Modulation of AMPK by esomeprazole and canagliflozin mitigates methotrexate-induced hepatotoxicity: involvement of MAPK/JNK/ERK, JAK1/STAT3, and PI3K/Akt signaling pathways

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 7, 2025

Abstract This research investigated the hepatoprotective effects of esomeprazole (ESOM) and canagliflozin (CANA) against methotrexate-induced liver toxicity, focusing on AMPK modulation its regulation MAPK/JNK/ERK, JAK1/STAT3, PI3K/Akt pathways. Fifty male Wistar rats were divided into five groups: control, MTX, three pretreatment groups receiving ESOM (30 mg/kg), CANA or their combination. administered for 8 days before 1 day after a single MTX injection (20 mg/kg, intraperitoneally) 9 to induce hepatotoxicity. Liver injury, oxidative stress, inflammation, apoptosis assessed using biochemical, histopathological, immunohistochemical, qRT-PCR, western blot analyses. Data analyzed by one-way analysis variance (ANOVA) Tukey’s post hoc test, with significance at p < 0.05. Results presented as mean ± standard error (SE). Rats that received showed significant damage, marked elevated ALT, AST, MDA, MPO, iNOS, TNF-α, IL-6, IL-1β levels ( 0.01) decreased antioxidant enzymes (HO-1, Nrf2, GSH). Immunohistochemistry revealed increased NF-kB p65 caspase-9 expression 0.01), correlating histopathological changes. Pretreatment reduced enzyme levels, improved histology, restored balance, inhibited inflammatory pathways via p38MAPK/NF-kB JAK1/STAT3 0.01). Moreover, preserved activity prevented caspase-dependent Additionally, combination treatment synergistic effects, demonstrated improvements in all measured parameters. These findings suggested had potential therapeutic agents alleviating MTX-induced hepatotoxicity warranted further investigation future research.

Language: Английский

Melatonin augments anti-tumor activity and alleviates nephrotoxicity of gemcitabine in a pancreatic cancer xenograft model targeting P62/Keap1 pathway

Naunyn-Schmiedeberg s Archives of Pharmacology, Journal Year: 2025, Volume and Issue: unknown

Published: March 18, 2025

Abstract Although gemcitabine is a primary chemotherapy for pancreatic cancer, its effectiveness limited by chemoresistance and nephrotoxicity, posing significant clinical challenges. Therefore, the development of novel therapeutic approaches to prevent malignancy remains crucial. This study aimed investigate potential melatonin in enhancing gemcitabine’s anticancer efficacy while mitigating nephrotoxic effects through modulation Keap1/p62 pathway. A cancer xenograft model was established rats, which received either (50 mg/kg, I.P.), or their combination three times per week 2 weeks. Our findings demonstrate that potentiates cancer-suppressing via Kelch-like-ECH associated protein-1 (Keap1)/p62 pathway, resulting reduced fibrosis, oxidative stress, inflammatory markers. Additionally, significantly mitigated gemcitabine-induced nephrotoxicity. These results suggest may serve as an adjuvant therapy treatment, reducing adverse effects.

Language: Английский