Downregulation of Glutathione-Mediated Detoxification Capacity by Binge Drinking Aggravates Acetaminophen-Induced Liver Injury through IRE1α ER Stress Signaling

Overdose of acetaminophen (APAP) can cause severe liver injury. Although alcohol is considered a risk factor for APAP toxicity, the mechanism underlying the interaction between alcohol and APAP remains unclear. Binge alcohol (5 g/kg every 12 h, 3 doses) reduced the concentration of cysteine and glutathione (GSH) and decreased expression of cystathionine β-synthase (CβS), cystathionine γ-lyase (CγL), and glutamate cysteine ligase catalytic subunit (GCLC) in the livers of male C57BL/6 mice. Furthermore, the levels of GSH S-transferase (GST) and GSH peroxidase (GPx) were decreased. To evaluate the effect of binge drinking on APAP-induced liver injury, 300 mg APAP was administered following alcohol binges. APAP in the binge group significantly amplified the serum ALT more than two fold and enhanced the pro-apoptotic proteins with a severe centrilobular necrosis compared to APAP alone. APAP treatment after alcohol binges caused lower levels of hepatic cysteine and GSH than APAP alone over 24 h, indicating that alcohol binges reduced GSH regenerating potential. Exposure to APAP after binge treatment significantly increased oxidative stress (lipid peroxidation) and endoplasmic reticulum (ER) stress (Grp78 and ATF6) markers at 6 h after treatment. Notably, the IRE1α/ASK1/MKK4/JNK pathway was activated, whereas CHOP expression was reduced by APAP administration in mice with pre-exposed alcohol binges compared with APAP alone. Thus, pretreatment with binge alcohol decreases GSH-mediated antioxidant capacity and contributes to augmentation of liver injury caused by subsequent APAP administration through differential ER stress signaling pathway.

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The role of oxidative/nitrosative stress in pathogenesis of paracetamol-induced toxic hepatitis

Medicinski pregled ◽

10.2298/mpns1012827r ◽

2010 ◽

Vol 63 (11-12) ◽

pp. 827-832 ◽

Cited By ~ 7

Author(s):

Tatjana Radosavljevic ◽

Dusan Mladenovic ◽

Danijela Vucevic ◽

Rada Jesic-Vukicevic

Keyword(s):

Oxidative Stress ◽

Nitric Oxide ◽

Reactive Oxygen Species ◽

Liver Injury ◽

Kupffer Cells ◽

Reactive Oxygen ◽

Oxygen Species ◽

Severe Liver ◽

Hepatocellular Necrosis

Introduction. Paracetamol is an effective analgesic/antipyretic drug when used at therapeutic doses. However, the overdose of paracetamol can cause severe liver injury and liver necrosis. The mechanism of paracetamol-induced liver injury is still not completely understood. Reactive metabolite formation, depletion of glutathione and alkylation of proteins are the triggers of inhibition of mitochondrial respiration, adenosine triphosphate depletion and mitochondrial oxidant stress leading to hepatocellular necrosis. Role of oxidative stress in paracetamol-induced liver injury. The importance of oxidative stress in paracetamol hepatotoxicity is controversial. Paracetamol induced liver injury cause the formation of reactive oxygen species. The potent sources of reactive oxygen are mitochondria, neutrophils, Kupffer cells and the enzyme xatnine oxidase. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. Role of mitochondria in paracetamol-induced oxidative stress. The production of mitochondrial reactive oxygen species is increased, and the glutathione content is decreased in paracetamol overdose. Oxidative stress in mitochondria leads to mito?chondrial dysfunction with adenosine triphosphate depletion, increase mitochondrial permeability transition, deoxyribonu?cleic acid fragmentation which contribute to the development of hepatocellular necrosis in the liver after paracetamol overdose. Role of Kupffer cells in paracetamol-induced liver injury. Paracetamol activates Kupffer cells, which then release numerous cytokines and signalling molecules, including nitric oxide and superoxide. Kupffer cells are important in peroxynitrite formation. On the other hand, the activated Kupffer cells release anti-inflammatory cytokines. Role of neutrophils in paracetamol-induced liver injury. Paracetamol-induced liver injury leads to the accumulation of neutrophils, which release lysosomal enzymes and generate superoxide anion radicals through the enzyme nicotinamide adenine dinucleotide phosphate oxidase. Hydrogen peroxide, which is influenced by the neutrophil-derived enzyme myeloperoxidase, generates hypochlorus acid as a potent oxidant. Role of peroxynitrite in paracetamol-induced oxidative stress. Superoxide can react with nitric oxide to form peroxynitrite, as a potent oxidant. Nitrotyrosine is formed by the reaction of tyrosine with peroxynitrite in paracetamol hepatotoxicity. Conclusion. Overdose of paracetamol may produce severe liver injury with hepatocellular necrosis. The most important mechanisms of cell injury are metabolic activation of paracetamol, glutathione depletion, alkylation of proteins, especially mitochondrial proteins, and formation of reactive oxygen/nitrogen species.

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ATF6 Decreases Myocardial Ischemia/Reperfusion Damage and Links ER Stress and Oxidative Stress Signaling Pathways in the Heart

Circulation Research ◽

10.1161/circresaha.116.310266 ◽

2017 ◽

Vol 120 (5) ◽

pp. 862-875 ◽

Cited By ~ 90

Author(s):

Jung-Kang Jin ◽

Erik A. Blackwood ◽

Khalid Azizi ◽

Donna J. Thuerauf ◽

Asal G. Fahem ◽

...

Keyword(s):

Oxidative Stress ◽

Myocardial Ischemia ◽

Er Stress ◽

Signaling Pathways ◽

Ischemia Reperfusion ◽

Stress Signaling ◽

Reperfusion Damage ◽

Myocardial Ischemia Reperfusion ◽

And Oxidative Stress

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Ginseng (Panax ginseng Meyer) Oligopeptides Protect Against Binge Drinking-Induced Liver Damage through Inhibiting Oxidative Stress and Inflammation in Rats

Nutrients ◽

10.3390/nu10111665 ◽

2018 ◽

Vol 10 (11) ◽

pp. 1665 ◽

Cited By ~ 12

Author(s):

Rui Liu ◽

Qi-He Chen ◽

Jin-Wei Ren ◽

Bin Sun ◽

Xia-Xia Cai ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Liver Injury ◽

Binge Drinking ◽

Nuclear Factor Κb ◽

Nuclear Factor ◽

Oxidative Stress Markers ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Stress Markers

Panax ginseng C.A. Meyer (ginseng) is an edible and traditional medicinal herb, which is reported to have a wide range of biological activity and pharmaceutical properties. There were more studies on ginsenoside and polysaccharides, but fewer on ginseng oligopeptides (GOPs), which are small molecule oligopeptides extracted from ginseng. The present study was designed to investigate the effects and underlying mechanism of ginseng oligopeptide (GOPs) on binge drinking-induced alcohol damage in rats. Sprague Dawley rats were randomly assigned to six groups (n = 10), rats in normal control group and alcohol model group was administered distilled water; rats in four GOPs intervention groups (at a dose of 0.0625, 0.125, 0.25, 0.5 g/kg of body weight, respectively) were administered GOPs once a day for 30 days. Experiment rats were intragastrically administered ethanol at a one-time dose of 7 g/kg of body weight after 30 days. The liver injury was measured through traditional liver enzymes, inflammatory cytokines, expression of oxidative stress markers, and histopathological examination. We found that the GOPs treatment could significantly improve serum alanine aminotransferase and aspartate aminotransferase, plasma lipopolysaccharide, and inflammatory cytokine levels, as well as the oxidative stress markers that were altered by alcohol. Moreover, GOPs treatment inhibited the protein expression of toll-like receptor 4, and repressed the inhibitor kappa Bα and nuclear factor-κB p65 in the liver. These findings suggested that GOPs have a significant protective effect on binge drinking-induced liver injury, and the mechanism possibly mediated by the partial inhibition of lipopolysaccharide—toll-like receptor 4-nuclear factor-κB p65 signaling in the liver.

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The Protective Effect of Hispidin against Hydrogen Peroxide-Induced Oxidative Stress in ARPE-19 Cells via Nrf2 Signaling Pathway

Biomolecules ◽

10.3390/biom9080380 ◽

2019 ◽

Vol 9 (8) ◽

pp. 380 ◽

Cited By ~ 4

Author(s):

Huang ◽

Chang ◽

Chau ◽

Chiu

Keyword(s):

Oxidative Stress ◽

Hydrogen Peroxide ◽

Protective Effect ◽

Retinal Pigment ◽

Heme Oxygenase 1 ◽

Related Factor ◽

Dependent Manner ◽

Glutamate Cysteine Ligase ◽

Jnk Pathway ◽

Nrf2 Signaling Pathway

Hispidin, a polyphenol compound isolated from Phellinus linteus, has been reported to possess antioxidant activities. In this study, we aimed to investigate the mechanisms underlying the protective effect of hispidin against hydrogen peroxide (H2O2)-induced oxidative stress on Adult Retinal Pigment Epithelial cell line-19 (ARPE-19) cells. Hispidin was not cytotoxic to ARPE-19 cells at concentrations of less than 50 μM. The levels of intracellular reactive oxygen species (ROS) were analyzed by dichlorofluorescin diacetate (DCFDA) staining. Hispidin significantly restored H2O2-induced cell death and reduced the levels of intracellular ROS. The expression levels of antioxidant enzymes, such as NAD(P)H:Quinine oxidoreductase-1 (NQO-1), heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutamate-cysteine ligase modiﬁer subunit (GCLM) were examined using real-time PCR and Western blotting. Our results showed that hispidin markedly enhanced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), HO-1, NQO-1, GCLM, and GCLC in a dose-dependent manner. Furthermore, knockdown experiments revealed that transfection with Nrf2 siRNA successfully suppresses the hispidin activated Nrf2 signaling in ARPE-19 cells. Moreover, activation of the c-Jun N-terminal kinase (JNK) pathway is involved in mediating the protective effects of hispidin on the ARPE-19 cells. Thus, the present study demonstrated that hispidin provides protection against H2O2-induced damage in ARPE-19 cells via activation of Nrf2 signaling and up-regulation of its downstream targets, including Phase II enzymes, which might be associated with the activation of the JNK pathway.

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Oxyresveratrol Induces Autophagy via the ER Stress Signaling Pathway, and Oxyresveratrol-Induced Autophagy Stimulates MUC2 Synthesis in Human Goblet Cells

Antioxidants ◽

10.3390/antiox9030214 ◽

2020 ◽

Vol 9 (3) ◽

pp. 214

Author(s):

Jiah Yeom ◽

Seongho Ma ◽

Young-Hee Lim

Keyword(s):

Er Stress ◽

Signaling Pathway ◽

Expression Profiles ◽

Peptide Mass Fingerprinting ◽

Goblet Cells ◽

Stress Signaling ◽

Cell Protection ◽

Peptide Mass ◽

Muc2 Expression ◽

Stress Signaling Pathway

Background: Autophagy is a cell protection system invoked to eliminate the damaged organelles and misfolded proteins that induce various stresses, including endoplasmic reticulum (ER) stress. Autophagy can control mucin secretion in goblet cells. Oxyresveratrol (OXY), an antioxidant, stimulates expression of MUC2. Thus, we investigated the effect of OXY on autophagy and found that OXY-induced autophagy stimulates MUC2 expression in human intestinal goblet cells. Methods: Autophagy-related genes and proteins were examined by quantitative real-time PCR (qPCR) and Western blotting, respectively. Autophagy was assessed by immunocytochemistry (ICC). To analyze the protein expression profiles of OXY-treated LS 174T goblet cells, two-dimensional electrophoresis (2DE) and peptide mass fingerprinting (PMF) were performed. MUC2 expression in cells was evaluated by ICC. Results: OXY significantly increased the expression levels of genes related to autophagy induction, and activated phagosome elongation resulted in the formation of autophagosomes. OXY also activated the ER stress signaling pathway and promoted MUC2 synthesis, which was inhibited by treatment with an autophagy inhibitor. Conclusion: OXY induces autophagy via the ER stress signaling pathway, and OXY-induced autophagy increases MUC2 production in intestinal goblet cells.

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PKR-dependent CHOP induction limits hyperoxia-induced lung injury

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00166.2010 ◽

2011 ◽

Vol 300 (3) ◽

pp. L422-L429 ◽

Cited By ~ 33

Author(s):

Tricia I. Lozon ◽

Alison J. Eastman ◽

Gustavo Matute-Bello ◽

Peter Chen ◽

Teal S. Hallstrand ◽

...

Keyword(s):

Oxidative Stress ◽

Lung Injury ◽

Er Stress ◽

Initiation Factor ◽

Mouse Lung ◽

Epithelial Cell Line ◽

Lung Edema ◽

Α Subunit ◽

Chop Expression

Supplemental O2is commonly employed in patients with respiratory failure; however, hyperoxia is also a potential contributor to lung injury. In animal models, hyperoxia causes oxidative stress in the lungs, resulting in increased inflammation, edema, and permeability. We hypothesized that oxidative stress from prolonged hyperoxia leads to endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) and induction of CCAAT enhancer-binding protein homologous protein (CHOP), a transcription factor associated with cell death in the setting of persistent ER stress. To test this hypothesis, we exposed the mouse lung epithelial cell line MLE-12 to 95% O2for 8–24 h and evaluated for evidence of UPR induction and CHOP induction. Hyperoxia caused increased CHOP expression without other evidence of UPR activation. Because CHOP expression is preceded by phosphorylation of the α-subunit of the eukaryotic initiation factor-2 (eIF2α), we evaluated the role of double-stranded RNA-activated protein kinase (PKR), a non-UPR-associated eIF2α kinase. Hyperoxia caused PKR phosphorylation, and RNA interference knockdown of PKR attenuated hyperoxia-induced CHOP expression. In vivo, hyperoxia induced PKR phosphorylation and CHOP expression in the lungs without other biochemical evidence for ER stress. Additionally, Ddit3−/−(CHOP-null) mice had increased lung edema and permeability, indicating a previously unknown protective role for CHOP after prolonged hyperoxia. We conclude that hyperoxia increases CHOP expression via an ER stress-independent, PKR-dependent pathway and that increased CHOP expression protects against hyperoxia-induced lung injury.

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Oxidative Stress Signaling Pathway of Heme Regulated eIF2α Kinase in mitigating the Severity of β-Thalassemia

Blood ◽

10.1182/blood.v112.11.127.127 ◽

2008 ◽

Vol 112 (11) ◽

pp. 127-127 ◽

Cited By ~ 3

Author(s):

Rajasekhar NVS Suragani ◽

Sijin Liu ◽

Wanting Zhao ◽

Jane-Jane Chen

Keyword(s):

Oxidative Stress ◽

Protein Synthesis ◽

Stress Response ◽

Signaling Pathway ◽

Fetal Liver ◽

Stress Signaling ◽

Erythroid Precursors ◽

Inhibition Of Protein Synthesis ◽

And Oxidative Stress ◽

Stress Signaling Pathway

Abstract Maturation of erythroid precursors requires active synthesis of hemoglobin which consists of two pairs of α- and β-globin subunits with each monomer bound to a heme moiety. Heme Regulated Inhibitor (HRI) is the only eIF2αkinase responsible for the balanced synthesis of heme and globin at translational level in erythroid cells. Activation of HRI in heme deficiency leads to phosphorylation of the α-subunit of eukaryotic initiation factor (eIF2α) and inhibition of protein synthesis. HRI is also activated by denatured proteins and oxidative stress. In addition to general inhibition of protein synthesis, phosphorylation of eIF2α (eIF2αP) also leads to the induction of a stress signaling pathway. Activating transcription factor 4 (Atf4) mRNA is preferentially translated amidst global inhibition of protein synthesis. Atf4 activates transcription of stress response proteins, Chop (CCAAT/enhancer binding protein homologous protein-10) and the non-enzymatic cofactor of eIF2α phosphatase (PP1A) Gadd34. These stress response proteins help cells in mitigating the stress. While the role of HRI in translational regulation of non-nucleated reticulocytes is well established, the HRIdependent Atf4 stress signaling pathway of nucleated erythroid precursors is unknown. Sodium arsenite toxicity was used as a model system of oxidative stress to elucidate the HRI signaling pathway in Hri +/+ and −/− E14.5 mouse fetal liver erythroid precursors. In HRI deficiency, erythroid precursors were more sensitive to arsenite toxicity with decreased cell viability and increased apoptosis, by caspase 3 executed intrinsic apoptotic pathway. HRI was activated by autophosphorylation as early as 15 minutes following arsenite treatment. In addition to increased eIF2αP, there was induction of Atf4, Chop and Gadd34 in Hri+/+ fetal liver cells. Importantly, in Hri−/− cells neither the phosphorylation of eIF2α nor the expression of Atf4, Chop and Gadd34 was increased upon arsenite treatment. In addition, we also observed HRI dependent induction of Heme Oxygenase 1 (HO-1) that plays a pivotal role in adaptation to oxidative stress. These results demonstrate that HRI induces a signaling pathway for adaptive gene expression to protect the nucleated erythroid precursors from apoptosis upon oxidative stress. Iron overload, accumulation of unpaired α-globin and oxidative stress are well documented in β-thalassemia. Recently, HRI was discovered to be necessary for the survival of β-thalassemic mice. β-thalassemic mice lacking one copy of HRI (Hri+/− Hbb−/−) also manifest a more severe syndrome of the disease. We have investigated the activation of eIF2αP/Atf4 signaling pathway in Hri+/−Hbb−/− β-thalassemic erythroid cells using eIF2αP phosphatase (Gadd34) inhibitor salubrinal. Treatment of reticulocytes from Hri+/−Hbb−/− mice with salubrinal increased eIF2αP and resulted in inhibition of newly synthesized globin protein synthesis. The decreased globin protein synthesis also resulted in decreased aggregation of the unpaired α-globins. Furthermore, treatment of salubrinal in nucleated fetal liver erythroblasts also increased Chop expression and decreased apoptosis. Thus, activation of the eIF2αP/Atf4 pathway by small chemicals might be a novel pharmaceutical approach to decrease proteotoxicity and apoptosis for the treatment of β-thalassemia.

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