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
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
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
After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures...After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures.The neuroprotective drug davunetide has shown substantial therapeutic effects on brain diseases,but its role in treating spinal cord injury remains unclear.Therefore,the aim of this study was to investigate the effects of davunetide on cell death after spinal cord injury.To do this,we established a mouse model of spinal cord contusion and administered davunetide intranasally daily at a dose of 0.5μg/5μL.Mouse locomotor function was assessed using footprint analysis and Basso Mouse Scale scoring,while the extent of spinal cord injury was evaluated using Masson’s trichrome staining.The expression levels of proteins related to locomotor function and spinal cord injury were analyzed by Western blotting and immunofluorescence staining,and protein-protein interactions were evaluated using immunoprecipitation techniques.Our results demonstrated that davunetide not only reduced the size of the injury area but also promoted the recovery of locomotor function after spinal cord injury.Specifically,davunetide exerted its effects by enhancing autophagy and inhibiting necroptosis.Inhibition of autophagy reversed the protective effects of davunetide on necroptosis.Further investigation revealed that davunetide acted through the SIRT1-FOXO1-TFEB signaling pathway,which is key to its therapeutic effects.These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms.This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury.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
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
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
Alzheimer s disease is a devastating neurodegenerative disorder affecting millions worldwide,with current treatments offering only limited benefits.Central to emerging research is the role of autophagy and endolysosom...Alzheimer s disease is a devastating neurodegenerative disorder affecting millions worldwide,with current treatments offering only limited benefits.Central to emerging research is the role of autophagy and endolysosomal pathways,which are essential for clearing misfolded proteins and damaged organelles.Bridging integrator 1(BIN1),traditionally recognized for its role in membrane remodeling and endocytosis,has recently emerged as a top genetic risk factor for Alzheimer's disease,linking cellular clearance mechanisms to the development of toxic amyloid-beta plaques and tau tangles.In this review,we provide an accessible overview of how disruptions in autophagy and endolysosomal trafficking contribute to the neurodegeneration process in Alzheimer's disease,positioning BIN1 as a central mediator within this complex network.Recent advances have shown that alte rations in BIN1 expression and isoform distribution are associated with increased tau pathology and changes in amyloid-beta processing.Moreover,BIN1 appears to also influence synaptic transmission,neuroinflammation,and overall cellular homeostasis.The integration of recent findings not only deepens our understanding of Alzheimer s disease pathology but also opens new avenues for the development of targeted treatments.This timely perspective underscores the potential of modulating BIN1 activity to enhance cellular clearance mechanisms and offers hope for more effective inte rventions for Alzheimer's disease.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
Parkinson’s disease is the second most common neurodegenerative disorder.ATPase H+transporting V0 subunit A1(ATP6V0A1)is a component of vacuolar H+-ATPase(V-ATPase),an ATP-dependent proton pump.Our previous research ...Parkinson’s disease is the second most common neurodegenerative disorder.ATPase H+transporting V0 subunit A1(ATP6V0A1)is a component of vacuolar H+-ATPase(V-ATPase),an ATP-dependent proton pump.Our previous research identified an association between the ATP6V0A1 rs601999 variant and Parkinson’s disease;however,the underlying mechanisms of ATP6V0A1 in Parkinson’s disease remain elusive.In this study,we generated ATP6V0A1 knockdown and overexpression models and then examined the degeneration of dopaminergic neurons,lysosomal function,and the autophagy-lysosomal pathway using immunohistochemistry,western blotting,and transmission electron microscopy.We found that ATP6V0A1 protected against lysosomal dysfunction,regulated autophagic flux,and decreased phosphorylatedα-synuclein levels in vitro.In vivo,ATP6V0A1 reduced levels ofα-synuclein and phosphorylatedα-synuclein proteins,mitigated degeneration of dopaminergic neurons,and improved motor dysfunction.Collectively,these findings show that ATP6V0A1 plays a protective role in Parkinson’s disease by modulating the autophagy-lysosomal pathway.A correlation between ATP6V0A1 and Parkinson’s disease susceptibility may serve as a biomarker for Parkinson’s disease,while the protective effects of ATP6V0A1 could represent a potential therapeutic target for the disease.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
Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 m...Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases.In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes,ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways(e.g.,apoptosis,necroptosis,pyroptosis,ferroptosis,and NETosis).This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death.In addition,we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases,aiming to provide a novel theoretical framework for human disease treatment.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
OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and his...OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and histopathology.METHODS:A migraine rat model was established by a single subcutaneous nitroglycerin(NTG)injection into the posterior neck.QGJY was administered via gavage for 7 d prior to NTG induction.Behavioral changes,central sensitization biomarkers,and inflammatory cytokine levels were analyzed to evaluate migraine severity.Western blot,immunofluorescence,quantitative real-time PCR,and transmission electron microscopy were employed to assess P2X7R expression and autophagy activity in trigeminal nucleus caudalis(TNC)tissues.The P2X7R agonist 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate(Bz ATP)was further utilized to validate QGJY's regulatory effects.RESULTS:QGJY significantly reduced cage-climbing and head-scratching frequencies in NTG-induced migraine rats,downregulated serum and TNC levels of interleukin-1 beta,interleukin-6,and tumor necrosis factor-alpha,and suppressed central sensitization markers(substance P;calcitonin gene-related peptide;and c-fos induced growth factor)in TNC tissues(P<0.05).QGJY markedly decreased microglial cell counts and average immunofluorescence intensity in TNC tissues and promoted elongation of microglial protrusions(P<0.05).Concurrently,QGJY downregulated P2X7R protein and m RNA expression,reduced the light chain 3(LC3)-II/LC3-I ratio,elevated ubiquitin-binding protein p62 levels,and diminished autophagosome numbers in TNC tissues(P<0.05).Furthermore,QGJY reversed Bz ATP-induced P2X7R upregulation(P<0.05).CONCLUSIONS:QGJY alleviates migraine and inhibits central sensitization in rats,potentially by downregulating P2X7R expression,concomitantly suppressing autophagy,attenuating microglial activation,and reducing pro-inflammatory cytokine release.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
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
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
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
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 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 Natural Science Foundation of Zhejiang Province,No.LY21H060009(to WN)National Natural Science Foundation of China,Nos.82072192 and 82372540(to KZ)+2 种基金Medical and Health Technology Plan Project of Zhejiang Province,No.2024KY155(to KZ)Natural Science Foundation of Ningbo,No.2023J256(to KZ)Science and Technology Bureau Foundation of Wenzhou,No.Y20220211(to CW).
文摘After spinal cord injury,programmed cell death is common.In this context,autophagy plays a crucial role in clearing cellular debris,while necroptosis exacerbates neuroinflammation and further damages neural structures.The neuroprotective drug davunetide has shown substantial therapeutic effects on brain diseases,but its role in treating spinal cord injury remains unclear.Therefore,the aim of this study was to investigate the effects of davunetide on cell death after spinal cord injury.To do this,we established a mouse model of spinal cord contusion and administered davunetide intranasally daily at a dose of 0.5μg/5μL.Mouse locomotor function was assessed using footprint analysis and Basso Mouse Scale scoring,while the extent of spinal cord injury was evaluated using Masson’s trichrome staining.The expression levels of proteins related to locomotor function and spinal cord injury were analyzed by Western blotting and immunofluorescence staining,and protein-protein interactions were evaluated using immunoprecipitation techniques.Our results demonstrated that davunetide not only reduced the size of the injury area but also promoted the recovery of locomotor function after spinal cord injury.Specifically,davunetide exerted its effects by enhancing autophagy and inhibiting necroptosis.Inhibition of autophagy reversed the protective effects of davunetide on necroptosis.Further investigation revealed that davunetide acted through the SIRT1-FOXO1-TFEB signaling pathway,which is key to its therapeutic effects.These findings suggest the potential of davunetide in the treatment of spinal cord injury and provide valuable insights into the underlying mechanisms.This study offers strong scientific evidence to support the development of new therapeutic strategies for spinal cord injury.
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.
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.
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National Institutes of Health,No.R01AG083943Alzheimer's Association Strategic Fund No.ABA-22-965518(to YWAH)。
文摘Alzheimer s disease is a devastating neurodegenerative disorder affecting millions worldwide,with current treatments offering only limited benefits.Central to emerging research is the role of autophagy and endolysosomal pathways,which are essential for clearing misfolded proteins and damaged organelles.Bridging integrator 1(BIN1),traditionally recognized for its role in membrane remodeling and endocytosis,has recently emerged as a top genetic risk factor for Alzheimer's disease,linking cellular clearance mechanisms to the development of toxic amyloid-beta plaques and tau tangles.In this review,we provide an accessible overview of how disruptions in autophagy and endolysosomal trafficking contribute to the neurodegeneration process in Alzheimer's disease,positioning BIN1 as a central mediator within this complex network.Recent advances have shown that alte rations in BIN1 expression and isoform distribution are associated with increased tau pathology and changes in amyloid-beta processing.Moreover,BIN1 appears to also influence synaptic transmission,neuroinflammation,and overall cellular homeostasis.The integration of recent findings not only deepens our understanding of Alzheimer s disease pathology but also opens new avenues for the development of targeted treatments.This timely perspective underscores the potential of modulating BIN1 activity to enhance cellular clearance mechanisms and offers hope for more effective inte rventions for Alzheimer's disease.
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 Youth Program of the National Natural Science Foundation of China,Nos.81901282(to XC),82101326(to WG),81870992(to PX),and 81870856the Guangdong Basic and Applied Basic Research Foundation of the Science Foundation,Nos.2024A1515012919(to XC)and 2019A1515011189(to XC)+5 种基金the Central Government Guiding Local Science and Technology Development Projects,No.ZYYD2022C17(to PX)the Key Project of the Guangzhou Health Commission,No.2019-ZD-09(to PX)the Basic and Applied Basic Research of the City and School Jointly Funded Projects,No.20220102397(to QL)the Guangdong College Students Innovation and Entrepreneurship Training Program,No.S202310570017(to WY)the Science and Technology Planning Project of Guangzhou,Nos.2023B03J0631(to PX),2024A03J1152(to XC),and 202102010010(to PX)the Basic Research Program of the Guangzhou Science and Technology Bureau Jointly-funded Dengfeng Hospital Project,No.20232031(to XC).
文摘Parkinson’s disease is the second most common neurodegenerative disorder.ATPase H+transporting V0 subunit A1(ATP6V0A1)is a component of vacuolar H+-ATPase(V-ATPase),an ATP-dependent proton pump.Our previous research identified an association between the ATP6V0A1 rs601999 variant and Parkinson’s disease;however,the underlying mechanisms of ATP6V0A1 in Parkinson’s disease remain elusive.In this study,we generated ATP6V0A1 knockdown and overexpression models and then examined the degeneration of dopaminergic neurons,lysosomal function,and the autophagy-lysosomal pathway using immunohistochemistry,western blotting,and transmission electron microscopy.We found that ATP6V0A1 protected against lysosomal dysfunction,regulated autophagic flux,and decreased phosphorylatedα-synuclein levels in vitro.In vivo,ATP6V0A1 reduced levels ofα-synuclein and phosphorylatedα-synuclein proteins,mitigated degeneration of dopaminergic neurons,and improved motor dysfunction.Collectively,these findings show that ATP6V0A1 plays a protective role in Parkinson’s disease by modulating the autophagy-lysosomal pathway.A correlation between ATP6V0A1 and Parkinson’s disease susceptibility may serve as a biomarker for Parkinson’s disease,while the protective effects of ATP6V0A1 could represent a potential therapeutic target for the disease.
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supported by the State Key Program of the National Natural Science Foundation of China(82030059)the National Science and Technology Major Project(2023ZD0505501)+2 种基金the National Natural Science Foundation of China(81701952 and 82172127)the National Key Research and Development Program of China(2020YFC1512700)the Key Research and Development Program of Shandong Province(2021SFGC0503 and 2022ZLGX03).
文摘Aldehyde dehydrogenase 2(ALDH2),a mitochondrial enzyme,is the main acetaldehyde dehydrogenase involved in the scavenging of alcohol-derived acetaldehyde and endogenous aldehydes.The ALDH2^(rs671)mutation affects 560 million East Asians and is closely related to an increased risk of various human diseases.In addition to its well-known function in detoxifying alcohol-derived acetaldehyde and endogenous aldehydes,ALDH2 is implicated in human health through its regulation of autophagic machinery and multiple cell death pathways(e.g.,apoptosis,necroptosis,pyroptosis,ferroptosis,and NETosis).This review summarizes the current knowledge of ALDH2 and the regulatory mechanism through which ALDH2 regulates autophagy and cell death.In addition,we outline the potential role of ALDH2 in the regulation of autophagy and cell death during the occurrence and progression of human diseases,aiming to provide a novel theoretical framework for human disease treatment.
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.
基金Supported by the China Academy of Chinese Medical Sciences Innovation Fund:Multicenter Randomized Controlled Study on the Intervention of Yiqi Huoxue Huatan Tongluo decoction in Post-Stent Restenosis of Vertebral Arteries(No.CI2021A01308)In-Hospital Mentorship Program of Xiyuan Hospital,China Academy of Chinese Medical Sciences-Zhou Shaohua(No.0203055)。
文摘OBJECTIVE:To investigate the effects of optimizing Qinggan Jieyu decoction(清肝解郁方)on purinergic receptor P2X ligand-gated ion channel 7(P2X7R)and autophagy in migraine model rats based on molecular biology and histopathology.METHODS:A migraine rat model was established by a single subcutaneous nitroglycerin(NTG)injection into the posterior neck.QGJY was administered via gavage for 7 d prior to NTG induction.Behavioral changes,central sensitization biomarkers,and inflammatory cytokine levels were analyzed to evaluate migraine severity.Western blot,immunofluorescence,quantitative real-time PCR,and transmission electron microscopy were employed to assess P2X7R expression and autophagy activity in trigeminal nucleus caudalis(TNC)tissues.The P2X7R agonist 2'(3')-O-(4-Benzoylbenzoyl)adenosine-5'-triphosphate(Bz ATP)was further utilized to validate QGJY's regulatory effects.RESULTS:QGJY significantly reduced cage-climbing and head-scratching frequencies in NTG-induced migraine rats,downregulated serum and TNC levels of interleukin-1 beta,interleukin-6,and tumor necrosis factor-alpha,and suppressed central sensitization markers(substance P;calcitonin gene-related peptide;and c-fos induced growth factor)in TNC tissues(P<0.05).QGJY markedly decreased microglial cell counts and average immunofluorescence intensity in TNC tissues and promoted elongation of microglial protrusions(P<0.05).Concurrently,QGJY downregulated P2X7R protein and m RNA expression,reduced the light chain 3(LC3)-II/LC3-I ratio,elevated ubiquitin-binding protein p62 levels,and diminished autophagosome numbers in TNC tissues(P<0.05).Furthermore,QGJY reversed Bz ATP-induced P2X7R upregulation(P<0.05).CONCLUSIONS:QGJY alleviates migraine and inhibits central sensitization in rats,potentially by downregulating P2X7R expression,concomitantly suppressing autophagy,attenuating microglial activation,and reducing pro-inflammatory cytokine release.
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 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,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.
