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.
Humans ; Endoplasmic Reticulum Stress/genetics* ; Unfolded Protein Response ; Endoplasmic Reticulum/pathology* ; Apoptosis ; Epilepsy/genetics*

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.
Humans ; Non-alcoholic Fatty Liver Disease ; Endoplasmic Reticulum Stress ; Exercise ; Unfolded Protein Response ; Insulin Resistance

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.
Endoplasmic Reticulum/metabolism* ; Endoplasmic Reticulum Stress ; Herpesviridae ; Signal Transduction ; Unfolded Protein Response

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.
Mitochondria ; Mitochondrial Proteins/metabolism* ; Oxidative Stress ; Signal Transduction ; Unfolded Protein Response

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.
Apoptosis ; Cardiovascular Diseases ; physiopathology ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress ; Humans ; Unfolded Protein Response

Despite considerable efforts to prevent and treat cardiovascular disease (CVD), it has become the leading cause of death worldwide. Cardiac mitochondria are crucial cell organelles responsible for creating energy-rich ATP and mitochondrial dysfunction is the root cause for developing heart failure. Therefore, maintenance of mitochondrial quality control (MQC) is an essential process for cardiovascular homeostasis and cardiac health. In this review, we describe the major mechanisms of MQC system, such as mitochondrial unfolded protein response and mitophagy. Moreover, we describe the results of MQC failure in cardiac mitochondria. Furthermore, we discuss the prospects of 2 drug candidates, urolithin A and spermidine, for restoring mitochondrial homeostasis to treat CVD.
Adenosine Triphosphate ; Cardiovascular Diseases ; Cause of Death ; Heart Failure ; Heart ; Homeostasis ; Mitochondria ; Mitochondrial Degradation ; Organelles ; Quality Control ; Spermidine ; Unfolded Protein Response

The signaling network of the mitochondrial unfolded protein response (UPR(mt)) and mitohormesis is a retrograde signaling pathway through which mitochondria-to-nucleus communication occurs in organisms. Recently, it has been shown that the UPR(mt) is closely associated with metabolic disorders and conditions involving insulin resistance, such as alcoholic and non-alcoholic fatty liver and fibrotic liver disease. Scientific efforts to understand the UPR(mt) and mitohormesis, as well as to establish the mitochondrial proteome, have established the importance of mitochondrial quality control in the development and progression of metabolic liver diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). In this review, we integrate and discuss the recent data from the literature on the UPR(mt) and mitohormesis in metabolic liver diseases, including NAFLD/NASH and fibrosis.
Alcoholics ; Fatty Liver ; Fibrosis ; Humans ; Insulin Resistance ; Liver Diseases ; Metabolism ; Mitochondria ; Non-alcoholic Fatty Liver Disease ; Obesity ; Proteome ; Quality Control ; Unfolded Protein Response

The Endoplasmic reticulum (ER), an indispensable sub-cellular component of the eukaryotic cell carries out essential functions, is critical to the survival of the organism. The chaperone proteins and the folding enzymes which are multi-domain ER effectors carry out 3-dimensional conformation of nascent polypeptides and check misfolded protein aggregation, easing the exit of functional proteins from the ER. Diverse conditions, for instance redox imbalance, alterations in ionic calcium levels, and inflammatory signaling can perturb the functioning of the ER, leading to a build-up of unfolded or misfolded proteins in the lumen. This results in ER stress, and aiming to reinstate protein homeostasis, a well conserved reaction called the unfolded protein response (UPR) is elicited. Equally, in protracted cellular stress or inadequate compensatory reaction, UPR pathway leads to cell loss. Dysfunctional ER mechanisms are responsible for neuronal degeneration in numerous human diseases, for instance Alzheimer's, Parkinson's and Huntington's diseases. In addition, mounting proof indicates that ER stress is incriminated in psychiatric diseases like major depressive disorder, bipolar disorder, and schizophrenia. Accumulating evidence suggests that pharmacological agents regulating the working of ER may have a role in diminishing advancing neuronal dysfunction in neuropsychiatric disorders. Here, new findings are examined which link the foremost mechanisms connecting ER stress and cell homeostasis. Furthermore, a supposed new pathogenic model of major neuropsychiatry disorders is provided, with ER stress proposed as the pivotal step in disease development.
Apoptosis ; Biological Psychiatry ; Bipolar Disorder ; Calcium ; Depressive Disorder, Major ; Endoplasmic Reticulum Stress* ; Endoplasmic Reticulum* ; Eukaryotic Cells ; Homeostasis ; Humans ; Neurons ; Neuropsychiatry ; Oxidation-Reduction ; Peptides ; Proteostasis Deficiencies ; Schizophrenia ; Unfolded Protein Response

PURPOSE: Protein overloading in the endoplasmic reticulum (ER) leads to endoplasmic reticulum stress, which exacerbates various disease conditions. Emodin, an anthraquinone compound, is known to have several health benefits. The effect of emodin against palmitic acid (PA) - induced ER stress in HepG2 cells was investigated. METHODS: HepG2 cells were treated with varying concentrations of palmitic acid to determine the working concentration that induced ER stress. ER stress associated genes such as ATF4, XBP1s, CHOP and GRP78 were checked using RT- PCR. In addition, the expression levels of unfolded protein response (UPR) associated proteins such as IRE1α, eIF2α and CHOP were checked using immunoblotting to confirm the induction of ER stress. The effect of emodin on ER stress was analyzed by treating HepG2 cells with 750 µM palmitic acid and varying concentrations of emodin, then analyzing the expression of UPR associated genes. RESULTS: It was evident from the mRNA and protein expression results that palmitic acid significantly increased the expression of UPR associated genes and thereby induced ER stress. Subsequent treatment with emodin reduced the mRNA expression of ATF4, GRP78, and XBP1s. Furthermore, the protein levels of p-IRE1α, p-elF2α and CHOP were also reduced by the treatment of emodin. Analysis of sirtuin mRNA expression showed that emodin increased the levels of SIRT4 and SIRT7, indicating a possible role in decreasing the expression of UPR-related genes. CONCLUSION: Altogether, the results suggest that emodin could exert a protective effect against fatty acid-induced ER stress and could be an agent for the management of various ER stress related diseases.
Emodin ; Endoplasmic Reticulum Stress ; Endoplasmic Reticulum ; Hep G2 Cells ; Immunoblotting ; Insurance Benefits ; Palmitic Acid ; Polymerase Chain Reaction ; RNA, Messenger ; Sirtuins ; Unfolded Protein Response

Endoplasmic reticulum (ER) stress is mediated by disturbance of Ca²⁺ homeostasis. The store-operated calcium (SOC) channel is the primary Ca²⁺ channel in non-excitable cells, but its participation in agent-induced ER stress is not clear. In this study, the effects of tunicamycin on Ca²⁺ influx in human umbilical vein endothelial cells (HUVECs) were observed with the fluorescent probe Fluo-4 AM. The effect of tunicamycin on the expression of the unfolded protein response (UPR)-related proteins BiP and CHOP was assayed by western blotting with or without inhibition of Orai1. Tunicamycin induced endothelial dysfunction by activating ER stress. Orai1 expression and the influx of extracellular Ca²⁺ in HUVECs were both upregulated during ER stress. The SOC channel inhibitor SKF96365 reversed tunicamycin-induced endothelial cell dysfunction by inhibiting ER stress. Regulation of tunicamycin-induced ER stress by Orai1 indicates that modification of Orai1 activity may have therapeutic value for conditions with ER stress-induced endothelial dysfunction.
Blotting, Western ; Calcium ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress ; Endothelial Cells ; Homeostasis ; Human Umbilical Vein Endothelial Cells ; Tunicamycin ; Unfolded Protein Response