Ovarian cancer(OC),a common malignancy of the female reproductive system,has the highest mortality rate among gynecological cancers.A distinguishing feature of OC cells(OCCs)is their reduced autophagic flux compared w...Ovarian cancer(OC),a common malignancy of the female reproductive system,has the highest mortality rate among gynecological cancers.A distinguishing feature of OC cells(OCCs)is their reduced autophagic flux compared with normal cells.This phenomenon indicates that excessive autophagy activation or impaired autophagosome–lysosome fusion may lead to OCC death.This study investigated the anti-OC effects of dihydrotanshinone I(DHT),a tanshinone compound from Salvia miltiorrhiza.Proteomic analysis suggested that DHT suppressed OC growth via the autophagy–lysosome pathway,with sortilin 1(SORT1)identified as a critical target.In vitro,DHT promoted autophagosome formation mediated by microtubule-associated protein 1 light chain 3-II(LC3-II),while inhibiting autophagosome–lysosome fusion.The results of an orthotopic OC model corroborated these findings,showing that DHT induced autophagic cell death(ACD)and suppressed SORT1 expression in tumors.Further RNA interference experiments confirmed that SORT1 depletion caused autophagosomes to accumulate in OCCs.Notably,we found that SORT1 interacted with autophagy-related gene(ATG)-encoded proteins ATG5 and ATG16L1,and that depleting SORT1 increased the levels of these proteins.Co-immunoprecipitation,ubiquitination,and cellular thermal shift assay analyses revealed that DHT directly targeted and promoted ubiquitin-dependent degradation of SORT1.By degrading SORT1,ATG5 and ATG16L1 were released,which enhanced autophagosome formation and disrupted the autophagic flux.These findings identified DHT as a novel autophagosome inducer that induced ACD by targeting SORT1,making it a promising therapeutic candidate for OC.展开更多
Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord inj...Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord injury mainly relies on pharmacological and surgical interventions;however,significant challenges remain in the protection and repair of neural tissues.Autophagy,an intracellular process responsible for the degradation and recycling of macromolecular components,plays a vital role in spinal cord injury,alleviating the severity of injury by inhibiting cell apoptosis and inflammatory responses.In this review,we provide an overview of the physiological mechanisms underlying autophagy and spinal cord injury and detail the crosstalk between autophagy and other modes of cell death in spinal cord injury.In addition,we discuss the potential of targeting autophagy as a therapeutic strategy for spinal cord injury through approaches that focus on promoting or inhibiting this process,targeting specific autophagic substrates or pathways,and combining autophagy modulation with other neuroprotective or restorative interventions.In summary,this review proposes that strict regulation of autophagy may represent a viable strategy for the treatment of spinal cord injury.展开更多
Epigallocatechin-3-gallate(EGCG), a major polyphenolic compound in green tea, exhibits antiviral activity against multiple viruses, including hepatitis B virus(HBV). However, its role in HBV replication and the underl...Epigallocatechin-3-gallate(EGCG), a major polyphenolic compound in green tea, exhibits antiviral activity against multiple viruses, including hepatitis B virus(HBV). However, its role in HBV replication and the underlying mechanisms remain incompletely understood. In this study, we investigated the effects of EGCG on HBV replication and its modulation of autophagy using two established HBV cell models. Our results show that EGCG significantly reduces secreted levels of hepatitis B surface antigen(HBsAg) and HBV deoxyribonucleic acid(DNA), as well as intracellular HBV DNA replicative intermediates, encapsidated pregenomic ribonucleic acid(pgRNA), and core protein(HBc), without affecting total HBV messenger RNAs(mRNAs) or pgRNA levels. EGCG enhances autophagic flux, evidenced by increased autophagosome formation and accelerated turnover of the selective autophagy receptor p62 and LC3-Ⅱ. This enhanced autophagy promotes HBc degradation. Pharmacological inhibition of autophagy with 3-methyladenine(3-MA), chloroquine(CQ), or bafilomycin A1(BafA1) abolished the suppressive effect of EGCG on HBV. Notably, treatment with CQ or BafA1 together with EGCG markedly increased HBV production by blocking autophagic degradation and inducing accumulation of autophagosomes—effects similar to those induced by the autophagy activator rapamycin, which facilitates HBV replication. Mechanistically, EGCG activates the adenosine 5'-monophosphate-activated protein kinase(AMPK)/transcription factor EB(TFEB)signaling axis, leading to enhanced lysosomal biogenesis and ATP production, thereby promoting autophagic clearance. Pharmacological or genetic inhibition of AMPK attenuated TFEB transcriptional activity, suppressed lysosomal biogenesis and ATP generation, impaired autophagic degradation, increased HBc levels, and ultimately enhanced HBV replication. Conversely, pharmacological activation of AMPK produced opposing effects. These findings reveal a novel mechanism by which EGCG inhibits HBV: EGCG promotes autophagic degradation of the viral core protein via activation of the AMPK/TFEB signaling pathway.展开更多
Background Environmental hypoxia is a common phenomenon in aquaculture,which causes gill tissue injury in fish.Glutathione(GSH)is a vital antioxidant in animal tissues,and its levels decrease under hypoxic conditions....Background Environmental hypoxia is a common phenomenon in aquaculture,which causes gill tissue injury in fish.Glutathione(GSH)is a vital antioxidant in animal tissues,and its levels decrease under hypoxic conditions.However,the effects of glutathione on fish under hypoxic stress remain poorly understood.This study aimed to investigate the impact of glutathione on gill tissue damage in fish under hypoxic stress and explore the underlying mechanisms.Methods Six experimental diets with varying glutathione concentrations.The actual glutathione levels in these diets,measured by high-performance liquid chromatography,were 0.00,145.95,291.90,437.85,583.80,and 729.75 mg/kg,respectively.Fish were fed these diets for 70 d,after which a 96-h hypoxic stress experiment was conducted.The experiment was set up with normoxic and hypoxic groups,in which the dissolved oxygen in the group was 6 mg/L,and that in the group was 1 mg/L.Results This research revealed that glutathione could enhance the growth performance and antioxidant capability of juvenile grass carp while mitigating the structural damage to gill tissues induced by hypoxia stress.Mechanistic investigations further indicated that glutathione mitigated hypoxia-induced oxidative injury in gill tissues and improved their antioxidant capacity.In addition,glutathione attenuated gill apoptosis induced by hypoxia stress.Glutathione also inhibited the initiation,nucleation,elongation,and degradation phases of autophagy,thereby attenuating hypoxia-induced gill autophagy.Moreover,glutathione was found to alleviate hypoxia-induced endoplasmic reticulum stress(ERS)in gills,a response potentially linked to the suppression of PERK,IRE1,and ATF6 signaling pathways.Finally,based on the ROS and PC contents in gill tissue,the optimum glutathione supplementation levels for juvenile grass carp under hypoxia stress were 437.10 and 495.00 mg/kg,respectively.Conclusions In conclusion,our experimental results demonstrated the effectiveness of glutathione in alleviating gill tissue damage caused by hypoxic stress.This study confirms the feasibility and effectiveness of dietary glutathione addition to alleviate hypoxic stress in fish.展开更多
Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance...Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.展开更多
Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that M...Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that Moutan Cortex terpene glycoside(MCTG)improved diabetic kidney disease(DKD)by targeting sirtuin 1(SIRT1)mediated autophagy pathway.Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells(HUVECs)to delineate how MCTG operated in the treatment of DKD.Furthermore,network pharmacology was used to identify the primary metabolic pathways affected by MCTG,with key targets being confirmed through polymerase chain reaction(PCR),Western blot,Transmission electron microscope,immunofluorescence staining and monodansylcadaverine(MDC)staining.Finally,small interfering RNA transfection testified SIRT1 in advanced glycation end-products(AGEs)-induced HUVECs injury.MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators.Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex,and the main targets were verified by PCR and protein experiments.Based on these results,we found that Moutan Cortex could improve DKD and SIRT1 was a potential target.Furthermore,knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 II/I(LC3 II/I)in HUVECs.In summary,this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.展开更多
Background:Parkinson’s disease(PD)is one of the most common movement disorders worldwide.Ziyin Xifeng Decoction(ZYXFD),a traditional Chinese medicine compound formula,has shown therapeutic efficacy in treating PD,but...Background:Parkinson’s disease(PD)is one of the most common movement disorders worldwide.Ziyin Xifeng Decoction(ZYXFD),a traditional Chinese medicine compound formula,has shown therapeutic efficacy in treating PD,but its specific mechanisms of action have not been fully elucidated.Methods:Firstly,we employed network pharmacology and untargeted metabolomics analysis to identify the core targets,pathways,and key metabolites of ZYXFD in the treatment of PD.Subsequently,we evaluated the protective effects of ZYXFD and further investigated its anti-PD mechanisms by validating the analytical results.Results:Combined analyses of network pharmacology and metabolomics identify the core targets including EGFR,SRC,PTGS2,and CDK2,while the effects of ZYXFD against PD are likely mediated primarily through the PI3K/AKT/mTOR signaling pathway.Pharmacodynamic evaluation demonstrated that a high dose of ZYXFD significantly improved behavioral deficits in chronic PD mice,downregulatedα-synuclein protein expression,and protected dopaminergic neurons.It also regulated the expression of core targets,inhibited the PI3K/AKT/mTOR signaling pathway,promoted autophagy,and reduced apoptosis.In vitro experiments further verified that the therapeutic effect of ZYXFD on PD is dependent on autophagy regulation.Conclusion:The findings demonstrated that ZYXFD alleviates PD by modulating related proteins and metabolites,inhibiting the PI3K/AKT/mTOR signaling pathway,and enhancing autophagy.This provides a theoretical basis for its broader application in PD treatment.展开更多
Objective:To assess the antitumor activity of the novel chitinase produced by fermented,isolated Trichoderma viride in a hepatocellular carcinoma(HCC)male rat model.Methods:Diethyl-nitrosamine induction combined with ...Objective:To assess the antitumor activity of the novel chitinase produced by fermented,isolated Trichoderma viride in a hepatocellular carcinoma(HCC)male rat model.Methods:Diethyl-nitrosamine induction combined with ionizing radiation exposure was used to establish the HCC rat model.All rats were divided into 4 groups:the control group,the chitinase group,the HCC group,and the HCC+chitinase group.The antiproliferative effect of chitinase was evaluated in human HCC cells.The effect of chitinase in vivo on oxidative stress,endoplasmic reticulum stress chaperones,autophagy markers,PI3K/AKT/mTOR,AMPK pathway expression,and apoptotic indicators was determined and confirmed by histological examination.Results:Chitinase significantly inhibited the viabilities of HepG2 cells.Moreover,in the Wistar male rat model of HCC,chitinase decreased ATP levels,modulated endoplasmic reticulum stress,mediated autophagy factors,and promoted apoptosis.Conclusions:Chitinase might play a role in the apoptosis as well as autophagy pathways and may act as a potential tumor suppressor.展开更多
Nekemias megalophylla is a popular folk tea consumed by people in the Western Hubei(China)of which ampelopsin(AMP)is the main active ingredient.In this study,we investigated the effect of AMP on cervical cancer and ex...Nekemias megalophylla is a popular folk tea consumed by people in the Western Hubei(China)of which ampelopsin(AMP)is the main active ingredient.In this study,we investigated the effect of AMP on cervical cancer and explored its mechanism of action,focusing on apoptosis and autophagy.Firstly,we verified that AMP strongly inhibited the growth of C-33A cells and observed apoptosis and autophagy phenomenon in vivo,and found that AMP induces C-33A cell apoptosis via death receptor or mitochondrial pathways.The results also indicated that AMP-induced autophagy occurs via the PI3K/Akt/m TOR pathway.Secondly,when autophagy was inhibited,the AMP-induced apoptosis of C-33A cells was strengthened,when apoptosis was inhibited,the AMP-induced autophagy of C-33A cells was strengthened.PI3K/Akt/m TOR pathway activation enhances AMP-induced apoptosis in C-33A cells,while its inhibition strengthens AMP-induced autophagy.Finally,we confirmed that AMP inhibited cell growth and induced apoptosis and autophagy of C-33A cells in an in vivo nude mouse model of C-33A tumor xenografts.These results elucidate that AMP bidirectionally regulates apoptosis and autophagy in human cervical cancer C-33A cells by mediating the PI3K/Akt/m TOR pathway.展开更多
Autophagy is well-known for delivering cargo materials to lysosomes for proteolytic digestion.Recently,autophagy has emerged as a key mechanism in unconventional protein secretion(UPS).This perspective introduces unco...Autophagy is well-known for delivering cargo materials to lysosomes for proteolytic digestion.Recently,autophagy has emerged as a key mechanism in unconventional protein secretion(UPS).This perspective introduces unconventional secretion pathways,focusing on secretory autophagy and its role in secreting protein aggregates associated with neurodegenerative disorders.We also explore additional neuronal functions of secretory autophagy beyond the release of protein aggregates.We propose autophagosomes as transport organelles that deliver cargo material directly from the endoplasmatic reticulum(ER)to the plasma membrane rather than solely to lysosomes.展开更多
In the early stages of traumatic spinal cord injury,extensive accumulation of autophagosomes creates a neurotoxic microenvironment,exacerbating neuronal cell death and worsening tissue damage,ultimately hindering neur...In the early stages of traumatic spinal cord injury,extensive accumulation of autophagosomes creates a neurotoxic microenvironment,exacerbating neuronal cell death and worsening tissue damage,ultimately hindering neurofunctional recovery.Activin A is a critical growth factor necessary for the development of the embryonic nervous system and for maintaining neuronal function in the adult cerebral cortex.It can inhibit excessive autophagy in ischemic stroke to reduce neuronal damage.However,the specific mechanism through which Activin A functions in the spinal cord remains poorly understood.In this study,we administered different concentrations of Activin A to neural stem cells from the spinal cord and found that Activin A stimulated the proliferation and neuronal differentiation of neural stem cells.Then,we established an in vitro oxidative stress model by using hydrogen peroxide to stimulate the neural stem cells-induced neurons.We found that Activin A could reduce apoptosis caused by oxidative stress.Subsequently,we treated a mouse model of spinal cord contusion with intrathecal injection of Activin A.Behavioral and electrophysiological results showed that Activin A promoted recovery of motor function and reconstruction of neural circuits in the model mice.Finally,RNA sequencing indicated that Activin A inhibited autophagy by activating the PI3K/AKT/mTOR pathway and upregulating the expression of synaptogenesis-related factor Sema3A in the spinal cord.These results suggest that Activin A may mediate the excessive autophagic response after spinal cord injury,promote the reconstruction of damaged neural circuits,and restore neurological function in the injured spinal cord.展开更多
Autophagy is a major cellular pathway used to degrade long-lived proteins or organelles that may be damaged due to increased reactive oxygen species（ROS） generated by cellular stress. Autophagy typically enhances ce...Autophagy is a major cellular pathway used to degrade long-lived proteins or organelles that may be damaged due to increased reactive oxygen species（ROS） generated by cellular stress. Autophagy typically enhances cell survival, but it may also act to promote cell death under certain conditions. The mechanism underlying this paradox, however, remains unclear. We showed that Tetrahymena cells exerted increased membranebound vacuoles characteristic of autophagy followed by autophagic cell death（referred to as cell death with autophagy） after exposure to hydrogen peroxide. Inhibition of autophagy by chloroquine or 3-methyladenine significantly augmented autophagic cell death induced by hydrogen peroxide. Blockage of the mitochondrial electron transport chain or starvation triggered activation of autophagy followed by cell death by inducing the production of ROS due to the loss of mitochondrial membrane potential. This indicated a regulatory role of mitochondrial ROS in programming autophagy and autophagic cell death in Tetrahymena. Importantly, suppression of autophagy enhanced autophagic cell death in Tetrahymena in response to elevated ROS production from starvation, and this was reversed by antioxidants. Therefore, our results suggest that autophagy was activated upon oxidative stress to prevent the initiation of autophagic cell death in Tetrahymena until the accumulation of ROS passed the point of no return, leading to delayed cell death in Tetrahymena.展开更多
The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role i...The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.展开更多
Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulat...Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.展开更多
Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular...Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.展开更多
Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are ne...Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.展开更多
Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cereb...Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.展开更多
Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environme...Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.展开更多
Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necr...Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necroptosis,and phagoptosis,among which autophagy is the most studied.We have reviewed studies published in the past 5 years regarding the association between autophagy and cerebral I/R injury.To the best of our knowledge,this is the first review article summarizing potential candidates targeting autophagic pathways in the treatment of I/R injury post ischemic stroke.The findings of this review may help to better understand the pathogenesis and mechanisms of I/R events and bridge the gap between basic and translational research that may lead to the development of novel therapeutic approaches for I/R injury.展开更多
Lung cancer exhibits the highest incidence and mortality rates among cancers globally,with a five-year overall survival rate alarmingly below 20%.Targeting autophagy,though a controversial therapeutic strategy,is exte...Lung cancer exhibits the highest incidence and mortality rates among cancers globally,with a five-year overall survival rate alarmingly below 20%.Targeting autophagy,though a controversial therapeutic strategy,is extensively employed in clinical practice.Current research is actively pursuing various therapeutic strategies using small molecules to exploit the dual function of autophagy.Nevertheless,the pivotal question of enhancing or inhibiting autophagy in cancer therapy merits further attention.This review aims to provide a comprehensive overview of the mechanisms of autophagy in lung cancer.It also explores recent advances in targeting cytotoxic autophagy and inhibiting protective autophagy with small molecules to induce cell death in lung cancer cells.Notably,most autophagy-targeting drugs,primarily natural small molecules,have demonstrated that activating cytotoxic autophagy effectively induces cell death in lung cancer,as opposed to inhibiting protective autophagy.These insights contribute to identifying druggable targets and drug candidates for potential autophagy-related lung cancer therapies,offering promising approaches to combat this disease.展开更多
基金supported by the National Key Research and Development Program of China(2023YFC3503900)the National Natural Science Foundation of China(82305001)+3 种基金the Zhejiang Provincial Natural Science Foundation of China(LQ24H280011)the Science Research Fund of Administration of Traditional Chinese Medicine of Zhejiang Province(2023ZR014)the National Young Qihuang Scholars Training Programthe Research Project of Zhejiang Chinese Medical University(2022RCZXZK18,2023JKZKTS17)。
文摘Ovarian cancer(OC),a common malignancy of the female reproductive system,has the highest mortality rate among gynecological cancers.A distinguishing feature of OC cells(OCCs)is their reduced autophagic flux compared with normal cells.This phenomenon indicates that excessive autophagy activation or impaired autophagosome–lysosome fusion may lead to OCC death.This study investigated the anti-OC effects of dihydrotanshinone I(DHT),a tanshinone compound from Salvia miltiorrhiza.Proteomic analysis suggested that DHT suppressed OC growth via the autophagy–lysosome pathway,with sortilin 1(SORT1)identified as a critical target.In vitro,DHT promoted autophagosome formation mediated by microtubule-associated protein 1 light chain 3-II(LC3-II),while inhibiting autophagosome–lysosome fusion.The results of an orthotopic OC model corroborated these findings,showing that DHT induced autophagic cell death(ACD)and suppressed SORT1 expression in tumors.Further RNA interference experiments confirmed that SORT1 depletion caused autophagosomes to accumulate in OCCs.Notably,we found that SORT1 interacted with autophagy-related gene(ATG)-encoded proteins ATG5 and ATG16L1,and that depleting SORT1 increased the levels of these proteins.Co-immunoprecipitation,ubiquitination,and cellular thermal shift assay analyses revealed that DHT directly targeted and promoted ubiquitin-dependent degradation of SORT1.By degrading SORT1,ATG5 and ATG16L1 were released,which enhanced autophagosome formation and disrupted the autophagic flux.These findings identified DHT as a novel autophagosome inducer that induced ACD by targeting SORT1,making it a promising therapeutic candidate for OC.
基金funded by the National Natural Science Foundation of China,No.82271395(to GL),the Guangdong Basic and Applied Basic Research Foundation,No.2023A1515030073(to GL)the grants from University of Macao Research Committee,China,No.MYRG2022-00074-ICMS(to CTV)Guangzhou Science and Technology Program Project,No.2025A04J4740(to GL).
文摘Spinal cord injury is a neurological disorder resulting from trauma,typically affecting sensory and motor function at the injury site,even leading to paralysis and internal dysfunction.The treatment of spinal cord injury mainly relies on pharmacological and surgical interventions;however,significant challenges remain in the protection and repair of neural tissues.Autophagy,an intracellular process responsible for the degradation and recycling of macromolecular components,plays a vital role in spinal cord injury,alleviating the severity of injury by inhibiting cell apoptosis and inflammatory responses.In this review,we provide an overview of the physiological mechanisms underlying autophagy and spinal cord injury and detail the crosstalk between autophagy and other modes of cell death in spinal cord injury.In addition,we discuss the potential of targeting autophagy as a therapeutic strategy for spinal cord injury through approaches that focus on promoting or inhibiting this process,targeting specific autophagic substrates or pathways,and combining autophagy modulation with other neuroprotective or restorative interventions.In summary,this review proposes that strict regulation of autophagy may represent a viable strategy for the treatment of spinal cord injury.
基金supported by the National Natural Science Foundation of China (No. 81600470)the Natural Science Foundation of Shandong Province of China (Nos. ZR2022MC053 and ZR2023MH122)。
文摘Epigallocatechin-3-gallate(EGCG), a major polyphenolic compound in green tea, exhibits antiviral activity against multiple viruses, including hepatitis B virus(HBV). However, its role in HBV replication and the underlying mechanisms remain incompletely understood. In this study, we investigated the effects of EGCG on HBV replication and its modulation of autophagy using two established HBV cell models. Our results show that EGCG significantly reduces secreted levels of hepatitis B surface antigen(HBsAg) and HBV deoxyribonucleic acid(DNA), as well as intracellular HBV DNA replicative intermediates, encapsidated pregenomic ribonucleic acid(pgRNA), and core protein(HBc), without affecting total HBV messenger RNAs(mRNAs) or pgRNA levels. EGCG enhances autophagic flux, evidenced by increased autophagosome formation and accelerated turnover of the selective autophagy receptor p62 and LC3-Ⅱ. This enhanced autophagy promotes HBc degradation. Pharmacological inhibition of autophagy with 3-methyladenine(3-MA), chloroquine(CQ), or bafilomycin A1(BafA1) abolished the suppressive effect of EGCG on HBV. Notably, treatment with CQ or BafA1 together with EGCG markedly increased HBV production by blocking autophagic degradation and inducing accumulation of autophagosomes—effects similar to those induced by the autophagy activator rapamycin, which facilitates HBV replication. Mechanistically, EGCG activates the adenosine 5'-monophosphate-activated protein kinase(AMPK)/transcription factor EB(TFEB)signaling axis, leading to enhanced lysosomal biogenesis and ATP production, thereby promoting autophagic clearance. Pharmacological or genetic inhibition of AMPK attenuated TFEB transcriptional activity, suppressed lysosomal biogenesis and ATP generation, impaired autophagic degradation, increased HBc levels, and ultimately enhanced HBV replication. Conversely, pharmacological activation of AMPK produced opposing effects. These findings reveal a novel mechanism by which EGCG inhibits HBV: EGCG promotes autophagic degradation of the viral core protein via activation of the AMPK/TFEB signaling pathway.
基金financially supported by the Sichuan Science and Technology Program(2024YFNH0016,2024NSFSC2072)the earmarked fund for CARS(CARS-45)+2 种基金the National Science Fund for Distinguished Young Scholars of China(32425056)the National Key Research and Development Program of China(2023YFD2400600)Sichuan Innovation Team of National Modern Agricultural Industry Technology System(SCCXTD-2024-15)。
文摘Background Environmental hypoxia is a common phenomenon in aquaculture,which causes gill tissue injury in fish.Glutathione(GSH)is a vital antioxidant in animal tissues,and its levels decrease under hypoxic conditions.However,the effects of glutathione on fish under hypoxic stress remain poorly understood.This study aimed to investigate the impact of glutathione on gill tissue damage in fish under hypoxic stress and explore the underlying mechanisms.Methods Six experimental diets with varying glutathione concentrations.The actual glutathione levels in these diets,measured by high-performance liquid chromatography,were 0.00,145.95,291.90,437.85,583.80,and 729.75 mg/kg,respectively.Fish were fed these diets for 70 d,after which a 96-h hypoxic stress experiment was conducted.The experiment was set up with normoxic and hypoxic groups,in which the dissolved oxygen in the group was 6 mg/L,and that in the group was 1 mg/L.Results This research revealed that glutathione could enhance the growth performance and antioxidant capability of juvenile grass carp while mitigating the structural damage to gill tissues induced by hypoxia stress.Mechanistic investigations further indicated that glutathione mitigated hypoxia-induced oxidative injury in gill tissues and improved their antioxidant capacity.In addition,glutathione attenuated gill apoptosis induced by hypoxia stress.Glutathione also inhibited the initiation,nucleation,elongation,and degradation phases of autophagy,thereby attenuating hypoxia-induced gill autophagy.Moreover,glutathione was found to alleviate hypoxia-induced endoplasmic reticulum stress(ERS)in gills,a response potentially linked to the suppression of PERK,IRE1,and ATF6 signaling pathways.Finally,based on the ROS and PC contents in gill tissue,the optimum glutathione supplementation levels for juvenile grass carp under hypoxia stress were 437.10 and 495.00 mg/kg,respectively.Conclusions In conclusion,our experimental results demonstrated the effectiveness of glutathione in alleviating gill tissue damage caused by hypoxic stress.This study confirms the feasibility and effectiveness of dietary glutathione addition to alleviate hypoxic stress in fish.
基金supported by the Academic Leader Training Programof Pudong New Area Health System in Shanghai(Grant No.PWRd2021-13)Shanghai Municipal Health Commission(Grant No.202340094).
文摘Objectives:Ribosomal protein S6 kinase A2(RPS6KA2)has been identified as a potential prognostic biomarker in several cancers,including breast cancer,glioblastoma,and prostate cancer.However,its functional significance in ovarian cancer is not well characterized.This study was designed to explore the therapeutic relevance of modulating RPS6KA2 in the context of ovarian cancer,particularly in relation to cisplatin resistance.Methods:The expression levels of RPS6KA2 and key regulators involved in autophagy and ferroptosis were assessed using quantitative reverse transcription-PCR,immunofluorescence staining,immunohistochemistry,and western blotting.Prognostic associations were conducted using the Kaplan-Meier Plotter database.Autophagy flux assays and visualization of autophagosomes were performed to assess autophagy activity.Ferroptosis-related parameters,including intracellular iron content,glutathione(GSH)levels,reactive oxygen species(ROS)generation,and mitochondrial membrane potential,were measured to determine ferroptotic changes.In vivo experiments were carried out to determine the antitumor efficacy of RPS6KA2 modulation in combination with pathway-specific agents.Results:Using ovarian cancer cell lines and clinical tissue samples,we demonstrated that RPS6KA2 expression was significantly downregulated in cisplatin-resistant cells and tissues compared to their sensitive counterparts.Low RPS6KA2 expression correlated with unfavorable patient outcomes and enhanced chemoresistance.Mechanistically,RPS6KA2 inhibited autophagy by modulating the phosphatidylinositol 3-kinase-protein kinase B-mammalian target of rapamycin(PI3K-AKT-mTOR)signaling pathway,which in turn increased sensitivity to cisplatin.Additionally,RPS6KA2 facilitated ferroptosis,contributing to its tumor-suppressive function.miR-512-3p was identified as a negative regulator of RPS6KA2,driving cisplatin resistance through suppression of RPS6KA2 expression.In vivo validation confirmed that combining RPS6KA2 targeting with autophagy inhibitors or ferroptosis inducers significantly enhanced cisplatin sensitivity in ovarian cancer models.Conclusion:These results collectively indicate that targeting the miR-512-3p/RPS6KA2 regulatory axis may offer a novel and effective strategy for overcoming cisplatin resistance in ovarian cancer.
基金supported by grants from the National Natural Science Foundation of China(82474093,81973536)Jiangsu Province“Blue and Green Project”(184080H10240)+2 种基金Graduate Research Innovation Program of Jiangsu(KYCX23_0871)the National Natural Science Foundation of the Youth Science Fund Project(81703775)Health Research Program of Wuxi Municipal Health Commission(Q202107).
文摘Moutan Cortex terpene glycoside is derived from the dried root bark of Paeonia suffruticosa Andr.in the Paeoniaceae family,which holds significant value as a traditional Chinese medicine.This study investigated that Moutan Cortex terpene glycoside(MCTG)improved diabetic kidney disease(DKD)by targeting sirtuin 1(SIRT1)mediated autophagy pathway.Mechanistic insights were gained using DKD model rats and human umbilical vein endothelial cells(HUVECs)to delineate how MCTG operated in the treatment of DKD.Furthermore,network pharmacology was used to identify the primary metabolic pathways affected by MCTG,with key targets being confirmed through polymerase chain reaction(PCR),Western blot,Transmission electron microscope,immunofluorescence staining and monodansylcadaverine(MDC)staining.Finally,small interfering RNA transfection testified SIRT1 in advanced glycation end-products(AGEs)-induced HUVECs injury.MCTG effectively decreased blood glucose rise in DKD rats and reduced levels of cytokines and biochemical indicators.Network pharmacology revealed that metabolism was the main pathway of Moutan Cortex,and the main targets were verified by PCR and protein experiments.Based on these results,we found that Moutan Cortex could improve DKD and SIRT1 was a potential target.Furthermore,knockdown of SIRT1 attenuated AGEs-induced the expression of Beclin 1 and microtubule-associated protein 1 light chain 3 II/I(LC3 II/I)in HUVECs.In summary,this study demonstrated that Moutan Cortex could alleviate DKD via down-regulating SIRT1-mediated autophagy pathway.
基金funded by Zhejiang Province Traditional Chinese Medicine Science and Technology Program(No.2021ZZ012)The Changlin Qiu National Distinguished Senior Traditional Chinese Medicine Expert Heritage Workshop Project(No.GZS2021007).
文摘Background:Parkinson’s disease(PD)is one of the most common movement disorders worldwide.Ziyin Xifeng Decoction(ZYXFD),a traditional Chinese medicine compound formula,has shown therapeutic efficacy in treating PD,but its specific mechanisms of action have not been fully elucidated.Methods:Firstly,we employed network pharmacology and untargeted metabolomics analysis to identify the core targets,pathways,and key metabolites of ZYXFD in the treatment of PD.Subsequently,we evaluated the protective effects of ZYXFD and further investigated its anti-PD mechanisms by validating the analytical results.Results:Combined analyses of network pharmacology and metabolomics identify the core targets including EGFR,SRC,PTGS2,and CDK2,while the effects of ZYXFD against PD are likely mediated primarily through the PI3K/AKT/mTOR signaling pathway.Pharmacodynamic evaluation demonstrated that a high dose of ZYXFD significantly improved behavioral deficits in chronic PD mice,downregulatedα-synuclein protein expression,and protected dopaminergic neurons.It also regulated the expression of core targets,inhibited the PI3K/AKT/mTOR signaling pathway,promoted autophagy,and reduced apoptosis.In vitro experiments further verified that the therapeutic effect of ZYXFD on PD is dependent on autophagy regulation.Conclusion:The findings demonstrated that ZYXFD alleviates PD by modulating related proteins and metabolites,inhibiting the PI3K/AKT/mTOR signaling pathway,and enhancing autophagy.This provides a theoretical basis for its broader application in PD treatment.
文摘Objective:To assess the antitumor activity of the novel chitinase produced by fermented,isolated Trichoderma viride in a hepatocellular carcinoma(HCC)male rat model.Methods:Diethyl-nitrosamine induction combined with ionizing radiation exposure was used to establish the HCC rat model.All rats were divided into 4 groups:the control group,the chitinase group,the HCC group,and the HCC+chitinase group.The antiproliferative effect of chitinase was evaluated in human HCC cells.The effect of chitinase in vivo on oxidative stress,endoplasmic reticulum stress chaperones,autophagy markers,PI3K/AKT/mTOR,AMPK pathway expression,and apoptotic indicators was determined and confirmed by histological examination.Results:Chitinase significantly inhibited the viabilities of HepG2 cells.Moreover,in the Wistar male rat model of HCC,chitinase decreased ATP levels,modulated endoplasmic reticulum stress,mediated autophagy factors,and promoted apoptosis.Conclusions:Chitinase might play a role in the apoptosis as well as autophagy pathways and may act as a potential tumor suppressor.
基金supported by the Major Science and Technology Project of Hubei Province(2020ACA007)the Scientific and Technological Bureau of Wuhan(2018060401011308).
文摘Nekemias megalophylla is a popular folk tea consumed by people in the Western Hubei(China)of which ampelopsin(AMP)is the main active ingredient.In this study,we investigated the effect of AMP on cervical cancer and explored its mechanism of action,focusing on apoptosis and autophagy.Firstly,we verified that AMP strongly inhibited the growth of C-33A cells and observed apoptosis and autophagy phenomenon in vivo,and found that AMP induces C-33A cell apoptosis via death receptor or mitochondrial pathways.The results also indicated that AMP-induced autophagy occurs via the PI3K/Akt/m TOR pathway.Secondly,when autophagy was inhibited,the AMP-induced apoptosis of C-33A cells was strengthened,when apoptosis was inhibited,the AMP-induced autophagy of C-33A cells was strengthened.PI3K/Akt/m TOR pathway activation enhances AMP-induced apoptosis in C-33A cells,while its inhibition strengthens AMP-induced autophagy.Finally,we confirmed that AMP inhibited cell growth and induced apoptosis and autophagy of C-33A cells in an in vivo nude mouse model of C-33A tumor xenografts.These results elucidate that AMP bidirectionally regulates apoptosis and autophagy in human cervical cancer C-33A cells by mediating the PI3K/Akt/m TOR pathway.
基金supported by the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)grant LU 2347/3-1(to PL).
文摘Autophagy is well-known for delivering cargo materials to lysosomes for proteolytic digestion.Recently,autophagy has emerged as a key mechanism in unconventional protein secretion(UPS).This perspective introduces unconventional secretion pathways,focusing on secretory autophagy and its role in secreting protein aggregates associated with neurodegenerative disorders.We also explore additional neuronal functions of secretory autophagy beyond the release of protein aggregates.We propose autophagosomes as transport organelles that deliver cargo material directly from the endoplasmatic reticulum(ER)to the plasma membrane rather than solely to lysosomes.
基金supported by the National Natural Science Foundation of China,Nos.82271419,81901902(to YZ),82202702(to ZW),82202351(to XH),82301550(to LYang),82271418(to XX)the Shanghai Rising-Star Program,No.22QA1408200(to YZ)the Fundamental Research Fundsfor the Central Universities,No.22120220555(to YZ).
文摘In the early stages of traumatic spinal cord injury,extensive accumulation of autophagosomes creates a neurotoxic microenvironment,exacerbating neuronal cell death and worsening tissue damage,ultimately hindering neurofunctional recovery.Activin A is a critical growth factor necessary for the development of the embryonic nervous system and for maintaining neuronal function in the adult cerebral cortex.It can inhibit excessive autophagy in ischemic stroke to reduce neuronal damage.However,the specific mechanism through which Activin A functions in the spinal cord remains poorly understood.In this study,we administered different concentrations of Activin A to neural stem cells from the spinal cord and found that Activin A stimulated the proliferation and neuronal differentiation of neural stem cells.Then,we established an in vitro oxidative stress model by using hydrogen peroxide to stimulate the neural stem cells-induced neurons.We found that Activin A could reduce apoptosis caused by oxidative stress.Subsequently,we treated a mouse model of spinal cord contusion with intrathecal injection of Activin A.Behavioral and electrophysiological results showed that Activin A promoted recovery of motor function and reconstruction of neural circuits in the model mice.Finally,RNA sequencing indicated that Activin A inhibited autophagy by activating the PI3K/AKT/mTOR pathway and upregulating the expression of synaptogenesis-related factor Sema3A in the spinal cord.These results suggest that Activin A may mediate the excessive autophagic response after spinal cord injury,promote the reconstruction of damaged neural circuits,and restore neurological function in the injured spinal cord.
文摘Autophagy is a major cellular pathway used to degrade long-lived proteins or organelles that may be damaged due to increased reactive oxygen species（ROS） generated by cellular stress. Autophagy typically enhances cell survival, but it may also act to promote cell death under certain conditions. The mechanism underlying this paradox, however, remains unclear. We showed that Tetrahymena cells exerted increased membranebound vacuoles characteristic of autophagy followed by autophagic cell death（referred to as cell death with autophagy） after exposure to hydrogen peroxide. Inhibition of autophagy by chloroquine or 3-methyladenine significantly augmented autophagic cell death induced by hydrogen peroxide. Blockage of the mitochondrial electron transport chain or starvation triggered activation of autophagy followed by cell death by inducing the production of ROS due to the loss of mitochondrial membrane potential. This indicated a regulatory role of mitochondrial ROS in programming autophagy and autophagic cell death in Tetrahymena. Importantly, suppression of autophagy enhanced autophagic cell death in Tetrahymena in response to elevated ROS production from starvation, and this was reversed by antioxidants. Therefore, our results suggest that autophagy was activated upon oxidative stress to prevent the initiation of autophagic cell death in Tetrahymena until the accumulation of ROS passed the point of no return, leading to delayed cell death in Tetrahymena.
基金supported by the National Natural Science Foundation of China,Nos.92049120 and 81870897STI2030-Major Projects,No.2021ZD0204001+6 种基金Guangdong Key Project for Development of New Tools for the Diagnosis and Treatment of Autism,No.2018B030335001the Natural Science Foundation of Jiangsu Province,No.BK20181436the National Major Scientific and Technological Special Project for Significant New Drug Development,No.2019ZX09301102the Discipline Construction Program of the Second Affiliated Hospital of Soochow University,No.XKTJ-TD202003Sino-German Cooperation Mobility Programme,No.M-0679the Science and Technology Project of Suzhou,No.SKY2022161Research Project of Neurological Diseases of the Second Affiliated Hospital of Soochow University Medical Center,No.ND2023A01(all to QHM)。
文摘The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.
基金supported by the National Natural Science Foundation of China,Nos.82271411(to RG),51803072(to WLiu)grants from the Department of Finance of Jilin Province,Nos.2022SCZ25(to RG),2022SCZ10(to WLiu),2021SCZ07(to RG)+2 种基金Jilin Provincial Science and Technology Program,No.YDZJ202201ZYTS038(to WLiu)The Youth Support Programmed Project of China-Japan Union Hospital of Jilin University,No.2022qnpy11(to WLuo)The Project of China-Japan Union Hospital of Jilin University,No.XHQMX20233(to RG)。
文摘Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.
基金supported by the National Natural Science Foundation of China,No.82101340(to FJ).
文摘Parkinson’s disease is a common neurodegenerative disease with movement disorders associated with the intracytoplasmic deposition of aggregate proteins such asα-synuclein in neurons.As one of the major intracellular degradation pathways,the autophagy-lysosome pathway plays an important role in eliminating these proteins.Accumulating evidence has shown that upregulation of the autophagy-lysosome pathway may contribute to the clearance ofα-synuclein aggregates and protect against degeneration of dopaminergic neurons in Parkinson’s disease.Moreover,multiple genes associated with the pathogenesis of Parkinson’s disease are intimately linked to alterations in the autophagy-lysosome pathway.Thus,this pathway appears to be a promising therapeutic target for treatment of Parkinson’s disease.In this review,we briefly introduce the machinery of autophagy.Then,we provide a description of the effects of Parkinson’s disease–related genes on the autophagy-lysosome pathway.Finally,we highlight the potential chemical and genetic therapeutic strategies targeting the autophagy–lysosome pathway and their applications in Parkinson’s disease.
基金supported by the Natural Science Foundation of Fujian Province,No.2021J02035(to WX).
文摘Regulated cell death is a form of cell death that is actively controlled by biomolecules.Several studies have shown that regulated cell death plays a key role after spinal cord injury.Pyroptosis and ferroptosis are newly discovered types of regulated cell deaths that have been shown to exacerbate inflammation and lead to cell death in damaged spinal cords.Autophagy,a complex form of cell death that is interconnected with various regulated cell death mechanisms,has garnered significant attention in the study of spinal cord injury.This injury triggers not only cell death but also cellular survival responses.Multiple signaling pathways play pivotal roles in influencing the processes of both deterioration and repair in spinal cord injury by regulating pyroptosis,ferroptosis,and autophagy.Therefore,this review aims to comprehensively examine the mechanisms underlying regulated cell deaths,the signaling pathways that modulate these mechanisms,and the potential therapeutic targets for spinal cord injury.Our analysis suggests that targeting the common regulatory signaling pathways of different regulated cell deaths could be a promising strategy to promote cell survival and enhance the repair of spinal cord injury.Moreover,a holistic approach that incorporates multiple regulated cell deaths and their regulatory pathways presents a promising multi-target therapeutic strategy for the management of spinal cord injury.
基金supported by the National Natural Science Foundation of China,Nos.82260245(to YX),81660207(to YX),81960253(to YL),82160268(to YL),U1812403(to ZG)Science and Technology Projects of Guizhou Province,Nos.[2019]1440(to YX),[2020]1Z067(to WH)+1 种基金Cultivation Foundation of Guizhou Medical University,No.[20NSP069](to YX)Excellent Young Talents Plan of Guizhou Medical University,No.(2022)101(to WH)。
文摘Several studies have shown that activation of unfolded protein response and endoplasmic reticulum(ER)stress plays a crucial role in severe cerebral ischemia/reperfusion injury.Autophagy occurs within hours after cerebral ischemia,but the relationship between ER stress and autophagy remains unclear.In this study,we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury.We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase(PERK)/eukaryotic translation initiation factor 2 subunit alpha(e IF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP),increased neuronal apoptosis,and induced autophagy.Furthermore,inhibition of ER stress using inhibitors or by si RNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis,indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy.Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis,indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury.Findings from this study indicate that cerebral ischemia/reperfusion injury can trigger neuronal ER stress and promote autophagy,and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury.
基金supported by the National Natural Science Foundation of China,Nos.82271283(to XC),91854115(to JW),31970044(to JW)the Natural Science Foundation of Beijing,No.7202001(to XC)the Scientific Research Project of Beijing Educational Committee,No.KM202010005022(to XC)。
文摘Salsolinol(1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,Sal)is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,an environmental toxin that causes Parkinson's disease.However,the mechanism by which Sal mediates dopaminergic neuronal death remains unclear.In this study,we found that Sal significantly enhanced the global level of N~6-methyladenosine(m~6A)RNA methylation in PC12 cells,mainly by inducing the downregulation of the expression of m~6A demethylases fat mass and obesity-associated protein(FTO)and alk B homolog 5(ALKBH5).RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway.The m~6A reader YTH domain-containing family protein 2(YTHDF2)promoted the degradation of m~6A-containing Yes-associated protein 1(YAP1)mRNA,which is a downstream key effector in the Hippo signaling pathway.Additionally,downregulation of YAP1 promoted autophagy,indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity.These findings reveal the role of Sal on m~6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy.Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.
基金Shanghai Rehabilitation Medical Association,Grant/Award Number:2023JGKT24China Rehabilitation Medical Association,Grant/Award Number:KFKT-2023Shanghai“14th Five-Year Plan”Traditional Chinese Medicine Specialty and Traditional Chinese Medicine Emergency Capacity Improvement Project,Grant/Award Number:ZYTSZK2-7。
文摘Cerebral ischemia/reperfusion(I/R)injury is an important pathophysiological condition of ischemic stroke that involves a variety of physiological and pathological cell death pathways,including autophagy,apoptosis,necroptosis,and phagoptosis,among which autophagy is the most studied.We have reviewed studies published in the past 5 years regarding the association between autophagy and cerebral I/R injury.To the best of our knowledge,this is the first review article summarizing potential candidates targeting autophagic pathways in the treatment of I/R injury post ischemic stroke.The findings of this review may help to better understand the pathogenesis and mechanisms of I/R events and bridge the gap between basic and translational research that may lead to the development of novel therapeutic approaches for I/R injury.
基金supported by the National Natural Science Foundation of China(Grant Nos.:81503272,81630101,and 81891012)the Application Foundation Research Project of Sichuan Provincial Department of Science and Technology,China(Grant No.:2017JY0187)+4 种基金the Xinglin Scholar Research Premotion Project of Chengdu University of Traditional Chinese Medicine,China(Grant No.:2018016)the Regional Joint Fund of the National Natural Science Foundation of China(Grant No.:U19A2010)the National Interdisciplinary Innovation Team of Traditional Chinese Medicine,China(Grant No.:ZYYCXTD-D-202209)the Sichuan Traditional Chinese Medicine Technology Industry Innovation Team,China(Grant No.:2022C001)the Sichuan Provincial Administration of Traditional Chinese Medicine Project,China(Grant Nos.:2020JC0031 and 2024ZD02).
文摘Lung cancer exhibits the highest incidence and mortality rates among cancers globally,with a five-year overall survival rate alarmingly below 20%.Targeting autophagy,though a controversial therapeutic strategy,is extensively employed in clinical practice.Current research is actively pursuing various therapeutic strategies using small molecules to exploit the dual function of autophagy.Nevertheless,the pivotal question of enhancing or inhibiting autophagy in cancer therapy merits further attention.This review aims to provide a comprehensive overview of the mechanisms of autophagy in lung cancer.It also explores recent advances in targeting cytotoxic autophagy and inhibiting protective autophagy with small molecules to induce cell death in lung cancer cells.Notably,most autophagy-targeting drugs,primarily natural small molecules,have demonstrated that activating cytotoxic autophagy effectively induces cell death in lung cancer,as opposed to inhibiting protective autophagy.These insights contribute to identifying druggable targets and drug candidates for potential autophagy-related lung cancer therapies,offering promising approaches to combat this disease.
