Inducible nitric oxide synthase: Good or bad?

Lind, Maggie; Hayes, Alan; Čaprnda, Martin; Petrovič, Daniel; Rodrigo, Luı́s; Kružliak, Peter; Zulli, Anthony

doi:10.1016/j.biopha.2017.06.036

Cited by 175 publications

(128 citation statements)

References 65 publications

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“…The inhibitory effects of TQ as a decrease in the iNOS expression of macrophages were confirmed for protection of neuroinflammation which occurred due to some pathophysiological conditions . Moreover, there are some studies showing the increased activity of iNOS as a protective mechanism due to the anti‐apoptotic properties of NO derived from iNOS . In molecular level, the MAPK pathway most likely contributes to iNOS gene expression, as parallel to our results .…”

Section: Discussionsupporting

confidence: 87%

Thymoquinone Can Improve Neuronal Survival and Promote Neurogenesis in Rat Hippocampal Neurons

Beker

Dalli

Elibol

2018

Molecular Nutrition Food Res

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Section: Discussionsupporting

confidence: 87%

Thymoquinone Can Improve Neuronal Survival and Promote Neurogenesis in Rat Hippocampal Neurons

Beker

Dalli

Elibol

2018

Molecular Nutrition Food Res

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“…NOS1 and NOS3 are constitutively expressed mainly in neurons and in endothelial cells, respectively, whereas NOS2 is mainly expressed in immune cells (Mungrue et al, 2003). The binding of calcium (Ca 2 + ) and calmodulin to nNOS and eNOS transiently activates them to produce nanomolar concentrations of NO, whereas iNOS expression is induced by inflammatory cytokines or by bacterial products, such as lipopolysaccharide (LPS), to produce micromolar concentrations of NO (Lind et al, 2017). Interestingly, in addition to cytosolic NOS, there is a mitochondrial variant of NOS that contributes to the regulation of NO-related mitochondrial activities (Ghafourifar and Richter, 1997).…”

Section: No Synthesis and Metabolismmentioning

confidence: 99%

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Keshet

Erez

2018

Disease Models &Amp; Mechanisms

106

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Nitric oxide (NO) is a signaling molecule that plays important roles in diverse biological processes and thus its dysregulation is involved in the pathogenesis of various disorders. In cancer, NO has broad and sometimes dichotomous roles; it is involved in cancer initiation and progression, but also restricts cancer proliferation and invasion, and contributes to the anti-tumor immune response. The importance of NO in a range of cellular processes is exemplified by its tight spatial and dosage control at multiple levels, including via its transcriptional, post-translational and metabolic regulation. In this Review, we focus on the regulation of NO via the synthesis and availability of its precursor, arginine, and discuss the implications of this metabolic regulation for cancer biology and therapy. Despite the established contribution of NO to cancer pathogenesis, the implementation of NO-related cancer therapeutics remains limited, likely due to the challenge of targeting and inducing its protective functions in a cell- and dosage-specific manner. A better understanding of how arginine regulates the production of NO in cancer might thus support the development of anti-cancer drugs that target this key metabolic pathway, and other metabolic pathways involved in NO production.

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“…In contrast to eNOS, iNOS is not expressed in healthy states but is expressed under inflammatory conditions 38 . Moreover, the expression of iNOS has been proposed to be associated with disease states in the cardiovascular and renal systems 37,39 . Our results showed that targeting calpain could be a therapeutic approach for suppressing iNOS expression and further decreasing renal injury.…”

Section: Discussionmentioning

confidence: 99%

Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

Liu

Zheng

et al. 2020

Exp Mol Med

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To explore the role of calpain and its signaling pathway in lipopolysaccharide (LPS)-induced acute kidney injury (AKI), animal models of endotoxemia were established by administration of LPS to mice with endothelial-specific Capn4 knockout (TEK/Capn4 −/− ), mice with calpastatin (an endogenous calpain inhibitor) overexpression (Tg-CAST) and mice with myeloid-specific Capn4 knockout (LYZ/Capn4 −/− ). Mouse pulmonary microvascular endothelial cells (PMECs) were used as a model of the microvascular endothelium and were stimulated with LPS. Renal function, renal inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) expression, cellular apoptosis, plasma and renal levels of NO and reactive oxygen species (ROS), and phosphorylation of mitogenactivated protein kinase (MAPK) family members (p38, ERK1/2, and JNK1/2) were examined. Moreover, a calpain inhibitor, calpastatin overexpression adenoviruses and MAPK inhibitors were used. Significant renal dysfunction was induced by LPS stimulation, and recovery was observed in TEK/Capn4 −/− and Tg-CAST mice but not in LYZ/ Capn4 −/− mice. Endothelial Capn4 knockout also abrogated the LPS-induced increases in renal iNOS expression, caspase-3 activity and apoptosis and plasma and renal NO and ROS levels but did not obviously affect renal eNOS expression. Moreover, LPS increased both calpain and caspase-3 activity, and only the expression of iNOS in PMECs was accompanied by increased phosphorylation of p38 and JNK. Inhibiting calpain activity or p38 phosphorylation alleviated the increased iNOS expression, NO/ROS production, and cellular apoptosis induced by LPS. These results suggest that endothelial calpain plays a protective role in LPS-induced AKI by inhibiting p38 phosphorylation, thus attenuating iNOS expression and further decreasing NO and ROS overproduction-induced endothelial apoptosis.

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Inducible nitric oxide synthase: Good or bad?

Cited by 175 publications

References 65 publications

Thymoquinone Can Improve Neuronal Survival and Promote Neurogenesis in Rat Hippocampal Neurons

Thymoquinone Can Improve Neuronal Survival and Promote Neurogenesis in Rat Hippocampal Neurons

Arginine and the metabolic regulation of nitric oxide synthesis in cancer

Protective role of endothelial calpain knockout in lipopolysaccharide-induced acute kidney injury via attenuation of the p38-iNOS pathway and NO/ROS production

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