The unfolded protein response(UPR)is a cellular stress response pathway activated when the endoplasmic reticulum,a crucial organelle for protein folding and modification,encounters an accumulation of unfolded or misfo...The unfolded protein response(UPR)is a cellular stress response pathway activated when the endoplasmic reticulum,a crucial organelle for protein folding and modification,encounters an accumulation of unfolded or misfolded proteins.The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity,reducing protein biosynthesis,and promoting protein degradation.It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress.Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system.Here,we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions,and highlight the critical role of the UPR in brain development,memory storage,retinal cone development,myelination,and maintenance of myelin thickness.展开更多
Objective:The purpose of this study was to investigate the role of the unfolded protein response,specifically the inositol-requiring enzyme 1(IRE1)signaling pathway,in hypoxia-induced autophagy in human umbilical veno...Objective:The purpose of this study was to investigate the role of the unfolded protein response,specifically the inositol-requiring enzyme 1(IRE1)signaling pathway,in hypoxia-induced autophagy in human umbilical venous endothelial cells(HUVECs).Methods:The expression of IRE1 and autophagy relative protein in HUVECs with hypoxia was explored by Western blotting,qRT-PCR and confocal microscopy.Further,we evaluated the biological effects of HUVECs by tube formation assay and wound healing assay in vitro.Finally,we examined the function of IRE1 in local blood vessels through animal models,Results:Hypoxia activated the IRE1 signaling pathway and induced autophagy in a time-dependent manner in HUVECs and further influenced the biological effects of HUVECs.Intraperitoneal injection of IRE1 inhibitors inhibited local vascular autophagy levels and lipid accumulation in model animals.Conclusion:Hypoxia can induce autophagy and activate the IRE1 signaling pathway in HUVECs and the IRE1 signaling pathway is involved in autophagy in hypoxic conditions.展开更多
In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS...In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.展开更多
The mitochondrial unfolded protein response(UPRmt)is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress.Under physiological and pathological conditions,the UPRmt is t...The mitochondrial unfolded protein response(UPRmt)is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress.Under physiological and pathological conditions,the UPRmt is the key to maintaining intracellular homeostasis and proteostasis.Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development,metabolism,and immune processes.UPRmt dysfunction leads to a variety of pathologies,including cancer,inflammation,neurodegenerative disease,metabolic disease,and immune disease.Stem cells have a special ability to selfrenew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues.These cells are involved in development,tissue renewal,and some disease processes.Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported,the roles of the UPRmt in stem cells are not fully understood.The roles and functions of the UPRmt depend on stem cell type.Therefore,this paper summarizes the potential significance of the UPRmt in embryonic stem cells,tissue stem cells,tumor stem cells,and induced pluripotent stem cells.The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.展开更多
The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate(ATP) to generate visual signal ...The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate(ATP) to generate visual signal and transmit the information to the brain. Disruptions in retinal metabolism can cause neuronal dysfunction and degeneration resulting in severe visual impairment and even blindness. The homeostasis of retinal metabolism is tightly controlled by multiple signaling pathways, such as the unfolded protein response(UPR), and the close interactions between retinal neurons and other retinal cell types including vascular cells and Müller glia. The UPR is a highly conserved adaptive cellular response and can be triggered by many physiological stressors and pathophysiological conditions. Activation of the UPR leads to changes in glycolytic rate, ATP production, de novo serine synthesis, and the hexosamine biosynthetic pathway, which are considered critical components of Müller glia metabolism and provide metabolic support to surrounding neurons. When these pathways are disrupted, neurodegeneration occurs rapidly. In this review, we summarize recent advance in studies of the UPR in Müller glia and highlight the potential role of the UPR in retinal degeneration through regulation of Müller glia metabolism.展开更多
Sustained dysfunction of the intestinal barrier caused by early weaning is a major factor that induces postweaning diarrhea in weaned piglets.In both healthy and diseased states,the intestinal barrier is regulated by ...Sustained dysfunction of the intestinal barrier caused by early weaning is a major factor that induces postweaning diarrhea in weaned piglets.In both healthy and diseased states,the intestinal barrier is regulated by goblet cells.Alterations in the characteristics of goblet cells are linked to intestinal barrier dysfunction and inflammatory conditions during pathogenic infections.In this review,we summarize the current understanding of the mechanisms of the unfolded protein response(UPR)and anterior gradient2(AGR2)in maintaining intestinal barrier function and how modifications to these systems affect mucus barrier characteristics and goblet cell dysregulation.We highlight a novel mechanism underlying the UPR-AGR2 pathway,which affects goblet cell differentiation and maturation and the synthesis and secretion of mucin by regulating epidermal growth factor receptor and mucin 2.This study provides a theoretical basis and new insights into the regulation of intestinal health in weaned piglets.展开更多
Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Met...Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Methods:HT22 mouse hippocampus neuronal cells were exposed to continuous wave 900 MHz radiofrequency fields(RF)at 120μW/cm2 power intensity for 4 h/d for 5 consecutive days.The positive control cells were irradiated with 4 Gy of 60Coγ-rays at a dose rate of 0.5 Gy/min(GR).Twenty-four hours after the last exposure,cells were collected,and the expressions of sensor transmembrane proteins were detected using Western blot analysis.Results:The expression levels of Ire1,PERK,p-IRE1 and p-PERK,GRP78 and CHOP proteins were detected.There were no statistically significant differences in the expression levels of IRE1 and PERK proteins in control(CT),sham(SH)-,RF-and GR-exposed cells(P<0.05).The phosphorylated protein levels of p-IRE1 and p-PERK were significantly increased in cells exposed to RF and GR(P<0.05).The expression levels of GRP78 and CHOP were significantly increased in RF-and GR-exposed cells compared to CT and SH-exposed cells(P<0.05).Cells treated with 1μg/ml TM for 24 h showed significantly increased expression levels of GRP78 and CHOP proteins compared to controls(P<0.05).In the presence of 2 mmol/L PBA,TM-induced increased levels of GRP78 and CHOP proteins were reduced(P<0.05).Conclusions:The exposure of non-ionizing 900 MHz RF was able to cause stress in HT22 mouse neuronal cells and activated UPR in ER.Since UPR plays an important role in both cell survival(when UPR is mitigated)and apoptosis/death(under unresolvable stress conditions),further studies are required to determine the fate of the cells exposed to RF.展开更多
The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role i...The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.展开更多
Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan...Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.展开更多
Objective:In some patients with adenomatous polyposis,an identifiable pathogenic variant of known associated genes cannot be found.Researchers have studied this for decades;however,few new genes have been identified.M...Objective:In some patients with adenomatous polyposis,an identifiable pathogenic variant of known associated genes cannot be found.Researchers have studied this for decades;however,few new genes have been identified.Methods:Adenomatous polyposis coli(APC)negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification.Then,whole-exome sequencing(WES)was used to determine candidate genes harboring pathogenic variants.Functional experiments were performed to explore their effects.Subsequently,using Sanger sequencing,we found other polyposis patients carrying variants of the DUOX2 gene,encoding dual oxidase 2,and analyzed them.Results:From 88 patients with suspected familial adenomatous polyposis,25 unrelated APC negative polyposis patients were identified.Based on the WES results of 3 patients and 2 healthy relatives from a family,the germline nonsense variant(c.1588 A>T;p.K530 X)of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis.During functional experiments,we observed that the truncated protein,h Duox2 K530,was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant,causing abnormal cell proliferation through endoplasmic reticulum(ER)retention.In addition,we found two unrelated APC negative patients carrying DUOX2 missense variants(c.3329 G>A,p.R1110 Q;c.4027 C>T,p.L1343 F).Given the results of the in silico analysis,these two missense variants might exert a negative influence on the function of h Duox2.Conclusions:To our knowledge,this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis.With an autosomal dominant inheritance,it causes ER retention,inducing an unfolded protein response.展开更多
Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that ar...Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.g.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.e.regulating activation of initiation and elongation factors,inhibiting unfolded protein response activation or inducing chaperone expression and activity).This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis.We strive to highlight the importance of research on drugs that,not only restore protein imbalance without compromising translational activity of cells,but are also as safe as possible for the patients.展开更多
BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1(YAP-1).Dysregulation in Hippo pathway has been prop...BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1(YAP-1).Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis.The levels of reactive oxygen species(ROS)increase during the progression from early to advanced hepatocellular carcinoma(HCC).AIM To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.METHODS The expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761)was quantified using real-time polymerase chain reaction and immunoblotting.Human HCC cells were treated with H2O2,which is a major component of ROS in living organisms,and with either YAP-1 small interfering RNA(siRNA)or control siRNA.To investigate the role of YAP-1 in HCC cells under oxidative stress,MTS assays were performed.Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1.Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses.RESULTS H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761).Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo(both P<0.05).The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway,leading to the upregulation of components of the unfolded protein response(UPR),including 78-kDa glucoseregulated protein and activating transcription factor-6(ATF-6).The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues(P<0.05)and were positively correlated with the ATF-6 Levels(Pearson’s coefficient=0.299;P<0.05).CONCLUSION This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC.The ROS-induced activation of YAP-1 via the c-Myc pathway,which leads to the activation of the UPR pathway,might be a therapeutic target in HCC.展开更多
Abstract The unfolded protein response(UPR)is an important protective and compensatory strategy used during endoplasmic reticulum stress caused by factors including glucose starvation,low pH,or heat shock.However,ther...Abstract The unfolded protein response(UPR)is an important protective and compensatory strategy used during endoplasmic reticulum stress caused by factors including glucose starvation,low pH,or heat shock.However,there is very little information on the possible role(s)of the UPR under adverse conditions experienced by marine invertebrates.We observed that rough endoplasmic reticulum(ER)was dramatically expanded and numerous autophagosomes were accumulated in the intestinal cells of sea cucumbers,Apostichopus japonicus,under heat stress(4 h at 25°C compared with 15°C controls).Moreover,heat stress led to sharp increases in the relative transcript and protein expression levels of two primary ER chaperones:the endoplasmic reticulum resident protein 29-like(ERP29)and protein disulfi de-isomerase A6-like(PDIA6).These results suggest a potential adaptive mechanism to deal with heat-induced stress in sea cucumber intestine.展开更多
Cellular stress responses are powerful mechanisms that prevent and cope with the accumulation of macromolecular damage in the cells and also boost host defenses against pathogens. Cells can initiate either protective ...Cellular stress responses are powerful mechanisms that prevent and cope with the accumulation of macromolecular damage in the cells and also boost host defenses against pathogens. Cells can initiate either protective or destructive stress responses depending, to a large extent, on the nature and duration of the stressing stimulus as well as the cell type. The productive replication of a virus within a given cell places inordinate stress on the metabolism machinery of the host and, to assure the continuity of its replication, many viruses have developed ways to modulate the cell stress responses. Poxviruses are among the viruses that have evolved a large number of strategies to manipulate host stress responses in order to control cell fate and enhance their replicative success. Remarkably, nearly every step of the stress responses that is mounted during infection can be targeted by virally encoded functions. The fine-tuned interactions between poxviruses and the host stress responses has aided virologists to understand specific aspects of viral replication; has helped cell biologists to evaluate the role of stress signaling in the uninfected cell; and has tipped immunologists on how these signals contribute to alert the cells against pathogen invasionand boost subsequent immune responses. This review discusses the diverse strategies that poxviruses use to subvert host cell stress responses.展开更多
The methanol inducible alcohol oxidase 1 promoter and the Saccharomyces cerevisiae alpha-factor prepro secretion signal were used to drive expression and secretion of a mucin-type fusion protein by Pichia pastoris in ...The methanol inducible alcohol oxidase 1 promoter and the Saccharomyces cerevisiae alpha-factor prepro secretion signal were used to drive expression and secretion of a mucin-type fusion protein by Pichia pastoris in 1 L scale bioreactors. The aim of the study was to understand how varying expression rates influenced the secretion dynamics of the fusion protein in terms of intracellular- and extracellular concentrations. Endoplasmic reticulum (ER) folding stress was assessed by the relative expression of the unfolded protein response controlled KAR2 gene. Three predefined methanol feeding models were applied to control the fusion protein synthesis rate. To track the fusion protein synthesis in a non-invasive manner and to follow its intracellular distribution, its C-terminal was linked to the green fluorescent protein. Under all conditions the fusion protein was found to partially accumulate intracellularly, where the major fraction was an insoluble, fluorescent full-sized protein. The high degree of glycosylation of the insoluble fusion protein indicated a secretory bottle-neck in the Golgi-system. This result was consistent with low ER folding stress as quantified by the relative expression of the KAR2 gene. Reduction of recombinant protein synthesis rate, by using lower feed rates of methanol, enhanced extracellular concentrations from 8 to 18 mg·L–1 and reduced the rate of intracellular accumulation. This clearly demonstrates the importance of tuning the synthesis rate with secretory bottle-necks to maintain secretion.展开更多
Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.How...Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.However,myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-M arie-To oth disease.Charcot-Marie-To oth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal,demyelinating or dysmyelinating,or as intermediate.The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes:peripheral myelin protein 22,myelin protein ze ro and gap junction beta 1(coding for Connexin 32) causing Charcot-M arie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B,and X-linked Charcot-M arie-Tooth disease type 1,respectively.The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients.No treatment to cure or slow down the disease progression is currently available on the market,howeve r,scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies.In this review,we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease,the rodent models used in research,and the emerging therapeutic approaches to cure or counteract the progression of the disease.展开更多
Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and a...Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.展开更多
Pyroptosis plays an important role in hemorrhagic stroke.Excessive endoplasmic reticulum stress can cause endoplasmic reticulum dysfunction and cellular pyroptosis by regulating the nucleotide-binding oligomerization ...Pyroptosis plays an important role in hemorrhagic stroke.Excessive endoplasmic reticulum stress can cause endoplasmic reticulum dysfunction and cellular pyroptosis by regulating the nucleotide-binding oligomerization domain and leucine-rich repeat pyrin domain-containing protein 3(NLRP3)pathway.However,the relationship between pyroptosis and endoplasmic reticulum stress after intraventricular hemorrhage is unclear.In this study,we established a mouse model of intraventricular hemorrhage and found pyroptosis and endoplasmic reticulum stress in brain tissue.Intraperitoneal injection of the selective GPR120 agonist TUG-891 inhibited endoplasmic reticulum stress,pyroptosis,and inflammation and protected neurons.The neuroprotective effect of TUG-891 appears related to inhibition of endoplasmic reticulum stress and pyroptosis activation.展开更多
The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neuro...The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.展开更多
The endoplasmic reticulum(ER),an organelle present in various eukaryotic cells,is responsible for intracellular protein synthesis,post-translational modification,and folding and transport,as well as the regulation of ...The endoplasmic reticulum(ER),an organelle present in various eukaryotic cells,is responsible for intracellular protein synthesis,post-translational modification,and folding and transport,as well as the regulation of lipid and steroid metabolism and Ca2+homeostasis.Hypoxia,nutrient deficiency,and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER,thus activating ER stress(ERS)and the unfolded protein response,and resulting in either restoration of cellular homeostasis or cell death.ERS plays a crucial role in cancer oncogenesis,progression,and response to therapies.This article reviews current studies relating ERS to ovarian cancer,the most lethal gynecologic malignancy among women globally,and discusses pharmacological agents and possible targets for therapeutic intervention.展开更多
基金supported by grants from the National Institutes of Health,No.NS105689(to WL)the Department of Defense through the Multiple Sclerosis Research Program,No.W81XWH-22-1-0757(to WL).
文摘The unfolded protein response(UPR)is a cellular stress response pathway activated when the endoplasmic reticulum,a crucial organelle for protein folding and modification,encounters an accumulation of unfolded or misfolded proteins.The UPR aims to restore endoplasmic reticulum homeostasis by enhancing protein folding capacity,reducing protein biosynthesis,and promoting protein degradation.It also plays a pivotal role in coordinating signaling cascades to determine cell fate and function in response to endoplasmic reticulum stress.Recent research has highlighted the significance of the UPR not only in maintaining endoplasmic reticulum homeostasis but also in influencing various physiological processes in the nervous system.Here,we provide an overview of recent findings that underscore the UPR’s involvement in preserving the function and viability of neuronal and myelinating cells under physiological conditions,and highlight the critical role of the UPR in brain development,memory storage,retinal cone development,myelination,and maintenance of myelin thickness.
基金supported by the National Natural Science Foundation of China(No.81670409).
文摘Objective:The purpose of this study was to investigate the role of the unfolded protein response,specifically the inositol-requiring enzyme 1(IRE1)signaling pathway,in hypoxia-induced autophagy in human umbilical venous endothelial cells(HUVECs).Methods:The expression of IRE1 and autophagy relative protein in HUVECs with hypoxia was explored by Western blotting,qRT-PCR and confocal microscopy.Further,we evaluated the biological effects of HUVECs by tube formation assay and wound healing assay in vitro.Finally,we examined the function of IRE1 in local blood vessels through animal models,Results:Hypoxia activated the IRE1 signaling pathway and induced autophagy in a time-dependent manner in HUVECs and further influenced the biological effects of HUVECs.Intraperitoneal injection of IRE1 inhibitors inhibited local vascular autophagy levels and lipid accumulation in model animals.Conclusion:Hypoxia can induce autophagy and activate the IRE1 signaling pathway in HUVECs and the IRE1 signaling pathway is involved in autophagy in hypoxic conditions.
文摘In the process of tumor proliferation and metastasis,tumor cells encounter hypoxia,low glucose,acidosis,and other stressful environments.These conditions prompt tumor cells to generate endoplasmic reticulum stress(ERS).As a signal mechanism that mitigates ERS in eukaryotic cells,the unfolded protein response(UPR)pathway can activate cells and tissues,regulating pathological activities in various cells,and maintaining ER homeostasis.It forms the most crucial adaptive and defensive mechanism for cells.However,under the continuous influence of chemotherapy drugs,the quantity of unfolded proteins and erroneous proteins produced by tumor cells significantly increases,surpassing the normal regulatory range of UPR.Consequently,ERS fails to function properly,fostering tumor cell proliferation and the development of drug resistance.This review delves into the study of three UPR pathways(PERK,IRE1,and ATF6),elucidating the mechanisms of drug resistance and research progress in the signal transduction pathway of UPR related to cancers.It provides a profound understanding of the role and relationship between UPR and anti-tumor drugs,offering a new direction for effective clinical treatment.
基金Supported by the Key Projects of Natural Science Foundation of Ningxia,No.2020AAC02020the Funds of Ningxia Medical University,No.XY201808.
文摘The mitochondrial unfolded protein response(UPRmt)is an evolutionarily conserved adaptive mechanism for improving cell survival under mitochondrial stress.Under physiological and pathological conditions,the UPRmt is the key to maintaining intracellular homeostasis and proteostasis.Important roles of the UPRmt have been demonstrated in a variety of cell types and in cell development,metabolism,and immune processes.UPRmt dysfunction leads to a variety of pathologies,including cancer,inflammation,neurodegenerative disease,metabolic disease,and immune disease.Stem cells have a special ability to selfrenew and differentiate into a variety of somatic cells and have been shown to exist in a variety of tissues.These cells are involved in development,tissue renewal,and some disease processes.Although the roles and regulatory mechanisms of the UPRmt in somatic cells have been widely reported,the roles of the UPRmt in stem cells are not fully understood.The roles and functions of the UPRmt depend on stem cell type.Therefore,this paper summarizes the potential significance of the UPRmt in embryonic stem cells,tissue stem cells,tumor stem cells,and induced pluripotent stem cells.The purpose of this review is to provide new insights into stem cell differentiation and tumor pathogenesis.
基金supported,in part,by NIH/NEI grants EY019949 and EY025061an Unrestricted Grant to the Department of Ophthalmology,SUNY-Buffalo,from Research to Prevent Blindness
文摘The retina is one of the most energy demanding tissues in the body. Like most neurons in the central nervous system, retinal neurons consume high amounts of adenosine-5′-triphosphate(ATP) to generate visual signal and transmit the information to the brain. Disruptions in retinal metabolism can cause neuronal dysfunction and degeneration resulting in severe visual impairment and even blindness. The homeostasis of retinal metabolism is tightly controlled by multiple signaling pathways, such as the unfolded protein response(UPR), and the close interactions between retinal neurons and other retinal cell types including vascular cells and Müller glia. The UPR is a highly conserved adaptive cellular response and can be triggered by many physiological stressors and pathophysiological conditions. Activation of the UPR leads to changes in glycolytic rate, ATP production, de novo serine synthesis, and the hexosamine biosynthetic pathway, which are considered critical components of Müller glia metabolism and provide metabolic support to surrounding neurons. When these pathways are disrupted, neurodegeneration occurs rapidly. In this review, we summarize recent advance in studies of the UPR in Müller glia and highlight the potential role of the UPR in retinal degeneration through regulation of Müller glia metabolism.
基金supported by the National Natural Science Foundation of China(32172816)the National Natural Science of Anhui Province(2208085MC77)+1 种基金Excellent Research Innovation Team in Universities in Anhui Province(2022AH010088)the College Student Innovation and Entrepreneurship Project(202110879058).
文摘Sustained dysfunction of the intestinal barrier caused by early weaning is a major factor that induces postweaning diarrhea in weaned piglets.In both healthy and diseased states,the intestinal barrier is regulated by goblet cells.Alterations in the characteristics of goblet cells are linked to intestinal barrier dysfunction and inflammatory conditions during pathogenic infections.In this review,we summarize the current understanding of the mechanisms of the unfolded protein response(UPR)and anterior gradient2(AGR2)in maintaining intestinal barrier function and how modifications to these systems affect mucus barrier characteristics and goblet cell dysregulation.We highlight a novel mechanism underlying the UPR-AGR2 pathway,which affects goblet cell differentiation and maturation and the synthesis and secretion of mucin by regulating epidermal growth factor receptor and mucin 2.This study provides a theoretical basis and new insights into the regulation of intestinal health in weaned piglets.
基金This research is supported by funding from the National Natural Science Foundation of China(Grant No.81373025).
文摘Objective:To examine whether exposure of mouse neuronal cells to radiofrequency fields used in mobile communication devices can induce stress in endoplasmic reticulum(ER)and activate unfolded protein response(UPR).Methods:HT22 mouse hippocampus neuronal cells were exposed to continuous wave 900 MHz radiofrequency fields(RF)at 120μW/cm2 power intensity for 4 h/d for 5 consecutive days.The positive control cells were irradiated with 4 Gy of 60Coγ-rays at a dose rate of 0.5 Gy/min(GR).Twenty-four hours after the last exposure,cells were collected,and the expressions of sensor transmembrane proteins were detected using Western blot analysis.Results:The expression levels of Ire1,PERK,p-IRE1 and p-PERK,GRP78 and CHOP proteins were detected.There were no statistically significant differences in the expression levels of IRE1 and PERK proteins in control(CT),sham(SH)-,RF-and GR-exposed cells(P<0.05).The phosphorylated protein levels of p-IRE1 and p-PERK were significantly increased in cells exposed to RF and GR(P<0.05).The expression levels of GRP78 and CHOP were significantly increased in RF-and GR-exposed cells compared to CT and SH-exposed cells(P<0.05).Cells treated with 1μg/ml TM for 24 h showed significantly increased expression levels of GRP78 and CHOP proteins compared to controls(P<0.05).In the presence of 2 mmol/L PBA,TM-induced increased levels of GRP78 and CHOP proteins were reduced(P<0.05).Conclusions:The exposure of non-ionizing 900 MHz RF was able to cause stress in HT22 mouse neuronal cells and activated UPR in ER.Since UPR plays an important role in both cell survival(when UPR is mitigated)and apoptosis/death(under unresolvable stress conditions),further studies are required to determine the fate of the cells exposed to RF.
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funded by the National Natural Science Foundation of China (32371341,31872674)the Scientific and Technologic Foundation of Jilin Province (20230202050NC)the Fundamental Research Funds for the Central Universities (CGZH202206)。
文摘Type 1 diabetes mellitus(T1DM) lacks insulin secretion due to autoimmune deficiency of pancreaticβ-cells.Protecting pancreatic islets and enhancing insulin secretion has been therapeutic approaches.Mannogalactoglucan is the main type of polysaccharide from natural mushroom,which has potential medicinal prospects.Nevertheless,the antidiabetic property of mannogalactoglucan in T1DM has not been fully elucidated.In this study,we obtained the neutral fraction of alkali-soluble Armillaria mellea polysaccharide(AAMP-N) with the structure of mannogalactoglucan from the fruiting body of A.mellea and investigated the potential therapeutic value of AAMP-N in T1DM.We demonstrated that AAMP-N lowered blood glucose and improved diabetes symptoms in T1DM mice.AAMP-N activated unfolded protein response(UPR) signaling pathway to maintain ER protein folding homeostasis and promote insulin secretion in vivo.Besides that,AAMP-N promoted insulin synthesis via upregulating the expression of transcription factors,increased Ca^(2+) signals to stimulate intracellular insulin secretory vesicle transport via activating calcium/calmodulin-dependent kinase Ⅱ(CamkⅡ) and cAMP/PKA signals,and enhanced insulin secretory vesicle fusion with the plasma membrane via vesicle-associated membrane protein 2(VAMP2).Collectively,these studies demonstrated that the therapeutic potential of AAMP-N on pancreatic islets function,indicating that mannogalactoglucan could be natural nutraceutical used for the treatment of T1DM.
基金supported by the National Key R&D Program of China(Grant No.2017YFC0908200)the National Natural Science Foundation of China(Grant Nos.81872481 and 81902956)。
文摘Objective:In some patients with adenomatous polyposis,an identifiable pathogenic variant of known associated genes cannot be found.Researchers have studied this for decades;however,few new genes have been identified.Methods:Adenomatous polyposis coli(APC)negative polyposis patients were identified through next-generation sequencing and multiplex ligation-dependent probe amplification.Then,whole-exome sequencing(WES)was used to determine candidate genes harboring pathogenic variants.Functional experiments were performed to explore their effects.Subsequently,using Sanger sequencing,we found other polyposis patients carrying variants of the DUOX2 gene,encoding dual oxidase 2,and analyzed them.Results:From 88 patients with suspected familial adenomatous polyposis,25 unrelated APC negative polyposis patients were identified.Based on the WES results of 3 patients and 2 healthy relatives from a family,the germline nonsense variant(c.1588 A>T;p.K530 X)of the DUOX2 gene was speculated to play a decisive role in the pedigree in relation to adenomatous polyposis.During functional experiments,we observed that the truncated protein,h Duox2 K530,was overexpressed in the adenoma in a carrier of the DUOX2 nonsense variant,causing abnormal cell proliferation through endoplasmic reticulum(ER)retention.In addition,we found two unrelated APC negative patients carrying DUOX2 missense variants(c.3329 G>A,p.R1110 Q;c.4027 C>T,p.L1343 F).Given the results of the in silico analysis,these two missense variants might exert a negative influence on the function of h Duox2.Conclusions:To our knowledge,this is the first study that reports the possible association of DUOX2 germline variants with adenomatous polyposis.With an autosomal dominant inheritance,it causes ER retention,inducing an unfolded protein response.
基金supported by research grants to LMI from University of Buenos Aires(UBACyT)the Agencia Nacional de Promoción Científica y Tecnológica(ANPCyT)under grants PICT 2015-0975 and PICT 2017-2140。
文摘Protein synthesis is essential for cells to perform life metabolic processes.Pathological alterations of protein content can lead to particular diseases.Cells have an intrinsic array of mechanisms and pathways that are activated when protein misfolding,accumulation,aggregation or mislocalization occur.Some of them(like the unfolded protein response)represent complex interactions between endoplasmic reticulum sensors and elongation factors that tend to increase expression of chaperone proteins and/or repress translation in order to restore protein homeostasis(also known as proteostasis).This is even more important in neurons,as they are very susceptible to harmful effects associated with protein overload and proteostatic mechanisms are less effective with age.Several neurodegenerative pathologies such as Alzheimer’s,Parkinson’s,and Huntington’s diseases,amyotrophic lateral sclerosis and frontotemporal dementia exhibit a particular molecular signature of distinct,unbalanced protein overload.In amyotrophic lateral sclerosis and frontotemporal dementia,the majority of cases present intracellular inclusions of ubiquitinated transactive response DNA-binding protein of 43 kDa(TDP-43).TDP-43 is an RNA binding protein that participates in RNA metabolism,among other functions.Dysregulation of TDP-43(e.g.aggregation and mislocalization)can dramatically affect neurons,and this has been linked to disease development.Expression of amyotrophic lateral sclerosis/frontotemporal dementia TDP-43-related mutations in cellular and animal models has been shown to recapitulate key features of the amyotrophic lateral sclerosis/frontotemporal dementia disease spectrum.These variants can be causative of degeneration onset and progression.Most neurodegenerative diseases(including amyotrophic lateral sclerosis and frontotemporal dementia)have no cure at the moment;however,modulating translation has recently emerged as an attractive approach that can be performed at several steps(i.e.regulating activation of initiation and elongation factors,inhibiting unfolded protein response activation or inducing chaperone expression and activity).This review focuses on the features of protein imbalance in neurodegenerative disorders and the relevance of developing therapeutical compounds aiming at restoring proteostasis.We strive to highlight the importance of research on drugs that,not only restore protein imbalance without compromising translational activity of cells,but are also as safe as possible for the patients.
文摘BACKGROUND The Hippo signaling pathway regulates organ size by regulating cell proliferation and apoptosis with terminal effectors including Yes-associated protein-1(YAP-1).Dysregulation in Hippo pathway has been proposed as one of the therapeutic targets in hepatocarcinogenesis.The levels of reactive oxygen species(ROS)increase during the progression from early to advanced hepatocellular carcinoma(HCC).AIM To study the activation of YAP-1 by ROS-induced damage in HCC and the involved signaling pathway.METHODS The expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761)was quantified using real-time polymerase chain reaction and immunoblotting.Human HCC cells were treated with H2O2,which is a major component of ROS in living organisms,and with either YAP-1 small interfering RNA(siRNA)or control siRNA.To investigate the role of YAP-1 in HCC cells under oxidative stress,MTS assays were performed.Immunoblotting was performed to evaluate the signaling pathway responsible for the activation of YAP-1.Eighty-eight surgically resected frozen HCC tissue samples and 88 nontumor liver tissue samples were used for gene expression analyses.RESULTS H2O2 treatment increased the mRNA and protein expression of YAP-1 in HCC cells(Huh-7,HepG2,and SNU-761).Suppression of YAP-1 using siRNA transfection resulted in a significant decrease in tumor proliferation during H2O2 treatment both in vitro and in vivo(both P<0.05).The oncogenic action of YAP-1 occurred via the activation of the c-Myc pathway,leading to the upregulation of components of the unfolded protein response(UPR),including 78-kDa glucoseregulated protein and activating transcription factor-6(ATF-6).The YAP-1 mRNA levels in human HCC tissues were upregulated by 2.6-fold compared with those in nontumor tissues(P<0.05)and were positively correlated with the ATF-6 Levels(Pearson’s coefficient=0.299;P<0.05).CONCLUSION This study shows a novel connection between YAP-1 and the UPR through the c-Myc pathway during oxidative stress in HCC.The ROS-induced activation of YAP-1 via the c-Myc pathway,which leads to the activation of the UPR pathway,might be a therapeutic target in HCC.
基金Supported by the National Natural Science Foundation of China(No.41676124)。
文摘Abstract The unfolded protein response(UPR)is an important protective and compensatory strategy used during endoplasmic reticulum stress caused by factors including glucose starvation,low pH,or heat shock.However,there is very little information on the possible role(s)of the UPR under adverse conditions experienced by marine invertebrates.We observed that rough endoplasmic reticulum(ER)was dramatically expanded and numerous autophagosomes were accumulated in the intestinal cells of sea cucumbers,Apostichopus japonicus,under heat stress(4 h at 25°C compared with 15°C controls).Moreover,heat stress led to sharp increases in the relative transcript and protein expression levels of two primary ER chaperones:the endoplasmic reticulum resident protein 29-like(ERP29)and protein disulfi de-isomerase A6-like(PDIA6).These results suggest a potential adaptive mechanism to deal with heat-induced stress in sea cucumber intestine.
文摘Cellular stress responses are powerful mechanisms that prevent and cope with the accumulation of macromolecular damage in the cells and also boost host defenses against pathogens. Cells can initiate either protective or destructive stress responses depending, to a large extent, on the nature and duration of the stressing stimulus as well as the cell type. The productive replication of a virus within a given cell places inordinate stress on the metabolism machinery of the host and, to assure the continuity of its replication, many viruses have developed ways to modulate the cell stress responses. Poxviruses are among the viruses that have evolved a large number of strategies to manipulate host stress responses in order to control cell fate and enhance their replicative success. Remarkably, nearly every step of the stress responses that is mounted during infection can be targeted by virally encoded functions. The fine-tuned interactions between poxviruses and the host stress responses has aided virologists to understand specific aspects of viral replication; has helped cell biologists to evaluate the role of stress signaling in the uninfected cell; and has tipped immunologists on how these signals contribute to alert the cells against pathogen invasionand boost subsequent immune responses. This review discusses the diverse strategies that poxviruses use to subvert host cell stress responses.
基金This work was supported by the Research Council of NorrbottenIn-novationsbron and Langmanska foretagarfonden.J.H.was supported by the Swedish Research Council(No.K2011-65X-3031-01-6)the County Council of Vastra Gotaland(ALF).
文摘The methanol inducible alcohol oxidase 1 promoter and the Saccharomyces cerevisiae alpha-factor prepro secretion signal were used to drive expression and secretion of a mucin-type fusion protein by Pichia pastoris in 1 L scale bioreactors. The aim of the study was to understand how varying expression rates influenced the secretion dynamics of the fusion protein in terms of intracellular- and extracellular concentrations. Endoplasmic reticulum (ER) folding stress was assessed by the relative expression of the unfolded protein response controlled KAR2 gene. Three predefined methanol feeding models were applied to control the fusion protein synthesis rate. To track the fusion protein synthesis in a non-invasive manner and to follow its intracellular distribution, its C-terminal was linked to the green fluorescent protein. Under all conditions the fusion protein was found to partially accumulate intracellularly, where the major fraction was an insoluble, fluorescent full-sized protein. The high degree of glycosylation of the insoluble fusion protein indicated a secretory bottle-neck in the Golgi-system. This result was consistent with low ER folding stress as quantified by the relative expression of the KAR2 gene. Reduction of recombinant protein synthesis rate, by using lower feed rates of methanol, enhanced extracellular concentrations from 8 to 18 mg·L–1 and reduced the rate of intracellular accumulation. This clearly demonstrates the importance of tuning the synthesis rate with secretory bottle-necks to maintain secretion.
基金supported by the Deutsche Forschungsgemeinshaft (to CJ)。
文摘Schwann cells,the myelinating glia of the peripheral nervous system,wrap axons multiple times to build their myelin sheath.Myelin is of paramount importance for axonal integrity and fast axon potential propagation.However,myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-M arie-To oth disease.Charcot-Marie-To oth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal,demyelinating or dysmyelinating,or as intermediate.The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes:peripheral myelin protein 22,myelin protein ze ro and gap junction beta 1(coding for Connexin 32) causing Charcot-M arie-Tooth disease type 1A,Charcot-Marie-Tooth disease type 1B,and X-linked Charcot-M arie-Tooth disease type 1,respectively.The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients.No treatment to cure or slow down the disease progression is currently available on the market,howeve r,scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies.In this review,we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease,the rodent models used in research,and the emerging therapeutic approaches to cure or counteract the progression of the disease.
基金Work at the authors’laboratories is supported by grants from"la Caixa"FoundationGrant Agreement LCF/PR/HR21/52410002+4 种基金EJP RD COFUND-EJP N°825575"Alexander"to DPS and MPAgencia Estatal de Investigacion,MICINN and ERDF Grant No.RTI2018-097624-B-I00 and PID2021-126827OB-I00 to DPSgrants from the Swedish Research Council(2017-02255)ALF Gothenburg(146051)The Swedish Society for Medical Research,Hj?rnfonden,S?derberg’s Foundations,Hagstr?mer’s Foundation Millennium,Ami?v’s Foundation,E.Jacobson’s Donation Fund,the Swedish Stroke Foundation,NanoNet COST Action(BM1002),EU FP 7 Program TargetBraln(279017)to MP。
文摘Alexander disease is a rare neurodegenerative disorder caused by mutations in the glial fibrillary acidic protein,a type III intermediate filament protein expressed in astrocytes.Both early(infantile or juvenile)and adult onsets of the disease are known and,in both cases,astrocytes present characteristic aggregates,named Rosenthal fibers.Mutations are spread along the glial fibrillary acidic protein sequence disrupting the typical filament network in a dominant manner.Although the presence of aggregates suggests a proteostasis problem of the mutant forms,this behavior is also observed when the expression of wild-type glial fibrillary acidic protein is increased.Additionally,several isoforms of glial fibrillary acidic protein have been described to date,while the impact of the mutations on their expression and proportion has not been exhaustively studied.Moreover,the posttranslational modification patterns and/or the protein-protein interaction networks of the glial fibrillary acidic protein mutants may be altered,leading to functional changes that may modify the morphology,positioning,and/or the function of several organelles,in turn,impairing astrocyte normal function and subsequently affecting neurons.In particular,mitochondrial function,redox balance and susceptibility to oxidative stress may contribute to the derangement of glial fibrillary acidic protein mutant-expressing astrocytes.To study the disease and to develop putative therapeutic strategies,several experimental models have been developed,a collection that is in constant growth.The fact that most cases of Alexander disease can be related to glial fibrillary acidic protein mutations,together with the availability of new and more relevant experimental models,holds promise for the design and assay of novel therapeutic strategies.
文摘Pyroptosis plays an important role in hemorrhagic stroke.Excessive endoplasmic reticulum stress can cause endoplasmic reticulum dysfunction and cellular pyroptosis by regulating the nucleotide-binding oligomerization domain and leucine-rich repeat pyrin domain-containing protein 3(NLRP3)pathway.However,the relationship between pyroptosis and endoplasmic reticulum stress after intraventricular hemorrhage is unclear.In this study,we established a mouse model of intraventricular hemorrhage and found pyroptosis and endoplasmic reticulum stress in brain tissue.Intraperitoneal injection of the selective GPR120 agonist TUG-891 inhibited endoplasmic reticulum stress,pyroptosis,and inflammation and protected neurons.The neuroprotective effect of TUG-891 appears related to inhibition of endoplasmic reticulum stress and pyroptosis activation.
基金supported by the National Natural Science Foundation of China,Nos.30772368(to DH),81371034(to XH)the Key Project of Natural Science Foundation of Shaanxi Province,No.2017JZ025(to DH).
文摘The retinal ganglion cells of the optic nerve have a limited capacity for self-repair after injury.Valproate is a histone deacetylase inhibitor and multitarget drug,which has been demonstrated to protect retinal neurons.In this study,we established rat models of optic nerve-crush injury and injected valproate into the vitreous cavity immediately after modeling.We evaluated changes in the ultrastructure morphology of the endoplasmic reticulum of retinal ganglion cells over time via transmission electron microscope.Immunohistochemistry and western blot assay revealed that valproate upregulated the expression of the endoplasmic reticulum stress marker glucose-regulated protein 78 and downregulated the expression of transcription factor C/EBP homologous protein,phosphorylated eukaryotic translation initiation factor 2α,and caspase-12 in the endoplasmic reticulum of retinal ganglion cells.These findings suggest that valproate reduces apoptosis of retinal ganglion cells in the rat after optic nerve-crush injury by attenuating phosphorylated eukaryotic translation initiation factor 2α-C/EBP homologous protein signaling and caspase-12 activation during endoplasmic reticulum stress.These findings represent a newly discovered mechanism that regulates how valproate protects neurons.
基金supported by the National Natural Science Foundation of China(Grant Nos.NSF-82072876 and NSF-82002618)。
文摘The endoplasmic reticulum(ER),an organelle present in various eukaryotic cells,is responsible for intracellular protein synthesis,post-translational modification,and folding and transport,as well as the regulation of lipid and steroid metabolism and Ca2+homeostasis.Hypoxia,nutrient deficiency,and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER,thus activating ER stress(ERS)and the unfolded protein response,and resulting in either restoration of cellular homeostasis or cell death.ERS plays a crucial role in cancer oncogenesis,progression,and response to therapies.This article reviews current studies relating ERS to ovarian cancer,the most lethal gynecologic malignancy among women globally,and discusses pharmacological agents and possible targets for therapeutic intervention.