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.

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.

The autophagy-lysosome pathway:a potential target in the chemical and gene therapeutic strategies for Parkinson’s disease

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.

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.

Pyroptosis,ferroptosis,and autophagy in spinal cord injury:regulatory mechanisms and therapeutic targets

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.

Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

Endoplasmic reticulum stress and autophagy in cerebral ischemia/reperfusion injury:PERK as a potential target for intervention

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.

Autophagy prevents autophagic cell death in Tetrahymena in response to oxidative stress

Autophagy is a major cellular pathway used to degrade long-lived proteins or organelles that may be damaged due to increased reactive oxygen species（ROS） generated by cellular stress. Autophagy typically enhances cell survival, but it may also act to promote cell death under certain conditions. The mechanism underlying this paradox, however, remains unclear. We showed that Tetrahymena cells exerted increased membranebound vacuoles characteristic of autophagy followed by autophagic cell death（referred to as cell death with autophagy） after exposure to hydrogen peroxide. Inhibition of autophagy by chloroquine or 3-methyladenine significantly augmented autophagic cell death induced by hydrogen peroxide. Blockage of the mitochondrial electron transport chain or starvation triggered activation of autophagy followed by cell death by inducing the production of ROS due to the loss of mitochondrial membrane potential. This indicated a regulatory role of mitochondrial ROS in programming autophagy and autophagic cell death in Tetrahymena. Importantly, suppression of autophagy enhanced autophagic cell death in Tetrahymena in response to elevated ROS production from starvation, and this was reversed by antioxidants. Therefore, our results suggest that autophagy was activated upon oxidative stress to prevent the initiation of autophagic cell death in Tetrahymena until the accumulation of ROS passed the point of no return, leading to delayed cell death in Tetrahymena.

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.

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.

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.

Taurine attenuates activation of hepatic stellate cells by inhibiting autophagy and inducing ferroptosis

BACKGROUND Liver fibrosis is a compensatory response during the tissue repair process in chronic liver injury,and finally leads to liver cirrhosis or even hepatocellular carcinoma.The pathogenesis of hepatic fibrosis is associated with the progressive accumulation of activated hepatic stellate cells(HSCs),which can transdiffer-entiate into myofibroblasts to produce an excess of the extracellular matrix(ECM).Myofibroblasts are the main source of the excessive ECM responsible for hepatic fibrosis.Therefore,activated hepatic stellate cells(aHSCs),the principal ECM producing cells in the injured liver,are a promising therapeutic target for the treatment of hepatic fibrosis.AIM To explore the effect of taurine on aHSC proliferation and the mechanisms involved.METHODS Human HSCs(LX-2)were randomly divided into five groups:Normal control group,platelet-derived growth factor-BB(PDGF-BB)(20 ng/mL)treated group,mmol/L,respectively)with PDGF-BB(20 ng/mL)treated group.Cell Counting Kit-8 method was performed to evaluate the effect of taurine on the viability of aHSCs.Enzyme-linked immunosorbent assay was used to estimate the effect of taurine on the levels of reactive oxygen species(ROS),malondialdehyde,glutathione,and iron concen-tration.Transmission electron microscopy was applied to observe the effect of taurine on the autophagosomes and ferroptosis features in aHSCs.Quantitative real-time polymerase chain reaction and Western blot analysis were performed to detect the effect of taurine on the expression ofα-SMA,Collagen I,Fibronectin 1,LC3B,ATG5,Beclin 1,PTGS2,SLC7A11,and p62.RESULTS Taurine promoted the death of aHSCs and reduced the deposition of the ECM.Treatment with taurine could alleviate autophagy in HSCs to inhibit their activation,by decreasing autophagosome formation,downregulating LC3B and Beclin 1 protein expression,and upregulating p62 protein expression.Meanwhile,treatment with taurine triggered ferroptosis and ferritinophagy to eliminate aHSCs characterized by iron overload,lipid ROS accumu-lation,glutathione depletion,and lipid peroxidation.Furthermore,bioinformatics analysis demonstrated that taurine had a direct targeting effect on nuclear receptor coactivator 4,exhibiting the best average binding affinity of-20.99 kcal/mol.CONCLUSION Taurine exerts therapeutic effects on liver fibrosis via mechanisms that involve inhibition of autophagy and trigger of ferroptosis and ferritinophagy in HSCs to eliminate aHSCs.

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.

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.

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.

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.

Ethylene accelerates maize leaf senescence in response to nitrogen deficiency by regulating chlorophyll metabolism and autophagy

Leaf senescence is an orderly and highly coordinated process,and finely regulated by ethylene and nitrogen(N),ultimately affecting grain yield and nitrogen-use efficiency(NUE).However,the underlying regulatory mechanisms on the crosstalk between ethylene-and N-regulated leaf senescence remain a mystery in maize.In this study,ethylene biosynthesis gene ZmACS7 overexpressing(OE-ZmACS7)plants were used to study the role of ethylene regulating leaf senescence in response to N deficiency,and they exhibited the premature leaf senescence accompanied by increased ethylene release,decreased chlorophyll content and F_v/F_m ratio,and accelerated chloroplast degradation.Then,we investigated the dynamics changes of transcriptome reprogramming underlying ethylene-accelerated leaf senescence in response to N deficiency.The differentially expressed genes(DEGs)involved in chlorophyll biosynthesis were significantly down-regulated,while DEGs involved in chlorophyll degradation and autophagy processes were significantly up-regulated,especially in OE-ZmACS7 plants in response to N deficiency.A gene regulatory network(GRN)was predicted during ethylene-accelerated leaf senescence in response to N deficiency.Three transcription factors(TFs)ZmHSF4,Zmb HLH106,and ZmEREB147 were identified as the key regulatory genes,which targeted chlorophyll biosynthesis gene ZmLES22,chlorophyll degradation gene ZmNYC1,and autophagy-related gene ZmATG5,respectively.Furthermore,ethylene signaling key genes might be located upstream of these TFs,generating the signaling cascade networks during ethylene-accelerated leaf senescence in response to N deficiency.Collectively,these findings improve our molecular knowledge of ethylene-accelerated maize leaf senescence in response to N deficiency,which is promising to improve NUE by manipulating the progress of leaf senescence in maize.

More on the interplay between gut microbiota,autophagy,and inflammatory bowel disease is needed

The concept of inflammatory bowel disease(IBD),which encompasses Crohn’s disease and ulcerative colitis,represents a complex and growing global health concern resulting from a multifactorial etiology.Both dysfunctional autophagy and dysbiosis contribute to IBD,with their combined effects exacerbating the related inflammatory condition.As a result,the existing interconnection between gut microbiota,autophagy,and the host’s immune system is a decisive factor in the occurrence of IBD.The factors that influence the gut microbiota and their impact are another important point in this regard.Based on this initial perspective,this manuscript briefly highlighted the intricate interplay between the gut microbiota,autophagy,and IBD pathogenesis.In addition,it also addressed the potential targeting of the microbiota and modulating autophagic pathways for IBD therapy and proposed suggestions for future research within a more specific and expanded context.Further studies are warranted to explore restoring microbial balance and regulating autophagy mechanisms,which may offer new therapeutic avenues for IBD management and to delve into personalized treatment to alleviate the related burden.