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Pathophysiological mechanisms of oxidative stress | Mechanism (with references) |
Increasing prooxidant | Decreasing antioxidant |
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Mitochondrial dysfunction | Impairment of oxidative capacity of ETC, resulting in an “electron leakage” [21] | GSH depletion with reduction of GPx activity [41] |
Accumulation of Cer and DAGs due to incomplete betaoxidation of acyl-carnitine [34] | Reduced activity of MnSOD, polymorphism C47T of SOD2 gene [42] |
mtDNA mutation [25] | Impaired activity of cytochrome C [35] |
Production of reactive aldehydes (MDA, 4-HNE) through lipid peroxidation [43] |
Increase activity of CYP2E1, polymorphism of C2 allele [37–40] |
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ER stress | Prolonged activation of UPR leading to (i) overexpression of ERO1 [49] (ii) calcium disruption due to reduced activity or SERCA [55] (iii) upregulation of CHOP mediated by activation of PERK and ATF6 [50] | Prolonged activation of UPR leading to (i) inhibition of Nrf2 by PERK resulting in the depletion of GSH [59] |
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Iron metabolism derangements | Disruption of peroxisomal membrane [66] | GSH depletion—decreased GPx efficiency [67] |
Enhanced iNOS expression via NF-κB activation [67] | Inhibition of HO-1 by activation of BACH-1 [70–74] |
Production of reactive aldehydes (MDA) through lipid peroxidation [64] | Iron actin as a direct competitive antagonist of antioxidant enzymes [69] |
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Inappropriate inflammatory response mediated by GUT-liver axis | Upregulation of proinflammatory pathways and NADPH oxidase system due to bacterial and bacterial product translocation [80, 81] | Lack of inhibition of inflammatory response by NPRL-3 and -6 [85, 86] |
Activation of inflammasomes resulting in cleavage of cytokines precursors (pro-IL1β, pro-IL18) [82] |
Endogenous alcoholic production by alcohol-producing bacteria [89] |
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Insulin resistance and endothelial dysfunction | Upregulation of Ras/MAPK pathway involved in cell proliferation [94] | Decrease of eNOS activation due to IR [94] |
Enhanced iNOS activity due to increase expression of proinflammatory cytokines in IR [96] |
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