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The TGF-\u03b21\/Smad signaling pathway, particularly Smad2 and Smad3 mediate pro-fibrotic responses, while Smad7 exerts inhibitory effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>The study aimed to evaluate the therapeutic potential of paraxanthine (Para), an active caffeine metabolite, and azilsartan (Azil), an angiotensin II receptor blocker, in attenuating gentamicin (GM)-induced renal fibrosis through targeting Smad pathway and miRNA-21\/200b.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Seventy male albino mice were randomized into seven groups (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200910): Control, GM, SIS3\u2009+\u2009GM, Para\u2009+\u2009GM, Azil\u2009+\u2009GM, Para\u2009+\u2009SIS3\u2009+\u2009GM, and Azil\u2009+\u2009SIS3\u2009+\u2009GM. GM (40\u2009mg\/kg, I.P.) was administered daily for 7\u2009days. Subsequently, Para (20.5\u2009mg\/kg) and Azil (5\u2009mg\/kg) were given orally, while SIS3 (2\u2009mg\/kg, I.P.) was administered for 7\u2009days. Serum and urine renal function markers were measured. Renal histopathology, protein expression of TGF-\u03b21, CTGF, Smad3, Smad2 and Smad7, and gene expression of miRNA-21 and miRNA-200b were evaluated.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GM caused significant (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.001) nephrotoxicity with elevated BUN, serum creatinine, urinary albumin\/creatinine ratio, and KIM-1 and increased fibrosis and marked type I collagen deposition compared to normal control. However, treatments with Para &amp; Azil resulted in significant (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.05) improvement in renal functions. Pro-fibrotic markers TGF-\u03b21, connective tissue growth factor (CTGF), Type I Collagen, Smad 2 and Smad3 were reduced, while Smad7 was increased in treated groups\n                      <jats:italic>versus<\/jats:italic>\n                      GM group. Additionally, miRNA-21 was downregulated and miRNA-200b was upregulated following treatments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Paraxanthine and azilsartan demonstrated significantl restoring of kidney function and suppressing fibrotic progression. Their actions were mediated through regulation of Smad3\/7 signaling and modulation of miRNA-21 and miRNA-200b expression, highlighting these pathways as promising therapeutic targets for the treatment of renal fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08051-y","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T11:26:13Z","timestamp":1778498773000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Paraxanthine and azilsartan attenuate gentamicin-induced renal fibrosis via modulation of TGF-\u03b21\/Smad3\/7 signaling and miRNA-21\/miRNA-200b expression"],"prefix":"10.1186","volume":"24","author":[{"given":"Nany Saad","family":"Rizk El-Adwy","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahla E.","family":"El-Ashmawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghada M.","family":"Al-Ashmawy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4539-8940","authenticated-orcid":false,"given":"Naglaa F.","family":"Khedr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,11]]},"reference":[{"key":"8051_CR1","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/s00441-017-2754-1","volume":"372","author":"I Loeffler","year":"2018","unstructured":"Loeffler I, Liebisch M, Allert S, Kunisch E, Kinne RW, Wolf G. 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