Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats

Fayez, Ahmed M.; Zakaria, Soad; Moustafa, Dina

doi:10.1016/j.biopha.2018.05.145

Cited by 48 publications

(34 citation statements)

References 36 publications

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“…Thus, it can resist oxidative stress and reduce cytotoxicity . The result was consistent with Fayez et al, who showed that α‐LA antagonizes oxidative stress by reducing ROS levels in the liver of mice.…”

Section: Discussionsupporting

confidence: 88%

α‐Lipoic acid protects against microcystin‐LR induced hepatotoxicity through regeneration of glutathione via activation of Nrf2

Bai

et al. 2020

Environmental Toxicology

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Microcystins (MCs), as the most dominant bloom-forming strains in eutrophic surface water, can induce hepatotoxicity by oxidative stress. Alpha-lipoic acid (α-LA) is a super antioxidant that can induce the synthesis of antioxidants, such as glutathione (GSH), by nuclear factor erythroid 2-related factor 2 (Nrf2). However, the potential molecular mechanism of α-LA regeneration of GSH remains unclear. The present study aimed to investigate whether α-LA could reduce the toxicity of MCs induced in human hepatoma (HepG2), Bel7420 cells, and BALB/c mice by activating Nrf2 to regenerate GSH. Results showed that exposure to 10 μM microcystin-leucine arginine (MC-LR) reduced viability of HepG2 and Bel7402 cells and promoted the formation of reactive oxygen species (ROS) compared with untreated cells. Moreover, the protection of α-LA included reducing the level of ROS, increasing superoxide dismutase activity, and decreasing malondialdehyde. Levels of reduced glutathione (rGSH) and rGSH/oxidized glutathione were significantly increased in cells cotreated with α-LA and MC-LR compared to those treated with MC-LR alone, indicating an ability of α-LA to attenuate oxidative stress and MC-LR-induced cytotoxicity by increasing the amount of rGSH. α-LA can mediate GSH regeneration through the Nrf2 pathway under the action of glutathione reductase in MC-LR cell lines. Furthermore, the data also showed that α-LA-induced cytoprotection against MC-LR is associated with Nrf2 mediate pathway in vivo. These findings demonstrated the potential of α-LA to resist MC-LR-induced oxidative damage of liver. K E Y W O R D S alpha-lipoic acid, glutathione, MC-LR, Nrf2, regeneration

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Section: Discussionsupporting

confidence: 88%

α‐Lipoic acid protects against microcystin‐LR induced hepatotoxicity through regeneration of glutathione via activation of Nrf2

Bai

et al. 2020

Environmental Toxicology

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“…MgIG can reduce collagen deposition and COX-2 expression in the liver. Collagen deposition is mainly responsible for liver fibrosis, and COX-2 can promote MTX-induced hepatic inflammatory response and activation of hepatic stellate cells, further accelerating the progression of liver fibrosis (Fayez et al, 2018). Additionally, MTX is often first used to control rheumatism by modifying the immune system, and commonly prescribed with other drugs, including NSAIDs such as aspirin (Fries et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Magnesium Glycyrrhizinate on Methotrexate-Induced Hepatotoxicity and Intestinal Toxicity May Be by Reducing COX-2

et al. 2019

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Magnesium isoglycyrrhizinate (MgIG), which has been widely employed to treat chronic hepatitis, is synthesized from 18-β glycyrrhizic acid, a main component of traditional Chinese medicine Glycyrrhiza uralensis Fisch. Although the protective effects of MgIG on methotrexate (MTX)-induced liver toxicity have been well-documented, the underlying mechanism remains elusive. MTX was initially used to treat pediatric acute leukemia, and has been widely applied to psoriasis therapy. However, its clinical applications are limited due to hepatotoxicity and intestinal toxicity. Herein, prophylactic administration of MgIG (9 and 18 mg/kg/day) significantly reduced the levels of aspartate aminotransferase and alanine aminotransferase in the serum of rats receiving intravenous injection of MTX (20 mg/kg body weight). MgIG also attenuated MTX-induced hepatic fibrosis. Moreover, it better protected against MTX-induced hepatocyte apoptosis and decreased the serum level of malondialdehyde than reduced glutathione (80 mg/kg/day) did. Interestingly, MTX-induced cyclooxygenase-2 (COX-2) expression, intestinal permeability and inflammation were attenuated after MgIG administration. In addition, MgIG (9 and 18 mg/kg) reduced MTX-induced colocalization of zonula occludens-1 (ZO-1) and connexin 43 (Cx43) in intestinal villi. In conclusion, MgIG exerted beneficial effects on MTX-induced hepatotoxicity and intestinal damage, as a potentially eligible drug for alleviating the hepatic and intestinal side effects of MTX during chemotherapy.

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“…Our results show a decline in transcriptional activity of Nrf2 in the liver of the GK group fed with HFD that leads to a decrement in glutathione levels, which is reversible with lipoic acid treatment. It was recently described that α-LA exerts its antioxidant effect via Nrf2 activation in methotrexate-treated rats [ 26 ]. In addition, it was previously shown that α-LA was able to induce the de novo synthesis and regeneration of GSH by activating the transcriptional factor Nrf2 [ 12 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation

Sena

Cipriano²,

Botelho

et al. 2018

IJMS

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Prevention of hepatic fat accumulation may be an important approach for liver diseases due to the increased relevance of hepatic steatosis in this field. This study was conducted to investigate the effects of the antioxidant α-lipoic acid (α-LA) on hepatic steatosis, hepatocellular function, and oxidative stress in a model of type 2 diabetes fed with a high fat diet (HFD). Goto-Kakizaki rats were randomly divided into four groups. The first group received only a standard rat diet (control GK) including groups 2 (HFD), 3 (vehicle group), and 4 (α-LA group), which were given HFD, ad libitum during three months. Wistar rats are the non-diabetic control group. Carbohydrate and lipid metabolism, liver function, plasma and liver tissue malondialdehyde (MDA), liver GSH, tumor necrosis factor-α (TNF-α) and nuclear factor E2 (erythroid-derived 2)-related factor-2 (Nrf2) levels were assessed in the different groups. Liver function was assessed using quantitative hepatobiliary scintigraphy, serum aspartate, and alanine aminotransferases (AST, ALT), alkaline phosphatase, gamma-glutamyltranspeptidase, and bilirubin levels. Histopathologically steatosis and fibrosis were evaluated. Type 2 diabetic animals fed with HFD showed a marked hepatic steatosis and a diminished hepatic extraction fraction and both were fully prevented with α-LA. Plasma and liver tissue MDA and hepatic TNF-α levels were significantly higher in the HFD group when compared with the control group and significantly lower in the α-LA group. Systemic and hepatic cholesterol, triglycerides, and serum uric acid levels were higher in hyperlipidemic GK rats and fully prevented with α-LA. In addition, nuclear Nrf2 activity was significantly diminished in GK rats and significantly augmented after α-LA treatment. In conclusion, α-LA strikingly ameliorates steatosis in this animal model of diabetes fed with HFD by decrementing the inflammatory marker TNF-α and reducing oxidative stress. α-LA might be considered a useful therapeutic tool to prevent hepatic steatosis by incrementing antioxidant defense systems through Nrf2 and consequently decreasing oxidative stress and inflammation in type 2 diabetes.

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Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats

Cited by 48 publications

References 36 publications

α‐Lipoic acid protects against microcystin‐LR induced hepatotoxicity through regeneration of glutathione via activation of Nrf2

α‐Lipoic acid protects against microcystin‐LR induced hepatotoxicity through regeneration of glutathione via activation of Nrf2

Protective Effects of Magnesium Glycyrrhizinate on Methotrexate-Induced Hepatotoxicity and Intestinal Toxicity May Be by Reducing COX-2

Lipoic Acid Prevents High-Fat Diet-Induced Hepatic Steatosis in Goto Kakizaki Rats by Reducing Oxidative Stress Through Nrf2 Activation

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