Redox alterations in inflammatory diseases : diabetes, kidney failure and cancer

Sammanfattning: In order to combat oxidative stress and maintain the intracellular redox homeostasis, cells are equipped with antioxidant systems. The thioredoxin and glutaredoxin systems are the major thiol reducing systems and central antioxidant systems in mammalian cells. The fundamental functions of thioredoxins include redox regulation, transcription factor activation and regulation of intra and extracellular signaling. Glutaredoxins are crucial for catalyzing redox reactions, DNA synthesis and apoptosis. The thioredoxins as well as glutaredoxins are affected in chronic inflammatory diseases. The aim of this thesis was to study how these redox systems are altered in chronic inflammation and how they may be modulated by treatment of the underlying disease. In Paper I, we investigated the effect of anti-cancer drug, histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) on thioredoxin 1 (Trx1). SAHA treatment of HeLa cells induced a shift in Trx1 oxidation state to more oxidized, leading to less reducing capacity. Additionally, SAHA treatment increased the expression of Trx1 inhibitor Txnip. Thus the cytotoxicity of SAHA may at least partially be explained by Trx1 inhibition and by multiple mechanisms, decreasing its capacity to scavenge reactive oxygen species. In Paper II, the potential redox effects of antioxidant CoQ10 was studied in diabetes patients undergoing three months of CoQ10 or placebo treatment. CoQ10 treatment significantly decreased total antioxidant capacity and Grx activity in diabetes mellitus patients, correcting the disrupted redox balance in diabetes patients. We also demonstrated that Grx catalyzes the reduction of CoQ10 by GSH. In conclusion CoQ10 decreases serum Grx activity toward normalization. In Paper III, we measured serum Grx levels in patients at different stages of CKD, at dialysis start and again after 2 years of dialysis. Grx levels were increased in CKD compared to control subject and correlated well with oxidative stress marker pentosidine. Grx levels were significantly higher in hemodialysis (HD) patients compared to peritoneal dialysis (PD) patients. In conclusion, CKD patients have oxidized extracellular environment and Grx may be a useful marker of the degree of oxidative stress in CKD during treatment. In Paper IV, we investigated the effect selenium compounds on ovarian cancer cells and immune cells. At cytotoxic doses, selenium compounds (selenite and methylseleninic acid (MSA)) were cytotoxic to ovarian cancer cells but not to immune cells. Improved T cell function was observed after T cell incubation in preconditioned media from MSA treated tumor cells. MSA decreased tumor cell HIF 1-α, VEGF and PDL1 expression, suggesting that MSA enhances T cell mediated killing of ovarian cancer cells via decreasing PDL1 and VEGF expression. In conclusion, both the intra- and extra-cellular redox balance is perturbed in chronic inflammation, and may be corrected by treatment of the underlying disease.