{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T13:03:55Z","timestamp":1771506235242,"version":"3.50.1"},"reference-count":43,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T00:00:00Z","timestamp":1737849600000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["21H03115"],"award-info":[{"award-number":["21H03115"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["iubmb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["BioFactors"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>SARS\u2010CoV\u20102\u2010related proteins, ACE2 and TMPRSS2, are determinants of SARS\u2010CoV\u20102 infection. Although these proteins are expressed in oral\u2010related tissues, their expression patterns and modulatory mechanisms in the salivary glands remain unknown. We herein showed that full\u2010length ACE2, which has both a fully functional enzyme catalytic site and high\u2010affinity SARS\u2010CoV\u20102 spike S1\u2010binding sites, was more highly expressed in salivary glands than in oral mucosal epithelial cells and the lungs. Regarding TMPRSS2, zymogen and the cleaved form were both expressed in the salivary glands, whereas only zymogen was expressed in murine lacrimal glands and the lungs. Metformin, an AMPK activator, increased stimulated saliva secretion and full\u2010length ACE2 expression and decreased cleaved TMPRSS2 expression in the salivary glands, and exerted the same effects on soluble ACE2 (sACE2) and sTMPRSS2 in saliva. Moreover, metformin decreased the expression of beta\u2010galactosidase, a senescence marker, and ADAM17, a sheddase of ACE2 to sACE2, in the salivary glands. In aged mice, the expression of ACE2 was decreased in the salivary glands, whereas that of sACE2 was increased in saliva, presumably by the up\u2010regulated expression of ADAM17. The expression of TMPRSS2 in the salivary glands and sTMPRSS2 in saliva were both increased. Collectively, these results suggest that the protein expression patterns of ACE2 and TMPRSS2 in the salivary glands differ from those in other oral\u2010related cells and tissues, and also that metformin and aging affect the salivary expression of ACE2 and TMPRSS2, which have the potential as targets for preventing the transmission of SARS\u2010CoV\u20102.<\/jats:p>","DOI":"10.1002\/biof.2154","type":"journal-article","created":{"date-parts":[[2025,1,26]],"date-time":"2025-01-26T23:48:10Z","timestamp":1737935290000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Involvement of metformin and aging in salivary expression of\n                    <scp>ACE2<\/scp>\n                    and\n                    <scp>TMPRSS2<\/scp>"],"prefix":"10.1002","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0495-8393","authenticated-orcid":false,"given":"Yosuke","family":"Shikama","sequence":"first","affiliation":[{"name":"Department of Oral Disease Research National Center for Geriatrics and Gerontology  Obu Japan"},{"name":"Department of Geriatric Oral Science, Graduate School of Dentistry Tohoku University  Sendai Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3546-8143","authenticated-orcid":false,"given":"Kunihiro","family":"Otsuka","sequence":"additional","affiliation":[{"name":"Department of Oral Molecular Pathology Tokushima University Graduate School of Biomedical Sciences  Tokushima Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuka","family":"Shikama","sequence":"additional","affiliation":[{"name":"Department of Oral Disease Research National Center for Geriatrics and Gerontology  Obu 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