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.

Lipocalin-2-Mediated Insufficient Oligodendrocyte Progenitor Cell Remyelination for White Matter Injury After Subarachnoid Hemorrhage via SCL22A17 Receptor/Early Growth Response Protein 1 Signaling

Insufficient remyelination due to impaired oligodendrocyte precursor cell(OPC)differentiation and maturation is strongly associated with irreversible white matter injury(WMI)and neurological deficits.We analyzed whole transcriptome expression to elucidate the potential role and underlying mechanism of action of lipocalin-2(LCN2)in OPC differentiation and WMI and identified the receptor SCL22A17 and downstream transcription factor early growth response protein 1(EGR1)as the key signals contributing to LCN2-mediated insufficient OPC remyelination.In LCN-knockdown and OPC EGR1 conditional-knockout mice,we discovered enhanced OPC differentiation in developing and injured white matter(WM);consistent with this,the specific inactivation of LCN2/SCl22A17/EGR1 signaling promoted remyelination and neurological recovery in both atypical,acute WMI due to subarachnoid hemorrhage and typical,chronic WMI due to multiple sclerosis.This potentially represents a novel strategy to enhance differentiation and remyelination in patients with white matter injury.

Hippocampal expression of synaptic structural proteins and phosphorylated cAMP response element-binding protein in a rat model of vascular dementia induced by chronic cerebral hypoperfusion

The present study established a rat model of vascular dementia induced by chronic cerebral hypoperfusion through permanent ligation of bilateral common carotid arteries.At 60 days after modeling,escape latency and swimming path length during hidden-platform acquisition training in Morris water maze significantly increased in the model group.In addition,the number of accurate crossings over the original platform significantly decreased,hippocampal CA1 synaptophysin and growth-associated protein 43 expression significantly decreased,cAMP response element-binding protein expression remained unchanged,and phosphorylated cAMP response element-binding protein expression significantly decreased.Results suggested that abnormal expression of hippocampal synaptic structural protein and cAMP response element-binding protein phosphorylation played a role in cognitive impairment following chronic cerebral hypoperfusion.

Tonicity response element binding protein associated with neuronal cell death in the experimental diabetic retinopathy

AIM: To study the contribution of tonicity response element binding protein(Ton EBP) in retinal ganglion cell(RGC) death of diabetic retinopathy(DR).METHODS: Diabetes was induced in C57BL/6 mice by five consecutive intraperitoneal injections of 55 mg/kg streptozotocin(STZ). Control mice received vehicle(phosphate-buffered saline). All mice were killed 2mo after injections, and the extent of cell death and the protein expression levels of Ton EBP and aldose reductase(AR) were examined.RESULTS: The Ton EBP and AR protein levels and the death of RGC were significantly increased in the retinas of diabetic mice compared with controls 2mo after the induction of diabetes. Terminal deoxynucleotidyl transferase(Td T)-mediated d UTP nick end labeling(TUNEL)-positive signals co-localized with Ton EBP immunoreactive RGC. These changes were increased in the diabetic retinas compared with controls.CONCLUSION: The present data show that AR and Ton EBP are upregulated in the DR and Ton EBP may contribute to apoptosis of RGC in the DR.

Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway in depressive disorder

The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway plays an important role in the mechanism of action of antidepressant drugs and has dominated recent studies on the pathogenesis of depression. In the present review we summarize the known roles of extracellular signal-regulated kinase, cAMP response element-binding protein and brain-derived neurotrophic factor in the pathogenesis of depression and in the mechanism of action of antidepressant medicines. The extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor pathway has potential to be used as a biological index to help diagnose depression, and as such it is considered as an important new target in the treatment of depression.

Icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels in the hippocampus of the senescence-accelerated mouse

At 8 weeks after intragastric administration of icariin to senescence-accelerated mice （P8 strain）, Morris water maze results showed that escape latency was shortened, and the number of platform crossings was increased. Immunohistochemical staining and western blot assay detected significantly increased levels of cyclic adenosine monophosphate response element binding protein These results suggest that icariin upregulates phosphorylated cyclic adenosine monophosphate response element binding protein levels and improves learning and memory functions in hippocampus of the senescence-accelerated mouse.

Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer＇s disease

Alzheimer’s disease（AD）is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles.Prior to the development of these characteristic pathological hallmarks of AD,anterograde axonal transport is impaired.However,the key proteins that initiate these intracellular impairments remain elusive.The collapsin response mediator protein-2（CRMP-2）plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2releases kinesin-1.Here,we tested the hypothesis that amyloid-beta（Aβ）-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1（an anterograde axonal motor transport protein）in AD.We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site.Additionally,in the transgenic Tg2576 mouse model of familial AD（FAD）that exhibits Aβaccumulation in the brain with age,we found substantial co-localization of p T555CRMP-2and dystrophic neurites.In SH-SY5Y differentiated neuronal cultures,Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1.The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation.These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function,leading to neuronal defects.

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.

A cellular response protein induced during HSV-1 infection inhibits viral replication by interacting with ATF5

Studies of herpes simplex virus type 1 （HSV-1） infection have shown that many known and unknown cellular molecules in- volved in viral proliferation are up-regulated following HSV-1 infection. In this study, using two-dimensional polyacrylamide gel electrophoresis, we found that the expression of the HSV-1 infection response repressive protein （HIRRP, GI 16552881） was up-regulated in human L02 cells infected with HSV-1. HIRRP, an unknown protein, was initially localized in the cytoplasm and then translocated into the nucleus of HSV-l-infected cells. Further analysis showed that HIRRP represses HSV-1 proliferation by inhibiting transcription of the viral genome by interacting with the cellular transcription factor, ATFS, via its N-terminal domain. ATF5 represses the transcription of many host genes but can also act as an activator of genes containing a specific motif. We found that ATF5 promotes the proliferation of HSV-1 via a potential mechanism by which ATF5 enhances the transcription of viral genes during the course of an HSV-1 infection; HIRRP then induces feedback repression of this tran- scription by interacting with ATFS.

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.

Effects of basic fibroblast growth factor on hippocampal and parietal cortical neuronal cAMP-response element-binding protein expression in a rat model of focal cerebral ischemia/reperfusion

BACKGROUND： cAMP-response element binding protein （CREB） is a key modulator of various signaling pathways. CREB activation initiates a series of intracellular signaling pathways that promote neuronal survival. OBJECTIVE： To investigate the regulatory effects of basic fibroblast growth factor （bFGF） on cerebral neuronal CREB expression following ischemia/reperfusion injury. DESIGN, TIME AND SETTING： An immunohistochemical detection experiment was performed at the Department of Anatomy, Shenyang Medical College, between October 2006 and April 2008. MATERIALS： A total of 60 healthy, adult, Wistar rats were randomly divided into three groups： sham-operated （n =12）, ischemia/reperfusion （n = 24）, and bFGF-treated （n = 24）. Rabbit anti-rat CREB （1： 100） and biotin labeled goat anti-rabbit IgG were purchased from the Wuhan Boster Company, China. MetaMorph-evolution MP5.0-BX51 microscopy imaging system was provided by China Medical University, China. METHODS： Rat models of cerebral ischemia/reperfusion injury were developed using the suture method for right middle cerebral artery occlusion. Two-hour ischemia was followed by reperfusion. Rats from the bFGF-treated and ischemia/reperfusion groups were intraperitoneally administered endogenous bFGF （500 IU/mL, 2 000 IU/kg） or an equal amount of physiological saline. Rats from the sham-operated group underwent a similar surgical procedure, without induction of ischemia/reperfusion injury and drug administration. MAIN OUTCOME MEASURES： After 48-hour reperfusion, hippocampal and parietal cortical neuronal CREB expression was detected by immunohistochemistry, and the absorbance of hippocampal CREB-positive products was determined using MetaMorph-evolutionMP5.0-BX51 microscopy imaging system. RESULTS： The sham-operated group exhibited noticeable CREB expression in hippocampal and parietal cortical neurons. In the ischemia/reperfusion group, the CREB expression was discrete and neurons were poorly arranged. The bFGF-treated group exhibited increased CREB expression and better neuronal arrangement compared with the ischemia/reperfusion group. The mean absorbance of CREB-immunoreactive products in the hippocampus and parietal cortex was significantly higher in the ischemia/reperfusion group than in the sham-operated group （P 〈 0.05）, and significantly higher in the bFGF-treated group than in the ischemia/reperfusion group （P 〈 0.05）. CONCLUSION： bFGF significantly upregulates CREB expression in hippocampal and parietal cortical neurons following ischemia/reperfusion injury.

Antibody to collapsin response mediator protein 1 promotes neurite outgrowth from rat hippocampal neurons

This study examined the role of collapsin response mediator protein 1 （CRMP-1） on neurite outgrowth from rat hippocampal neurons by blocking its function using an antibody. Hippocampal neurons, cultured in vitro, were treated （blocked） using a polyclonal antibody to CRMP-1, and neurite outgrowth and cytoskeletal changes were captured using atomic force microscopy and laser confocal microscopy. Control cells, treated with normal rabbit IgG, established their characteristic morphology and had a large number of processes emerging from the soma, including numerous branches. Microtubules were clearly visible in the soma, formed an elaborate network, and were aligned in parallel arrays to form bundles which projected into neurites. After blocking with CRMP-1 antibody, the number of branches emerging from axons and dendrites significantly increased and were substantially longer, compared with control cells. However, the microtubule network nearly disappeared and only a few remnants were visible. When CRMP-1 antibody-blocked neurons were treated with the Rho inhibitor, Y27632, numerous neurites emerged from the soma, and branches were more abundant than in control neurons. Although the microtubules were not as clearly visible compared with neurons cultured in control medium, the microtubule network recovered in cells treated with Y27632, when compared with cells that were blocked by CRMP-1 antibody （but not treated with Y27632）. These results demonstrate that neurite outgrowth from hippocampal neurons can be promoted by blocking CRMP-1 with a polyclonal antibody.

Spastin interacts with collapsin response mediator protein 3 to regulate neurite growth and branching

Cytoskeletal microtubule rearrangement and movement are crucial in the repair of spinal cord injury.Spastin plays an important role in the regulation of microtubule severing.Both spastin and collapsin response mediator proteins can regulate neurite growth and branching;however,whether spastin interacts with collapsin response mediator protein 3(CRMP3)during this process remains unclear,as is the mechanism by which CRMP3 participates in the repair of spinal cord injury.In this study,we used a proteomics approach to identify key proteins associated with spinal cord injury repair.We then employed liquid chromatography-mass spectrometry to identify proteins that were able to interact with glutathione S-transferase-spastin.Then,co-immunoprecipitation and staining approaches were used to evaluate potential interactions between spastin and CRMP3.Finally,we co-transfected primary hippocampal neurons with CRMP3 and spastin to evaluate their role in neurite outgrowth.Mass spectrometry identified the role of CRMP3 in the spinal cord injury repair process.Liquid chromatography-mass spectrometry pulldown assays identified three CRMP3 peptides that were able to interact with spastin.CRMP3 and spastin were co-expressed in the spinal cord and were able to interact with one another in vitro and in vivo.Lastly,CRMP3 overexpression was able to enhance the ability of spastin to promote neurite growth and branching.Therefore,our results confirm that spastin and CRMP3 play roles in spinal cord injury repair by regulating neurite growth and branching.These proteins may therefore be novel targets for spinal cord injury repair.The Institutional Animal Care and Use Committee of Jinan University,China approved this study(approval No.IACUS-20181008-03)on October 8,2018.

Sevoflurane effects on cyclic adenosine monophosphate response element binding protein,phosphorylated cyclic adenosine monophosphate response element binding protein,and Livin expression in the cortex and hippocampus of a vascular cognitive impairment rat

BACKGROUND： Neuronal necrosis and apoptosis play important roles in the pathophysiology of cerebral ischemia and resulting cognitive impairment. However, inhibition of neuronal necrosis and apoptosis has been shown to attenuate cognitive impairment following cerebral ischemia. OBJECTIVE： To investigate the effects of sevoflurane on cyclic adenosine monophosphate response element binding protein （CREB）, phosphorylated CREB （pCREB）, and Livin expression in the cortex and hippocampus of a rat model of vascular cognitive impairment.DESIGN, TIME AND SETTING： A randomized, controlled experiment was performed in the Chongqing Key Laboratory of Neurology between June 2007 and July 2008.MATERIALS： Sevoflurane was provided by Abbott Laboratory, UK; Morris water maze was provided by Chinese Academy of Medical Sciences, China; goat anti-rat CREB, goat anti-rat pCREB and goat anti-rat Livin antibodies were provided by Biosource International, USA. METHODS： A total of 42 female, Wistar rats were randomly assigned to the following groups： sham operation, vascular cognitive impairment, and sevoflurane treatment. The vascular cognitive impairment rat model was established by permanent bilateral occlusion of both common carotid arteries, and 1.0 MAC sevoflurane was immediately administered by inhalation for 2 hours. MAIN OUTCOME MEASURES： CREB, pCREB, and Livin expression was measured in the cortex and hippocampus by Western blot and reverse transcription-polymerase chain reaction. Behavior was evaluated with Morris water maze. RESULTS： CREB, pCREB, and Livin expression in the sevoflurane treatment group was significantly greater than the vascular cognitive impairment group （P 〈 0.01）. However, expression of CREB and pCREB was significantly less in the sevoflurane treatment and vascular cognitive impairment groups, compared with the sham operation group （P 〈 0.01）. Livin expression in the sevoflurane treatment and vascular cognitive impairment groups was significantly greater than the sham operation group （P 〈 0.01）. Learning, memory, and behavior disorders were observed in the vascular cognitive impairment group. Sevoflurane treatment significantly improved these observed disorders. CONCLUSION： Sevoflurane improved cognitive impairment due to permanent bilateral occlusion of both common carotid arteries. Improved function was associated with increased CREB, pCREB, and Livin expression in the cortex and hippocampus.

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.

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.

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.