMT in various diseases. However, the specific impact and underlying mechanisms of AP on EMT in RPE cells remain poorly understood. In this study, we have successfully validated the inhibitory effects of AP on high glucose-induced EMT in ARPE-19 cells and diabetic db/db mice. Notably, our findings have identified CBP/p300 as a potential therapeutic target for EMT in RPE cells and have further substantiated that AP effectively downregulates the expression of EMT-related genes by attenuating the activity of CBP/p300, consequently reducing histone acetylation alterations within the promoter region of these genes. Taken together, our results provide novel evidence supporting the inhibitory effect of AP on EMT in RPE cells, and highlight the potential of specifically targeting CBP/p300 as a strategy for inhibiting retinal fibrosis in the context of DR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: High glucose (HG)-induced oxidative stress is associated with apoptosis in pancreatic β-cells. The protective effect of astaxanthin-s-allyl cysteine diester (AST-SAC) against HG-induced oxidative stress in pancreatic β-cells (βTC-tet cell line) in in vitro was studied. Materials and Methods: βTC-tet cell line was exposed to HG in the presence and absence of AST-SAC. Various parameters such as cell viability, reactive oxygen species generation, mitochondrial membrane potential, DNA fragmentation and expression of proteins involved in apoptosis [p53, B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X (Bax), cytochrome c and caspase 3] were studied. Results: Pre-treatment of βTC-tet cells with AST-SAC (4, 8 and 12 μg/ml) in the presence of HG (25 mM) protected the viability of the cells in a dose-dependent manner. AST-SAC treatment mitigated the oxidative stress thereby preventing the mitochondrial dysfunction, DNA damage and apoptosis in βTC-tet cells against HG toxicity. Treatment with AST-SAC prevented the increased expression of p53 under HG conditions. Further, AST-SAC treatment maintained the level of pro-apoptotic (Bax, cleaved caspase-3 and cytochrome c) and anti-apoptotic (Bcl-2) proteins to that of the control level under HG exposed conditions in βTC-tet cells. Conclusion: Altogether, AST-SAC alleviated HG-induced oxidative damage and apoptosis in pancreatic β-cells by enhancing the antioxidant status and altering apoptotic-related protein expression.

Background: Cell division cycle 42 (CDC42) modulates metabolism, inflammation, and fibrosis to engage in the pathology of diabetic complications. This study intended to further investigate the influence of CDC42 on viability, apoptosis, inflammation, epithelial-mesenchymal transition, and fibrosis in high glucose (HG)-treated renal tubular epithelial cells., Methods: HK-2 cells were exposed to HG medium (30 mM) to establish the diabetic nephropathy (DN) cellular model, then the cells were transfected with scramble overexpression control (oeNC) or CDC42 overexpression (oeCDC42) vectors., Results: Both the level of CDC42 mRNA and protein were decreased in HG-treated HK-2 cells in a dose- and time-dependent manner. Then HG-treated HK-2 cells were proposed for the following experiments. It was found that CDC42 increased CCK-8 detected viability and EdU positive cells. On the contrary, CDC42 reduced cell apoptosis, which was reflected by decreased TUNEL positive rate, increased BCL2, and reduced BAX. Interestingly, CDC42 inhibited fibrosis, which was reflected by increased E-Cadherin, as well as decreased Vimentin, TGF-β1, Collagen1, and α-SMA. Apart from these, CDC42 also attenuated proinflammatory cytokine production, including TNF-α, IL-1β, and IL-6. Moreover, CDC42 activated the PAK1/AKT pathway, which was reflected by increased p-PAK1 and p-AKT. However, CDC42 did not affect p-ERK., Conclusion: CDC42 may retard DN progression via its regulation of renal tubular epithelial cell functions, which may be due to its stimulation of the PAK1/AKT pathway., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Vitexin, a polyphenolic flavonoid, has been reported to be traditionally applied in the treatment of diabetes, cancer and cardiovascular diseases., Objective: The aim of this study was to investigate the anti-apoptosis and anti-oxidation effect and the potential mechanism of vitexin on high glucose-induced HUVECs., Materials and Methods: A high dose of glucose was added to HUVECs to establish an in vitro model. The cell viability was detected by CCK8 and flow cytometry assays. 2,7-dichlorodihydrofluorescein diacetate, colorimetry, and enzyme-linked immunosorbent assay were performed to detect oxidative stress. Besides, top flash and western blotting were employed to evaluate the effect of vitexin on Wnt/β-catenin. Furthermore, a Wnt/β-catenin inhibitor (KYA1797K) was used to confirm whether Wnt/β-catenin is involved in the protection of vitexin. At the same time, RT-PCR and western blot were performed to determine the effect of vitexin on Nrf2, while immunofluorescence assays were employed for the assessment of Nrf2 localisation. Then, in order to validate that Nrf2 plays an important role in the anti-oxidant effect of vitexin, methods were utilised to silence Nrf2 gene., Results: Herein, vitexin inhibited the proliferation and apoptosis of HG-mediated HUVECs. Mechanically, vitexin disrupted Wnt/β-catenin signalling pathway, thus resulting in the decrease of apoptosis in HG-induced HUVECs. A Wnt/β-catenin inhibitor (KYA1797K), was used for reverse verification. In the meantime, vitexin administration decreased reactive oxygen species (ROS) production and malondialdehyde (MDA) content and increased superoxide dismutase (SOD) activity in HG-induced HUVECs. Further investigations have revealed vitexin activated Nrf2 in HUVEC under high glucose, which was involved in its anti-oxidant effects., Conclusion: Our investigation demonstrated that vitexin protected HUVECs from high glucose-induced injury via up-regulation of Wnt/β-catenin and Nrf2 signalling pathway. These results suggested that vitexin might serve as a potential drug for atherosclerosis and cardiovascular complications of diabetes.

The aim of the present study was to create a suitable model of the glucose toxicity and elucidate the ability of zinc-binding proteins metallothioneins in the crucian carp Carassius auratus to reflect it. For that, fish was loaded by three waterborne concentrations of glucose (low (5.55 mM, LC), middle (55.5 mM, MC) or high (111 mM, HC)) for 21 days. The level of blood glucose, responses of metallothioneins, oxidative stress, DNA instability in the liver, as well as erythrocytes indices, cholinesterase activity in the brain and morphometric variables were evaluated. An increase in blood glucose levels (up to 3–5 times), glycated hemoglobin (HbA1c, only by the HC, by 55%), methemoglobin (by two times), oxyradicals (16-57%) and TBARS levels (up to 57%), frequency of the micronucleated erythrocytes, DNA fragmentation in hepatocytes, body mass and hepatosomatic indices and a decrease in metallothioneins concentration (40-74%), cholinesterase activity (~70%), total hemoglobin (by 18%) and red blood cells count (only after HC-treatment, by 47%) were detected. The lysosomal membrane stability, evaluated by the neutral red retention time, was affected by all studied concentrations of glucose (decreased by 58%). The most prominent changes were observed after the HC of glucose. CART analysis revealed the significant splitting parameters for studied group differentiation including HbA1c, lysosomal membrane stability and lipid peroxidation. We could consider the crucian carp is a useful model organism to perform DM studies and in the future, this fish model can help in mechanistic investigations and testing therapeutic interventions under glycemic states.

Background: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism., Methods and Results: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα)., Conclusion: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection., (© 2024. The Author(s).)

Background: Recent years of evidence suggest the crucial role of renal tubular cells in developing diabetic kidney disease. Scopoletin (SCOP) is a plant-based coumarin with numerous biological activities. This study aimed to determine the effect of SCOP on renal tubular cells in developing diabetic kidney disease and to elucidate mechanisms., Methods and Results: In this study, SCOP was evaluated in vitro using renal proximal tubular (HK-2) cells under hyperglycemic conditions to understand its mechanism of action. In HK-2 cells, SCOP alleviated the high glucose-generated reactive oxygen species (ROS), restored the levels of reduced glutathione, and decreased lipid peroxidation. High glucose-induced alteration in the mitochondrial membrane potential was markedly restored in the SCOP-treated cells. Moreover, SCOP significantly reduced the high glucose-induced apoptotic cell population in the Annexin V-FITC flow cytometry study. Furthermore, high glucose markedly elevated the mRNA expression of fibrotic and extracellular matrix (ECM) components, namely, transforming growth factor (TGF)-β, alfa-smooth muscle actin (α-SMA), collagen I, and collagen III, in HK-2 cells compared to the untreated cells. SCOP treatment reduced these mRNA expressions compared to the high glucose-treated cells. Collagen I and TGF-β protein levels were also significantly reduced in the SCOP-treated cells. Further findings in HK-2 cells revealed that SCOP interfered with the epithelial-mesenchymal transition (EMT) in the high glucose-treated HK-2 cells by normalizing E-cadherin and downregulating the vimentin and α-SMA proteins., Conclusions: In conclusion, SCOP modulates the high glucose-generated renal tubular cell oxidative damage and accumulation of ECM components and may be a promising molecule against diabetic nephropathy., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Diabetic kidney disease (DKD) is a leading cause of kidney failure. However, the involvement of renal fibroblasts and their communications with renal epithelial cells during DKD remain poorly understood. We investigated the potential role of renal proximal tubular epithelial cells (PTECs) in renal fibroblast activation that might lead to DKD. Additionally, the protective effects of curcumin, a known antioxidant, against renal fibroblast activation induced by high glucose-treated PTECs were investigated. Secretome was collected from HK-2 PTECs under normal glucose, high glucose, high glucose pretreated/cotreated with curcumin, or osmotic control condition for 24 h. Such secretome was then used to treat BHK-21 renal fibroblasts for 24 h. BHK-21 cells treated with high glucose-induced secretome had increased levels of fibroblast activation markers, including spindle index, F-actin, α-smooth muscle actin (α-SMA), fibronectin, collagen I, matrix metalloproteinase-2 (MMP-2) and MMP-9, as compared with normal glucose and osmotic control conditions. However, all these increases were successfully mitigated by curcumin. In addition, high glucose markedly increased intracellular reactive oxygen species (ROS) and transforming growth factor-β (TGF-β) secretion, but did not affect the secretion of platelet-derived growth factor A (PDGFA) and interleukin-1β (IL-1β), in HK-2 renal cells as compared with normal glucose and osmotic control conditions. Both intracellular ROS and secreted TGF-β levels were successfully mitigated by curcumin. Therefore, curcumin prevents the high glucose-induced stimulatory effects of renal cell secretome on fibroblast activation, at least in part, via mitigating intracellular ROS and TGF-β secretion., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Histone modifications play a critical role in chromatin remodelling and regulate gene expression in health and disease. Histone methyltransferases EZH1, EZH2, and demethylases UTX, JMJD3, and UTY catalyse trimethylation of lysine 27 on histone H3 (H3K27me3). This study was designed to investigate whether H3K27me3 triggers hyperglycemia-induced oxidative and inflammatory transcriptional programs in the endothelium., Methods: We studied human aortic endothelial cells exposed to high glucose (HAEC) or isolated from individuals with diabetes (D-HAEC). RT-qPCR, immunoblotting, chromatin immunoprecipitation (ChIP-qPCR), and confocal microscopy were performed to investigate the role of H3K27me3. We determined superoxide anion (O 2 - ) production by ESR spectroscopy, NF-κB binding activity, and monocyte adhesion. Silencing/overexpression and pharmacological inhibition of chromatin modifying enzymes were used to modulate H3K27me3 levels. Furthermore, isometric tension studies and immunohistochemistry were performed in aorta from wild-type and db/db mice., Results: Incubation of HAEC to high glucose showed that upregulation of EZH2 coupled to reduced demethylase UTX and JMJD3 was responsible for the increased H3K27me3. ChIP-qPCR revealed that repressive H3K27me3 binding to superoxide dismutase and transcription factor JunD promoters is involved in glucose-induced O 2 - generation. Indeed, loss of JunD transcriptional inhibition favours NOX4 expression. Furthermore, H3K27me3-driven oxidative stress increased NF-κB p65 activity and downstream inflammatory genes. Interestingly, EZH2 inhibitor GSK126 rescued these endothelial derangements by reducing H3K27me3. We also found that H3K27me3 epigenetic signature alters transcriptional programs in D-HAEC and aortas from db/db mice., Conclusions: EZH2-mediated H3K27me3 represents a key epigenetic driver of hyperglycemia-induced endothelial dysfunction. Targeting EZH2 may attenuate oxidative stress and inflammation and, hence, prevent vascular disease in diabetes., (© 2024. The Author(s).)

Purpose: Circular RNAs (circRNAs) have been verified to participate in multiple biological processes and disease progression. Yet, the role of circRNAs in the pathogenesis of diabetic retinopathy (DR) is still poorly understood and deserves further study. This study aimed to investigate the role of circRNAs in the regulation of high glucose (HG)-induced apoptosis of retinal microvascular endothelial cells (RMECs)., Methods: Epiretinal membranes from patients with DR and nondiabetic patients with idiopathic macular epiretinal membrane were collected for this study. The circRNA microarrays were performed using high-throughput sequencing. Hierarchical clustering, functional enrichment, and network regulation analyses were used to analyze the data generated by high-throughput sequencing. Next, RMECs were subjected to HG (25 mM) conditions to induce RMECs apoptosis in vitro. A series of experiments, such as Transwell, the Scratch wound, and tube formation, were conducted to explore the regulatory effect of circRNA on RMECs. Fluorescence in situ hybridization (FISH), immunofluorescence staining, and Western blot were used to study the mechanism underlying circRNA-mediated regulation., Results: A total of 53 differentially expressed circRNAs were found in patients with DR. Among these, hsa&#95;circ&#95;0000880 was significantly upregulated in both the diabetic epiretinal membranes and in an in vitro DR model of HG-treated RMECs. Hsa&#95;circ&#95;0000880 knockout facilitated RMECs vitality and decreased the paracellular permeability of RMECs under hyperglycemia. More importantly, silencing of hsa&#95;circ&#95;0000880 significantly inhibited HG-induced ROS production and RMECs apoptosis. Hsa&#95;circ&#95;0000880 acted as an endogenous sponge for eukaryotic initiation factor 4A-III (EIF4A3). Knockout of hsa&#95;circ&#95;0000880 reversed HG-induced decrease in EIF4A3 protein level., Conclusions: Our findings suggest that hsa&#95;circ&#95;0000880 is a novel circRNA can induce RMECs apoptosis in response to HG conditions by sponging EIF4A3, offering an innovative treatment approach against DR., Translational Relevance: The circRNAs participate in the dysregulation of microvascular endothelial function induced by HG conditions, indicating a promising therapeutic target for DR.

Hyperglycemia is a potent risk factor for the development and progression of diabetes-induced nephropathy. Dendropanoxide (DPx) is a natural compound isolated from Dendropanax morbifera (Araliaceae) that exerts various biological effects. However, the role of DPx in hyperglycemia-induced renal tubular cell injury remains unclear. The present study explored the protective mechanism of DPx on high glucose (HG)-induced cytotoxicity in kidney tubular epithelial NRK-52E cells. The cells were cultured with normal glucose (5.6 mM), HG (30 mM), HG + metformin (10 µM), or HG + DPx (10 µM) for 48 h, and cell cycle and apoptosis were analyzed. Malondialdehyde (MDA), advanced glycation end products (AGEs), and reactive oxygen species (ROS) were measured. Protein-based nephrotoxicity biomarkers were measured in both the culture media and cell lysates. MDA and AGEs were significantly increased in NRK-52E cells cultured with HG, and these levels were markedly reduced by pretreatment with DPx or metformin. DPx significantly reduced the levels of kidney injury molecule-1 (KIM-1), pyruvate kinase M2 (PKM2), selenium-binding protein 1 (SBP1), or neutrophil gelatinase-associated lipocalin (NGAL) in NRK-52E cells cultured under HG conditions. Furthermore, treatment with DPx significantly increased antioxidant enzyme activity. DPx protects against HG-induced renal tubular cell damage, which may be mediated by its ability to inhibit oxidative stress through the protein kinase B/mammalian target of the rapamycin (AKT/mTOR) signaling pathway. These findings suggest that DPx can be used as a new drug for the treatment of high glucose-induced diabetic nephropathy., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Diabetic nephropathy (DN) is one of the complications of diabetes mellitus and the main cause of end-stage renal disease (ESRD), which is a serious threat to human health. In DN, mesangial cells (MCs) are a critical target cell that perform a variety of key functions, and abnormal proliferation of MCs is a common and prominent pathological change in DN. In recent years, the investigation of Chinese medicine interventions for DN has increased significantly in recent years due to the many potential adverse effects and controversies associated with the treatment of DN with Western medicines. In this study, we evaluated the protective effect of resveratrol (RES), an active ingredient known as a natural antioxidant, on HMCs under high glucose and explored its possible mechanism of action. We found that RES inhibited the proliferation of human mesangial cell (HMC) under high glucose and blocked cell cycle progression. In the high glucose environment, RES upregulated miR-1231, reduced IGF1 expression, inhibited the activity of the extracellular signal-regulated kinase (ERK) signaling pathway and reduced levels of the inflammatory factors TNF-α and IL-6. In addition, we found that miR-1231 mimics were synergistically inhibited with RES, whereas miR-1231 inhibitor attenuated the protective effect of RES on HMCs. Thus, our results suggest that the protective effect of RES on HMCs under high glucose is achieved, at least in part, through modulation of the miR-1231/IGF1/ERK pathway. The discovery of this potential mechanism may provide a new molecular therapeutic target for the prevention and treatment of DN, and may also bring new ideas for the clinical research in DN., (© 2023 Wiley Periodicals LLC.)

Mitochondrial DNA damage in retinal ganglion cells (RGCs) may be closely related to lesions of glaucoma. RGCs were cultured with different concentrations of glucose and grouped into 3 groups, namely normal control (NC) group, Low-Glu group, and High-Glu group. Cell viability was measured with cell counting kit-8, and cell apoptosis was measured using flow cytometry. The DNA damage was measured with comet assay, and the morphological changes of damaged mitochondria in RGCs were observed using TEM. Western blot analyzed the expression of MRE11, RAD50, and NBS1 protein. Cell viability of RGCs in Low-Glu and High-Glu groups were lower than that of NC group in 48 and 96 h. The cell apoptosis in NC group was 4.9%, the Low-Glu group was 12.2% and High-Glu group was 24.4%. The comet imaging showed that NC cells did not have tailings, but the low-Glu and high-Glu group cells had tailings, indicating that the DNA of RGCs had been damaged. TEM, mitochondrial membrane potential, ROS, mitochondrial oxygen consumption, and ATP content detection results showed that RGCs cultured with high glucose occurred mitochondrial morphology changes and dysfunction. MRE11, RAD50, and NBS1 protein expression associated with DNA damage repair pathway in High-Glu group declined compared with Low-Glu group. Mitochondrial DNA damage caused by high glucose will result in apoptosis of retinal ganglion cells in glaucoma.

Diabetic retinopathy (DR) severely affects vision in individuals with diabetes. High glucose (HG) induces oxidative stress in retinal cells, a key contributor to DR development. Previous studies suggest that fibroblast growth factor-1 (FGF-1) can mitigate hyperglycemia and protect tissues from HG-induced damage. However, the specific effects and mechanisms of FGF-1 on DR remain unclear. In our study, FGF-1-pretreated adult retinal pigment epithelial (ARPE)-19 cells were employed to investigate. Results indicate that FGF-1 significantly attenuated HG-induced oxidative stress, including reactive oxygen species, DNA damage, protein carbonyl content, and lipid peroxidation. FGF-1 also modulated the expression of oxidative and antioxidative enzymes. Mechanistic investigations showed that HG induced high endoplasmic reticulum (ER) stress and upregulated specific proteins associated with apoptosis. FGF-1 effectively alleviated ER stress, reduced apoptosis, and restored autophagy through the adenosine monophosphate-activated protein kinase/mammalian target of the rapamycin signaling pathway. We observed that the changes induced by HG were dose-dependently reversed by FGF-1. Higher concentrations of FGF-1 (5 and 10 ng/mL) exhibited increased effectiveness in mitigating HG-induced damage, reaching statistical significance ( p < 0.05). In conclusion, our study underscores the promising potential of FGF-1 as a safeguard against DR. FGF-1 emerges as a formidable intervention, attenuating oxidative stress, ER stress, and apoptosis, while concurrently promoting autophagy. This multifaceted impact positions FGF-1 as a compelling candidate for alleviating retinal cell damage in the complex pathogenesis of DR.

-To explore the effect of TRPC1 on endothelial cell function damage under a high glucose environment and its downstream molecular mechanism, and provide new theory and strategy for improving diabetic endothelial cell function and promoting vascular injury repair. In vitro, we use high glucose to treat human umbilical vein endothelial cells (HUVECs) and upregulated TRPC1 with adenovirus infection. HUVECs were split into 4 groups: (i) NG Group: Treated with normal glucose; (ii) HG Group: Treated with high glucose; (iii) HG + adGFP Group: High glucose + the control adenovirus (adGFP); (iv) HG + adTRPC1 Group: High glucose + recombinant adenovirus encoding TRPC1. We found that high glucose significantly decreased the expression level of TRPC1 protein, and impaired the proliferation and migration of HUVECs, which could be reversed by overexpression of TRPC1. In addition, high glucose induced an increase in ROS and MDA and a decrease in SOD activity, whereas TRPC1 overexpression could inhibit the growth of oxidative stress level. These findings suggest that overexpression of TRPC1 prevents HUVECs proliferation and migration dysfunction induced by high glucose via inhibiting oxidative stress injuries., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Alisol A can ameliorate glucose metabolism disorders, however, there is no data regarding its role in diabetic nephropathy (DN). The present work evaluates the role of Alisol A in DN and the underlying mechanism., Methods: RNA expression of circ&#95;0001831, miR-346, and lin-28 homolog B (LIN28B) was detected by qRT-PCR. Cell viability and proliferation were investigated by MTT assay and EdU assay, respectively. The inflammatory cytokines were examined by ELISAs. Oxidative stress was evaluated by the commercial kits. Protein expression was detected by western blotting. The interactions among circ&#95;0001831, miR-346, and LIN28B were identified by dual-luciferase reporter assay and RIP assay. DN mouse model assay was used to analyse the effect of Alisol A on renal injury of diabetic mice., Results: HG treatment promoted HRMC proliferation, fibrosis, inflammation, and oxidative stress; however, these effects were reversed after Alisol A treatment. Alisol A treatment ameliorated STZ-induced renal injury of diabetic mice. Additionally, circ&#95;0001831 or LIN28B overexpression or miR-346 downregulation relieved Alisol A-induced effects under HG conditions. Mechanistically, circ&#95;0001831 acted as a miR-346 sponge, and LIN28B was identified as a target gene of miR-346. Further, the regulation of circ&#95;0001831 in HG-induced HRMC dysfunction involved LIN28B., Conclusion: Alisol A ameliorated HG-induced HRMC fibrosis, inflammation, and oxidative stress and STZ-induced renal injury of diabetic mice by regulating the circ&#95;0001831/miR-346/LIN28B pathway., (© 2023 Asian Pacific Society of Nephrology.)

Purpose: The regulation of mitophagy by Sirt3 has rarely been studied in ocular diseases. In the present study, we determined the effects of Sirt3 on AMPK/mTOR/ULK1 signaling pathway-mediated mitophagy in retinal pigment epithelial (RPE) cells in a high glucose environment., Methods: The mRNA expression levels of Sirt3, AMPK, mTOR, ULK1, and LC3B in RPE cells under varying glucose conditions were measured by real-time polymerase chain reaction (RT-PCR). The expressions of Sirt3, mitophagy protein, and AMPK/mTOR/ULK1 signaling pathway-related proteins were detected by Western blotting. Lentivirus (LV) transfection mediated the stable overexpression of Sirt3 in cell lines. The experimental groups were NG (5.5 mM glucose), hypertonic, HG (30 mM glucose), HG + LV-GFP, and HG + LV-Sirt3. Western blotting was performed to detect the expressions of mitophagy proteins and AMPK/mTOR/ULK1-related proteins in a high glucose environment during the overexpression of Sirt3. Reactive oxygen species (ROS) production in a high glucose environment was measured by DCFH-DA staining. Mitophagy was detected by labeling mitochondria and lysosomes with MitoTracker and LysoTracker probes, respectively. Apoptosis was detected by flow cytometry., Results: Sirt3 expression was reduced in the high glucose group, inhibiting the AMPK/mTOR/ULK1 pathway, with diminished mitophagy and increased intracellular ROS production. The overexpression of Sirt3, increased expression of p-AMPK/AMPK and p-ULK1/ULK1, and decreased expression of p-mTOR/mTOR inhibited cell apoptosis and enhanced mitophagy., Conclusions: Sirt3 protected RPE cells from high glucose-induced injury by activating the AMPK/mTOR/ULK1 signaling pathway., Translational Relevance: By identifying new targets of action, we aimed to establish effective therapeutic targets for diabetic retinopathy treatment.

Previous studies have implicated targeting Pim-1 proto-oncogene, serine/threonine kinase (PIM1) as a preventive measure against high glucose-induced cellular stress and apoptosis. This study aimed to reveal the potential role and regulatory mechanism of PIM1 in diabetic retinopathy. Human retinal microvascular endothelial cells (hRMECs) underwent high glucose induction, and fluctuations in PIM1 levels were assessed. By overexpressing PIM1, its effects on the levels of inflammatory factors, oxidative stress indicators, migration and tube formation abilities, tight junction protein expression levels, and ferroptosis in hRMECs were identified. Afterwards, hRMECs were treated with the ferroptosis-inducing agent erastin, and the effect of erastin on the above PIM1 regulatory functions was focused on. PIM1 was downregulated upon high glucose, and its overexpression inhibited the inflammatory response, oxidative stress, cell migration, and tube formation potential in hRMECs, whereas elevated tight junction protein levels. Furthermore, PIM1 overexpression reduced intracellular iron ion levels, lipid peroxidation, and levels of proteins actively involved in ferroptosis. Erastin treatment reversed the impacts of PIM1 on hRMECs, suggesting the mediation of ferroptosis in PIM1 regulation. The current study has yielded critical insights into the role of PIM1 in ameliorating high glucose-induced hRMEC dysfunction through the inhibition of ferroptosis., (© 2024. The Society for In Vitro Biology.)

Endothelial dysfunction is recognized as the initial detectable stage of cardiovascular disease, a serious complication of diabetes. In this study, we evaluated effects of myricetin on high glucose (HG)‐elicited oxidative damage in human umbilical vein endothelial cells (HUVECs). The cells were pre‐incubated with myricetin and then treated with HG to induce apoptosis. The effect of myricetin on viability was investigated by MTT assay. The levels of lipid peroxidation (LPO) were determined by thiobarbituric acid (TBA) method. The protein expression of Bax, Bcl‐2 and caspase‐3 was measured by western blot analysis. Moreover, the effect of myricetin on total antioxidant capacity (TAC) and total thiol molecules was also determined. Our results showed that myricetin was able to markedly restore the viability of endothelial cells under oxidative stress. Myricetin reduced HG‐caused increase in LPO levels. Also, TAC and total thiol molecules were notably elevated by myricetin. Incubation with myricetin decreased the protein expression levels of Bax, whereas it increased the expression levels of the Bcl‐2, compared with HG treatment alone. Furthermore, myricetin significantly decreased cleaved caspase‐3 protein expression. It is concluded that myricetin may protect HUVECs from oxidative stress induced by HG via increasing cell TAC and reducing Bax/Bcl‐2 protein ratio, and caspase‐3 expression. [ABSTRACT FROM AUTHOR]

Fundamental pancreatic β-cell function is to produce and secrete insulin in response to blood glucose levels. However, when β-cells are chronically exposed to hyperglycemia in type 2 diabetes mellitus (T2DM), insulin biosynthesis and secretion are decreased together with reduced expression of insulin transcription factors. Glucagon-like peptide-1 (GLP-1) plays a crucial role in pancreatic β-cells; GLP-1 binds to the GLP-1 receptor (GLP-1R) in the β-cell membrane and thereby enhances insulin secretion, suppresses apoptotic cell death and increase proliferation of β-cells. However, GLP-1R expression in β-cells is reduced under diabetic conditions and thus the GLP-1R activator (GLP-1RA) shows more favorable effects on β-cells at an early stage of T2DM compared to an advanced stage. On the other hand, it has been drawing much attention to the idea that GLP-1 signaling is important in arterial cells; GLP-1 increases nitric oxide, which leads to facilitation of vascular relaxation and suppression of arteriosclerosis. However, GLP-1R expression in arterial cells is also reduced under diabetic conditions and thus GLP-1RA shows more protective effects on arteriosclerosis at an early stage of T2DM. Furthermore, it has been reported recently that administration of GLP-1RA leads to the reduction of cardiovascular events in various large-scale clinical trials. Therefore, we think that it would be better to start GLP-1RA at an early stage of T2DM for the prevention of arteriosclerosis and protection of β-cells against glucose toxicity in routine medical care.

Abstract Background Growing evidence indicates that oxidative stress (OS) plays a pivotal role in Diabetic nephropathy (DN). In a previous study we demonstrated that ALA/LA protected HK-2 cells against high glucose-induced cytotoxicity. So we aimed to establish the glucose injury model of HK-2 cells and investigate the beneficial effects of ALA/LA on high glucose-induced excessive production of TGF-β1 and the possible mechanisms mediating the effects. Methods The expression of OS markers in high glucose-induced HK-2 cells treated with ALA/LA., including the antioxidant enzymes and reactive oxygen species (ROS) production, as well as the apoptosis rate were assayed by ELISA and flow cytometry. The p38/transforming growth factor β1 (TGF-β1) signal pathway were measured by real-time RT-PCR and western blot. Results The modeling condition of glucose toxicity on HK-2 cells was at the glucose concentration of 40.9 mM. ALA/LA can significantly increase the activities of antioxidant enzymes and decrease ROS production stimulated by high glucose. The study also found that ALA/LA caused a decrease in the apoptosis rate and TGF-β1 level of HK-2 cells under high glucose stress through the ROS/p38 pathway. Conclusions ALA/LA exerts protective effects in vitro through inhibition of ROS generation, down regulation of the activation of the p38MAPK pathway and the expression of TGF-β1 in HK-2 cells.