Background:Exercise training protects against heart failure.However,the mechanism underlying the protective effect of exercise training on angiotensinⅡ(AngⅡ)-induced cardiac fibrosis remains unclear.Methods:An exerc...Background:Exercise training protects against heart failure.However,the mechanism underlying the protective effect of exercise training on angiotensinⅡ(AngⅡ)-induced cardiac fibrosis remains unclear.Methods:An exercise model involving C57BL/6N mice and 6 weeks of treadmill training was used.AngⅡ(1.44 mg/kg/day)was administered to induce cardiac fibrosis.RNA sequencing and bioinformatic analysis were used to identify the key factors mediating the effects of exercise training on cardiac fibrosis.Primary adult mouse cardiac fibroblasts(CFs)were used in vitro.Adeno-associated virus serotype 9 was used to overexpress POU domain,class 2,transcription factor 1(POU2F1)in vivo.Results:Exercise training attenuated AngⅡ-induced cardiac fibrosis and reversed 39 gene expression changes.The transcription factor regulating the largest number of these genes was POU2F1.Compared to controls,POU2F1 was shown to be signififcantly upregulated by AngⅡ,which is itself reduced by exercise training.In vivo,POU2F1 overexpression nullified the benefits of exercise training on cardiac fibrosis.In CFs,POU2F1 promoted cardiac fibrosis.CCAAT enhancer-binding proteinβ(C/EBPβ)was predicted to be the transcription factor of POU2F1and verified using a dual-luciferase reporter assay.In vivo,exercise training activated AMP-activated protein kinase(AMPK)and alleviated the increase in C/EBPβinduced by AngⅡ.In CFs,AMPK agonist inhibited the increase in C/EBPβand POU2F1 induced by Ang II,whereas AMPK inhibitor reversed this effect.Conclusion:Exercise training attenuates AngⅡ-induced cardiac fibrosis by reducing POU2F1.Exercise training inhibits POU2F1 by activating AMPK,which is followed by the downregulation of C/EBPβ,the transcription factor of POU2F1.展开更多
BACKGROUND Embryonic stem cells(ESCs)serve as a crucial ex vivo model,representing epiblast cells derived from the inner cell mass of blastocyst-stage embryos.ESCs exhibit a unique combination of self-renewal potency,...BACKGROUND Embryonic stem cells(ESCs)serve as a crucial ex vivo model,representing epiblast cells derived from the inner cell mass of blastocyst-stage embryos.ESCs exhibit a unique combination of self-renewal potency,unlimited proliferation,and pluripotency.The latter is evident by the ability of the isolated cells to differ-entiate spontaneously into multiple cell lineages,representing the three primary embryonic germ layers.Multiple regulatory networks guide ESCs,directing their self-renewal and lineage-specific differentiation.Apoptosis,or programmed cell death,emerges as a key event involved in sculpting and forming various organs and structures ensuring proper embryonic development.How-ever,the molecular mechanisms underlying the dynamic interplay between diffe-rentiation and apoptosis remain poorly understood.AIM To investigate the regulatory impact of apoptosis on the early differentiation of ESCs into cardiac cells,using mouse ESC(mESC)models-mESC-B-cell lym-phoma 2(BCL-2),mESC-PIM-2,and mESC-metallothionein-1(MET-1)-which overexpress the anti-apoptotic genes Bcl-2,Pim-2,and Met-1,respectively.METHODS mESC-T2(wild-type),mESC-BCL-2,mESC-PIM-2,and mESC-MET-1 have been used to assess the effect of potentiated apoptotic signals on cardiac differentiation.The hanging drop method was adopted to generate embryoid bodies(EBs)and induce terminal differentiation of mESCs.The size of the generated EBs was measured in each condition compared to the wild type.At the functional level,the percentage of cardiac differentiation was measured by calculating the number of beating cardiomyocytes in the manipulated mESCs compared to the control.At the molecular level,quantitative reverse transcription-polymerase chain reaction was used to assess the mRNA expression of three cardiac markers:Troponin T,GATA4,and NKX2.5.Additionally,troponin T protein expression was evaluated through immunofluorescence and western blot assays.RESULTS Our findings showed that the upregulation of Bcl-2,Pim-2,and Met-1 genes led to a reduction in the size of the EBs derived from the manipulated mESCs,in comparison with their wild-type counterpart.Additionally,a decrease in the count of beating cardiomyocytes among differentiated cells was observed.Furthermore,the mRNA expression of three cardiac markers-troponin T,GATA4,and NKX2.5-was diminished in mESCs overexpressing the three anti-apoptotic genes compared to the control cell line.Moreover,the overexpression of the anti-apoptotic genes resulted in a reduction in troponin T protein expression.CONCLUSION Our findings revealed that the upregulation of Bcl-2,Pim-2,and Met-1 genes altered cardiac differentiation,providing insight into the intricate interplay between apoptosis and ESC fate determination.展开更多
目的分析糖尿病肾病患者单独使用胰高血糖素样肽-1(GLP-1)受体激动剂利拉鲁肽以及联合钠-葡萄糖协同转运蛋白2抑制剂恩格列净治疗的效果,以及对心肾功能,血管内皮生长因子(VEGF)、VEGF-A水平的影响。方法选择该院2022年4月至2023年5月...目的分析糖尿病肾病患者单独使用胰高血糖素样肽-1(GLP-1)受体激动剂利拉鲁肽以及联合钠-葡萄糖协同转运蛋白2抑制剂恩格列净治疗的效果,以及对心肾功能,血管内皮生长因子(VEGF)、VEGF-A水平的影响。方法选择该院2022年4月至2023年5月收治的84例糖尿病肾病患者纳入研究对象,分为对照组和试验组,各42例。对照组患者单独使用GLP-1受体激动剂利拉鲁肽治疗,试验组使用GLP-1受体激动剂利拉鲁肽与恩格列净治疗,分析、比较两种不同方案对患者疗效的影响。结果治疗前,两组糖化血红蛋白(HbA1c)、餐后2 h血糖(2 h PG)、空腹血糖(FBG)、左室射血分数(LVEF)、左室后壁厚度(LVPWT)、左室舒张末期内径(LVEDD)、左室舒张早期充盈峰/舒张末期充盈峰(E/A)、尿微量清蛋白/尿肌酐(ACR)、血肌酐(Scr)、尿肌酐(Ucr)、胰岛素用量比较,差异均无统计学意义(P>0.05),治疗后,与对照组比较,试验组HbA1c、2 h PG、FBG、LVPWT、LVEDD、ACR、Scr、Ucr水平更低,胰岛素用量更少,E/A、LVEF更高,差异均有统计学意义(P<0.05)。治疗前,两组患者VEGF、VEGF-A比较,差异均无统计学意义(P>0.05),治疗后,试验组VEGF、VEGF-A水平低于对照组(P<0.05)。试验组与对照组患者的低血糖、腹泻、低血压等不良反应总发生率比较,差异无统计学意义(P>0.05)。结论糖尿病肾病患者使用GLP-1受体激动剂利拉鲁肽联合恩格列净治疗的降糖效果较好且安全,还可以改善心肾功能,抑制VEGF、VEGF-A的过度表达,并减少胰岛素用量。展开更多
基金supported by the National Natural Science Foundation of China(82030072 to HX,81871850 to HY,81972149 to WG,and 81830009 to YZ)Beijing Natural Science Foundation(No.7212125 to HY)+2 种基金National Key R&D Program of China(Grant No.2020YFA0803800 to HY)the Key Clinical Projects of Peking University Third Hospital(BYSYZD2019022 to HX)Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(No.2021-I2M-5-003 to HX and YZ)。
文摘Background:Exercise training protects against heart failure.However,the mechanism underlying the protective effect of exercise training on angiotensinⅡ(AngⅡ)-induced cardiac fibrosis remains unclear.Methods:An exercise model involving C57BL/6N mice and 6 weeks of treadmill training was used.AngⅡ(1.44 mg/kg/day)was administered to induce cardiac fibrosis.RNA sequencing and bioinformatic analysis were used to identify the key factors mediating the effects of exercise training on cardiac fibrosis.Primary adult mouse cardiac fibroblasts(CFs)were used in vitro.Adeno-associated virus serotype 9 was used to overexpress POU domain,class 2,transcription factor 1(POU2F1)in vivo.Results:Exercise training attenuated AngⅡ-induced cardiac fibrosis and reversed 39 gene expression changes.The transcription factor regulating the largest number of these genes was POU2F1.Compared to controls,POU2F1 was shown to be signififcantly upregulated by AngⅡ,which is itself reduced by exercise training.In vivo,POU2F1 overexpression nullified the benefits of exercise training on cardiac fibrosis.In CFs,POU2F1 promoted cardiac fibrosis.CCAAT enhancer-binding proteinβ(C/EBPβ)was predicted to be the transcription factor of POU2F1and verified using a dual-luciferase reporter assay.In vivo,exercise training activated AMP-activated protein kinase(AMPK)and alleviated the increase in C/EBPβinduced by AngⅡ.In CFs,AMPK agonist inhibited the increase in C/EBPβand POU2F1 induced by Ang II,whereas AMPK inhibitor reversed this effect.Conclusion:Exercise training attenuates AngⅡ-induced cardiac fibrosis by reducing POU2F1.Exercise training inhibits POU2F1 by activating AMPK,which is followed by the downregulation of C/EBPβ,the transcription factor of POU2F1.
基金Supported by the National Council for Scientific Research in Lebanon,CNRS-L.
文摘BACKGROUND Embryonic stem cells(ESCs)serve as a crucial ex vivo model,representing epiblast cells derived from the inner cell mass of blastocyst-stage embryos.ESCs exhibit a unique combination of self-renewal potency,unlimited proliferation,and pluripotency.The latter is evident by the ability of the isolated cells to differ-entiate spontaneously into multiple cell lineages,representing the three primary embryonic germ layers.Multiple regulatory networks guide ESCs,directing their self-renewal and lineage-specific differentiation.Apoptosis,or programmed cell death,emerges as a key event involved in sculpting and forming various organs and structures ensuring proper embryonic development.How-ever,the molecular mechanisms underlying the dynamic interplay between diffe-rentiation and apoptosis remain poorly understood.AIM To investigate the regulatory impact of apoptosis on the early differentiation of ESCs into cardiac cells,using mouse ESC(mESC)models-mESC-B-cell lym-phoma 2(BCL-2),mESC-PIM-2,and mESC-metallothionein-1(MET-1)-which overexpress the anti-apoptotic genes Bcl-2,Pim-2,and Met-1,respectively.METHODS mESC-T2(wild-type),mESC-BCL-2,mESC-PIM-2,and mESC-MET-1 have been used to assess the effect of potentiated apoptotic signals on cardiac differentiation.The hanging drop method was adopted to generate embryoid bodies(EBs)and induce terminal differentiation of mESCs.The size of the generated EBs was measured in each condition compared to the wild type.At the functional level,the percentage of cardiac differentiation was measured by calculating the number of beating cardiomyocytes in the manipulated mESCs compared to the control.At the molecular level,quantitative reverse transcription-polymerase chain reaction was used to assess the mRNA expression of three cardiac markers:Troponin T,GATA4,and NKX2.5.Additionally,troponin T protein expression was evaluated through immunofluorescence and western blot assays.RESULTS Our findings showed that the upregulation of Bcl-2,Pim-2,and Met-1 genes led to a reduction in the size of the EBs derived from the manipulated mESCs,in comparison with their wild-type counterpart.Additionally,a decrease in the count of beating cardiomyocytes among differentiated cells was observed.Furthermore,the mRNA expression of three cardiac markers-troponin T,GATA4,and NKX2.5-was diminished in mESCs overexpressing the three anti-apoptotic genes compared to the control cell line.Moreover,the overexpression of the anti-apoptotic genes resulted in a reduction in troponin T protein expression.CONCLUSION Our findings revealed that the upregulation of Bcl-2,Pim-2,and Met-1 genes altered cardiac differentiation,providing insight into the intricate interplay between apoptosis and ESC fate determination.
文摘目的分析糖尿病肾病患者单独使用胰高血糖素样肽-1(GLP-1)受体激动剂利拉鲁肽以及联合钠-葡萄糖协同转运蛋白2抑制剂恩格列净治疗的效果,以及对心肾功能,血管内皮生长因子(VEGF)、VEGF-A水平的影响。方法选择该院2022年4月至2023年5月收治的84例糖尿病肾病患者纳入研究对象,分为对照组和试验组,各42例。对照组患者单独使用GLP-1受体激动剂利拉鲁肽治疗,试验组使用GLP-1受体激动剂利拉鲁肽与恩格列净治疗,分析、比较两种不同方案对患者疗效的影响。结果治疗前,两组糖化血红蛋白(HbA1c)、餐后2 h血糖(2 h PG)、空腹血糖(FBG)、左室射血分数(LVEF)、左室后壁厚度(LVPWT)、左室舒张末期内径(LVEDD)、左室舒张早期充盈峰/舒张末期充盈峰(E/A)、尿微量清蛋白/尿肌酐(ACR)、血肌酐(Scr)、尿肌酐(Ucr)、胰岛素用量比较,差异均无统计学意义(P>0.05),治疗后,与对照组比较,试验组HbA1c、2 h PG、FBG、LVPWT、LVEDD、ACR、Scr、Ucr水平更低,胰岛素用量更少,E/A、LVEF更高,差异均有统计学意义(P<0.05)。治疗前,两组患者VEGF、VEGF-A比较,差异均无统计学意义(P>0.05),治疗后,试验组VEGF、VEGF-A水平低于对照组(P<0.05)。试验组与对照组患者的低血糖、腹泻、低血压等不良反应总发生率比较,差异无统计学意义(P>0.05)。结论糖尿病肾病患者使用GLP-1受体激动剂利拉鲁肽联合恩格列净治疗的降糖效果较好且安全,还可以改善心肾功能,抑制VEGF、VEGF-A的过度表达,并减少胰岛素用量。
