Clear cell renal cell carcinoma(ccRCC)is a common kidney malignancy characterized by a poor prognosis.Suppressor of variegation 3-9 homolog 1(SUV39H1),which encodes a histone H3 lysine 9 methyltransferase,has been rep...Clear cell renal cell carcinoma(ccRCC)is a common kidney malignancy characterized by a poor prognosis.Suppressor of variegation 3-9 homolog 1(SUV39H1),which encodes a histone H3 lysine 9 methyltransferase,has been reported to act as an oncogene in many cancers.However,it is unclear whether SUV39H1 is involved in ccRCC.Here,we report that SUV39H1 expression is frequently upregulated in ccRCC tumors and is significantly correlated with ccRCC progression.SUV39H1 expression level is an independent risk factor for cancer prognosis,and integration with several known prognostic factors predicted ccRCC patient prognosis with improved accuracy than the conventional SSIGN(stage,size,grade and necrosis)prognostic model.Mechanistically,we discovered that siRNA knockdown or pharmacological inhibition of SUV39 H1 induced iron accumulation and lipid peroxidation,leading to ferroptosis that disrupted ccRCC cell growth in vitro and in vivo.We also show that SUV39H1 deficiency modulated the H3K9me3 status of the DPP4(dipeptidyl-peptidase-4)gene promoter,resulting in upregulation of its expression that contributes to ferroptosis.Taken together,our findings provide the mechanistic insight into SUV39H1-dependent epigenetic control of ccRCC tumor growth and indicate that SUV39H1 may serve as a potential therapeutic target for ccRCC treatment.展开更多
Dipeptidyl peptidase 4(DPP4)is recognised as an attractive anti-diabetic drug target,and several DPP4 inhibitors are already on the market.As members of the same gene family,dipeptidyl peptidase 8(DPP8)and dipeptidyl ...Dipeptidyl peptidase 4(DPP4)is recognised as an attractive anti-diabetic drug target,and several DPP4 inhibitors are already on the market.As members of the same gene family,dipeptidyl peptidase 8(DPP8)and dipeptidyl peptidase 9(DPP9)share high sequence and structural homology as well as functional activity with DPP4.However,the inhibition of their activities was reported to cause severe toxicities.Thus,the development of DPP4 inhibitors that do not have DPP8 and DPP9 inhibitory activity is critical for safe anti-diabetic therapy.To achieve this goal,we established a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins expressed by Rosetta cells.In this method,we used purified recombinant 120 kDa DPP8 or DPP9 protein from the Rosetta expression system.The optimum concentrations of the recombinant DPP8 and DPP9 proteins were 30 ng/mL and 20 ng/mL,respectively,and the corresponding concentrations of their substrates were both 0.2 mmol/L.This method was highly reproducible and reliable for the evaluation of the DPP8 and DPP9 selectivity for DPP4 inhibitor candidates,which would provide valuable guidance in the development of safe DPP4 inhibitors.展开更多
Dipeptidyl peptidase Ⅳ（DPP4） inhibitors are proven in the treatment of type 2 diabetes.We designed and synthesized a series of novel indole compounds that selectively inhibit the activity of DPP4 over dipeptidyl pe...Dipeptidyl peptidase Ⅳ（DPP4） inhibitors are proven in the treatment of type 2 diabetes.We designed and synthesized a series of novel indole compounds that selectively inhibit the activity of DPP4 over dipeptidyl peptidase 9（DPP9）（〉200 fold）.We further co-crystallized DPP4 with indole sulfonamide（compound 1） to confirm a proposed binding mode.Good metabolic stability of the indole compounds represents another positive attribute for further development.展开更多
BACKGROUND Dipeptidyl peptidase-4(DPP4)is commonly targeted to achieve glycemic control and has potent anti-inflammatory and immunoregulatory effects.Recent structural analyses indicated a potential tight interaction ...BACKGROUND Dipeptidyl peptidase-4(DPP4)is commonly targeted to achieve glycemic control and has potent anti-inflammatory and immunoregulatory effects.Recent structural analyses indicated a potential tight interaction between DPP4 and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),raising a promising hypothesis that DPP4 inhibitor(DPP4i)drugs might be an optimal strategy for treating coronavirus disease 2019(COVID-19)among patients with diabetes.However,there has been no direct clinical evidence illuminating the associations between DPP4i use and COVID-19 outcomes.AIM To illuminate the associations between DPP4i usage and the adverse outcomes of COVID-19.METHODS We conducted a multicenter,retrospective analysis including 2563 patients with type 2 diabetes who were hospitalized due to COVID-19 at 16 hospitals in Hubei Province,China.After excluding ineligible individuals,142 patients who received DPP4i drugs and 1115 patients who received non-DPP4i oral anti-diabetic drugs were included in the subsequent analysis.We performed a strict propensity score matching(PSM)analysis where age,sex,comorbidities,number of oral hypoglycemic agents,heart rate,blood pressure,pulse oxygen saturation(SpO2)<95%,CT diagnosed bilateral lung lesions,laboratory indicators,and proportion of insulin usage were matched.Finally,111 participants treated with DPP4i drugs were successfully matched to 333 non-DPP4i users.Then,a linear logistic model and mixed-effect Cox model were applied to analyze the associations between inhospital DPP4i use and adverse outcomes of COVID-19.RESULTS After rigorous matching and further adjustments for imbalanced variables in the linear logistic model and Cox adjusted model,we found that there was no significant association between in-hospital DPP4i use(DPP4i group)and 28-d allcause mortality(adjusted hazard ratio=0.44,95%CI:0.09-2.11,P=0.31).Likewise,the incidences and risks of secondary outcomes,including septic shock,acute respiratory distress syndrome,or acute organ(kidney,liver,and cardiac)inj展开更多
目的观察二甲双胍单药治疗及联合DPP-4抑制剂对初发老年2型糖尿病患者胰岛β细胞功能的影响。方法选择初发老年2型糖尿病患者110例随机分为沙格列汀联合二甲双胍治疗组(联用组)55例及二甲双胍单药治疗组(单用组)55例,测定治疗前及12 w...目的观察二甲双胍单药治疗及联合DPP-4抑制剂对初发老年2型糖尿病患者胰岛β细胞功能的影响。方法选择初发老年2型糖尿病患者110例随机分为沙格列汀联合二甲双胍治疗组(联用组)55例及二甲双胍单药治疗组(单用组)55例,测定治疗前及12 w后空腹血糖(FPG)、空腹胰岛素(FIns)、餐后2 h血糖(2 h PG)、糖化血红蛋白(Hb A1c),并计算胰岛素分泌指数(HOMA-β)。结果①单用组治疗12 w后FPG、2 h PG及Hb A1c均较治疗前下降(P<0.05),FIns、HOMA-β较治疗前升高但无统计学意义(P>0.05);②联用组治疗12 w后FPG、2 h PG及Hb A1c均较治疗前明显下降(P<0.05),且FIns、HOMA-β均高于同组治疗前(P<0.05);③与单用组治疗12 w后比较,联用组治疗12 w后FPG、2 h PG及Hb A1c均显著降低(P<0.05),且FIns、HOMA-β均增加(P<0.05)。结论在初发老年2型糖尿病患者中二甲双胍联合DPP-4抑制剂不仅可有效地控制血糖,而且可改善胰岛素β细胞功能。展开更多
目的:系统评价二甲双胍分别联合二线降糖药DPP4抑制剂或磺脲类药物对二甲双胍单药治疗仍血糖控制不佳的2型糖尿病患者的疗效及安全性比较。方法:计算机检索国内外权威医学数据库,根据纳入标准筛选文献,采用Rev Man 5.1.4软件进行Meta分...目的:系统评价二甲双胍分别联合二线降糖药DPP4抑制剂或磺脲类药物对二甲双胍单药治疗仍血糖控制不佳的2型糖尿病患者的疗效及安全性比较。方法:计算机检索国内外权威医学数据库,根据纳入标准筛选文献,采用Rev Man 5.1.4软件进行Meta分析。结果:共纳入8个RCT,13 260例患者。Meta分析结果显示:与MET+SU组相比,MET+DPP4-I组可更有效地使Hb A1c达标(OR=0.89,95%CI 0.81~0.97,P=0.008),且MET+DPP4-I组可更有效的减轻体重(WMD=-1.82,95%CI-2.46^-1.17,P<0.000 01),改善胰岛素抵抗,同时其低血糖及不良反应的风险更小,心脑血管事件的发生率更低。结论:MET联合DPP4抑制剂治疗2型糖尿病是一种更为安全有效的选择。展开更多
基金supported by the advanced technology promotion project of Shanghai Municipal Commission of Health and Family Planning(No.27 HYR 2013,China)Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine(BXJ201919,China)
文摘Clear cell renal cell carcinoma(ccRCC)is a common kidney malignancy characterized by a poor prognosis.Suppressor of variegation 3-9 homolog 1(SUV39H1),which encodes a histone H3 lysine 9 methyltransferase,has been reported to act as an oncogene in many cancers.However,it is unclear whether SUV39H1 is involved in ccRCC.Here,we report that SUV39H1 expression is frequently upregulated in ccRCC tumors and is significantly correlated with ccRCC progression.SUV39H1 expression level is an independent risk factor for cancer prognosis,and integration with several known prognostic factors predicted ccRCC patient prognosis with improved accuracy than the conventional SSIGN(stage,size,grade and necrosis)prognostic model.Mechanistically,we discovered that siRNA knockdown or pharmacological inhibition of SUV39 H1 induced iron accumulation and lipid peroxidation,leading to ferroptosis that disrupted ccRCC cell growth in vitro and in vivo.We also show that SUV39H1 deficiency modulated the H3K9me3 status of the DPP4(dipeptidyl-peptidase-4)gene promoter,resulting in upregulation of its expression that contributes to ferroptosis.Taken together,our findings provide the mechanistic insight into SUV39H1-dependent epigenetic control of ccRCC tumor growth and indicate that SUV39H1 may serve as a potential therapeutic target for ccRCC treatment.
基金supported by National Natural Science Foundation of China(Grant 20973108)Shanghai Education Committee(Grant 11ZZ83)Shanghai Leading Academic Discipline Project(Grant J50101)~~
基金We greatly appreciate Prof.Haihong Huang and Dr.Bei Han for the chemical synthesis of UAMC00132sitagliptin.This work was supported by a fund from National Mega-project for Innova-tive Drugs(2012ZX09301002-004,China).
文摘Dipeptidyl peptidase 4(DPP4)is recognised as an attractive anti-diabetic drug target,and several DPP4 inhibitors are already on the market.As members of the same gene family,dipeptidyl peptidase 8(DPP8)and dipeptidyl peptidase 9(DPP9)share high sequence and structural homology as well as functional activity with DPP4.However,the inhibition of their activities was reported to cause severe toxicities.Thus,the development of DPP4 inhibitors that do not have DPP8 and DPP9 inhibitory activity is critical for safe anti-diabetic therapy.To achieve this goal,we established a selective evaluation method for DPP4 inhibitors based on recombinant human DPP8 and DPP9 proteins expressed by Rosetta cells.In this method,we used purified recombinant 120 kDa DPP8 or DPP9 protein from the Rosetta expression system.The optimum concentrations of the recombinant DPP8 and DPP9 proteins were 30 ng/mL and 20 ng/mL,respectively,and the corresponding concentrations of their substrates were both 0.2 mmol/L.This method was highly reproducible and reliable for the evaluation of the DPP8 and DPP9 selectivity for DPP4 inhibitor candidates,which would provide valuable guidance in the development of safe DPP4 inhibitors.
基金supported in part by funds from the Ministry of Science and Technology (No. 2014CB910300)the Natural Science Foundation of Zhejiang Province (No. R2100439)the Specialized Research Fund for the Doctoral Program of Higher Education (No. 20110101110122)
文摘Dipeptidyl peptidase Ⅳ（DPP4） inhibitors are proven in the treatment of type 2 diabetes.We designed and synthesized a series of novel indole compounds that selectively inhibit the activity of DPP4 over dipeptidyl peptidase 9（DPP9）（〉200 fold）.We further co-crystallized DPP4 with indole sulfonamide（compound 1） to confirm a proposed binding mode.Good metabolic stability of the indole compounds represents another positive attribute for further development.
基金Supported by National Key R&D Program of China,No.2019YFC2004702 and No.2020YFC0845500the National Natural Science Foundation of China,No.81970070 and No.81970011the Hubei Science and Technology Support Project,No.2019BFC582 and No.2018BEC473.
文摘BACKGROUND Dipeptidyl peptidase-4(DPP4)is commonly targeted to achieve glycemic control and has potent anti-inflammatory and immunoregulatory effects.Recent structural analyses indicated a potential tight interaction between DPP4 and severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),raising a promising hypothesis that DPP4 inhibitor(DPP4i)drugs might be an optimal strategy for treating coronavirus disease 2019(COVID-19)among patients with diabetes.However,there has been no direct clinical evidence illuminating the associations between DPP4i use and COVID-19 outcomes.AIM To illuminate the associations between DPP4i usage and the adverse outcomes of COVID-19.METHODS We conducted a multicenter,retrospective analysis including 2563 patients with type 2 diabetes who were hospitalized due to COVID-19 at 16 hospitals in Hubei Province,China.After excluding ineligible individuals,142 patients who received DPP4i drugs and 1115 patients who received non-DPP4i oral anti-diabetic drugs were included in the subsequent analysis.We performed a strict propensity score matching(PSM)analysis where age,sex,comorbidities,number of oral hypoglycemic agents,heart rate,blood pressure,pulse oxygen saturation(SpO2)<95%,CT diagnosed bilateral lung lesions,laboratory indicators,and proportion of insulin usage were matched.Finally,111 participants treated with DPP4i drugs were successfully matched to 333 non-DPP4i users.Then,a linear logistic model and mixed-effect Cox model were applied to analyze the associations between inhospital DPP4i use and adverse outcomes of COVID-19.RESULTS After rigorous matching and further adjustments for imbalanced variables in the linear logistic model and Cox adjusted model,we found that there was no significant association between in-hospital DPP4i use(DPP4i group)and 28-d allcause mortality(adjusted hazard ratio=0.44,95%CI:0.09-2.11,P=0.31).Likewise,the incidences and risks of secondary outcomes,including septic shock,acute respiratory distress syndrome,or acute organ(kidney,liver,and cardiac)inj
文摘目的观察二甲双胍单药治疗及联合DPP-4抑制剂对初发老年2型糖尿病患者胰岛β细胞功能的影响。方法选择初发老年2型糖尿病患者110例随机分为沙格列汀联合二甲双胍治疗组(联用组)55例及二甲双胍单药治疗组(单用组)55例,测定治疗前及12 w后空腹血糖(FPG)、空腹胰岛素(FIns)、餐后2 h血糖(2 h PG)、糖化血红蛋白(Hb A1c),并计算胰岛素分泌指数(HOMA-β)。结果①单用组治疗12 w后FPG、2 h PG及Hb A1c均较治疗前下降(P<0.05),FIns、HOMA-β较治疗前升高但无统计学意义(P>0.05);②联用组治疗12 w后FPG、2 h PG及Hb A1c均较治疗前明显下降(P<0.05),且FIns、HOMA-β均高于同组治疗前(P<0.05);③与单用组治疗12 w后比较,联用组治疗12 w后FPG、2 h PG及Hb A1c均显著降低(P<0.05),且FIns、HOMA-β均增加(P<0.05)。结论在初发老年2型糖尿病患者中二甲双胍联合DPP-4抑制剂不仅可有效地控制血糖,而且可改善胰岛素β细胞功能。
