Apoptosis triggered by phagocytosis-related oxidative stress through FLIPSdown-regulation and JNK activation

2007 ◽  
Vol 82 (5) ◽  
pp. 1344-1352 ◽  
Author(s):  
Atsuhiro Kanayama ◽  
Yusei Miyamoto
Keyword(s):  
Oxidative Stress ◽  
Jnk Activation

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

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.

scholarly journals JNK Activation of BIM Promotes Hepatic Oxidative Stress, Steatosis, and Insulin Resistance in Obesity

Diabetes ◽  
2017 ◽  
Vol 66 (12) ◽  
pp. 2973-2986 ◽  
Author(s):  
Sara A. Litwak ◽  
Lokman Pang ◽  
Sandra Galic ◽  
Mariana Igoillo-Esteve ◽  
William J. Stanley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Hepatic Oxidative Stress ◽  
Jnk Activation

P2-065: TIME COURSE STUDY OF JNK ACTIVATION IN RESPONSE TO H2O2 INDUCED OXIDATIVE STRESS

2014 ◽  
Vol 10 ◽  
pp. P493-P493
Author(s):  
Maryam Moosavi ◽  
Rasoul Ghasemi ◽  
Asadollah Zarifkar ◽  
Karim Rastegar ◽  
Nader Maghsoudi
Keyword(s):  
Oxidative Stress ◽  
Time Course ◽  
Time Course Study ◽  
Jnk Activation

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

Abstract 1271: IKKβ/NF-κB Pathway Protects Hearts from Hemodynamic Stress Mediated through Regulating MnSOD Expression

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Shungo Hikoso ◽  
Kinya Otsu ◽  
Osamu Yamaguchi ◽  
Toshihiro Takeda ◽  
Masayuki Taniike ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Cardiac Remodeling ◽  
Weight Ratio ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Negative Regulator ◽  
Iκb Kinase ◽  
Jnk Activation

Objectives: We have previously reported that NF-κB contributes to GPCR agonist-induced hypertrophy in cultured cardiomyocytes. However, the in vivo role of this pathway in the pathogenesis of cardiac remodeling remains to be elucidated. Although IκB kinase β (IKKβ)/NF-κB pathway is a major negative regulator of cell death, it can sensitize cells to death-inducing stimuli in some instances, thus it can be either anti- or pro-apoptotic. In this study, we aimed to clarify the role of IKKβ/NF-κB signaling in cardiac remodeling using cardiac-specific IKKβ deficient mice. Methods and Results: We crossed mice bearing an IKK β flox allele with mice expressing the Cre recombinase under the control of the myosin light chain 2v promoter ( MLC2v-Cre +/− ) to generate IKK β flox/flox ; MLC2v-Cre +/− mice (conditional knockout:CKO). Then, CKO mice (n=14) and control littermates bearing IKK β flox/flox (CTRL, n=14) were subjected to pressure overload by means of transverse aortic constriction (TAC). EMSA analysis revealed NF-κB DNA binding activity after TAC had attenuated in CKO hearts. One week after TAC, echocardiography showed significantly lower left ventricular fractional shortening (26.9±2.7% vs. 41.4±0.9%, p<0.01), and higher left ventricular end-diastolic dimension (4.02±0.14 mm vs. 3.47±0.08 mm, p<0.01) and lung weight/body weight ratio (11.1±1.4 vs. 5.5±0.1, p<0.01) in CKO mice compared with CTRL mice, indicating the development of heart failure in CKO mice. Number of apoptotic cells had increased in CKO hearts after TAC, suggesting that the enhanced apoptosis is a cause for heart failure. The expression levels of MnSOD mRNA and protein after TAC, which is one of NF-κB target genes, were significantly lower in CKO than those in CTRL mice. As a consequence, oxidative stress and JNK activation in CKO hearts after TAC had significantly increased compared with those in CTRL heart, suggesting that increased oxidative stress and enhanced JNK activity resulted in cardiomyocyte apoptosis in CKO hearts. Conclusion: These results show that IKKβ/NF-κB pathway in cardiomyocyte plays a protective role mediated through attenuation of oxidative stress and JNK activation in response to pressure overload.

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