The physiological role of the unfolded protein response in the nervous system

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.

Mesenchymal stromal cells modulate unfolded protein response and preserve β-cell mass in type 1 diabetes

Introduction:Transplantation of mesenchymal stromal cells(MSCs)is a promising therapy for type 1 diabetes(T1D).However,whether the infused MSCs affect the endoplasmic reticulum stress or subsequent unfolded protein response inβcells remains unclear.Methods:To investigate this,we induced early-onset T1D in non-obese diabetic mice using streptozotocin.Subsequently,T1D mice were randomly assigned to receive either MSCs or phosphate-buffered saline.We observed the in vivo homing of MSCs and assessed their effectiveness by analyzing blood glucose levels,body weight,histopathology,pancreatic protein expression,and serum levels of cytokines,proinsulin,and C-peptide.Results:Infused MSCs were found in the lungs,liver,spleen,and pancreas of T1D mice.They exhibited various effects,including reducing blood glucose levels,regulating immunity,inhibiting inflammation,increasingβ-cell areas,and reducing the expression of key proteins in the unfolded protein response pathway.Fasting serum proinsulin and C-peptide levels were significantly higher in the MSCs treatment group than in the T1D model group.However,there was no significant difference in the biomarker ofβ-cell endoplasmic reticulum stress,the ratio of fasting serum proinsulin to C-peptide,between the two groups.Conclusion:Ourfindings reveal that MSCs infusion does not alleviate endoplasmic reticulum stress inβcells directly but modulates the unfolded protein response pathway to preserveβ-cell mass and function in T1D mice.

Hypoxia Affects Autophagy in Human Umbilical Vein Endothelial Cells via the IRE1 Unfolded Protein Response

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.

The Role and Mechanism of Unfolded Protein Response Pathway in Tumor Drug Resistance

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.

Acinar cell injury induced by inadequate unfolded protein response in acute pancreatitis

Acute pancreatitis (AP) is an inflammatory disorder of pancreatic tissue initiated in injured acinar cells. Severe AP remains a significant challenge due to the lack of effective treatment. The widely-accepted autodigestion theory of AP is now facing challenges, since inhibiting protease activation has negligible effectiveness for AP treatment despite numerous efforts. Furthermore, accumulating evidence supports a new concept that malfunction of a self-protective mechanism, the unfolded protein response(UPR), is the driving force behind the pathogenesis of AP. The UPR is induced by endoplasmic reticulum(ER) stress, a disturbance frequently found in acinar cells, to prevent the aggravation of ER stress that can otherwise lead to cell injury. In addition, the UPR's signaling pathways control NFκB activation and autophagy flux, and these dysregulations cause acinar cell inflammatory injury in AP, but with poorly understood mechanisms. We therefore summarize the protective role of the UPR in AP, propose mechanistic models of how inadequate UPR could promote NFκB's pro-inflammatory activity and impair autophagy's protective function in acinar cells, and discuss its relevance to current AP treatment. We hope that insight provided in this review will help facilitate the research and management of AP.

Roles of mitochondrial unfolded protein response in mammalian stem cells

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.

The unfolded protein response signaling and retinal Müller cell metabolism

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.

Unfolded p53 in non-neuronal cells supports bacterial etiology of Alzheimer’s disease

Alzheimer’s disease has proven to be largely intractable to treatment,despite years of research,and numerous trials of therapies that target the hallmarks of the disease-amyloid plaques and neurofibrillary tangles.The etiology of Alzheimer’s disease remains elusive.There is a growing body of evidence for an infectious trigger of Alzheimer’s disease,and,in particular,the focus has been on the oral pathogen Porphyromonas gingivalis(P.gingivalis).Reports of the expression of a misfolded form of p53 in non-neuronal cells(fibroblasts,peripheral blood mononuclear cells,and B cells)and serum,which appears several years before clinical symptoms manifest,may provide further support for the role of bacteria in general,and P.gingivalis in particular,in the initiation of the disease.This review presents a model of the pathway from initial oral infection with P.gingivalis to amyloid plaque formation and neuronal degeneration,via the steps of chronic periodontitis;secretion of the inflammagens lipopolysaccharide and gingipains into the bloodstream;induction of an inflammatory response in both peripheral cells and tissues;disruption of the blood-brain barrier,and entry into the central nervous system of the inflammagens and the P.gingivalis bacteria themselves.In this model,the misfolded p53(or“unfolded p53”;up53)is induced in non-neuronal cells and upregulated in serum as a result of oxidative stress due to lipopolysaccharide from P.gingivalis.up53 is therefore a potential biomarker for early diagnosis of the presence of a causative agent of Alzheimer’s disease.Fastidious dental hygiene and aggressive antibiotic treatment may prevent the patient progressing to clinical Alzheimer’s disease if serum up53 is detected at this pre-symptomatic stage.

Role of unfolded protein response in lipogenesis

The signal transduction network in regulating lipid metabolism is a hot topic of biomedical research. Recent research endeavors reveal that intracellular stress signaling from a cellular organelle called endoplasmic reticulum (ER) is critically involved in lipid homeostasis and the development of metabolic disease. The ER is a site where newly-synthesized proteins are folded and assembled into their three-dimensional structures, modified and transported to their precise cellular destinations. A wide range of biochemical, physiological and pathological stimuli can interrupt the protein folding process in the ER and cause accumulation of unfolded or misfolded proteins in the ER lumen, a condition referred to as ER stress. To cope with this stress condition, the ER has evolved highly-specifi c signaling pathways collectively termed Unfolded Protein Response (UPR) or ER stress response. The UPR regulates transcriptionaland translational programs, affecting broad aspects of cellular metabolism and cell fate. Lipogenesis, the metabolic process of de novo lipid biosynthesis, occurs primarily in the liver where metabolic signals regulate expression of key enzymes in glycolytic and lipogenic pathways. Recent studies suggest that the UPR plays crucial roles in modulating lipogenesis under metabolic conditions. Here we address some of recent representative evidence regarding the role of the UPR in lipogenesis.

DOA Estimation Based on Subspace Compensation for Unfolded Coprime Array

Direction of arrival(DOA)estimation for unfolded coprime array(UFCA)is discussed,and a method based on subspace compensation is proposed.Conventional DOA estimation meth-ods partition the UFCA into two subarrays for separate estimations,which are then combined for unique DOA determination.However,the DOA estimation performance loss is caused as only the partial array aperture is exploited.We use the estimations from one subarray as initial estimations,and then enhance the estimation results via a compensation based on the whole array,which is im-plemented via a simple least squares(LS)operation constructed from the initial estimation and first-order Taylor expansion.Compared to conventional methods,the DOA estimation performance is improved while the computational complexity is in the same level.Multiple simulations are con-ducted to verify the efficiency of the proposed approach.

3-52 Unfolded Protein Response Induced by X-rays in Breast Cancer Cells

Expand ER stress is triggered due to the loss of homeostasis in the ER which causes the accumulation ofmisfolded proteins within the ER lumen. Severe or prolonged ER stress may induce the unfolded protein response(UPR), which is an adaptive mechanism aimed at reducing levels of unfolded proteins and keeping balance in theER. CHOP, Bip, JNK, EIF2 are major elements in these pathways.In this study, we investigated the activation of CHOP, Bip, total JNK and phosphorylated JNK (P-JNK), totalEIF2 and phosphorylated EIF2 (P- EIF2) in response to X-rays in breast cancer MCF-7 and MDA-MB-231 cellsusing western blot analysis.

Unfolded Drawings and Views for Irregular Spiral Surface Given Boundary Equations Based on CAD

Taking spiral chute as example, a method of unfolded drawings and views about irregular spiral surface is introduced. The surface is undevelopable and too complicated to get its views or to draw unfolded drawings by manual method. In this article, a series of the boundary equations of the spiral chute are derived by the movement rule of coal flow, and the solid and views of the spiral chute are generated based on redevelopment of SolidWorks. Unfolded drawing is drawn applying triangular development principle. The views and unfolded drawings not only are produced automatically, precisely and parameterized, but also involve more technological information. So it has an important significance on the irregular spiral surface＇s developments and processing.

Generation of Unfolded DNA in Human Neutrophils Following Hypothermal Treatment

By visualizing DNA with diamidino phenylindole (DAPI), we found that hypothermal incubation followed by rewarming of human neutrophils resulted in an increased number of DAPI-positive objects representative of extensive DNA unfolding seemingly similar to neutrophil extracellular traps (NETs). In contrast to canonical NET formation, diphenylene iodonium (DPI), an NADPH oxidase inhibitor, exhibited negligible effects on formation of the DAPI-positive objects. Moreover, multiple instances of DNA damage were detected in the objects, but not in canonical NETs. Our results thus suggest the potential of hypothermia for triggering DNA structural alteration in neutrophils, which is similar to but distinct from NET formation.

Unfolded annealing molecular dynamics conformers for wild-type and disease-associated variants of alpha-synuclein show no propensity for beta-sheetformation

Aggregation of alpha-synuclein leads to the formation of Lewy bodies in the brains of patients affected by Parkinson's disease (PD). Native human alpha-synuclein is unfolded in solution but assumes a partial alpha-helical conformation upon transient binding to lipid membranes. Annealing Molecular Dynamics (AMD) was used to generate a diverse set of unfolded conformers of free monomeric wild-type alpha-synuclein and PD-associated mutants A30P and A53T. The AMD conformers were compared in terms of secondary structure, hydrogen bond network, solvent-accessible surface per residue, and molecular volume. The objective of these simulations was to identify structural properties near mutation sites and the non-amyloid component (NAC) region that differ between wild- type and disease-associated variants and may be associated to aggregation of alpha- synuclein. Based on experimental evidence, a hypothesis exists that aggregation involves the formation of intermolecular beta sheets. According to our results, disease-associated mutants of alpha-synuclein are no more propense to contain extended beta regions than wild-type alpha-synuclein. Moreover, extended beta structures (necessary for beta sheet formation) were not found at or around positions 30 and 53, or the NAC region in any unfolded conformer of wild-type, A30P or A53T alpha-synuclein, under the conditions of the simulations. These results do not support the hypothesis that the mutant's higher propensity to aggregation results solely from changes in amino acid sequence leading to changes in secondary structure folding propensity.

A vicinal oxygen chelate protein facilitates viral infection by triggering the unfolded protein response in Nicotiana benthamiana

Vicinal oxygen chelate(VOC)proteins are members of an enzyme superfamily with dioxygenase or non-dioxygenase activities.However,the biological functions of VOC proteins in plants are poorly understood.Here,we show that a VOC in Nicotiana benthamiana(NbVOC1)facilitates viral infection.NbVOC1 was significantly induced by infection by beet necrotic yellow vein virus(BNYVV).Transient overexpression of NbVOC1 or its homolog from Beta vulgaris(BvVOC1)enhanced BNYVV infection in N.benthamiana,which required the nuclear localization of VOC1.Consistent with this result,overexpressing NbVOC1 facilitated BNYVV infection,whereas,knockdown and knockout of NbVOC1 inhibited BNYVV infection in transgenic N.benthamiana plants.NbVOC1 interacts with the basic leucine zipper transcription factors bZIP17/28,which enhances their self-interaction and DNA binding to the promoters of unfolded protein response(UPR)-related genes.We propose that bZIP17/28 directly binds to the NbVOC1 promoter and induces its transcription,forming a positive feedback loop to induce the UPR and facilitating BNYVV infection.Collectively,our results demonstrate that NbVOC1 positively regulates the UPR that enhances viral infection in plants.

New insights into the unfolded protein response(UPR)-anterior gradient 2(AGR2)pathway in the regulation of intestinal barrier function in weaned piglets

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.

Regulation and function of endoplasmic reticulum autophagy in neurodegenerative diseases

The endoplasmic reticulum,a key cellular organelle,regulates a wide variety of cellular activities.Endoplasmic reticulum autophagy,one of the quality control systems of the endoplasmic reticulum,plays a pivotal role in maintaining endoplasmic reticulum homeostasis by controlling endoplasmic reticulum turnover,remodeling,and proteostasis.In this review,we briefly describe the endoplasmic reticulum quality control system,and subsequently focus on the role of endoplasmic reticulum autophagy,emphasizing the spatial and temporal mechanisms underlying the regulation of endoplasmic reticulum autophagy according to cellular requirements.We also summarize the evidence relating to how defective or abnormal endoplasmic reticulum autophagy contributes to the pathogenesis of neurodegenerative diseases.In summary,this review highlights the mechanisms associated with the regulation of endoplasmic reticulum autophagy and how they influence the pathophysiology of degenerative nerve disorders.This review would help researchers to understand the roles and regulatory mechanisms of endoplasmic reticulum-phagy in neurodegenerative disorders.

Mannogalactoglucan from mushrooms protects pancreatic islets via restoring UPR and promotes insulin secretion in TIDM mice

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.

Knockdown of RCN1 contributes to the apoptosis of colorectal cancer via regulating IP3R1

Background:The incidence of colorectal cancer(CRC)has been increasing in recent years.Thus,the discovery of factors that can assist in alleviating CRC is urgently warranted.Methods:To identify a potential factor involved in the development of CRC,we screened the upregulated genes in tumor tissues through four datasets from an online database.The expression of reticulocalbin 1(RCN1),a Ca2+-binding protein,was upregulated in the four datasets.Based on loss-offunction experiments,the effect of RCN1 on cell viability was assessed by Cell Counting Kit-8(CCK-8)assay.The regulatory effect of RCN1 on apoptosis was evaluated through Annexin V-fluorescein 5-isothiocyanate(FITC)/propidium iodide(PI)staining assay and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling(TUNEL)assay in RKO and SW480 cells.Activation of endoplasmic reticulum(ER)stress signaling pathways was confirmed by estimating the phosphorylation and expression of PRKR-like ER kinase(PERK),inositol-requiring kinase-1(IRE1),transcription factor 6(ACT6),and CCAAT/enhancer-binding protein-homologous protein(CHOP).The intracellular Ca2+homeostasis regulated by RCN1 was determined through the detection of Ca2+concentration and mitochondrial membrane potential(MMP)measurement.Moreover,whether inositol 1,4,5-trisphosphate receptor type 1(IP3R1)was involved in the regulation of RCN1 in CRC was verified through the depletion of IP3R1 in RKO cells.Results:Knockdown of RCN1 reduced cell viability and facilitated apoptosis in RKO and SW480 cells.Phosphorylation of PERK and IRE1,activation of ATF6,and upregulation of CHOP were induced by the absence of RCN1,suggesting that the unfolded protein response(UPR)was activated in CRC cells.The concentration of Ca2+in mitochondria was increased after RCN1 depletion,followed by reduction in the MMP and release of cytochrome c from mitochondria to the cytoplasm in RKO and SW480 cells.Moreover,it was demonstrated that IP3R1 mediates the effect of RCN1 on apoptosis induced by ER stress in CRC cells.The downregulation of IP3R1 restored the RCN1 loss-induced apoptosis and the increased Ca2+concentration.Conclusion:Taken together,our results confirmed that silencing of RCN1 disrupted intracellular Ca2+homeostasis and promoted cell apoptosis caused by TG-induced ER stress by regulating IP3R1 and activating the UPR signaling pathways.

Correlation Between Unfolded States of Apocytochrome c and Its Ability to Pass Lipid Bilayer

In contrast to the horse heart apocytochrome c,the chicken heart apocytochrome c under-went a conformational change from random coil to partial folding during a renaturation process.When theapocytochrome horse heart and that of chicken heart c were subjected to a translocation assay in vitro usinglarge trypsin-enclosed unilamellar vesicles from soybean phospholipids,the ability of the chicken heart apoc-ytochrome c to penetrate into the liposomes was found to decrease markedly with the renaturation procedure,while that of horse heart apocytochrome c remained relatively constant.Observations from circular dichroismmeasurement on the induction of secondary folding of these two species of apocytochrome c upon interactionwith soybean phospholipid vesicles suggested that a more flexible structure of apocytochrome c embedded inthe lipid matrix be required for its efficient translocation across the bilayer.