【Abstract】 Objective To summarize the recent progress in related research on transforming growth factor β1 （TGF-β1）/Smad3 signal transduction pathway and post-traumatic scar formation. Methods Recent related literature at home and abroad on TGF-β1/Smad3 signal transduction pathway and post-traumatic scar formation was reviewed and summarized. Results TGF-β1 is an important influence factor of fibrotic diseases, and it plays biological effects by TGF-β1/Smad3 signal transduction pathway. The pathway is regulated by many factors and has crosstalk with other signal pathways at cellular and molecular levels. The pathway is involved in the early post-traumatic inflammatory response, wound healing, and late pathological scar formation. Intervening the transduction pathway at the molecular level can influence the process of fibrosis and extracellular matrix deposition. Conclusion TGF-β1/Smad3 signal transduction pathway is an important way to affect post-traumatic scar formation and extracellular matrix deposition. The further study on the pathway will provide a theoretical basis for promotion of wound healing, as well as prevention and treatment of pathological scar formation.
Citation： YU Rong,CEN Ying. TRANSFORMING GROWTH FACTOR β1/Smad3 SIGNAL TRANSDUCTION PATHWAY AND POST-TRAUMATIC SCAR FORMATION. Chinese Journal of Reparative and Reconstructive Surgery, 2012, 26(3): 330-335. doi: Copy
Copyright ? the editorial department of Chinese Journal of Reparative and Reconstructive Surgery of West China Medical Publisher. All rights reserved
| 1. | 46 Takagawa S, Lakos G, Mori Y, et al. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. J Invest Dermatol, 2003, 121(1): 41-50. 47 Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracelluar matrix remodeling and wound healing. J Dermatol Sci, 2004, 35(2): 83-92. |
| 2. | |
| 3. | Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 2000, 103(2): 295-309. |
| 4. | Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nature Genet, 2001, 29(2): 117-129. |
| 5. | Rhett JM, Ghatnekar GS, Palatinus JA, et al. Novel therapies for scar reduction and regenerative healing of skin wounds. Trends Biotechnol, 2008, 26(4): 173-180. |
| 6. | Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res, 1994, 5(1): 99-118. |
| 7. | Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta, 2008, 1782(4): 197-228. |
| 8. | 曾惠芬, 王慶文. 轉化生長因子-β及其Smad信號轉導的研究進展. 中國藥物與臨床, 2010, 10(10): 1145-1147. |
| 9. | Khalil N. TGF-beta: from latent to active. J Microbes Infect, 1999, 1(15): 1255-1263. |
| 10. | Horimoto M, Kato J, Takimoto R, et al. Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line. Br J Cancer, 1995, 72(3): 676-682. |
| 11. | Huse M, Chen YG, Massagué J, et al. Crystal structure of the cytoplasmic domain of the type I TGFbeta receptor in complex with FKBP12. Cell, 1999, 96(3): 425-436. |
| 12. | Massagué J. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67: 753-791. |
| 13. | Letamendía A, Lastres P, Botella LM, et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem, 1998, 273(49): 33011-33019. |
| 14. | 趙會平, 肖嶸, 劉伏友, 等. Smad家族與硬皮病. 國外醫學: 生理、病理科學與臨床分冊, 2005, 25(2): 169-171. |
| 15. | Shi Y, Wang YF, Jayaraman L, et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell, 1998, 94(5): 585-594. |
| 16. | Wu G, Chen YG, Ozdamar B, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science, 2000, 287(5450): 92-97. |
| 17. | Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem, 2000, 267(24): 6954-6967. |
| 18. | Feng XH, Derynck R. A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity. EMBO J, 1997, 16(13): 3912-3923. |
| 19. | Ishisaki A, Yamato K, Nakao A. et al. Smad7 is an Activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells. J Biol Chem, 1998, 273(38): 24293-24296. |
| 20. | Tan R, He W, Lin X, et al. Smad ubiquitination regulatory factor-2 in the fibrotic kindney: regulation, target specificity, and functional implication. Am J Physiol Renal Physiol, 2008, 294(5): F1076-1083. |
| 21. | Dong C, Li Z, Alvarez R Jr, et al. Microtubule binding to Smads may regulate TGF beta activity. Mol Cell, 2000, 5(1): 27-34. |
| 22. | Lo RS, Massagué J. Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol, 1999, 1(8): 472-478. |
| 23. | Kretzschmar M, Doody J, Timokhina I, et al. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev, 1999, 13(7): 804-816. |
| 24. | Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest, 1999, 103(2): 197-206. |
| 25. | Boone B, Haspeslagh M, Brochez L. Clinical significance of the expression of c-Ski and SnoN, possible mediators in TGF-beta resistance, in primary cutaneous melanoma. J Dermatol Sci, 2009, 53(1): 26-33. |
| 26. | 張斌, 馬顯杰, 劉賓, 等. JNK和TGF-β信號途徑協同介導CTGF在瘢痕疙瘩成纖維細胞中過度表達. 中國美容醫學, 2009, 18(4): 506-509. |
| 27. | Cuschieri J, Maier RV. Mitogen-activated protein kinase (MAPK). Crit Care Med, 2005, 33(12 Suppl): S417-419. |
| 28. | Palmer EM, Beilfuss BA, Naqai T, et al. Human helper T cell activation and differentiation is suppressed by porcine small intestinal submucosa. Tissue Eng, 2002, 8(5): 893-900. |
| 29. | 邱振中, 李銳, 魏振雪. 皮膚傷口愈合中轉化生長因子β 信號轉導分子表達. 中國燒傷創瘍雜志, 2003, 15(3): 173-175. |
| 30. | 陳偉, 付小兵, 王海濱, 等. 增生性瘢痕形成和成熟過程中轉化生長因子-β1及下游信號分子的基因表達變化. 中華實驗外科雜志, 2005, 22(6): 740-742. |
| 31. | Xia W, Phan TT, Lim IJ, et al. Complex epithelial-mesenchymal interactions modulate transforming growth factor-beta expression in keloid-derived cells. Wound Repair Regen, 2004, 12(5): 546-556. |
| 32. | 羅梅, 姬永忠. 反義TGF-β1 抑制兔耳增生性瘢痕的實驗研究. 中國美容醫學, 2004, 13(1): 18-21. |
| 33. | Schultze-Mosqau S, Blaese MA, Grabenbauer G, et al. Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1) -treatment in irradiated rat tissue. Radiother Oncol, 2004, 70(3): 249-259. |
| 34. | 龐久玲, 馬征, 劉軍, 等. Smad3和轉化生長因子β1在瘢痕疙瘩、增生性瘢痕及正常皮膚中的表達: 48∶40∶40例標本病理檢測. 中國組織工程研究與臨床康復, 2010, 14(11): 1927-1930. |
| 35. | 孫燚, 宋建星, 汪滋民, 等. TGF-βRⅠ、Smad2、Smad3及Smad7在瘢痕疙瘩中的表達. 中華整形外科雜志, 2006, 22(5): 368-370. |
| 36. | 安綱, 蔡景龍, 董紅, 等. 轉化生長因子-β1Ⅱ型受體基因在瘢痕疙瘩中改變的實驗研究. 中國美容整形外科雜志, 2006, 17(5): 328-331. |
| 37. | Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg, 2001, 108(2): 423-429. |
| 38. | Bock O, Yu H, Zitron S, et al. Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblasts of keloids and hypertrophic scars. Acta Derm Venereol, 2005, 85(3): 216-220. |
| 39. | Goldberg HJ, Huszár T, Mózes MM, et al. Overexpression of the type II transforming growth factor-beta receptor inhibits fibroblast proliferation and activates extracellular signal regulated kinase and c-Jun N-terminal kinase. Cell Biol Int, 2002, 26(2): 165-174. |
| 40. | Bran GM, Goessler UR, Schardt CS, et al. Effect of the abrogation of TGF-beta1 by antisense oligonucleotides on the expression of TGF-beta-isoforms and their receptors I and II in isolated fibroblasts from keloid scars. Int J Mol Med, 2010, 25(6): 915-921. |
| 41. | Wang Y, Moges H, Bharucha Y, et al. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex. Exp Neurol, 2007, 203(1): 168-184. |
| 42. | 毛春明, 楊曉, 張莉, 等. Smad3基因缺失加快小鼠皮膚創面收縮速度機制研究. 中國臨床康復, 2004, 8(26): 5538-5540. |
| 43. | Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol, 2002, 160(3): 1057-1068. |
| 44. | 但洋, 沈為民, 果磊. shRNA抑制Smad3基因的表達對瘢痕疙瘩成纖維細胞Smad7表達的影響. 第三軍醫大學學報, 2009, 31(12): 1172-1176. |
| 45. | 但洋, 沈為民. shRNA對瘢痕疙瘩成纖維細胞Smad3及Ⅰ型膠原表達的影響. 激光雜志, 2009, 30(2): 78-80. |
| 46. | 劉波, 張恒術, 果磊. siRNA沉默Smad3對人KFB細胞增殖、凋亡及合成MMP3的影響. 免疫學雜志, 2009, 25(3): 301-307. |
| 47. | Yu H, Bock O, Bayat A, et al. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. J Plast Reconstr Aesthet Surg, 2006, 59(3): 221-229. |
| 48. | Saika S, Yamanaka O, Nishikawa-Ishida I, et al. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse mode. Arch Ophtalmol, 2007, 125(5): 647-654. |
| 49. | Kato M, Zhang J, Wang M, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A, 2007, 104(9): 3432-3437. |
| 50. | Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J, 2003, 22(10): 2443-2452. |
| 51. | Zhang ZF, Zhang YG, Hu DH, et al. Smad interacting protein 1 as a regulator of skin fibrosis in pathological scars. Burns, 2011, 37(4): 665-672. |
| 52. | Phan TT, Lim IJ, Chan SY, et al. Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. J Trauma, 2004, 57(5): 1032-1037. |
| 53. | Wendling J, Marchand A, Mauviel A, et al. 5-fluorouracil blocks transforming growth feator-beta-induced alpha 2 type Ⅰcollagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 actvation. Mol Pharmacol, 2003, 64(3): 707-713. |
| 54. | Suzawa H, Kikuchi S, Arai N, et al. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol, 1992, 60(2): 91-96. |
| 55. | Tang B, Zhu B, Liang Y, et al. Asiaticoside suppresses collagen expression and TGF-β/Smad signaling through inducing Smad7 and inhibiting TGF-βRI and TGF-βRII in keloid fibroblasts. Arch Dermatol Res, 2011, 303(8): 563-572. |
- 1. 46 Takagawa S, Lakos G, Mori Y, et al. Sustained activation of fibroblast transforming growth factor-beta/Smad signaling in a murine model of scleroderma. J Invest Dermatol, 2003, 121(1): 41-50. 47 Schiller M, Javelaud D, Mauviel A. TGF-beta-induced SMAD signaling and gene regulation: consequences for extracelluar matrix remodeling and wound healing. J Dermatol Sci, 2004, 35(2): 83-92.
- 2.
- 3. Massagué J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell, 2000, 103(2): 295-309.
- 4. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nature Genet, 2001, 29(2): 117-129.
- 5. Rhett JM, Ghatnekar GS, Palatinus JA, et al. Novel therapies for scar reduction and regenerative healing of skin wounds. Trends Biotechnol, 2008, 26(4): 173-180.
- 6. Burt DW, Law AS. Evolution of the transforming growth factor-beta superfamily. Prog Growth Factor Res, 1994, 5(1): 99-118.
- 7. Gordon KJ, Blobe GC. Role of transforming growth factor-beta superfamily signaling pathways in human disease. Biochim Biophys Acta, 2008, 1782(4): 197-228.
- 8. 曾惠芬, 王慶文. 轉化生長因子-β及其Smad信號轉導的研究進展. 中國藥物與臨床, 2010, 10(10): 1145-1147.
- 9. Khalil N. TGF-beta: from latent to active. J Microbes Infect, 1999, 1(15): 1255-1263.
- 10. Horimoto M, Kato J, Takimoto R, et al. Identification of a transforming growth factor beta-1 activator derived from a human gastric cancer cell line. Br J Cancer, 1995, 72(3): 676-682.
- 11. Huse M, Chen YG, Massagué J, et al. Crystal structure of the cytoplasmic domain of the type I TGFbeta receptor in complex with FKBP12. Cell, 1999, 96(3): 425-436.
- 12. Massagué J. TGF-beta signal transduction. Annu Rev Biochem, 1998, 67: 753-791.
- 13. Letamendía A, Lastres P, Botella LM, et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem, 1998, 273(49): 33011-33019.
- 14. 趙會平, 肖嶸, 劉伏友, 等. Smad家族與硬皮病. 國外醫學: 生理、病理科學與臨床分冊, 2005, 25(2): 169-171.
- 15. Shi Y, Wang YF, Jayaraman L, et al. Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell, 1998, 94(5): 585-594.
- 16. Wu G, Chen YG, Ozdamar B, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science, 2000, 287(5450): 92-97.
- 17. Itoh S, Itoh F, Goumans MJ, et al. Signaling of transforming growth factor-beta family members through Smad proteins. Eur J Biochem, 2000, 267(24): 6954-6967.
- 18. Feng XH, Derynck R. A kinase subdomain of transforming growth factor-beta (TGF-beta) type I receptor determines the TGF-beta intracellular signaling specificity. EMBO J, 1997, 16(13): 3912-3923.
- 19. Ishisaki A, Yamato K, Nakao A. et al. Smad7 is an Activin-inducible inhibitor of activin-induced growth arrest and apoptosis in mouse B cells. J Biol Chem, 1998, 273(38): 24293-24296.
- 20. Tan R, He W, Lin X, et al. Smad ubiquitination regulatory factor-2 in the fibrotic kindney: regulation, target specificity, and functional implication. Am J Physiol Renal Physiol, 2008, 294(5): F1076-1083.
- 21. Dong C, Li Z, Alvarez R Jr, et al. Microtubule binding to Smads may regulate TGF beta activity. Mol Cell, 2000, 5(1): 27-34.
- 22. Lo RS, Massagué J. Ubiquitin-dependent degradation of TGF-beta-activated smad2. Nat Cell Biol, 1999, 1(8): 472-478.
- 23. Kretzschmar M, Doody J, Timokhina I, et al. A mechanism of repression of TGFbeta/Smad signaling by oncogenic Ras. Genes Dev, 1999, 13(7): 804-816.
- 24. Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest, 1999, 103(2): 197-206.
- 25. Boone B, Haspeslagh M, Brochez L. Clinical significance of the expression of c-Ski and SnoN, possible mediators in TGF-beta resistance, in primary cutaneous melanoma. J Dermatol Sci, 2009, 53(1): 26-33.
- 26. 張斌, 馬顯杰, 劉賓, 等. JNK和TGF-β信號途徑協同介導CTGF在瘢痕疙瘩成纖維細胞中過度表達. 中國美容醫學, 2009, 18(4): 506-509.
- 27. Cuschieri J, Maier RV. Mitogen-activated protein kinase (MAPK). Crit Care Med, 2005, 33(12 Suppl): S417-419.
- 28. Palmer EM, Beilfuss BA, Naqai T, et al. Human helper T cell activation and differentiation is suppressed by porcine small intestinal submucosa. Tissue Eng, 2002, 8(5): 893-900.
- 29. 邱振中, 李銳, 魏振雪. 皮膚傷口愈合中轉化生長因子β 信號轉導分子表達. 中國燒傷創瘍雜志, 2003, 15(3): 173-175.
- 30. 陳偉, 付小兵, 王海濱, 等. 增生性瘢痕形成和成熟過程中轉化生長因子-β1及下游信號分子的基因表達變化. 中華實驗外科雜志, 2005, 22(6): 740-742.
- 31. Xia W, Phan TT, Lim IJ, et al. Complex epithelial-mesenchymal interactions modulate transforming growth factor-beta expression in keloid-derived cells. Wound Repair Regen, 2004, 12(5): 546-556.
- 32. 羅梅, 姬永忠. 反義TGF-β1 抑制兔耳增生性瘢痕的實驗研究. 中國美容醫學, 2004, 13(1): 18-21.
- 33. Schultze-Mosqau S, Blaese MA, Grabenbauer G, et al. Smad-3 and Smad-7 expression following anti-transforming growth factor beta 1 (TGFbeta1) -treatment in irradiated rat tissue. Radiother Oncol, 2004, 70(3): 249-259.
- 34. 龐久玲, 馬征, 劉軍, 等. Smad3和轉化生長因子β1在瘢痕疙瘩、增生性瘢痕及正常皮膚中的表達: 48∶40∶40例標本病理檢測. 中國組織工程研究與臨床康復, 2010, 14(11): 1927-1930.
- 35. 孫燚, 宋建星, 汪滋民, 等. TGF-βRⅠ、Smad2、Smad3及Smad7在瘢痕疙瘩中的表達. 中華整形外科雜志, 2006, 22(5): 368-370.
- 36. 安綱, 蔡景龍, 董紅, 等. 轉化生長因子-β1Ⅱ型受體基因在瘢痕疙瘩中改變的實驗研究. 中國美容整形外科雜志, 2006, 17(5): 328-331.
- 37. Chin GS, Liu W, Peled Z, et al. Differential expression of transforming growth factor-beta receptors I and II and activation of Smad 3 in keloid fibroblasts. Plast Reconstr Surg, 2001, 108(2): 423-429.
- 38. Bock O, Yu H, Zitron S, et al. Studies of transforming growth factors beta 1-3 and their receptors I and II in fibroblasts of keloids and hypertrophic scars. Acta Derm Venereol, 2005, 85(3): 216-220.
- 39. Goldberg HJ, Huszár T, Mózes MM, et al. Overexpression of the type II transforming growth factor-beta receptor inhibits fibroblast proliferation and activates extracellular signal regulated kinase and c-Jun N-terminal kinase. Cell Biol Int, 2002, 26(2): 165-174.
- 40. Bran GM, Goessler UR, Schardt CS, et al. Effect of the abrogation of TGF-beta1 by antisense oligonucleotides on the expression of TGF-beta-isoforms and their receptors I and II in isolated fibroblasts from keloid scars. Int J Mol Med, 2010, 25(6): 915-921.
- 41. Wang Y, Moges H, Bharucha Y, et al. Smad3 null mice display more rapid wound closure and reduced scar formation after a stab wound to the cerebral cortex. Exp Neurol, 2007, 203(1): 168-184.
- 42. 毛春明, 楊曉, 張莉, 等. Smad3基因缺失加快小鼠皮膚創面收縮速度機制研究. 中國臨床康復, 2004, 8(26): 5538-5540.
- 43. Flanders KC, Sullivan CD, Fujii M, et al. Mice lacking Smad3 are protected against cutaneous injury induced by ionizing radiation. Am J Pathol, 2002, 160(3): 1057-1068.
- 44. 但洋, 沈為民, 果磊. shRNA抑制Smad3基因的表達對瘢痕疙瘩成纖維細胞Smad7表達的影響. 第三軍醫大學學報, 2009, 31(12): 1172-1176.
- 45. 但洋, 沈為民. shRNA對瘢痕疙瘩成纖維細胞Smad3及Ⅰ型膠原表達的影響. 激光雜志, 2009, 30(2): 78-80.
- 46. 劉波, 張恒術, 果磊. siRNA沉默Smad3對人KFB細胞增殖、凋亡及合成MMP3的影響. 免疫學雜志, 2009, 25(3): 301-307.
- 47. Yu H, Bock O, Bayat A, et al. Decreased expression of inhibitory SMAD6 and SMAD7 in keloid scarring. J Plast Reconstr Aesthet Surg, 2006, 59(3): 221-229.
- 48. Saika S, Yamanaka O, Nishikawa-Ishida I, et al. Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse mode. Arch Ophtalmol, 2007, 125(5): 647-654.
- 49. Kato M, Zhang J, Wang M, et al. MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A, 2007, 104(9): 3432-3437.
- 50. Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J, 2003, 22(10): 2443-2452.
- 51. Zhang ZF, Zhang YG, Hu DH, et al. Smad interacting protein 1 as a regulator of skin fibrosis in pathological scars. Burns, 2011, 37(4): 665-672.
- 52. Phan TT, Lim IJ, Chan SY, et al. Suppression of transforming growth factor beta/smad signaling in keloid-derived fibroblasts by quercetin: implications for the treatment of excessive scars. J Trauma, 2004, 57(5): 1032-1037.
- 53. Wendling J, Marchand A, Mauviel A, et al. 5-fluorouracil blocks transforming growth feator-beta-induced alpha 2 type Ⅰcollagen gene (COL1A2) expression in human fibroblasts via c-Jun NH2-terminal kinase/activator protein-1 actvation. Mol Pharmacol, 2003, 64(3): 707-713.
- 54. Suzawa H, Kikuchi S, Arai N, et al. The mechanism involved in the inhibitory action of tranilast on collagen biosynthesis of keloid fibroblasts. Jpn J Pharmacol, 1992, 60(2): 91-96.
- 55. Tang B, Zhu B, Liang Y, et al. Asiaticoside suppresses collagen expression and TGF-β/Smad signaling through inducing Smad7 and inhibiting TGF-βRI and TGF-βRII in keloid fibroblasts. Arch Dermatol Res, 2011, 303(8): 563-572.