Central nervous system injuries have a high rate of resulting in disability and mortality;however,at present,effective treatments are lacking.Programmed cell death,which is a genetically determined fo rm of active and...Central nervous system injuries have a high rate of resulting in disability and mortality;however,at present,effective treatments are lacking.Programmed cell death,which is a genetically determined fo rm of active and ordered cell death with many types,has recently attra cted increasing attention due to its functions in determining the fate of cell survival.A growing number of studies have suggested that programmed cell death is involved in central nervous system injuries and plays an important role in the progression of brain damage.In this review,we provide an ove rview of the role of programmed cell death in central nervous system injuries,including the pathways involved in mitophagy,pyroptosis,ferroptosis,and necroptosis,and the underlying mechanisms by which mitophagy regulates pyroptosis,ferroptosis,and necro ptosis.We also discuss the new direction of therapeutic strategies to rgeting mitophagy for the treatment of central nervous system injuries,with the aim to determine the connection between programmed cell death and central nervous system injuries and to identify new therapies to modulate programmed cell death following central nervous system injury.In conclusion,based on these properties and effects,interventions targeting programmed cell death could be developed as potential therapeutic agents for central nervous system injury patients.展开更多
BACKGROUND Necroptosis has emerged as a novel molecular pathway that can be targeted by chemotherapy agents in the treatment of cancer.OSW-1,which is derived from the bulbs of Ornithogalum saundersiae Baker,exerts a w...BACKGROUND Necroptosis has emerged as a novel molecular pathway that can be targeted by chemotherapy agents in the treatment of cancer.OSW-1,which is derived from the bulbs of Ornithogalum saundersiae Baker,exerts a wide range of pharmaco-logical effects.AIM To explore whether OSW-1 can induce necroptosis in colorectal cancer(CRC)cells,thereby expanding its range of clinical applications.METHODS We performed a sequence of functional experiments,including Cell Counting Kit-8 assays and flow cytometry analysis,to assess the inhibitory effect of OSW-1 on CRC cells.We utilized quantitative proteomics,employing tandem mass tag label-ing combined with liquid chromatography-tandem mass spectrometry,to analyze changes in protein expression.Subsequent bioinformatic analysis was conducted to elucidate the biological processes associated with the identified proteins.Transmission electron microscopy(TEM)and immunofluorescence studies were also performed to examine the effects of OSW-1 on necroptosis.Finally,western blotting,siRNA experiments,and immunoprecipitation were employed to evaluate protein interactions within CRC cells.RESULTS The results revealed that OSW-1 exerted a strong inhibitory effect on CRC cells,and this effect was accompanied by a necroptosis-like morphology that was observable via TEM.OSW-1 was shown to trigger necroptosis via activation of the RIPK1/RIPK3/MLKL pathway.Furthermore,the accumulation of p62/SQSTM1 was shown to mediate OSW-1-induced necroptosis through its interaction with RIPK1.CONCLUSION We propose that OSW-1 can induce necroptosis through the RIPK1/RIPK3/MLKL signaling pathway,and that this effect is mediated by the RIPK1-p62/SQSTM1 complex,in CRC cells.These results provide a theoretical foundation for the use of OSW-1 in the clinical treatment of CRC.展开更多
Nonalcoholic fatty liver disease(NAFLD)is the most prevalent type of chronic liver disease.However,the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies.Several studies...Nonalcoholic fatty liver disease(NAFLD)is the most prevalent type of chronic liver disease.However,the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies.Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoe-tiology and suggest functional therapeutic and diagnostic options.Pyroptosis,ferroptosis,and necroptosis are the main subtypes of non-apoptotic regulated cell deaths(RCDs),each of which represents particular characteristics.Considering the complexity of the findings,the present study aimed to review these types of RCDs and their contribution to NAFLD progression,and subsequently discuss in detail the role of necroptosis in the pathoetiology,diagnosis,and treatment of the disease.The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer,hence it has potential in diagnostic and therapeutic approaches.Nevertheless,further studies are necessary.展开更多
Digestive system diseases refer to organic and functional disorders of the digestive system,which are prone to recurrence and frequently accompanied by multiple complications.Necroptosis is a regulated mode of cell de...Digestive system diseases refer to organic and functional disorders of the digestive system,which are prone to recurrence and frequently accompanied by multiple complications.Necroptosis is a regulated mode of cell death mediated by death receptors,dependent on receptor protein activation,and could be specifically inhibited by necrostatin-1.Necroptosis is involved in pathological and physiological processes of various diseases,and plays an important role in the growth and development of organisms and the homeostasis of organ tissues.This paper reviewed the research advancement of necroptosis in digestive system disorders,and discussed the relationship between necroptosis and digestive system diseases,aiming to provide theoretical basis for the cure of these diseases.展开更多
Background:Necroptosis and pyroptosis are newly identified forms of programmed cell death,which play a vital role in development of many gastrointestinal disorders.Although plant polyphenols have been reported to prot...Background:Necroptosis and pyroptosis are newly identified forms of programmed cell death,which play a vital role in development of many gastrointestinal disorders.Although plant polyphenols have been reported to protect intestinal health,it is still unclear whether there is a beneficial role of plant polyphenols in modulating necroptosis and pyroptosis in intestinal porcine epithelial cell line(IPEC-1)infected with enterotoxigenic Escherichia coli(ETEC)K88.This research was conducted to explore whether plant polyphenols including protocatechuic acid(PCA)and quercetin(Que),attenuated inflammation and injury of IPEC-1 caused by ETEC K88 through regulating necroptosis and pyroptosis signaling pathways.Methods:IPEC-1 cells were treated with PCA(40μmol/L)or Que(10μmol/L)in the presence or absence of ETEC K88.Results:PCA and Que decreased ETEC K88 adhesion and endotoxin level(P<0.05)in cell supernatant.PCA and Que increased cell number(P<0.001)and decreased lactate dehydrogenases(LDH)activity(P<0.05)in cell supernatant after ETEC infection.PCA and Que improved transepithelial electrical resistance(TEER)(P<0.001)and reduced fluorescein isothiocyanate-labeled dextran(FD4)flux(P<0.001),and enhanced membrane protein abundance of occludin,claudin-1 and ZO-1(P<0.05),and rescued distribution of these tight junction proteins(P<0.05)after ETEC infection.PCA and Que also declined cell necrosis ratio(P<0.05).PCA and Que reduced mRNA abundance and concentration of tumor necrosis factor-α(TNF-α),interleukin(IL)-6 and IL-8(P<0.001),and down-regulated gene expression of toll-like receptors 4(TLR4)and its downstream signals(P<0.001)after ETEC infection.PCA and Que down-regulated protein abundance of total receptor interacting protein kinase 1(t-RIP1),phosphorylated-RIP1(p-RIP1),p-RIP1/t-RIP1,t-RIP3,p-RIP3,mixed lineage kinase domain-like protein(MLKL),p-MLKL,dynamin-related protein 1(DRP1),phosphoglycerate mutase 5(PGAM5)and high mobility group box 1(HMGB1)(P<0.05)after ETEC infection.Moreover,PCA and Que reduced protein abundance of nod-like receptor protein 3(NLRP3),nod-like receptors family CARD domain-containing protein 4(NLRC4),apoptosis-associated speck-like protein containing a CARD(ASC),gasdermin D(GSDMD)and caspase-1(P<0.05)after ETEC infection.Conclusions:In general,our data suggest that PCA and Que are capable of attenuating ETEC-caused intestinal inflammation and damage via inhibiting necroptosis and pyroptosis signaling pathways.展开更多
BACKGROUND Gastric carcinoma(GC)is the third most frequent cause of cancer-related death,highlighting the pressing need for novel clinical treatment options.In this regard,microRNAs(miRNAs)have emerged as a promising ...BACKGROUND Gastric carcinoma(GC)is the third most frequent cause of cancer-related death,highlighting the pressing need for novel clinical treatment options.In this regard,microRNAs(miRNAs)have emerged as a promising therapeutic strategy.Studies have shown that miRNAs can regulate related signaling pathways,acting as tumor suppressors or tumor promoters.AIM To explore the effect of miR-204-3p on GC cells.METHODS We measured the expression levels of miR-204-3p in GC cells using quantitative real-time polymerase chain reaction,followed by the delivery of miR-204-3p overexpression and miR-204-3p knockdown vectors into GC cells.CCK-8 was used to detect the effect of miR-204-3p on the proliferation of GC cells,and the colony formation ability of GC cells was detected by the clonal formation assay.The effects of miR-204-3p on GC cell cycle and apoptosis were detected by flow cytometry.The BABL/c nude mouse subcutaneous tumor model using MKN-45 cells was constructed to verify the effect of miR-204-3p on the tumorigenicity of GC cells.Furthermore,the study investigated the effects of miR-204-3p on various proteins related to the MAPK signaling pathway,necroptosis signaling pathway and apoptosis signaling pathway on GC cells using Western blot techniques.RESULTS Firstly,we found that the expression of miR-204-3p in GC was low.When treated with the lentivirus overexpression vector,miR-204-3p expression significantly increased,but the lentivirus knockout vector had no significant effect on miR-204-3p.In vitro experiments confirmed that miR-204-3p overexpression inhibited GC cell viability,promoted cell apoptosis,blocked the cell cycle,and inhibited colony formation ability.In vivo animal experiments confirmed that miR-204-3p overexpression inhibited subcutaneous tumorigenesis ability in BABL/c nude mice.Simultaneously,our results verified that miR-204-3p overexpression can inhibit GC cell proliferation by inhibiting protein expression levels of KRAS and p-ERK1/2 in the MAPK pathway,as well as inhibiting protein expression levels of p-RIP1 and p-MLK1 in the necroptosis pathway to promote the BCL-2/BAX/Caspase-3 apoptosis pathway.CONCLUSION MiR-204-3p overexpression inhibited GC cell proliferation by inhibiting the MAPK pathway and necroptosis pathway to promote apoptosis of GC cells.Thus,miR-204-3p may represent a new potential therapeutic target for GC.展开更多
Objective This study investigated how the natural phytophenol and potent SIRT1 activator resveratrol(RSV)regulate necroptosis during Vibrio vulnificus(V.vulnificus)-induced sepsis and the potential mechanism.Methods T...Objective This study investigated how the natural phytophenol and potent SIRT1 activator resveratrol(RSV)regulate necroptosis during Vibrio vulnificus(V.vulnificus)-induced sepsis and the potential mechanism.Methods The effect of RSV on V.vulnificus cytolysin(VVC)-induced necroptosis was analyzed in vitro using CCK-8 and Western blot assays.Enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reaction,western blot,and immunohistochemistry and survival analyses were performed to elucidate the effect and mechanism of RSV on necroptosis in a V.vulnificus-induced sepsis mouse model.Results RSV relieved necroptosis induced by VVC in RAW264.7 and MLE12 cells.RSV also inhibited the inflammatory response,had a protective effect on histopathological changes,and reduced the expression level of the necroptosis indicator pMLKL in peritoneal macrophages,lung,spleen,and liver tissues of V.vulnificus-induced septic mice in vivo.Pretreatment with RSV downregulated the mRNA of the necroptosis indicator and protein expression in peritoneal macrophages and tissues of V.vulnificusinduced septic mice.RSV also improved the survival of V.vulnificus-induced septic mice.Conclusion Our findings collectively demonstrate that RSV prevented V.vulnificus-induced sepsis by attenuating necroptosis,highlighting its potency in the clinical management of V.vulnificus-induced sepsis.展开更多
Retinal injury after blunt ocular trauma may directly affect prognosis and lead to vision loss.To investigate the pathological changes and molecular mechanisms involved in retinal injury after blunt ocular trauma,we e...Retinal injury after blunt ocular trauma may directly affect prognosis and lead to vision loss.To investigate the pathological changes and molecular mechanisms involved in retinal injury after blunt ocular trauma,we established a weight drop injury model of blunt ocular trauma in male Beagle dogs.Hematoxylin-eosin staining,immunofluorescence staining,western blotting,and TUNEL assays were performed to investigate retinal injury within 14 days after blunt ocular trauma.Compared with the control group,the thicknesses of the inner and outer nuclear layers,as well as the number of retinal ganglion cells,gradually decreased within 14 days after injury.The number of bipolar cells in the inner nuclear layer began to decrease 1 day after injury,while the numbers of cholinergic and amacrine cells in the inner nuclear layer did not decrease until 7 days after injury.Moreover,retinal cell necroptosis increased with time after injury;it progressed from the ganglion cell layer to the outer nuclear layer.Visual electrophysiological findings indicated that visual impairment began on the first day after injury and worsened over time.Additionally,blunt ocular trauma induced nerve regeneration and Müller glial hyperplasia;it also resulted in the recruitment of microglia to the retina and polarization of those microglia to the M1 phenotype.These findings suggest that necroptosis plays an important role in exacerbating retinal injury after blunt ocular trauma via gliosis and neuroinflammation.Such a role has important implications for the development of therapeutic strategies.展开更多
Spinal cord injury(SCI),a complex neurological disorder,triggers a series of devastating neuropathological events such as ischemia,oxidative stress,inflammatory events,neuronal apoptosis,and motor dysfunction.However,...Spinal cord injury(SCI),a complex neurological disorder,triggers a series of devastating neuropathological events such as ischemia,oxidative stress,inflammatory events,neuronal apoptosis,and motor dysfunction.However,the classical necrosome,which consists of receptor-interacting protein(RIP)1,RIP3,and mixed-lineage kinase domain-like protein,is believed to control a novel type of programmed cell death called necroptosis,through tumour necrosis factor-alpha/tumour necrosis factor receptor-1 signalling or other stimuli.Several studies reported that necroptosis plays an important role in neural cell damage,release of intracellular pro-inflammatory factors,lysosomal dysfunction and endoplasmic reticulum stress.Recent research indicates that necroptosis is crucial to the pathophysiology of a number of neurological disorders and SCIs.In our review,we summarize the potential role of programmed cell death regulated by necroptosis in SCI based on its molecular and pathophysiological mechanisms.We also summarize the targets of several necroptosis pathways,which provide a more reliable reference for the treatment of SCI.展开更多
Polo-like kinase 1(PLK1)plays a crucial role in cell mitosis and has been associated with necroptosis.However,the role of PLK1 and necroptosis in lung adenocarcinoma(LA)remains unclear.In this study,we analyzed The Ca...Polo-like kinase 1(PLK1)plays a crucial role in cell mitosis and has been associated with necroptosis.However,the role of PLK1 and necroptosis in lung adenocarcinoma(LA)remains unclear.In this study,we analyzed The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression databases to evaluate the prognostic value and mechanistic role of PLK1 in LA.PLK1 was found to be highly expressed in LA and was positively associated with advanced disease staging and poor survival outcomes.Functional enrichment analysis showed that PLK1 was involved in cell mitosis,neurotransmitter transmission,and drug metabolism.Further analysis using single-sample gene set enrichment analysis and ESTIMATE algorithm revealed a correlation between PLK1 expression and immune infiltration in LA.Silencing of PLK1 using miRNA transfection in LA cells reduced cell proliferation and increased apoptosis,as well as upregulating the expression of necroptosis-related proteins,such as RIPK1,RIPK3,and MLKL.Additionally,nude mouse transplantation tumor experiments demonstrated that silencing PLK1 reduced the growth capacity of LA cells.These findings suggest that PLK1 plays a critical role in LA progression by regulating necroptosis and immune infiltration,and may serve as a potential therapeutic target for immunotherapy.Furthermore,PLK1 expression can be used as a prognostic biomarker for LA patients.展开更多
BACKGROUND Tumor recurrence and metastasis lead to a poor prognosis in colorectal cancer(CRC).Necroptosis is closely related to the tumor microenvironment(TME)and affects tumor recurrence and metastasis.We aimed to st...BACKGROUND Tumor recurrence and metastasis lead to a poor prognosis in colorectal cancer(CRC).Necroptosis is closely related to the tumor microenvironment(TME)and affects tumor recurrence and metastasis.We aimed to stratify CRC patients according to necroptosis-related long noncoding RNAs(lncRNAs),which can be used to not only evaluate prognosis and improve precision medicine in clinical practice but also screen potential immunotherapy drugs.AIM To stratify CRC patients according to necroptosis-related lncRNAs(NRLs),which can be used to not only evaluate prognosis and improve precision medicine in clinical practice but also screen potential immunotherapy drugs.METHODS LncRNA expression profiles were collected from The Cancer Genome Atlas.NRLs were identified by coexpression analysis.Cox regression analysis identified a NRL signature.Then,the value of this signature was comprehensively and multidimensionally evaluated,and its reliability for CRC prognosis prediction was assessed with clinical CRC data and compared with that of six other lncRNA were also performed according to the risk score(RS)of the signature.RESULTS An 8-lncRNA signature significantly associated with overall survival(OS)was constructed,and its reliability was validated with clinical CRC data.Most of the areas under the receiver operating characteristic curves(AUCs)values for 1-,3-and 5-year OS for this signature were higher than those for the other six lncRNA signatures.OS,disease-specific survival and the progression-free interval were all significantly poorer in the high-risk group.The RS of the signature showed good concordance with the predicted prognosis,with AUCs for 1-,3-and 5-year OS of 0.79,0.81 and 0.77,respectively.Additionally,the calibration plots for this signature combined with clinical factors showed that this combination could effectively improve the ability to predict OS.The RS was correlated with tumor stage,lymph node metastasis and distant metastasis.Most of the enriched Kyoto Encyclopedia of Genes and Genomes and Gene Ontology terms were tumor metastasis-related pathways in the high-risk group;these patients showed greater infiltration of immunosuppressive cells,such as cancer-associated fibroblasts,hematopoietic stem cells and M2 macrophages,but less infiltration of infiltrating antitumor effector immune cells,such as cluster of differentiation 8+T cells and regulatory T cells(Tregs).We explored additional potential immune checkpoint genes and potential immunotherapeutic and chemotherapeutic drugs with relatively low IC_(50) values.CONCLUSION We identified an NRL signature with strong fidelity that could stably predict prognosis and might be an indicator of the TME of CRC.Furthermore,additional potential immunotherapeutic and chemotherapeutic drugs were explored.展开更多
Knee osteoarthritis,as a chronic disabling disease,not only brings trouble to the patients,but also brings great psychological and economic burden to their families.Although there are various treatment methods,the cur...Knee osteoarthritis,as a chronic disabling disease,not only brings trouble to the patients,but also brings great psychological and economic burden to their families.Although there are various treatment methods,the curative effect is not good,mainly relieving symptoms,and cannot intervene the disease progression.Necroptosis and ferroptosis are two new pathways of programmed cell death discovered in recent years,they play a key role in the occurrence and development of knee osteoarthritis and also provide a new opportunity for the prevention and treatment of knee osteoarthritis.This article reviews necroptosis and ferroptosis and their related studies in knee osteoarthritis.展开更多
Objective:To analyze the basis and medication rules of Chinese herbs in the regulation of necroptosis.Methods:With the help of GeneCards,DrugBank,TTD,DisGeNET,OMIM database to collect the action targets of necroptosis...Objective:To analyze the basis and medication rules of Chinese herbs in the regulation of necroptosis.Methods:With the help of GeneCards,DrugBank,TTD,DisGeNET,OMIM database to collect the action targets of necroptosis,the TCMSP database to obtain the target‑related compounds and Chinese herbs,and the ADME criteria and Lipinski rule as the conditions for screening,to build the target‑compound,target‑compound‑Chinese herbs network.The information of Chinese herbal medicine's sexual taste and meridian was collected,and the drug use pattern was analyzed.The information on the property,flavor and channel tropism of Chinese herbs was collected to analyze the medication laws.Molecular docking of core targets and compounds in the network with AutoDockTools software,and PyMOL software was used to display the combinations with good docking results.Results:A total of 12 potential targets acting on necroptosis were obtained,matching to 191 candidate compounds and 366 herbal medicines.Quercetin,wogonin,triptolide,licochalcone a,ellipticine are more important and may be the main small molecule substances underlying the regulation of necroptosis.The more important Chinese herbs are Licorice,Forsythia,Salivae Miltiorrhizae,Ginkgo Leaf,Eucommia ulmoides Oliv,etc.The herbal medicines are mainly bitter and pungent,with cold and warm taste,which were attributed to the liver and lung meridians.BCL2‑beta‑sitosterol、MAPK14‑luteolin、MAPK14‑formononetin、TP53‑formononetin are better molecular docking results,which have strong docking activity.Conclusion:The study systematically analyzes the material basis of regulating necroptosis and summarizes the general rule of regulating necroptosis in Chinese medicine,which provides ideas for clinical development of agents to interfere with necroptosis.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
目的:探讨活性氧自由基(ROS)在肾小管上皮细胞necroptosis中的作用。方法:构建肾小管上皮细胞HK-2细胞necroptosis模型,检测其ROS升高程度。并使用NADPH酶抑制剂Apocynin抑制HK-2细胞necroptosis模型中ROS的生成,通过流式细胞计数及检测...目的:探讨活性氧自由基(ROS)在肾小管上皮细胞necroptosis中的作用。方法:构建肾小管上皮细胞HK-2细胞necroptosis模型,检测其ROS升高程度。并使用NADPH酶抑制剂Apocynin抑制HK-2细胞necroptosis模型中ROS的生成,通过流式细胞计数及检测necroptosis的关键蛋白观察HK-2细胞necroptosis的变化。结果:使用肿瘤坏死因子α、苄氧羰酰-缬氨酰-丙氨酰-天冬氨酰-氟甲基酮及抗霉素A成功建立了HK-2细胞necroptosis模型,并观察到HK-2细胞发生necroptosis时ROS显著升高(43.29±2.49 vs 25.90±1.27,P<0.001),而使用necrostatin-1抑制necroptosis后ROS生成受到抑制(35.58±1.08 vs 43.29±2.49,P=0.002)。当对necroptosis模型使用Apocynin干预时,HK-2细胞ROS明显下降(30.71±2.82 vs 43.29±2.49,P<0.001),并且流式细胞计数结果显示坏死细胞比例减少(2.00%±0.30%vs 6.99%±2.79%,P<0.001),同时受体相关蛋白3和混合系列蛋白激酶样结构域的磷酸化水平降低。结论:ROS参与了HK-2细胞的necroptosis,并且通过抑制ROS的生成可减少necroptosis发生,提高损伤状态下HK-2细胞存活率,减轻急性肾小管坏死。展开更多
基金supported by the National Natural Science Foundation of China,No.82101461(to ZL)。
文摘Central nervous system injuries have a high rate of resulting in disability and mortality;however,at present,effective treatments are lacking.Programmed cell death,which is a genetically determined fo rm of active and ordered cell death with many types,has recently attra cted increasing attention due to its functions in determining the fate of cell survival.A growing number of studies have suggested that programmed cell death is involved in central nervous system injuries and plays an important role in the progression of brain damage.In this review,we provide an ove rview of the role of programmed cell death in central nervous system injuries,including the pathways involved in mitophagy,pyroptosis,ferroptosis,and necroptosis,and the underlying mechanisms by which mitophagy regulates pyroptosis,ferroptosis,and necro ptosis.We also discuss the new direction of therapeutic strategies to rgeting mitophagy for the treatment of central nervous system injuries,with the aim to determine the connection between programmed cell death and central nervous system injuries and to identify new therapies to modulate programmed cell death following central nervous system injury.In conclusion,based on these properties and effects,interventions targeting programmed cell death could be developed as potential therapeutic agents for central nervous system injury patients.
基金Supported by the Natural Science Foundation of Liaoning Province,No.2022-MS-330and Key Projects in Liaoning Province,No.2020JH2/10300046.
文摘BACKGROUND Necroptosis has emerged as a novel molecular pathway that can be targeted by chemotherapy agents in the treatment of cancer.OSW-1,which is derived from the bulbs of Ornithogalum saundersiae Baker,exerts a wide range of pharmaco-logical effects.AIM To explore whether OSW-1 can induce necroptosis in colorectal cancer(CRC)cells,thereby expanding its range of clinical applications.METHODS We performed a sequence of functional experiments,including Cell Counting Kit-8 assays and flow cytometry analysis,to assess the inhibitory effect of OSW-1 on CRC cells.We utilized quantitative proteomics,employing tandem mass tag label-ing combined with liquid chromatography-tandem mass spectrometry,to analyze changes in protein expression.Subsequent bioinformatic analysis was conducted to elucidate the biological processes associated with the identified proteins.Transmission electron microscopy(TEM)and immunofluorescence studies were also performed to examine the effects of OSW-1 on necroptosis.Finally,western blotting,siRNA experiments,and immunoprecipitation were employed to evaluate protein interactions within CRC cells.RESULTS The results revealed that OSW-1 exerted a strong inhibitory effect on CRC cells,and this effect was accompanied by a necroptosis-like morphology that was observable via TEM.OSW-1 was shown to trigger necroptosis via activation of the RIPK1/RIPK3/MLKL pathway.Furthermore,the accumulation of p62/SQSTM1 was shown to mediate OSW-1-induced necroptosis through its interaction with RIPK1.CONCLUSION We propose that OSW-1 can induce necroptosis through the RIPK1/RIPK3/MLKL signaling pathway,and that this effect is mediated by the RIPK1-p62/SQSTM1 complex,in CRC cells.These results provide a theoretical foundation for the use of OSW-1 in the clinical treatment of CRC.
文摘Nonalcoholic fatty liver disease(NAFLD)is the most prevalent type of chronic liver disease.However,the disease is underappreciated as a remarkable chronic disorder as there are rare managing strategies.Several studies have focused on determining NAFLD-caused hepatocyte death to elucidate the disease pathoe-tiology and suggest functional therapeutic and diagnostic options.Pyroptosis,ferroptosis,and necroptosis are the main subtypes of non-apoptotic regulated cell deaths(RCDs),each of which represents particular characteristics.Considering the complexity of the findings,the present study aimed to review these types of RCDs and their contribution to NAFLD progression,and subsequently discuss in detail the role of necroptosis in the pathoetiology,diagnosis,and treatment of the disease.The study revealed that necroptosis is involved in the occurrence of NAFLD and its progression towards steatohepatitis and cancer,hence it has potential in diagnostic and therapeutic approaches.Nevertheless,further studies are necessary.
基金Supported by Innovation Project of Guangxi Graduate Education(YCSW2023432).
文摘Digestive system diseases refer to organic and functional disorders of the digestive system,which are prone to recurrence and frequently accompanied by multiple complications.Necroptosis is a regulated mode of cell death mediated by death receptors,dependent on receptor protein activation,and could be specifically inhibited by necrostatin-1.Necroptosis is involved in pathological and physiological processes of various diseases,and plays an important role in the growth and development of organisms and the homeostasis of organ tissues.This paper reviewed the research advancement of necroptosis in digestive system disorders,and discussed the relationship between necroptosis and digestive system diseases,aiming to provide theoretical basis for the cure of these diseases.
基金provided by National Key R&D Program of China(2022YFD1300403)National Natural Science Foundation of China(No.U22A20517,32272906,and 31802070)Wuhan Science and Technology Bureau(No.2022020801010391)。
文摘Background:Necroptosis and pyroptosis are newly identified forms of programmed cell death,which play a vital role in development of many gastrointestinal disorders.Although plant polyphenols have been reported to protect intestinal health,it is still unclear whether there is a beneficial role of plant polyphenols in modulating necroptosis and pyroptosis in intestinal porcine epithelial cell line(IPEC-1)infected with enterotoxigenic Escherichia coli(ETEC)K88.This research was conducted to explore whether plant polyphenols including protocatechuic acid(PCA)and quercetin(Que),attenuated inflammation and injury of IPEC-1 caused by ETEC K88 through regulating necroptosis and pyroptosis signaling pathways.Methods:IPEC-1 cells were treated with PCA(40μmol/L)or Que(10μmol/L)in the presence or absence of ETEC K88.Results:PCA and Que decreased ETEC K88 adhesion and endotoxin level(P<0.05)in cell supernatant.PCA and Que increased cell number(P<0.001)and decreased lactate dehydrogenases(LDH)activity(P<0.05)in cell supernatant after ETEC infection.PCA and Que improved transepithelial electrical resistance(TEER)(P<0.001)and reduced fluorescein isothiocyanate-labeled dextran(FD4)flux(P<0.001),and enhanced membrane protein abundance of occludin,claudin-1 and ZO-1(P<0.05),and rescued distribution of these tight junction proteins(P<0.05)after ETEC infection.PCA and Que also declined cell necrosis ratio(P<0.05).PCA and Que reduced mRNA abundance and concentration of tumor necrosis factor-α(TNF-α),interleukin(IL)-6 and IL-8(P<0.001),and down-regulated gene expression of toll-like receptors 4(TLR4)and its downstream signals(P<0.001)after ETEC infection.PCA and Que down-regulated protein abundance of total receptor interacting protein kinase 1(t-RIP1),phosphorylated-RIP1(p-RIP1),p-RIP1/t-RIP1,t-RIP3,p-RIP3,mixed lineage kinase domain-like protein(MLKL),p-MLKL,dynamin-related protein 1(DRP1),phosphoglycerate mutase 5(PGAM5)and high mobility group box 1(HMGB1)(P<0.05)after ETEC infection.Moreover,PCA and Que reduced protein abundance of nod-like receptor protein 3(NLRP3),nod-like receptors family CARD domain-containing protein 4(NLRC4),apoptosis-associated speck-like protein containing a CARD(ASC),gasdermin D(GSDMD)and caspase-1(P<0.05)after ETEC infection.Conclusions:In general,our data suggest that PCA and Que are capable of attenuating ETEC-caused intestinal inflammation and damage via inhibiting necroptosis and pyroptosis signaling pathways.
文摘BACKGROUND Gastric carcinoma(GC)is the third most frequent cause of cancer-related death,highlighting the pressing need for novel clinical treatment options.In this regard,microRNAs(miRNAs)have emerged as a promising therapeutic strategy.Studies have shown that miRNAs can regulate related signaling pathways,acting as tumor suppressors or tumor promoters.AIM To explore the effect of miR-204-3p on GC cells.METHODS We measured the expression levels of miR-204-3p in GC cells using quantitative real-time polymerase chain reaction,followed by the delivery of miR-204-3p overexpression and miR-204-3p knockdown vectors into GC cells.CCK-8 was used to detect the effect of miR-204-3p on the proliferation of GC cells,and the colony formation ability of GC cells was detected by the clonal formation assay.The effects of miR-204-3p on GC cell cycle and apoptosis were detected by flow cytometry.The BABL/c nude mouse subcutaneous tumor model using MKN-45 cells was constructed to verify the effect of miR-204-3p on the tumorigenicity of GC cells.Furthermore,the study investigated the effects of miR-204-3p on various proteins related to the MAPK signaling pathway,necroptosis signaling pathway and apoptosis signaling pathway on GC cells using Western blot techniques.RESULTS Firstly,we found that the expression of miR-204-3p in GC was low.When treated with the lentivirus overexpression vector,miR-204-3p expression significantly increased,but the lentivirus knockout vector had no significant effect on miR-204-3p.In vitro experiments confirmed that miR-204-3p overexpression inhibited GC cell viability,promoted cell apoptosis,blocked the cell cycle,and inhibited colony formation ability.In vivo animal experiments confirmed that miR-204-3p overexpression inhibited subcutaneous tumorigenesis ability in BABL/c nude mice.Simultaneously,our results verified that miR-204-3p overexpression can inhibit GC cell proliferation by inhibiting protein expression levels of KRAS and p-ERK1/2 in the MAPK pathway,as well as inhibiting protein expression levels of p-RIP1 and p-MLK1 in the necroptosis pathway to promote the BCL-2/BAX/Caspase-3 apoptosis pathway.CONCLUSION MiR-204-3p overexpression inhibited GC cell proliferation by inhibiting the MAPK pathway and necroptosis pathway to promote apoptosis of GC cells.Thus,miR-204-3p may represent a new potential therapeutic target for GC.
基金supported by the Beijing Municipal Natural Science Foundation[7204314]the Medical Innovation Project Foundation[CX19027]the Young Researcher Supporting Program[QNF19066]of the Chinese PLA General Hospital.
文摘Objective This study investigated how the natural phytophenol and potent SIRT1 activator resveratrol(RSV)regulate necroptosis during Vibrio vulnificus(V.vulnificus)-induced sepsis and the potential mechanism.Methods The effect of RSV on V.vulnificus cytolysin(VVC)-induced necroptosis was analyzed in vitro using CCK-8 and Western blot assays.Enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reaction,western blot,and immunohistochemistry and survival analyses were performed to elucidate the effect and mechanism of RSV on necroptosis in a V.vulnificus-induced sepsis mouse model.Results RSV relieved necroptosis induced by VVC in RAW264.7 and MLE12 cells.RSV also inhibited the inflammatory response,had a protective effect on histopathological changes,and reduced the expression level of the necroptosis indicator pMLKL in peritoneal macrophages,lung,spleen,and liver tissues of V.vulnificus-induced septic mice in vivo.Pretreatment with RSV downregulated the mRNA of the necroptosis indicator and protein expression in peritoneal macrophages and tissues of V.vulnificusinduced septic mice.RSV also improved the survival of V.vulnificus-induced septic mice.Conclusion Our findings collectively demonstrate that RSV prevented V.vulnificus-induced sepsis by attenuating necroptosis,highlighting its potency in the clinical management of V.vulnificus-induced sepsis.
基金supported by the National Natural Science Foundation of China,No.81600738the Youth Development Project of Air Force Medical University,No.21QNPY072(both to FF)。
文摘Retinal injury after blunt ocular trauma may directly affect prognosis and lead to vision loss.To investigate the pathological changes and molecular mechanisms involved in retinal injury after blunt ocular trauma,we established a weight drop injury model of blunt ocular trauma in male Beagle dogs.Hematoxylin-eosin staining,immunofluorescence staining,western blotting,and TUNEL assays were performed to investigate retinal injury within 14 days after blunt ocular trauma.Compared with the control group,the thicknesses of the inner and outer nuclear layers,as well as the number of retinal ganglion cells,gradually decreased within 14 days after injury.The number of bipolar cells in the inner nuclear layer began to decrease 1 day after injury,while the numbers of cholinergic and amacrine cells in the inner nuclear layer did not decrease until 7 days after injury.Moreover,retinal cell necroptosis increased with time after injury;it progressed from the ganglion cell layer to the outer nuclear layer.Visual electrophysiological findings indicated that visual impairment began on the first day after injury and worsened over time.Additionally,blunt ocular trauma induced nerve regeneration and Müller glial hyperplasia;it also resulted in the recruitment of microglia to the retina and polarization of those microglia to the M1 phenotype.These findings suggest that necroptosis plays an important role in exacerbating retinal injury after blunt ocular trauma via gliosis and neuroinflammation.Such a role has important implications for the development of therapeutic strategies.
基金supported by the National Natural Science Foundation of China(Grant Nos.81771319,82202436)the Medical Research Project of Jiangsu Commission of Health(Grant No.ZDB2020004)+1 种基金the Scientific Research Project of Nantong Municipal Health Commission(Grant No.MA2021016)The First People’s Hospital of Nantong Provincial and Ministerial High-Level Science and Technology Project Cultivation Fund(Grant No.YPYJJZD009).
文摘Spinal cord injury(SCI),a complex neurological disorder,triggers a series of devastating neuropathological events such as ischemia,oxidative stress,inflammatory events,neuronal apoptosis,and motor dysfunction.However,the classical necrosome,which consists of receptor-interacting protein(RIP)1,RIP3,and mixed-lineage kinase domain-like protein,is believed to control a novel type of programmed cell death called necroptosis,through tumour necrosis factor-alpha/tumour necrosis factor receptor-1 signalling or other stimuli.Several studies reported that necroptosis plays an important role in neural cell damage,release of intracellular pro-inflammatory factors,lysosomal dysfunction and endoplasmic reticulum stress.Recent research indicates that necroptosis is crucial to the pathophysiology of a number of neurological disorders and SCIs.In our review,we summarize the potential role of programmed cell death regulated by necroptosis in SCI based on its molecular and pathophysiological mechanisms.We also summarize the targets of several necroptosis pathways,which provide a more reliable reference for the treatment of SCI.
基金supported by the Natural Science Research Project of Colleges and Universities in Anhui Province(KJ2021A0557)the grants from the Opening Project of Zhejiang Provincial Preponderant and Characteristic Subject of Key University(Chinese Traditional Medicine)(ZYXZD2019004)+2 种基金Zhejiang Chinese Medical Universitythe National Natural Science Foundation of China(ZYXZD81973643)Zhejiang Chinese Medicine Science and Technology Project(No.2023ZL467).
文摘Polo-like kinase 1(PLK1)plays a crucial role in cell mitosis and has been associated with necroptosis.However,the role of PLK1 and necroptosis in lung adenocarcinoma(LA)remains unclear.In this study,we analyzed The Cancer Genome Atlas(TCGA)and Genotype-Tissue Expression databases to evaluate the prognostic value and mechanistic role of PLK1 in LA.PLK1 was found to be highly expressed in LA and was positively associated with advanced disease staging and poor survival outcomes.Functional enrichment analysis showed that PLK1 was involved in cell mitosis,neurotransmitter transmission,and drug metabolism.Further analysis using single-sample gene set enrichment analysis and ESTIMATE algorithm revealed a correlation between PLK1 expression and immune infiltration in LA.Silencing of PLK1 using miRNA transfection in LA cells reduced cell proliferation and increased apoptosis,as well as upregulating the expression of necroptosis-related proteins,such as RIPK1,RIPK3,and MLKL.Additionally,nude mouse transplantation tumor experiments demonstrated that silencing PLK1 reduced the growth capacity of LA cells.These findings suggest that PLK1 plays a critical role in LA progression by regulating necroptosis and immune infiltration,and may serve as a potential therapeutic target for immunotherapy.Furthermore,PLK1 expression can be used as a prognostic biomarker for LA patients.
基金Supported by the Joint Funds for the Innovation of Science and Technology,Fujian Province,No.2019Y9133.
文摘BACKGROUND Tumor recurrence and metastasis lead to a poor prognosis in colorectal cancer(CRC).Necroptosis is closely related to the tumor microenvironment(TME)and affects tumor recurrence and metastasis.We aimed to stratify CRC patients according to necroptosis-related long noncoding RNAs(lncRNAs),which can be used to not only evaluate prognosis and improve precision medicine in clinical practice but also screen potential immunotherapy drugs.AIM To stratify CRC patients according to necroptosis-related lncRNAs(NRLs),which can be used to not only evaluate prognosis and improve precision medicine in clinical practice but also screen potential immunotherapy drugs.METHODS LncRNA expression profiles were collected from The Cancer Genome Atlas.NRLs were identified by coexpression analysis.Cox regression analysis identified a NRL signature.Then,the value of this signature was comprehensively and multidimensionally evaluated,and its reliability for CRC prognosis prediction was assessed with clinical CRC data and compared with that of six other lncRNA were also performed according to the risk score(RS)of the signature.RESULTS An 8-lncRNA signature significantly associated with overall survival(OS)was constructed,and its reliability was validated with clinical CRC data.Most of the areas under the receiver operating characteristic curves(AUCs)values for 1-,3-and 5-year OS for this signature were higher than those for the other six lncRNA signatures.OS,disease-specific survival and the progression-free interval were all significantly poorer in the high-risk group.The RS of the signature showed good concordance with the predicted prognosis,with AUCs for 1-,3-and 5-year OS of 0.79,0.81 and 0.77,respectively.Additionally,the calibration plots for this signature combined with clinical factors showed that this combination could effectively improve the ability to predict OS.The RS was correlated with tumor stage,lymph node metastasis and distant metastasis.Most of the enriched Kyoto Encyclopedia of Genes and Genomes and Gene Ontology terms were tumor metastasis-related pathways in the high-risk group;these patients showed greater infiltration of immunosuppressive cells,such as cancer-associated fibroblasts,hematopoietic stem cells and M2 macrophages,but less infiltration of infiltrating antitumor effector immune cells,such as cluster of differentiation 8+T cells and regulatory T cells(Tregs).We explored additional potential immune checkpoint genes and potential immunotherapeutic and chemotherapeutic drugs with relatively low IC_(50) values.CONCLUSION We identified an NRL signature with strong fidelity that could stably predict prognosis and might be an indicator of the TME of CRC.Furthermore,additional potential immunotherapeutic and chemotherapeutic drugs were explored.
基金National Natural Science Foundation Regional Fund Project (No.82160912)。
文摘Knee osteoarthritis,as a chronic disabling disease,not only brings trouble to the patients,but also brings great psychological and economic burden to their families.Although there are various treatment methods,the curative effect is not good,mainly relieving symptoms,and cannot intervene the disease progression.Necroptosis and ferroptosis are two new pathways of programmed cell death discovered in recent years,they play a key role in the occurrence and development of knee osteoarthritis and also provide a new opportunity for the prevention and treatment of knee osteoarthritis.This article reviews necroptosis and ferroptosis and their related studies in knee osteoarthritis.
基金National Natural Science Foundation Project(No.82174415)Science and Technology Innovation Project of the China Academy of Chinese Medical Sciences(No.CI2021A05054)Science and Technology Innovation Project of the China Academy of Chinese Medical Sciences(No.CI2021A01818)。
文摘Objective:To analyze the basis and medication rules of Chinese herbs in the regulation of necroptosis.Methods:With the help of GeneCards,DrugBank,TTD,DisGeNET,OMIM database to collect the action targets of necroptosis,the TCMSP database to obtain the target‑related compounds and Chinese herbs,and the ADME criteria and Lipinski rule as the conditions for screening,to build the target‑compound,target‑compound‑Chinese herbs network.The information of Chinese herbal medicine's sexual taste and meridian was collected,and the drug use pattern was analyzed.The information on the property,flavor and channel tropism of Chinese herbs was collected to analyze the medication laws.Molecular docking of core targets and compounds in the network with AutoDockTools software,and PyMOL software was used to display the combinations with good docking results.Results:A total of 12 potential targets acting on necroptosis were obtained,matching to 191 candidate compounds and 366 herbal medicines.Quercetin,wogonin,triptolide,licochalcone a,ellipticine are more important and may be the main small molecule substances underlying the regulation of necroptosis.The more important Chinese herbs are Licorice,Forsythia,Salivae Miltiorrhizae,Ginkgo Leaf,Eucommia ulmoides Oliv,etc.The herbal medicines are mainly bitter and pungent,with cold and warm taste,which were attributed to the liver and lung meridians.BCL2‑beta‑sitosterol、MAPK14‑luteolin、MAPK14‑formononetin、TP53‑formononetin are better molecular docking results,which have strong docking activity.Conclusion:The study systematically analyzes the material basis of regulating necroptosis and summarizes the general rule of regulating necroptosis in Chinese medicine,which provides ideas for clinical development of agents to interfere with necroptosis.
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.
文摘目的:探讨活性氧自由基(ROS)在肾小管上皮细胞necroptosis中的作用。方法:构建肾小管上皮细胞HK-2细胞necroptosis模型,检测其ROS升高程度。并使用NADPH酶抑制剂Apocynin抑制HK-2细胞necroptosis模型中ROS的生成,通过流式细胞计数及检测necroptosis的关键蛋白观察HK-2细胞necroptosis的变化。结果:使用肿瘤坏死因子α、苄氧羰酰-缬氨酰-丙氨酰-天冬氨酰-氟甲基酮及抗霉素A成功建立了HK-2细胞necroptosis模型,并观察到HK-2细胞发生necroptosis时ROS显著升高(43.29±2.49 vs 25.90±1.27,P<0.001),而使用necrostatin-1抑制necroptosis后ROS生成受到抑制(35.58±1.08 vs 43.29±2.49,P=0.002)。当对necroptosis模型使用Apocynin干预时,HK-2细胞ROS明显下降(30.71±2.82 vs 43.29±2.49,P<0.001),并且流式细胞计数结果显示坏死细胞比例减少(2.00%±0.30%vs 6.99%±2.79%,P<0.001),同时受体相关蛋白3和混合系列蛋白激酶样结构域的磷酸化水平降低。结论:ROS参与了HK-2细胞的necroptosis,并且通过抑制ROS的生成可减少necroptosis发生,提高损伤状态下HK-2细胞存活率,减轻急性肾小管坏死。
