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Artemisia alleviates AGE-induced liver complications via MAPK and RAGE signaling pathways modulation: a combinatorial study

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Abstract

Artemisia herba-alba (AHA) is a traditionally used plant to treat various diseases, including diabetes and metabolic dysfunctions. Plant extracts are generally explored empirically without a deeper assessment of their mechanism of action. Here, we describe a combinatorial study of biochemical, molecular, and bioinformatic (metabolite-protein pharmacology network) analyses to elucidate the mechanism of action of AHA and shed light on its multilevel effects in the treatment of diabetes-related advanced glycation end-products (AGE)-induced liver damages. The extract’s polyphenols and flavonoids content were measured and then identified via LC-Q-TOF–MS/MS. Active compounds were used to generate a metabolite-target interaction network via Swiss Target Prediction and other databases. The extract was tested for its antiglycation and aggregation properties. Next, THLE-2 liver cells were challenged with AGEs, and the mechanistic markers were measured [TNF-α, IL-6, nitric oxide, total antioxidant capacity, lipid peroxidation (LPO), and caspase 3]. Metabolite and network screening showed the involvement of AHA in diabetes, glycation, liver diseases, aging, and apoptosis. Experimental confirmation showed that AHA inhibited protein modification and AGE formation. Additionally, AHA reduced inflammatory mediators (IL-6, TNFα), oxidative stress markers (NO, LPO), and apoptosis (Caspase 3). On the other hand, cellular total antioxidant capacity was restored to normal levels. The combinatorial study showed that AHA regulates AGE-induced liver damages through MAPK-AKT and AGE-RAGE signaling pathways. This report highlights the combination of experimental and network pharmacology for the exact elucidation of AHA mechanism of action as a multitarget option in the therapy of diabetes and AGEs-related diseases.

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All data generated or analyzed during this study are included in this published article and its supplementary information files. Further data is available from the corresponding author on reasonable request.

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Acknowledgements

This project was funded by The Scientific and Technological Research Council of Turkey—TUBITAK (120Z200). The current project was partially funded by the Projets de Recherche-Formation Universitaire (PRFU) (D01N01UN160420180008). EGE MATAL (EGE University) is acknowledged for the LC-Q-TOF-MS/MS analyses and cell culture experiments.

Funding

Ministère de l'Enseignement Supérieur et de la Recherche Scientifique (D01N01UN160420180008), Türkiye Bilimsel ve Teknolojik Araştirma Kurumu (120Z200).

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  1. These authors Hichem Moulahoum and Faezeh Ghorbanizamani have contributed equally.

Authors and Affiliations

  1. Biochemistry Department, Faculty of Sciences, Ege University, Bornova, 35100, Izmir, Turkey

    Hichem Moulahoum, Faezeh Ghorbanizamani, Kerem Tok, Suna Timur & Figen Zihnioglu

  2. Laboratory of Ethnobotany and Natural Substances, Department of Natural Sciences, Higher Normal School Kouba, Vieux-Kouba, BP No. 92, 16308, Algiers, Algeria

    Zineb Khiari

  3. Laboratory of Cellular and Molecular Biology (BCM), Biochemistry & extracellular matrix remodelling, Faculty of Biological Sciences (FSB), USTHB, El Alia. Bab Ezzouar, BP 31, 16111, Algiers, Algeria

    Zineb Khiari & Yasmina Benazzoug

  4. Laboratory of REVIECO, Faculty of Sciences, University of Algiers 1, Benyoucef Benkhedda, Algiers, Algeria

    Mohamed Toumi

  5. Central Research Test and Analysis Laboratory Application and Research Center, Ege University, Bornova, 35100, Izmir, Turkey

    Suna Timur

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  1. Hichem Moulahoum
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Contributions

HM: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Writing—Original Draft, Visualization. FG: Methodology, Investigation, Writing—Original Draft. ZK: Methodology, Investigation, Resources, Funding acquisition. MT: Conceptualization, Validation, Resources. YB: Conceptualization, Validation, Resources. KT: Investigation, Visualization. ST: Conceptualization, Methodology, Validation, Resources, Supervision. FZ: Conceptualization, Methodology, Validation, Resources, Writing—Review & Editing, Supervision, Funding acquisition.

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Correspondence to Hichem Moulahoum.

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Moulahoum, H., Ghorbanizamani, F., Khiari, Z. et al. Artemisia alleviates AGE-induced liver complications via MAPK and RAGE signaling pathways modulation: a combinatorial study. Mol Cell Biochem 477, 2345–2357 (2022). https://doi.org/10.1007/s11010-022-04437-w

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