Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04179 (MnSOD)
 2,777 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proinflammatory cytokines (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha], and gamma-interferon [IFN-gamma]) initiate a variety of signal cascades in pancreatic beta-cells that affect the expression level of genes involved in both the destruction and the protection of the beta-cell. The generation of nitric oxide (NO) via the inducible NO synthase (iNOS) and oxygen free radicals play a key role in cytokine-mediated beta-cell destruction. Within these signal cascades, the activation of the transcription factor nuclear factor-kappaB (NF-kappaB) is crucial, and many cytokine-sensitive genes contain binding sites for this transcription factor in their promoter regions. The aim of this study was to characterize the cytokine-mediated activation of NF-kappaB and the subsequent expression of iNOS protein in insulin-producing RINm5F cells with an improved antioxidant defense status by overexpression of the cytoprotective enzymes catalase (Cat), glutathione peroxidase (Gpx), and the cytoplasmic Cu/Zn superoxide dismutase (Cu/ZnSOD). RINm5F cells with diverse mitochondrial antioxidative defense status were generated by stable overexpression of MnSOD constructs in sense (MnSOD sense) and antisense orientation (MnSOD antisense). Cytokine-induced (IL-1beta or cytokine mix consisting of IL-1beta + TNF-alpha + IFN-gamma) activation of NF-kappaB in RINm5F cells was reduced by >80% through overexpression of MnSOD. The activity of the iNOS promoter remained at basal levels in cytokine-stimulated MnSOD sense cells. In contrast, the suppression of MnSOD gene expression in cytokine-stimulated MnSOD antisense cells resulted in a threefold higher activation of NF-kappaB and a twofold higher activation of the iNOS promoter as compared with control cells. The iNOS protein expression was significantly reduced after a 6- and 8-h cytokine incubation of MnSOD sense cells. The low activity level of MnSOD in RINm5F MnSOD antisense cells increased the iNOS protein expression in particular during the early phase of cytokine-mediated toxicity. Cat, Gpx, and the cytoplasmic Cu/ZnSOD did not affect the activation of NF-kappaB and the iNOS promoter. In conclusion, the overexpression of MnSOD, which inactivates specifically mitochondrially derived oxygen free radicals, significantly reduced the activation of NF-kappaB in insulin-producing cells. As a consequence of this protective effect in the early cytokine signaling pathways, the induction of iNOS, an important event in the beta-cell destruction process, was also significantly reduced. The results provide evidence that mitochondrially derived reactive oxygen species (ROS) play a critical role in the activation of the cytokine-sensitive transcription factor NF-kappaB. Overexpression of MnSOD may thus be beneficial for beta-cell survival through suppression of oxygen free radical formation, prevention of NF-kappaB activation, and iNOS expression.
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PMID:Improvement of the mitochondrial antioxidant defense status prevents cytokine-induced nuclear factor-kappaB activation in insulin-producing cells. 1250 98

There are numerous studies to indicate that irradiation induces reactive oxygen species (ROS), which play an important causative role in radiation damage of the cell. We evaluated the effects of ginsan, a polysaccharide fraction extracted from Panax ginseng, on the gamma-radiation induced alterations of some antioxidant systems in the spleen of Balb/c mice. On the 5th day after sublethal whole-body irradiation, homogenized spleen tissues of the irradiated mice expressed only marginally increased mRNA levels of Mn-SOD (superoxide dimutase) in contrast to Cu/Zn-SOD, however, catalase mRNA was decreased by approximately 50% of the control. In vivo treatment of non-irradiated mice with ginsan (100 mg kg(-1), intraperitoneal administration) had no significant effect, except for glutathione peroxidase (GPx) mRNA, which increased to 144% from the control. However, the combination of irradiation with ginsan effectively increased the SODs and GPx transcription as well as their protein expressions and enzyme activities. In addition, the expression of heme oxygenase-1 and non-protein thiol induced by irradiation was normalized by the treatment of ginsan. Evidence indicated that transforming growth factor-beta and other important cytokines such as IL-1, TNF and IFN-gamma might be involved in evoking the antioxidant enzymes. Therefore, we propose that the modulation of antioxidant enzymes by ginsan was partly responsible for protecting the animal from radiation, and could be applied as a therapeutic remedy for various ROS-related diseases.
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PMID:Modulation of radiation-induced disturbances of antioxidant defense systems by ginsan. 1632 11