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

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

Cellular stress severely disrupts endoplasmic reticulum (ER) function, leading to the abnormal accumulation of unfolded or misfolded proteins in the ER and subsequent development of endoplasmic reticulum stress (ERS). To accommodate the occurrence of ERS, cells have evolved a highly conserved, self-protecting signal transduction pathway called the unfolded protein response. Notably, ERS signaling is involved in the development of a variety of diseases and is closely related to tumor development, particularly in breast cancer. This review discusses recent research regarding associations between ERS and tumor metastasis. The information presented here will help researchers elucidate the precise mechanisms underlying ERS-mediated tumor metastasis and provide new directions for tumor therapies.
Breast Neoplasms* ; Breast* ; Endoplasmic Reticulum Stress* ; Endoplasmic Reticulum* ; Neoplasm Metastasis* ; 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

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

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*

The endoplasmic reticulum (ER) is an important subcellular organelle that is involved in numerous activities required to achieve and maintain functional proteins in addition to its role in the biosynthesis of lipids and as a repository of intracellular Ca²⁺. The inability of the ER to cope with protein folding beyond its capacity causes disturbances that evoke ER stress. Cells possess molecular mechanisms aimed at clearing unwanted cargo from the ER lumen as an adaptive response, but failing to do so navigates the system towards cell death. This systemic approach is called the unfolded protein response. Aging insults cells through various perturbations in homeostasis that involve curtailing ER function by mitigating the expression of its resident chaperones and enzymes. Here the unfolded protein response (UPR) cannot protect the cell due to the weakening of its protective arm, which exacerbates imbalanced homeostasis. Aging predisposed breast malignancy activates the UPR, but tumor cells maneuver the mechanistic details of the UPR, favoring tumorigenesis and thereby eliciting a treacherous condition. Tumor cells exploit UPR pathways via crosstalk involving various signaling cascades that usher tumor cells to immortality. This review aims to present a collection of data that can delineate the missing links of molecular signatures between aging and breast cancer.
Aging* ; Arm ; Breast Neoplasms* ; Breast* ; Carcinogenesis ; Cell Death ; Endoplasmic Reticulum* ; Homeostasis ; Organelles ; Protein Folding ; Unfolded Protein Response*

Chronic endoplasmic reticulum (ER) stress culminating in proteotoxicity contributes to the development of insulin resistance and progression to type 2 diabetes mellitus. Pharmacologic interventions targeting several different nuclear receptors have emerged as potential treatments for insulin resistance. The mechanistic basis for these antidiabetic effects has primarily been attributed to multiple metabolic and inflammatory functions. Here we review recent advances in our understanding of the association of ER stress with insulin resistance and the role of nuclear receptors in promoting ER stress resolution and improving insulin resistance in the liver.
Diabetes Mellitus, Type 2 ; Endoplasmic Reticulum Stress* ; Endoplasmic Reticulum* ; Insulin Resistance* ; Insulin* ; Liver ; Receptors, Cytoplasmic and Nuclear* ; 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

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