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The global prevalence of gestational diabetes mellitus (GDM) is approximately 13. 4% and is expected to increase annually. However, the precise mechanism behind GDM remains to be established. Increasing evidence suggests that insulin resistance (IR) and β-cell impairment are key factors in the pathogenesis of GDM. Endoplasmic reticulum stress (ERS) is characterized by the activation of the unfolded protein response through three key endoplasmic reticulum transmembrane proteins: protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6). ERS is implicated in IR in adipose tissue, liver, skeletal muscle, and placenta, and also plays a crucial role in β-cell impairment through processes such as apopto-sis, pyroptosis, and autophagy. Therefore, targeting ERS could be a potential therapeutic approach for the prevention and treatment of GDM. This review explores the potential role of ERS in IR and β-cell dysfunction in GDM, and provides evidence for the preventive and intervention effects of bioactive compounds on GDM based on the ERS pathway. This aims to enhance our understanding of the molecular pathological basis of GDM and offer new strategies for its prevention and treatment. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum stress (ERS) is a protective cellular response that occurs when cells face hypoxia or nutrient deprivation. It alleviates protein accumulation in the endoplasmic reticulum (ER) by the unfolded protein response. Unfolded or misfolded proteins that are not efficiently cleared by the unfolded protein response pathway are degraded by endoplasmic reticulum-phagy (ER-phagy), which is trigged by ERS to restore ER morphology. ER-phagy is mediated by ER-phagy receptors. In mammalian and yeast cells, various ER-phagy receptors exist that promote ER fragment formation, capture autophagic cargos and deliver them to autolysosomes for degradation. Each ER-phagy receptor has unique structural features that determine its mode of cargo capture. Additionally, ERS regulates ER-phagy by mediating the expression and phosphorylation of ER-phagy receptors. Research has shown that ERS-induced ER-phagy plays a crucial role in the pathogenesis of various human diseases. Therefore, elucidating the specific mechanisms underlying ERS-induced ER-phagy provides a theoretical basis for the prevention and treatment of ER-phagy-related diseases. Herein, we review the molecular mechanisms of ERS-induced ER-phagy mediated by ER-phagy receptors in mammals (FAM134B, RTN3L, SEC62, CCPG1) and yeasts (Atg39, Atg40, Erp1), as well as the connection between ERS-induced ER-phagy and human diseases such as neurodegenerative disorders and cancer, aiming to provide new strategies for the prevention and treatment of ER-phagy-related diseases. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether endoplasmic reticulum transmembrane protein IRE1 (encoded by Ern1) can modulate the immunogenicity and tumorigenicity of cancer cells and explore the underlying mechanism. Methods: Correlation between ERN1 expression and the overall survival of cancer patients was explored with public cancer databases. CRISPR-Cas9 technology was used to delete Ern1 in mouse tumor cell lines MCA205 and TC-1. By CCK-8, flow cytometry, ELISA, luciferase reporter systems, subcutaneous tumor models, prime-boost regimens, we analyzed impact of Ern1 on tumor cell proliferation in vitro and tumor growth in vivo, intratumoral immune cell composition, tunicamycin-induced immunogenic cell death and activation of anti-tumor effector T cells. The growth kinetics of Ern1-/- tumors was also monitored in Ifnar-/- mice. Results: ERN1 expression was found to be negatively correlated with the overall survival of cancer patients across multiple cancer types. Although Ern1 deficiency didn't affect tumor cell proliferation in vitro, it largely delayed tumor growth or caused spontaneous tumor regression in immune-competent mice. As compared to wild type counterparts, Ern1 tumors harbored much more neutrophils but significantly less CD4T cells. Upon tunicamycin-induced endoplasmic reticulum stress, Ern1-/- cells were more vulnerable to cell death. Although Ern1-deficiency reduced HMGB1 release and calreticulin exposure, IFN-α/β secretion was increased, and strongly elevated type I IFN response in tumor cells and augmented IFN-γ production by anti-tumor effector T cells. Ern1-/- tumor cells restored the tumorigenic capacity in Ifnar-/- mice. Conclusion: Ern1 deficiency can enhance the immunogenicity of tumor cells and inhibit tumor outgrowth by boosting endoplasmic reticulum stress-induced type I IFN response. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER) is the predominant membrane structure in eukaryotic cells and is a key organelle for the occurrence of important intracellular physiological processes. Under the action of various internal and external factors, the homeostasis of ER is disrupted to block protein processing and transport, and the accumulation of unfolded or misfolded proteins in the ER lumen, forms endoplasmic reticulum stress (ERS) and triggers the unfolded protein response (UPR). Moderate ERS reduces protein synthesis, promotes protein degradation, and increases molecular chaperones that assist protein folding through the UPR signaling pathway, ultimately relieving ER stress. However, if the ERS is too strong or prolonged and exceeds the cell􀆳s ability to regulate itself, the UPR can initiate apoptosis and lead to diseases. Numerous studies have shown that ERS is closely associated with the development of several cardiovascular diseases (CVD). This review focuses on the research progress of UPR in several common types of CVD and targets UPR as a potential therapeutic approach for CVD. [ABSTRACT FROM AUTHOR]

The biosynthesis and maturation of proteins are primarily regulated by the endoplasmic reticulum in its physiological state. Thus, the disruption of physiological homeostasis initiates the buildup of unfolded and misfolded proteins in the endoplasmic reticulum, resulting in endoplasmic reticulum stress (ERS) and unfolded protein response (UPR). One of the important pathways by which UPR maintains intracellular homeostasis under ERS is activating protein kinase R-like endoplasmic reticulum kinase (PERK). The activation of the PERK pathway stimulates eukaryotic translation initiation factor 2 subunit-α (eIF2α) phosphorylation and the selective translation of active transcription factor 4 (ATF4), and PERK induces cell apoptosis by directly binding to the promoter of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). This signaling pathway is also one of the important mechanisms by which UPR participates in the regulation of hematological malignancies and immune cells in a tumor microenvironment. This article provides an overview of advancements in research into the PERK-eIF2α-ATF4-CHOP signaling pathway in hematological malignancies and the potential therapeutic benefits of targeting this signaling pathway.

The biosynthesis and maturation of proteins are primarily regulated by the endoplasmic reticulum in its physiological state. Thus, the disruption of physiological homeostasis initiates the buildup of unfolded and misfolded proteins in the endoplasmic reticulum, resulting in endoplasmic reticulum stress (ERS) and unfolded protein response (UPR). One of the important pathways by which UPR maintains intracellular homeostasis under ERS is activating protein kinase R-like endoplasmic reticulum kinase (PERK). The activation of the PERK pathway stimulates eukaryotic translation initiation factor 2 subunit-α (eIF2α) phosphorylation and the selective translation of active transcription factor 4 (ATF4), and PERK induces cell apoptosis by directly binding to the promoter of pro-apoptotic transcription factor C/EBP homologous protein (CHOP). This signaling pathway is also one of the important mechanisms by which UPR participates in the regulation of hematological malignancies and immune cells in a tumor microenvironment. This article provides an overview of advancements in research into the PERK-eIF2α-ATF4-CHOP signaling pathway in hematological malignancies and the potential therapeutic benefits of targeting this signaling pathway. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum (ER) is an important membranous organelle responsible for protein synthesis, folding and processing, lipid synthesis, and Ca2+balance. Under the influence of some factors, the structure and function of ER are disturbed, leading to ER stress. Under ER stress, ER maintains its normal structure and function mainly through the processes of unfolded protein reaction and ER autophagy. There is a close relationship between ER stress and many diseases, such as cancer, inflammatory diseases, neurodegenerative diseases, osteoporosis, and so on. Under ER stress, the unfolded protein response and ER autophagy may participate in the regulation of bone metabolism, which may be a potential target for the treatment of osteoporosis. Therefore, we review the existing relevant literature and the latest research reports, aiming to elucidate the influence and mechanism of the unfolded protein response and ER autophagy on osteoporosis, and to provide new ideas for further clarifying the pathogenesis and treatment of osteoporosis. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum is the main site of protein folding and post-translational modification in eukaryotic cells. It also participates in the regulation of Ca2+ and lipid storage and synthesis, and has important physiological functions. Herpesviruses is a class of enveloped DNA viruses. The synthesis and processing of its surface glycosylated envelope proteins depends on the endoplasmic reticulum. During virus replication, a large number of synthesized glycosylated envelope proteins are excessive in the endoplasmic reticulum. Accumulation causes endoplasmic reticulum stress (ERS), which in turn leads to unfolded protein response (UPR) . Some herpesviruses may have evolved mechanisms to regulate the UPR to create an optimal egoistic environment for the replication process. When they replicate in host cells, they will cause related endoplasmic reticulum UPR signaling cascades, such as cell damage, inflammation, apoptosis, etc. In this paper, the mechanism of endoplasmic reticulum stress/unfolded protein response (ERS/UPR) response to viruses was reviewed, and the molecular mechanism and related signaling pathways of ERS caused by herpes simplex virus type I, pseudorabies virus, marek virus, duck enteritis virus and other herpes viruses were expounded, which provided theoretical basis for the research and development of herpes virus-related vaccines and drug targets. [ABSTRACT FROM AUTHOR]

Hypoxic pulmonary hypertension (HPH) is a serious complication caused by long-term hypoxia,which is characterized by persistent vasoconstriction and irreversible vascular remodeling. The hypoxia may destroy protein folding process in endoplasmic reticulum and activate endoplasmic reticulum stress(ERS). As the core response of cell stress, ERS is closely related to the development of HPH.

Osteoarthritis is a common degenerative disease in which endoplasmic reticulum stress(ER stress) plays an important role in the pathogenesis of chondrocyte apoptosis. To limit the adverse effects of endoplasmic reticulum stress, cells activate the unfolded protein response (UPR). However, when endoplasmic reticulum stress persists beyond the maximum tolerance of UPR, cells may trigger endoplasmic reticulum dysfunction through three pathways of UPR leading to chondrocyte apoptosis.

Objective To elucidate the mechanism of action of icariin to protect photoreceptor cells suffering from endoplasmic reticulum stress. Methods Thapsigargin(0. 2 μmol/L), was used to induce endoplasmic reticulum stress in the mouse cone cell line 661W. AlamarBlue staining was used to detect cell viability. The levels of proteins related to the unfolded protein response p-PERK,GRP78,CHOP were analyzed by Western blotting. The intracellular Ca2+ level was analyzed by fluorescence imaging and the F340/F380 ratio method. Permeability transition pore protein and the membrane potential in mitochondria were analyzed by fluorescence staining. The binding and interaction between icariin and SERCA2b were analyzed in vitro by molecular docking. Results Thapsigargin induced 661W cell death. Icariin significantly inhibited 661W cell death caused by thapsigargin in the concentration of 2. 22 - 20. 00 nmol/L (P < 0. 01). Thapsigargin induced the unfolded protein responses in 661W cells, significantly promoting the phosphorylation of PERK (Thr980) (P <0. 01) and increasing the protein levels of transcription factor CHOP (P <0. 01). Icariin (2. 0 μmol/L) significantly downregulated the expression of CHOP protein (P <0. 01) and had the trend of inhibitation of phosphorylation of PERK (Thr980). Within 10 minutes after thapsigargin acting on 661 W cells, the calcium ions in the cytosol increased. Icariin pretreatment (1. 0 μmol/L) inhibited an increase of intracellular calcium content. Thapsigargin induced the opening of mitochondrial permeability transition pores in 661W cells, which in turn caused a decrease in mitochondrial membrane potential. Icariin (2. 0 μmol/L) inhibited thapsigargin-induced mitochondrial permeability transition pore opening and mitochondrial membrane potential reduction. In vitro molecular docking analysis showed that icariin stably bound to the nucleotidebinding and phosphorylation domains of SERCA2b, with a binding energy of - 8. 776 kcal/mol and multiple hydrogen bonds. Conclusion Icariin partially antagonized the effect on the binding of thapsigargin and SERCA, which maintained Ca2+ homeostasis in cones, contributing to mitochondrial health. This may be one mechanism of action of icariin in cone cell protection. [ABSTRACT FROM AUTHOR]

BackgroundFlurochloridone (FLC) can induce apoptosis in Sertoli cells, but the specific mechanism remains unknown.ObjectiveTo investigate the testicular cell apoptosis in mice as well as apoptosis and activation of endoplasmic reticulum stress in TM4 cell line induced by FLC through in vivo and in vitro study designs respectively, and study the role of inosital-requiring enzyme 1α (IRE1α)-c-Jun N-terminal kinase (JNK) signaling pathway in the process of FLC-induced apoptosis in TM4 cells through intervention study design.MethodsTesticular tissues were collected from male C57BL/6 mice which were treated with 3, 15, 75, and 375 mg·（kg·d）−1 FLC by oral perfusion for 28 d. Apoptosis was observed by TUNEL staining, and the levels of apoptosis-related proteins were detected by Western blotting, including B-cell lymphoma-2 (Bcl-2), Bcl-2 interacting mediator of cell death (Bim), and Bcl-2 associated X protein (Bax). In the in vitro study, TM4 cells were treated with different concentrations of FLC (40, 80, and 160 μmol·L−1) for 6 h, then apoptosis rate was detected by flow cytometry, and the levels of apoptosis-related proteins (Bcl-2, Bim, and Bax) and endoplasmic reticulum stress-related proteins [glucose regulated protein 78 (GRP78), phosphorylated-protein kinase R like endoplasmic reticulum kinase (p-PERK), activating transcription factor 6 (ATF6), phosphorylated-inosital-requiring enzyme 1α (p-IRE1α), and phosphorylated-JNK (p-JNK)] were measured by Western blotting. In the intervention study, TM4 cells were pretreated with IRE1α phosphorylation inhibitor 4μ8C and JNK phosphorylation inhibitor SP600125 for 6 h, then treated with 160 μmol·L−1 FLC for 6 h. The levels of apoptosis-related proteins and endoplasmic reticulum stress-related proteins were measured by Western blotting, and cell viability was detected by cell counting kit-8.ResultsAfter the male C57BL/6 mice orally exposed to FLC for 28 d, apoptosis occurred in the seminiferous tubule. The protein expression level of Bcl-2, apoptosis inhibitor, was decreased in the 75 and 375 mg·(kg·d)−1 groups (P

Hypoxic pulmonary hypertension (HPH) is a serious complication caused by long-term hypoxia, which is characterized by persistent vasoconstriction and irreversible vascular remodeling. The hypoxia may destroy protein folding process in endoplasmic reticulum and activate endoplasmic reticulum stress (ERS). As the core response of cell stress, ERS is closely related to the development of HPH. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a common degenerative disease in which endoplasmic reticulum stress (ER stress) plays an important role in the pathogenesis of chondrocyte apoptosis. To limit the adverse effects of endoplasmic reticulum stress, cells activate the unfolded protein response (UPR). However, when endoplasmic reticulum stress persists beyond the maximum tolerance of UPR, cells may trigger endoplasmic reticulum dysfunction through three pathways of UPR leading to chondrocyte apoptosis. [ABSTRACT FROM AUTHOR]

Objective This study is undertaken to elucidate the protective effect and molecular mechanism of genipin against cecal ligation and puncture (CLP)-induced sepsis. Methods Male C57BL/6 mice were assigned to three groups: vehicle-treated sham group, vehicle-treated CLP group, and genipin-treated CLP group. Genipin (2.5 mg/kg) and vehicle (0.9% saline) were respectively administered to corresponding group via the tail vein at 0 h and 20 h after the CLP. First, for the survival experiment, mortality was monitored up to 120 h after the CLP procedure. Second, based on the survival test, 36 h time point after CLP was selected for further tests. The serum concentrations of tumor necrosis factor α (TNF- α) and interleukin 6 (IL-6) were detected by enzym-linked immunosorbent assay (ELISA). The pathological damages to lung and liver tissue were detected by hematoxylineosin staining (HE staining). The expression levels of endoplasmic reticulum (ER) stress-related proteins such as glucose regulated protein78 (GRP78), protein kinase r-like endoplasmic reticulum kinase (PERK), p-eukaryotic initation factor 2α (p-eIF2α), and C/EBP homologous protein (CHOP) were determined by Western Blot. Detection of splenocyte apoptosis was performed by using the terminal-deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method. Results Compared with the vehicle-treated CLP group, genipin significantly improved the survival of septic mice, decreased the serum levels of TNF-α and IL-6, and alleviated histopathological damages to lung and liver such as edema and inflammatory cell infiltration. Moreover, genipin significantly downregulated the expression levels of splenic GRP78, PERK, p-eIF2α, and CHOP, and lessened ERinduced splenocyte apoptosis. Conclusion Genipin significantly attenuates sepsis-induced organ injury and the excessive inflammatory response and improves the outcome of sepsis. The effect mechanisms of genipin against sepsis are probably associated with decreasing splenocyte apoptosis by attenuating ER stress to further block the ER stress-induced apoptosis.

The infection caused by hepatitis C virus(HCV) often disturbs the momeostasis of endoplasmic reticulum. Accumulation of replication intermediates can lead to endoplasmic reticulum stress(ERS), which is closely related to the occurrence of many diseases. In order to prevent the harmful effects of endoplasmic reticulum stress, cells activate unfolded protein response(UPR) and apoptosis pathway. In early stage of virus infection, unfolded protein reaction is a main function to remove the proteins and other intermediates produced by the virus and when the infection deepens and the homeostasis is no longer to be maintained, the cell activates the apoptosis pathway. However, these pathways can also be manipulated by viral proteins to deepen infection and inhitit antiviral mechanism.

Copyright of Acta Agriculturae Zhejiangensis is the property of Acta Agriculturae Zhejiangensis Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Type 1 diabetes (T1D) is a T lymphocyte-mediated autoimmune disease caused by pancreatic β‍-cell destruction, which eventually leads to reduced insulin level and increased blood glucose level (Syed, 2022). As a multifactorial disease, T1D is characterized by a genetic predisposition associated with various environmental and cellular elements (Syed, 2022). Pancreatic β cells have long been considered the "innocent victims" in T1D pathogenesis since the pancreas is attacked by the immune cells, resulting in a process known as insulitis, in which the immune cells infiltrate pancreatic islets and secrete pro-inflammatory cytokines. However, growing evidence suggests that various β‍-cell stresses, dysfunction, and death contribute to T1D pathogenesis, as it has been observed that β‍-cell dysfunction in autoantibody-positive (Aab + ) individuals exists long before T1D diagnosis (Evans-Molina et al., 2018).

BACKGROUND: Studies have shown that there is a certain correlation between programmed osteocyte death and steroid-induced avascular necrosis of the femoral head, and there is an interaction between autophagy and apoptosis. Endoplasmic reticulum stress pathway is involved in the regulation of osteocyte autophagy and apoptosis. OBJECTIVE: To review the related pathways of autophagy and apoptosis regulated by endoplasmic reticulum stress, and summarize the research progress of autophagy and apoptosis pathways in the pathogenesis of steroid-induced avascular necrosis of the femoral head. METHODS: A computer-based online retrieval of PubMed, Web of Science, CNKI and WanFang databases was performed for relevant literatures published from database inception to May 2020 with the keywords of “steroid; necrosis of the femoral head; cell autophagy; ER stress; unfolded protein response” in Chinese and English, respectively. The articles concerning autophagy and apoptosis regulating steroid-induced avascular necrosis of the femoral head related to endoplasmic reticulum stress pathways were included, and the redundant and old articles or Meta-analysis were excluded. RESULTS AND CONCLUSION: Endoplasmic reticulum stress regulates autophagy mainly through PERK/eIF2α pathway, IRE1-TRAF2-JNK pathway and regulation of intracellular Ca2+ concentration. Endoplasmic reticulum stress regulates apoptosis by activating C/EBP homologous protein of PERK/eIF2α pathway, IRE1α- ASK1-JNK pathway, IRE1α-XBP1-CHOP pathway and Caspase-12 pathway. In mild endoplasmic reticulum stress, the endoplasmic reticulum can initiate autophagy by activating unfolded protein response pathway to restore endoplasmic reticulum homeostasis and promote cell survival. Endoplasmic reticulum stress stimulation that is too strong and persistent will over-induce autophagy or activate apoptosis pathway to cause cell death. Endoplasmic reticulum stress can participate in the regulation of autophagy or apoptosis through a variety of signal pathways; there is a complex interaction between autophagy and apoptosis. Endoplasmic reticulum stress is involved in the regulation of programmed death of osteocytes and osteoblasts in the pathogenesis of steroidinduced avascular necrosis of the femoral head, but the specific mechanism is not clear. [ABSTRACT FROM AUTHOR]

BACKGROUND: The pathogenesis of steroid-induced avascular necrosis of the femoral head is not clear, which may be related to endoplasmic reticulum stress. Controlling endoplasmic reticulum stress signal pathway may regulate autophagy and apoptosis, which has a certain preventive and therapeutic effect on the disease. OBJECTIVE: To explore the relationship between endoplasmic reticulum stress and hormone-induced autophagy and apoptosis, and to summarize the research progress of endoplasmic reticulum stress in the pathogenesis of steroid-induced avascular necrosis of the femoral head. METHODS: Relevant articles published from 2000 to 2020 were retrieved from PubMed, Web of Science, CNKI, WanFang, and VIP databases. The keywords were “endoplasmic reticulum stress, femur head necrosis, unfolded protein response, glucocorticoid, autophagy, apoptosis, ischaemia” in English and Chinese, respectively. The old and duplicate articles were excluded, and 81 articles were included for analysis and discussion. RESULTS AND CONCLUSION: Unfolded protein response can induce autophagy and apoptosis in cells to alleviate the three downstream signal pathways caused by endoplasmic reticulum stress. Endoplasmic reticulum stress is closely related to hormone-induced autophagy and apoptosis and femoral head ischemia. Endoplasmic reticulum stress may be a pathological link in the process of steroid-induced avascular necrosis of the femoral head. Hormone induces autophagy and apoptosis of cells by activating endoplasmic reticulum during ischemia and hypoxia and finally leads to osteonecrosis of the femoral head. [ABSTRACT FROM AUTHOR]

Copyright of Practical Oncology Journal is the property of Journal of Practical Oncology Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Acute kidney injury (AKI) is a common critical condition in clinical practice, characterized by a rapid decline in renal function within a short period. The pathogenesis of AKI is complex and has not been fully elucidated. In recent years, studies have found that the activation of endoplasmic reticulum stress (ERS) and the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome are closely related to the occurrence of AKI. When the kidneys is damaged, the internal environment of the kidney cells is disrupted, leading to the activation of ERS. Excessive ERS can induce apoptosis of renal cells, leading to the occurrence of AKI. Additionally, the NLRP3 inflammasome can mediate the recognition of endogenous and exogenous danger signal molecules by the host, subsequently activating caspase-1, pro-inflammatory cytokines such as IL-1β and IL-18, inducing inflammatory responses, and promoting apoptosis of renal cells. In animal models of AKI, the upregulation of ERS markers is often accompanied by increased expression levels of NLRP3 inflammasome-related proteins, indicating that ERS can regulate the activation process of the NLRP3 inflammasome. Clarifying the role and mechanism of ERS and NLRP3 inflammasome in AKI is expected to provide new insights for the prevention and treatment of AKI.

Liver failure is a severe liver disease with a complex pathological process, rapid disease progression, and a high mortality rate, and in-depth studies are needed to explore its pathogenesis. Early and mild endoplasmic reticulum stress( ERS) can maintain the stability of intracellular environment through unfolded protein reaction, while persistent and severe ERS may promote inflammatory response and apoptosis and cause cell death, and therefore, ERS plays a key role in the development and progression of liver failure. This article elaborates on the role of ERS and related signaling pathways in the pathogenesis of liver failure, so as to provides new ideas for the treatment of liver failure. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) is a common clinical persistent arrhythmia and an independent risk factor for stroke and heart failure. However, the exact pathogenesis of AF is not completely clear. Endoplasmic reticulum is a major organelle that regulates protein synthesis, intracellular Ca2+ concentration, oxidative stress level, and induces apoptotic signaling pathways. A variety of pathogenic factors can lead to endoplasmic reticulum stress (ERS), which mainly restores the homeostasis of endoplasmic reticulum through the unfolded protein response (UPR). Excessive activation of ERS can lead to Ca2+ overload of atrial myocytes, imbalance of oxidative stress and apoptosis, playing an important role in the pathogenesis of AF. The purpose of this review is to summarize the research progress of ERS and AF. [ABSTRACT FROM AUTHOR]

Objective To observe the expression changes of centromere protein F( CENPF) mRNA in the lung adenocarcinoma cell lines, and to analyze the expression changes of CENPF mRNA in the lung adenocarcinoma tissues and to explore its related regulatory signaling pathways. Methods ① The real-time quantitative PCR was used to detect the CENPF mRNA in the normal lung epithelial cell line BEAS-2 B and lung adenocarcinoma cell lines( A549, NCI-H1650, NCIH23, and NCI-H1975). ② The relationships of CENPF mRNA with clinicopathological characteristics and prognosis of lung adenocarcinoma were analyzed by the lung adenocarcinoma dataset of Cancer Genome Atlas( TCGA). Cox regression model was used to analyze the prognostic factors of lung adenocarcinoma patients. Gene Set Enrichment Analysis( GSEA) was used to analyze the signal pathways involved in lung adenocarcinoma regulated by CENPF. Results The relative expression of CENPF mRNA in the A549, NCI-H1650, NCI-H23, NCI-H1975, and BEAS-2 B cells were 4. 333 ±0. 271, 3. 193 ± 0. 188, 2. 770 ± 0. 091, 5. 491 ± 0. 249, and 1. 006 ± 0. 071, respectively. The relative expression of CENPF mRNA in the A549, H1650, NCI-H23, and NCI-H1975 cells was higher than that in the BEAS-2 B cells( P <0. 05). The relative expression levels of CENPF mRNA in the lung adenocarcinoma and adjacent normal tissues were9. 632 ± 0. 059 and 6. 472 ± 0. 093, with significant difference( P < 0. 001). CENPF mRNA expression was related to gender, age, T stage, N stage, and TNM stage( all P < 0. 05). Survival analysis showed that patients with high CENPF mRNA expression had poorer prognosis compared with patients with low CENPF mRNA expression( P = 0. 001). Cox regression model analysis showed that CENPF mRNA expression and TNM staging were independent risk factors for the prognosis of lung adenocarcinoma patients( HR = 1. 667 and 1. 414, respectively, both P < 0. 01). The lung adenocarcinoma regulatory signaling pathway associated with high expression of CENPF mRNA included G2 M checkpoint( P < 0. 001, FDR <0. 001), mitotic spindle( P < 0. 001, FDR < 0. 001), E2 F target gene( P < 0. 001, FDR < 0. 001), MYC target gene( P< 0. 001, FDR = 0. 001), m TOR signaling pathway( P = 0. 002, FDR = 0. 005), spermatogenesis( P = 0. 002, FDR =0. 009), unfolded protein response( P = 0. 002, FDR = 0. 020), and PI3 K/Akt/m TOR signaling pathway( P = 0. 015, FDR = 0. 117). Conclusions CENPF mRNA is highly expressed in the lung adenocarcinoma tissues and cell lines. The high expression of CENPF mRNA is closely related to the clinicopathological characteristics and poor prognosis of lung adenocarcinoma patients. High expression of CENPF mRNA is an independent risk factor for the prognosis of lung adenocarcinoma patients. CENPF mRNA may play an important role in the development and progression of lung adenocarcinoma by regulating G2 M checkpoint, mitotic spindle, E2 F target gene, MYC target gene, m TOR signaling pathway, spermatogenesis, unfolded protein response, and PI3 K/Akt/m TOR signaling pathway. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, the endoplasmic reticulum (ER) is essential for the folding and translocation of proteins. The disturbance of the endoplasmic reticulum homeostasis, caused by multiple pathological factors will lead to the accumulation of unfolded or misfolded proteins in the ER lumen, known as endoplasmic reticulumstress(ERS). Cells react to ERS by activating an defensive process known as the Unfolded Protein Response (UPR) to restore the endoplasmic reticulum homeostasis. Autophagy is a cellular catabolic process which can be described as a "self-eating", it emerged as an essential protective mechanism upon ER stress through the bulk removal and degradation of unfolded proteins and damaged organelles. Recent studies show that these 2 systems are interconnected, and the ER stress can induce autophagy in a variety of ways. In this review, we will summarize the current knowledge about the molecular mechanismof autophagy by Endoplasmic Reticulum Stress especially the UPR, to guide further study on ER stress and autophagy. [ABSTRACT FROM AUTHOR]

Epilepsies are a group of chronic neurological disorders characterized by spontaneous recurrent seizures caused by abnormal synchronous firing of neurons and transient brain dysfunction. The underlying mechanisms are complex and not yet fully understood. Endoplasmic reticulum (ER) stress, as a condition of excessive accumulation of unfolded and/or misfolded proteins in the ER lumen, has been considered as a pathophysiological mechanism of epilepsy in recent years. ER stress can enhance the protein processing capacity of the ER to restore protein homeostasis through unfolded protein response, which may inhibit protein translation and promote misfolded protein degradation through the ubiquitin-proteasome system. However, persistent ER stress can also cause neuronal apoptosis and loss, which may aggravate the brain damage and epilepsy. This review has summarized the role of ER stress in the pathogenesis of genetic epilepsy.

Non-alcoholic fatty liver disease (NAFLD) is one of the main diseases of metabolic syndrome. With the increasing popularity of NAFLD in the world, the prevention and therapy of NAFLD are facing great challenges. In recent years, scholars at home and abroad have carried out a large number of studies on NAFLD, but its pathogenesis is still unclear. Endoplasmic reticulum stress (ERS) is caused by the accumulation of unfolded or misfolded proteins. In response to ERS, cells help restore normal endoplasmic reticulum function by initiating a protective mechanism known as the unfolded protein response (UPR). Abnormal accumulation of lipids in hepatocytes, aggravated inflammatory response, increased apoptosis of hepatocytes and insulin resistance (IR) are the main pathogenic factors and characteristics of NAFLD, which are closely related to hepatic ERS. A large number of studies have shown that exercise, as a low-cost treatment, can prevent and improve NAFLD effectively, and its mechanism is related to exercise regulating the level of ERS. This paper reviews the research progress on the mechanism of exercise improving NAFLD from the point of view of ERS. The mechanism of exercise improving NAFLD is related to the regulation of hepatocyte lipid metabolism, alleviation of inflammatory reaction, reduction of hepatocyte apoptosis and improvement of IR through regulating ERS.

Ischemia/reperfusion (I/R) caused by cardiac arrest (CA) and subsequent cardiopulmonary resuscitation (CPR) was the primary cause of post-cardiac arrest syndrome (PCAS), including post-cardiac arrest myocardial dysfunction and post-cardiac arrest brain injury. Disturbance of endoplasmic reticulum proteostasis, so-called endoplasmic reticulum stress (ERS) was one of the pathological changes induced by I/R injury. The unfolded protein response (UPR) was an adaptive response triggered by ERS in cells. Modulating the UPR arms to alleviate ERS to promote cell survival was promising for attenuating I/R injury. Activating the activating transcription factor6 (ATF6) signaling pathway, one of the arms of the UPR, confers protection against I/R injury in multiple tissues by restoring endoplasmic reticulum proteostasis and reducing oxygen free radicals. This article reviewed the structural characteristics and biological function of ATF6 and focused on its essential role in cardiac and cerebral I/R injury as well as potential therapeutic targets, hoping to provide new ideas for the effective treatment of PCAS.

The mitochondrial unfolded protein response is an important component of the mitochondrial protein quality control program. It can effectively remove unfolded or misfolded proteins under stress, and maintain a stable and healthy mitochondrial pool. The mitochondrial unfolded protein response is coordinated by multiple signaling pathways. The classical ATF4/ATF5-CHOP pathway is induced by accumulation of unfolded or misfolded proteins in the mitochondrial matrix, which reduces stress toxicity by regulating molecular chaperones and proteases. Sirt3-FOXO3a-SOD2 pathway, located in the mitochondrial matrix, plays an important role in anti-oxidative damage. The ERα-NRF1-HTRA2 pathway mainly removes unfolded proteins in the mitochondrial membrane space and improves the quality control of mitochondrial proteins. These three signaling pathways work both independently and cooperatively to enhance mitochondrial capacity and maintain health under stress.

Mitochondrial unfolded protein response (UPR mt ) is a protein-toxic stress response, which regulates the communication from mitochondria to the nucleus. It is activated when a large number of unfolded or misfolded proteins accumulate in the mitochondria. The activation of UPR mt increases the expression of a series of chaperones and proteases, and maintains the homeostasis and function of mitochondrial proteins. Mitochondria play an important role in maintaining cardiomyocyte homeostasis. The damage of myocardial mitochondria leads to the metabolic disorder of cells suffering from ischemia/reperfusion injury. It is the key mechanism of myocardial cell death. This article mainly reviews the regulatory pathway of UPR mt and the research progress of UPR mt in myocardial ischemia/reperfusion injury (MIRI), in order to provide new ideas for the treatment of MIRI.

Endoplasmic reticulum (ER) is an important organelle where folding and post-translational modification of secretory and transmembrane proteins take place. During virus infection, cellular or viral unfolded and misfolded proteins accumulate in the ER in an event called ER stress. To maintain the equilibrium homeostasis of the ER, signal-transduction pathways, known as unfolded protein response (UPR), are activated. The viruses in turn manipulate UPR to maintain an environment favorable for virus survival and replication. Herpesviruses are enveloped DNA viruses that produce over 70 viral proteins. Modification and maturation of large quantities of viral glycosylated envelope proteins during virus replication may induce ER stress, while ER stress play both positive and negative roles in virus infection. Here we summarize the research progress of crosstalk between herpesvirus infection and the virus-induced ER stress.

Metastasis is a multistep and low-efficiency biological process driven by acquisition of genetic and/or epigenetic alterations within tumor cells. These evolutionary alterations enable tumor cells to thrive in the inhospitable microenvironment they encounter in the process of metastasis and eventually lead to macroscopic metastases in distant organs. The unfolded protein response (UPR) induced by endoplasmic reticulum (ER) stress is one of the most important mechanisms regulating cellular adaptation to an adverse microenvironment. UPR is involved in all stages of metastasis, playing an important role in tumor cell growth, survival, and differentiation and the process of maintaining protein hemostasis. Sustained activation of ER stress sensors endows tumor cells with better epithelial-mesenchymal transition (EMT), survival, immune escape, angiogenesis, cellular adhesion, dormancy-to reactivation capacity in the process of metastasis. Here, we discussed the role of UPR in regulating the above-mentioned abilities of tumor cells during metastasis, providing a reference for development of new targets for the treatment of tumor metastasis.UPR in regulating the above-mentioned characteristics and mechanisms of tumor cells during metastasis, providing a reference for development of new targets for the treatment of tumor metastasis., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Idiopathic pulmonary fibrosis(IPF)is a progressive lung disease characterized by pulmonary interstitial fibrosis and pulmonary dysfunction.Cell microenvironment is mainly composed of cell components,extracellular matrix,extracellular regulators,and liquid substances.Changes in microenvironment components are closely related to IPF.This article elaborates the roles of cell microenvironments including cytokines,mesenchymal cells,extracellular matrix,and unfolded proteins in the pathogenesis of IPF.

Endoplasmic reticulum (ER) is an important organelle for protein folding, post-transcriptional modification and transport, which plays an important role in maintaining cell homeostasis. A variety of internal and external environmental stimuli can cause the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum, and then result in ER stress. ER stress activates the unfolded protein response (UPR) and initiates a cluster of downstream signals to maintain ER homeostasis. However, severe and persistent ER stress activates UPR, which eventually leads to apoptosis and diseases. In recent years, a lot of researches suggest that ER stress plays an important role in the pathogenesis of various cardiovascular diseases (CVD), including ischemic heart disease, diabetic cardiomyopathy, heart failure, atherosclerosis and vascular calcification, high blood pressure and aortic aneurysm. ER stress might be one of the important targets for treatment of multiple CVD. Herein, the regulation mechanism of ER stress by activating UPR pathways in various common CVD and the new research advances in relationship of ER stress and CVD are briefly reviewed.

Objective: To explore whether bortezomib and a Bcl-2 inhibitor exhibit synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells., Methods: MTT assay was used to determine the cytotoxicity of bortezomib in the absence or presence of Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) in Jurkat cells. The effects of drug treatment on the expression of Bcl-2 family proteins, LC3B, p62, ubiquitin, BiP/Grp78, p-JNK, p-p38 and CHOP proteins were examined by Western blotting. Flow cytometry was used to determine the effects of bortezomib and Bcl-2 inhibitors (obatoclax, AT-101 and ABT-199) on cell apoptosis. Quantitative real-time PCR was used to measure the mRNA expression levels of the key regulatory factors of unfolded protein reaction (UPR). A zebrafish xenograft model was used to study the anti-tumor effect of bortezomib, obatoclax and their combination in vivo., Results: Bortezomib or Bcl-2 inhibitors alone inhibited the cell viability of Jurkat cells, but only obatoclax and bortezomib showed synergistic cytotoxicity and pro-apoptotic effect. Obatoclax, rather than AT-101 and ABT- 199, blocked autophagic flux in the cells evidenced by concomitant accumulation of LC3B-Ⅱ and p62. Both bortezomib and obatoclax alone caused accumulation of polyubiquinated proteins, and their combination showed a synergistic effect, which was consistent with their synergistic cytotoxicity. The dual blockade of proteasome and autophagy by the combination of bortezomib and obatoclax triggered unfolded protein response followed by cell apoptosis. Preventing UPS dysfunction by tauroursodeoxycholic acid (TUDCA) significantly attenuated the cytotoxicity and pro-apoptotic effect of bortezomib in combination with obatoclax. In zebrafish xenograft models, bortezomib combined with obatoclax significantly decreased tumor foci formation., Conclusions: Bortezomib and obatoclax for dual blockade of protein degradation pathways show synergistic anti-tumor effect in human acute T lymphoblastic leukemia cells.

Endoplasmic reticulum stress (ERS) is one of the major defense networks in mammals, but continuous ERS will lead to cell apoptosis, inducing initiation and progression of many human diseases. Biochemical, physiological and pathological stimuli induced ERS may help the cells adapt to and survive stress conditions by activating unfolded protein response (UPR), ER-overload response and sterol modulation cascade reaction. Abundant outcomes of clinical and experimental studies in recent 5 years showed that acupuncture and moxibustion therapies are effective in improving some symptoms of nervous system diseases as stroke, Parkinson's disease, convulsion, cardiovascular diseases, diabetes mellitus, non-alcoholic fatty liver disease, spinal cord injury, muscular injury, etc., which is closely associated with their functions in relieving excessive ERS and cell apoptosis via modulating UPR pathway. Some important molecules or signaling pathways such as glucose-regulated protein 78(GRP78), Caspase-12, ER transmembrane kinase inositol-requiring and ER-to-nucleus signaling protein (IRE1P), phosphorylated extracellular signal-regulated kinase (p-ERK)/eukaryotic translation initiation factor 2α(eIF2α), activating transcription factor 4 (ATF4), CCAAT/enhancer-binding protein homologous protein (CHOP), etc. have been demonstrated to be involved in the effects of acupuncture-moxibustion interventions. But, the mechanism of acupuncture-moxibustion underlying improvement of ERS remains far more unclear. Future studies targeting the combination of molecules and holistic function, verification of changes of the involved protein molecules and multiple signaling pathways, balancing regulation between the cell survival and apoptosis, etc. by adopting syndrome-differentiation-based acupoints are definitely needed.

A mammalian nonclassical secretion sequence derived from mouse Engrailed2 homeoprotein (En2) was used to direct the secretion of the enhanced green fluorescent protein from Pichia pastoris. This signal peptide conferred the transport of enhanced green fluorescent protein into periplasm through an endoplasmic reticulum-golgi independent pathway, without inducing severe unfolded protein response as compared with Saccharomyces cerevisae α-factor preprosequence. This study implies that this mammalian nonclassical signal peptide could be developed as a useful tool for delivering cargoes to the cell surface of yeast.

Objective: To study the inhibition and mechanism on lung cancer A549 cells xenografts in BALB / c nude mice., Methods: 40 BALB / c mice were selected to establish lung cancer xenografts models with human lung adenocarcinoma A549 cells,which were randomized into model group,cisplatin group( 0. 002 g / kg), Yiqi Chutan Formula low-dose group( 3. 0 g / kg),Yiqi Chutan Formula high-dose group( 6. 0 g / kg) and combination group[Yiqi Chutan Formula 6. 0( g / kg) / cisplatin 0. 002( g / kg) ], with eight mice in each group. Yiqi Chutan Formula was given once a day with 0. 2 m L from 8th day after modeling,and successive medication for14 days. After given cisplatin with 0. 2 m L by intraperitoneal injection once a day in 17 th day,and modeling for 5 days. The tumor weight and tumor volume were detected. And the tumor inhibitory rate were calculated. The expression of CNX and XBP1 was detected by immunohistochemistry,Western blotting and and real-time quantitative PCR., Results: Compared with the model group, the tumor weight and the tumor volume were lower in cisplatin group, Yiqi Chutan Formula high-dose group and combination group( P < 0. 01);and the combination group was better than the cisplatin group( P < 0. 01). The results of immunohistochemistry, Western blotting and real-time quantitative PCR showed that, compared with the model group, the expression of CNX and XBP1 were lower in cisplatin group, Yiqi Chutan Formula high-dose group and combination group( P < 0. 01),and the combination group was better than the cisplatin group( P < 0. 05 or P < 0. 01)., Conclusion: Yiqi Chutan Formula can inhibit A549 lung cancer cells in BALB/c nude mice. Combined with chemotherapy drugs, the killing effect on lung cancer can be enhanceed. Its mechanism may be related to down-regulating CNX and XBP1 to inhibit the unfolded protein response to lead to apoptosis.

Objective: To investigate the roles of PI3K/Akt signaling in the unfolded protein response (UPR) and non-UPR signaling pathways of endoplasmic reticulum stress and apoptosis in hepatocytes under conditions of saturated fatty acid-induced steatosis., Methods: A steatosis model of hepatocytes (L02 cell and HepG2 cell line) was induced by palmitate sodium saturated fatty acids.The hepatocytes were divided into normal control group,experimental group (treated with palmitate sodium) and intervention group (treated with palmitate sodium and LY294002, a PI3K/Akt inhibitor). Cell apoptosis was detected by flow cytometry with Annexin V/PI double-staining.Western blot analysis was used to examine the protein expression of GRP78, PI3K, P-PI3K,Akt, P-Akt, CHOP and Bax.The F test and t-test were used in statistical analyses., Results: Flow cytometry showed that palmitate sodium induced cell apoptosis in steatotic hepatocytes;moreover, a significant increase in cell apoptosis was observed in the palmitate sodium-induced steatotic hepatocytes in the presence of LY294002.For the normal control group, the experimental group and the intervention group, the apoptosis ratios of L02 cells were 4.41 ± 0.78% vs. 6.01 ± 1.49% vs. 19.50 ± 2.53% after 24 hours of treatment,and 12.56 ± 2.78% vs. 29.72 ± 6.39% vs. 44.60 ± 4.17% after 48 hours of treatment in respectively (all P < 0.05),and of HepG2 cells were 11.16 ± 1.15% vs. 17.50 ± 6.83% vs. 30.41 ± 3.62% after 24 hours of treatment, and 22.37 ± 1.24% vs. 33.85 ± 5.79% vs. 48.56 ± 4.21% after 48 hours of treatment (all P < 0.05). Western blot analysis showed that expression of GRP78 was significantly upregulated in the palmitate sodium-induced steatosis hepatocytes, indicating activation of endoplasmic reticulum stress. In addition, the palmitate sodium treatment also activated the PI3K/Akt pathway,induced expression of CHOP and Bax of the UPR and non-UPR signaling pathways respectively. Moreover, Pretreatment with LY294002 inhibited the palmitate sodium induced-phosphorylation of PI3K and Akt, and promoted upregulation of CHOP and Bax induced by palmitate sodium., Conclusion: The PI3K/Akt pathway may be involved in regulation of the UPR and non-UPR signaling pathways of endoplasmic reticulum stress and may promote apoptosis of hepatocytes by enhancing the expression of CHOP and Bax protein in saturated fatty acid-induced steatotic hepatocytes.

Endoplasmic reticulum is the organelle where proteins get folded and assembled, and all kinds of damage factors can lead to the accumulation of unfolded proteins, therefore initiate endoplasmic reticulum stress (ERS) by activating the intracellular signal transduction pathways-cumulatively called the unfolded protein response, either to protect cells or to induce cell apoptosis. PERK pathway has been considered as a main signal transduction pathway of ERS, and a lot of eye diseases are correlated with PERK pathway mediated ERS. This article mainly summarize the progress of the eye diseases associated with PERK pathway mediated ERS.

Due to the potential for producing soluble, correctly folded protein with high yield, Pichia pastoris is currently one of the most effective hosts for the expression of heterologous proteins. However, limitations of expression efficiency are often reported for many different heterologous proteins. Accumulating evidences suggest that protein folding and processing of heterologous protein is a major bottleneck during secretion process in yeast. Apart from optimization of the fermentation process, the current strategies for strain engineering for improving protein secretion are focused mainly on folding and processing, and systematic engineering by high-throughput screening for potential secretion enhancers. This article reviews the genetic engineering progresses of these aspects.

Objective: To explore the molecular mechanism of myeloma cell differentiation induced by low dose tunicamycin., Method: U266 and RPMI8226 cells were incubated with low dose tunicamycin for 72h. Surface CD49e expression was assayed by flow cytometer (FCM), light chain protein in the cell culture supernatant by ELISA, the unfolded protein response (UPR) related gene GRP78 and GRP94 by real time PCR, and XBP1u and XBP1s transcription and translation changes by real time PCR and Western blot. After XBP1u gene was interfered with small RNA, and constructed plasmid was transfected into myeloma cells to up-regulated gene XBP-1u and XBP-1s reseparately, the differentiation of myeloma cells was observed again., Results: Small dose tunicamycin could induce both U266 and RPMI8226 myeloma cells differentiation. Compared with the control group, cell morphology changed to mature feature, the nucleo- cytoplasm ratio decreased and nucleolus reduced or disappearance, CD49e expression increased the light chain protein concentration of cell culture supernatant was up-regulated and UPR related gene GRP78 and GRP94 were up-regulated during the differentiation. XBP-1u was up-regulated at both transcription and translation level, while XBP-1s down-regulated. After XBP1u gene expression interfered with small RNA, cell differentiation was disturbed. Cell differentiation was induced while XBP-1u gene was up-regulated by plasmid transfection., Conclusion: Low dosage of tunicamycin could induce myeloma cell UPR and differentiation, while XBP-1u a key role during the process.