The enteroprotective effect of nifuroxazide against methotrexate-induced intestinal injury involves co-activation of PPAR-γ, SIRT1, Nrf2, and suppression of NF-κB and JAK1/STAT3 signals

Abd-alhameed, Esraa K.; Azouz, Amany A.; Abo-Youssef, Amira M.; Ali, Fares E.M.

doi:10.1016/j.intimp.2023.111298

International Immunopharmacology

2024

DOI: 10.1016/j.intimp.2023.111298

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The enteroprotective effect of nifuroxazide against methotrexate-induced intestinal injury involves co-activation of PPAR-γ, SIRT1, Nrf2, and suppression of NF-κB and JAK1/STAT3 signals

Esraa K. Abd-alhameed,

Amany A. Azouz,

Amira M. Abo-Youssef

et al.

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Cited by 3 publications

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Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies

Ali,

Hassanein,

Mohamed

2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Methotrexate (MTX) is a folic acid reductase inhibitor that manages various malignancies as well as immune-mediated inflammatory chronic diseases. Despite being frequently prescribed, MTX’s severe multiple toxicities can occasionally limit its therapeutic potential. Intestinal toxicity is a severe adverse effect associated with the administration of MTX, and patients are significantly burdened by MTX-provoked intestinal mucositis. However, the mechanism of such intestinal toxicity is not entirely understood, mechanistic studies demonstrated oxidative stress and inflammatory reactions as key factors that lead to the development of MTX-induced intestinal injury. Besides, MTX causes intestinal cells to express pro-inflammatory cytokines like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which activate nuclear factor-kappa B (NF-κB). This is followed by the activation of the Janus kinase/signal transducer and activator of the transcription3 (JAK/STAT3) signaling pathway. Moreover, because of its dual anti-inflammatory and antioxidative properties, nuclear factor erythroid-2-related factor 2/heme oxygenase-1 (Nrf2/HO-1) has been considered a critical signaling pathway that counteracts oxidative stress in MTX-induced intestinal injury. Several agents have potential protective effects in counteracting MTX-provoked intestinal injury such as omega-3 polyunsaturated fatty acids, taurine, umbelliferone, vinpocetine, perindopril, rutin, hesperidin, lycopene, quercetin, apocynin, lactobacillus, berberine, zinc, and nifuroxazide. This review aims to summarize the potential redox molecular mechanisms of MTX-induced intestinal injury and how they can be alleviated. In conclusion, studying these molecular pathways might open the way for early alleviation of the intestinal damage and the development of various agent plans to attenuate MTX-mediated intestinal injury. Graphical Abstract

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Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies

Ali,

Hassanein,

Mohamed

2024

Naunyn-Schmiedeberg's Arch Pharmacol

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Neurotoxic effects of triclosan in adolescent mice: Pyruvate kinase M2 dimer regulated Signal transducer and activator of transcription 3 phosphorylation mediated microglia activation and neuroinflammation

Wei,

Ni,

Cui

et al. 2024

Science of The Total Environment

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Elucidating the gastroprotective mechanisms of Imperata cylindrica Beauv.var. major (Nees) C.E.Hubb through UHPLC-MS/MS and systems network pharmacology

Zhou,

Hu,

Liu

et al. 2024

Sci Rep

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Imperata cylindrica Beauv.var. major (Nees) C.E.Hubb., commonly known as BaiMaoGen (BMG), a medicinal and edible traditional Chinese medicinal (TCM) herb commonly used in health supplements, has been observed to offer protective effects against gastrointestinal disorders. However, the specific bioactive compounds and their molecular mechanisms have not been fully elucidated. This study employed ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) and systematic network pharmacology to analyze and identify the key active components and their interactions with biological targets. Thirty-six main active compounds, including 3,4-dihydroxybenzoic acid and p -hydroxybenzoic acid, were identified and analyzed for their interaction with key protein targets using molecular docking and dynamic simulations. This combined approach highlighted the therapeutic pathways involved, particularly the PI3K/AKT signaling pathways, providing new insights into the molecular basis of BMG’s gastroprotective effects. Our findings suggested that BMG’s complex multi-target action can potentially be harnessed to develop effective treatments for gastrointestinal toxicity. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-79483-z.

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The enteroprotective effect of nifuroxazide against methotrexate-induced intestinal injury involves co-activation of PPAR-γ, SIRT1, Nrf2, and suppression of NF-κB and JAK1/STAT3 signals

Cited by 3 publications

References 39 publications

Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies

Molecular mechanisms underlying methotrexate-induced intestinal injury and protective strategies

Neurotoxic effects of triclosan in adolescent mice: Pyruvate kinase M2 dimer regulated Signal transducer and activator of transcription 3 phosphorylation mediated microglia activation and neuroinflammation

Elucidating the gastroprotective mechanisms of Imperata cylindrica Beauv.var. major (Nees) C.E.Hubb through UHPLC-MS/MS and systems network pharmacology

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