Glutathione (GSH) is the most abundant cellular tripeptide (L-γglutamate-L-cysteinyl-glycine) which is as critical as oxygen and water. This low molecular mass antioxidant has a very high intracellular concentration that ranges from 1-10 mM and reaches extreme concentration points in malignant cell types. This defender of the cell is compartmentalized in mitochondria, nucleus, peroxisomes, endoplasmic reticulum (ER), and cytosol where it is synthesized. The enzymes involved in GSH redox cycling are important for both cellular free radical and nonradical detoxification. The present review article is covering the crucial roles of GSH to combat oxidative/nitrosative stress related to different diseases/disorders and possible drug designing for new therapies.
The sensing of double-stranded RNA (dsRNA) in the liver is important for antiviral defenses but can also contribute to sterile inflammation during liver injury. Hepatocytes are often the target of viral infection and are easily injured by inflammatory insults. Here we sought to establish the pathways involved in the production of type I interferons (IFN-I) in response to extracellular poly(I:C), a dsRNA mimetic, in hepatocytes. This was of interest because hepatocytes are long-lived and, unlike most immune cells that readily die after activation with dsRNA, are not viewed as cells with robust antimicrobial capacity. We found that poly(I:C) leads to rapid up-regulation of inducible nitric oxide synthase (iNOS), double-stranded RNA-dependent protein kinase (PKR), and Src. The production of IFN-β was dependent on iNOS, PKR, and Src and partially dependent on TLR3/Trif. iNOS and Src up-regulation was partially dependent on TLR3/Trif but entirely dependent on PKR. The phosphorylation of TLR3 on tyrosine 759 was shown to increase in parallel to IFN-β production in an iNOS- and Src-dependent manner, and Src was found to directly interact with TLR3 in the endosomal compartment of poly(I:C)-treated cells. Furthermore, we identified a robust NO/cGMP/PKG-dependent feedforward pathway for the amplification of iNOS expression. These data identify iNOS/NO as an integral component of IFN-β production in response to dsRNA in hepatocytes in a pathway that involves the coordinated activities of TLR3/Trif and PKR.
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