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
Since the first electron micrograph of“lace-like structures”over 75 years ago,the endoplasmic reticulum(ER)is now viewed as a highly dynamic,constantly remodeling,continuous network of tubules and cisternae that pla...Since the first electron micrograph of“lace-like structures”over 75 years ago,the endoplasmic reticulum(ER)is now viewed as a highly dynamic,constantly remodeling,continuous network of tubules and cisternae that plays an important role in a broad range of cellular activities from calcium regulation to protein synthesis and trafficking.In neurons,the ER extends from the soma through the axon to presynaptic terminals,and throughout the dendritic arbor into as many as half of all postsynaptic dendritic spines at any given time(Falahati et al.,2022).展开更多
BACKGROUND Proteins play a central role in regulating biological functions,and various pathways regulate their synthesis and secretion.Endoplasmic reticulum-associated protein degradation(ERAD)is crucial for monitorin...BACKGROUND Proteins play a central role in regulating biological functions,and various pathways regulate their synthesis and secretion.Endoplasmic reticulum-associated protein degradation(ERAD)is crucial for monitoring protein synthesis and processing unfolded or misfolded proteins in actively growing tumor cells.However,the role of the multiple ERAD complexes in liver cancer remains unclear.AIM To elucidate the effects of SEL1L-mediated ERAD on Huh7 and explore the underlying mechanisms in vivo and in vitro.METHODS Huh7 cells were treated with ERAD inhibitor to identify ERAD’s role.Cell counting kit-8,5-ethynyl-2’-deoxyuridine and colony formation experiments were performed.Apoptosis level and migration ability were assessed using fluorescence activated cell sorting and Transwell assay,respectively.Huh7 SEL1L knockout cell line was established via clustered regularly interspaced short palindromic repeats,proliferation,apoptosis,and migration were assessed through previous experiments.The role of SEL1L in vivo and the downstream target of SEL1L were identified using Xenograft and mass spectrometry,respectively.RESULTS The ERAD inhibitor suppressed cell proliferation and migration and promoted apoptosis.SEL1L-HRD1 significantly influenced Huh7 cell growth.SEL1L knockout suppressed tumor cell proliferation and migration and enhanced apoptosis.Mass spectrometry revealed EXT2 is a primary substrate of ERAD.SEL1L knockout significantly increased the protein expression of EXT2.Furthermore,EXT2 knockdown partially restored the effect of SEL1L knockout.CONCLUSION ERAD inhibition suppressed the proliferation and migration of Huh7 and promoted its apoptosis.EXT2 plays an important role and ERAD might be a potential treatment for Huh7 hepatocellular carcinoma.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
The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to...The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to intestinal inflammation,a hallmark of inflammatory bowel disease(IBD).While the role of the gut microbiome in IBD is increasingly recognized,the underlying mechanisms,particularly those involving endoplasmic reticulum(ER)stress,autophagy,and cell death,remain incompletely understood.ER stress,a cellular response to various stressors,can trigger inflammation and cell death.Autophagy,a cellular degradation process,can either alleviate or exacerbate ER stress-induced inflammation,depending on the specific context.The gut microbiome can influence both ER stress and autophagy pathways,further complicating the interplay between these processes.This review delves into the intricate relationship between ER stress,autophagy,and the gut microbiome in the context of intestinal inflammation.By exploring the molecular mechanisms underlying these interactions,we aim to provide a comprehensive theoretical framework for developing novel therapeutic strategies for IBD.A deeper understanding of the ER stress-autophagy axis,the gut microbial-ER stress axis,and the gut microbial-autophagy axis may pave the way for targeted interventions to restore intestinal health and mitigate the impact of IBD.展开更多
In Candida species,the endoplasmic reticulum(ER)stress response—regulated by the unfolded protein response(UPR)—serves as a critical adaptive mechanism affecting both pathogenicity and antifungal resistance.This rev...In Candida species,the endoplasmic reticulum(ER)stress response—regulated by the unfolded protein response(UPR)—serves as a critical adaptive mechanism affecting both pathogenicity and antifungal resistance.This review aims to synthesize current knowledge on ER stress pathways in Candida glabrata and Candida albicans,highlighting their species-specific adaptations and therapeutic implications.We systematically analyzed peer-reviewed literature on ER stress mechanisms in Candida,focusing on comparative studies of UPR signaling.Emphasis was placed on C.glabrata’s inositol-requiring enzyme 1(IRE1)-dependent Regulated IRE1-Dependent Decay(RIDD)pathway and C.albicans’IRE1/HAC1 and calcium-mediated pathways.Connections to virulence and drug resistance were evaluated through genetic,transcriptomic,and phenotypic evidence.Candida species employ divergent UPR strategies:C.glabrata mitigates ER stress primarily via RIDD-mediated mRNA decay to reduce protein load,while C.albicans enhances folding capacity through HAC1 splicing and calcium homeostasis.These adaptations promote survival in hostile host environments(e.g.,oxidative stress,immune attacks)and are linked to resistance against azoles and echinocandins.Pharmacological disruption of UPR components(e.g.,IRE1 inhibitors)sensitizes Candida to antifungals in experimental models.ER stress response pathways are promising targets for antifungal drug development.Understanding species-specific UPR mechanisms in Candida could guide novel therapies to overcome resistance and improve treatment outcomes.展开更多
Foods and animal feeds frequently become contaminated with the nephrotoxic ochratoxin A(OTA).Our prior research has indicated that ursolic acid(UA),which is widely present in fruits and medicinal plants,has the potent...Foods and animal feeds frequently become contaminated with the nephrotoxic ochratoxin A(OTA).Our prior research has indicated that ursolic acid(UA),which is widely present in fruits and medicinal plants,has the potential to alleviate nephrotoxicity triggered by OTA.Additionally,excessive induction of endoplasmic reticulum(ER)-phagy exacerbates OTA-induced apoptosis.Therefore,further investigation is essential to comprehend whether UA can mitigate OTA-induced apoptosis by influencing ER-phagy.This objective is accomplished through a series of experiments involving assessments of cell viability,apoptosis,fluorescence microscopy,and western blot analysis.The outcomes of these experiments reveal that pre-treatment with 4μmol/L UA for 2 h can markedly reverse the elevated apoptotic rate,the co-localization of ER and lysosomes,and the protein expressions of GRP78,p-eIF2α,Chop,Bax,and Bak,as well as the reduced cell viability and the protein expressions of Lonp1,Trap1,p62,Tex264,FAM134B,Bcl-2,and Bcl-xl,all caused by exposure to 1μmol/L OTA for 24 h in human proximal tubule epithelial-originated kidney-2(HK-2)cells(P<0.05).Interestingly,the increased expression of LC3B-II induced by OTA is further amplified by UA pre-treatment(P<0.05).In conclusion,OTA triggers a harmful feedback loop between ER stress(ERS)and excessive ER-phagy,thereby further promoting ERS-and mitochondrial-mediated apoptosis in vitro.However,this effect is significantly mitigated by UA through the inhibition of autophagosome-lysosome fusion,consequently blocking the excessive ER-phagic flux.展开更多
BACKGROUND Plantamajoside(PMS)has shown potential in mitigating cell damage caused by high glucose(HG)levels.Despite this,the precise therapeutic effects of PMS on type 2 diabetes mellitus(T2DM)and the underlying regu...BACKGROUND Plantamajoside(PMS)has shown potential in mitigating cell damage caused by high glucose(HG)levels.Despite this,the precise therapeutic effects of PMS on type 2 diabetes mellitus(T2DM)and the underlying regulatory mechanisms require further exploration.AIM To investigate PMS therapeutic effects on T2DM in mice and elucidate its mechanisms of action through in vivo and in vitro experiments.METHODS An in vitro damage model of MIN6 cells was established using HG and palmitic acid(PA).PMS's protective effect on cell damage was assessed.Next,transcriptomics was employed to examine how PMS treatment affects gene expression of MIN6 cells.Furthermore,the effect of PMS on protein processing in endoplasmic reticulum and apoptosis pathways was validated.A T2DM mouse model was used to validate the therapeutic effects and mechanisms of PMS in vivo.RESULTS PMS intervention ameliorated cell injury in HG+PA-induced MIN6 cell damage.Transcriptomic analysis revealed that protein processing in the endoplasmic reticulum and apoptosis pathways were enriched in cells treated with PMS,with significant downregulation of the gene Dnajc1.Further validation indicated that PMS significantly inhibited the expression of apoptosis-related factors(Bax,CytC)and endoplasmic reticulum stress(ERS)-related factors[ATF6,XBP1,Ddit3(CHOP),GRP78],while promoting the expression of Bcl-2 and Dnajc1.Additionally,the inhibitory effects of PMS on ERS and apoptosis were abolished upon Dnajc1 silencing.Furthermore,in vivo experiments demonstrated that PMS intervention effectively improved pancreatic damage,suppressed the expression of apoptosis-related factors(Bax,CytC),and ERS-related factors[ATF6,XBP1,Ddit3(CHOP),GRP78],while promoting the expression of Bcl-2 and Dnajc1 in a T2DM model mice.CONCLUSION PMS intervention could alleviate pancreatic tissue damage effectively.The mechanism of action involves Dnajc1 activation,which subsequently inhibits apoptosis and ERS,ameliorating damage to pancreaticβ-cells.展开更多
BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous...BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous cell carcinoma(ESCC)cells,while the histone deacetylase inhibitor(HDACi)shows complex effects on tumor functions.AIM To comprehensively elucidate the impact and molecular mechanisms of trichostatin A(TSA),an HDACi,on cell migration in ESCC through bromodomain-containing protein(BRD4)/cellular myelocytomatosis oncogene(c-Myc)/endoplasmic reticulum(ER)-stress.METHODS The effects of TSA on ESCC cell lines Eca109 and EC9706 migration were evaluated using Transwell assays,with small interfering transfection and pathway-specific inhibitors to elucidate underlying mechanisms.The mRNA levels involved were examined by quantitative real-time polymerase chain reaction.Protein levels of acetylated histones H3(acH3)and acetylated histones H4,BRD4,c-Myc,as well as markers of ER stress and epithelial-mesenchymal transition(EMT),were analyzed using western blot.Additionally,this method was also used to examine acH3 levels in esophageal cancer tissues and adjacent tissues.Patient outcomes were subsequently tracked to identify prognostic indicators using Log-Rank tests and Cox multivariate analysis.RESULTS TSA promoted the migration of ESCC cells by stimulating the EMT process.TSA-mediated histone acetylation facilitated the recruitment of BRD4,a bromodomain-containing protein,triggering the expression of c-Myc.This cascade induced ER stress and enhanced EMT in ESCC cells.To further elucidate the underlying mechanism,we employed various interventions including the ER stress inhibitor 4-phenylbutyric acid,knockdown of c-Myc and BRD4 expression,and utilization of the BRD4 inhibitor carboxylic acid as well as the inhibitor of TSA 1.Mechanist-ically,these studies revealed that TSA-mediated histone acetylation facilitated the recruitment of BRD4,which in turn triggered the expression of c-Myc.This sequential activation induced ER stress and subsequently enhanced EMT,thereby promoting the migration of ESCC cells.Additionally,we examined histone acetylation levels in specimens from 43 patients with ESCC,including both tumor tissues and paired adjacent tissues.Statistical analysis unveiled a negative correlation between the level of histone acetylation and the long-term prognosis of patients with ESCC.CONCLUSION TSA promoted ESCC cell migration through the BRD4/c-Myc/ER stress pathway.Moreover,elevated histone acetylation in ESCC tissues correlated with poor ESCC prognosis.These findings enhance our understanding of ESCC migration and HDACi therapy.展开更多
17α-methyltestosterone(17α-MT)is an emerging pollutant,which is harmful to the endocrine system and reproduction of fish.We investigated the effects of different concentrations of 17α-MT(0,5,30,60,and 100 mg/kg)on ...17α-methyltestosterone(17α-MT)is an emerging pollutant,which is harmful to the endocrine system and reproduction of fish.We investigated the effects of different concentrations of 17α-MT(0,5,30,60,and 100 mg/kg)on endoplasmic reticulum stress(ERS)and apoptosis in the liver of Takifugu fasciatus.Results show that:(1)with the increase of 17α-MT treatment concentration,liver transaminases(alanine aminotransferase;aspartate aminotransferase)and the mRNA expression of ERS marker genes(glucose-regulated protein 78;calreticulin)of T.fasciatus were significantly increased compared with the control group(P<0.05);(2)the activity of succinate dehydrogenase(SDH),Caspase3 and Caspase9 in the liver of T.fasciatus increased with the increase of 17α-MT concentration compared with the control group(P<0.05);(3)by using 4-phenylbutyricacid(4-PBA)inhibitors to stimulate ERS through in vitro experiments,the expression of ERS and apoptosis-related genes significantly decreased(P<0.05),and the apoptosis rate of T.fasciatus hepatocytes was significantly inhibited(P<0.05)under 17α-MT treatment.This study confirmed that ERS played an important role in the induction of apoptosis in the hepatocytes of T.fasciatus,which enriched the ecotoxicological information of environmental androgens.展开更多
The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response...The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response fails to restore endoplasmic reticulum homeostasis,it can trigger proinflammatory and pro-death signals,which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases.This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases.The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise.Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies,including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid,which enhance protein folding and reduce endoplasmic reticulum stress.Small molecule modulators that influence endoplasmic reticulum stress sensors,including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1,are also potential therapeutic agents.Additionally,inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1,a key endoplasmic reticulum stress sensor,represent another class of drugs that could prevent the formation of toxic aggregates.The activation of nuclear receptors,such as PPAR and FXR,may also help mitigate ER stress.Furthermore,enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins.Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored.Despite these potential therapeutic strategies,significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration,and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective,well-tolerated drugs.The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects,which have hindered their clinical translation.Moreover,signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance.Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies.In conclusion,while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases,additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.展开更多
Eukaryotic cells contain the endoplasmic reticulum(ER),a prevalent and intricate membranous structural system.During the development of inflammatory bowel disease(IBD),the stress on the ER and the start of the unfolde...Eukaryotic cells contain the endoplasmic reticulum(ER),a prevalent and intricate membranous structural system.During the development of inflammatory bowel disease(IBD),the stress on the ER and the start of the unfolded protein response are very important.Some chemicals,including 4μ8C,small molecule agonists of X-box binding protein 1,and ISRIB,work on the inositol-requiring enzyme 1,turn on transcription factor 6,and activate protein kinase RNA-like ER kinase path-ways.This may help ease the symptoms of IBD.Researchers investigating the gut microbiota have discovered a correlation between ER stress and it.This suggests that changing the gut microbiota could help make new medicines for IBD.This study looks at how ER stress works and how it contributes to the emergence of IBD.It also talks about its possible clinical importance as a therapeutic target and looks into new ways to treat this condition.展开更多
BACKGROUND Hypertrophy obesity is closely associated with obesity-related metabolic diseases.The senescence of adipose-derived mesenchymal stem cells(ASCs)is believed to play a significant role in the development of h...BACKGROUND Hypertrophy obesity is closely associated with obesity-related metabolic diseases.The senescence of adipose-derived mesenchymal stem cells(ASCs)is believed to play a significant role in the development of hypertrophy obesity.AIM To investigate the relationship between ASC senescence,endoplasmic reticulum(ER)stress,and nuclear factor erythroid-derived 2(NRF2)activity in a mouse model of hypertrophy obesity.Additionally,we explored the mechanism through which NRF2 affects ASC senescence via mitofusin-2(MFN2).METHODS We observed the senescent phenotype and ER stress(ERS)in ASCs from hypertrophic obese mouse models,and determined NRF2 activity.Chromatin immunoprecipitation-quantitative polymerase chain reaction(qPCR)was used to analyze the transcriptional activity of NRF2 on Mfn2.Additionally,co-immunoprecipitation experiments were conducted to investigate the interaction between MFN2 and binding immunoglobulin protein.The impact of NRF2 and MFN2 on the therapeutic effect of ASC transplantation against insulin resistance was explored through ASC transplantation.RESULTS The study found significant increases in senescence and ERS,accompanied by decreased NRF2 activity in ASCs from hypertrophic obese mouse models.Simultaneously,chromatin immunoprecipitation-qPCR analysis revealed a reduction in NRF2 transcriptional activity on Mfn2.The downregulation of NRF2 activity and Mfn2 expression promoted senescence and ERS in ASCs,subsequently impacting the anti-insulin resistance effect of ASC transplantation.Furthermore,there exists a direct or indirect binding between MFN2 and binding immunoglobulin protein.CONCLUSION The research outcomes suggest that NRF2 may regulate ERS and senescence in subcutaneous ASCs of hypertrophic obese mice by modulating Mfn2.These discoveries offer new insights into understanding metabolic diseases associated with hypertrophic obesity and potentially provide a foundation for intervention strategies.展开更多
Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and m...Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis(BCBM).Methods:Migrasomes were isolated and purified from BCBM cells(231-BR)and non-specific organotropic parental counterparts(MDA-MB-231),specifically designated as Mig-BCBM and Mig-BC,respectively.The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model.The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR,western blotting,immunofluorescence,ex vivo fluorescence imaging,and a series of rescue experiments.Results:Mig-BCBM potently augmented the permeability of vascular endothelial layers,which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro.The administration of Mig-BCBM significantly disrupted the blood-brain barrier(BBB)and accelerated BCBM progression in vivo,as evidenced in mouse models,compared to the Mig-BC and control groups.Mechanistically,Mig-BCBM harbored ATF6,a critical transducer of endoplasmic reticulum(ER)stress.Upon internalization into hCMEC/D3 cells,ATF6 elicited robust ER stress responses,culminating in downregulation of ZO-1 and VE-cadherin.Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.Conclusions:This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis,suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.展开更多
Mucin 2(MUC2)is a critical component of the intestinal mucus barrier.Lactic acid bacteria(LAB)strains can improve mucosal homeostasis.In this study,we determined the expression of Muc2 induced by dead bacteria and cel...Mucin 2(MUC2)is a critical component of the intestinal mucus barrier.Lactic acid bacteria(LAB)strains can improve mucosal homeostasis.In this study,we determined the expression of Muc2 induced by dead bacteria and cell-free conditioned medium(CM)of 50 LAB strains in the human goblet cell line,LS174T.Dead bacteria or CM of LAB affected the Muc2 expression in a species-and strain-specific manner under homeostasis.Next,LAB strains with different regulatory abilities were selected,gavaged into mice,and exposed to dextran sodium sulfate(DSS)after 1 week.Different LAB strains inhibited intestinal injury to different degrees,with Lactobacillus acidophilus FCQHC4L1 exerting the most potent effect.FCQHC4L1 significantly decreased the secretion of pro-inflammatory factors,promoted the expression and secretion of mucin,and inhibited colitis development.This strain also regulated the gut microbiota and increased the secretion of butyric acid.Moreover,CM of FCQHC4L1 inhibited endoplasmic reticulum(ER)stress and ameliorated the abnormal expression of MUC2 by suppressing the activation of the GRP78/ATF6 and GRP78/IRE1/XBP1 signaling pathways.Our results highlight the potential of FCQHC4L1 as a therapeutic agent for strengthening the mucus barrier and improving the gut health.展开更多
Background The use of conventional two-dimensional(2D)culture of the porcine intestinal epithelial cell(IEC)line IPEC-J2 in animal nutrition research has the disadvantage that IEC function is studied under unphysiolog...Background The use of conventional two-dimensional(2D)culture of the porcine intestinal epithelial cell(IEC)line IPEC-J2 in animal nutrition research has the disadvantage that IEC function is studied under unphysiological conditions,which limits the ability of transferring knowledge to the in vivo-situation.Thus,the aim of the present study was to establish a more convincing and meaningful three-dimensional(3D)culture of IPEC-J2 cells,which allows to study cell function in a more tissue-like environment,and to compare the effect of the endoplasmic reticulum(ER)stress inducer tunicamycin(TM)on ER stress indicators and the expression of tight junction proteins(TJP),inflammatory and apoptosis-related genes and the modulatory role of 1,25-dihydroxy-vitamin D_(3)(1,25D_(3))on these parameters in 2D and 3D cultures of IPEC-J2 cells.Results A published protocol for 3D culture of Caco-2 cells was successfully adopted to IPEC-J2 cells as evident from fully differentiated 3D IPEC-J2 spheroids showing the characteristic spherical architecture with a single layer of IPEC-J2 cells surrounding a central lumen.Treatment of 2D IPEC-J2 cells and 3D IPEC-J2 spheroids with TM for 24 h markedly increased m RNA and/or protein levels of the ER stress target genes,heat shock protein family A(Hsp70)member 5(HSPA5)and DNA damage inducible transcript 3(DDIT3),whereas co-treatment with TM and 1,25D_(3) did not mitigate TM-induced ER stress in IPEC-J2 cells in the 2D and the 3D cell culture.In contrast,TM-induced expression of pro-inflammatory[interleukin-6(IL6),IL8]and pro-apoptotic genes[BCL2 associated X,apoptosis regulator(BAX),caspase 3(CASP3),CASP8]and genes encoding TJP[TJP1,claudin 1(CLDN1),CLDN3,occludin(OCLN),cadherin 1(CDH1),junctional adhesion molecule 1(JAM1)]was reduced by co-treatment with TM and 1,25D_(3) in 3D IPEC-J2 spheroids but not in the 2D cell culture.Conclusions The effect of 1,25D_(3) in the IPEC-J2 cell culture is dependent on the culture model applied.While 1,25D_(3) does not inhibit TM-induced expression of genes involved in inflammation,apoptosis and TJP in conventional 2D cultures of IPEC-J2 cells,TM-induced expression of these genes is abrogated by 1,25D_(3) in the more meaningful 3D IPEC-J2 cell culture model.展开更多
Background:Mechanical ventilation(MV)provides life support for patients with severe respiratory distress but can simultaneously cause ventilator-induced lung injury(VILI).However,due to a poor understanding of its mec...Background:Mechanical ventilation(MV)provides life support for patients with severe respiratory distress but can simultaneously cause ventilator-induced lung injury(VILI).However,due to a poor understanding of its mechanism,there is still a lack of effective remedies for the often-deadly VILI.Recent studies indicate that the stretch associated with MV can enhance the secretion of extracellular vesicles(EVs)and induce endoplasmic reticulum(ER)stress in airway smoothmuscle cells(ASMCs),both of which can contribute to VILI.But whetherMVassociated stretch enhances the secretion of EVs via ER stress in ASMCs as an underlying mechanism of VILI remains unknown.Methods:In this study,we exposed cultured human ASMCs to stretch(13%strain)and mouse models to MV at tidal volume(18 mL/kg).Subsequently,the amount of secreted EVs in the culture medium of ASMCs and the bronchoalveolar lavage fluid(BALF)of mousemodels was quantitatively evaluated by ultracentrifugation,transmission electron microscopy,Western blot,flow cytometry,and nanoparticle tracking analysis.The cultured ASMCs and the lung tissues of mouse models were assessed for expression of biomarkers of EVs(cluster of differentiation antigen 63,CD63),ER stress(heat shock protein family A member 5,HSPA5),and EVs regulating molecule Rab27a by immunofluorescence microscopy,immunohistochemistry(IHC)and enzyme-linked immunosorbent assay(ELISA),respectively.MicroRNAs(miRNAs)in EVs from ASMCs were measured with miRNA whole genome sequencing(miRNA-Seq).Results:We found that stretch enhanced EV secretion from cultured ASMCs.In addition,the cultured ASMCs and the mouse models were either or not pretreated with ER stress inhibitor(tauroursodeoxycholic acid,TUDCA)/EV secretion inhibitor(GW4869)prior to stretch or MV.We found that MV-associated stretch enhanced the expression of CD63,HSPA5,and Rab27a in cultured ASMCs and BALF/lung tissues of mousemodels,which could all be attenuated with TUDCA/GW4869 pretreatment.miRNA-Seq data show that differentially expressed miRNAs in EVsmainlymodulate gene transcription.Furthermore,the EVs fromcultured ASMCs under stretch tended to enhance detachment and expression of inflammatory cytokines,i.e.,transforming growth factor-β1(TGF-β1),interleukin-10(IL-10)in cultured airway epithelial cells.The expression of TGF-β1 and IL-10 in BALF of the mouse models also increased in response to MV,which was attenuated together with partial improvement of lung injury by pretreatment with TUDCA,GW4869/Rab27a siRNAs.Conclusion:Taken together,our data indicate thatMV-associated stretch can enhance the secretion of EVs from ASMCs via ER stress signaling to mediate airway inflammation and VILI,which provides new insight for further exploring EVs for the diagnosis and treatment of VILI.展开更多
Diabetes mellitus(DM)is a metabolic disorder characterized by persistent hyperglycemia and other symptoms,which pose significant challenges to individual health,life expectancy,and public healthcare systems.The escala...Diabetes mellitus(DM)is a metabolic disorder characterized by persistent hyperglycemia and other symptoms,which pose significant challenges to individual health,life expectancy,and public healthcare systems.The escalating global prevalence of diabetes underscores the need for innovative therapeutic interventions.In this article,we critically comment on the study by Wang et al,published in the World Journal of Diabetes,which elucidates the therapeutic potential of Plantamajoside(PMS)in type 2 DM(T2DM)management.The authors provide evidence for the mechanism of action of PMS in T2DM models,demonstrating prevention of endoplasmic reticulum stress and apoptosis of pancreaticβ-cells via activation of DNAJC1.This manuscript provides a brief review of the pathogenesis of T2DM,explores the various roles of PMS in disease therapy in addition to the DNAJC-related apoptotic and autophagic functions,critically evaluates the experimental approaches employed by Wang et al,and provides recommendations for advancing future research.展开更多
BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but th...BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but the detailed mechanism is still unclear.Most studies ofβ-cell dedifferentiation rely on rodent models and human pathological specimens.The development of in vitro systems can facilitate the exploration ofβ-cell dedifferentiation.AIM To investigate the molecular mechanism ofβ-cell dedifferentiation.Hence,an in vitro model ofβ-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1832/13 cell line.METHODS The study was further analyzed using RNA-sequencing,transmission electron microscopy,quantitative real-time polymerase chain reaction and Western blot.RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulatedβ-cell forbidden genes and endocrine precursor cell marker genes,and down-regulated the expression ofβ-cell specific markers.Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum(ER)stressrelated genes.Moreover,the results also showed that forkhead box O1(Foxo1)inhibition potentiated genetic changes inβ-cell dedifferentiation induced by palmitic acid and high glucose.CONCLUSION ER stress is sufficient to triggerβ-cell dedifferentiation and is necessary for palmitic acid and high glucose-inducedβ-cell dedifferentiation.Foxo1 inhibition can further enhance these phenomena.展开更多
β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unkno...β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.展开更多
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 AHA Career Development Award 938683 (to PJD)NIH grant R01MH123700 (to MLD)
文摘Since the first electron micrograph of“lace-like structures”over 75 years ago,the endoplasmic reticulum(ER)is now viewed as a highly dynamic,constantly remodeling,continuous network of tubules and cisternae that plays an important role in a broad range of cellular activities from calcium regulation to protein synthesis and trafficking.In neurons,the ER extends from the soma through the axon to presynaptic terminals,and throughout the dendritic arbor into as many as half of all postsynaptic dendritic spines at any given time(Falahati et al.,2022).
基金Supported by the National Natural Science Foundation of China,No.82241219,No.82127808 and No.81921004The Shenzhen Science and Technology Program,No.JCYJ20210324120813037.
文摘BACKGROUND Proteins play a central role in regulating biological functions,and various pathways regulate their synthesis and secretion.Endoplasmic reticulum-associated protein degradation(ERAD)is crucial for monitoring protein synthesis and processing unfolded or misfolded proteins in actively growing tumor cells.However,the role of the multiple ERAD complexes in liver cancer remains unclear.AIM To elucidate the effects of SEL1L-mediated ERAD on Huh7 and explore the underlying mechanisms in vivo and in vitro.METHODS Huh7 cells were treated with ERAD inhibitor to identify ERAD’s role.Cell counting kit-8,5-ethynyl-2’-deoxyuridine and colony formation experiments were performed.Apoptosis level and migration ability were assessed using fluorescence activated cell sorting and Transwell assay,respectively.Huh7 SEL1L knockout cell line was established via clustered regularly interspaced short palindromic repeats,proliferation,apoptosis,and migration were assessed through previous experiments.The role of SEL1L in vivo and the downstream target of SEL1L were identified using Xenograft and mass spectrometry,respectively.RESULTS The ERAD inhibitor suppressed cell proliferation and migration and promoted apoptosis.SEL1L-HRD1 significantly influenced Huh7 cell growth.SEL1L knockout suppressed tumor cell proliferation and migration and enhanced apoptosis.Mass spectrometry revealed EXT2 is a primary substrate of ERAD.SEL1L knockout significantly increased the protein expression of EXT2.Furthermore,EXT2 knockdown partially restored the effect of SEL1L knockout.CONCLUSION ERAD inhibition suppressed the proliferation and migration of Huh7 and promoted its apoptosis.EXT2 plays an important role and ERAD might be a potential treatment for Huh7 hepatocellular carcinoma.
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 fund for the Project of the National Key Research and Development Program of China(2024YFD1300203)Project support was provided by the Fund opened from Key Laboratory of Fujian Universities Preventive Veterinary Medicine and Biotechnology,Longyan University(grant No.2021KF01)the Cyanine Project of Yangzhou University(2020)。
文摘The intestinal tract,a complex organ responsible for nutrient absorption and digestion,relies heavily on a balanced gut microbiome to maintain its integrity.Disruptions to this delicate microbial ecosystem can lead to intestinal inflammation,a hallmark of inflammatory bowel disease(IBD).While the role of the gut microbiome in IBD is increasingly recognized,the underlying mechanisms,particularly those involving endoplasmic reticulum(ER)stress,autophagy,and cell death,remain incompletely understood.ER stress,a cellular response to various stressors,can trigger inflammation and cell death.Autophagy,a cellular degradation process,can either alleviate or exacerbate ER stress-induced inflammation,depending on the specific context.The gut microbiome can influence both ER stress and autophagy pathways,further complicating the interplay between these processes.This review delves into the intricate relationship between ER stress,autophagy,and the gut microbiome in the context of intestinal inflammation.By exploring the molecular mechanisms underlying these interactions,we aim to provide a comprehensive theoretical framework for developing novel therapeutic strategies for IBD.A deeper understanding of the ER stress-autophagy axis,the gut microbial-ER stress axis,and the gut microbial-autophagy axis may pave the way for targeted interventions to restore intestinal health and mitigate the impact of IBD.
文摘In Candida species,the endoplasmic reticulum(ER)stress response—regulated by the unfolded protein response(UPR)—serves as a critical adaptive mechanism affecting both pathogenicity and antifungal resistance.This review aims to synthesize current knowledge on ER stress pathways in Candida glabrata and Candida albicans,highlighting their species-specific adaptations and therapeutic implications.We systematically analyzed peer-reviewed literature on ER stress mechanisms in Candida,focusing on comparative studies of UPR signaling.Emphasis was placed on C.glabrata’s inositol-requiring enzyme 1(IRE1)-dependent Regulated IRE1-Dependent Decay(RIDD)pathway and C.albicans’IRE1/HAC1 and calcium-mediated pathways.Connections to virulence and drug resistance were evaluated through genetic,transcriptomic,and phenotypic evidence.Candida species employ divergent UPR strategies:C.glabrata mitigates ER stress primarily via RIDD-mediated mRNA decay to reduce protein load,while C.albicans enhances folding capacity through HAC1 splicing and calcium homeostasis.These adaptations promote survival in hostile host environments(e.g.,oxidative stress,immune attacks)and are linked to resistance against azoles and echinocandins.Pharmacological disruption of UPR components(e.g.,IRE1 inhibitors)sensitizes Candida to antifungals in experimental models.ER stress response pathways are promising targets for antifungal drug development.Understanding species-specific UPR mechanisms in Candida could guide novel therapies to overcome resistance and improve treatment outcomes.
基金financially supported by the National Natural Science Foundation of China(82060598,32260587)the Natural Science Foundation of Guizhou Province(QKH-J-ZK[2021]181)+4 种基金the Scientific Research Program of Guizhou Provincial Department of Education(QJJ[2023]019)the Science&Technology Program of Guizhou Province(QKHPTRC-CXTD[2022]014)the Excellent Youth Talents of Zunyi Medical University(17zy-006)the Innovation and Entrepreneurship Training Program for College Students of Guizhou Province(S202210661138)the Innovation and Entrepreneurship Training Program for College Students of Zunyi Medical University(ZYDC2021108)。
文摘Foods and animal feeds frequently become contaminated with the nephrotoxic ochratoxin A(OTA).Our prior research has indicated that ursolic acid(UA),which is widely present in fruits and medicinal plants,has the potential to alleviate nephrotoxicity triggered by OTA.Additionally,excessive induction of endoplasmic reticulum(ER)-phagy exacerbates OTA-induced apoptosis.Therefore,further investigation is essential to comprehend whether UA can mitigate OTA-induced apoptosis by influencing ER-phagy.This objective is accomplished through a series of experiments involving assessments of cell viability,apoptosis,fluorescence microscopy,and western blot analysis.The outcomes of these experiments reveal that pre-treatment with 4μmol/L UA for 2 h can markedly reverse the elevated apoptotic rate,the co-localization of ER and lysosomes,and the protein expressions of GRP78,p-eIF2α,Chop,Bax,and Bak,as well as the reduced cell viability and the protein expressions of Lonp1,Trap1,p62,Tex264,FAM134B,Bcl-2,and Bcl-xl,all caused by exposure to 1μmol/L OTA for 24 h in human proximal tubule epithelial-originated kidney-2(HK-2)cells(P<0.05).Interestingly,the increased expression of LC3B-II induced by OTA is further amplified by UA pre-treatment(P<0.05).In conclusion,OTA triggers a harmful feedback loop between ER stress(ERS)and excessive ER-phagy,thereby further promoting ERS-and mitochondrial-mediated apoptosis in vitro.However,this effect is significantly mitigated by UA through the inhibition of autophagosome-lysosome fusion,consequently blocking the excessive ER-phagic flux.
基金Yuansong Wang National Famous Traditional Chinese Medicine Expert Heritage Studio,No.4(2022).
文摘BACKGROUND Plantamajoside(PMS)has shown potential in mitigating cell damage caused by high glucose(HG)levels.Despite this,the precise therapeutic effects of PMS on type 2 diabetes mellitus(T2DM)and the underlying regulatory mechanisms require further exploration.AIM To investigate PMS therapeutic effects on T2DM in mice and elucidate its mechanisms of action through in vivo and in vitro experiments.METHODS An in vitro damage model of MIN6 cells was established using HG and palmitic acid(PA).PMS's protective effect on cell damage was assessed.Next,transcriptomics was employed to examine how PMS treatment affects gene expression of MIN6 cells.Furthermore,the effect of PMS on protein processing in endoplasmic reticulum and apoptosis pathways was validated.A T2DM mouse model was used to validate the therapeutic effects and mechanisms of PMS in vivo.RESULTS PMS intervention ameliorated cell injury in HG+PA-induced MIN6 cell damage.Transcriptomic analysis revealed that protein processing in the endoplasmic reticulum and apoptosis pathways were enriched in cells treated with PMS,with significant downregulation of the gene Dnajc1.Further validation indicated that PMS significantly inhibited the expression of apoptosis-related factors(Bax,CytC)and endoplasmic reticulum stress(ERS)-related factors[ATF6,XBP1,Ddit3(CHOP),GRP78],while promoting the expression of Bcl-2 and Dnajc1.Additionally,the inhibitory effects of PMS on ERS and apoptosis were abolished upon Dnajc1 silencing.Furthermore,in vivo experiments demonstrated that PMS intervention effectively improved pancreatic damage,suppressed the expression of apoptosis-related factors(Bax,CytC),and ERS-related factors[ATF6,XBP1,Ddit3(CHOP),GRP78],while promoting the expression of Bcl-2 and Dnajc1 in a T2DM model mice.CONCLUSION PMS intervention could alleviate pancreatic tissue damage effectively.The mechanism of action involves Dnajc1 activation,which subsequently inhibits apoptosis and ERS,ameliorating damage to pancreaticβ-cells.
基金Supported by the Henan Province Science and Technology Development Plan,No.242102311124Key Medical Scientific and Technological Project of Henan Province,No.SBGJ202102188+1 种基金Henan Provincial Medical Science and Technology Project,No.LHGJ20221012Fundamental Research Funds for the Universities of Henan Province,No.NSFRF240308.
文摘BACKGROUND The causes of death in patients with advanced esophageal cancer are multi-factorial,with tumor metastasis being one of the important factors.Histone acetylation promotes the migration of esophageal squamous cell carcinoma(ESCC)cells,while the histone deacetylase inhibitor(HDACi)shows complex effects on tumor functions.AIM To comprehensively elucidate the impact and molecular mechanisms of trichostatin A(TSA),an HDACi,on cell migration in ESCC through bromodomain-containing protein(BRD4)/cellular myelocytomatosis oncogene(c-Myc)/endoplasmic reticulum(ER)-stress.METHODS The effects of TSA on ESCC cell lines Eca109 and EC9706 migration were evaluated using Transwell assays,with small interfering transfection and pathway-specific inhibitors to elucidate underlying mechanisms.The mRNA levels involved were examined by quantitative real-time polymerase chain reaction.Protein levels of acetylated histones H3(acH3)and acetylated histones H4,BRD4,c-Myc,as well as markers of ER stress and epithelial-mesenchymal transition(EMT),were analyzed using western blot.Additionally,this method was also used to examine acH3 levels in esophageal cancer tissues and adjacent tissues.Patient outcomes were subsequently tracked to identify prognostic indicators using Log-Rank tests and Cox multivariate analysis.RESULTS TSA promoted the migration of ESCC cells by stimulating the EMT process.TSA-mediated histone acetylation facilitated the recruitment of BRD4,a bromodomain-containing protein,triggering the expression of c-Myc.This cascade induced ER stress and enhanced EMT in ESCC cells.To further elucidate the underlying mechanism,we employed various interventions including the ER stress inhibitor 4-phenylbutyric acid,knockdown of c-Myc and BRD4 expression,and utilization of the BRD4 inhibitor carboxylic acid as well as the inhibitor of TSA 1.Mechanist-ically,these studies revealed that TSA-mediated histone acetylation facilitated the recruitment of BRD4,which in turn triggered the expression of c-Myc.This sequential activation induced ER stress and subsequently enhanced EMT,thereby promoting the migration of ESCC cells.Additionally,we examined histone acetylation levels in specimens from 43 patients with ESCC,including both tumor tissues and paired adjacent tissues.Statistical analysis unveiled a negative correlation between the level of histone acetylation and the long-term prognosis of patients with ESCC.CONCLUSION TSA promoted ESCC cell migration through the BRD4/c-Myc/ER stress pathway.Moreover,elevated histone acetylation in ESCC tissues correlated with poor ESCC prognosis.These findings enhance our understanding of ESCC migration and HDACi therapy.
基金Supported by the Jiangsu Agriculture Science and Technology Innovation Fund(No.CX(22)2029)the National Natural Science Foundation of China(Nos.32172948,31800436)+1 种基金the“JBGS”Project of Seed Industry Revitalization in Jiangsu Province(No.JBGS(2021)034)the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.SJCX23_0616)。
文摘17α-methyltestosterone(17α-MT)is an emerging pollutant,which is harmful to the endocrine system and reproduction of fish.We investigated the effects of different concentrations of 17α-MT(0,5,30,60,and 100 mg/kg)on endoplasmic reticulum stress(ERS)and apoptosis in the liver of Takifugu fasciatus.Results show that:(1)with the increase of 17α-MT treatment concentration,liver transaminases(alanine aminotransferase;aspartate aminotransferase)and the mRNA expression of ERS marker genes(glucose-regulated protein 78;calreticulin)of T.fasciatus were significantly increased compared with the control group(P<0.05);(2)the activity of succinate dehydrogenase(SDH),Caspase3 and Caspase9 in the liver of T.fasciatus increased with the increase of 17α-MT concentration compared with the control group(P<0.05);(3)by using 4-phenylbutyricacid(4-PBA)inhibitors to stimulate ERS through in vitro experiments,the expression of ERS and apoptosis-related genes significantly decreased(P<0.05),and the apoptosis rate of T.fasciatus hepatocytes was significantly inhibited(P<0.05)under 17α-MT treatment.This study confirmed that ERS played an important role in the induction of apoptosis in the hepatocytes of T.fasciatus,which enriched the ecotoxicological information of environmental androgens.
基金supported by the Natural Science Foundation of Shaanxi Province(Key Program),No.2021JZ-60(to HZ)。
文摘The unfolded protein response is a cellular pathway activated to maintain proteostasis and prevent cell death when the endoplasmic reticulum is overwhelmed by unfolded proteins.However,if the unfolded protein response fails to restore endoplasmic reticulum homeostasis,it can trigger proinflammatory and pro-death signals,which are implicated in various malignancies and are currently being investigated for their role in retinal degenerative diseases.This paper reviews the role of the unfolded protein responsein addressing endoplasmic reticulumstress in retinal degenerative diseases.The accumulation of ubiquitylated misfolded proteins can lead to rapid destabilization of the proteome and cellular demise.Targeting endoplasmic reticulum stress to alleviate retinal pathologies involves multiple strategies,including the use of chemical chaperones such as 4-phenylbutyric acid and tauroursodeoxycholic acid,which enhance protein folding and reduce endoplasmic reticulum stress.Small molecule modulators that influence endoplasmic reticulum stress sensors,including those that increase the expression of the endoplasmic reticulum stress regulator X-box binding protein 1,are also potential therapeutic agents.Additionally,inhibitors of the RNAse activity of inositol-requiring transmembrane kinase/endoribonuclease 1,a key endoplasmic reticulum stress sensor,represent another class of drugs that could prevent the formation of toxic aggregates.The activation of nuclear receptors,such as PPAR and FXR,may also help mitigate ER stress.Furthermore,enhancing proteolysis through the induction of autophagy or the inhibition of deubiquitinating enzymes can assist in clearing misfolded proteins.Combination treatments that involve endoplasmicreticulum-stress-targeting drugs and gene therapies are also being explored.Despite these potential therapeutic strategies,significant challenges remain in targeting endoplasmic reticulum stress for the treatment of retinal degeneration,and further research is essential to elucidate the mechanisms underlying human retinal diseases and to develop effective,well-tolerated drugs.The use of existing drugs that target inositol-requiring transmembrane kinase/endoribonuclease 1 and X-box binding protein 1 has been associated with adverse side effects,which have hindered their clinical translation.Moreover,signaling pathways downstream of endoplasmic reticulum stress sensors can contribute to therapy resistance.Addressing these limitations is crucial for developing drugs that can be effectively used in treating retinal dystrophies.In conclusion,while the unfolded protein response is a promising therapeutic target in retinal degenerative diseases,additional research and development efforts are imperative to overcome the current limitations and improve patient outcomes.
基金Supported by the National Natural Science Foundation of China,No.81873297the Fundamental Research Funds for the Central Public Welfare Research Institutes,No.ZZ13-YQ-006+1 种基金China Academy of Chinese Medical Sciences Innovation Fund,No.CI2021A01003the Hospital Capability Enhancement Project of Xiyuan Hospital,China Academy of Chinese Medical Sciences,No.XYZX0303-07.
文摘Eukaryotic cells contain the endoplasmic reticulum(ER),a prevalent and intricate membranous structural system.During the development of inflammatory bowel disease(IBD),the stress on the ER and the start of the unfolded protein response are very important.Some chemicals,including 4μ8C,small molecule agonists of X-box binding protein 1,and ISRIB,work on the inositol-requiring enzyme 1,turn on transcription factor 6,and activate protein kinase RNA-like ER kinase path-ways.This may help ease the symptoms of IBD.Researchers investigating the gut microbiota have discovered a correlation between ER stress and it.This suggests that changing the gut microbiota could help make new medicines for IBD.This study looks at how ER stress works and how it contributes to the emergence of IBD.It also talks about its possible clinical importance as a therapeutic target and looks into new ways to treat this condition.
基金Supported by the National Natural Science Foundation of China,No.32000511Medical Science and Technology Joint Construction Program of Henan Province,No.LHGJ20230053.
文摘BACKGROUND Hypertrophy obesity is closely associated with obesity-related metabolic diseases.The senescence of adipose-derived mesenchymal stem cells(ASCs)is believed to play a significant role in the development of hypertrophy obesity.AIM To investigate the relationship between ASC senescence,endoplasmic reticulum(ER)stress,and nuclear factor erythroid-derived 2(NRF2)activity in a mouse model of hypertrophy obesity.Additionally,we explored the mechanism through which NRF2 affects ASC senescence via mitofusin-2(MFN2).METHODS We observed the senescent phenotype and ER stress(ERS)in ASCs from hypertrophic obese mouse models,and determined NRF2 activity.Chromatin immunoprecipitation-quantitative polymerase chain reaction(qPCR)was used to analyze the transcriptional activity of NRF2 on Mfn2.Additionally,co-immunoprecipitation experiments were conducted to investigate the interaction between MFN2 and binding immunoglobulin protein.The impact of NRF2 and MFN2 on the therapeutic effect of ASC transplantation against insulin resistance was explored through ASC transplantation.RESULTS The study found significant increases in senescence and ERS,accompanied by decreased NRF2 activity in ASCs from hypertrophic obese mouse models.Simultaneously,chromatin immunoprecipitation-qPCR analysis revealed a reduction in NRF2 transcriptional activity on Mfn2.The downregulation of NRF2 activity and Mfn2 expression promoted senescence and ERS in ASCs,subsequently impacting the anti-insulin resistance effect of ASC transplantation.Furthermore,there exists a direct or indirect binding between MFN2 and binding immunoglobulin protein.CONCLUSION The research outcomes suggest that NRF2 may regulate ERS and senescence in subcutaneous ASCs of hypertrophic obese mice by modulating Mfn2.These discoveries offer new insights into understanding metabolic diseases associated with hypertrophic obesity and potentially provide a foundation for intervention strategies.
基金supported by the National Natural Science Foundation of China(Grant No.81702884)Natural Science Foundation of Shandong Province(Grant Nos.ZR2022MH272,ZR2020QH216,and ZR2023QH115)Medicine and Health Science and Technology Foundation of Shandong Province(Grant Nos.202402060623 and 202202080721).
文摘Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis(BCBM).Methods:Migrasomes were isolated and purified from BCBM cells(231-BR)and non-specific organotropic parental counterparts(MDA-MB-231),specifically designated as Mig-BCBM and Mig-BC,respectively.The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model.The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR,western blotting,immunofluorescence,ex vivo fluorescence imaging,and a series of rescue experiments.Results:Mig-BCBM potently augmented the permeability of vascular endothelial layers,which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro.The administration of Mig-BCBM significantly disrupted the blood-brain barrier(BBB)and accelerated BCBM progression in vivo,as evidenced in mouse models,compared to the Mig-BC and control groups.Mechanistically,Mig-BCBM harbored ATF6,a critical transducer of endoplasmic reticulum(ER)stress.Upon internalization into hCMEC/D3 cells,ATF6 elicited robust ER stress responses,culminating in downregulation of ZO-1 and VE-cadherin.Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.Conclusions:This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis,suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo.
基金funded by the Guangdong Province Key Research and Development Project(2022B111107006)the National Natural Science Foundation of China(32021005 and 31820103010)the Fundamental Research Funds for the Central Universities(JUSRP622013)。
文摘Mucin 2(MUC2)is a critical component of the intestinal mucus barrier.Lactic acid bacteria(LAB)strains can improve mucosal homeostasis.In this study,we determined the expression of Muc2 induced by dead bacteria and cell-free conditioned medium(CM)of 50 LAB strains in the human goblet cell line,LS174T.Dead bacteria or CM of LAB affected the Muc2 expression in a species-and strain-specific manner under homeostasis.Next,LAB strains with different regulatory abilities were selected,gavaged into mice,and exposed to dextran sodium sulfate(DSS)after 1 week.Different LAB strains inhibited intestinal injury to different degrees,with Lactobacillus acidophilus FCQHC4L1 exerting the most potent effect.FCQHC4L1 significantly decreased the secretion of pro-inflammatory factors,promoted the expression and secretion of mucin,and inhibited colitis development.This strain also regulated the gut microbiota and increased the secretion of butyric acid.Moreover,CM of FCQHC4L1 inhibited endoplasmic reticulum(ER)stress and ameliorated the abnormal expression of MUC2 by suppressing the activation of the GRP78/ATF6 and GRP78/IRE1/XBP1 signaling pathways.Our results highlight the potential of FCQHC4L1 as a therapeutic agent for strengthening the mucus barrier and improving the gut health.
文摘Background The use of conventional two-dimensional(2D)culture of the porcine intestinal epithelial cell(IEC)line IPEC-J2 in animal nutrition research has the disadvantage that IEC function is studied under unphysiological conditions,which limits the ability of transferring knowledge to the in vivo-situation.Thus,the aim of the present study was to establish a more convincing and meaningful three-dimensional(3D)culture of IPEC-J2 cells,which allows to study cell function in a more tissue-like environment,and to compare the effect of the endoplasmic reticulum(ER)stress inducer tunicamycin(TM)on ER stress indicators and the expression of tight junction proteins(TJP),inflammatory and apoptosis-related genes and the modulatory role of 1,25-dihydroxy-vitamin D_(3)(1,25D_(3))on these parameters in 2D and 3D cultures of IPEC-J2 cells.Results A published protocol for 3D culture of Caco-2 cells was successfully adopted to IPEC-J2 cells as evident from fully differentiated 3D IPEC-J2 spheroids showing the characteristic spherical architecture with a single layer of IPEC-J2 cells surrounding a central lumen.Treatment of 2D IPEC-J2 cells and 3D IPEC-J2 spheroids with TM for 24 h markedly increased m RNA and/or protein levels of the ER stress target genes,heat shock protein family A(Hsp70)member 5(HSPA5)and DNA damage inducible transcript 3(DDIT3),whereas co-treatment with TM and 1,25D_(3) did not mitigate TM-induced ER stress in IPEC-J2 cells in the 2D and the 3D cell culture.In contrast,TM-induced expression of pro-inflammatory[interleukin-6(IL6),IL8]and pro-apoptotic genes[BCL2 associated X,apoptosis regulator(BAX),caspase 3(CASP3),CASP8]and genes encoding TJP[TJP1,claudin 1(CLDN1),CLDN3,occludin(OCLN),cadherin 1(CDH1),junctional adhesion molecule 1(JAM1)]was reduced by co-treatment with TM and 1,25D_(3) in 3D IPEC-J2 spheroids but not in the 2D cell culture.Conclusions The effect of 1,25D_(3) in the IPEC-J2 cell culture is dependent on the culture model applied.While 1,25D_(3) does not inhibit TM-induced expression of genes involved in inflammation,apoptosis and TJP in conventional 2D cultures of IPEC-J2 cells,TM-induced expression of these genes is abrogated by 1,25D_(3) in the more meaningful 3D IPEC-J2 cell culture model.
基金funded by the Natural Science Foundation of China(NSFC),Grants No.12072048 to M.L.,12272063,and 11532003 to L.D.partially supported by the Science and Technology Innovation Leading Plan of High-Tech Industry in Hunan Province,China,Grant No.2020SK2018 to L.D.
文摘Background:Mechanical ventilation(MV)provides life support for patients with severe respiratory distress but can simultaneously cause ventilator-induced lung injury(VILI).However,due to a poor understanding of its mechanism,there is still a lack of effective remedies for the often-deadly VILI.Recent studies indicate that the stretch associated with MV can enhance the secretion of extracellular vesicles(EVs)and induce endoplasmic reticulum(ER)stress in airway smoothmuscle cells(ASMCs),both of which can contribute to VILI.But whetherMVassociated stretch enhances the secretion of EVs via ER stress in ASMCs as an underlying mechanism of VILI remains unknown.Methods:In this study,we exposed cultured human ASMCs to stretch(13%strain)and mouse models to MV at tidal volume(18 mL/kg).Subsequently,the amount of secreted EVs in the culture medium of ASMCs and the bronchoalveolar lavage fluid(BALF)of mousemodels was quantitatively evaluated by ultracentrifugation,transmission electron microscopy,Western blot,flow cytometry,and nanoparticle tracking analysis.The cultured ASMCs and the lung tissues of mouse models were assessed for expression of biomarkers of EVs(cluster of differentiation antigen 63,CD63),ER stress(heat shock protein family A member 5,HSPA5),and EVs regulating molecule Rab27a by immunofluorescence microscopy,immunohistochemistry(IHC)and enzyme-linked immunosorbent assay(ELISA),respectively.MicroRNAs(miRNAs)in EVs from ASMCs were measured with miRNA whole genome sequencing(miRNA-Seq).Results:We found that stretch enhanced EV secretion from cultured ASMCs.In addition,the cultured ASMCs and the mouse models were either or not pretreated with ER stress inhibitor(tauroursodeoxycholic acid,TUDCA)/EV secretion inhibitor(GW4869)prior to stretch or MV.We found that MV-associated stretch enhanced the expression of CD63,HSPA5,and Rab27a in cultured ASMCs and BALF/lung tissues of mousemodels,which could all be attenuated with TUDCA/GW4869 pretreatment.miRNA-Seq data show that differentially expressed miRNAs in EVsmainlymodulate gene transcription.Furthermore,the EVs fromcultured ASMCs under stretch tended to enhance detachment and expression of inflammatory cytokines,i.e.,transforming growth factor-β1(TGF-β1),interleukin-10(IL-10)in cultured airway epithelial cells.The expression of TGF-β1 and IL-10 in BALF of the mouse models also increased in response to MV,which was attenuated together with partial improvement of lung injury by pretreatment with TUDCA,GW4869/Rab27a siRNAs.Conclusion:Taken together,our data indicate thatMV-associated stretch can enhance the secretion of EVs from ASMCs via ER stress signaling to mediate airway inflammation and VILI,which provides new insight for further exploring EVs for the diagnosis and treatment of VILI.
文摘Diabetes mellitus(DM)is a metabolic disorder characterized by persistent hyperglycemia and other symptoms,which pose significant challenges to individual health,life expectancy,and public healthcare systems.The escalating global prevalence of diabetes underscores the need for innovative therapeutic interventions.In this article,we critically comment on the study by Wang et al,published in the World Journal of Diabetes,which elucidates the therapeutic potential of Plantamajoside(PMS)in type 2 DM(T2DM)management.The authors provide evidence for the mechanism of action of PMS in T2DM models,demonstrating prevention of endoplasmic reticulum stress and apoptosis of pancreaticβ-cells via activation of DNAJC1.This manuscript provides a brief review of the pathogenesis of T2DM,explores the various roles of PMS in disease therapy in addition to the DNAJC-related apoptotic and autophagic functions,critically evaluates the experimental approaches employed by Wang et al,and provides recommendations for advancing future research.
基金Supported by the Natural Science Foundation of China,No.81471081the Natural Science Foundation of Fujian Province,No.2023D009+1 种基金the Natural Science Foundation of Xiamen City,No.3502Z202373104 and No.3502Z20227162Scientific Research Foundation for Advanced Talents,Xiang’an Hospital of Xiamen University,No.PM201809170005。
文摘BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but the detailed mechanism is still unclear.Most studies ofβ-cell dedifferentiation rely on rodent models and human pathological specimens.The development of in vitro systems can facilitate the exploration ofβ-cell dedifferentiation.AIM To investigate the molecular mechanism ofβ-cell dedifferentiation.Hence,an in vitro model ofβ-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1832/13 cell line.METHODS The study was further analyzed using RNA-sequencing,transmission electron microscopy,quantitative real-time polymerase chain reaction and Western blot.RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulatedβ-cell forbidden genes and endocrine precursor cell marker genes,and down-regulated the expression ofβ-cell specific markers.Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum(ER)stressrelated genes.Moreover,the results also showed that forkhead box O1(Foxo1)inhibition potentiated genetic changes inβ-cell dedifferentiation induced by palmitic acid and high glucose.CONCLUSION ER stress is sufficient to triggerβ-cell dedifferentiation and is necessary for palmitic acid and high glucose-inducedβ-cell dedifferentiation.Foxo1 inhibition can further enhance these phenomena.
基金supported by the National Natural Science Foundation of China,Nos.82104158(to XT),31800887(to LY),31972902(to LY),82001422(to YL)China Postdoctoral Science Foundation,No.2020M683750(to LY)partially by Young Talent Fund of University Association for Science and Technology in Shaanxi Province of China,No.20200307(to LY).
文摘β-Sitosterol is a type of phytosterol that occurs naturally in plants.Previous studies have shown that it has anti-oxidant,anti-hyperlipidemic,anti-inflammatory,immunomodulatory,and anti-tumor effects,but it is unknown whetherβ-sitosterol treatment reduces the effects of ischemic stroke.Here we found that,in a mouse model of ischemic stroke induced by middle cerebral artery occlusion,β-sitosterol reduced the volume of cerebral infarction and brain edema,reduced neuronal apoptosis in brain tissue,and alleviated neurological dysfunction;moreover,β-sitosterol increased the activity of oxygen-and glucose-deprived cerebral cortex neurons and reduced apoptosis.Further investigation showed that the neuroprotective effects ofβ-sitosterol may be related to inhibition of endoplasmic reticulum stress caused by intracellular cholesterol accumulation after ischemic stroke.In addition,β-sitosterol showed high affinity for NPC1L1,a key transporter of cholesterol,and antagonized its activity.In conclusion,β-sitosterol may help treat ischemic stroke by inhibiting neuronal intracellular cholesterol overload/endoplasmic reticulum stress/apoptosis signaling pathways.
