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*

Neurofi brillary tangles (NFTs) of microtubule-associated protein tau are a pathological hallmark of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress has been known to be involved in the pathogenesis of AD. However, the exact role of ER stress in tau pathology has not yet been clearly elucidated. In present study, the possible relationship between tau pathology and ER stress was examined in terms of sorcin, which is a calcium binding protein and plays an important role in calcium homeostasis. Our previous yeast two hybrid study showed that sorcin is a novel tau interacting protein. Caspase-3-cleaved tau (T4C3) showed significantly increased tau-sorcin interaction compared to wild type tau (T4). Thapsigargin-induced ER stress and co-expression of constitutively active GSK3β (GSK3β-S9A) also exhibited significantly increased tau-sorcin interactions. T4C3-expressing cells showed potentiated thapsigargin-induced apoptosis and disruption of intracellular calcium homeostasis compared to T4-expressing cells. Overexpression of sorcin signifi cantly attenuated thapsigargin-induced apoptosis and disruption of calcium homeostasis. In contrary, siRNA-mediated knock-down of sorcin showed significantly increased thapsigargin-induced apoptosis and disruption of calcium homeostasis. These data strongly suggest that sequestration of sorcin by aberrant forms of tau compromises the function of sorcin, such as calcium homeostasis and cellular resistance by ER stress, which may consequently result in the contribution to the progression of AD.
Alzheimer Disease ; Apoptosis ; Calcium* ; Carrier Proteins ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress ; Homeostasis* ; Pathology ; Thapsigargin ; Yeasts

Endoplasmic reticulum stress (ERS) is a new pathway of apoptosis following the discovery of death receptor signaling pathway and mitochondrial pathway. By activating the unfolded protein response (UPR), ERS can suspend protein synthesis, restore the endoplasmic reticulum homeostasis, and thus play a protective role for cells; however, if the inducing factors of ERS persist, ERS will continue to trigger C/EBP homologous protein, JNK, caspase, or other pathways to induce apoptosis. In addition, the injury and apoptosis of vascular endothelial cells are key links in various diseases and pathophysiologic processes, and research has also shown that vascular endothelial cell apoptosis is closely related with the ERS. Effective intervention of ERS may restrain apoptosis and protect the vascular endothelium. This article reviews the recent research advances in ERS and its role in vascular endothelial cell apoptosis.
Animals ; Apoptosis ; Endoplasmic Reticulum Stress ; Endothelial Cells ; pathology ; Humans

Sarcoplasmic reticulum is a principal subcellular organelle which regulates calcium homeostasis, protein synthesis, and apoptosis of cardiomyocytes. Endoplasmic reticulum (ER) stress is defined as the perturbation of ER function which is caused by the alterations in the ER environment, such as the perturbation of Ca(2+) homeostasis, elevated protein synthesis, the deprivation of glucose, altered glycosylation, and the accumulation of misfolded proteins. Moderate ER stress is able to restore cellular homeostasis, i.e., to exert a compensatory effect on cardiomyocytes. However, intense or persistent ER stress may cause ER stress-induced apoptosis, which shifts the hypertrophied myocardium to failure, and affects the pathogenesis and development of myocardial hypertrophy. The article reviewed the role of ER stress response in the pathogenesis and development of myocardial hypertrophy.
Animals ; Apoptosis ; Endoplasmic Reticulum Stress ; Homeostasis ; Hypertrophy ; pathology ; Myocardium ; pathology ; Myocytes, Cardiac ; pathology ; Protein Biosynthesis ; Sarcoplasmic Reticulum ; pathology

Apoptosis ; Endoplasmic Reticulum ; pathology ; Endothelium, Vascular ; pathology ; Gene Expression Regulation ; physiology ; Humans ; Stress, Physiological

Trypanosoma cruzi infection results in debilitating cardiomyopathy, which is a major cause of mortality and morbidity in the endemic regions of Chagas disease (CD). The pathogenesis of Chagasic cardiomyopathy (CCM) has been intensely studied as a chronic inflammatory disease until recent observations reporting the role of cardio-metabolic dysfunctions. In particular, we demonstrated accumulation of lipid droplets and impaired cardiac lipid metabolism in the hearts of cardiomyopathic mice and patients, and their association with impaired mitochondrial functions and endoplasmic reticulum (ER) stress in CD mice. In the present study, we examined whether treating infected mice with an ER stress inhibitor can modify the pathogenesis of cardiomyopathy during chronic stages of infection. T. cruzi infected mice were treated with an ER stress inhibitor 2-Aminopurine (2AP) during the indeterminate stage and evaluated for cardiac pathophysiology during the subsequent chronic stage. Our study demonstrates that inhibition of ER stress improves cardiac pathology caused by T. cruzi infection by reducing ER stress and downstream signaling of phosphorylated eukaryotic initiation factor (P-elF2α) in the hearts of chronically infected mice. Importantly, cardiac ultrasound imaging showed amelioration of ventricular enlargement, suggesting that inhibition of ER stress may be a valuable strategy to combat the progression of cardiomyopathy in Chagas patients.
2-Aminopurine ; Animals ; Cardiomyopathies ; Chagas Disease ; Endoplasmic Reticulum ; Endoplasmic Reticulum Stress ; Heart ; Humans ; Lipid Droplets ; Lipid Metabolism ; Mice ; Mortality ; Pathology ; Peptide Initiation Factors ; Trypanosoma cruzi ; Ultrasonography

OBJECTIVETo explore the effects of endoplasmic reticulum stress (ERS) related proteins and their mediated apoptosis in the formation of deep tissue injury of pressure ulcer in rats.

METHODSForty male Sprague-Dawley rats were divided into normal control group and groups A, B, C, D according to the random number table, with 8 rats in each group. Rats in group A were loaded with 22.47 kPa pressure with a special pressure apparatus for 2.0 h in the region over gracilis, and then unloaded for 0.5 h. Rats in group B were treated with the same manoeuvre as that in group A for 3 times in one day. Rats in groups C and D were treated with the same manoeuvre as that in group B for 2 and 3 days. Rats in normal control group were free from pressure loading. Rats in groups A, B, C, and D were sacrificed after pressure loading, and then the central part of pressure loaded muscular tissues were harvested for observation of histomorphological change with HE staining; apoptotic nucleoli per millimeter pressure loaded muscular tissue were counted with Hoechst 33258 staining; the levels of binding protein (BIP), protein disulfide isomerase (PDI), C/EBP homologous protein (CHOP), and caspase-12 were assessed with Western blotting (denoted as gray level ratio of target protein to GAPDH). The same parts of gracilis of rats in normal control group were harvested for determination of all the indexes as above. Data were processed with one-way analysis of variance, LSD-t test was applied for paired comparison.

RESULTS(1) Histomorphological observation. Some pathological changes, including inflammatory cell infiltration, myofibers lysis, and vacuolar degeneration, etc. were observed in pressure loaded muscular tissue of rats in groups A, B, C, and D, but not in the same parts of gracilis muscle of rats in normal control group. Compared with those in normal control group [(2.7 ± 1.4) per millimeter muscular tissue], the number of apoptotic nuclei was significantly increased in pressure loaded muscular tissue of rats in groups A, B, C, and D [(14.5 ± 4.4), (11.0 ± 2.9) , (13.8 ± 5.1), (21.3 ± 6.0) per millimeter pressure loaded muscular tissue, with t values from 4.223 to 6.000, P values all below 0.01). (2) Western blotting. The protein expressions of BIP and PDI in rats of normal control group and groups A, B, C, D were respectively 0.64 ± 0.12, 1.20 ± 0.34, 1.59 ± 0.24, 1.17 ± 0.28, 1.44 ± 0.33; 0.48 ± 0.15, 0.61 ± 0.19, 1.23 ± 0.38, 0.37 ± 0.19, 0.29 ± 0.15, and they showed significant statistical difference (with F values respectively 5.32, 7.95, P < 0.05 or P < 0.01). The protein expressions of CHOP and caspase-12 in rats of normal control group and groups A, B, C, D were respectively 0.58 ± 0.18, 1.48 ± 0.27, 1.03 ± 0.21, 0.95 ± 0.30, 1.69 ± 0.34; 0.55 ± 0.12, 1.08 ± 0.31, 0.69 ± 0.24, 1.79 ± 0.20, 2.06 ± 0.47, with significant statistical difference (with F values respectively 8.17, 15.48, P values all below 0.01).

CONCLUSIONSERS related proteins and their apoptotic pathway may play an important role in the formation of deep tissue injury of pressure ulcer in rats.

Animals ; Endoplasmic Reticulum ; metabolism ; Fatty Liver ; metabolism ; pathology ; Humans ; Mitochondria ; metabolism ; Non-alcoholic Fatty Liver Disease

Vesicle-mediated transport of proteins is a highly regulated, multi-step process. When the vesicle is approaching its target membrane compartment, many factors are required to provide specificity and tethering between the incoming vesicle and the target membrane, before vesicle fusion can occur. Tethering factors, which include multisubunit complexes, coiled-coil proteins, with the help of small GTPases, provide the initial interaction between the vesicle and its target membrane. Of the multisubunit tethering factors, the transport protein particle (TRAPP) complexes function in a number of trafficking steps, including endoplasmic reticulum (ER)-to-Golgi transport, intra- and post-Golgi traffic and autophagosome formation. In this review, we summarize the updated progress in structure and function of TRAPP complexes as well as human diseases caused by genetic mutations in TRAPP.
Animals ; Endoplasmic Reticulum ; pathology ; physiology ; Golgi Apparatus ; pathology ; physiology ; Humans ; Mutation ; Protein Transport ; Vesicular Transport Proteins ; genetics ; physiology

Histochemical, immunohistochemical and ultrastructural studies were performed on cases of hepatocellular carcinoma (HCC) with pale bodies (PB). HCC containing PBs was observed in 3 (5.5%) of 55 consecutively resected HCC cases. Histologically, a large number of hepatocytes displayed pale or eosinophilic staining of the cytoplasm, resulting in ground-glass appearance. They were aggregated in nodular pattern, or diffusely intermixed with other malignant hepatocytes. PBs were negative for periodic-acid Schiff and Masson's trichrome staining. The inclusions showed a strong positive reaction for fibrinogen and some of them were weakly positive for albumin but negative for hepatitis B surface antigen, hepatitis B core antigen, alpha-fetoprotein and alpha-1-antitrypsin. Ultrastructurally, PBs were membrane-bound and contained granular materials of moderate electron density, and were closely related to dilated rough endoplasmic reticulum. These findings support that PBs are secretory fibrinogen accumulated in cystic ER and that such intracellular accumulation possibly reflects a defective transport of fibrinogen.
Albumins/analysis ; Carcinoma, Hepatocellular/pathology* ; Cytoplasm/ultrastructure ; Cytoplasm/pathology ; Cytoplasm/chemistry ; Endoplasmic Reticulum, Rough/ultrastructure ; Endoplasmic Reticulum, Rough/pathology ; Endoplasmic Reticulum, Rough/chemistry ; Fibrinogen/analysis ; Human ; Inclusion Bodies/ultrastructure ; Inclusion Bodies/pathology* ; Inclusion Bodies/chemistry ; Liver Neoplasms/pathology* ; Male ; Microscopy, Electron ; Middle Age ; Periodic Acid-Schiff Reaction