Cytoprotective and suicidal signaling in oxidative stress

Oxidative stress is an imbalance between pro-oxidants and antioxidants in favor of the pro-oxidants, leading to different responses depending on the level of pro-oxidants achieved and the duration of exposure. In this article, we discuss the cytoprotective or suicidal signaling mechanisms associated with oxidative stress by addressing: (i) the development of an acute and mild pro-oxidant state by thyroid hormone administration eliciting the redox upregulation of the expression of proteins affording cell protection as a preconditioning strategy against ischemia-reperfusion liver injury; and (ii) the role of prolonged and severe oxidative stress and insulin resistance as determinant factors in the pathogenesis of non-alcoholic fatty liver disease associated with obesity.

Upregulation of liver inducible nitric oxide synthase following thyroid hormone preconditioning: suppression by N-acetylcysteine

3,3-5-L-Triiodothyronine (T3) exerts significant protection against ischemia-reperfusion (IR) liver injury in rats. Considering that the underlying mechanisms are unknown, the aim of this study was to assess the involvement of inducible nitric oxide synthase (iNOS) expression and oxidative stress in T3 preconditioning (PC). Male Sprague-Dawley rats given a single dose of 0.1 mg of T3/kg were subjected to 1-hour ischemia followed by 20 hours reperfusion, in groups of animals pretreated with 0.5 g of N-acetylcysteine (NAC)/kg 0.5-hour prior to T3 or with the respective control vehicles. At the end of the reperfusion period, liver samples were taken for analysis of iNOS mRNA levels (RT-PCR), liver NOS activity, and hepatic histology. T3 protected against hepatic IR injury, with 119 percent enhancement in liver iNOS mRNA/18S rRNA ratios (p<0.05) and 12.7-fold increase (p<0.05) in NOS activity in T3-treated animals subjected to IR over values in control-sham operated rats, with a net 7.7-fold enhancement (p<0.05) in the net effect of T3 on liver iNOS expression and a net enhancement of 0.58 units in NOS activity, changes that were abolished by NAC treatment before T3. It is concluded that T3-induced liver PC is associated with upregulation of iNOS expression as a protective mechanisms against IR injury, which is achieved through development of transient and reversible oxidative stress.