{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T15:21:54Z","timestamp":1785770514913,"version":"3.56.0"},"reference-count":43,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T00:00:00Z","timestamp":1699833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81570995"],"award-info":[{"award-number":["81570995"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2020CFB617"],"award-info":[{"award-number":["2020CFB617"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Hubei Provincial Natural Science Foundation of China","award":["81570995"],"award-info":[{"award-number":["81570995"]}]},{"name":"Hubei Provincial Natural Science Foundation of China","award":["2020CFB617"],"award-info":[{"award-number":["2020CFB617"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fibrosis commonly arises from salivary gland injuries induced by factors such as inflammation, ductal obstruction, radiation, aging, and autoimmunity, leading to glandular atrophy and functional impairment. However, effective treatments for these injuries remain elusive. Transforming growth factor-beta 1 (TGF-\u03b21) is fundamental in fibrosis, advancing fibroblast differentiation into myofibroblasts and enhancing the extracellular matrix in the salivary gland. The involvement of the SMAD pathway and reactive oxygen species (ROS) in this context has been postulated. Metformin, a type 2 diabetes mellitus (T2DM) medication, has been noted for its potent anti-fibrotic effects. Through human samples, primary salivary gland fibroblasts, and a rat model, this study explored metformin\u2019s anti-fibrotic properties. Elevated levels of TGF-\u03b21 (p &lt; 0.01) and alpha-smooth muscle actin (\u03b1-SMA) (p &lt; 0.01) were observed in human sialadenitis samples. The analysis showed that metformin attenuates TGF-\u03b21-induced fibrosis by inhibiting SMAD phosphorylation (p &lt; 0.01) through adenosine 5\u2032-monophosphate (AMP)-activated protein kinase (AMPK)-independent pathways and activating the AMPK pathway, consequently suppressing NADPH oxidase 4 (NOX4) (p &lt; 0.01), a main ROS producer. Moreover, in rats, metformin not only reduced glandular fibrosis post-ductal ligation but also protected acinar cells from ligation-induced injuries, thereby normalizing the levels of aquaporin 5 (AQP5) (p &lt; 0.05). Overall, this study underscores the potential of metformin as a promising therapeutic option for salivary gland fibrosis.<\/jats:p>","DOI":"10.3390\/ijms242216260","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T08:35:52Z","timestamp":1699864552000},"page":"16260","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Metformin Attenuates TGF-\u03b21-Induced Fibrosis in Salivary Gland: A Preliminary Study"],"prefix":"10.3390","volume":"24","author":[{"given":"Lianhao","family":"Wang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nian-Nian","family":"Zhong","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaofeng","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boyuan","family":"Peng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"},{"name":"Department of Oral Radiology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"},{"name":"Department of Oral Radiology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6435-2027","authenticated-orcid":false,"given":"Yuhong","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Cheng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"},{"name":"Department of Oral Radiology, School & Hospital of Stomatology, Wuhan University, Wuhan 430079, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Zhang, X.L., Yun, J.S., Han, D., Yook, J.I., Kim, H.S., and Cho, E.S. 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