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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.
Biomed Pharmacother. 2018 Sep; 105:428-433.BP

Abstract

Hepatic injury is a major side effect associated with methotrexate (MTX) therapy resulting from inflammatory reactions and oxidative stress induction. Therefore, liver fibrosis incidence is augmented with long-term MTX therapy. Alpha lipoic acid (ALA) is a naturally occurring compound with potent antioxidant activity. This study explored the hepatoprotective mechanisms of ALA against MTX-induced hepatic injury in rats. Hepatic injury was induced in MTX group by 20 mg/kg body weight ip. injection of MTX. ALA group was pretreated with ALA 60 mmol/kg body weight ip. for five days followed by a single dose of MTX in the sixth day. Blood samples and liver tissues were then obtained to assess several biochemical parameters as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), reduced glutathione (GSH), total antioxidant capacity (TAC) and lipid peroxidation. Nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway was studied by determining the extent of mRNA Nrf2 expression and the level of HO-1. Hepatic stellate cells (HSCs) activation was evaluated by estimating the expression of α-smooth muscle actin (α-SMA) and hydroxyproline content. Also, tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and caspase-3 were assessed by ELISA in addition to histopathological examination of liver samples. Results showed that ALA pretreatment improved liver function since serum ALT, AST and ALP levels were reduced. Additionally, ALA restored GSH and TAC levels when compared to MTX group and decreased lipid peroxidation. ALA exerted its antioxidant effect via Nrf2/HO-1 pathway as well as it showed anti-inflammatory and antiapoptotic effects by reducing TNF-α, iNOS, COX-2 and caspase-3 levels in liver tissue homogenate. Finally, ALA suppressed HSCs activation by decreasing α-SMA expression and hydroxyproline content in liver. It was concluded that ALA has hepatoprotective effects against MTX-induced hepatic injury mediated by Nrf2/HO-1 pathway as well as anti-inflammatory and antiapoptotic properties.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Faculty of Pharmacy, MSA University, 6 October City, Giza, Egypt.Department of Pharmacology and Toxicology, Faculty of Pharmacy, October 6 University, 6 October City, Giza, Egypt. Electronic address: soadzakaria@o6u.edu.eg.Department of Pharmacology and Toxicology, Faculty of Pharmacy, October 6 University, 6 October City, Giza, Egypt.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29879626

Citation

Fayez, Ahmed M., et al. "Alpha Lipoic Acid Exerts Antioxidant Effect Via Nrf2/HO-1 Pathway Activation and Suppresses Hepatic Stellate Cells Activation Induced By Methotrexate in Rats." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 105, 2018, pp. 428-433.
Fayez AM, Zakaria S, Moustafa D. Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats. Biomed Pharmacother. 2018;105:428-433.
Fayez, A. M., Zakaria, S., & Moustafa, D. (2018). Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 105, 428-433. https://doi.org/10.1016/j.biopha.2018.05.145
Fayez AM, Zakaria S, Moustafa D. Alpha Lipoic Acid Exerts Antioxidant Effect Via Nrf2/HO-1 Pathway Activation and Suppresses Hepatic Stellate Cells Activation Induced By Methotrexate in Rats. Biomed Pharmacother. 2018;105:428-433. PubMed PMID: 29879626.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alpha lipoic acid exerts antioxidant effect via Nrf2/HO-1 pathway activation and suppresses hepatic stellate cells activation induced by methotrexate in rats. AU - Fayez,Ahmed M, AU - Zakaria,Soad, AU - Moustafa,Dina, Y1 - 2018/06/05/ PY - 2017/11/17/received PY - 2018/05/26/revised PY - 2018/05/28/accepted PY - 2018/6/8/pubmed PY - 2018/11/7/medline PY - 2018/6/8/entrez KW - Alpha lipoic acid KW - Hepatic stellate cells KW - Inflammatory responses KW - Methotrexate KW - Nrf2/HO-1 pathway KW - Oxidative stress KW - α-Smooth muscle actin SP - 428 EP - 433 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed Pharmacother VL - 105 N2 - Hepatic injury is a major side effect associated with methotrexate (MTX) therapy resulting from inflammatory reactions and oxidative stress induction. Therefore, liver fibrosis incidence is augmented with long-term MTX therapy. Alpha lipoic acid (ALA) is a naturally occurring compound with potent antioxidant activity. This study explored the hepatoprotective mechanisms of ALA against MTX-induced hepatic injury in rats. Hepatic injury was induced in MTX group by 20 mg/kg body weight ip. injection of MTX. ALA group was pretreated with ALA 60 mmol/kg body weight ip. for five days followed by a single dose of MTX in the sixth day. Blood samples and liver tissues were then obtained to assess several biochemical parameters as serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), reduced glutathione (GSH), total antioxidant capacity (TAC) and lipid peroxidation. Nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) pathway was studied by determining the extent of mRNA Nrf2 expression and the level of HO-1. Hepatic stellate cells (HSCs) activation was evaluated by estimating the expression of α-smooth muscle actin (α-SMA) and hydroxyproline content. Also, tumor necrosis factor alpha (TNF-α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and caspase-3 were assessed by ELISA in addition to histopathological examination of liver samples. Results showed that ALA pretreatment improved liver function since serum ALT, AST and ALP levels were reduced. Additionally, ALA restored GSH and TAC levels when compared to MTX group and decreased lipid peroxidation. ALA exerted its antioxidant effect via Nrf2/HO-1 pathway as well as it showed anti-inflammatory and antiapoptotic effects by reducing TNF-α, iNOS, COX-2 and caspase-3 levels in liver tissue homogenate. Finally, ALA suppressed HSCs activation by decreasing α-SMA expression and hydroxyproline content in liver. It was concluded that ALA has hepatoprotective effects against MTX-induced hepatic injury mediated by Nrf2/HO-1 pathway as well as anti-inflammatory and antiapoptotic properties. SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/29879626/Alpha_lipoic_acid_exerts_antioxidant_effect_via_Nrf2/HO_1_pathway_activation_and_suppresses_hepatic_stellate_cells_activation_induced_by_methotrexate_in_rats_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0753-3322(17)36198-X DB - PRIME DP - Unbound Medicine ER -