BACKGROUND Diabetic cystopathy(DCP)is a complication affecting the lives of people with diabetes.However,the pathogenesis of DCP is not well known.AIM To investigate the potential mechanisms by which cAMP-responsive e...BACKGROUND Diabetic cystopathy(DCP)is a complication affecting the lives of people with diabetes.However,the pathogenesis of DCP is not well known.AIM To investigate the potential mechanisms by which cAMP-responsive elementbinding protein 3 like 3(CREB3 L3)promotes the occurrence and development of DCP.METHODS High-throughput sequencing was used to analyze differentially expressed genes(DEGs)in bladder urothelium from patients with DCP and healthy controls.Gene enrichment analysis was conducted to assess the biological functions of DEG.Small interfering RNA technology was performed to silence the CREB3 L3 gene in both in vitro and in vivo experiments.Morphological changes in bladder urothelium from a DCP rat model were observed.Immunofluorescence and western blotting assay were performed to determine associated protein expression.RESULTS We identified significant DEGs through high-throughput sequencing.These genes were primarily enriched in inflammatory activation,epithelial-mesenchymal transition(EMT)and tight junction organization.Upregulated expression of both CREB3 L3 and C-reactive protein(CRP)in bladder urothelium from patients with DCP was accompanied by upregulated EMT markers including N-cadherin and vimentin proteins,but downregulated E-cadherin.Silencing CREB3 L3 attenuated the protein expression of CRP and EMT in SV-HUC-1 urothelial cells under hyperglycemic conditions and in the diabetes mellitus rat model at 4,8,and 12 weeks.CREB3 L3 knockdown also reversed downregulation of the tight junction proteins occludin and claudin 1.CONCLUSION Hyperglycemia induces the upregulation of CREB3 L3 expression,thereby promoting the EMT and impairing tight junctions in bladder urothelial cells.Targeting CREB3 L3 in bladder urothelial cells is likely to be a key approach in preventing and treating DCP.展开更多
Plant polyphenols are potential substitutes for clinicalα-glucosidase inhibitors.Our previous studies indicated that prodelphinidins from Chinese bayberry leaves(BLPs)have strongerα-glucosidase inhibitory activity t...Plant polyphenols are potential substitutes for clinicalα-glucosidase inhibitors.Our previous studies indicated that prodelphinidins from Chinese bayberry leaves(BLPs)have strongerα-glucosidase inhibitory activity than other common polyphenols,but they have no safe history of consumption.There is a reasonable prospect that prodelphinidins from Chinese bayberry fruits(BFPs)can improve postprandial hyperglycemia,though known active components are only myricetin and cyanidin-3-O-glucoside.Hence,the aim of this study was to analyze structure and hypoglycemic effect of BFPs of“Biqi”(BQPs)and“Dongkui”(DKPs)cultivars,and compare their difference with BLPs.The contents of BQPs and DKPs were(221.73±0.60)and(136.82±4.33)mg epicatechin(EC)equivalents/g dry weight,respectively.The most subunits were epigallocatechin gallate along with a small amount of epigallocatechin,epicatechin gallate and EC connected by B-type linkages and a small portion of A-type linkages with mean polymerization degree of 4.25 and 4.08,respectively.Importantly,BQPs and DKPs wereα-glucosidase inhibitors with half inhibitory concentration of 11.91 and 9.47μg/m L respectively,which were significantly stronger than BLPs.DKPs could also improve postprandial hyperglycemia of normal mice and high fat diet-induced type II diabetic mice.Therefore,edible prodelphinidins,which have stronger hypoglycemic effect than BLPs,were first found in Chinese bayberry fruits.展开更多
BACKGROUND Acute myocardial infarction(AMI)is a major cause of mortality worldwide.The stress hyperglycemia ratio(SHR),which integrates glucose and glycated hemoglobin A1c levels,better reflects acute metabolic stress...BACKGROUND Acute myocardial infarction(AMI)is a major cause of mortality worldwide.The stress hyperglycemia ratio(SHR),which integrates glucose and glycated hemoglobin A1c levels,better reflects acute metabolic stress.This study assessed the SHR and longterm prognosis of patients with AMI.METHODS This study was a post-hoc analysis based on the prospective,multicenter OPTIMAL registry(http://www.clinicaltrials.gov,NCT number:NCT03084991).A total of 3384 consecutive patients who underwent percutaneous coronary intervention(PCI)at Department of Cardiology,The 2nd Affiliated Hospital of Harbin Medical University,Harbin,China were included in the present analysis after exclusions.Patients were stratified into quartiles according to the SHR.The primary endpoint was cardiovascular death,with all-cause death and major adverse cardiovascular events as secondary endpoints.The median follow-up duration was 24.1 months,with a completion rate of 99.5%.RESULTS Kaplan-Meier survival curves showed progressively worse survival across SHR quartiles(log-rank P<0.001),with patients in Q4(SHR≥1.34)experiencing the highest risk.Multivariate Cox regression analysis confirmed that the SHR was an independent predictor of cardiovascular death[hazard ratio(HR)=1.56],all-cause death(HR=1.48),and major adverse cardiovascular events(HR=1.34)for Q4(SHR≥1.34)versus Q2(SHR:0.93–1.11).Restricted cubic spline analysis revealed a J-shaped association between SHR and outcomes,with the lowest risk observed at an SHR of approximately 1.0.CONCLUSIONS The SHR is an independent predictor of long-term adverse outcomes in patients with AMI undergoing PCI,supporting its use for early risk stratification and glycemic management.展开更多
BACKGROUND Diabetes and its associated microvascular complications,such as nephropathy and retinopathy,significantly impact global health.These complications often begin in the prediabetic stage,emphasizing the import...BACKGROUND Diabetes and its associated microvascular complications,such as nephropathy and retinopathy,significantly impact global health.These complications often begin in the prediabetic stage,emphasizing the importance of early detection and intervention.Inflammatory pathways are key contributors to these conditions,and recent research has identified members of the tumor necrosis factor(TNF)receptor superfamily as potential biomarkers.However,their association with renal and retinal dysfunction in individuals with intermediate hyperglycemia(IH)remains underexplored.The Early Prevention of Diabetes Complications(ePREDICE)trial provides a valuable cohort to investigate these associations and improve risk assessment strategies.AIM To identify inflammatory biomarkers associated with early renal and retinal dysfunction in individuals with IH.Specifically,we evaluate the diagnostic and prognostic potential of TNF receptor superfamily members[TNF receptor 1(TNF-R1),TNF receptor 2(TNF-R2)],T-cell immunoglobulin and mucin domain 3(TIM-3)/HAVCR2,galectin-3,and interleukin-6(IL-6)in detecting kidney dysfunction and retinopathy in this high-risk population.By understanding their roles,we seek to enhance early screening methods and inform personalized intervention strategies.METHODS A cross-sectional analysis of 967 individuals with IH from the ePREDICE trial was conducted.Participants underwent comprehensive anthropometric and biochemical assessments.Key inflammatory biomarkers,including TNF-R1,TNF-R2,TIM-3/HAVCR2,galectin-3,and IL-6,were quantified using immunoassays.Renal function was assessed using estimated glomerular filtration rate(eGFR)and albuminuria,while retinopathy was evaluated through fundoscopic examination.Statistical analyses included adjusted mean comparisons,correlation studies,and receiver operating characteristic curve analysis to assess biomarker diagnostic accuracy.RESULTS TNF-R1,TNF-R2,and TIM-3/HAVCR2 were significantly associated with reduced filtration function(eGFR<60 mL/minute/1.73 m^(2))and albuminuria,with area under the curve(AUC)values between 0.815 and 0.845.TIM-3/HAVCR2 emerged as the strongest predictor of retinopathy(AUC=0.737).Strong correlations(r>0.75)were observed among TNF-R1,TNF-R2,and TIM-3/HAVCR2,suggesting a coordinated role in inflammatory pathways.CONCLUSION Our findings highlight the potential of TNF receptor superfamily members as biomarkers for early-stage renal and retinal complications in individuals with IH.Their integration into clinical screening protocols could facilitate earlier detection,improving patient stratification and personalized management strategies.Further longitudinal studies are necessary to validate their predictive value and potential for guiding therapeutic interventions in IH and early diabetes management.展开更多
Objective To elucidate the regulatory mechanism of circRNAs in diabetic retinopathy.Methods Next-generation sequencing(NGS)was employed to identify circRNAs that are abnormally expressed in endothe-lial progenitor cel...Objective To elucidate the regulatory mechanism of circRNAs in diabetic retinopathy.Methods Next-generation sequencing(NGS)was employed to identify circRNAs that are abnormally expressed in endothe-lial progenitor cells(EPCs)under hyperglycemia(HG)conditions.The regulatory mechanism and predicted targets of this circRNA were also studied via bioinformatics analysis,luciferase reporter assays,angiogenic differentiation experiments,flow cytometry,and RT-qPCR.Results Circ-astrotactin 1(circ-Astn1)expression was decreased in EPCs under HG conditions,and circ-Astn1 overexpres-sion inhibited HG-induced endothelial damage.The miR-138-5p and silencing information regulator 2 related enzyme 1(SIRT1)were identified as circ-Astn1 downstream targets,which were further verified through luciferase reporter assays.SIRT1 silencing or miR-138-5p overexpression reversed the protective effect of circ-Astn1 on HG-induced endothelial cell dysfunction,as evidenced by increased apoptosis,abnormal vascular differentiation,and inflammatory factor secretion.SIRT1 overexpression reversed miR-138-5p-induced endothelial cell dysfunction under HG conditions.In vivo experiments confirmed that circ-Astnl overexpression promoted skin wound healing through the regulation of SIRT1.Conclusions These findings suggest that circ-Astn1 promotes SIRT1 expression by sponging miR-138-5p.Circ-Astn1 over-expression suppresses HG-induced endothelial cell damage via miR-138-5p/SIRT1 axis.展开更多
BACKGROUND Stress-induced hyperglycemia(SIH)is common in critically ill patients and has been associated with adverse cardiovascular outcomes.Intensive insulin therapy(IIT)has been proposed to mitigate these risks by ...BACKGROUND Stress-induced hyperglycemia(SIH)is common in critically ill patients and has been associated with adverse cardiovascular outcomes.Intensive insulin therapy(IIT)has been proposed to mitigate these risks by achieving tighter glycemic control.AIM To evaluate the efficacy of IIT for managing SIH in critically ill patients and to explore its potential effect on cardiac function.METHODS A retrospective study was conducted at our hospital from January 2021 to December 2024,adhering to STROBE guidelines.A total of 186 critically ill pa-tients were divided into normal glycemia(n=85)and SIH(n=101)groups.The SIH cohort was further subdivided into conventional treatment(n=50)and IIT(n=51)groups.Hemodynamic parameters-including right atrial pressure(RAP),pulmonary artery pressure(PAP),pulmonary capillary wedge pressure(PAWP),cardiac output(CO),cardiac index(CI),and B-type natriuretic peptide(BNP)-were measured at baseline and post-treatment.Clinical outcomes such as intensive care unit(ICU)length of stay,mechanical ventilation requirements,and mortality were also recorded.Statistical analyses were conducted using inde-pendent samples t-tests and χ^(2)/Fisher’s exact tests.RESULTS SIH markedly worsened haemodynamics versus normal glycaemia:RAP 9.8±5.1 vs 6.1±3.5 mmHg,PAP 35.2±16.0 vs 26.2±10.3 mmHg,PAWP 16.0±7.0 vs 8.6±6.4 mmHg,CO 3.3±2.3 vs 6.0±3.3 L/min,CI 1.88±0.24 vs 2.70±0.50 L/min/m2,BNP 465±250 vs 180±53 pg/mL(all P<0.001).Within the SIH cohort,IIT outperformed conventional therapy:RAP 7.0±2.2 vs 8.3±3.9 mmHg(P=0.04),PAP 21.6±3.7 vs 29.3±6.5 mmHg(P<0.001),PAWP 10.2±5.4 vs 13.8±5.3 mmHg(P=0.001),CO 4.9±2.2 vs 4.0±1.4 L/min(P=0.022),CI 2.58±0.32 vs 2.11±0.31 L/min/m2,P<0.001),BNP 202±62 vs 346±171 pg/mL(P<0.001).Clinically,IIT shortened ICU stay(10.3±3.4 vs 14.5±2.6 days,P<0.001),reduced ventilator use(56.9%vs 76.0%,P=0.042),and lowered mortality(23.5%vs 42.0%,P=0.048).CONCLUSION IIT significantly reduced cardiac filling pressures,improved cardiac function,and was associated with favorable clinical outcomes in SIH patients,suggesting potential benefits of stricter glycaemic control in critically ill patients.However,given the retrospective design and absence of glucose-variability monitoring,these findings should be interpreted with caution.展开更多
目的观察木犀草素对高糖诱导的视网膜血管内皮细胞(RVECs)损伤的影响,并探究可能的机制。方法该研究于2023年5月至2024年1月进行。RVECs购自青旗(上海)生物技术有限公司,木犀草素购自西安弘康生物技术有限责任公司。体外常规培养RVECs,...目的观察木犀草素对高糖诱导的视网膜血管内皮细胞(RVECs)损伤的影响,并探究可能的机制。方法该研究于2023年5月至2024年1月进行。RVECs购自青旗(上海)生物技术有限公司,木犀草素购自西安弘康生物技术有限责任公司。体外常规培养RVECs,用含有30 mmol/L葡萄糖的DMEM培养液处理建立损伤模型,分为高糖组(高糖处理)、木犀草素组(高糖处理+30μmol/L木犀草素)、LY294002[磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(AKT)通路阻断剂]组(高糖处理+10μmol/L LY294002)、联合组(高糖处理+30μmol/L木犀草素+10μmol/L LY294002)。另取不作任何处理的RVECs为空白组。培养24 h后,细胞计数试剂盒(CCK-8)法、膜联蛋白V(Annexin V)/碘化丙啶(PI)双染法、血管拟态实验检测各组细胞活力、凋亡率、血管新生能力;检测细胞膜通透性及氧化应激指标;免疫印迹法检测各组AKT、p-AKT、哺乳动物雷帕霉素靶蛋白(mTOR)、p-mTOR蛋白表达量。结果与空白组比较,高糖组凋亡率[(2.87±0.45)%比(10.15±3.45)%]、荧光强度(0.21±0.06比0.52±0.13)、丙二醛含量[(5.02±1.30)nmol/mg比(18.87±3.65)nmol/mg]升高(P<0.05),新生血管数量增加(P<0.05),细胞存活率及SOD、CAT活性降低(P<0.05);与高糖组比较,木犀草素组凋亡率、荧光强度、丙二醛含量降低(P<0.05),细胞存活率升高(P<0.05),新生血管数量减少(P<0.05),SOD活性、CAT活性增强(P<0.05),LY294002组凋亡率、荧光强度、丙二醛含量升高(P<0.05),新生血管数量增加(P<0.05),SOD活性、CAT活性降低(P<0.05);与木犀草素组比较,联合组凋亡率、荧光强度、丙二醛含量升高(P<0.05),新生血管数量增加(P<0.05),细胞存活率及SOD活性、CAT活性降低(P<0.05);与LY294002组比较,联合组凋亡率、荧光强度、丙二醛含量降低(P<0.05),细胞存活率升高(P<0.05),新生血管数量减少(P<0.05),SOD活性、CAT活性增强(P<0.05)。与空白组比较,高糖组p-AKT/AKT、p-mTOR/mTOR降低(P<0.05);与高糖组比较,木犀草素组p-AKT/AKT、p-mTOR/mTOR升高(P<0.05),LY294002组p-AKT/AKT、p-mTOR/mTOR降低(P<0.05);与木犀草素组比较,联合组p-A K T/A K T、p-mTOR/mTOR降低(P<0.05);与LY294002组比较,联合组p-AKT/AKT、p-mTOR/mTOR升高(P<0.05)。结论木犀草素可抑制高糖诱导的RVECs凋亡及血管生成,增强细胞活力,降低细胞膜通透性,减轻氧化应激,从而保护细胞损伤,可能通过激活PI3K/AKT通路来实现。展开更多
Background Exercise is an effective intervention for obesity and type 2 diabetes,with significant physiological benefits over pharmacological interventions.However,there is limited preclinical data available comparing...Background Exercise is an effective intervention for obesity and type 2 diabetes,with significant physiological benefits over pharmacological interventions.However,there is limited preclinical data available comparing endurance and resistance exercise for the impacts on obesogenic pathology and glycemic control.Methods Male mice were subjected to 8 weeks of diet-induced obesity(DIO)by high-fat diet(HFD)feeding concurrent with voluntary wheel running(endurance exercise(E_(EX)))or weightlifting(resistance exercise(R_(EX))).Sedentary(SED)mice fed on normal chow(NC)or HFD were used as controls.Results E_(EX) and R_(EX) interventions significantly attenuated weight gain vs.HFD-SED due to reduction of fat mass,not changes in lean mass,as assessed by EchoMRI.While REX suppressed visceral and subcutaneous fat accumulation significantly,only E_(EX) enlarged brown fat mass.Exercise tolerance testing(i.e.,run-to-fatigue)revealed significantly improved exercise capacity in E_(EX) group vs.NC-SED.Interestingly,although HFD led to trends of increased skeletal muscle mass,only E_(EX) with HFD led to significant muscle weight gain.Neither exercise modality resulted in significant changes of hindlimb skeletal muscle contractile properties and cardiac function compared to SED mice on HFD.Importantly,REX showed significantly enhanced benefits over EEX in improving homeostatic model assessment of insulin resistance(HOMA-IR),glucose tolerance,and insulin tolerance.Conclusion These results provide a direct and translatable comparison of endurance and resistance exercise training in a preclinical context of obesity and hyperglycemia.The current data set demonstrates an advantage of resistance exercise over endurance exercise in improving glucose and insulin tolerance under the condition of obesity,and that these improvements are independent of significant alterations of muscle weight gain and exercise performance.展开更多
Everolimus is an orally administered rapamycin analogue that has been approved to treat several types of solid tumors. However, some patients develop hyperglycemia after being treated with everolimus. In this meta-ana...Everolimus is an orally administered rapamycin analogue that has been approved to treat several types of solid tumors. However, some patients develop hyperglycemia after being treated with everolimus. In this meta-analysis, we aimed to evaluate the incidence and risk of hyperglycemia in patients with cancer who received everolimus. We searched the medical literature, as index in the Cochrane Library, PubMed, EMBASE, and abstracts from the top scientific meetings （AACR, ASCO, and ESMO）. Our meta-analysis included the randomly controlled trials published before November 2014. We calculated overall incidence, relative risk （RR） and 95% confidence intervals （CI） using fixed-effects or random-effects models, depending on the heterogene- ity among the trials. A total of 3377 patients （everolimus： 1971; control： 1406） from 8 randomized clinical trials were included in the meta-analysis. In the everolimus groups, the incidence of all grades of hyperglycemia was 20.0% （95% CI： 11.0%-29.0%）, while the incidence of high-grade hyperglycemia was 6.0% （95% CI： 3.0%-8.0%）. Patients treated with everolimus had an in- creased risk of hyperglycemia as compared with that of controls （all-grade RR： 2.94, 95% CI： 2.34-3.70; high-grade RR： 4.66, 95% CI： 2.75-7.89）. Everolimus significantly increased the risk of hyperglycemia. This risk may depend on the tumor type and the everolimus dosage.展开更多
基金Supported by Guangxi Natural Science Foundation,No.2024GXNSFAA010031.
文摘BACKGROUND Diabetic cystopathy(DCP)is a complication affecting the lives of people with diabetes.However,the pathogenesis of DCP is not well known.AIM To investigate the potential mechanisms by which cAMP-responsive elementbinding protein 3 like 3(CREB3 L3)promotes the occurrence and development of DCP.METHODS High-throughput sequencing was used to analyze differentially expressed genes(DEGs)in bladder urothelium from patients with DCP and healthy controls.Gene enrichment analysis was conducted to assess the biological functions of DEG.Small interfering RNA technology was performed to silence the CREB3 L3 gene in both in vitro and in vivo experiments.Morphological changes in bladder urothelium from a DCP rat model were observed.Immunofluorescence and western blotting assay were performed to determine associated protein expression.RESULTS We identified significant DEGs through high-throughput sequencing.These genes were primarily enriched in inflammatory activation,epithelial-mesenchymal transition(EMT)and tight junction organization.Upregulated expression of both CREB3 L3 and C-reactive protein(CRP)in bladder urothelium from patients with DCP was accompanied by upregulated EMT markers including N-cadherin and vimentin proteins,but downregulated E-cadherin.Silencing CREB3 L3 attenuated the protein expression of CRP and EMT in SV-HUC-1 urothelial cells under hyperglycemic conditions and in the diabetes mellitus rat model at 4,8,and 12 weeks.CREB3 L3 knockdown also reversed downregulation of the tight junction proteins occludin and claudin 1.CONCLUSION Hyperglycemia induces the upregulation of CREB3 L3 expression,thereby promoting the EMT and impairing tight junctions in bladder urothelial cells.Targeting CREB3 L3 in bladder urothelial cells is likely to be a key approach in preventing and treating DCP.
基金supported by grants from the National Key Research and Development Program of China(2022YFF1100204)the National Natural Science Foundation of China(31972088,32001715)。
文摘Plant polyphenols are potential substitutes for clinicalα-glucosidase inhibitors.Our previous studies indicated that prodelphinidins from Chinese bayberry leaves(BLPs)have strongerα-glucosidase inhibitory activity than other common polyphenols,but they have no safe history of consumption.There is a reasonable prospect that prodelphinidins from Chinese bayberry fruits(BFPs)can improve postprandial hyperglycemia,though known active components are only myricetin and cyanidin-3-O-glucoside.Hence,the aim of this study was to analyze structure and hypoglycemic effect of BFPs of“Biqi”(BQPs)and“Dongkui”(DKPs)cultivars,and compare their difference with BLPs.The contents of BQPs and DKPs were(221.73±0.60)and(136.82±4.33)mg epicatechin(EC)equivalents/g dry weight,respectively.The most subunits were epigallocatechin gallate along with a small amount of epigallocatechin,epicatechin gallate and EC connected by B-type linkages and a small portion of A-type linkages with mean polymerization degree of 4.25 and 4.08,respectively.Importantly,BQPs and DKPs wereα-glucosidase inhibitors with half inhibitory concentration of 11.91 and 9.47μg/m L respectively,which were significantly stronger than BLPs.DKPs could also improve postprandial hyperglycemia of normal mice and high fat diet-induced type II diabetic mice.Therefore,edible prodelphinidins,which have stronger hypoglycemic effect than BLPs,were first found in Chinese bayberry fruits.
基金supported by the National Natural Science Foundation of China(No.62135002)the Key Research and Development Program of Heilongjiang Province(No.2022ZX01A28).
文摘BACKGROUND Acute myocardial infarction(AMI)is a major cause of mortality worldwide.The stress hyperglycemia ratio(SHR),which integrates glucose and glycated hemoglobin A1c levels,better reflects acute metabolic stress.This study assessed the SHR and longterm prognosis of patients with AMI.METHODS This study was a post-hoc analysis based on the prospective,multicenter OPTIMAL registry(http://www.clinicaltrials.gov,NCT number:NCT03084991).A total of 3384 consecutive patients who underwent percutaneous coronary intervention(PCI)at Department of Cardiology,The 2nd Affiliated Hospital of Harbin Medical University,Harbin,China were included in the present analysis after exclusions.Patients were stratified into quartiles according to the SHR.The primary endpoint was cardiovascular death,with all-cause death and major adverse cardiovascular events as secondary endpoints.The median follow-up duration was 24.1 months,with a completion rate of 99.5%.RESULTS Kaplan-Meier survival curves showed progressively worse survival across SHR quartiles(log-rank P<0.001),with patients in Q4(SHR≥1.34)experiencing the highest risk.Multivariate Cox regression analysis confirmed that the SHR was an independent predictor of cardiovascular death[hazard ratio(HR)=1.56],all-cause death(HR=1.48),and major adverse cardiovascular events(HR=1.34)for Q4(SHR≥1.34)versus Q2(SHR:0.93–1.11).Restricted cubic spline analysis revealed a J-shaped association between SHR and outcomes,with the lowest risk observed at an SHR of approximately 1.0.CONCLUSIONS The SHR is an independent predictor of long-term adverse outcomes in patients with AMI undergoing PCI,supporting its use for early risk stratification and glycemic management.
基金Supported by the Instituto de Salud Carlos Ⅲ(ISCⅢ)Through the Project Co-Funded by the European Union,No.PI20-00487,No.PI23-00119 and No.PI24-01630.
文摘BACKGROUND Diabetes and its associated microvascular complications,such as nephropathy and retinopathy,significantly impact global health.These complications often begin in the prediabetic stage,emphasizing the importance of early detection and intervention.Inflammatory pathways are key contributors to these conditions,and recent research has identified members of the tumor necrosis factor(TNF)receptor superfamily as potential biomarkers.However,their association with renal and retinal dysfunction in individuals with intermediate hyperglycemia(IH)remains underexplored.The Early Prevention of Diabetes Complications(ePREDICE)trial provides a valuable cohort to investigate these associations and improve risk assessment strategies.AIM To identify inflammatory biomarkers associated with early renal and retinal dysfunction in individuals with IH.Specifically,we evaluate the diagnostic and prognostic potential of TNF receptor superfamily members[TNF receptor 1(TNF-R1),TNF receptor 2(TNF-R2)],T-cell immunoglobulin and mucin domain 3(TIM-3)/HAVCR2,galectin-3,and interleukin-6(IL-6)in detecting kidney dysfunction and retinopathy in this high-risk population.By understanding their roles,we seek to enhance early screening methods and inform personalized intervention strategies.METHODS A cross-sectional analysis of 967 individuals with IH from the ePREDICE trial was conducted.Participants underwent comprehensive anthropometric and biochemical assessments.Key inflammatory biomarkers,including TNF-R1,TNF-R2,TIM-3/HAVCR2,galectin-3,and IL-6,were quantified using immunoassays.Renal function was assessed using estimated glomerular filtration rate(eGFR)and albuminuria,while retinopathy was evaluated through fundoscopic examination.Statistical analyses included adjusted mean comparisons,correlation studies,and receiver operating characteristic curve analysis to assess biomarker diagnostic accuracy.RESULTS TNF-R1,TNF-R2,and TIM-3/HAVCR2 were significantly associated with reduced filtration function(eGFR<60 mL/minute/1.73 m^(2))and albuminuria,with area under the curve(AUC)values between 0.815 and 0.845.TIM-3/HAVCR2 emerged as the strongest predictor of retinopathy(AUC=0.737).Strong correlations(r>0.75)were observed among TNF-R1,TNF-R2,and TIM-3/HAVCR2,suggesting a coordinated role in inflammatory pathways.CONCLUSION Our findings highlight the potential of TNF receptor superfamily members as biomarkers for early-stage renal and retinal complications in individuals with IH.Their integration into clinical screening protocols could facilitate earlier detection,improving patient stratification and personalized management strategies.Further longitudinal studies are necessary to validate their predictive value and potential for guiding therapeutic interventions in IH and early diabetes management.
基金supported by grants from the National Natural Science Foundation of China(No.81770483)Shanghai Tenth Hospital’s improvement plan for NSFC(No.04.03.17.070).
文摘Objective To elucidate the regulatory mechanism of circRNAs in diabetic retinopathy.Methods Next-generation sequencing(NGS)was employed to identify circRNAs that are abnormally expressed in endothe-lial progenitor cells(EPCs)under hyperglycemia(HG)conditions.The regulatory mechanism and predicted targets of this circRNA were also studied via bioinformatics analysis,luciferase reporter assays,angiogenic differentiation experiments,flow cytometry,and RT-qPCR.Results Circ-astrotactin 1(circ-Astn1)expression was decreased in EPCs under HG conditions,and circ-Astn1 overexpres-sion inhibited HG-induced endothelial damage.The miR-138-5p and silencing information regulator 2 related enzyme 1(SIRT1)were identified as circ-Astn1 downstream targets,which were further verified through luciferase reporter assays.SIRT1 silencing or miR-138-5p overexpression reversed the protective effect of circ-Astn1 on HG-induced endothelial cell dysfunction,as evidenced by increased apoptosis,abnormal vascular differentiation,and inflammatory factor secretion.SIRT1 overexpression reversed miR-138-5p-induced endothelial cell dysfunction under HG conditions.In vivo experiments confirmed that circ-Astnl overexpression promoted skin wound healing through the regulation of SIRT1.Conclusions These findings suggest that circ-Astn1 promotes SIRT1 expression by sponging miR-138-5p.Circ-Astn1 over-expression suppresses HG-induced endothelial cell damage via miR-138-5p/SIRT1 axis.
文摘BACKGROUND Stress-induced hyperglycemia(SIH)is common in critically ill patients and has been associated with adverse cardiovascular outcomes.Intensive insulin therapy(IIT)has been proposed to mitigate these risks by achieving tighter glycemic control.AIM To evaluate the efficacy of IIT for managing SIH in critically ill patients and to explore its potential effect on cardiac function.METHODS A retrospective study was conducted at our hospital from January 2021 to December 2024,adhering to STROBE guidelines.A total of 186 critically ill pa-tients were divided into normal glycemia(n=85)and SIH(n=101)groups.The SIH cohort was further subdivided into conventional treatment(n=50)and IIT(n=51)groups.Hemodynamic parameters-including right atrial pressure(RAP),pulmonary artery pressure(PAP),pulmonary capillary wedge pressure(PAWP),cardiac output(CO),cardiac index(CI),and B-type natriuretic peptide(BNP)-were measured at baseline and post-treatment.Clinical outcomes such as intensive care unit(ICU)length of stay,mechanical ventilation requirements,and mortality were also recorded.Statistical analyses were conducted using inde-pendent samples t-tests and χ^(2)/Fisher’s exact tests.RESULTS SIH markedly worsened haemodynamics versus normal glycaemia:RAP 9.8±5.1 vs 6.1±3.5 mmHg,PAP 35.2±16.0 vs 26.2±10.3 mmHg,PAWP 16.0±7.0 vs 8.6±6.4 mmHg,CO 3.3±2.3 vs 6.0±3.3 L/min,CI 1.88±0.24 vs 2.70±0.50 L/min/m2,BNP 465±250 vs 180±53 pg/mL(all P<0.001).Within the SIH cohort,IIT outperformed conventional therapy:RAP 7.0±2.2 vs 8.3±3.9 mmHg(P=0.04),PAP 21.6±3.7 vs 29.3±6.5 mmHg(P<0.001),PAWP 10.2±5.4 vs 13.8±5.3 mmHg(P=0.001),CO 4.9±2.2 vs 4.0±1.4 L/min(P=0.022),CI 2.58±0.32 vs 2.11±0.31 L/min/m2,P<0.001),BNP 202±62 vs 346±171 pg/mL(P<0.001).Clinically,IIT shortened ICU stay(10.3±3.4 vs 14.5±2.6 days,P<0.001),reduced ventilator use(56.9%vs 76.0%,P=0.042),and lowered mortality(23.5%vs 42.0%,P=0.048).CONCLUSION IIT significantly reduced cardiac filling pressures,improved cardiac function,and was associated with favorable clinical outcomes in SIH patients,suggesting potential benefits of stricter glycaemic control in critically ill patients.However,given the retrospective design and absence of glucose-variability monitoring,these findings should be interpreted with caution.
文摘目的观察木犀草素对高糖诱导的视网膜血管内皮细胞(RVECs)损伤的影响,并探究可能的机制。方法该研究于2023年5月至2024年1月进行。RVECs购自青旗(上海)生物技术有限公司,木犀草素购自西安弘康生物技术有限责任公司。体外常规培养RVECs,用含有30 mmol/L葡萄糖的DMEM培养液处理建立损伤模型,分为高糖组(高糖处理)、木犀草素组(高糖处理+30μmol/L木犀草素)、LY294002[磷脂酰肌醇3激酶(PI3K)/蛋白激酶B(AKT)通路阻断剂]组(高糖处理+10μmol/L LY294002)、联合组(高糖处理+30μmol/L木犀草素+10μmol/L LY294002)。另取不作任何处理的RVECs为空白组。培养24 h后,细胞计数试剂盒(CCK-8)法、膜联蛋白V(Annexin V)/碘化丙啶(PI)双染法、血管拟态实验检测各组细胞活力、凋亡率、血管新生能力;检测细胞膜通透性及氧化应激指标;免疫印迹法检测各组AKT、p-AKT、哺乳动物雷帕霉素靶蛋白(mTOR)、p-mTOR蛋白表达量。结果与空白组比较,高糖组凋亡率[(2.87±0.45)%比(10.15±3.45)%]、荧光强度(0.21±0.06比0.52±0.13)、丙二醛含量[(5.02±1.30)nmol/mg比(18.87±3.65)nmol/mg]升高(P<0.05),新生血管数量增加(P<0.05),细胞存活率及SOD、CAT活性降低(P<0.05);与高糖组比较,木犀草素组凋亡率、荧光强度、丙二醛含量降低(P<0.05),细胞存活率升高(P<0.05),新生血管数量减少(P<0.05),SOD活性、CAT活性增强(P<0.05),LY294002组凋亡率、荧光强度、丙二醛含量升高(P<0.05),新生血管数量增加(P<0.05),SOD活性、CAT活性降低(P<0.05);与木犀草素组比较,联合组凋亡率、荧光强度、丙二醛含量升高(P<0.05),新生血管数量增加(P<0.05),细胞存活率及SOD活性、CAT活性降低(P<0.05);与LY294002组比较,联合组凋亡率、荧光强度、丙二醛含量降低(P<0.05),细胞存活率升高(P<0.05),新生血管数量减少(P<0.05),SOD活性、CAT活性增强(P<0.05)。与空白组比较,高糖组p-AKT/AKT、p-mTOR/mTOR降低(P<0.05);与高糖组比较,木犀草素组p-AKT/AKT、p-mTOR/mTOR升高(P<0.05),LY294002组p-AKT/AKT、p-mTOR/mTOR降低(P<0.05);与木犀草素组比较,联合组p-A K T/A K T、p-mTOR/mTOR降低(P<0.05);与LY294002组比较,联合组p-AKT/AKT、p-mTOR/mTOR升高(P<0.05)。结论木犀草素可抑制高糖诱导的RVECs凋亡及血管生成,增强细胞活力,降低细胞膜通透性,减轻氧化应激,从而保护细胞损伤,可能通过激活PI3K/AKT通路来实现。
基金supported by National Institutes of Health(No.NIH-R01AR050429 and No.NIH-R01AR077440)a grant by Red Gates Foundation to ZY.
文摘Background Exercise is an effective intervention for obesity and type 2 diabetes,with significant physiological benefits over pharmacological interventions.However,there is limited preclinical data available comparing endurance and resistance exercise for the impacts on obesogenic pathology and glycemic control.Methods Male mice were subjected to 8 weeks of diet-induced obesity(DIO)by high-fat diet(HFD)feeding concurrent with voluntary wheel running(endurance exercise(E_(EX)))or weightlifting(resistance exercise(R_(EX))).Sedentary(SED)mice fed on normal chow(NC)or HFD were used as controls.Results E_(EX) and R_(EX) interventions significantly attenuated weight gain vs.HFD-SED due to reduction of fat mass,not changes in lean mass,as assessed by EchoMRI.While REX suppressed visceral and subcutaneous fat accumulation significantly,only E_(EX) enlarged brown fat mass.Exercise tolerance testing(i.e.,run-to-fatigue)revealed significantly improved exercise capacity in E_(EX) group vs.NC-SED.Interestingly,although HFD led to trends of increased skeletal muscle mass,only E_(EX) with HFD led to significant muscle weight gain.Neither exercise modality resulted in significant changes of hindlimb skeletal muscle contractile properties and cardiac function compared to SED mice on HFD.Importantly,REX showed significantly enhanced benefits over EEX in improving homeostatic model assessment of insulin resistance(HOMA-IR),glucose tolerance,and insulin tolerance.Conclusion These results provide a direct and translatable comparison of endurance and resistance exercise training in a preclinical context of obesity and hyperglycemia.The current data set demonstrates an advantage of resistance exercise over endurance exercise in improving glucose and insulin tolerance under the condition of obesity,and that these improvements are independent of significant alterations of muscle weight gain and exercise performance.
文摘Everolimus is an orally administered rapamycin analogue that has been approved to treat several types of solid tumors. However, some patients develop hyperglycemia after being treated with everolimus. In this meta-analysis, we aimed to evaluate the incidence and risk of hyperglycemia in patients with cancer who received everolimus. We searched the medical literature, as index in the Cochrane Library, PubMed, EMBASE, and abstracts from the top scientific meetings （AACR, ASCO, and ESMO）. Our meta-analysis included the randomly controlled trials published before November 2014. We calculated overall incidence, relative risk （RR） and 95% confidence intervals （CI） using fixed-effects or random-effects models, depending on the heterogene- ity among the trials. A total of 3377 patients （everolimus： 1971; control： 1406） from 8 randomized clinical trials were included in the meta-analysis. In the everolimus groups, the incidence of all grades of hyperglycemia was 20.0% （95% CI： 11.0%-29.0%）, while the incidence of high-grade hyperglycemia was 6.0% （95% CI： 3.0%-8.0%）. Patients treated with everolimus had an in- creased risk of hyperglycemia as compared with that of controls （all-grade RR： 2.94, 95% CI： 2.34-3.70; high-grade RR： 4.66, 95% CI： 2.75-7.89）. Everolimus significantly increased the risk of hyperglycemia. This risk may depend on the tumor type and the everolimus dosage.
