Protective effects of alpha-lipoic acid on bleomycin-induced skin fibrosis through the repression of NADPH Oxidase 4 and TGF-β1/Smad3 signaling pathways

Abstract

The aim of this study was to determine the protective effects of alpha-lipoic acid (ALA), which is known as a powerful antioxidant, and the possible related molecular mechanisms that mediate its favorable action on skin fibrosis in the bleomycin (BLM)-induced scleroderma (SSc) model in mice. The experimental design was established with four groups of eight mice: Control, ALA (100 mg/kg), BLM (5 μg/kg), and BLM + ALA group. BLM was administered via subcutaneous ( sc) once a day while ALA was injected intraperitoneally ( ip) twice a week for 21 days. Histopathological and biochemical analyses showed that ALA significantly reduced BLM-induced dermal thickness, inflammation score, and mRNA expression of tumor necrosis factor-alpha (TNF-α) in the skin. Besides, the mRNA expressions of the subunits of NADPH oxidase, which are Nox4 and p22phox, were found to be significantly induced in the BLM group. However, ALA significantly reduced their mRNA expression, which were in parallel to its decreasing effect on serum total oxidant status (TOS) level. Moreover, it was found that ALA downregulated the mRNA expressions of alpha-smooth muscle actin (α-SMA), collagen type I and fibronectin in the skin tissue of the BLM group. Additionally, it was shown that ALA reduced significantly the TGF-β1 and p-Smad3 protein expressions in the BLM + ALA group. On the other hand, ALA did not exhibit any significant effect on the p38 mitogen-activated kinase (MAPK) activation induced by BLM. All these findings point out that ALA may be a promising treatment for the attenuation of skin fibrosis in SSc patients.

Effects of Antioxidant Combinations on the Renal Toxicity Induced Rats by Gold Nanoparticles

“…It also prevented salt-induced hypertension, hypertrophy, and rostral ventrolateral medulla (RVM) oxidative damage by suppressing NOX4 and the generation of ROS [ 71 ]. α-LA also prevented iron-induced acute renal injury, busulfan-induced pulmonary injury, and bleomycin-induced skin fibrosis by suppressing NOX4 [ 72 , 73 ]. On the other hand, QUR is a well-known antioxidant protective agent that stimulates and prevents organ damage, including nephropathy, by stimulating mitochondrial biogenesis and respiration [ 74 , 75 , 76 ].…”

Potential of Plant-Derived Compounds in Preventing and Reversing Organ Fibrosis and the Underlying Mechanisms

“…Furthermore, ALA treatment also resulted in decreased serum levels of TGF-β and IFN-γ, a pro-fibrotic factor that exhibits stage-specific participation in pulmonary inflammation. A reduction in α-SMA, collagen I and fibronectin by ALA was also described in a mouse model of bleomycin-induced scleroderma [ 171 ]. These studies illustrated that ALA treatment ameliorated bleomycin-induced Nox4 and p22phox expression and total oxidant status.…”

“…Similar to a number of other plant-derived compounds, studies have demonstrated that one of the mechanisms through which ALA exerts its anti-fibrotic activity is by inhibiting the TGF-β/Smad2/3 signaling pathway [ 170 , 171 ]. In a study conducted by Ibrahim and colleagues, male Wistar rats were subjected to amiodarone, an anti-arrhythmic drug that induces pulmonary fibrosis.…”

NRF2 in dermo‐cosmetic: From scientific knowledge to skin care products

“…It is also a cosmetic ingredient classified as an AOX 117 . Various studies have suggested applications in anti‐fibrosis, 171 wound healing, 172 skin lightening, 173 UV‐induced pigmentation control, 174 protection from skin damage induced by smoke, 175 as well as anti‐aging, 176,177 photoaging 178 and photoprotection, 179 although this is controversial 180 . Among its various mechanisms of action, lipoic acid is an Nrf2‐dependent inducer of phase II detoxification enzymes 181 .…”