Endoplasmic Reticulum Stress Damage Research Articles

Sinapic acid protects against lead acetate-induced lung toxicity by reducing oxidative stress, apoptosis, inflammation, and endoplasmic reticulum stress damage.

Lead acetate (PbAc) is a compound that produces toxicity in many tissues after exposure. Sinapic acid (SNP) possesses many biological and pharmacological properties. This study aimed to investigate the efficacy of SNP on the toxicity of PbAc in lung tissue. PbAc was administered orally at 30 mg/kg and SNP at 5 or 10 mg/kg for 7 days. Biochemical, genetic, and histological methods were used to investigate inflammatory, apoptotic, endoplasmic reticulum stress, and oxidative stress damage levels in lung tissue. SNP administration induced PbAc-reduced antioxidant (GSH, SOD, CAT, and GPx) and expression of HO-1 in lung tissue. It also reduced MDA, induced by PbAc, and thus alleviated oxidative stress. SNP decreased the inflammatory markers NF-κB, TNF-α and IL-1β levels induced by PbAc in lung tissue and exhibited anti-inflammatory effect. PbAc increased apoptotic Bax, Apaf-1, and Caspase-3 mRNA transcription levels and decreased anti-apoptotic Bcl-2 in lung tissues. SNP decreased apoptotic damage by reversing this situation. On the other hand, SNP regulated these markers and brought them closer to the levels of the control group. PbAc caused prolonged ER stress by increasing the levels of ATF6, PERK, IRE1α, GRP78 and this activity was stopped and tended to retreat with SNP. After evaluating all the data, While PbAc caused toxic damage in lung tissue, SNP showed a protective effect by reducing this damage.

Asaronic Acid Inhibits ER Stress and Ameliorates Impaired ERAD in 7Β-Hydroxycholesterol-Loaded Macrophages

Abstract Objectives Misfolded proteins were formed in the endoplasmic reticulum (ER) due to diverse stresses including metabolic stress and oxidative stress. Accumulation of unfolded proteins in the ER stimulates chaperone expression and ER-associated degradation (ERAD) process. This process involves the recognition of misfolded proteins to maintain the protein quality control, which in turn eliminates in association with the ER membrane. Upregulation of ubiquitination enzymes is an essential mechanism by which ER stress enhances ERAD. Asaronic acid (2,4,5-trimethoxybenzoic acid), identified as one of purple perilla constituents, has anti-diabetic and anti-inflammatory effects. This study attempted to examine whether asaronic acid attenuated the 7Β-hydroxycholesterol-elicited ER stress of macrophages. Methods J774A.1 murine macrophage was incubated with 28 μM 7Β-hydroxycholesterol in absence and presence of 1–20 μΜ asaronic acid up to 24 h. Cytotoxicity was assessed by MTT assay. Expression levels of ER stress-responsive chaperones and ERAD biomarkers were measured by Western blot analysis and immunocytochemical staining with a specific antibody. Results Asaronic acid at 1–20 μM had a cytoprotective effect on macrophages against 7Β-hydroxycholesterol-induced toxicity. Asaronic acid diminished the induction and activation of ER stress sensors such as Grp/BiP, IRE1, and PERK in macrophages exposed to 7Β-hydroxycholesterol. Also, asaronic acid positively influenced the induction of ERAD process-linked components of EDEM1, OS9, SEl1L, HRD1, and VCP1/p97. Furthermore, asaronic acid promoted subsequent degradation reduced by 7Β-hydroxycholesterol via the cytosolar ubiquitin-proteasome system of macrophages. Conclusions These results demonstrate that asaronic acid attenuated 7Β-hydroxycholesterol-induced ER stress and improved impaired ER stress-mediated degradation systems. Therefore, asaronic acid may be a potent agent protecting macrophages against pathological ER stress damage. Funding Sources This work was supported by the BK21 FOUR(Fostering Outstanding Universities for Research, 4220200913807) funded by the National Research Foundation of Korea (NRF).

Protective effects of folic acid on oxidative damage of rat spleen induced by lead acetate

Lead (Pb) is a heavy metal environmental pollutant that can cause functional damage and anemia of immune organs. More and more evidence indicate that the toxicity of lead was related to apoptosis driven by oxidative stress and endoplasmic reticulum stress. This article mainly discusses the protective effect and mechanism of folic acid intervention on lead-induced spleen injury and apoptosis. In this study, Sprague-Dawley rats were randomly divided into control group, lead exposure group (0.2% lead acetate), folic acid + lead group (0.4 mg/kg folic acid and 0.2% lead acetate), and folic acid group (0.4 mg/kg folic acid). By recording and calculating the rat's initial body weight, final body weight, net weight gain, daily weight gain, and spleen index, observe the rat's weight change and spleen weight. And adopt the immunofluorescence staining method to determine the expression level of NrF2, HO-1, GRP78, CHOP protein in the spleen. The results showed that The 0.4 mg/kg folic acid diet did not significantly improve in the body weight and spleen index of lead-exposed rats (P > 0.05). While compared with the control group, the expression levels of HO-1 and CHOP protein were significantly increased in the lead exposure group (P < 0.05), and the expression levels of HO-1 and CHOP protein were significantly reduced in the folic acid intervention group (P < 0.05). In conclusion, lead exposure increased the expression levels of HO-1 and CHOP in the spleen of rats, and caused damage to the spleen. Folic acid down-regulated the expression levels of HO-1 and CHOP proteins through the two pathways of NrF2/HO-1 and GRP78/CHOP, thereby exerting a certain protective effect and alleviating the spleen caused by lead-induced oxidative stress and endoplasmic reticulum stress damage.

DiDang Tang Inhibits Endoplasmic Reticulum Stress-Mediated Apoptosis Induced by Oxygen Glucose Deprivation and Intracerebral Hemorrhage Through Blockade of the GRP78-IRE1/PERK Pathways.

DiDang Tang (DDT), a Chinese traditional medicine formula, contains 4 Chinese traditional medicine substances, has been widely used to treat intracerebral hemorrhage (ICH) patients. However, the molecular mechanisms of DDT for protecting neurons from oxygen and glucose deprivation (OGD)-induced endoplasmic reticulum (ER) stress and apoptosis after ICH still remains elusive. In this study, high-performance liquid chromatography fingerprint analysis was performed to learn the features of the chemical compositions of DDT. OGD-induced ER stress, Ca2+ overload, and mitochondrial apoptosis were investigated in nerve growth factor -induced PC12, primary neuronal cells, and ICH rats to evaluate the protective effect of DDT. We found that DDT treatment protected neurons against OGD-induced damage and apoptosis by increasing cell viability and reducing the release of lactate dehydrogenase. DDT decreased OGD-induced Ca2+ overload and ER stress through the blockade of the glucose-regulated protein 78 (GRP78)- inositol-requiring protein 1α (IRE1)/ protein kinase RNA-like ER kinase (PERK) pathways and also inhibited apoptosis by decreasing mitochondrial damage. Moreover, we observed similar findings when we studied DDT for inhibition of ER stress in a rat model of ICH. In addition, our experiments further confirmed the neuroprotective potential of DDT against tunicamycin (TM)-induced neural damage. Our in vitro and in vivo results indicated that the neuroprotective effect of DDT against ER stress damage and apoptosis occurred mainly by blocking the GPR78-IRE1/PERK pathways. Taken together, it provides reliable experimental evidence and explains the molecular mechanism of DDT for the treatment of patients with ICH.

Melatonin plays a pivotal role in conferring tolerance against endoplasmic reticulum stress via mitogen-activated protein kinases and bZIP60 in Arabidopsis thaliana

Melatonin has diverse roles as a signaling molecule that activates a number of downstream defense systems against various biotic and abiotic stresses in plants. However, there have been no reports regarding a direct protective role of melatonin against endoplasmic reticulum (ER) stress. Here, we report that exogenous melatonin treatment attenuated ER stress damage by preserving ER structure and enhancing secretory protein folding capacity in response to tunicamycin treatment. Further transgenic experiments indicated that melatonin-deficient snat1 mutant was hypersensitive to ER stress, whereas melatonin-proficient SNAT1 overexpression (OE) was tolerant to ER stress, as evidenced by reduced ion leakage and higher transcript levels of ER chaperones, including luminal binding protein (BIP) 2, BIP3, and CNX1, compared to wild-type controls. Moreover, this melatonin-mediated ER stress tolerance was dependent on the bZIP60 transcription factor and mitogen-activated protein kinase. Our data suggest that melatonin is actively involved in maintaining homeostasis of the ER during normal plant growth, and also has a protective effect against many environmental stressors that induce ER stress.

In vitro neuroprotective effect of charantin from Momordica charantia against neurotoxin and endoplasmic reticulum stress-induced cell death in SH-SY5Y cells

Aim: The study deals with the evaluation of neuroprotective effect of charantin. Charantin was isolated from Momordica charantia (MC) L. (Bitter gourd) and characterized by performing infrared (IR), nuclear magnetic resonance (NMR). As it was earlier proved that amyloid beta deposition and cognition are inter-related, neuroblastoma cell lines SH-SY5Y were utilized in this study to prove the effectiveness of charantin on the against neurotoxin and endoplasmic reticulum (ER) stress-induced cell death. Materials and Methods: Charantin was isolated from MC and characterized using IR, NMR spectroscopy studies. The cell viability analysis and IC50 determination for charantin in SH-SY5Y neuroblastoma cell line were performed by MTT assay and neuronal red uptake assay. The neuroprotective effect in SH-SY5Y cells against the MPP+ and ER stress damage was evaluated. The cell viability assays were performed at various concentration ranges from 0.5 to 1 mg/ml. Charantin was added at 0 h, 8 h, and 16 h post the neurotoxin treatment. Brine shrimp lethality assay and MTT assay were also performed to observe the cytotoxicity of charantin at different doses. Results and Discussion: Charantin was found to have a significant IC50 value in SH-SY5Y cells. IN case of MPP+ treatment 0.5 mg, 1 mg/ml concentration of charantin showed significant neuroprotection and improvement in cell viability. In tunicamycin-induced damage, the protection was seen at 0 h and not at 8 h and 16 h post-treatment. At the same time, it has less/no toxicity at therapeutic doses; very high doses may pronounce cytotoxicity. Conclusion: The present investigation shows the neuroprotective effect of MC and charantin obtained from the plant can be employed as a memory enhancer in Alzheimer’s related dementias; further to be evaluated clinically by formulating charantin.

BhbZIP60 from Resurrection Plant Boea hygrometrica Is an mRNA Splicing-Activated Endoplasmic Reticulum Stress Regulator Involved in Drought Tolerance.

Adverse environmental conditions cause endoplasmic reticulum (ER) stress in plants. To mitigate ER stress damage, ER associated transcription factors and inositol-requiring enzyme-1 (IRE1)-mediated bZIP60 mRNA splicing are activated in plants. A drought-induced gene, encoding the ortholog of AtbZIP60, was identified in the resurrection plant Boea hygrometrica, termed BhbZIP60. In response to ER stress and dehydration, BhbZIP60 mRNA can be spliced to create a frame shift in the C terminus by the excision of 23b segment in a manner of its ortholog in other plants, thus translocating to the nucleus instead of the cytoplasm. The splicing-activated BhbZIP60 (BhbZIP60S) could function in the same way as its Arabidopsis ortholog by restoring the molecular phenotype of the mutant atbzip60. When overexpressed in Arabidopsis, BhbZIP60S provided transgenic plants with enhanced tolerance to drought, tunicamycin and mannitol stresses with upregulation of the expressions of ER quality control (QC) genes (BiP2, BiP3, CNX1, and sPDI) and abscisic acid (ABA) responsive genes (RD29A, RAB18, and RD17). Furthermore, in the yeast one-hybrid system, BhbZIP60S was capable of interacting with ER stress responsive elements (ERSE and ERSE-II) that exist in the promoters of known ER-QC genes, but not binding to ABA responsive cis-elements (ABREs). Our results demonstrated that drought-induced BhbZIP60 may have a function in drought tolerance via the splicing-activated BhbZIP60S to mediate ER-QC by direct binding to the promoters of ER-QC genes. This study evidently demonstrates the involvement of ER-QC in the drought tolerance of Arabidopsis and the desiccation tolerance of the resurrection plant B. hygrometrica.

Neuropathology of sporadic Parkinson disease before the appearance of parkinsonism: preclinical Parkinson disease

Parkinson disease (PD) is no longer considered a complex motor disorder characterized by parkinsonism but rather a systemic disease with variegated non-motor deficits and neurological symptoms, including impaired olfaction, sleep disorders, gastrointestinal and urinary abnormalities and cardiovascular dysfunction, in addition to other symptoms and signs such as pain, depression and mood disorders. Many of these alterations appear before or in parallel with motor deficits and then worsen with disease progression. Although there is a close relation between motor symptoms and the presence of Lewy bodies (LBs) and neurites filled with abnormal α-synuclein, other neurological alterations are independent of LBs, thereby indicating that different mechanisms probably converge in the degenerative process. This review presents cardinal observations at very early stages of PD and provides personal experience based on the study of a consecutive series of brains with PD-related pathology and without parkinsonism, mainly cases categorized as stages 2-3 of Braak. Alterations in the substantia nigra, striatum and frontal cortex in pPD are here revised in detail. Early modifications in the substantia nigra at pre-motor stages of PD (preclinical PD: pPD) include abnormal small aggregates of α-synuclein which is phosphorylated, nitrated and oxidized, and which exhibits abnormal solubility and truncation. This occurs in association with a plethora of altered molecular events including increased oxidative stress, altered oxidative stress responses, altered balance of L-ferritin and H-ferritin, reduced expression of neuronal globin α and β chains in neurons with α-synuclein deposits, increased expression of endoplasmic reticulum stress markers, increased p62 and ubiquitin immunoreactivity in relation to α-synuclein deposits, and altered distribution of LC3 and other autophagosome/lysosome markers. In spite of the relatively small decrease in the number of dopaminergic neurons in the substantia nigra, which does not reach thresholds causative of parkinsonism, levels of tyrosine hydroxylase and cannabinoid 1 receptor are reduced, whereas levels of adenosine receptor 2A are increased in the caudate in pPD. Moreover, biochemical alterations are also present in the cerebral cortex (at least in the frontal cortex) in pPD including increased oxidative stress and oxidative damage to proteins α-synuclein, β-synuclein, superoxide dismutase 2, aldolase A, enolase 1, and glyceraldehyde dehydrogenase, among others, indicating post-translational modifications of PD-related proteins, and suggesting altered function of pathways involved in glycolysis and energy metabolism in the cerebral cortex in pPD. Current evidence suggests convergence of several altered metabolic pathways leading to chronic neuronal dysfunction, mainly manifested as sub-optimal energy metabolism, altered synaptic function, oxidative and endoplasmic reticulum stress damage and corresponding altered responses, among others. By understanding that these alterations occur at very early stages of PD and that neuronal fatigue and exhaustion may precede, for years, cell death and neuronal loss, we may direct therapeutic strategies towards the prevention and delay of disease progression starting at pre-parkinsonian stages of PD.