Theaflavins from black tea effectively improve insulin secretion in obesity and diabetes,but the molecular mechanisms are unclear.Here,the palmitic acid(PA)-induced pancreaticβ-TC-6 cells and high fat-/high glucose-i...Theaflavins from black tea effectively improve insulin secretion in obesity and diabetes,but the molecular mechanisms are unclear.Here,the palmitic acid(PA)-induced pancreaticβ-TC-6 cells and high fat-/high glucose-induced zebrafish were used.The effects of theaflavin-3,3'-digallate(TF3)on glucolipotoxicityinduced insulin secretion dysfunction,ferroptosis and endoplasmic reticulum(ER)stress were investigated by a variety of molecular biological approaches,inductively coupled plasma-mass spectrometry(ICP-MS),transmission electron microscopy(TEM)and widely targeted metabolomics analysis.TF3 was found to potently inhibit glucolipotoxicity-induced insulin secretion dysfunction and ferroptosis inβ-TC-6 cells and zebrafish,with increasing glutathione peroxidase 4(GPX4)expression,suppressing lipid peroxidation and iron accumulation and protecting mitochondria.Additionally,TF3 attenuated ER stress by regulating 3 unfolded protein response(UPR)pathways inβ-TC-6 cells,and significantly modulated linoleic acid metabolism and L-kynurenine signalling in zebrafish.The expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2(SERCA2)was obviously enhanced by TF3.Thapsigargin,a SERCA2 inhibitor,remarkably reversed the effects of TF3 on insulin production,ferroptosis,ER stress and the kynurenine signalling.Together,this work revealed the critical role of SERCA2 in ferroptosis regulation,and demonstrated TF3 targeted SERCA2 to inhibit ER stress and ferropto sis,thereby protectingβ-cell secretory function from glucolipotoxicity.展开更多
目的分析贫血与过早死亡之间的关联,以及患有不同种类贫血对过早死亡的影响。方法采用回顾性队列研究,从1999-2010年的美国国家健康和营养检查调查(National Health and Nutrition Examination Survey,NHANES)中提取参与者的人口统计学...目的分析贫血与过早死亡之间的关联,以及患有不同种类贫血对过早死亡的影响。方法采用回顾性队列研究,从1999-2010年的美国国家健康和营养检查调查(National Health and Nutrition Examination Survey,NHANES)中提取参与者的人口统计学和临床数据,其基线与2019年美国全国死亡指数(national death index,NDI)记录相关联。根据世界卫生组织的指标对贫血以及缺铁性贫血进行定义。过早死亡定义为75岁之前发生的死亡。加权单变量和多变量Cox比例风险模型用于协变量筛选和探索贫血、缺铁性贫血和其他种类贫血与全因过早死亡率之间的关联。评价指标是风险比(hazard ratios,HR)和95%置信区间(confidence intervals,CI)。采用Kaplan-Meier曲线评估参与者不同分组情况下的生存状态。此外,还进行了多个协变量分层的亚组分析。结果随访时期内共发生1054例全因过早死亡。在调整了包括性别、年龄、种族、贫困收入比(poverty-to-income ratio,PIR)、婚姻状况、吸烟状况、饮酒状况、肥胖在内的协变量后,与非贫血人群相比,总贫血人群具有更高的过早死亡风险(HR=1.40,95%CI:1.09~1.78,P=0.007)。将总贫血人群分为缺铁性贫血人群与其他种类贫血人群,与非贫血人群相比,缺铁性贫血对过早死亡风险无显著影响(HR=0.76,95%CI:0.40~1.46,P=0.416),其他种类贫血与过早死亡风险呈正相关(HR=1.66,95%CI:1.29~2.14,P<0.001),趋势在各亚组间基本保持一致。结论贫血是过早死亡的风险因素,患有缺铁性贫血或其他种类贫血对全因过早死亡具有不同的影响,贫血的不同类型与全因过早死亡风险之间可能存在关联。展开更多
基金supported by National Natural Science Foundation of China(32272303)Natural Science Foundation of Zhejiang Province,China(LY21C200010)。
文摘Theaflavins from black tea effectively improve insulin secretion in obesity and diabetes,but the molecular mechanisms are unclear.Here,the palmitic acid(PA)-induced pancreaticβ-TC-6 cells and high fat-/high glucose-induced zebrafish were used.The effects of theaflavin-3,3'-digallate(TF3)on glucolipotoxicityinduced insulin secretion dysfunction,ferroptosis and endoplasmic reticulum(ER)stress were investigated by a variety of molecular biological approaches,inductively coupled plasma-mass spectrometry(ICP-MS),transmission electron microscopy(TEM)and widely targeted metabolomics analysis.TF3 was found to potently inhibit glucolipotoxicity-induced insulin secretion dysfunction and ferroptosis inβ-TC-6 cells and zebrafish,with increasing glutathione peroxidase 4(GPX4)expression,suppressing lipid peroxidation and iron accumulation and protecting mitochondria.Additionally,TF3 attenuated ER stress by regulating 3 unfolded protein response(UPR)pathways inβ-TC-6 cells,and significantly modulated linoleic acid metabolism and L-kynurenine signalling in zebrafish.The expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2(SERCA2)was obviously enhanced by TF3.Thapsigargin,a SERCA2 inhibitor,remarkably reversed the effects of TF3 on insulin production,ferroptosis,ER stress and the kynurenine signalling.Together,this work revealed the critical role of SERCA2 in ferroptosis regulation,and demonstrated TF3 targeted SERCA2 to inhibit ER stress and ferropto sis,thereby protectingβ-cell secretory function from glucolipotoxicity.
文摘目的分析贫血与过早死亡之间的关联,以及患有不同种类贫血对过早死亡的影响。方法采用回顾性队列研究,从1999-2010年的美国国家健康和营养检查调查(National Health and Nutrition Examination Survey,NHANES)中提取参与者的人口统计学和临床数据,其基线与2019年美国全国死亡指数(national death index,NDI)记录相关联。根据世界卫生组织的指标对贫血以及缺铁性贫血进行定义。过早死亡定义为75岁之前发生的死亡。加权单变量和多变量Cox比例风险模型用于协变量筛选和探索贫血、缺铁性贫血和其他种类贫血与全因过早死亡率之间的关联。评价指标是风险比(hazard ratios,HR)和95%置信区间(confidence intervals,CI)。采用Kaplan-Meier曲线评估参与者不同分组情况下的生存状态。此外,还进行了多个协变量分层的亚组分析。结果随访时期内共发生1054例全因过早死亡。在调整了包括性别、年龄、种族、贫困收入比(poverty-to-income ratio,PIR)、婚姻状况、吸烟状况、饮酒状况、肥胖在内的协变量后,与非贫血人群相比,总贫血人群具有更高的过早死亡风险(HR=1.40,95%CI:1.09~1.78,P=0.007)。将总贫血人群分为缺铁性贫血人群与其他种类贫血人群,与非贫血人群相比,缺铁性贫血对过早死亡风险无显著影响(HR=0.76,95%CI:0.40~1.46,P=0.416),其他种类贫血与过早死亡风险呈正相关(HR=1.66,95%CI:1.29~2.14,P<0.001),趋势在各亚组间基本保持一致。结论贫血是过早死亡的风险因素,患有缺铁性贫血或其他种类贫血对全因过早死亡具有不同的影响,贫血的不同类型与全因过早死亡风险之间可能存在关联。
