Effects of alpha lipoic acid and pirfenidone on liver cells antioxidant modulation against oxidative damage [Efecto del ácido alfa lipoico y la pirfenidona en la modulación antioxidante celular contra el daño oxidativo]

Background: Liver fibrogenic processes are related to cellular redox state. Glutathione (GSH) is the major cellular antioxidant. GSH induced activation could be related to antifibrogenic effects. Aim: To explore the association between the antifibrogenic effect and pro-antioxidant mechanisms of alpha-lipoic acid (ALA) and pirfenidone (PFD). Material and Methods: HepG2 cells and primary HSC cultures were exposed to menadione 0.1 ?M (MEN) as oxidative stress inducer and treated to ALA (5 mM) or PFD (10 ?M, 100 ?M y 1000 ?M). Results: In HSC, PFD decreased cell proliferation and the expression of COL1A1, TGF-?1, TIMP1, IL6, TNF? and MCP1 induced by MEN. Furthermore it was confirmed that ALA and PFD activate diverse antioxidants mediators, however MEN decreases this response. Then, MEN, ALA and PFD induce an antioxidant response, the first one as a response to injury and the latter two as pro-antioxidant inducers. Therefore, when cells are exposed to oxidative stress, endogenous systems activate a battery of mediators that increase the antioxidant potential. When these cells are treated with ALA and PFD, de novo formation of protective genes decreases since previous elicited protection induced in response to injury, enhance ALA and PFD effects. Conclusion: Regardless of the route of action, ALA and PFD induce the biosynthesis of antioxidants mediators which is associated with modulation of fibrogenic processes. 2014, Sociedad Medica de Santiago. All rights reserved

Alpha-lipoic acid regulates heme oxygenase gene expression and nuclear Nrf2 activation as a mechanism of protection against arsenic exposure in HepG2 cells

Oxidative stress is a known mechanism induced, among other things, by arsenic toxicity. As a response, the cell triggers the synthesis of antioxidant and stress response elements like glutathione and heme oxygenase. Alpha-lipoic acid (ALA) is a well-known antioxidant that confers protection to oxidative stress conditions. We analyzed the effect of ALA pretreatment on Nrf2-responsive gene expression of HepG2 cells exposed to As3+. Cells were treated with 5mM ALA and 8h later exposed to 50?M As3+ for 24h, analyzing MTT-activity, glutathione content, Nrf2 induction and antioxidant gene expression. As3+ increased glutathione (154%), heme oxygenase, glutamate cystein ligase, modifier subunit and metallothionein (35-fold, 10-fold and 9-fold, respectively). ALA prevented the strong expression of heme oxygenase by As3+ exposure (from 35- to 5-times of control cells), which correlated with the reduction of Nrf2 observed in As3+ group. ALA pretreatment can down-modulate the response mediated by Nrf2 and provide protection to As3+ exposed HepG2 cells. Zapotitlán 2010 Elsevier B.V