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      Tangeretin attenuates bleomycin-induced pulmonary fibrosis by inhibiting epithelial-mesenchymal transition via the PI3K/Akt pathway

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          Abstract

          Background: Pulmonary fibrosis (PF) is a terminal pathological change in a variety of lung diseases characterized by excessive deposition of extracellular matrix, for which effective treatment is lacking. Tangeretin (Tan), a flavonoid derived from citrus, has been shown to have a wide range of pharmacological effects. This study aimed to investigate the role and potential mechanisms of Tan on pulmonary fibrosis.

          Methods: A model of pulmonary fibrosis was established by administering bleomycin through tracheal drip, followed by administering Tan or pirfenidone through gavage. HE and Masson staining were employed to assess the extent of pulmonary fibrosis. Subsequently, Western blot, enzyme-linked immunosorbent assay (ELISA), RNA sequencing, and immunohistochemistry techniques were employed to uncover the protective mechanism of Tan in PF mice. Furthermore, A549 cells were stimulated with TGF-β1 to induce epithelial-mesenchymal transition (EMT) and demonstrate the effectiveness of Tan in mitigating PF.

          Results: Tan significantly ameliorated bleomycin-induced pulmonary fibrosis, improved fibrotic pathological changes, and collagen deposition in the lungs, and reduced lung inflammation and oxidative stress. The KEGG pathway enrichment analysis revealed a higher number of enriched genes in the PI3K/Akt pathway. Additionally, Tan can inhibit the EMT process related to pulmonary fibrosis.

          Conclusion: Taken together, the above research results indicate that Tan suppresses inflammation, oxidative stress, and EMT in BLM-induced pulmonary fibrosis via the PI3K/Akt pathway and is a potential agent for the treatment of pulmonary fibrosis.

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          Most cited references58

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          TGF-β: the master regulator of fibrosis.

          Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease (CKD). Inhibition of the TGF-β isoform, TGF-β1, or its downstream signalling pathways substantially limits renal fibrosis in a wide range of disease models whereas overexpression of TGF-β1 induces renal fibrosis. TGF-β1 can induce renal fibrosis via activation of both canonical (Smad-based) and non-canonical (non-Smad-based) signalling pathways, which result in activation of myofibroblasts, excessive production of extracellular matrix (ECM) and inhibition of ECM degradation. The role of Smad proteins in the regulation of fibrosis is complex, with competing profibrotic and antifibrotic actions (including in the regulation of mesenchymal transitioning), and with complex interplay between TGF-β/Smads and other signalling pathways. Studies over the past 5 years have identified additional mechanisms that regulate the action of TGF-β1/Smad signalling in fibrosis, including short and long noncoding RNA molecules and epigenetic modifications of DNA and histone proteins. Although direct targeting of TGF-β1 is unlikely to yield a viable antifibrotic therapy due to the involvement of TGF-β1 in other processes, greater understanding of the various pathways by which TGF-β1 controls fibrosis has identified alternative targets for the development of novel therapeutics to halt this most damaging process in CKD.
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            Akt signalling in health and disease.

            Akt (also known as protein kinase B or PKB) comprises three closely related isoforms Akt1, Akt2 and Akt3 (or PKBα/β/γ respectively). We have a very good understanding of the mechanisms by which Akt isoforms are activated by growth factors and other extracellular stimuli as well as by oncogenic mutations in key upstream regulatory proteins including Ras, PI3-kinase subunits and PTEN. There are also an ever increasing number of Akt substrates being identified that play a role in the regulation of the diverse array of biological effects of activated Akt; this includes the regulation of cell proliferation, survival and metabolism. Dysregulation of Akt leads to diseases of major unmet medical need such as cancer, diabetes, cardiovascular and neurological diseases. As a result there has been substantial investment in the development of small molecular Akt inhibitors that act competitively with ATP or phospholipid binding, or allosterically. In this review we will briefly discuss our current understanding of how Akt isoforms are regulated, the substrate proteins they phosphorylate and how this integrates with the role of Akt in disease. We will furthermore discuss the types of Akt inhibitors that have been developed and are in clinical trials for human cancer, as well as speculate on potential on-target toxicities, such as disturbances of heart and vascular function, metabolism, memory and mood, which should be monitored very carefully during clinical trial. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Non-Smad Signaling Pathways of the TGF-β Family.

              Ying Zhang (2017)
              Transforming growth factor β (TGF-β) and structurally related factors use several intracellular signaling pathways in addition to Smad signaling to regulate a wide array of cellular functions. These non-Smad signaling pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. This review summarizes the current knowledge of the mechanisms by which non-Smad signaling pathways are directly activated in response to ligand binding, how activation of these pathways impinges on Smads and non-Smad targets, and how final cellular responses are affected in response to these noncanonical signaling modes.
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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
                15 September 2023
                2023
                : 14
                : 1247800
                Affiliations
                [1] 1 College of Veterinary Medicine , Jilin University , Changchun, China
                [2] 2 Department of Internal Medicine-Cardiovascular , The Third Affiliated Hospital of Changchun University of Traditional Chinese Medicine , Changchun, China
                Author notes

                Edited by: Yan Huang, Anhui Medical University, China

                Reviewed by: Manish Bodas, Centers for Disease Control and Prevention (CDC), United States

                Ayyanar Sivanantham, Boston University, United States

                *Correspondence: Pengfei Yi, yipengfei@ 123456jlu.edu.cn
                [ † ]

                These authors have contributed equally to this work

                Article
                1247800
                10.3389/fphar.2023.1247800
                10540689
                37781713
                9d9cc442-f5e3-4942-875c-1705b8a29288
                Copyright © 2023 Li, Wei, Song, Wang, Yang, Li, Yu, Su, Peng, Fu and Yi.

                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
                : 26 June 2023
                : 06 September 2023
                Funding
                This Work was funded by the National Natural Science Foundation of China, Grant Number 31972724.
                Categories
                Pharmacology
                Original Research
                Custom metadata
                Inflammation Pharmacology

                Pharmacology & Pharmaceutical medicine
                pulmonary fibrosis,tangeretin,pi3k/akt signaling pathway,epithelial-mesenchymal transition,bleomycin

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