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      Using Drosophila melanogaster as a suitable platform for drug discovery from natural products in inflammatory bowel disease

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          Abstract

          Inflammatory bowel disease (IBD) is a chronic and life-treating inflammatory disease that can occur in multiple parts of the human intestine and has become a worldwide problem with a continually increasing incidence. Because of its mild early symptoms, most of them will not attract people’s attention and may cause more serious consequences. There is an urgent need for new therapeutics to prevent disease progression. Natural products have a variety of active ingredients, diverse biological activities, and low toxicity or side effects, which are the new options for preventing and treating the intestinal inflammatory diseases. Because of multiple genetic models, less ethical concerns, conserved signaling pathways with mammals, and low maintenance costs, the fruit fly Drosophila melanogaster has become a suitable model for studying mechanism and treatment strategy of IBD. Here, we review the advantages of fly model as screening platform in drug discovery, describe the conserved molecular pathways as therapetic targets for IBD between mammals and flies, dissect the feasibility of Drosophila model in IBD research, and summarize the natural products for IBD treatment using flies. This review comprehensively elaborates that the benefit of flies as a perfact model to evaluate the therapeutic potential of phytochemicals against IBD.

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          Most cited references158

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          Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

          The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.
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            Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism

            The multifunctional regulator nuclear factor erythroid 2-related factor (Nrf2) is considered not only as a cytoprotective factor regulating the expression of genes coding for anti-oxidant, anti-inflammatory and detoxifying proteins, but it is also a powerful modulator of species longevity. The vertebrate Nrf2 belongs to Cap ‘n’ Collar (Cnc) bZIP family of transcription factors and shares a high homology with SKN-1 from Caenorhabditis elegans or CncC found in Drosophila melanogaster. The major characteristics of Nrf2 are to some extent mimicked by Nrf2-dependent genes and their proteins including heme oxygenase-1 (HO-1), which besides removing toxic heme, produces biliverdin, iron ions and carbon monoxide. HO-1 and their products exert beneficial effects through the protection against oxidative injury, regulation of apoptosis, modulation of inflammation as well as contribution to angiogenesis. On the other hand, the disturbances in the proper HO-1 level are associated with the pathogenesis of some age-dependent disorders, including neurodegeneration, cancer or macular degeneration. This review summarizes our knowledge about Nrf2 and HO-1 across different phyla suggesting their conservative role as stress-protective and anti-aging factors.
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              Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut.

              Cells in intestinal epithelia turn over rapidly due to damage from digestion and toxins produced by the enteric microbiota. Gut homeostasis is maintained by intestinal stem cells (ISCs) that divide to replenish the intestinal epithelium, but little is known about how ISC division and differentiation are coordinated with epithelial cell loss. We show here that when enterocytes (ECs) in the Drosophila midgut are subjected to apoptosis, enteric infection, or JNK-mediated stress signaling, they produce cytokines (Upd, Upd2, and Upd3) that activate Jak/Stat signaling in ISCs, promoting their rapid division. Upd/Jak/Stat activity also promotes progenitor cell differentiation, in part by stimulating Delta/Notch signaling, and is required for differentiation in both normal and regenerating midguts. Hence, cytokine-mediated feedback enables stem cells to replace spent progeny as they are lost, thereby establishing gut homeostasis.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                05 December 2022
                2022
                : 13
                : 1072715
                Affiliations
                [1] 1 College of Public Health , Gansu University of Chinese Medicine , Lanzhou, China
                [2] 2 Provincial-level Key Laboratory for Molecular Medicine of Major Diseases and the Prevention and Treatment with Traditional Chinese Medicine Research in Gansu Colleges and University , Gansu University of Chinese Medicine , Lanzhou, China
                [3] 3 Key Laboratory of Dunhuang Medicine , Ministry of Education , Lanzhou, China
                [4] 4 College of Basic Medicine , Gansu University of Chinese Medicine , Lanzhou, China
                Author notes

                Edited by: Andresa Heemann Betti, Feevale University, Brazil

                Reviewed by: Jay V. Patankar, University of Erlangen Nuremberg, Germany

                Saeideh Momtaz, Academic Center for Education, Culture and Research, Iran

                *Correspondence: Jianzheng He, hejianzheng1006@ 123456163.com

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                [ † ]

                These authors have contributed equally to this work

                Article
                1072715
                10.3389/fphar.2022.1072715
                9760693
                36545307
                6757d082-7910-4186-a0ce-30e8c756f2e7
                Copyright © 2022 Xiu, Wang, Yang, Zhang, Dai, Liu, Lin, Li and He.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 17 October 2022
                : 24 November 2022
                Funding
                Funded by: National Natural Science Foundation of China , doi 10.13039/501100001809;
                Funded by: Gansu University of Chinese Medicine , doi 10.13039/501100012562;
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                inflammatory bowel disease,drosophila melanogaster,natural products,drug discovery,molecular pathways

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