Objective Numerous studies have indicated that excitatory amino acid toxicity,such as glutamate toxicity,is involved in glaucoma.In addition,excessive glutamate can lead to an intracellular calcium overload,resulting ...Objective Numerous studies have indicated that excitatory amino acid toxicity,such as glutamate toxicity,is involved in glaucoma.In addition,excessive glutamate can lead to an intracellular calcium overload,resulting in regulated necrosis.Our previous studies have found that the calpastatin(CAST)-calpain pathway plays an important role in retinal neuron-regulated necrosis after glutamate injury.Although inhibition of the calpain pathway can decrease regulated necrosis,necrotic cells remain.It has been suggested that there are other molecules that participate in retinal neuron-regulated necrosis.CAST is an important regulator of dynamin-related protein 1(Drp1)-mediated mitochondrial defects.Thus,the aim of this study was to determine whether the CAST-Drp1 pathway may be an underlying signaling axis in neuron-regulated necrosis.Methods Using cultured retinal neurons and in an in-vivo glaucoma model induced by glutamate overload,members of the CAST-Drp1 pathway were assessed by immunofluorescence,Western blotting,Phos-tagTM SDS-PAGE,and co-immunoprecipitation assays.Moreover,the black and white box test was performed on the rats.Results We found that more retinal neuron-regulated necrosis and Drp1 activation as well as lower CAST levels were present in the glutamate-induced glaucoma model.Rats with glutamate-induced glaucoma exhibited impaired visual function.We also observed retinal neuron-regulated necrosis and Drp1 activity decreased,and impaired vision recovered after CAST active peptide application,indicating that the CAST-Drp1 pathway plays a critical role in retinal neuron-regulated necrosis and visual function.Conclusion The results of this study indicate that the CAST-Drp1 pathway protects against retinal neuron-regulated necrosis,which may expand the therapeutic targets for the treatment of neurodegenerative disorders involving dysfunction of glutamate metabolism,such as glaucoma.展开更多
Objective:To investigate the effects of hepatitis B virus(HBV)X protein(HBx)on the expression of tumor necrosis factor-α(TNF-α)in glomerular mesangial cells(GMCs)and the underlying intracellular signal pathways.Meth...Objective:To investigate the effects of hepatitis B virus(HBV)X protein(HBx)on the expression of tumor necrosis factor-α(TNF-α)in glomerular mesangial cells(GMCs)and the underlying intracellular signal pathways.Methods:The plasmid pCI-neo-X that carries the X gene of hepatitis B virus was transfected into cultured GMCs.HBx expression in the transfected GMCs was assessed by Western-blot.TNF-αprotein and mRNA were assessed by ELISA and semi-quantitative RT-PCR,respectively.Three kinase inhibitors-U0126,an inhibitor of extracellular signal-regulated kinases(ERKs);lactacvstin,an inhibitor of nuclear factor-κB(NF-κB);and SB203580,a selective inhibitor of p38 MAP kinase(p38 MAPK)were used to determine which intracellular signal pathways may underlie the action of HBx on TNF-αexpression in transfected GMCs.Results:A significant increase in HBx expression in pCI-neo-X transfected GMCs was detected at 36 h and 48 h,which was not affected by any of those kinase inhibitors mentioned above.A similar increase in the expression of both TNF-αprotein and mRNA was also observed at 36 h and 48 h,which was significantly decreased in the presence of U0126 or lactacytin,but not SB203580.Conclusions:HBx upregulates TNF-αexpression in cultured GMCs,possibly through ERKs and NF-κB pathway,but not p38 MAPK pathway.展开更多
Necroptosis is a newly found type of programmed cell death.It is elicited by death receptor ligands under the condition of apoptotic inhibition,and can be specifically blocked by necrostatin-1,a small-molecule compoun...Necroptosis is a newly found type of programmed cell death.It is elicited by death receptor ligands under the condition of apoptotic inhibition,and can be specifically blocked by necrostatin-1,a small-molecule compound.The pathway of necroptosis starts from the activation of death receptors by death receptor ligands,and is relayed in turn with aggregation and activation of RIP1 and RIP3,activation of energy metabolism-related enzymes including glycogen phosphorylase,glutamate-ammonia ligase as well as glutamate dehydrogenase 1.The process increases the substrates of tricarboxylic acid cycle,enhances the mitochondria respiratory chain,and induces excessive production of OFR.OFR destroys the cellular membranes,resulting in cease of ATP production and leakage of lysoenzymes.Consequently,cell necrosis happens. Necroptosis may be one of the main types of cell necrosis in diseases.Necroptosis and apoptosis convert to each other.Necroptosis may be important to cure of two kinds of diseases.One involves acute critical diseases such as acute ischemia,acute inflammation and acute organ failure,etc.The other includes malignant tumors and virus infections.Prevention from necroptosis is beneficial to the therapy for the former.On the contrary,promotion to necroptosis is beneficial to that for the latter.Collectively,the findings of necroptosis make modulation of necrosis possible.The research on necroptosis will certainly promote our understanding in cell death and disease mechanisms as well as clinical therapy.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
Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ�...Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ’s physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ’s physiological function can be prevented.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
AIM: To clone the cDNA fragment of human TRAIL (TNF-related apoptosis inducing ligand) into a tetracycline-regulated gene expression system, the RevTet-On system, transduce expression vectors into a gastric carcinoma ...AIM: To clone the cDNA fragment of human TRAIL (TNF-related apoptosis inducing ligand) into a tetracycline-regulated gene expression system, the RevTet-On system, transduce expression vectors into a gastric carcinoma cell line-NCI-N87 and examine the effects of controlled expression of TRAIL in vitro on the gastric carcinoma cells. METHODS: The full-length cDNA of TRAIL was inserted into a vector under the control of the tetracycline-responsive element (TRE) to obtain the plasmid pRevTRE-TRAIL, which was transfected into a packaging cell line PT67. In addition, vector pRev-Tet On and pRevTRE were also transfected into PT67 separately. After hygromycin and G418 selection, the viral titer was determined. The medium containing retroviral vectors was collected and used to transduce a gastric carcinoma cell line NCI-N87. The resulting cell line NCI-N87-Tet On TRE-TRAIL and a control cell line, NCI-N87 Tet On-TRE, were established. TRAIL expression in the cell line was induced by incubating cells with doxycycline (Dox), which is a tetracycline analogue. The killing effect on gastric carcinoma cells was analyzed after induction. RESULTS: The recombinant plasmid pRev-TRE-TRAIL was constructed. After hygromycin or G418 selection, the producer cell lines PT67-TRE, PT67-TRE-TRAIL and PT67-Tet On were obtained,with titers of about 10(8)CFU.L(-1). By transducing NCI-N87 cells with retroviral vectors from these cell lines, stable cell lines NCI-N87-Tet-On TRE-TRAIL (NN3T) and control cell line NCI-N87-Tet-On-TRE (NN2T) were established. The growth curves of the selected cell lines were the same with the wild type NCI-N87. When Dox was added, cell death was obvious in the test groups (29%-77%), whereas no difference was observed in control and wild type cell lines. With the addition of a medium from the test group, human leukemia cell line Jurkat was activated till death (83%), indicating the secretion of active TRAIL proteins from the test cells to the medium. CONCLUSION: With the use of the RevTet-On system, a regulated expression system for TRAIL was constructed. Using this system, the selected killing effect of TRAIL on gastric carcinoma cell line NCI-N87 could be observed.展开更多
Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules,particles,and organelles.Currently,the pivotal role of lysosome in regulating cell death is drawing great attention...Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules,particles,and organelles.Currently,the pivotal role of lysosome in regulating cell death is drawing great attention.Over the past decades,we largely focused on how lysosome influences apoptosis and autophagic cell death.However,extensive studies showed that lysosome is also prerequisite for the execution of regulated necrosis(RN).Different types of RN have been uncovered,among which,necroptosis,ferroptosis,and pyroptosis are under the most intensive investigation.It becomes a hot topic nowadays to target RN as a therapeutic intervention,since it is important in many patho/physiological settings and contributing to numerous diseases.It is promising to target lysosome to control the occurrence of RN thus altering the outcomes of diseases.Therefore,we aim to give an introduction about the common factors influencing lysosomal stability and then summarize the current knowledge on the role of lysosome in the execution of RN,especially in that of necroptosis,ferroptosis,and pyroptosis.展开更多
Regulated cell death predominantly involves apoptosis,autophagy,and regulated necrosis.It is vital that we understand how key regulatory signals can control the process of cell death.Pin1 is a cis-trans isomerase that...Regulated cell death predominantly involves apoptosis,autophagy,and regulated necrosis.It is vital that we understand how key regulatory signals can control the process of cell death.Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein,thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved.However,we know very little about how Pin1-associated pathways might play a role in regulated cell death.In this paper,we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death.Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases,accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy,thereby exhibiting distinct effects,including both neurotoxic and neuroprotective effects.Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.展开更多
Globally,ischemic stroke causes millions of deaths per year.The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region.In the ...Globally,ischemic stroke causes millions of deaths per year.The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region.In the infarct region,cell injuries follow either the regulated pathway involving precise signaling cascades,such as apoptosis and autophagy,or the nonregulated pathway,which is uncontrolled by any molecularly defined effector mechanisms such as necrosis.However,numerous studies have recently found that a certain type of necrosis can be regulated and potentially modified by drugs and is nonapoptotic;this type of necrosis is referred to as regulated necrosis.Depending on the signaling pathway,various elements of regulated necrosis contribute to the development of ischemic stroke,such as necroptosis,pyroptosis,ferroptosis,pathanatos,mitochondrial permeability transition pore-mediated necrosis and oncosis.In this review,we aim to summarize the underlying molecular mechanisms of regulated necrosis in ischemic stroke and explore the crosstalk and interplay among the diverse types of regulated necrosis.We believe that targeting these regulated necrosis pathways both pharmacologically and genetically in ischemiainduced neuronal death and protection could be an efficient strategy to increase neuronal survival and regeneration in ischemic stroke.展开更多
Regulated cell death(RCD)is a controlled form of cell death orchestrated by one or more cascading signaling pathways,making it amenable to pharmacological intervention.RCD subroutines can be categorized as apoptotic o...Regulated cell death(RCD)is a controlled form of cell death orchestrated by one or more cascading signaling pathways,making it amenable to pharmacological intervention.RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis,facilitating development,and modulating immunity.Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival.Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse,comparable to apoptosis.Moreover,they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs.With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines,a growing number of small-molecule compounds targeting single or multiple pathways have been discovered,providing novel strategies for current cancer therapy.In this review,we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines,mainly including autophagy-dependent cell death,ferroptosis,cuproptosis,disulfidptosis,necroptosis,pyroptosis,alkaliptosis,oxeiptosis,parthanatos,mitochondrial permeability transition(MPT)-driven necrosis,entotic cell death,NETotic cell death,lysosome-dependent cell death,and immunogenic cell death(ICD).Furthermore,we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds.In brief,these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines,ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.展开更多
基金supported by the National Natural Science Foundation of China(No.82101126)the Natural Science Foundation of Hunan Province(No.2021JJ40873).
文摘Objective Numerous studies have indicated that excitatory amino acid toxicity,such as glutamate toxicity,is involved in glaucoma.In addition,excessive glutamate can lead to an intracellular calcium overload,resulting in regulated necrosis.Our previous studies have found that the calpastatin(CAST)-calpain pathway plays an important role in retinal neuron-regulated necrosis after glutamate injury.Although inhibition of the calpain pathway can decrease regulated necrosis,necrotic cells remain.It has been suggested that there are other molecules that participate in retinal neuron-regulated necrosis.CAST is an important regulator of dynamin-related protein 1(Drp1)-mediated mitochondrial defects.Thus,the aim of this study was to determine whether the CAST-Drp1 pathway may be an underlying signaling axis in neuron-regulated necrosis.Methods Using cultured retinal neurons and in an in-vivo glaucoma model induced by glutamate overload,members of the CAST-Drp1 pathway were assessed by immunofluorescence,Western blotting,Phos-tagTM SDS-PAGE,and co-immunoprecipitation assays.Moreover,the black and white box test was performed on the rats.Results We found that more retinal neuron-regulated necrosis and Drp1 activation as well as lower CAST levels were present in the glutamate-induced glaucoma model.Rats with glutamate-induced glaucoma exhibited impaired visual function.We also observed retinal neuron-regulated necrosis and Drp1 activity decreased,and impaired vision recovered after CAST active peptide application,indicating that the CAST-Drp1 pathway plays a critical role in retinal neuron-regulated necrosis and visual function.Conclusion The results of this study indicate that the CAST-Drp1 pathway protects against retinal neuron-regulated necrosis,which may expand the therapeutic targets for the treatment of neurodegenerative disorders involving dysfunction of glutamate metabolism,such as glaucoma.
基金Supported by National Nature Science Foundation of China(GrantNo.30772360)Nature Science Foundation of Health Department of Hubei Province,China(No.JX4B48)Fund of Yangtze University for Doctor(No.2009001)
文摘Objective:To investigate the effects of hepatitis B virus(HBV)X protein(HBx)on the expression of tumor necrosis factor-α(TNF-α)in glomerular mesangial cells(GMCs)and the underlying intracellular signal pathways.Methods:The plasmid pCI-neo-X that carries the X gene of hepatitis B virus was transfected into cultured GMCs.HBx expression in the transfected GMCs was assessed by Western-blot.TNF-αprotein and mRNA were assessed by ELISA and semi-quantitative RT-PCR,respectively.Three kinase inhibitors-U0126,an inhibitor of extracellular signal-regulated kinases(ERKs);lactacvstin,an inhibitor of nuclear factor-κB(NF-κB);and SB203580,a selective inhibitor of p38 MAP kinase(p38 MAPK)were used to determine which intracellular signal pathways may underlie the action of HBx on TNF-αexpression in transfected GMCs.Results:A significant increase in HBx expression in pCI-neo-X transfected GMCs was detected at 36 h and 48 h,which was not affected by any of those kinase inhibitors mentioned above.A similar increase in the expression of both TNF-αprotein and mRNA was also observed at 36 h and 48 h,which was significantly decreased in the presence of U0126 or lactacytin,but not SB203580.Conclusions:HBx upregulates TNF-αexpression in cultured GMCs,possibly through ERKs and NF-κB pathway,but not p38 MAPK pathway.
文摘Necroptosis is a newly found type of programmed cell death.It is elicited by death receptor ligands under the condition of apoptotic inhibition,and can be specifically blocked by necrostatin-1,a small-molecule compound.The pathway of necroptosis starts from the activation of death receptors by death receptor ligands,and is relayed in turn with aggregation and activation of RIP1 and RIP3,activation of energy metabolism-related enzymes including glycogen phosphorylase,glutamate-ammonia ligase as well as glutamate dehydrogenase 1.The process increases the substrates of tricarboxylic acid cycle,enhances the mitochondria respiratory chain,and induces excessive production of OFR.OFR destroys the cellular membranes,resulting in cease of ATP production and leakage of lysoenzymes.Consequently,cell necrosis happens. Necroptosis may be one of the main types of cell necrosis in diseases.Necroptosis and apoptosis convert to each other.Necroptosis may be important to cure of two kinds of diseases.One involves acute critical diseases such as acute ischemia,acute inflammation and acute organ failure,etc.The other includes malignant tumors and virus infections.Prevention from necroptosis is beneficial to the therapy for the former.On the contrary,promotion to necroptosis is beneficial to that for the latter.Collectively,the findings of necroptosis make modulation of necrosis possible.The research on necroptosis will certainly promote our understanding in cell death and disease mechanisms as well as clinical therapy.
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.
基金Supported by A grant of the Korea Healthcare technology R and D Project,Ministry of Health and Welfare,South Korea,NO.A121185
文摘Cell death has been extensively evaluated for decades and it is well recognized that pharmacological interventions directed to inhibit cell death can prevent significant cell loss and can thus improve an organ’s physiological function. For long, only apoptosis was considered as a sole form of programmed cell death. Recently necroptosis, a RIP1/RIP3-dependent programmed cell death, has been identified as an apoptotic backup cell death mechanism with necrotic morphology. The evidences of necroptosis and protective effects achieved by blocking necroptosis have been extensively reported in recent past. However, only a few studies reported the evidence of necroptosis and protective effects achieved by inhibiting necroptosis in liver related disease conditions. Although the number of necroptosis initiators is increasing; however, interestingly, it is still unclear that what actually triggers necroptosis in different liver diseases or if there is always a different necroptosis initiator in each specific disease condition followed by specific downstream signaling molecules. Understanding the precise mechanism of necroptosis as well as counteracting other cell death pathways in liver diseases could provide a useful insight towards achieving extensive therapeutic significance. By targeting necroptosis and/or other parallel death pathways, a significant cell loss and thus a decrement in an organ’s physiological function can be prevented.
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the National Natural Science Foundation of China,No.39870850
文摘AIM: To clone the cDNA fragment of human TRAIL (TNF-related apoptosis inducing ligand) into a tetracycline-regulated gene expression system, the RevTet-On system, transduce expression vectors into a gastric carcinoma cell line-NCI-N87 and examine the effects of controlled expression of TRAIL in vitro on the gastric carcinoma cells. METHODS: The full-length cDNA of TRAIL was inserted into a vector under the control of the tetracycline-responsive element (TRE) to obtain the plasmid pRevTRE-TRAIL, which was transfected into a packaging cell line PT67. In addition, vector pRev-Tet On and pRevTRE were also transfected into PT67 separately. After hygromycin and G418 selection, the viral titer was determined. The medium containing retroviral vectors was collected and used to transduce a gastric carcinoma cell line NCI-N87. The resulting cell line NCI-N87-Tet On TRE-TRAIL and a control cell line, NCI-N87 Tet On-TRE, were established. TRAIL expression in the cell line was induced by incubating cells with doxycycline (Dox), which is a tetracycline analogue. The killing effect on gastric carcinoma cells was analyzed after induction. RESULTS: The recombinant plasmid pRev-TRE-TRAIL was constructed. After hygromycin or G418 selection, the producer cell lines PT67-TRE, PT67-TRE-TRAIL and PT67-Tet On were obtained,with titers of about 10(8)CFU.L(-1). By transducing NCI-N87 cells with retroviral vectors from these cell lines, stable cell lines NCI-N87-Tet-On TRE-TRAIL (NN3T) and control cell line NCI-N87-Tet-On-TRE (NN2T) were established. The growth curves of the selected cell lines were the same with the wild type NCI-N87. When Dox was added, cell death was obvious in the test groups (29%-77%), whereas no difference was observed in control and wild type cell lines. With the addition of a medium from the test group, human leukemia cell line Jurkat was activated till death (83%), indicating the secretion of active TRAIL proteins from the test cells to the medium. CONCLUSION: With the use of the RevTet-On system, a regulated expression system for TRAIL was constructed. Using this system, the selected killing effect of TRAIL on gastric carcinoma cell line NCI-N87 could be observed.
基金supported by the National Major Scientific and Technological Special Project for“Significant New Drugs Development”(No.2018ZX09733001,China)the Development Program of China(No.2016YFA0201402)the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China(No.2019JDJQ008)
文摘Lysosome is a ubiquitous acidic organelle fundamental for the turnover of unwanted cellular molecules,particles,and organelles.Currently,the pivotal role of lysosome in regulating cell death is drawing great attention.Over the past decades,we largely focused on how lysosome influences apoptosis and autophagic cell death.However,extensive studies showed that lysosome is also prerequisite for the execution of regulated necrosis(RN).Different types of RN have been uncovered,among which,necroptosis,ferroptosis,and pyroptosis are under the most intensive investigation.It becomes a hot topic nowadays to target RN as a therapeutic intervention,since it is important in many patho/physiological settings and contributing to numerous diseases.It is promising to target lysosome to control the occurrence of RN thus altering the outcomes of diseases.Therefore,we aim to give an introduction about the common factors influencing lysosomal stability and then summarize the current knowledge on the role of lysosome in the execution of RN,especially in that of necroptosis,ferroptosis,and pyroptosis.
基金supported by the National Natural Science Foundation of China, Nos. 81971891 (to KX), 82101126 (to SCW), 81772134 (to KX), 82172196 (to KX)the Natural Science Foundation of Hunan Province of China, No. 2021JJ40873 (to SCW)
文摘Regulated cell death predominantly involves apoptosis,autophagy,and regulated necrosis.It is vital that we understand how key regulatory signals can control the process of cell death.Pin1 is a cis-trans isomerase that catalyzes the isomerization of phosphorylated serine or threonine-proline motifs of a protein,thereby acting as a crucial molecular switch and regulating the protein functionality and the signaling pathways involved.However,we know very little about how Pin1-associated pathways might play a role in regulated cell death.In this paper,we review the role of Pin1 in regulated cell death and related research progress and summarize Pin1-related pathways in regulated cell death.Aside from the involvement of Pin1 in the apoptosis that accompanies neurodegenerative diseases,accumulating evidence suggests that Pin1 also plays a role in regulated necrosis and autophagy,thereby exhibiting distinct effects,including both neurotoxic and neuroprotective effects.Gaining an enhanced understanding of Pin1 in neuronal death may provide us with new options for the development of therapeutic target for neurodegenerative disorders.
基金supported by the National Key Research and Development Program of China(No.2020YFC2008304)Natural Science Foundation of Henan Province(No.222300420350)+3 种基金National Natural Science Foundation of China(No.82204389),Medical Science and Technique Foundation of Henan Province(No.LHGJ20200310,SBGJ202102145)Foundation of Henan Educational Committee(No.21A310027,No.21A350014)National Natural Science Young Scientists Foundation of China(No.82200796)China Postdoctoral Science Foundation(No.2022M722901).
文摘Globally,ischemic stroke causes millions of deaths per year.The outcomes of ischemic stroke are largely determined by the amount of ischemia-related and reperfusion-related neuronal death in the infarct region.In the infarct region,cell injuries follow either the regulated pathway involving precise signaling cascades,such as apoptosis and autophagy,or the nonregulated pathway,which is uncontrolled by any molecularly defined effector mechanisms such as necrosis.However,numerous studies have recently found that a certain type of necrosis can be regulated and potentially modified by drugs and is nonapoptotic;this type of necrosis is referred to as regulated necrosis.Depending on the signaling pathway,various elements of regulated necrosis contribute to the development of ischemic stroke,such as necroptosis,pyroptosis,ferroptosis,pathanatos,mitochondrial permeability transition pore-mediated necrosis and oncosis.In this review,we aim to summarize the underlying molecular mechanisms of regulated necrosis in ischemic stroke and explore the crosstalk and interplay among the diverse types of regulated necrosis.We believe that targeting these regulated necrosis pathways both pharmacologically and genetically in ischemiainduced neuronal death and protection could be an efficient strategy to increase neuronal survival and regeneration in ischemic stroke.
基金supported by the National Natural Science Foundation of China(Grant No.22277102).
文摘Regulated cell death(RCD)is a controlled form of cell death orchestrated by one or more cascading signaling pathways,making it amenable to pharmacological intervention.RCD subroutines can be categorized as apoptotic or non-apoptotic and play essential roles in maintaining homeostasis,facilitating development,and modulating immunity.Accumulating evidence has recently revealed that RCD evasion is frequently the primary cause of tumor survival.Several non-apoptotic RCD subroutines have garnered attention as promising cancer therapies due to their ability to induce tumor regression and prevent relapse,comparable to apoptosis.Moreover,they offer potential solutions for overcoming the acquired resistance of tumors toward apoptotic drugs.With an increasing understanding of the underlying mechanisms governing these non-apoptotic RCD subroutines,a growing number of small-molecule compounds targeting single or multiple pathways have been discovered,providing novel strategies for current cancer therapy.In this review,we comprehensively summarized the current regulatory mechanisms of the emerging non-apoptotic RCD subroutines,mainly including autophagy-dependent cell death,ferroptosis,cuproptosis,disulfidptosis,necroptosis,pyroptosis,alkaliptosis,oxeiptosis,parthanatos,mitochondrial permeability transition(MPT)-driven necrosis,entotic cell death,NETotic cell death,lysosome-dependent cell death,and immunogenic cell death(ICD).Furthermore,we focused on discussing the pharmacological regulatory mechanisms of related small-molecule compounds.In brief,these insightful findings may provide valuable guidance for investigating individual or collaborative targeting approaches towards different RCD subroutines,ultimately driving the discovery of novel small-molecule compounds that target RCD and significantly enhance future cancer therapeutics.
