Thiol regulation of pro-inflammatory cytokines and innate immunity: protein S-thiolation as a novel molecular mechanism.
ABSTRACT Inflammation or inflammatory cytokines and oxidative stress have often been associated, and thiol antioxidants, particularly glutathione, have often been seen as possible anti-inflammatory mediators. However, whereas several cytokine inhibitors have been approved for drug use in chronic inflammatory diseases, this has not happened with antioxidant molecules. We outline the complexity of the role of protein thiol-disulfide oxidoreduction in the regulation of immunity and inflammation, the underlying molecular mechanisms (such as protein glutathionylation) and the key enzyme players such as Trx (thioredoxin) or Grx (glutaredoxin).
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ABSTRACT: Significance: Glutaredoxins are small oxidoreductases of the thioredoxin family of proteins regulating the thiol redox state of several proteins. Thereby, glutaredoxins are key elements in redox signaling. Recent Advances: Redox signaling via protein thiols depends on reversible oxidative modifications induced mainly by reactive oxygen/nitrogen species and glutathione in form of its oxidized disulfide or S-nitroso-glutathione. Glutaredoxins contribute to redox signaling by the catalysis of glutathionylation, de-glutathionylation, as well as reduction of disulfide bridges via two distinct enzymatic mechanisms. The dithiol mechanism utilizes both active site cysteines to reduce disulfides, whereas the monothiol mechanism utilizes only the N-terminal active site cysteine for the reduction of glutathione mixed disulfides. The sphere of action of glutaredoxins continues to grow with the recent identification of novel targets. Critical issues: Because of limited methodological tools the identification of new substrates for oxidoreductases in general is one of the biggest challenges in this research area. Future directions: With this review we provide a condensed summary of the current knowledge of thiol/disulfide exchange reactions catalyzed by glutaredoxins regarding mechanistic, structural, and functional aspects. The latter will be of high importance for future research directions, gaining novel insights into redox signaling in general and the role of glutaredoxins in particular.Antioxidants and Redox Signaling 12/2012; · 8.46 Impact Factor
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ABSTRACT: Cystic fibrosis is a lethal autosomal recessive condition caused by a defect of the transmembrane conductance regulator gene that has a key role in cell homeostasis. A dysfunctional cystic fibrosis transmembrane conductance regulator impairs the efflux of cell anions such as chloride and bicarbonate, and also that of other solutes such as reduced glutathione. This defect produces an increased viscosity of secretions together with other metabolic defects of epithelia that ultimately promote the obstruction and fibrosis of organs. Recurrent pulmonary infections and respiratory dysfunction are main clinical consequences of these pathogenetic events, followed by pancreatic and liver insufficiency, diabetes, protein-energy malnutrition, etc. This complex comorbidity is associated with the extensive injury of different biomolecular targets by reactive oxygen species, which is the biochemical hallmark of oxidative stress. These biological lesions are particularly pronounced in the lung, in which the extent of oxidative markers parallels that of inflammatory markers between chronic events and acute exacerbations along the progression of the disease. Herein, an abnormal flux of reactive oxygen species is present by the sustained activation of neutrophils and other cystic fibrosis-derived defects in the homeostatic processes of pulmonary epithelia and lining fluids. A sub-optimal antioxidant protection is believed to represent a main contributor to oxidative stress and to the poor control of immuno-inflammatory pathways in these patients. Observed defects include an impaired reduced glutathione metabolism and lowered intake and absorption of fat-soluble antioxidants (vitamin E, carotenoids, coenzyme Q-10, some polyunsaturated fatty acids, etc.) and oligoelements (such as Se, Cu and Zn) that are involved in reactive oxygen species detoxification by means of enzymatic defenses. Oral supplements and aerosolized formulations of thiols have been used in the antioxidant therapy of this inherited disease with the main aim of reducing the extent of oxidative lesions and the rate of lung deterioration. Despite positive effects on laboratory end points, poor evidence was obtained on the side of clinical outcome so far. These aspects examined in this critical review of the literature clearly suggest that further and more rigorous trials are needed together with new generations of pharmacological tools to a more effective antioxidant and anti-inflammatory therapy of cystic fibrosis patients. This article is part of a Special Issue entitled: Antioxidants and Antioxidant Treatment in Disease.Biochimica et Biophysica Acta 12/2011; 1822(5):690-713. · 4.66 Impact Factor