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Morin ameliorates methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling
Hamit Emre Kızıl1, Cuneyt Caglayan2, Ekrem Darendelioğlu3
1Vocational School of Health Sevices, Bayburt University, Bayburt, Turkey.
Background:
Organ toxicity limits the therapeutic efficacy of methotrexate (MTX), an anti-metabolite therapeutic that is frequently used as an anti-cancer and immunosuppressive medicine. Hepatocellular toxicity is among the most severe side effects of long-term MTX use. The present study unveils new confirmations as regards the remedial effects of morin on MTX-induced hepatocellular injury through regulation of oxidative stress, apoptosis and MAPK signaling.
Methods And Results:
Rats were subjected to oral treatment of morin (50 and 100 mg/kg body weight) for 10 days. Hepatotoxicity was induced by single intraperitoneal injection of MTX (20 mg/kg body weight) on the 5th day. MTX related hepatic injury was associated with increased MDA while decreased GSH levels, the activities of endogen antioxidants (glutathione peroxidase, superoxide dismutase and catalase) and mRNA levels of HO-1 and Nrf2 in the hepatic tissue. MTX treatment also resulted in apoptosis in the liver tissue via increasing mRNA transcript levels of Bax, caspase-3, Apaf-1 and downregulation of Bcl-2. Conversely, treatment with morin at different doses (50 and 100 mg/kg) considerably mitigated MTX-induced oxidative stress and apoptosis in the liver tissue. Morin also mitigated MTX-induced increases of ALT, ALP and AST levels, downregulated mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9), MAPK14 and MAPK15, JNK, Akt2 and FOXO1 genes.
Conclusion:
According to the findings of this study, morin may be a potential way to shield the liver tissue from the oxidative damage and apoptosis.
Insights
Morin supplementation may protect the liver from methotrexate (MTX)-induced damage. This study shows morin reduces oxidative stress and apoptosis in rat liver, offering a potential therapeutic strategy against MTX-induced hepatotoxicity.
Area of Science:
- Pharmacology
- Hepatology
- Toxicology
Background:
- Methotrexate (MTX) is a vital anti-cancer and immunosuppressive drug.
- Organ toxicity, particularly hepatocellular toxicity, limits MTX efficacy.
- Oxidative stress and apoptosis are key mechanisms in MTX-induced liver injury.
Purpose of the Study:
- To investigate the protective effects of morin against MTX-induced liver injury.
- To elucidate the mechanisms underlying morin's hepatoprotective action, focusing on oxidative stress, apoptosis, and MAPK signaling.
Main Methods:
- Hepatotoxicity was induced in rats using a single intraperitoneal injection of MTX.
- Rats were orally treated with morin (50 and 100 mg/kg) for 10 days.
- Liver tissue analysis included assessment of oxidative stress markers, apoptosis-related gene expression, and liver enzyme levels.
Main Results:
- MTX treatment increased oxidative stress (MDA, decreased GSH) and apoptosis (Bax, caspase-3) while downregulating protective genes (Bcl-2, HO-1, Nrf2).
- Morin treatment significantly mitigated MTX-induced oxidative stress and apoptosis.
- Morin reduced elevated liver enzymes (ALT, AST, ALP) and downregulated genes involved in inflammation and cell signaling (MMPs, MAPKs, Akt2, FOXO1).
Conclusions:
- Morin demonstrates significant hepatoprotective effects against MTX-induced liver injury.
- Morin's mechanism involves the regulation of oxidative stress and apoptosis pathways.
- Morin shows potential as a therapeutic agent to prevent MTX-related liver damage.
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