Clinical efficacy of Salvia miltiorrhiza in pathological scar treatment: A systematic review and meta-analysis

doi:10.5246/jcps.2024.09.063

Abstract

Abstract:

To systematically assess the clinical efficacy of Salvia miltiorrhiza (SM) in treating pathological scars and provide a reference basis for scar pharmacotherapy, we conducted a comprehensive literature search in both English and Chinese databases from database inception to December 2022. Key search terms included Salvia miltiorhiza, cryptotanshinone, tanshinone IIA, sodium-tanshinol, compound Salvia miltiorrhiza dripping pills, cicatrix, cicatrices, and scar. The inclusion criteria encompassed all clinical randomized controlled studies on the treatment of pathological scars with SM, without regard to blinding or allocation concealment, as well as irrespective of patient nationality, race, or age. Data from the selected literature were subjected to analysis using RevMan 5.4 software, employing the standard mean difference or weighted mean difference for numerical variables and odds ratios (ORs) for dichotomous variables. Statistical significance was set at P < 0.05. Six eligible studies involving a total of 778 patients met the inclusion criteria. The analysis revealed a significant therapeutic efficacy with an OR of 3.83 (95% CI: 2.65–5.54), indicating a substantially higher therapeutic efficacy rate in SM group compared to the control group. Furthermore, the total effective rate of treatment exhibited an OR of 6.94 (95% CI: 2.53–19.06), signifying a significantly superior treatment outcome in SM group. Regarding scar scores, no significant improvement was observed in SM group compared to the control group after 3 months of treatment (mean difference [MD] = –0.96, 95% CI: –2.29–0.36). However, after 6 months of treatment, the scar score demonstrated a noteworthy improvement in SM group (MD = –1.37, 95% CI: –2.44 to –0.30) compared to the control group. In summary, this study affirmed that SM treatment markedly enhanced the therapeutic efficacy and overall treatment efficiency for clinical scar patients, underscoring its positive clinical therapeutic impact on scar patients.

Key words: SM, Pathological scar, Meta-analysis, TGF-β

Supporting:

Zhihong Song, Jinji Yang, Hongzhuang Zhang, Wenxia Fan, Anqi Zhu, Shaojie Li, Hao Fu. Clinical efficacy of Salvia miltiorrhiza in pathological scar treatment: A systematic review and meta-analysis[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(9): 846-856.

Figures/Tables 6

References 38

[1]	Moretti, L.; Stalfort, J.; Barker, T.H.; Abebayehu, D. The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation. J. Biol. Chem. 2022, 298, 101530.
[2]	Griffin, M.F.; Borrelli, M.R.; Garcia, J.T.; Januszyk, M.; King, M.; Lerbs, T.; Cui, L.; Moore, A.L.; Shen, A.H.; Mascharak, S.; Diaz Deleon, N.M.; Adem, S.; Taylor, W.L.; desJardins-Park, H.E.; Gastou, M.; Patel, R.A.; Duoto, B.A.; Sokol, J.; Wei, Y.N.; Foster, D.; Chen, K.; Wan, D.C.; Gurtner, G.C.; Lorenz, H.P.; Chang, H.Y.; Wernig, G.; Longaker, M.T. JUN promotes hypertrophic skin scarring via CD36 in preclinical in vitro and in vivo models. Sci. Transl. Med. 2021, 13, eabb3312.
[3]	Li, S.Y.; Ding, H.F.; Yang, Y.; Yu, B.Y.; Chen, M.L. Global research status of pathological scar reported over the period 2001-2021: a 20-year bibliometric analysis. Int. Wound J. 2023, 20, 1725–1738.
[4]	Bian, Q.; Zhang, P.; Wei, Y. Prevention and treatment strategies and progress of pathological scars in traditional Chinese medicine and Western medicine. J. Chin. Int. Med. Surg. 2021, 3, 532–537.
[5]	Chen, S.X.; Cheng, J.; Watchmaker, J.; Dover, J.S.; Chung, H.J. Review of lasers and energy-based devices for skin rejuvenation and scar treatment with histologic correlations. Dermatol. Surg. 2022, 48, 441–448.
[6]	Qu, C.A.; Su, X.S.; Hu, J.T.; Zhan, S.E.; Li, Z.H.; Liu, Y.; Wang, L.Z. Clinical observation of microplasma radiofrequency technology combined with glucocorticoid injection in the treatment of hundreds of cases of hypertrophic scar after early deep burn and scald. J. Craniofac. Surg. 2023, 34, 687–690.
[7]	Zhang, Y.; Wu, K. Exploring the medication rules of traditional Chinese medicine in the treatment of pathological scars. Heilongjiang J. Tradit. Chin. Med. 2021, 3, 210–211.
[8]	Yang, Y.T.; Yang, J.H.; Fu, W.; Zhou, P.; He, Y.; Fang, M.S.; Wan, H.T.; Zhou, H.F. Pharmacokinetic comparison of nine bioactive compounds of Guanxinshutong capsule in normal and acute myocardial infarction rats. Eur. J. Drug Metab. Pharmacokinet. 2022, 47, 653–665.
[9]	Wang, D.F.; Yu, W.B.; Cao, L.; Xu, C.C.; Tan, G.Y.; Zhao, Z.X.; Huang, M.; Jin, J. Comparative pharmacokinetics and tissue distribution of cryptotanshinone, tanshinone IIA, dihydrotanshinone I, and tanshinone I after oral administration of pure tanshinones and liposoluble extract of Salvia miltiorrhiza to rats. Biopharm. Drug Dispos. 2020, 41, 54–63.
[10]	Yang, Z.; Qi, J.S.; Ping, D.B.; Sun, X.; Tao, Y.Y.; Liu, C.H.; Peng, Y. Salvia miltiorrhiza in thorax and abdomainal organ fibrosis: a review of its pharmacology. Front. Pharmacol. 2022, 13, 999604.
[11]	Unahabhokha, T.; Sucontphunt, A.; Nimmannit, U.; Chanvorachote, P.; Yongsanguanchai, N.; Pongrakhananon, V. Molecular signalings in keloid disease and current therapeutic approaches from natural based compounds. Pharm. Biol. 2015, 53, 457–463.
[12]	Chong, C.H.; Sun, J.M.; Liu, Y.X.; Tsai, Y.T.; Zheng, D.N.; Zhang, Y.F.; Yu, L. Salvianolic acid B attenuates hypertrophic scar formation in vivo and in vitro. Aesthetic Plast. Surg. 2023, 47, 1587–1597.
[13]	Chen, J.; Han, C.M.; Dong, H.L.; Qi, F.Z.; Chen, G.S. Study on the therapeutic effect of salvia miltiorrhiza and azone on scars. Chin. J. Plastic Surg. 2004, 3, 760–62.
[14]	Li, H.; Liu, Z; Lei, Y.M.; Cao, Y.H. Application of Salvia Miltiorrhiza Dexamethasone Cream in the Treatment of Scars. Chin. J. Doct. 2004, 6, 845–846.
[15]	Li, M. Clinical observation on the prevention of surgical scar formation in 42 cases by local application of salvia miltiorrhiza combined with TDP irradiation. Zhongyuan Yishu Kan. 2005, 19, 24–25.
[16]	Luo, W.; Chen, J.F.; Liu, Y.Y. Observation on the efficacy of Galla Chinensis and Salvia Miltiorrhiza cream combined with prednisolone in the treatment of keloid. Hunan J. Tradii. Chin. Med. 2009, 6, 17–18.
[17]	Yang, W.; Yang, M.L.; Lu, G.Z. Observation on the efficacy of drug injection in the treatment of 60 cases of hypertrophic scars. Chin. J. Cosmetic Med. 2010, 3, 323–325.
[18]	Wang, X.; Wu, W.Y.; Wang, C.Y. Research on the treatment of superficial depressed scars on the face and neck with ultrasound combined with compound Danshen cream. Chin. J. Modern Med. 2016, 15, 62–64.
[19]	Guo, Y.L.; Luo, P.Y.; Wang, Y.; Fang, R.H. Observation of the efficacy of narrow-band intense pulsed light combined with compound betamethasone injection in the treatment of pathological scars. J. Dermatol. Venereol. 2020, 4, 257–259.
[20]	Keskin, E.S.; Keskin, E.R.; Öztürk, M.B.; Çakan, D. The effect of MMP-1 on wound healing and scar formation. Aesthetic Plast. Surg. 2021, 45, 2973–2979.
[21]	Yang, J.X.; Chen, M.L.; He, L.R. To explore ideas from the altered metabolites: the metabolomics of pathological scar. J. Craniofac. Surg. 2022, 33, 1619–1625.
[22]	Eremenko, E.; Ding, J.; Kwan, P.; Tredget, E.E. The biology of extracellular matrix proteins in hypertrophic scarring. Adv. Wound Care. 2022, 11, 234–254.
[23]	Fredman, R.; Tenenhaus, M. Cushing’s syndrome after intralesional triamcinolone acetonide: a systematic review of the literature and multinational survey. Burns. 2013, 39, 549–557.
[24]	Gong, X.; Chen, M. The efficacy of different pulse width 595 nm dye laser combined with 5-FU in the treatment of hypertrophic scars and its impact on scar blood perfusion. Chin. J. Aesthetic Med. 2022, 12, 87–90.
[25]	Ogawa, R.; Akita, S.; Akaishi, S.; Aramaki-Hattori, N.; Dohi, T.; Hayashi, T.; Kishi, K.; Kono, T.; Matsumura, H.; Muneuchi, G.; Murao, N.; Nagao, M.; Okabe, K.; Shimizu, F.; Tosa, M.; Tosa, Y.; Yamawaki, S.; Ansai, S.; Inazu, N.; Kamo, T.; Kazki, R.; Kuribayashi, S. Diagnosis and treatment of keloids and hypertrophic scars-japan scar workshop consensus document 2018. Burns Trauma. 2019, 7, 39.
[26]	Berman, B.; Maderal, A.; Raphael, B. Keloids and hypertrophic scars: pathophysiology, classification, and treatment. Dermatol. Surg. 2017, 43, S3–S18.
[27]	Lin, Z.J.; Bao, Y.Y.; Hong, B.; Wang, Y.Y.; Zhang, X.M.; Wu, Y.P. Salvianolic acid B attenuated cisplatin-induced cardiac injury and oxidative stress via modulating Nrf2 signal pathway. J. Toxicol. Sci. 2021, 46, 199–207.
[28]	Tan, F.H.P.; Ting, A.C.J.; Leow, B.G.; Najimudin, N.; Watanabe, N.; Azzam, G. Alleviatory effects of Danshen, Salvianolic acid A and Salvianolic acid B on PC12 neuronal cells and Drosophila melanogaster model of Alzheimer’s disease. J. Ethnopharmacol. 2021, 279, 114389.
[29]	Wang, D.; Lu, X.N.; Wang, E.B.; Shi, L.G.; Ma, C.; Tan, X.D. Salvianolic acid B attenuates oxidative stress-induced injuries in enterocytes by activating Akt/GSK3β signaling and preserving mitochondrial function. Eur. J. Pharmacol. 2021, 909, 174408.
[30]	Sun, J.M.; Ho, C.K.; Gao, Y.; Chong, C.H.; Zheng, D.N.; Zhang, Y.F.; Yu, L. Salvianolic acid-B improves fat graft survival by promoting proliferation and adipogenesis. Stem Cell Res. Ther. 2021, 12, 507.
[31]	Wu, C.; Chen, W.Y.; Ding, H.Y.; Li, D.; Wen, G.H.; Zhang, C.; Lu, W.P.; Chen, M.; Yang, Y. Salvianolic acid B exerts anti-liver fibrosis effects via inhibition of MAPK-mediated phospho-Smad2/3 at linker regions in vivo and in vitro. Life Sci. 2019, 239, 116881.
[32]	Zhang, T.Y.; Liu, M.J.; Gao, Y.H.; Li, H.; Song, L.; Hou, H.P.; Chen, T.F.; Ma, L.N.; Zhang, G.P.; Ye, Z.G. Salvianolic acid B inhalation solution enhances antifibrotic and anticoagulant effects in a rat model of pulmonary fibrosis. Biomed. Pharmacother. 2021, 138, 111475.
[33]	Zhang, Y.F.; Wang, J.; Zhou, S.Z.; Xie, Z.B.; Wang, C.D.; Gao, Y.; Zhou, J.; Zhang, X.L.; Li, Q.F. Flavones hydroxylated at 5, 7, 3' and 4' ameliorate skin fibrosis via inhibiting activin receptor-like kinase 5 kinase activity. Cell Death Dis. 2019, 10, 124.
[34]	Li, Y.; Shi, S.; Gao, J.X.; Han, S.C.; Wu, X.; Jia, Y.H.; Su, L.L.; Shi, J.H.; Hu, D.H. Cryptotanshinone downregulates the profibrotic activities of hypertrophic scar fibroblasts and accelerates wound healing: a potential therapy for the reduction of skin scarring. Biomed. Pharmacother. 2016, 80, 80–86.
[35]	Xia, Z.H.; Wang, J.C.; Yang, S.L.; Liu, C.; Qin, S.; Li, W.B.; Cheng, Y.L.; Hu, H.; Qian, J.; Liu, Y.; Deng, C.L. Emodin alleviates hypertrophic scar formation by suppressing macrophage polarization and inhibiting the Notch and TGF-β pathways in macrophages. Braz. J. Med. Biol. Res. 2021, 54, e11184.
[36]	Yang, J.; Gong, Y.F.; Xu, W.J.; Li, L.L.; Shi, Z.H.; Wang, Q.; He, Y.H.; Zhang, C.; Luo, C.C.; Fang, Z.R.; Yang, Y. Smad3 gene C-terminal phosphorylation site mutation exacerbates CCl₄-induced hepatic fibrogenesis by promoting pSmad2L/C-mediated signaling transduction. Naunyn Schmiedebergs Arch. Pharmacol. 2021, 394, 1779–1786.
[37]	Wang, Q.L.; Tao, Y.Y.; Yuan, J.L.; Shen, L.; Liu, C.H. Salvianolic acid B prevents epithelial-to-mesenchymal transition through the TGF-β1 signal transduction pathway in vivo and in vitro. BMC Cell Biol. 2010, 11, 31.
[38]	Pakshir, P.; Hinz, B. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 2018, 68/69, 81–93.