目的:探讨石榴花水提物(pomegranate flower water extract,PFW)对2型糖尿病小鼠肝脏胰岛素信号传导的影响及机制。方法:将C57BL/6J随机分为正常组、模型组、二甲双胍组(Met)、石榴花水提物低剂量组(PFWL)和石榴花水提物高剂量组(PFWH)...目的:探讨石榴花水提物(pomegranate flower water extract,PFW)对2型糖尿病小鼠肝脏胰岛素信号传导的影响及机制。方法:将C57BL/6J随机分为正常组、模型组、二甲双胍组(Met)、石榴花水提物低剂量组(PFWL)和石榴花水提物高剂量组(PFWH)。连续给药11周后,称小鼠体质量,检测空腹血糖(FBG)、胰岛素(INS)、甘油三酯(TG)和总胆固醇(TC)的含量,计算胰岛素抵抗指数(HOMA-IR);苏木素-伊红(HE)染色观察肝组织病理变化;Western blot法检测肝组织中胰岛素受体底物1(IRS1)、p-IRS1(Ser307)、蛋白激酶B(AKT)、p-AKT(Ser473)、糖原合成酶激酶-3β(Gsk3β)、p-Gsk3β(S9)、芳香烃受体(AhR)、磷脂酰乙醇胺N-甲基转移酶(PEMT)、Bcl-2/腺病毒E1B-19kDa相互作用蛋白3(BNIP3)蛋白表达。结果:与模型组比较,PFWH组FBG、INS、HOMA-IR、TG和TC含量极显著降低(P<0.01);PFWH组小鼠肝细胞内脂肪滴明显减少;PFWH组极显著升高肝脏中IRS1、p-AKT(Ser473)/AKT、p-Gsk3β(S9)/Gsk3β、BNIP3蛋白表达(P<0.01),极显著降低p-IRS1(Ser307)/IRS1、AHR、PEMT蛋白表达(P<0.01)。结论:PFW可能通过调节AHR/BNIP3抑制肝脏脂质沉积,改善p-IRS1(Ser307)/p-AKT(Ser473)/p-GSK3β(S9)胰岛素信号通路转导。展开更多
目的 探究胰腺癌Bcl-2/腺病毒E1B-19k相关蛋白3(Bcl-2/E1B-19k-interacting protein 3,BNIP3)的蛋白表达水平及其与术后吉西他滨化疗敏感性的关系。方法 回顾性分析2016年7月至2021年8月内蒙古医科大学附属医院58例胰腺癌根治术,并在术...目的 探究胰腺癌Bcl-2/腺病毒E1B-19k相关蛋白3(Bcl-2/E1B-19k-interacting protein 3,BNIP3)的蛋白表达水平及其与术后吉西他滨化疗敏感性的关系。方法 回顾性分析2016年7月至2021年8月内蒙古医科大学附属医院58例胰腺癌根治术,并在术后规律应用吉西他滨辅助化疗或以吉西他滨为主的联合化疗患者的临床资料,选取胰腺癌术后组织切片,对其进行BNIP3免疫组织化学检测,通过实验染色强度及范围进行评分,并分析其与胰腺癌患者预后的关系。结果 与BNIP3低表达组比较,BNIP3高表达组的总生存时间(OS)[13(95%CI 11.378~14.622)个月 vs 18(95%CI 16.592~19.408)个月]和无病生存时间(DFS)[7(95%CI 4.082~9.938)个月 vs 14(95%CI 12.936~15.064)个月]均降低(P<0.05)。BNIP3的蛋白表达水平及淋巴转移情况是OS的独立预后因素,而BNIP3的蛋白表达水平及分化程度是DFS的独立预后因素。结论 胰腺癌组织中BNIP3的蛋白表达水平可能与应用吉西他滨化疗敏感性相关,BNIP3低表达患者行术后吉西他滨化疗的OS与DFS较高表达者更长。展开更多
目的丁苯酞氯化钠注射液后处理对X连锁凋亡抑制蛋白(X-inhibitor of apoptosis,XIAP)、Bcl-2/腺病毒E1B19k Da相互作用蛋白3(Bcl-2/adenovirus E1B19k Da interacting protein 3,BNIP3)的作用研究甚少。文中旨在观察丁苯酞氯化钠注射液...目的丁苯酞氯化钠注射液后处理对X连锁凋亡抑制蛋白(X-inhibitor of apoptosis,XIAP)、Bcl-2/腺病毒E1B19k Da相互作用蛋白3(Bcl-2/adenovirus E1B19k Da interacting protein 3,BNIP3)的作用研究甚少。文中旨在观察丁苯酞氯化钠注射液后处理对局灶性脑缺血再灌注损伤(ischemia reperfusion,IR)大鼠缺血侧海马CA1区XIAP、BNIP3表达的影响,探讨丁苯酞氯化钠注射液的脑保护机制。方法将清洁级雄性SD大鼠65只按随机数字表法分为假手术组(n=13)、IR组(n=13)、丁苯酞组(n=39),丁苯酞组按照剂量不同分为低剂量、中剂量和高剂量亚组,每组13只。IR组:采用改良线栓法制作大鼠大脑中动脉IR模型(缺血2 h,再灌注24 h)。低、中、高剂量亚组在大鼠缺血2 h后,予腹腔内分别注射2、4、6 mg/kg丁苯酞氯化钠注射液,余步骤同IR组。假手术组:栓线插入深度<10 mm,余步骤同IR组。各组于再灌注24 h处死大鼠,分别通过Zealonga法、TTC染色、TUNEL法观察各组大鼠的神经功能缺损评分、脑梗死体积、缺血侧海马CA1区凋亡阳性细胞数,通过免疫组化染色及RT-PCR法观察XIAP和BNIP3阳性细胞数及其mRNA的表达。结果丁苯酞低、中、高剂量亚组神经功能缺损评分均小于IR组(P<0.05),且各亚组之间比较差异有统计学意义(P<0.05)。低剂量亚组脑梗死体积大于中剂量亚组和高剂量亚组(P<0.05)。丁苯酞低、中、高剂量亚组海马CA1区凋亡细胞数逐渐减小,且均小于IR组(P<0.05)。IR组XIAP、BNIP3阳性细胞表达[(22.31±0.94)、(60.13±2.59)个/HP]较假手术组[(3.07±1.43)、(5.78±0.44)个/HP]明显增多(P<0.05);与IR组比较,丁苯酞低、中、高剂量亚组XIAP阳性细胞数[(28.70±1.18)、(32.79±0.88)、(37.01±1.24)个/HP]逐渐增加(P<0.05),BNIP3阳性细胞数[(52.07±1.02)、(40.30±2.00)、(31.04±0.43)个/HP]逐渐减少(P<0.05)。与IR组比较,丁苯酞低、中、高剂量亚组XIAP mRNA逐渐增加、BNIP3 mRNA逐渐减少(P<0.05)。结论丁苯酞氯化钠注射液后处理对大鼠IR具有神经保护作用,其机制与影响XIAP、BNIP3的表达有关,且XIAP、BNIP3阳性表达量与丁苯酞氯化钠注射液存在剂量依赖关系。展开更多
Organisms produce high levels of reactive oxygen species(ROS)to kill pathogens or act as signaling molecules to induce immune responses;however,excessive ROS can result in cell death.To maintain ROS balance and cell s...Organisms produce high levels of reactive oxygen species(ROS)to kill pathogens or act as signaling molecules to induce immune responses;however,excessive ROS can result in cell death.To maintain ROS balance and cell survival,mitophagy selectively eliminates damaged mitochondria via mitophagy receptors in vertebrates.In marine invertebrates,however,mitophagy and its functions remain largely unknown.In the current study,Vibrio splendidus infection damaged mitochondrial morphology in coelomocytes and reduced mitochondrial membrane potential(ΔΨm)and mitophagosome formation.The colocalization of mitochondria and lysosomes further confirmed that lipopolysaccharide(LPS)treatment increased mitophagy flux.To explore the regulatory mechanism of mitophagy,we cloned Bcl2/adenovirus E1 B 19 kDa protein-interacting protein 3(BNIP3),a common mitophagy receptor,from sea cucumber Apostichopus japonicus(Aj BNIP3)and confirmed that Aj BNIP3 was significantly induced and accumulated in mitochondria after V.splendidus infection and LPS exposure.At the mitochondrial membrane,Aj BNIP3 interacts with microtubule-associated protein 1 light chain 3(LC3)on phagophore membranes to mediate mitophagy.After Aj BNIP3 interference,mitophagy flux decreased significantly.Furthermore,Aj BNIP3-mediated mitophagy was activated by ROS following the addition of exogenous hydrogen peroxide(H2 O2),ROS scavengers,and ROS inhibitors.Finally,inhibition of BNIP3-mediated mitophagy by Aj BNIP3 small interfering RNA(si RNA)or high concentrations of lactate increased apoptosis and decreased coelomocyte survival.These findings highlight the essential role of Aj BNIP3 in damaged mitochondrial degradation during mitophagy.This mitophagy activity is required for coelomocyte survival in A.japonicus against V.splendidus infection.展开更多
Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-d...Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-documented,the cellular and molecular mechanisms under-lying the regulation of neuronal mitophagy remain unknown.So far,the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons,the latter being more likely activated by reperfusional injury.Specifically,given the polarized morphology of neurons,mitophagy is regulated by different neuronal compartments,with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult.A variety of molecules have been associated with neuronal adaptation to ischemia,including PTEN-induced kinase 1,Parkin,BCL2 and adenovirus E1B 19-kDa-interacting protein 3(Bnip3),Bnip3-like(Bnip3l)and FUN14 domain-containing 1.Moreover,it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury.Here,we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.展开更多
Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury(MIRI).Moderate mitophagy can remove damaged mitochondria,inhibit excessive reactive oxygen species a...Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury(MIRI).Moderate mitophagy can remove damaged mitochondria,inhibit excessive reactive oxygen species accumulation,and protect mitochondria from damage.However,excessive enhancement of mitophagy greatly reduces adenosine triphosphate production and energy supply for cell survival,and aggravates cell death.How dysfunctional mitochondria are selectively recognized and engulfed is related to the interaction of adaptors on the mitochondrial membrane,which mainly include phosphatase and tensin homolog deleted on chromosome ten(PTEN)-induced kinase 1/Parkin,hypoxia-inducible factor-1α/Bcl-2 and adenovirus e1b19k Da interacting protein 3,FUN-14 domain containing protein 1 receptor-mediated mitophagy pathway and so on.In this review,the authors briefly summarize the main pathways currently studied on mitophagy and the relationship between mitophagy and MIRI,and incorporate and analyze research data on prevention and treatment of MIRI with Chinese medicine,thereby provide relevant theoretical basis and treatment ideas for clinical prevention of MIRI.展开更多
文摘目的:探讨石榴花水提物(pomegranate flower water extract,PFW)对2型糖尿病小鼠肝脏胰岛素信号传导的影响及机制。方法:将C57BL/6J随机分为正常组、模型组、二甲双胍组(Met)、石榴花水提物低剂量组(PFWL)和石榴花水提物高剂量组(PFWH)。连续给药11周后,称小鼠体质量,检测空腹血糖(FBG)、胰岛素(INS)、甘油三酯(TG)和总胆固醇(TC)的含量,计算胰岛素抵抗指数(HOMA-IR);苏木素-伊红(HE)染色观察肝组织病理变化;Western blot法检测肝组织中胰岛素受体底物1(IRS1)、p-IRS1(Ser307)、蛋白激酶B(AKT)、p-AKT(Ser473)、糖原合成酶激酶-3β(Gsk3β)、p-Gsk3β(S9)、芳香烃受体(AhR)、磷脂酰乙醇胺N-甲基转移酶(PEMT)、Bcl-2/腺病毒E1B-19kDa相互作用蛋白3(BNIP3)蛋白表达。结果:与模型组比较,PFWH组FBG、INS、HOMA-IR、TG和TC含量极显著降低(P<0.01);PFWH组小鼠肝细胞内脂肪滴明显减少;PFWH组极显著升高肝脏中IRS1、p-AKT(Ser473)/AKT、p-Gsk3β(S9)/Gsk3β、BNIP3蛋白表达(P<0.01),极显著降低p-IRS1(Ser307)/IRS1、AHR、PEMT蛋白表达(P<0.01)。结论:PFW可能通过调节AHR/BNIP3抑制肝脏脂质沉积,改善p-IRS1(Ser307)/p-AKT(Ser473)/p-GSK3β(S9)胰岛素信号通路转导。
文摘目的 探究胰腺癌Bcl-2/腺病毒E1B-19k相关蛋白3(Bcl-2/E1B-19k-interacting protein 3,BNIP3)的蛋白表达水平及其与术后吉西他滨化疗敏感性的关系。方法 回顾性分析2016年7月至2021年8月内蒙古医科大学附属医院58例胰腺癌根治术,并在术后规律应用吉西他滨辅助化疗或以吉西他滨为主的联合化疗患者的临床资料,选取胰腺癌术后组织切片,对其进行BNIP3免疫组织化学检测,通过实验染色强度及范围进行评分,并分析其与胰腺癌患者预后的关系。结果 与BNIP3低表达组比较,BNIP3高表达组的总生存时间(OS)[13(95%CI 11.378~14.622)个月 vs 18(95%CI 16.592~19.408)个月]和无病生存时间(DFS)[7(95%CI 4.082~9.938)个月 vs 14(95%CI 12.936~15.064)个月]均降低(P<0.05)。BNIP3的蛋白表达水平及淋巴转移情况是OS的独立预后因素,而BNIP3的蛋白表达水平及分化程度是DFS的独立预后因素。结论 胰腺癌组织中BNIP3的蛋白表达水平可能与应用吉西他滨化疗敏感性相关,BNIP3低表达患者行术后吉西他滨化疗的OS与DFS较高表达者更长。
基金supported by the National Natural Science Foundation of China(32073003,32102825)Natural Science Foundation of Zhejiang Province(LZ19C190001)+1 种基金Key Project from Science Technology Department of Zhejiang Province(2019R52016)K.C.Wong Magna Fund in Ningbo University。
文摘Organisms produce high levels of reactive oxygen species(ROS)to kill pathogens or act as signaling molecules to induce immune responses;however,excessive ROS can result in cell death.To maintain ROS balance and cell survival,mitophagy selectively eliminates damaged mitochondria via mitophagy receptors in vertebrates.In marine invertebrates,however,mitophagy and its functions remain largely unknown.In the current study,Vibrio splendidus infection damaged mitochondrial morphology in coelomocytes and reduced mitochondrial membrane potential(ΔΨm)and mitophagosome formation.The colocalization of mitochondria and lysosomes further confirmed that lipopolysaccharide(LPS)treatment increased mitophagy flux.To explore the regulatory mechanism of mitophagy,we cloned Bcl2/adenovirus E1 B 19 kDa protein-interacting protein 3(BNIP3),a common mitophagy receptor,from sea cucumber Apostichopus japonicus(Aj BNIP3)and confirmed that Aj BNIP3 was significantly induced and accumulated in mitochondria after V.splendidus infection and LPS exposure.At the mitochondrial membrane,Aj BNIP3 interacts with microtubule-associated protein 1 light chain 3(LC3)on phagophore membranes to mediate mitophagy.After Aj BNIP3 interference,mitophagy flux decreased significantly.Furthermore,Aj BNIP3-mediated mitophagy was activated by ROS following the addition of exogenous hydrogen peroxide(H2 O2),ROS scavengers,and ROS inhibitors.Finally,inhibition of BNIP3-mediated mitophagy by Aj BNIP3 small interfering RNA(si RNA)or high concentrations of lactate increased apoptosis and decreased coelomocyte survival.These findings highlight the essential role of Aj BNIP3 in damaged mitochondrial degradation during mitophagy.This mitophagy activity is required for coelomocyte survival in A.japonicus against V.splendidus infection.
基金funded by National Natural Science Foundation of China(81973402)Natural Science Foundation of Zhejiang Province(LYY22H310009)+1 种基金Hospital Pharmacy Scientific Research Funding Project of Zhejiang Pharmaceutical Association(2020ZYY10)Clinical research fund project of Zhejiang Medical Association(2020ZYC-A07).
文摘Cerebral ischemia is a neurological disorder associated with complex pathological mechanisms,including autophagic degradation of neuronal mitochondria,or termed mitophagy,following ischemic events.Despite being well-documented,the cellular and molecular mechanisms under-lying the regulation of neuronal mitophagy remain unknown.So far,the evidence suggests neuronal autophagy and mitophagy are separately regulated in ischemic neurons,the latter being more likely activated by reperfusional injury.Specifically,given the polarized morphology of neurons,mitophagy is regulated by different neuronal compartments,with axonal mitochondria being degraded by autophagy in the cell body following ischemia-reperfusion insult.A variety of molecules have been associated with neuronal adaptation to ischemia,including PTEN-induced kinase 1,Parkin,BCL2 and adenovirus E1B 19-kDa-interacting protein 3(Bnip3),Bnip3-like(Bnip3l)and FUN14 domain-containing 1.Moreover,it is still controversial whether mitophagy protects against or instead aggravates ischemic brain injury.Here,we review recent studies on this topic and provide an updated overview of the role and regulation of mitophagy during ischemic events.
基金Supported by the Beijing University of Chinese Medicine Research and Innovation Team Project(No.2019-JYB-TD-08)Youth Science Fund Project of National Natural Science Foundation of China(No.81803906)。
文摘Mitophagy is one of the important targets for the prevention and treatment of myocardial ischemia/reperfusion injury(MIRI).Moderate mitophagy can remove damaged mitochondria,inhibit excessive reactive oxygen species accumulation,and protect mitochondria from damage.However,excessive enhancement of mitophagy greatly reduces adenosine triphosphate production and energy supply for cell survival,and aggravates cell death.How dysfunctional mitochondria are selectively recognized and engulfed is related to the interaction of adaptors on the mitochondrial membrane,which mainly include phosphatase and tensin homolog deleted on chromosome ten(PTEN)-induced kinase 1/Parkin,hypoxia-inducible factor-1α/Bcl-2 and adenovirus e1b19k Da interacting protein 3,FUN-14 domain containing protein 1 receptor-mediated mitophagy pathway and so on.In this review,the authors briefly summarize the main pathways currently studied on mitophagy and the relationship between mitophagy and MIRI,and incorporate and analyze research data on prevention and treatment of MIRI with Chinese medicine,thereby provide relevant theoretical basis and treatment ideas for clinical prevention of MIRI.
