The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3,adapter protein ASC,and inflammatory protease caspase-1 that responds to microbial infection,endogenous d...The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3,adapter protein ASC,and inflammatory protease caspase-1 that responds to microbial infection,endogenous danger signals,and environmental stimuli.The assembled NLRP3 inflammasome can activate the protease caspase‐1 to induce gasdermin D-dependent pyroptosis and facilitate the release of IL-1β and IL-18,which contribute to innate immune defense and homeostatic maintenance.However,aberrant activation of the NLRP3 inflammasome is associated with the pathogenesis of various inflammatory diseases,such as diabetes,cancer,and Alzheimer’s disease.Recent studies have revealed that NLRP3 inflammasome activation contributes to not only pyroptosis but also other types of cell death,including apoptosis,necroptosis,and ferroptosis.In addition,various effectors of cell death have been reported to regulate NLRP3 inflammasome activation,suggesting that cell death is closely related to NLRP3 inflammasome activation.In this review,we summarize the inextricable link between NLRP3 inflammasome activation and cell death and discuss potential therapeutics that target cell death effectors in NLRP3 inflammasome-associated diseases.展开更多
Cell death is a fundamental physiological process in all living organisms.Its roles extend from embryonic development,organ maintenance,and aging to the coordination of immune responses and autoimmunity.In recent year...Cell death is a fundamental physiological process in all living organisms.Its roles extend from embryonic development,organ maintenance,and aging to the coordination of immune responses and autoimmunity.In recent years,our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially.Different modalities of what has become known as‘programmed cell death’have been described,and some key players in these processes have been identified.We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death.These studies have highlighted the complex mechanisms tipping the balance between different cell fates.Here,we summarize the latest discoveries in the three most well understood modalities of cell death,namely,apoptosis,necroptosis,and pyroptosis,highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.展开更多
Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion(I/R)injury.Mitochondrial quality control(MQC)mechanisms,a series of adaptive responses that preserve mitochondrial structure and function,...Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion(I/R)injury.Mitochondrial quality control(MQC)mechanisms,a series of adaptive responses that preserve mitochondrial structure and function,ensure cardiomyocyte survival and cardiac function after I/R injury.MQC includes mitochondrial fission,mitochondrial fusion,mitophagy and mitochondria-dependent cell death.The interplay among these responses is linked to pathological changes such as redox imbalance,calcium overload,energy metabolism disorder,signal transduction arrest,the mitochondrial unfolded protein response and endoplasmic reticulum stress.Excessive mitochondrial fission is an early marker of mitochondrial damage and cardiomyocyte death.Reduced mitochondrial fusion has been observed in stressed cardiomyocytes and correlates with mitochondrial dysfunction and cardiac depression.Mitophagy allows autophagosomes to selectively degrade poorly structured mitochondria,thus maintaining mitochondrial network fitness.Nevertheless,abnormal mitophagy is maladaptive and has been linked to cell death.Although mitochondria serve as the fuel source of the heart by continuously producing adenosine triphosphate,they also stimulate cardiomyocyte death by inducing apoptosis or necroptosis in the reperfused myocardium.Therefore,defects in MQC may determine the fate of cardiomyocytes.In this review,we summarize the regulatory mechanisms and pathological effects of MQC in myocardial I/R injury,highlighting potential targets for the clinical management of reperfusion.展开更多
As the first line of immune defense for Mycobacterium tuberculosis （Mtb）, macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant ...As the first line of immune defense for Mycobacterium tuberculosis （Mtb）, macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant since ancient times. Triggered upon Mtb infection, multiple cellular pathways in macrophages are activated to initiate a tailored immune response toward the invading pathogen and regulate the cellular fates of the host as well. Toll-like receptors （TLRs） expressed on macrophages can recognize pathopatterns （PAMPs） on Mtb and mediate the production of immune-regulatory cytokines such as tumor necrosis factor （TNF） and type I Interferons （IFNs）. In addition, Vitamin D receptor （VDR） and Vitamin D-1- hydroxylase are up-regulated in Mtb-infected macrophages, by which Vitamin D participates in innate immune respon- ses. The signaling pathways that involve TNF, type I IFNs and Vitamin D are inter-connected, which play critical roles in the regulation of necroptosis, apoptosis, and autophagy of the infected macrophages. This review article summarizes cur- rent knowledge about the interactions between Mtb and macrophages, focusing on cellular fates of the Mtb-infected macrophages and the regulatory molecules and cellular pathways involved in those processes.展开更多
Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all...Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.展开更多
Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pat...Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases.展开更多
Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis fact...Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.展开更多
该研究通过检索中国知网(CNKI)、维普(VIP)、万方(Wanfang)、Web of Science(WoS)、PubMed数据库,2005年1月1日至2021年12月31日中医药调节坏死性凋亡(necroptosis)的相关文献。文献分别导入NoteExpress进行去重及筛选,将最终纳入文献...该研究通过检索中国知网(CNKI)、维普(VIP)、万方(Wanfang)、Web of Science(WoS)、PubMed数据库,2005年1月1日至2021年12月31日中医药调节坏死性凋亡(necroptosis)的相关文献。文献分别导入NoteExpress进行去重及筛选,将最终纳入文献发文量导入Excel中绘制发文趋势图。根据普莱斯定律确定核心作者,采用VOSviewer 1.6.17绘制核心作者合作网络及高频关键词排序,运用CiteSpace 5.8.R3进行关键词聚类、关键词突现、时间线分布展示。最终纳入中文文献98篇,英文文献72篇。中医药调节坏死性凋亡发文量逐年增加,中国发文量位居世界前列,国内作者在该领域发挥着核心作用。中文文献以刘华发文最多,英文文献以CHEN X P(陈秀萍)发文最多,核心作者合作网络显示团队内部合作较多,团队间合作较缺乏。中、英文关键词分别形成了10个有意义的聚类,显示中医药调节坏死性凋亡的研究热点主要集中于疾病、方药、相关因子、机制研究等。中、英文关键词分析显示,疾病治疗方面,肿瘤、缺血再灌注损伤、神经退行性疾病、炎症性疾病等研究较广泛;备受关注的中药成分是姜黄素、紫草素、丹参酮等;主要涉及的蛋白因子是Ripk1、Ripk3、Mlkl、TNF-α;主要信号通路为Ripk1/Ripk3/Mlkl通路、p53信号通路;主要集中于单味药及中药单体的研究。后续还需扩大经典中药复方的研究,深入探索其在各类疾病发生发展中的作用机制,为中医药治疗疾病提供新的思路和实验依据。展开更多
Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age...Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age of individuals increase globally and individuals become more susceptible to acute disorders such as stroke as well as chronic diseases that involve cognitive loss, Alzheimer＇s disease, and Parkinson＇s disease. Current therapies for such disorders are effective only for a small subset of individuals or provide symptomatic relief but do not alter disease progression. One exciting therapeutic approach that may turn the tide for addressing neurodegenerative disorders involves the mammalian target of rapamycin （mTOR）. mTOR is a component of the protein complexes roTOR Complex 1 （mTORC1） and mTOR Complex 2 （mTORC2） that are ubiquitous throughout the body and control multiple functions such as gene transcription, metabolism, cell survival, and cell senescence, roTOR through its relationship with phosphoinositide 3-kinas e （PI 3-K） and protein kinase B （Akt） and multiple downstream signaling pathways such as p70 ribosomal $6 kinase （p70S6K） and proline rich Akt substrate 40 kDa （PRAS40） promotes neuro- nal cell regeneration through stem cell renewal and oversees critical pathways such as apoptosis, autophagy, and necroptosis to foster protection against neurodegenerative disorders. Targeting by mTOR of specific pathways that drive long-term potentiation, synaptic plasticity, and [3-amyl old toxicity may offer new strategies for disorders such as stroke and Alzheimer＇s disease. Overall, mTOR is an essential neuroprotective pathway but must be carefully targeted to maximize clini- cal efficacy and eliminate any clinical toxic side effects.展开更多
Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson＇s disease. We hypothesized that necrostatin-1 c...Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson＇s disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range（5–30 μM） elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson＇s disease.展开更多
基金This work was supported by the Fundamental Research Funds for the Central Universities(WK2070000191,WK9110000037)the fellowship of China National Postdoctoral Program for Innovative Talents(BX20200325)the Natural Science Foundation of Anhui province(1808085QH244).
文摘The NLRP3 inflammasome is a cytosolic multiprotein complex composed of the innate immune receptor protein NLRP3,adapter protein ASC,and inflammatory protease caspase-1 that responds to microbial infection,endogenous danger signals,and environmental stimuli.The assembled NLRP3 inflammasome can activate the protease caspase‐1 to induce gasdermin D-dependent pyroptosis and facilitate the release of IL-1β and IL-18,which contribute to innate immune defense and homeostatic maintenance.However,aberrant activation of the NLRP3 inflammasome is associated with the pathogenesis of various inflammatory diseases,such as diabetes,cancer,and Alzheimer’s disease.Recent studies have revealed that NLRP3 inflammasome activation contributes to not only pyroptosis but also other types of cell death,including apoptosis,necroptosis,and ferroptosis.In addition,various effectors of cell death have been reported to regulate NLRP3 inflammasome activation,suggesting that cell death is closely related to NLRP3 inflammasome activation.In this review,we summarize the inextricable link between NLRP3 inflammasome activation and cell death and discuss potential therapeutics that target cell death effectors in NLRP3 inflammasome-associated diseases.
基金B.S.F.is supported by grants from the European Research Council(PLAT-IL-1,714175)B.S.F.and E.L.are further supported by grants from the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)(SFBTRR57)the DFG Germany’s Excellence Strategy-EXC 2151-390873048.
文摘Cell death is a fundamental physiological process in all living organisms.Its roles extend from embryonic development,organ maintenance,and aging to the coordination of immune responses and autoimmunity.In recent years,our understanding of the mechanisms orchestrating cellular death and its consequences on immunity and homeostasis has increased substantially.Different modalities of what has become known as‘programmed cell death’have been described,and some key players in these processes have been identified.We have learned more about the intricacies that fine tune the activity of common players and ultimately shape the different types of cell death.These studies have highlighted the complex mechanisms tipping the balance between different cell fates.Here,we summarize the latest discoveries in the three most well understood modalities of cell death,namely,apoptosis,necroptosis,and pyroptosis,highlighting common and unique pathways and their effect on the surrounding cells and the organism as a whole.
基金Research from the corresponding author’s laboratory was supported by grants from National Institutes of Health,USA(No.R01GM117628,R01GM122406,and R01DK123826)Merit Review Award(No.I01BX001690)from US Department of Veterans Affairs.
基金partially supported by the China Postdoctoral Science Foundation(2019TQ0128)the National Natural Science Foundation of China(NSFC81900252,81900254 and 81870249)
文摘Mitochondrial damage is a critical contributor to cardiac ischemia/reperfusion(I/R)injury.Mitochondrial quality control(MQC)mechanisms,a series of adaptive responses that preserve mitochondrial structure and function,ensure cardiomyocyte survival and cardiac function after I/R injury.MQC includes mitochondrial fission,mitochondrial fusion,mitophagy and mitochondria-dependent cell death.The interplay among these responses is linked to pathological changes such as redox imbalance,calcium overload,energy metabolism disorder,signal transduction arrest,the mitochondrial unfolded protein response and endoplasmic reticulum stress.Excessive mitochondrial fission is an early marker of mitochondrial damage and cardiomyocyte death.Reduced mitochondrial fusion has been observed in stressed cardiomyocytes and correlates with mitochondrial dysfunction and cardiac depression.Mitophagy allows autophagosomes to selectively degrade poorly structured mitochondria,thus maintaining mitochondrial network fitness.Nevertheless,abnormal mitophagy is maladaptive and has been linked to cell death.Although mitochondria serve as the fuel source of the heart by continuously producing adenosine triphosphate,they also stimulate cardiomyocyte death by inducing apoptosis or necroptosis in the reperfused myocardium.Therefore,defects in MQC may determine the fate of cardiomyocytes.In this review,we summarize the regulatory mechanisms and pathological effects of MQC in myocardial I/R injury,highlighting potential targets for the clinical management of reperfusion.
文摘As the first line of immune defense for Mycobacterium tuberculosis （Mtb）, macrophages also provide a major habitat for Mtb to reside in the host for years. The battles between Mtb and macrophages have been constant since ancient times. Triggered upon Mtb infection, multiple cellular pathways in macrophages are activated to initiate a tailored immune response toward the invading pathogen and regulate the cellular fates of the host as well. Toll-like receptors （TLRs） expressed on macrophages can recognize pathopatterns （PAMPs） on Mtb and mediate the production of immune-regulatory cytokines such as tumor necrosis factor （TNF） and type I Interferons （IFNs）. In addition, Vitamin D receptor （VDR） and Vitamin D-1- hydroxylase are up-regulated in Mtb-infected macrophages, by which Vitamin D participates in innate immune respon- ses. The signaling pathways that involve TNF, type I IFNs and Vitamin D are inter-connected, which play critical roles in the regulation of necroptosis, apoptosis, and autophagy of the infected macrophages. This review article summarizes cur- rent knowledge about the interactions between Mtb and macrophages, focusing on cellular fates of the Mtb-infected macrophages and the regulatory molecules and cellular pathways involved in those processes.
基金supported by the National Natural Science Foundation of China,Nos.81772134(to KX),81971891(to KX),82172196(to KX),81571939(to KX)the Fundamental Research Funds for the Central Universities of Central South University of China,No.2020zzts218,(to WTY)Hunan Provincial Innovation Foundation For Postgraduate of China,Nos.CX20200116(to WTY),CX20190139(to LSL).
文摘Some scholars have recently developed the concept of PANoptosis in the study of infectious diseases where pyroptosis,apoptosis and necroptosis act in consort in a multimeric protein complex,PANoptosome.This allows all the components of PANoptosis to be regulated simultaneously.PANoptosis provides a new way to study the regulation of cell death,in that different types of cell death may be regulated at the same time.To test whether PANoptosis exists in diseases other than infectious diseases,we chose cerebral ischemia/reperfusion injury as the research model,collected articles researching cerebral ischemia/reperfusion from three major databases,obtained the original research data from these articles by bibliometrics,data mining and other methods,then integrated and analyzed these data.We selected papers that investigated at least two of the components of PANoptosis to check its occurrence in ischemia/reperfusion.In the cell model simulating ischemic brain injury,pyroptosis,apoptosis and necroptosis occur together and this phenomenon exists widely in different passage cell lines or primary neurons.Pyroptosis,apoptosis and necroptosis also occurred in rat and mouse models of ischemia/reperfusion injury.This confirms that PANoptosis is observed in ischemic brain injury and indicates that PANoptosis can be a target in the regulation of various central nervous system diseases.
基金supported by the USA National Institutes of Health Grant R01-HL-079669USA National Institutes of Health Center Grant P50-GM-53789a USA VA Merit Award
文摘Cell death plays an important role in the regulation of inflammation and may be the result of inflammation. The maintenance of tissue homeostasis necessitates both the recognition and removal of invading microbial pathogens as well as the clearance of dying cells. In the past few decades, emerging knowledge on cell death and inflammation has enriched our molecular understanding of the signaling pathways that mediate various programs of cell death and multiple types of inflammatory responses. This review provides an overview of the major types of cell death related to inflammation. Modification of cell death pathways is likely to be a logical therapeutic target for inflammatory diseases.
基金supported by grants from the Heart and Stroke Foundation of Canada(HHC,AFRS)the Canadian Institutes of Health Research(to HHC and AFRS)supported by a Mid-Career Investigator Award from the Heart and Stroke Foundation of Ontario
文摘Ischemic brain injury triggers neuronal cell death by apoptosis via caspase activation and by necroptosis through activation of the receptor-interacting protein kinases （RIPK） associated with the tumor necrosis factor-alpha （TNF-a）/death receptor. Recent evidence shows RIPK inhibitors are neuroprotective and al- leviate ischemic brain injury in a number of animal models, however, most have not yet undergone clinical trials and safety in humans remains in question. Dabrafenib, originally identified as a B-raf inhibitor that is currently used to treat melanoma, was later revealed to be a potent RIPK3 inhibitor at micromolar con- centrations. Here, we investigated whether Dabrafenib would show a similar neuroprotective effect in mice subjected to ischemic brain injury by photothrombosis. Dabrafenib administered intraperitoneally at 10 mg/ kg one hour after photothrombosis-induced focal ischemic injury significantly reduced infarct lesion size in C57BL6 mice the following day, accompanied by a markedly attenuated upregulation of TNF-u. However, subsequent lower doses （5 mg/kg/day） failed to sustain this neuroprotective effect after 4 days. Dabrafenib bl ocked lipopolysaccharides-induced activation of TNF-ct in bone marrow-derived macrophages, suggesting that Dabrafenib may attenuate TNF-ct-induced necroptotic pathway after ischemic brain injury. Since Dab- rafenib is already in clinical use for the treatment of melanoma, it might be repurposed for stroke therapy.
文摘该研究通过检索中国知网(CNKI)、维普(VIP)、万方(Wanfang)、Web of Science(WoS)、PubMed数据库,2005年1月1日至2021年12月31日中医药调节坏死性凋亡(necroptosis)的相关文献。文献分别导入NoteExpress进行去重及筛选,将最终纳入文献发文量导入Excel中绘制发文趋势图。根据普莱斯定律确定核心作者,采用VOSviewer 1.6.17绘制核心作者合作网络及高频关键词排序,运用CiteSpace 5.8.R3进行关键词聚类、关键词突现、时间线分布展示。最终纳入中文文献98篇,英文文献72篇。中医药调节坏死性凋亡发文量逐年增加,中国发文量位居世界前列,国内作者在该领域发挥着核心作用。中文文献以刘华发文最多,英文文献以CHEN X P(陈秀萍)发文最多,核心作者合作网络显示团队内部合作较多,团队间合作较缺乏。中、英文关键词分别形成了10个有意义的聚类,显示中医药调节坏死性凋亡的研究热点主要集中于疾病、方药、相关因子、机制研究等。中、英文关键词分析显示,疾病治疗方面,肿瘤、缺血再灌注损伤、神经退行性疾病、炎症性疾病等研究较广泛;备受关注的中药成分是姜黄素、紫草素、丹参酮等;主要涉及的蛋白因子是Ripk1、Ripk3、Mlkl、TNF-α;主要信号通路为Ripk1/Ripk3/Mlkl通路、p53信号通路;主要集中于单味药及中药单体的研究。后续还需扩大经典中药复方的研究,深入探索其在各类疾病发生发展中的作用机制,为中医药治疗疾病提供新的思路和实验依据。
基金supported by the following grants to Kenneth Maiese:American DiabetesAssociation,American Heart Association(National),Bugher Foundation Award,Janssen Neuroscience Award,LEARN Foundation Award,NIH NIEHS,NIH NIA,NIH NINDS,and NIH ARRA
文摘Neurodegenerative disorders affect more than 30 million individuals throughout the world and lead to significant disability as well as death. These statistics will increase almost exponentially as the lifespan and age of individuals increase globally and individuals become more susceptible to acute disorders such as stroke as well as chronic diseases that involve cognitive loss, Alzheimer＇s disease, and Parkinson＇s disease. Current therapies for such disorders are effective only for a small subset of individuals or provide symptomatic relief but do not alter disease progression. One exciting therapeutic approach that may turn the tide for addressing neurodegenerative disorders involves the mammalian target of rapamycin （mTOR）. mTOR is a component of the protein complexes roTOR Complex 1 （mTORC1） and mTOR Complex 2 （mTORC2） that are ubiquitous throughout the body and control multiple functions such as gene transcription, metabolism, cell survival, and cell senescence, roTOR through its relationship with phosphoinositide 3-kinas e （PI 3-K） and protein kinase B （Akt） and multiple downstream signaling pathways such as p70 ribosomal $6 kinase （p70S6K） and proline rich Akt substrate 40 kDa （PRAS40） promotes neuro- nal cell regeneration through stem cell renewal and oversees critical pathways such as apoptosis, autophagy, and necroptosis to foster protection against neurodegenerative disorders. Targeting by mTOR of specific pathways that drive long-term potentiation, synaptic plasticity, and [3-amyl old toxicity may offer new strategies for disorders such as stroke and Alzheimer＇s disease. Overall, mTOR is an essential neuroprotective pathway but must be carefully targeted to maximize clini- cal efficacy and eliminate any clinical toxic side effects.
基金supported by grants from the Science and Technology Project of Xuzhou City in China,No.XM12B017the Priority Academic Program Development of Jiangsu Higher Education Institutions in China
文摘Necroptosis is characterized by programmed necrotic cell death and autophagic activation and might be involved in the death process of dopaminergic neurons in Parkinson＇s disease. We hypothesized that necrostatin-1 could block necroptosis and give protection to dopaminergic neurons. There is likely to be crosstalk between necroptosis and other cell death pathways, such as apoptosis and autophagy. PC12 cells were pretreated with necroststin-1 1 hour before exposure to 6-hydroxydopamine. We examined cell viability, mitochondrial membrane potential and expression patterns of apoptotic and necroptotic death signaling proteins. The results showed that the autophagy/lysosomal pathway is involved in the 6-hydroxydopamine-induced death process of PC12 cells. Mitochondrial disability induced overactive autophagy, increased cathepsin B expression, and diminished Bcl-2 expression. Necrostatin-1 within a certain concentration range（5–30 μM） elevated the viability of PC12 cells, stabilized mitochondrial membrane potential, inhibited excessive autophagy, reduced the expression of LC3-II and cathepsin B, and increased Bcl-2 expression. These findings suggest that necrostatin-1 exerted a protective effect against injury on dopaminergic neurons. Necrostatin-1 interacts with the apoptosis signaling pathway during this process. This pathway could be a new neuroprotective and therapeutic target in Parkinson＇s disease.
