{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T13:43:22Z","timestamp":1782827002582,"version":"3.54.5"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the key bioactive component of Salvia miltiorrhiza (Danshen) for repairing Achilles tendon injury and to elucidate its underlying mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A network pharmacology approach was employed to screen for common targets for Danshen in Achilles tendon repair, identifying Tanshinone IIA (Tan IIA) as the key bioactive component. Its targets were then subjected to Protein-Protein Interaction (PPI) and KEGG pathway analyses. Subsequently, a rat model of Achilles tendon injury was established. After a 4-week intervention with Tan IIA, its reparative effects were comprehensively evaluated using histological, biomechanical, immunohistochemical (IHC), and ELISA methods.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Network pharmacology predicted that Tan IIA acts through core targets such as AKT1 and EGFR to regulate pathways including PI3K-Akt and MAPK.\n                      <jats:italic>In vivo<\/jats:italic>\n                      experiments confirmed that, compared to the model group, Tan IIA significantly improved tissue structure (histological score,\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.001) and enhanced the ultimate tensile load (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01). It also upregulated Collagen Type I (COL\u2160) expression (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05) while downregulating Vascular Endothelial Growth Factor A (VEGFA) expression (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01), and effectively modulated serum inflammation by decreasing IL-6 (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01) while increasing IL-10 and TGF-\u03b2 (\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Tan IIA is the key bioactive component of Salvia miltiorrhiza for repairing Achilles tendon injury. It effectively promotes the structural and functional healing of the tendon by synergistically regulating key processes such as inflammation, matrix remodeling, and angiogenesis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1673962","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T06:32:01Z","timestamp":1763015521000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Salvia miltiorrhiza (Danshen) promotes Achilles tendon repair: from network pharmacology prediction to in vivo mechanistic validation"],"prefix":"10.3389","volume":"16","author":[{"given":"Yu","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianyan","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoyuan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziyan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqi","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junze","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxu","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yifeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiguo","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1089\/ten.teb.2022.0188","article-title":"Drug delivery approaches to improve Tendon healing","volume":"29","author":"Adjei-Sowah","year":"2023","journal-title":"Tissue Eng. Part B Rev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.5005\/jp-journals-10040-1113","article-title":"Nonoperative management of Achilles tendon rupture: a clinical debate","volume":"7","author":"Al-Dadah","year":"2020","journal-title":"J. Foot Ankle Surg. Asia Pac."},{"key":"B3","doi-asserted-by":"publisher","first-page":"031","DOI":"10.5606\/ehc.2015.08","article-title":"Effect of ankaferd blood stopper\u00ae on tendon healing: an experimental study in a rat model of Achilles tendon injury","volume":"26","author":"Ayd\u0131n","year":"2015","journal-title":"Jt. Dis. Relat. Surg."},{"key":"B4","doi-asserted-by":"publisher","first-page":"896336","DOI":"10.3389\/fbioe.2022.896336","article-title":"Dynamic load model systems of tendon inflammation and mechanobiology","volume":"10","author":"Benage","year":"2022","journal-title":"Front. Bioeng. Biotechnol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1690","DOI":"10.1002\/jbmr.3755","article-title":"VEGFA from early osteoblast lineage cells (Osterix+) is required in mice for fracture healing","volume":"34","author":"Buettmann","year":"2019","journal-title":"J. Bone Min. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"2406611","DOI":"10.1002\/advs.202406611","article-title":"CTHRC1 attenuates tendinopathy via enhancing EGFR\/MAPK signaling pathway","volume":"11","author":"Chen","year":"2024","journal-title":"Adv. Sci."},{"key":"B7","doi-asserted-by":"publisher","first-page":"384","DOI":"10.3390\/nu15020384","article-title":"Is curcumine useful in the treatment and prevention of the tendinopathy and myotendinous junction injury? A scoping review","volume":"15","author":"C\u00f3rdova","year":"2023","journal-title":"Nutrients"},{"key":"B8","doi-asserted-by":"publisher","first-page":"315","DOI":"10.30795\/jfootankle.2024.v18.1858","article-title":"Achilles tendon injuries in high-performance athletes: from tendinopathies to rupture","volume":"18","author":"De Oliveira J\u00fanior","year":"2024","journal-title":"J. Foot & Ankle"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1425","DOI":"10.1038\/s41598-022-25579-3","article-title":"Network pharmacology and experimental validation to identify the potential mechanism of Hedyotis diffusa willd against rheumatoid arthritis","volume":"13","author":"Deng","year":"2023","journal-title":"Sci. Rep."},{"key":"B10","doi-asserted-by":"publisher","first-page":"452","DOI":"10.1016\/j.aott.2018.06.012","article-title":"Role of a combination dietary supplement containing mucopolysaccharides, vitamin C, and collagen on tendon healing in rats","volume":"52","author":"Gemalmaz","year":"2018","journal-title":"Acta Orthop. traumatologica turcica"},{"key":"B11","doi-asserted-by":"publisher","first-page":"3734","DOI":"10.1038\/s41467-025-59010-y","article-title":"PI3K-Akt signalling regulates Scx-lineage tenocytes and Tppp3-lineage paratenon sheath cells in neonatal tendon regeneration","volume":"16","author":"Goto","year":"2025","journal-title":"Nat. Commun."},{"key":"B12","doi-asserted-by":"publisher","first-page":"23380","DOI":"10.1038\/s41598-024-74783-w","article-title":"Deprivation of loading during rat Achilles tendon healing affects extracellular matrix composition and structure, and reduces cell density and alignment","volume":"14","author":"Hammerman","year":"2024","journal-title":"Sci. Rep."},{"key":"B13","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1186\/1472-6882-14-493","article-title":"Salvianolic acid B promotes bone formation by increasing activity of alkaline phosphatase in a rat tibia fracture model: a pilot study","volume":"14","author":"He","year":"2014","journal-title":"BMC Complementary Altern. Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"600","DOI":"10.1016\/j.reth.2025.04.009","article-title":"Historical evolution, hotspots, and trends in tendon tissue engineering: a bibliometric analysis","volume":"29","author":"Hou","year":"2025","journal-title":"Regen. Ther."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3892\/ijmm.2023.5273","article-title":"Mesenchymal stem cells: an efficient cell therapy for tendon repair","volume":"52","author":"Jiang","year":"2023","journal-title":"Int. J. Mol. Med."},{"key":"B16","doi-asserted-by":"publisher","first-page":"857","DOI":"10.3390\/antiox9090857","article-title":"Overview of Salvia miltiorrhiza as a potential therapeutic agent for various diseases: an update on efficacy and mechanisms of action","volume":"9","author":"Jung","year":"2020","journal-title":"Antioxidants"},{"key":"B17","doi-asserted-by":"publisher","first-page":"5830","DOI":"10.1038\/s41598-021-84847-w","article-title":"Quantifying mechanical loading and elastic strain energy of the human Achilles tendon during walking and running","volume":"11","author":"Kharazi","year":"2021","journal-title":"Sci. Rep."},{"key":"B18","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1093\/bjs\/znab259.1043","article-title":"Could antiangiogenic drugs be the solution to Tendon injury? A literature review on the use of antiangiogenic drugs for tendon regeneration","author":"Kirchhoff","year":"2021","journal-title":"Excell. adversity"},{"key":"B19","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1016\/j.addr.2018.02.010","article-title":"Limiting angiogenesis to modulate scar formation","volume":"146","author":"Korntner","year":"2019","journal-title":"Adv. Drug Deliv. Rev."},{"key":"B20","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1186\/s13018-025-05483-y","article-title":"Mechanisms and new advances in the efficacy of plant active ingredients in tendon-bone healing","volume":"20","author":"Li","year":"2025","journal-title":"J. Orthop. Surg. Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1111\/sms.12892","article-title":"Microcirculation after Achilles tendon rupture correlates with functional and patient\u2010reported outcomes","volume":"28","author":"Praxitelous","year":"2018","journal-title":"Scand. J. Med. & Sci. sports"},{"key":"B22","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Reagan-Shaw","year":"2008","journal-title":"Faseb J."},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.60118\/001c.38922","article-title":"Surgical repair and augmentation of a midsubstance chronic achilles tendon rupture with a novel biocomposite scaffold: a case report","volume":"3","author":"Redler","year":"2022","journal-title":"J. Orthop. Exp. & Innovation"},{"key":"B24","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.coph.2009.04.008","article-title":"Anti-inflammatory and pro-inflammatory roles of TGF-\u03b2, IL-10, and IL-22 in immunity and autoimmunity","volume":"9","author":"Sanjabi","year":"2009","journal-title":"Curr. Opin. Pharmacol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1302\/2046-3758.118.BJR-2021-0576.R1","article-title":"Tendon healing: a concise review on cellular and molecular mechanisms with a particular focus on the Achilles tendon","volume":"11","author":"Schulze-Tanzil","year":"2022","journal-title":"Bone & Jt. Res."},{"key":"B26","doi-asserted-by":"publisher","first-page":"16","DOI":"10.17555\/jvc.2023.40.1.16","article-title":"Comparison of augmentation method for Achilles tendon repair: using thoracolumbar fascia and the polypropylene mesh","volume":"40","author":"Seo","year":"2023","journal-title":"J. veterinary Clin."},{"key":"B27","doi-asserted-by":"publisher","first-page":"641","DOI":"10.3390\/ijms24010641","article-title":"Acute inflammation in tissue healing","volume":"24","author":"Soliman","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B28","doi-asserted-by":"publisher","first-page":"4251","DOI":"10.2147\/JIR.S427024","article-title":"Radix Salvia miltiorrhiza ameliorates burn injuries by reducing inflammation and promoting wound healing","volume":"16","author":"Tian","year":"2023","journal-title":"J. Inflamm. Res."},{"key":"B29","doi-asserted-by":"publisher","first-page":"676","DOI":"10.52312\/jdrs.2021.10","article-title":"The effects of tendoflex\u00ae(polytendon complex) and Hypericum perforatum (St. John\u2019s wort oil) on repaired Achilles tendon healing in rats","volume":"32","author":"Tuncer","year":"2021","journal-title":"Jt. Dis. Relat. Surg."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1003183","DOI":"10.37349\/ei.2025.1003183","article-title":"The role of cytokines in wound healing: from mechanistic insights to therapeutic applications","volume":"5","author":"Wong","year":"2025","journal-title":"Explor. Immunol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1016\/j.jgr.2021.08.005","article-title":"Ginsenoside Rg1 enhances the healing of injured tendon in achilles tendinitis through the activation of IGF1R signaling mediated by oestrogen receptor","volume":"46","author":"Wu","year":"2022","journal-title":"J. Ginseng Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1002\/ptr.8372","article-title":"Tanshinone IIA alleviates pulmonary fibrosis by inhibiting pyroptosis of alveolar epithelial cells through the MAPK signaling pathway","volume":"39","author":"Xu","year":"2025","journal-title":"Phytother. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"09603271231180864","DOI":"10.1177\/09603271231180864","article-title":"Tanshinone IIA inhibits ischemia-reperfusion-induced inflammation, ferroptosis and apoptosis through activation of the PI3K\/Akt\/mTOR pathway","volume":"42","author":"Zhang","year":"2023","journal-title":"Hum. & Exp. Toxicol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1083","DOI":"10.7150\/ijms.44138","article-title":"Improved tendon healing by a combination of Tanshinone IIA and miR-29b inhibitor treatment through preventing tendon adhesion and enhancing tendon strength","volume":"17","author":"Zhou","year":"2020","journal-title":"Int. J. Med. Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1673962\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T06:32:02Z","timestamp":1763015522000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1673962\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,13]]},"references-count":34,"alternative-id":["10.3389\/fphar.2025.1673962"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1673962","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,13]]},"article-number":"1673962"}}