Enantioselective cytotoxicity of isocarbophos is mediated by oxidative stress-induced JNK activation in human hepatocytes

Toxicology ◽  
2010 ◽  
Vol 276 (2) ◽  
pp. 115-121 ◽  
Author(s):  
Huigang Liu ◽  
Jing Liu ◽  
Lihong Xu ◽  
Shanshan Zhou ◽  
Ling Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Hepatocytes ◽  
Jnk Activation

Continuous lipid treatment of primary human hepatocytes leads to an elevation of oxidative stress

2013 ◽  
Vol 51 (01) ◽  
Author(s):  
T Schulz ◽  
V Kegel ◽  
B Burkhardt ◽  
D Seehofer ◽  
M Glanemann ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Human Hepatocytes ◽  
Primary Human Hepatocytes

scholarly journals Alcohol-and-HIV-Induced Lysosomal Dysfunction Regulates Extracellular Vesicles Secretion in Vitro and in Liver-Humanized Mice

Biology ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 29
Author(s):  
Raghubendra Singh Dagur ◽  
Moses New-Aaron ◽  
Murali Ganesan ◽  
Weimin Wang ◽  
Svetlana Romanova ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Extracellular Vesicles ◽  
Treated Group ◽  
Human Hepatocytes ◽  
In Vivo Studies ◽  
People Living With Hiv ◽  
Humanized Mouse Model ◽  
And Function

Background: Alcohol abuse is common in people living with HIV-1 and dramaticallyenhances the severity of HIV-induced liver damage by inducing oxidative stress and lysosomaldysfunction in the liver cells. We hypothesize that the increased release of extracellular vesicles(EVs) in hepatocytes and liver humanized mouse model is linked to lysosome dysfunction. Methods:The study was performed on primary human hepatocytes and human hepatoma RLWXP-GFP (Huh7.5 cells stably transfected with CYP2E1 and XPack-GFP) cells and validated on ethanol-fed liverhumanizedfumarylacetoacetate hydrolase (Fah)-/-, Rag2-/-, common cytokine receptor gamma chainknockout (FRG-KO) mice. Cells and mice were infected with HIV-1ADA virus. Results: We observedan increase in the secretion of EVs associated with a decrease in lysosomal activity and expressionof lysosomal-associated membrane protein 1. Next-generation RNA sequencing of primary humanhepatocytes revealed 63 differentially expressed genes, with 13 downregulated and 50 upregulatedgenes in the alcohol–HIV-treated group. Upstream regulator analysis of differentially expressedgenes through Ingenuity Pathway Analysis identified transcriptional regulators affecting downstreamgenes associated with increased oxidative stress, lysosomal associated disease, and function andEVs biogenesis. Our in vitro findings were corroborated by in vivo studies on human hepatocytetransplantedhumanized mice, indicating that intensive EVs’ generation by human hepatocytes andtheir secretion to serum was associated with increased oxidative stress and reduction in lysosomalactivities triggered by HIV infection and ethanol diet. Conclusion: HIV-and-ethanol-metabolisminducedEVs release is tightly controlled by lysosome status in hepatocytes and participates in thedevelopment of double-insult-induced liver injury.

scholarly journals Maladaptive oxidative stress cascade drives type I interferon hyperactivity in TNF activated macrophages promoting necrosis in murine tuberculosis granulomas

2020 ◽  
Author(s):  
Eric Brownhill ◽  
Shivraj M. Yabaji ◽  
Vadim Zhernovkov ◽  
Oleksii S. Rukhlenko ◽  
Kerstin Seidel ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Iron Chelator ◽  
Pathogen Transmission ◽  
Type I ◽  
Macrophage Response ◽  
Intrinsic Mechanism ◽  
A Cell ◽  
Novel Therapeutic Strategies ◽  
Jnk Activation ◽  
Inflammatory Milieu

ABSTRACTTuberculosis remains a critical infectious disease world-wide. The development of novel therapeutic strategies requires greater understanding of host factors that contribute to disease susceptibility. A major unknown in TB pathogenesis is the mechanism of necrosis in TB granulomas that leads to the massive lung tissue damage and cavity formation necessary for the pathogen transmission. In humans, TB progression has been linked to hyperactivity of type I IFN (IFN-I) pathway, the primary cause of which remains elusive.We studied the mechanistic drivers of pulmonary TB progression using a unique model B6J.C3-Sst1C3HeB/Fej Krmn mice that develop human-like necrotic TB granulomas and IFN-I hyperactivity. We established that IFNβ super-induction occurred in the susceptible macrophages in response to continuous TNF stimulation in the context of a dysregulated antioxidant defense. We observed that unresolving oxidative stress amplified the induction of IFNβ through JNK activation and induced the Integrated Stress Response via PKR activation as a compensatory pathway. Subsequently, PKR amplifies IFNβ upregulation, forming a positive feedback loop, maintaining the hyperinflammatory state in susceptible macrophages and leading to mitochondrial dysfunction. Thus, within the inflammatory milieu, a cell-intrinsic mechanism of chronic regulatory dysfunction and unresolved stress gradually weakens the macrophage and ultimately promotes the necrotization of TB granulomas. The aberrant macrophage response to TNF can be prevented by an iron chelator and inhibitor of lipid peroxidation, ferrostatin-1. Moreover, ferrostatin treatment increased macrophage survival and boosted bacterial control in the TNF-stimulated macrophages infected with virulent Mtb. These findings identify targets for host-directed therapeutics to interrupt necrotization in TB granulomas.

scholarly journals Atg9 Interacts with dTRAF2/TRAF6 to Regulate Oxidative Stress-Induced JNK Activation and Autophagy Induction

2013 ◽  
Vol 27 (5) ◽  
pp. 489-503 ◽  
Author(s):  
Hong-Wen Tang ◽  
Hsiao-Man Liao ◽  
Wen-Hsin Peng ◽  
Hong-Ru Lin ◽  
Chun-Hong Chen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Autophagy Induction ◽  
Jnk Activation

Quercetin protects human hepatocytes from ethanol-derived oxidative stress by inducing heme oxygenase-1 via the MAPK/Nrf2 pathways

2007 ◽  
Vol 47 (2) ◽  
pp. 253-261 ◽  
Author(s):  
Ping Yao ◽  
Andreas Nussler ◽  
Liegang Liu ◽  
Liping Hao ◽  
Fangfang Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Human Hepatocytes ◽  
Heme Oxygenase 1

scholarly journals REDOX Reaction at ASK1-Cys250 Is Essential for Activation of JNK and Induction of Apoptosis

2009 ◽  
Vol 20 (16) ◽  
pp. 3628-3637 ◽  
Author(s):  
Philippe J. Nadeau ◽  
Steve J. Charette ◽  
Jacques Landry
Keyword(s):  
Oxidative Stress ◽  
Disulfide Bonds ◽  
Reductase Activity ◽  
The Other ◽  
Activation Loop ◽  
Cysteine Oxidation ◽  
Jnk Pathway ◽  
Induction Of Apoptosis ◽  
Thiol Reductase ◽  
Jnk Activation

ASK1 cysteine oxidation allows JNK activation upon oxidative stress. Trx1 negatively regulates this pathway by reducing the oxidized cysteines of ASK1. However, precisely how oxidized ASK1 is involved in JNK activation and how Trx1 regulates ASK1 oxidoreduction remains elusive. Here, we describe two different thiol reductase activities of Trx1 on ASK1. First, in H2O2-treated cells, Trx1 reduces the various disulfide bonds generated between cysteines of ASK1 by a rapid and transient action. Second, in untreated cells, Trx1 shows a more stable thiol reductase activity on cysteine 250 (Cys250) of ASK1. After H2O2 treatment, Trx1 dissociates from Cys250, which is not sufficient to activate the ASK1-JNK pathway. Indeed, in untreated cells, a Cys250 to alanine mutant of ASK1 (C250A), which cannot bind Trx1, does not constitutively activate JNK. On the other hand, in H2O2-treated cells, this mutant (C250A) fails to activate JNK and does not induce apoptosis, although it remains fully phosphorylated on Threonine 838 (Thr838) in its activation loop. Overall, our data show that Cys250 is essential for H2O2-dependent signaling downstream from ASK1 but at a step subsequent to the phosphorylation of ASK1 Thr838. They also clarify the thiol reductase function of Trx1 on ASK1 activity.

scholarly journals SchisandraLignan Extract Protects against Carbon Tetrachloride-Induced Liver Injury in Mice by Inhibiting Oxidative Stress and Regulating the NF-κB and JNK Signaling Pathways

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Qingshan Chen ◽  
Qi Zhan ◽  
Ying Li ◽  
Sen Sun ◽  
Liang Zhao ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Carbon Tetrachloride ◽  
Liver Injury ◽  
Signaling Pathways ◽  
Active Components ◽  
Traditional Chinese Herbal Medicine ◽  
Action Mechanisms ◽  
Antioxidative Stress ◽  
Jnk Activation ◽  
Different Doses

Schisandra chinensis(S. chinensis) is a traditional Chinese herbal medicine widely used for the treatment of liver disease, whose main active components are lignans. However, the action mechanisms of the lignans inS. chinensisremain unclear. This study aimed to investigate the protective effect and related molecular mechanism ofSchisandralignan extract (SLE) against carbon tetrachloride- (CCl4-) induced acute liver injury in mice. Different doses of SLE at 50, 100, and 200 mg/kg were administered daily by gavage for 5 days before CCl4treatment. The results showed that SLE significantly decreased the activities of serum ALT/AST and reduced liver pathologic changes induced by CCl4. Pretreatment with SLE not only decreased the content of MDA but increased SOD, GSH, and GSH-Px activities in the liver, suggesting that SLE attenuated CCl4-induced oxidative stress. The expression levels of inflammatory cytokines TNF-a, IL-1β, and IL-6 were decreased after oral administration of SLE, probably because lignans inhibited the NF-κB activity. Additionally, SLE also inhibited hepatocyte apoptosis by suppressing JNK activation and regulating Bcl-2/Bax signaling pathways. In conclusion, these results suggested that SLE prevented CCl4-induced liver injury through a combination of antioxidative stress, anti-inflammation, and antihepatocyte apoptosis and alleviated inflammation and apoptosis by regulating the NF-κB, JNK, and Bcl-2/Bax signaling pathways.

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