Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases

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.

Autophagy-targeting modulation to promote peripheral nerve regeneration

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.

Harnessing autophagy: A potential breakthrough in digestive disease treatment

Autophagy,a conserved cellular degradation process,is crucial for various cellular processes such as immune responses,inflammation,metabolic and oxidative stress adaptation,cell proliferation,development,and tissue repair and remodeling.Dysregulation of autophagy is suspected in numerous diseases,including cancer,neurodegenerative diseases,digestive disorders,metabolic syndromes,and infectious and inflammatory diseases.If autophagy is disrupted,for example,this can have serious consequences and lead to chronic inflammation and tissue damage,as occurs in diseases such as Chron's disease and ulcerative colitis.On the other hand,the influence of autophagy on the development and progression of cancer is not clear.Autophagy can both suppress and promote the progression and metastasis of cancer at various stages.From inflammatory bowel diseases to gastrointestinal cancer,researchers are discovering the intricate role of autophagy in maintaining gut health and its potential as a therapeutic target.Researchers should carefully consider the nature and progression of diseases such as cancer when trying to determine whether inhibiting or stimulating autophagy is likely to be beneficial.Multidisciplinary approaches that combine cutting-edge research with clinical expertise are key to unlocking the full therapeutic potential of autophagy in digestive diseases.

An overview of autophagy in the differentiation of dental stem cells

Dental stem cells(DSCs)have attracted significant interest as autologous stem cells since they are easily accessible and give a minimal immune response.These properties and their ability to both maintain self-renewal and undergo multi-lineage differentiation establish them as key players in regenerative medicine.While many regulatory factors determine the differentiation trajectory of DSCs,prior research has predominantly been based on genetic,epigenetic,and molecular aspects.Recent evidence suggests that DSC differentiation can also be influenced by autophagy,a highly conserved cellular process responsible for maintaining cellular and tissue homeostasis under various stress conditions.This comprehensive review endeavors to elucidate the intricate regulatory mechanism and relationship between autophagy and DSC differentiation.To achieve this goal,we dissect the intricacies of autophagy and its mechanisms.Subsequently,we elucidate its pivotal roles in impacting DSC differentiation,including osteo/odontogenic,neurogenic,and angiogenic trajectories.Furthermore,we reveal the regulatory factors that govern autophagy in DSC lineage commitment,including scaffold materials,pharmaceutical cues,and the extrinsic milieu.The implications of this review are far-reaching,underpinning the potential to wield autophagy as a regulatory tool to expedite DSC-directed differentiation and thereby promote the application of DSCs within the realm of regenerative medicine.

Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases

Autophagy is a cellular catabolic process characterized by the formation of double-membrane autophagosomes.Transmission electron microscopy is the most rigorous method to clearly visualize autophagic engulfment and degradation.A large number of studies have shown that autophagy is closely related to the digestion,secretion,and regeneration of gastrointestinal(GI)cells.However,the role of autophagy in GI diseases remains controversial.This article focuses on the morphological and biochemical characteristics of autophagy in GI diseases,in order to provide new ideas for their diagnosis and treatment.

Neuroprotective effects of chaperone-mediated autophagy in neurodegenerative diseases

Chaperone-mediated autophagy is one of three types of autophagy and is characterized by the selective degradation of proteins.Chaperone-mediated autophagy contributes to energy balance and helps maintain cellular homeostasis,while providing nutrients and support for cell survival.Chaperone-mediated autophagy activity can be detected in almost all cells,including neurons.Owing to the extreme sensitivity of neurons to their environmental changes,maintaining neuronal homeostasis is critical for neuronal growth and survival.Chaperone-mediated autophagy dysfunction is closely related to central nervous system diseases.It has been shown that neuronal damage and cell death are accompanied by chaperone-mediated autophagy dysfunction.Under certain conditions,regulation of chaperone-mediated autophagy activity attenuates neurotoxicity.In this paper,we review the changes in chaperone-mediated autophagy in neurodegenerative diseases,brain injury,glioma,and autoimmune diseases.We also summarize the most recent research progress on chaperone-mediated autophagy regulation and discuss the potential of chaperone-mediated autophagy as a therapeutic target for central nervous system diseases.

Autophagy in neural stem cells and glia for brain health and diseases

Autophagy is a multifaceted cellular process that not only maintains the homeostatic and adaptive responses of the brain but is also dynamically involved in the regulation of neural cell generation,maturation,and survival.Autophagy facilities the utilization of energy and the microenvironment for developing neural stem cells.Autophagy arbitrates structural and functional remodeling during the cell differentiation process.Autophagy also plays an indispensable role in the maintenance of stemness and homeostasis in neural stem cells during essential brain physiology and also in the instigation and progression of diseases.Only recently,studies have begun to shed light on autophagy regulation in glia(microglia,astrocyte,and oligodendrocyte)in the brain.Glial cells have attained relatively less consideration despite their unquestioned influence on various aspects of neural development,synaptic function,brain metabolism,cellular debris clearing,and restoration of damaged or injured tissues.Thus,this review composes pertinent information regarding the involvement of autophagy in neural stem cells and glial regulation and the role of this connexion in normal brain functions,neurodevelopmental disorders,and neurodegenerative diseases.This review will provide insight into establishing a concrete strategic approach for investigating pathological mechanisms and developing therapies for brain diseases.

Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer’s disease

Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer’s disease.Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases,including Parkinson’s and Huntington’s diseases,however,the effect of Citri Reticulatae Semen on Alzheimer’s disease remains unelucidated.In the current study,the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated.Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy.In addition,Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro,and suppress amyloid-beta-induced pathology such as paralysis,in a transgenic Caenorhabditis elegans in vivo model.Moreover,genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent.Most importantly,Citri Reticulatae Semen extract was confirmed to improve cognitive impairment,neuronal injury and amyloid-beta burden in 3×Tg Alzheimer’s disease mice.As revealed by both in vitro and in vivo models,these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer’s disease via its neuroprotective autophagic effects.

P7C3-A20 treats traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis

Traumatic brain injury is a severe health problem leading to autophagy and apoptosis in the brain.3,6-Dibromo-beta-fluoro-N-(3-methoxyphenyl)-9H-carbazole-9-propanamine(P7C3-A20)can be neuroprotective in various diseases,including ischemic stroke and neurodegenerative diseases.However,whether P7C3-A20 has a therapeutic effect on traumatic brain injury and its possible molecular mechanisms are unclear.Therefore,in the present study,we investigated the therapeutic effects of P7C3-A20 on traumatic brain injury and explored the putative underlying molecular mechanisms.We established a traumatic brain injury rat model using a modified weight drop method.P7C3-A20 or vehicle was injected intraperitoneally after traumatic brain injury.Severe neurological deficits were found in rats after traumatic brain injury,with deterioration in balance,walking function,and learning memory.Furthermore,hematoxylin and eosin staining showed significant neuronal cell damage,while terminal deoxynucleotidyl transferase mediated dUTP nick end labeling staining indicated a high rate of apoptosis.The presence of autolysosomes was observed using transmission electron microscope.P7C3-A20 treatment reversed these pathological features.Western blotting showed that P7C3-A20 treatment reduced microtubule-associated protein 1 light chain 3-Ⅱ(LC3-Ⅱ)autophagy protein,apoptosis-related proteins(namely,Bcl-2/adenovirus E1B 19-kDa-interacting protein 3[BNIP3],and Bcl-2 associated x protein[Bax]),and elevated ubiquitin-binding protein p62(p62)autophagy protein expression.Thus,P7C3-A20 can treat traumatic brain injury in rats by inhibiting excessive autophagy and apoptosis.

NLRP3-mediated autophagy dysfunction links gut microbiota dysbiosis to tau pathology in chronic sleep deprivation

Emerging evidence indicates that sleep deprivation(SD)can lead to Alzheimer’s disease(AD)-related pathological changes and cognitive decline.However,the underlying mechanisms remain obscure.In the present study,we identified the existence of a microbiota-gut-brain axis in cognitive deficits resulting from chronic SD and revealed a potential pathway by which gut microbiota affects cognitive functioning in chronic SD.Our findings demonstrated that chronic SD in mice not only led to cognitive decline but also induced gut microbiota dysbiosis,elevated NLRP3 inflammasome expression,GSK-3βactivation,autophagy dysfunction,and tau hyperphosphorylation in the hippocampus.Colonization with the“SD microbiota”replicated the pathological and behavioral abnormalities observed in chronic sleep-deprived mice.Remarkably,both the deletion of NLRP3 in NLRP3-/-mice and specific knockdown of NLRP3 in the hippocampus restored autophagic flux,suppressed tau hyperphosphorylation,and ameliorated cognitive deficits induced by chronic SD,while GSK-3βactivity was not regulated by the NLRP3 inflammasome in chronic SD.Notably,deletion of NLRP3 reversed NLRP3 inflammasome activation,autophagy deficits,and tau hyperphosphorylation induced by GSK-3βactivation in primary hippocampal neurons,suggesting that GSK-3β,as a regulator of NLRP3-mediated autophagy dysfunction,plays a significant role in promoting tau hyperphosphorylation.Thus,gut microbiota dysbiosis was identified as a contributor to chronic SD-induced tau pathology via NLRP3-mediated autophagy dysfunction,ultimately leading to cognitive deficits.Overall,these findings highlight GSK-3βas a regulator of NLRP3-mediated autophagy dysfunction,playing a critical role in promoting tau hyperphosphorylation.

Humanβ-defensin-1 affects the mammalian target of rapamycin pathway and autophagy in colon cancer cells through long noncoding RNA TCONS_00014506

BACKGROUND Colorectal cancer has a low 5-year survival rate and high mortality.Humanβ-defensin-1(hBD-1)may play an integral function in the innate immune system,contributing to the recognition and destruction of cancer cells.Long non-coding RNAs(lncRNAs)are involved in the process of cell differentiation and growth.AIM To investigate the effect of hBD-1 on the mammalian target of rapamycin(mTOR)pathway and autophagy in human colon cancer SW620 cells.METHODS CCK8 assay was utilized for the detection of cell proliferation and determination of the optimal drug concentration.Colony formation assay was employed to assess the effect of hBD-1 on SW620 cell proliferation.Bioinformatics was used to screen potentially biologically significant lncRNAs related to the mTOR pathway.Additionally,p-mTOR(Ser2448),Beclin1,and LC3II/I expression levels in SW620 cells were assessed through Western blot analysis.RESULTS hBD-1 inhibited the proliferative ability of SW620 cells,as evidenced by the reduction in the colony formation capacity of SW620 cells upon exposure to hBD-1.hBD-1 decreased the expression of p-mTOR(Ser2448)protein and increased the expression of Beclin1 and LC3II/I protein.Furthermore,bioinformatics analysis identified seven lncRNAs(2 upregulated and 5 downregulated)related to the mTOR pathway.The lncRNA TCONS_00014506 was ultimately selected.Following the inhibition of the lncRNA TCONS_00014506,exposure to hBD-1 inhibited p-mTOR(Ser2448)and promoted Beclin1 and LC3II/I protein expression.CONCLUSION hBD-1 inhibits the mTOR pathway and promotes autophagy by upregulating the expression of the lncRNA TCONS_00014506 in SW620 cells.

Exploring the autophagy-related pathogenesis of active ulcerative colitis

BACKGROUND The pathogenesis of ulcerative colitis(UC)is complex,and recent therapeutic advances remain unable to fully alleviate the condition.AIM To inform the development of novel UC treatments,bioinformatics was used to explore the autophagy-related pathogenesis associated with the active phase of UC.METHODS The GEO database was searched for UC-related datasets that included healthy controls who met the screening criteria.Differential analysis was conducted to obtain differentially expressed genes(DEGs).Au-tophagy-related targets were collected and intersected with the DEGs to identiy differentially expressed autophagy-related genes(DEARGs)associated with active UC.DEARGs were then subjected to KEGG,GO,and DisGeNET disease enrichment analyses using R software.Differential analysis of immune infiltrating cells was performed using the CiberSort algorithm.The least absolute shrinkage and selection operator algorithm and protein-protein interaction network were used to narrow down the DEARGs,and the top five targets in the Dgree ranking were designated as core targets.RESULTS A total of 4822 DEGs were obtained,of which 58 were classified as DEARGs.SERPINA1,BAG3,HSPA5,CASP1,and CX3CL1 were identified as core targets.GO enrichment analysis revealed that DEARGs were primarily enriched in processes related to autophagy regulation and macroautophagy.KEGG enrichment analysis showed that DEARGs were predominantly associated with NOD-like receptor signaling and other signaling pathways.Disease enrichment analysis indicated that DEARGs were significantly linked to diseases such as malignant glioma and middle cerebral artery occlusion.Immune infiltration analysis demonstrated a higher presence of immune cells like activated memory CD4 T cells and follicular helper T cells in active UC patients than in healthy controls.CONCLUSION Autophagy is closely related to the active phase of UC and the potential targets obtained from the analysis in this study may provide new insight into the treatment of active UC patients.

High expression circRALGPS2 in atretic follicle induces chicken granulosa cell apoptosis and autophagy via encoding a new protein

Background The reproductive performance of chickens mainly depends on the development of follicles.Abnor-mal follicle development can lead to decreased reproductive performance and even ovarian disease among chick-ens.Chicken is the only non-human animal with a high incidence of spontaneous ovarian cancer.In recent years,the involvement of circRNAs in follicle development and atresia regulation has been confirmed.Results In the present study,we used healthy and atretic chicken follicles for circRNA RNC-seq.The results showed differential expression of circRALGPS2.It was then confirmed that circRALGPS2 can translate into a protein,named cir-cRALGPS2-212aa,which has IRES activity.Next,we found that circRALGPS2-212aa promotes apoptosis and autophagy in chicken granulosa cells by forming a complex with PARP1 and HMGB1.Conclusions Our results revealed that circRALGPS2 can regulate chicken granulosa cell apoptosis and autophagy through the circRALGPS2-212aa/PARP1/HMGB1 axis.

Crosstalk between degradation and bioenergetics: how autophagy and endolysosomal processes regulate energy production

Cells undergo metabolic reprogramming to adapt to changes in nutrient availability, cellular activity, and transitions in cell states. The balance between glycolysis and mitochondrial respiration is crucial for energy production, and metabolic reprogramming stipulates a shift in such balance to optimize both bioenergetic efficiency and anabolic requirements. Failure in switching bioenergetic dependence can lead to maladaptation and pathogenesis. While cellular degradation is known to recycle precursor molecules for anabolism, its potential role in regulating energy production remains less explored. The bioenergetic switch between glycolysis and mitochondrial respiration involves transcription factors and organelle homeostasis, which are both regulated by the cellular degradation pathways. A growing body of studies has demonstrated that both stem cells and differentiated cells exhibit bioenergetic switch upon perturbations of autophagic activity or endolysosomal processes. Here, we highlighted the current understanding of the interplay between degradation processes, specifically autophagy and endolysosomes, transcription factors, endolysosomal signaling, and mitochondrial homeostasis in shaping cellular bioenergetics. This review aims to summarize the relationship between degradation processes and bioenergetics, providing a foundation for future research to unveil deeper mechanistic insights into bioenergetic regulation.

Quercetin Alleviates Lipopolysaccharide-Induced Cardiac Inflammation via Inhibiting Autophagy and Programmed Cell Death

Objective The aim of this study is to explore the potential modulatory role of quercetin against Endotoxin or lipopolysaccharide(LPS)induced septic cardiac dysfunction.Methods Specific pathogen-free chicken embryos(n=120)were allocated untreated control,phosphate buffer solution(PBS)vehicle,PBS with ethanol vehicle,LPS(500 ng/egg),LPS with quercetin treatment(10,20,or 40 nmol/egg,respectively),Quercetin groups(10,20,or 40 nmol/egg).Fifteenday-old embryonated eggs were inoculated with abovementioned solutions via the allantoic cavity.At embryonic day 19,the hearts of the embryos were collected for histopathological examination,RNA extraction,real-time polymerase chain reaction,immunohistochemical investigations,and Western blotting.Results They demonstrated that the heart presented inflammatory responses after LPS induction.The LPS-induced higher mRNA expressions of inflammation-related factors(TLR4,TNFα,MYD88,NF-κB1,IFNγ,IL-1β,IL-8,IL-6,IL-10,p38,MMP3,and MMP9)were blocked by quercetin with three dosages.Quercetin significantly decreased immunopositivity to TLR4 and MMP9 in the treatment group when compared with the LPS group.Quercetin significantly decreased protein expressions of TLR4,IFNγ,MMP3,and MMP9 when compared with the LPS group.Quercetin treatment prevented LPS-induced increase in the mRNA expression of Claudin 1 and ZO-1,and significantly decreased protein expression of claudin 1 when compared with the LPS group.Quercetin significantly downregulated autophagyrelated gene expressions(PPARα,SGLT1,APOA4,AMPKα1,AMPKα2,ATG5,ATG7,Beclin-1,and LC3B)and programmed cell death(Fas,Bcl-2,CASP1,CASP12,CASP3,and RIPK1)after LPS induction.Quercetin significantly decreased immunopositivity to APOA4,AMPKα2,and LC3-II/LC3-I in the treatment group when compared with the LPS group.Quercetin significantly decreased protein expressions of AMPKα1,LC3-I,and LC3-II.Quercetin significantly decreased the protein expression to CASP1 and CASP3 by immunohistochemical investigation or Western blotting in treatment group when compared with LPS group.Conclusion Quercetin alleviates cardiac inflammation induced by LPS through modulating autophagy,programmed cell death,and myocardiocytes permeability.

Salsolinol as an RNA m~6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy

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.

Autophagy and mitophagy as potential therapeutic targets in diabetic heart condition:Harnessing the power of nanotheranostics

Autophagy and mitophagy pose unresolved challenges in understanding the pathology of diabetic heart condition(DHC),which encompasses a complex range of cardiovascular issues linked to diabetes and associated cardiomyopathies.Despite significant progress in reducing mortality rates from cardiovascular diseases(CVDs),heart failure remains a major cause of increased morbidity among diabetic patients.These cellular processes are essential for maintaining cellular balance and removing damaged or dysfunctional components,and their involvement in the development of diabetic heart disease makes them attractive targets for diagnosis and treatment.While a variety of conventional diagnostic and therapeutic strategies are available,DHC continues to present a significant challenge.Point-of-care diagnostics,supported by nanobiosensing techniques,offer a promising alternative for these complex scenarios.Although conventional medications have been widely used in DHC patients,they raise several concerns regarding various physiological aspects.Modern medicine places great emphasis on the application of nanotechnology to target autophagy and mitophagy in DHC,offering a promising approach to deliver drugs beyond the limitations of traditional therapies.This article aims to explore the potential connections between autophagy,mitophagy and DHC,while also discussing the promise of nanotechnology-based theranostic interventions that specifically target these molecular pathways.

Icariin plus curcumol enhances autophagy through the mTOR pathway and promotes cathepsin B-mediated pyroptosis of prostate cancer cells

Objective:To examine the effect of icariin plus curcumol on prostate cancer cells PC3 and elucidate the underlying mechanisms.Methods:We employed the Cell Counting Kit 8 assay and colony formation assay to assess cell viability and proliferation.Autophagy expression was analyzed using monodansylcadaverine staining.Immunofluorescence and Western blot analyses were used to evaluate protein expressions related to autophagy,pyroptosis,and the mTOR pathway.Cellular damage was examined using the lactate dehydrogenase assay.Moreover,cathepsin B and NLRP3 were detected by co-immunoprecipitation.Results:Icariin plus curcumol led to a decrease in PC3 cell proliferation and an enhancement of autophagy.The levels of LC3-Ⅱ/LC3-Ⅰand beclin-1 were increased,while the levels of p62 and mTOR were decreased after treatment with icariin plus curcumol.These changes were reversed upon overexpression of mTOR.Furthermore,3-methyladenine resulted in a decrease in inflammatory cytokines,pyroptosis-related protein levels,and lactate dehydrogenase concentration,compared to the icariin plus curcumol group.Inhibiting cathepsin B reversed the regulatory effects of icariin plus curcumol.Conclusions:Icariin plus curcumol demonstrates great potential as a therapeutic agent for castration-resistant prostate cancer by enhancing autophagy via the mTOR pathway and promoting pyroptosis mediated by cathepsin B.These findings provide valuable insights into the molecular mechanisms underlying the therapeutic potential of icariin and curcumol for prostate cancer treatment.

Coated sodium butyrate ameliorates high‑energy and low‑protein diet induced hepatic dysfunction via modulating mitochondrial dynamics, autophagy and apoptosis in laying hens

Background Fatty liver hemorrhagic syndrome(FLHS),a fatty liver disease in laying hens,poses a grave threat to the layer industry,stemming from its ability to trigger an alarming plummet in egg production and usher in acute mortality among laying hens.Increasing evidence suggests that the onset and progression of fatty liver was closely related to mitochondria dysfunction.Sodium butyrate was demonstrated to modulate hepatic lipid metabolism,alle-viate oxidative stress and improve mitochondrial dysfunction in vitro and mice models.Nevertheless,there is limited existing research on coated sodium butyrate(CSB)to prevent FLHS in laying hens,and whether and how CSB exerts the anti-FLHS effect still needs to be explored.In this experiment,the FLHS model was induced by administering a high-energy low-protein(HELP)diet in laying hens.The objective was to investigate the effects of CSB on alleviating FLHS with a focus on the role of CSB in modulating mitochondrial function.Methods A total of 288 healthy 28-week-old Huafeng laying hens were arbitrarily allocated into 4 groups with 6 replicates each,namely,the CON group(normal diet),HELP group(HELP diet),CH500 group(500 mg/kg CSB added to HELP diet)and CH750 group(750 mg/kg CSB added to HELP diet).The duration of the trial encompassed a period of 10 weeks.Results The result revealed that CSB ameliorated the HELP-induced FLHS by improving hepatic steatosis and patho-logical damage,reducing the gene levels of fatty acid synthesis,and promoting the mRNA levels of key enzymes of fatty acid catabolism.CSB reduced oxidative stress induced by the HELP diet,upregulated the activity of GSH-Px and SOD,and decreased the content of MDA and ROS.CSB also mitigated the HELP diet-induced inflammatory response by blocking TNF-α,IL-1β,and F4/80.In addition,dietary CSB supplementation attenuated HELP-induced activation of the mitochondrial unfolded protein response(UPRmt),mitochondrial damage,and decline of ATPase activity.HELP diet decreased the autophagosome formation,and downregulated LC3B but upregulated p62 protein expression,which CSB administration reversed.CSB reduced HELP-induced apoptosis,as indicated by decreases in the Bax/Bcl-2,Caspase-9,Caspase-3,and Cyt C expression levels.Conclusions Dietary CSB could ameliorate HELP diet-induced hepatic dysfunction via modulating mitochondrial dynamics,autophagy,and apoptosis in laying hens.Consequently,CSB,as a feed additive,exhibited the capacity to prevent FLHS by modulating autophagy and lipid metabolism.

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson’s disease

Parkinson’s disease is a progressive neurodegenerative disease characterized by motor deficits,dopaminergic neuron loss,and brain accumulation ofα-synuclein aggregates called Lewy bodies.Dysfunction in protein degradation pathways,such as autophagy,has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson’s disease.However,it is less well understood how protein aggregates are eliminated in glia,the other cell type in the brain.In the present study,we show that autophagy-related gene 9(Atg9),the only transmembrane protein in the autophagy machinery,is highly expressed in Drosophila glia from adult brain.Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network,autophagosomes,and lysosomes in glia.Atg9 is persistently in contact with these organelles.Lacking glial atg9 reduces the number of omegasomes and autophagosomes,and impairs autophagic substrate degradation.This suggests that glial Atg9 participates in the early steps of autophagy,and hence the control of autophagic degradation.Importantly,loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons,locomotion deficits,and glial activation.Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson’s disease.These results may provide new insights on the underlying mechanism of Parkinson’s disease.