Role Of Endoplasmic Reticulum Stress Pathway Research Articles

Potential impacts of bisphenols on prostate cells: An overview of cytotoxicity, proliferation, oxidative stress, apoptosis, and ER-stress response activation

This study aimed to evaluate the toxic effects of Bisphenol A (BPA), Bisphenol F (BPF) and Bisphenol S (BPS) on PNT1A and PC-3 cells, focusing on their effects on endoplasmic reticulum (ER) stress and related pathways. PNT1A and PC-3 were treated with BPA, BPF and BPS at concentrations of 0.1, 1 and 10 μM for 48 h cytotoxicity, BrdU cell proliferation, ROS generation, apoptosis detection, gene expression analysis and Western blot analysis were performed. BPA induced proliferation and late apoptosis in PNT1A cells, whereas it induced both late apoptosis and early apoptosis in PC-3 cells. BPF and BPS induced late apoptosis in PC-3 cells. Increased ROS levels were observed in PNT1A cells exposed to 1–10 μM BPA. BPA, BPF and BPS increased the expression levels of ER stress-related genes in PNT1A cells. Furthermore, exposure to BPA increased the expression of ER stress-related CHOP/DDIT3 protein in PNT1A cells. These findings highlight the potential health risks associated with BPA, BPF and BPS exposure and emphasize the importance of investigating the underlying mechanisms by which these chemicals may affect human health. Further research is required to comprehensively understand the role of ER stress pathways in cellular responses to these substances.

Protective Effect of Nanoselenium on Renal Oxidative Damage Induced by Mercury in Laying Hens.

This study investigated the effects of dietary nanoselenium (nano-Se) supplementation protecting from renal oxidative damages induced by mercury (Hg) exposure in laying hens. Furthermore, endoplasmic reticulum (ER) stress pathway was explored to reveal the protective mechanism of nano-Se. A total of 576 40-week-old Hyline-White laying hens were randomly allocated to 4 groups with 6 pens per group and 24 hens per pen. The experimental groups were as follows: control (basal diet), control + 27.0mg/kg Hg, control + 5.0mg/kg nano-Se, and Hg27.0 + 5.0mg/kg nano-Se. The results revealed that dietary Hg exposure significantly reduced laying performance (P < 0.05) and egg quality (P < 0.05), whereas nano-Se supplementation partially reversed the reductions. Besides, dietary Hg exposure could induce histopathology damages and apoptosis in kidney, whereas nano-Se addition could alleviate these toxicities effectively. After Hg exposure, the activities and gene expressions of superoxidative dismutase (SOD) (P < 0.05), catalase (CAT) (P < 0.01), glutathione reductase (GR) (P < 0.05) and glutathione peroxidase (GSH-Px) (P < 0.05), and glutathione (GSH) content (P < 0.05) were significantly decreased, while the malondialdehyde (MDA) level was significantly increased (P < 0.05) in kidney. However, nano-Se supplementation partially reversed the levels and gene expressions of these antioxidant biomarkers in kidney. Furthermore, dietary Hg exposure significantly increased the gene expressions of PERK (P < 0.05), ATF4 (P < 0.05), CHOP (P < 0.05), IRE1α (P < 0.05), TRAF2 (P < 0.05), ASK1 (P < 0.05), Caspase-9 (P < 0.05), Caspase-8 (P < 0.05), Caspase-3 (P < 0.05), and Bax/Bcl-2 (P < 0.05), whereas nano-Se supplementation partially reversed these increases of gene expressions. In summary, this study provides evidence that dietary Hg exposure can induce renal oxidative damages, and elucidates an important role of ER stress pathway in nano-Se alleviating renal apoptosis in laying hens.

Protective effects of tetramethylpyrazine on dysfunction of the locus coeruleus in rats exposed to single prolonged stress by anti-ER stress mechanism.

Post-traumatic stress disorder (PTSD) is a serious stress-related neuropsychiatric disorder caused by major traumatic events. Abnormal activity of the locus coeruleus (LC)-noradrenergic system is related to the development of PTSD-like symptoms. Our previous studies have indicated that endoplasmic reticulum (ER) stress induced neuronal apoptosis of LC in rats with PTSD. The purpose of this study was to further investigate the role of ER stress pathways in LC neuronal dysfunction and elucidate the effect of the bioactive component tetramethylpyrazine (TMP) against ER stress response. We used an acute exposure to single prolonged stress (SPS) to model PTSD in rats. There were higher norepinephrine (NE) levels in the brain, increased tyrosine hydroxylase expression in LC, and enhanced anxiety-like behaviors in rats exposed to SPS, which were observed by enzyme-linked immunosorbent assay, western blot analysis and elevated plus maze test, respectively. In addition, the three major pathways of ER stress were activated by SPS exposure, which may be involved in the dysregulation of the LC-noradrenergic system of rats with PTSD. Furthermore, we found that TMP administration significantly suppressed the increased responsiveness of LC-noradrenergic system, effectively reduced the anxiety response of SPS rats, and selectively attenuated the activation of pro-apoptotic ER stress pathways. The results suggest that TMP was efficient in improving the LC-NE dysfunction induced by excessive ER stress. TMP exhibited a significant neuroprotective effect and potential therapeutics on PTSD-like symptoms.

Astragalus polysaccharides inhibits cardiomyocyte apoptosis during diabetic cardiomyopathy via the endoplasmic reticulum stress pathway

Ethnopharmacological relevanceTraditional Chinese medicine Astragalus membranaceus (Fisch.) Bunge (AM) has been utilized for the treatment of diabetes mellitus and its complications for centuries. Astragalus polysaccharides (APS), the main bioactive ingredient extracted from the root of AM, is prescribed widely in China and has definite cardioprotective effect during diabetic cardiomyopathy (DCM). Endoplasmic reticulum (ER) stress-induced apoptosis played a crucial role in the progression of DCM. However, the regulatory mechanisms of APS on ER stress pathway haven't been comprehensively studied so far.Aim of the study: The aim of this study was to identify the effect of APS on cardiomyocyte apoptosis and to investigate the mechanisms for the anti-apoptotic effect of APS during DCM. Materials and methodsDCM rat model was induced by intraperitoneal streptozotocin (STZ) injection and treated with APS for 16 weeks. Cardiac function, pathological changes and apoptotic cells were assessed by echocardiography, hematoxylin-eosin (HE) staining and TUNEL assay, respectively. Expressions of key molecules in ER stress pathway were detected by Western blot analysis. Cardiomyocytes were exposed to high glucose (HG) and treated with APS for 24 h. Cell viability, apoptosis and protein expressions were assessed by MTT, flow cytometer and Western blot analysis, respectively. Moreover, lentivirus over-expressing (OE) C/EBP homologous protein (CHOP) was employed to further investigate the causative role of ER stress pathway in APS-mediated effect on cardiomyocyte apoptosis. ResultsIn vivo, the results demonstrated that APS could improve heart function and attenuate myocardial apoptosis in DCM rat model. Further study demonstrated that APS could down-regulate the protein expressions of activating transcription factor 6 (ATF6) and protein kinase RNA-like ER kinase (PERK) related factors of ER stress pathway. In vitro, APS significantly inhibit HG stimulated H9C2 cell apoptosis and the expressions of ATF6 and PERK related proteins of ER stress pathway. However, after CHOP-OE lentivirus transfection, the protective effects of APS were diminished as increased apoptotic rate and higher expression of CHOP. ConclusionsAPS could attenuate cardiomyocyte apoptosis via down-regulating the expression of ATF6 and PERK related factors of ER stress pathway in DCM rats and HG-stimulated H9C2 cells.

Japanese encephalitis virus activates autophagy through XBP1 and ATF6 ER stress sensors in neuronal cells.

Endoplasmic reticulum (ER) stress and autophagy are key cellular responses to RNA virus infection. Recent studies have shown that Japanese encephalitis virus (JEV)-induced autophagy negatively influences virus replication in mouse neuronal cells and embryonic fibroblasts, and delays virus-induced cell death. Here, we evaluated the role of ER stress pathways in inducing autophagy during JEV infection. We observed that JEV infection of neuronal cells led to activation of all three sensors of ER stress mediated by eIF2α/PERK, IRE1/XBP1 and ATF6. The kinetics of autophagy induction as monitored by levels of SQSTM1 and LC3-II paralleled activation of ER stress. Inhibition of the eIF2α/PERK pathway by siRNA-mediated depletion of proteins and by the PERK inhibitor had no effect on autophagy and JEV replication. However, depletion of XBP1 and ATF6, alone or in combination, prevented autophagy induction and significantly enhanced JEV-induced cell death. JEV-infected cells depleted of XBP1 or ATF6 showed reduced transcription of ER chaperones, ERAD components and autophagy genes, resulting in reduced protein levels of the crucial autophagy effectors ATG3 and BECLIN-1. Conversely, pharmacological induction of ER stress in JEV-infected cells further enhanced autophagy and reduced virus titres. Our study thus demonstrates that a crucial link exists between the ER stress pathways and autophagy in virus-infected cells, and that these processes are highly regulated during virus infection.

Understanding the origin of non-immune cell-mediated weakness in the idiopathic inflammatory myopathies - potential role of ER stress pathways.

Discussion of endoplasmic reticulum (ER) stress pathway activation in idiopathic inflammatory myopathies (IIM), and downstream mechanisms causative of muscle weakness. In IIM, ER stress is an important pathogenic process, but how it causes muscle dysfunction is unknown. We discuss relevant pathways modified in response to ER stress in IIM: reactive oxygen species (ROS) generation and mitochondrial dysfunction, and muscle cytokine (myokine) generation. First, ER stress pathway activation can induce changes in mitochondrial bioenergetics and ROS production. ROS can oxidize cellular components, causing muscle contractile dysfunction and energy deficits. Novel compounds targeting ROS generation and/or mitochondrial dysfunction can improve muscle function in several myopathologies. Second, recent research has demonstrated that skeletal muscle produces multiple myokines. It is suggested that these play a role in causing muscle weakness. Myokines are capable of immune cell recruitment, thus contributing to perturbed muscle function. A characterization of myokines in IIM would clarify their pathogenic role, and so identify new therapeutic targets. ER stress pathway activation is clearly of etiological relevance in IIM. Research to better understand mechanisms of weakness downstream of ER stress is now required, and which may discover new therapeutic targets for nonimmune cell-mediated weakness.

Endoplasmic reticulum stress pathway mediates isoflurane-induced neuroapoptosis and cognitive impairments in aged rats

Postoperative cognitive dysfunction (POCD) is increasingly being recognized as an important clinical syndrome. Although it has been documented that volatile anesthetics induce neuronal apoptosis and cognitive deficits in several aged animal models, the underlying mechanisms are not well understood. Endoplasmic reticulum stress (ERS) is considered as an initial or early response of cells under stress and linked to neuronal death in various neurodegenerative diseases. The study was designed to explore the possible role of ERS pathway in isoflurane-induced neuroapoptosis and cognitive impairments. In the present study, twenty-month-old rats were exposed to 1.3% isoflurane for 4h. Two weeks later, the rats were subjected to behavioral study. Protein and mRNA expressions of ERS markers were evaluated. Meanwhile, hippocampal neuronal apoptosis was also detected. We found that isoflurane triggered ERS as evidenced by increased phosphorylation of eukaryotic initiation factor (EIF) 2α, and increased expression of 78-kDa glucose-regulated protein (GRP78), activating transcription factor (ATF) 4 and C/EBP homologous protein (CHOP). Furthermore, the level of apoptosis in the hippocampus was significantly up-regulated after isoflurane exposure, and salubrinal (ERS inhibitor) treatment attenuated the increase. More importantly, cognitive impairments caused by isoflurane were also effectively alleviated by salubrinal pretreatment. These results indicate that ERS-mediated apoptotic pathway is involved in isoflurane neurotoxicity in aged rats. Inhibition of ERS overactivation contributes to the relief of isoflurane-induced neurohistopathologic changes.