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During cerebral ischemia-reperfusion injury(CIRI),endoplasmic reticulum stress(ERS)leads to the development and progression of a series of deleterious physiological responses such as oxidative stress,dis-turbed calcium ion homeostasis,inflammation,apoptosis and autophagy.The unfolded protein response(UPR)is the main pathway activated by ERS,which regulates the expression of related factors within the endoplasmic reticu-lum(ER)and reduces protein translation levels.Prolonged and intense ERS may lead to cell death.Excessive ERS induces apoptosis mediated by C/EBP homologous pro-tein(CHOP),caspase-12 and c-Jun N-terminal kinase(JNK),thereby exacerbating brain damage.The thresh-old for the transition from adaptive mechanisms to apop-totic mechanisms during ERS depends on multiple fac-tors,including the cell status and environment,signaling pathway activity status,cumulative cascade,and the dose and time of ERS inducers.Further research is needed to completely elucidate the mechanism of ERS.Although the factors associated with the PERK and ATF6 path-ways are less extensively studied,their regulators still exist.Deficiency of protein tyrosine phosphatase 1B(PTP1B)leads to increased phosphorylation of PERK-eIF2α,while regulation of the proteasome and regulation of the XBP1 target gene WFS1 may also affect ATF6 sta-bility.In addition,differences in the structure,gene expres-sion,and metabolism of different types of neurons,as well as in their internal environment,may lead to differ-ences in their response to and impact on ERS.Differenc-es in UPR signaling pathways occur in hippocampal neurons and medial thalamic cells,and Purkinje cells and pyramidal cells may be more sensitive to ERS than other types of neurons.Our group's previous study found that ERS induced apoptosis in neurons after the onset of CIRI by regulating proteins such as GRP78,CHOP and caspase-12,but the effects of UPR activation on different cells need to be further investigated.
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Objective:To study the crosstalk between the activating transcription factor 6 (ATF6) and inositol-requiring enzyme 1 (IRE1) - X-box binding protein 1 (XBP1) pathway in oxygen-glucose deprivation/reoxygenation (OGD/R)-injured mouse hippocampal neuronal cell line HT22.Methods:The OGD/R-injured HT22 cell model was used to observe the changes of the indicators of endoplasmic reticulum stress (ERS), cell viability, and apoptosis at different OGD/R time points (0, 3, 6, 12, and 24 hours). HT22 cells in the logarithmic growth phase were randomized into blank control group, control+ATF6 activator (AA147) group, control+IRE1 inhibitor (4μ8c) group, OGD/R model group, OGD/R+AA147 group and OGD/R+4μ8c group (10 μmol/L AA147 or 16 μmol/L 4μ8c was given during the whole process in the AA147 group and 4μ8c group). Western blotting was used to detect the expression of ERS-related proteins [glucose-regulated protein 78 (GRP78), phosphorylated-inositol-requiring enzyme 1 (p-IRE1), and phosphorylated-eukaryotic translation initiation factor-2α (p-eIF2α)], and apoptosis-related proteins (Bcl-2, Bax, caspase-3, and cleaved caspase-3). The mRNA of ERS-related genes, and ATF6 [homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (Herpud1), protein disulfide isomerase associated 4 (Pdia4) and Sel-1 suppressor of lin-12-like (Sel1L)] and spliced XBP1 [XBP1s, include DnaJ heat shock protein family member B9 (Erdj4), Sec24 related gene family, member D (Sec24d) and signal sequence receptor, gamma (Ssr3)] induced transcriptional response-related genes were measured by real-time quantitative polymerase chain reaction (RT-qPCR). A cell counting kit-8 (CCK-8) assay was used to detect the viability of HT22 cells. Immunofluorescence was utilized to test the expression of cleaved caspase-3.Results:Compared with the blank control group, the expression of ERS-related proteins p-IRE1 and p-eIF2α were significantly increased at 12 hours and 3 hours following OGD/R, respectively (p-IRE1/β-actin: 2.09±0.10 vs. 1.00±0.00, p-eIF2α/β-actin: 1.39±0.11 vs. 1.00±0.00, both P < 0.01). The mRNA expressions of ERS-related genes [ATF6, XBP1s, unspliced XBP1 (XBP1u), activating transcription factor 4 (ATF4), CCAAT/EBP homologous protein (CHOP)] were also upregulated in different OGD/R timepoint in HT22 cells, which indicated ERS was activated in OGD/R-stimulated HT22 cells. Compared with the OGD/R model group, the expression of protein p-IRE1 was not changed, but the mRNA of XBP1s and XBP1u were obviously downregulated in the OGD/R+AA147 group [XBP1s (2 -ΔΔCt): 0.76 (0.71, 0.92) vs. 1.13 (1.03, 1.29), XBP1u (2 -ΔΔCt): 0.29±0.05 vs. 0.52±0.04, both P < 0.01], whereas the expressions of XBP1s-induced transcriptional response downstream genes did not change significantly. Compared with the OGD/R model group, the protein of short-form ATF6 (sATF6) and GRP78 were not changed after administration of 4μ8c, neither was the mRNA expression of ATF6-induced transcriptional response-related genes. These results showed that the mRNA expression of XBP1s and XBP1u were inhibited by AA147-induced activation of ATF6, but no crosstalk was observed between the transcriptional response induced by ATF6 and XBP1s. Compared with the blank control group, the cell viability decreased significantly at OGD/R 3 hours [(44.64±5.12) % vs. (99.13±5.76) %, P < 0.01], the ratios of apoptosis-related proteins Bax/Bcl-2 and cleaved caspase-3/caspase-3 were significantly increased at OGD/R 3 hours and OGD 0 hour, respectively (Bax/Bcl-2: 6.15±1.65 vs. 1.00±0.00, cleaved caspase-3/caspase-3: 17.48±2.75 vs. 1.00±0.00, both P < 0.01), which indicated that apoptosis was activated in OGD/R-treated HT22 cells. Compared with the OGD/R model group, the cell viability decreased significantly [(36.52±17.78)% vs. (69.90±9.43)%, P < 0.01], and the ratios of Bax/Bcl-2 and cleaved caspase-3/caspase-3 were significantly upregulated in the OGD/R+AA147 group in HT22 cells (Bax/Bcl-2: 2.06±0.31 vs. 1.10±0.25, cleaved caspase-3/caspase-3: 3.35±0.59 vs. 0.55±0.09, both P < 0.01). Conclusion:Under our experimental conditions, no obvious crosstalk between the transcriptional response induced by ATF6 and XBP1s was observed, while ATF6 activation induced by AA147 suppressed mRNA expression of XBP1s and XBP1u and promoted cell death in OGD/R-treated HT22 cells.
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Inositol requiring enzyme 1 alpha (IRE1α), a widespread transmembrane protein in mammals, is an endoplasmic reticulum stress (ER stress) receptor. Among the three signaling pathways of the unfolded protein response (UPR), the IRE1α pathway is the most conservative. And there is a growing body of evidence that the occurrence and development of tumors is closely related to the over-expression of IRE1α. Therefore, the study of the IRE1α inhibitors is of great significance to the discovery of new anti-tumor drugs and has been attracting more and more attention. In the hope of providing ideas for the research of targeting IRE1α for cancer therapy, this paper reviewed the data of representative IRE1α inhibitors, including inhibitory activity, the mechanism of action, structural characteristics, and so on.
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Acute respiratory distress syndrome(ARDS)is a severe respiratory disease in children and the pathogenesis is not fully defined.It is mainly related to various mechanisms of lung injury such as inflammation and autophagy.In recent years, studies have found that, endoplasmic reticulum stress(ERS)can aggravate lung injury in ARDS, in which protein homeostasis imbalance can induce activation of the unfolded protein response(UPR).The UPR reconstructs homeostasis by mediating transmembrane protein-related signaling pathways, while continuous excessive ERS will promote apoptosis and autophagy.This review summarizes the progress of the signaling pathway of UPR related to lung injury and its inflammatory effect in ARDS.
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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.
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Antibody-mediated rejection (AMR) is one of the major causes of graft loss after transplantation. Recently, the regulation of B cell differentiation and the prevention of donor-specific antibody (DSA) production have gained increased attention in transplant research. Herein, we established a secondary allogeneic in vivo skin transplant model to study the effects of romidepsin (FK228) on DSA. The survival of grafted skins was monitored daily. The serum levels of DSA and the number of relevant immunocytes in the recipient spleens were evaluated by flow cytometry. Then, we isolated and purified B cells from B6 mouse spleens in vitro by magnetic bead sorting. The B cells were cultured with interleukin-4 (IL-4) and anti-clusters of differentiation 40 (CD40) antibody with or without FK228 treatment. The immunoglobulin G1 (IgG1) and IgM levels in the supernatant were evaluated by enzyme-linked immunosorbent assay (ELISA). Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and western blotting were conducted to determine the corresponding levels of messenger RNA (mRNA) and protein expression in cultured cells and the recipient spleens. The results showed that FK228 significantly improved the survival of allogeneic skin grafts. Moreover, FK228 inhibited DSA production in the serum along with the suppression of histone deacetylase 1 (HADC1) and HDAC2 and the upregulation of the acetylation of histones H2A and H3. It also inhibited the differentiation of B cells to plasma cells, decreased the transcription of positive regulatory domain-containing 1 (Prdm1) and X-box-binding protein 1 (Xbp1), and decreased the expression of phosphorylated inositol-requiring enzyme 1 α (p-IRE1α), XBP1, and B lymphocyte-induced maturation protein-1 (Blimp-1). In conclusion, FK228 could decrease the production of antibodies by B cells via inhibition of the IRE1α-XBP1 signaling pathway. Thus, FK228 is considered as a promising therapeutic agent for the clinical treatment of AMR.
Subject(s)
Animals , Mice , Depsipeptides , Endoribonucleases , Hematopoietic Stem Cell Transplantation , Histone Deacetylase Inhibitors/pharmacology , Protein Serine-Threonine Kinases , Skin TransplantationABSTRACT
@#BACKGROUND: We aimed to investigate the gene expression of myocardial ischemia/reperfusion injury (MIRI) in patients with acute ST-elevation myocardial infarction (STEMI) using stress and toxicity pathway gene chip technology and try to determine the underlying mechanism. METHODS: The mononuclear cells were separated by ficoll centrifugation, and plasma total antioxidant capacity (T-AOC) was determined by the ferric reducing ability of plasma (FRAP) assay. The expression of toxic oxidative stress genes was determined and verified by oligo gene chip and quantitative real-time polymerase chain reaction (qRT-PCR). Additionally, gene ontology (GO) enrichment analysis was performed on DAVID website to analyze the potential mechanism further. RESULTS: The total numbers of white blood cells (WBC) and neutrophils (N) in the peripheral blood of STEMI patients (the AMI group) were significantly higher than those in the control group (WBC: 11.67±4.85 ×109/L vs. 6.41±0.72 ×109/L, P<0.05; N: 9.27±4.75 ×109/L vs. 3.89±0.81 ×109/ L, P<0.05), and WBCs were significantly associated with creatine kinase-myocardial band (CK-MB) on the first day (Y=8.945+0.018X, P<0.05). In addition, the T-AOC was significantly lower in the AMI group comparing to the control group (12.80±1.79 U/mL vs. 20.48±2.55 U/mL, P<0.05). According to the gene analysis, eight up-regulated differentially expressed genes (DEGs) included GADD45A, PRDX2, HSPD1, DNAJB1, DNAJB2, RAD50, TNFSF6, and TRADD. Four down-regulated DEGs contained CCNG1, CAT, CYP1A1, and ATM. TNFSF6 and CYP1A1 were detected by polymerase chain reaction (PCR) to verify the expression at different time points, and the results showed that TNFSF6 was up-regulated and CYP1A1 was down-regulated as the total expression. GO and kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis suggested that the oxidative stress genes mediate MIRI via various ways such as unfolded protein response (UPR) and apoptosis. CONCLUSIONS: WBCs, especially neutrophils, were the critical cells that mediating reperfusion injury. MIRI was regulated by various genes, including oxidative metabolic stress, heat shock, DNA damage and repair, and apoptosis-related genes. The underlying pathway may be associated with UPR and apoptosis, which may be the novel therapeutic target.
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@#Age-related macular degeneration(ARMD)is a main cause of irreversible visual impairment in the elderly. The major pathological features are drusen formation, macular pigment disorder, geographic atrophy and abnormal neovascularization. Retinal pigment epithelium(RPE)function is impaired in ARMD. Endoplasmic reticulum(ER)is an organelle in eukaryotes responsible for protein synthesis, modification, integration and quality control. ER also participates in the maintenance of calcium homeostasis and lipid biosynthesis. Stimuli from the external and internal environment may trigger ER stress and therefore activate the intracellular signal transduction pathway-the unfolded protein response(UPR), to restore cell homeostasis. However, prolonged ER stress may lead to apoptosis. The pathogenesis of ARMD has not been fully elucidated, nevertheless, compelling evidence demonstrates that ER stress is involved. In this article, we summarize recent advances in UPR pathways, as well as the role of ER stress in the physiological function of RPE and in the pathogenesis of ARMD.
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Background Flurochloridone (FLC) can induce apoptosis in Sertoli cells, but the specific mechanism remains unknown. Objective To 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. Methods Testicular 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. Results After 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<0.05), and the protein expression levels of Bim and Bax, apoptosis promoters, were increased in the 75 and 375 mg·(kg·d)−1 groups respectively (P<0.05). The percentages of apoptotic cells in the 0, 40, 80, and 160 μmol·L−1 FLC groups were 2.7%±0.2%, 4.8%±1.3%, 9.4%±0.3%, and 13.2%±0.2%, respectively, increased significantly compared with the control group (P<0.05). The protein expression level of Bcl-2 also was decreased in the 160 μmol·L−1 FLC group (P<0.05), while the levels of Bim and Bax were increased in both of the 80 and 160 μmol·L−1 groups (P<0.05). The expression levels of endoplasmic reticulum stress-related proteins (GRP78, p-PERK, ATF6, p-IRE1α, and p-JNK) were increased (P<0.05) or showed a rising trend in TM4 cells. Pre-treatment with 4μ8C (25 and 50 μmol·L−1) and SP600125 (10 and 20 μmol·L−1) significantly down-regulated the protein expression levels of GRP78, p-IRE1α, p-JNK, and Bax induced by FLC (P<0.05) or in a downward trend. Both of the inhibitors alleviated the decreased cell viability induced by FLC (P<0.05) or in alleviating fashion. Conclusion FLC could induce apoptosis in mice testis and TM4 cell apoptosis through activating endoplasmic reticulum stress and IRE1α-JNK signaling pathway.
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Sterol-regulatory element binding proteins (SREBPs) are the key transcriptional regulators of lipid metabolism. The activation of SREBP requires translocation of the SREBP precursor from the endoplasmic reticulum to the Golgi, where it is sequentially cleaved by site-1 protease (S1P) and site-2 protease and releases a nuclear form to modulate gene expression. To search for new genes regulating cholesterol metabolism, we perform a genome-wide CRISPR/Cas9 knockout screen and find that partner of site-1 protease (POST1), encoded by C12ORF49, is critically involved in the SREBP signaling. Ablation of POST1 decreases the generation of nuclear SREBP and reduces the expression of SREBP target genes. POST1 binds S1P, which is synthesized as an inactive protease (form A) and becomes fully mature via a two-step autocatalytic process involving forms B'/B and C'/C. POST1 promotes the generation of the functional S1P-C'/C from S1P-B'/B (canonical cleavage) and, notably, from S1P-A directly (non-canonical cleavage) as well. This POST1-mediated S1P activation is also essential for the cleavages of other S1P substrates including ATF6, CREB3 family members and the α/β-subunit precursor of N-acetylglucosamine-1-phosphotransferase. Together, we demonstrate that POST1 is a cofactor controlling S1P maturation and plays important roles in lipid homeostasis, unfolded protein response, lipoprotein metabolism and lysosome biogenesis.
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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.
Subject(s)
Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum Stress , Herpesviridae , Signal Transduction , Unfolded Protein ResponseABSTRACT
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.
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Endoplasmic reticulum （ER） is an important organelle responsible for protein， steroid， lipid and carbohydrate synthesis and calcium-dependent signal transduction in eukaryotic cells. ER homeostasis is essential for normal cell function. ER homeostasis imbalance can induce ER stress （ERS）， which participates in the occurrence and development of diseases of the digestive system， respiratory system， circulatory system， nervous system， reproductive system， and endocrine system， and affects body health. Among various diseases， cancers seriously endanger people′s health due to its high mortality rate， disability rate， and recurrence rate. Due to the survival characteristics of unlimited proliferation， tumor cells are often exposed to various internal and external stimuli such as hypoxia， ischemia， excessive proliferation， and starvation， which destroy intracellular protein balance and induce ERS to some extent for survival. ERS plays a major role in various tumors and has dual functions in the survival of tumor cells： promoting the survival of tumor cells by activating a series of adaptive responses， while inducing ERS-related apoptosis pathways， so as to promote tumor cell death and inhibit tumor growth and invasion. As multiple functions of ERS in tumors are reported， many scholars have tried to intervene in the progress of tumors from the perspective of ERS. The therapeutic effect of traditional Chinese medicine （TCM） on tumors has been widely recognized. TCM can participate in the regulation of tumors from many aspects， including ERS， chemoradiotherapy resistance， gastrointestinal adverse reactions caused by chemotherapy， postoperative recurrence and metastasis. Since there are few reports on the antitumor effect of TCM from the perspective of ERS， this paper expounds the influence of ERS on tumorigenesis and development and the progress of TCM intervention in tumor through ERS， in order to provide a new direction for tumor treatment.
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The clinical features of Alzheimer's disease (AD), for example the progressive memory loss, are produced by neuronal loss and synaptic dysfunction. These events have been associated with histopathological alterations in AD brain, including the presence of amyloid plaques and neurofibrillary tangles. Recent studies suggest that cellular stress produced by the aggregation of misfolded proteins leads to alterations in protein homeostasis, that is regulated for the most part by endoplasmic reticulum (ER). The ER is the main compartment involved in the folding and secretion of proteins and is drastically affected in AD neurons. Recent evidence implicates the participation of adaptive responses to stress within the ER in the disease process through a signaling pathway known as the Unfolded Protein Response (UPR) which alleviates the protein aggregation and ER stress. Based on the involvement of ER stress in several diseases, efforts are being done to identify small molecules that can inhibit or activate selective UPR components. Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed.
Subject(s)
Humans , Alzheimer Disease , Signal Transduction , Endoplasmic Reticulum , Unfolded Protein Response , Endoplasmic Reticulum StressABSTRACT
@#Recent outbreak of dengue virus （DENV） in subtropics and tropics and the increasing incidence of DENV infection have seriously threatened the public health. Upon virus infection，the host cells rapidly elicit various responses through activating different signaling pathways，to fight against the invasion of DENV. On the other hand，dengue virus has evolved many strategies of escaping，antagonizing or even utilizing these host responses. This review summarizes the progress of molecular biology of DENV and the cellular responses against DENV infection，including innate immune response，adaptive immune response，cell death，autophagy，unfolded protein response，and stress granule formation.
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The endoplasmic reticulum (ER) is a place where secreted proteins and membrane proteins are synthesized and folded. The homeostatic environment of the endoplasmic reticulum is necessary to keep ER protein synthesis proceed smoothly. When unfolded proteins and misfolded proteins aggregate in the ER abnormally, it often leads to protein synthesis disorder and triggers endoplasmic reticulum stress (ERS). The endoplasmic reticulum can maintain the endoplasmic reticulum homeostasis and restore cellular function by inducing an unfolded protein response (UPR). However, as the ERS increasingly intensify, the continuous UPR reaction will trigger programmed cell death. There is close relationship between the tumorigenesis of lung cancer and ERS in cells. This article will introduce ERS, UPR and related pathways, and summarize their main causes and their roles in lung cancer, aiming to providing new ideas and potential therapeutic targets for basic research and clinical treatment of lung cancer.
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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.
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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.
Subject(s)
Humans , Cellular Microenvironment , Extracellular Matrix , Idiopathic Pulmonary Fibrosis , LungABSTRACT
Objective: To investigate the relationship between celastrol inhibition against multiple myeloma cell growth and unfolded protein response (UPR) and the related molecular mechanism, so as to provide new drug targets for multiple myeloma treatment. Methods: Four multiple myeloma cell lines RPMI 8226, U266, SKO and KMS-11 were treated with different concentrations (proliferation: 0.0-10.0 μmol/L; apoptosis: 0.0-4.0 μmol/L; cell cycle: 0.0-1.5 μmol/L) of celastrol for different periods (proliferation: 1-3 d; apoptosis: 1 d; cell cycle: 1 d), and cell proliferation, apoptosis and cell cycle were examined. Western blotting analysis was used to detect the main molecules in the inositol-requiring enzyme 1 (IRE1), PRKR-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) signaling pathways of UPR, which included glucose-regulated protein 78 (GRP78), ATF6, PERK, eukaryotic initiation factor 2α (eIF2α), phosphorylated-eIF2α (p-eIF2α), C/EBP homologous protein (CHOP), IRE1 and phosphorylated-IRE1 (p-IRE1). After the lentivirus vector containing short hairpin RNA (shRNA) was used to interfere with eIF2α expression in RPMI 8226 cells, the effects of celastrol were detected on signaling molecule expression, apoptosis and cell cycle. Results: Celastrol inhibited the proliferation of 4 multiple myeloma cells, induced apoptosis, and arrested the cell cycle at G0/G1 phase in dose- and time-dependent manners. RPMI 8226 cells were most sensitive to celastrol. For RPMI 8226 cells, when 0.5-2.0 μmol/L of celastrol was used for 30 min to 24 h, the p-eIF2α levels in the PERK signaling pathway of UPR were significantly increased (P<0.05 or P<0.01), and the downstream CHOP expression was risen correspondingly (P<0.05 or P<0.01), but the other two pathways ATF6 and IRE1 were not affected obviously. After interference of eIF2α expression with lentivirus vector containing shRNA, the effects of celastrol to increase CHOP expression, induce apoptosis and arrest cell cycle were significantly attenuated or disappeared. Conclusion: Celastrol can inhibit the growth of a variety of multiple myeloma cells, and the activated eIF2α molecule in the UPR PERK signaling pathway may be one of the mechanisms.
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Acute respiratory distress syndrome (ARDS) is an acute pulmonary edema induced by non-cardiac factors and a clinical syndrome characterized by respiratory distress and refractory hypoxemia. The pathogenesis of ARDS is complex. Systemic or local damaging factors can aggravate the inflammatory injury of lung tissue dependent on the activation of endoplasmic reticulum stress (ERs) and unfolded protein responses (UPR) and correlation with various damaging mechanisms such as inflammatory response, oxidative stress, apoptosis, autophagy, and calcium homeostasis. This article reviews the progress of ERs associated with ARDS to help us understand the pathogenesis of ARDS.