摘要
瘢痕疙瘩是皮肤创伤后引发的以成纤维细胞异常增殖并分泌大量细胞外基质（extracellular matrix，ECM）为主要特征的一种皮肤纤维化疾病，治疗效果不佳，复发率较高，发病机制尚不清楚。近年来研究发现，组蛋白去乙酰化酶（histonedeacetylase，HDAC）活性增高与多种组织和器官纤维化的发生发展密切相关，使用HDAC抑制剂降低HDAC活性可抑制皮肤正常成纤维细胞ECM的合成。同时HDAC活性增高还是多种肿瘤发生的病理机制，使用HDAC抑制剂可以通过激活凋亡信号，使异常增殖的肿瘤细胞生长停滞，诱导其凋亡。所以我们也推测HDAC活性增加可能与瘢痕疙瘩成纤维细胞的增殖和分泌大量ECM密切相关。本课题将研究I型HDAC（HDAC1和HDAC2）在瘢痕疙瘩成纤维细胞中的表达情况，并使用HDAC抑制剂TSA进行体内和体外实验进行干预，以期阐明I型HDAC是如何参与瘢痕疙瘩形成的病理机制，为HDAC抑制剂类药物临床应用预防和治疗瘢痕疙瘩提供理论基础。
实验一HDAC1和HDAC2在瘢痕疙瘩成纤维细胞中表达的实验研究
目的：本实验旨在研究I型HDAC（HDAC1和HDAC2）在瘢痕疙瘩成纤维细胞中的表达情况，并与正常皮肤成纤维细胞相比较，以期为瘢痕疙瘩提供新的发病机制，及治疗的新切入点。
方法：我们首先进行瘢痕疙瘩成纤维细胞与正常皮肤成纤维细胞原代培养。接着通过RT-PCR和western blot方法检测HDAC1和HDAC2在瘢痕疙瘩成纤维细胞中的表达情况，并与正常皮肤成纤维细胞相比较。
结果：我们通过RT-PCR方法检测发现，瘢痕疙瘩成纤维细胞HDAC1和HDAC2mRNA的表达均比正常皮肤成纤维细胞明显增高。接着，用western blot方法检测同样证实瘢痕疙瘩成纤维细胞HDAC1和HDAC2蛋白的表达也均比正常皮肤成纤维细胞要高。
结论：我们的研究证实HDAC1和HDAC2在瘢痕疙瘩成纤维细胞中的表达明显增高。HDAC1和HDAC2的活性增强，可以使原有的基因表达平衡状态被打破，从而导致细胞增殖、凋亡和纤维化等生物学特征的异常，这可能是瘢痕疙瘩成纤维细胞过度增殖并合成大量ECM的病理新机制。
实验二HDAC抑制剂TSA诱导瘢痕疙瘩成纤维细胞凋亡的实验研究
目的：HDAC抑制剂TSA可以引起多种恶性增殖的细胞生长停滞，促进其发生凋亡，本实验旨在研究TSA是否可以诱导瘢痕疙瘩成纤维细胞发生凋亡及TSA对细胞HDAC1和HDAC2蛋白表达的影响。
方法：首先，我们向培养的瘢痕疙瘩成纤维细胞加入不同浓度的HDAC抑制剂TSA（200nmol/L、400nmol/L、600nmol/L和800nmol/L），运用MTT法检测TSA对细胞活力的影响。然后，通过Hoechst染色和流式细胞仪检测TSA诱导瘢痕疙瘩成纤维细胞发生凋亡的作用。最后，运用western blot方法检测TSA对瘢痕疙瘩成纤维细胞HDAC1和HDAC2蛋白表达的影响。
结果：通过MTT法检测TSA对细胞增殖的影响，结果发现随着浓度和时间的变化，TSA抑制细胞的增殖存在量效性和时效性的特点。成纤维细胞对于200nmol/L TSA作用耐受性良好，在600nmol/L和800nmol/LTSA作用下，细胞活力明显下降。随后600nmol/L TSA单独作用瘢痕疙瘩成纤维细胞，通过Hoechst染色和流式细胞仪检测同样证实TSA可以诱导瘢痕疙瘩成纤维细胞发生凋亡。最后，运用western blot方法检测发现600nmol/LTSA处理瘢痕疙瘩成纤维细胞48h后，瘢痕疙瘩成纤维细胞HDAC1和HDAC2蛋白的表达明显受到了抑制。
结论：我们的研究证实HDAC抑制剂TSA可以抑制瘢痕疙瘩成纤维细胞增殖，诱导其发生凋亡，这可能是通过抑制HDAC1和HDAC2的表达来实现的。
实验三HDAC抑制剂TSA抑制瘢痕疙瘩成纤维细胞胶原合成的实验研究
目的：本实验旨在研究HDAC抑制剂TSA是否可以抑制TGF-β促瘢痕疙瘩成纤维细胞胶原合成的作用。
方法：我们分别通过RT-PCR和western blot方法检测600nmol/LTSA单独作用或者联合5ng/ml TGF-β1蛋白对瘢痕疙瘩成纤维细胞I型胶原（collagen I）mRNA和蛋白表达的影响。
结果：通过RT-PCR检测发现，向培养的瘢痕疙瘩成纤维细胞加入5ng/ml TGF-β1，可以促进细胞collagen I mRNA合成，而同时加入600nmol/L TSA后，可以抑制TGF-β1促进细胞collagen I mRNA合成的作用。单独使用600nmol/L TSA后这种抑制作用会更加显著。Western blot方法检测同样证实TSA可以抑制细胞collagen I蛋白的合成。
结论：我们的研究证实HDAC抑制剂TSA可以抑制瘢痕疙瘩成纤维细胞胶原合成，这就为这种已经在临床治疗多种肿瘤的HDAC抑制剂应用于瘢痕疙瘩临床预防和治疗提供实验基础。
实验四HDAC抑制剂TSA抑制兔耳增生性瘢痕形成的实验研究
目的：已证实HDAC抑制剂TSA能够有效抑制体外培养的皮肤成纤维细胞胶原合成而起到抗纤维化作用，本部分实验拟通过兔耳增生性瘢痕模型验证TSA是否能够在体内实验抑制瘢痕的形成。
方法：建立兔耳增生性瘢痕模型。每个兔耳做4个直径为1cm，间距为2cm的圆形全层皮肤缺损创面。每只兔的左耳为TSA治疗组，分别在创面上皮化后创面局部注射TSA，每个创面使用0.02%TSA0.05ml。连续注射1周。右耳为对照组，分别在相同时间点局部注射相同剂量生理盐水0.05ml。术后第23d收集瘢痕标本，进行RT-PCR和western blot检测collagen I和纤维连接蛋白（fibronectin）mRNA和蛋白的表达情况。术后第45d收集瘢痕标本，行HE染色切片计算瘢痕增生指数（scarelevation index，SEI）。
结果：TSA治疗组瘢痕比对照组厚度较薄，术后45d时间点其SEI在TSA治疗组明显下降（1.45±0.09vs2.07±0.10），差异有统计学意义。同时，RT-PCR和western blot检测也证实在术后第23d（TSA治疗1周后），TSA可以有效的抑制collagen I和fibronectin表达。
结论：我们的研究证实HDAC抑制剂TSA可以在体通过抑制collagen I和fibronectin的合成，有效的抑制兔耳增生性瘢痕的形成。
Keloid is a pathological wound healing response to cutaneous injury andcharacterized by fibroblastic proliferation and accumulation of extracellular matrix.Clinically, keloids have proven to be very resistant to treatment. Despite the relativelyhigh prevalence of keloids in the general population, the mechanisms underlying keloidformation are only partially understood. Recent studies indicate that histone deacetylase（HDAC）activity is also associated with the development and progression of somechronic diseases characterized by fibrosis. And inhibition of HDAC activity of fibroblastsby a number of structurally divergent classes of HDAC inhibitors causes significantinhibition of extracellular matrix synthesis. Furthermore, HDAC inhibitors have been shown to induce arrest, differentiation, and/or apoptosis of proliferating cells. So wehypothesize that increased activity of HDAC may be associated with keloid fibroblastproliferation and accumulation of extracellular matrix. In this study, we will research ofclass I HDAC（HDAC1and HDAC2）expressions in keloid fibroblasts, and throughrespectively in vivo and in vitro experimental intervention with HDAC inhibitor TSA, toclarify how class I HDACs are involved in keloid fibroblasts proliferation and collagensecretion. Our study will open up the possibility of testing HDAC inhibitors for clinicalprevention and treatment of keloids.
Experiment1The study of HDAC1and HDAC2expressions in keloid fibroblasts
Purpose: To investigate HDAC1and HDAC2expressions in keloid fibroblasts andnormal fibroblasts. To provide new pathogenetic mechanisms for keloid formation andnew treatment point.
Methods: We cultured keloid fibroblasts and normal skin fibroblasts. Then, we researchedthe expressions of HDAC1and HDAC2in keloid fibroblasts and normal fibroblasts byRT-PCR and western blot.Results: The increase of HDAC1and HDAC2mRNA expressions were observed inkeloid fibroblasts compared to normal fibroblasts. These results were also confirmed bywestern blot analysis. Western blot analysis showed that the expressions of HDAC1andHDAC2protein were markedly up-regulated in keloid fibroblasts compared to normalfibroblasts.
Conclusion: Our study confirmed that expressions of HDAC1and HDAC2in thekeloid-derived fibroblasts were significantly higher. Enhanced HDAC1and HDAC2activity, which makes the original gene expression balance has been broken, leading toabnormal cell proliferation, apoptosis and fibrosis and other biological characteristics.HDAC1and HDAC2activity may be a new pathogenetic mechanism for keloidformation.
Experiment2Histone deacetylase inhibitor TSA induces apoptosis of keloidfibroblasts
Purpose: As TSA could induce growth arrest and apoptosis of many kind of cells, the aimof this study is to determine whether HDAC inhibitor trichostatin A（TSA）could induceapoptosis of proliferating keloid fibroblasts and inhibit the expressions of HDAC1andHDAC2.
Methods: We first studied the effect of escalating doses（200nmol/L,400nmol/L,600nmol/L or800nmol/L）of TSA on keloid fibroblasts viability using MTT proliferationassays. Then, to further investigate the inhibitory effect of TSA on proliferation of keloidfibroblasts, we stained cells using Hoechst staining after600nmol/L TSA treatment, andflow cytometry analysis was performed as a second independent method. Furthermore,after treatment with600nmol/L TSA for48h, we researched the expressions of HDAC1and HDAC2protein expressions in keloid fibroblasts by western blot.
Results: HDAC inhibitor TSA inhibited the growth of keloid fibroblasts indose-dependent and time-dependent manner monitored using MTT proliferation assays.Lower TSA doses of200nmol/L were well tolerated with preserved cell viability relativeto control. A statistically significant decrease in cell viability was observed at aconcentration of TSA（600nmol/L and800nmol/L）after incubation for12h, compared tocontrol. Hoechst staining and flow cytometry analysis showed significantly moreapoptotic cells were observed in600nmol/L TSA treated group compared to controls.Furthermore, treatment with TSA abrogated HDAC1and HDAC2expressionsdramatically. Western blot analysis showed that treatment with TSA for48h, theexpressions of HDAC1and HDAC2were markedly decreased in keloid fibroblasts.Conclusion: On the basis of our in vitro evidence we can state that TSA could inhibitproliferation and induce apoptosis of keloid fibroblasts with the decreased expressions ofHDAC1and HDAC2.
Experiment3Histone deacetylase inhibitor TSA inhibits collagen synthesis of keloid fibroblasts
Purpose: The aim of this study is to determine whether HDAC inhibitor TSA could causeabrogation of TGF-β induced collagen synthesis in keloid fibroblasts.
Methods: We researched the expressions of collagen I in keloid fibroblasts treatment with600nmol/L TSA or/and5ng/ml TGF-β1by RT-PCR and western blot.
Results: The addition of5ng/ml TGF-β1up-regulated collagen I mRNA expressioncompared to controls by RT-PCR analysis. But incubation with600nmol/L TSA, theincrease of collagen I mRNA expression induced by TGF-β1was reduced by50%compared to controls. Furthermore, treatment with TSA alone abrogated collagen I mRNAexpression dramatically. These results were confirmed by western blot analysis. Westernblot analysis showed that treatment with TSA, the expression of collagen I protein inducedby TGF-β1was markedly decreased.
Conclusion: On the basis of our in vitro evidence we can state that TSA inhibition ofECM may be an appropriate therapeutic strategy for the management of keloid. Our studyopens up the possibility of testing HDAC inhibitor, an agent already in clinical trials forthe treatment of many tumors, for clinical keloid treatment use.
Experiment4Histone deacetylase inhibitor TSA reduces hypertrophic scarring in arabbit ear model
Purpose: To test the ability of HDAC inhibitor TSA to reduce hypertrophic scar formationin a rabbit ear model, which had been confirmed to have potent anti-fibrogenic effects andsuppress collagen synthesis of skin fibroblasts.
Methods: We had developed a reliable model in rabbit that resulted in hypertrophicscarring. Four1cm full-thickness circular wounds were made on each ear. After thewounds re-epithelialized,0.02%TSA was intradermally injected to the wounds in thetreatment group. Collagen I and fibronectin expressions were detected by RT-PCR andwestern blot at postoperative day（POD）23. Scar hypertrophy was quantified by measurement of the scar elevation index（SEI）at POD45.
Results: Compared to the control group, the injection of TSA led to much morenormal-looking of scars in the rabbit ear. SEI at POD45was significantly decreased afterinjections of TSA versus untreated scars（1.45±0.09vs.2.07±0.10）. Further more, weconfirmed the decreased expression of collagen I and fibronectin at POD23（after beingtreated with TSA for one week）in the treated scars compared to the control by RT-PCRand western blot analysis.
Conclusions: The introduction of TSA can result in the decreased formation ofhypertrophic scars in a rabbit ear model, which is corroborated by evidence of decreasedcollagen I and fibronectin synthesis.
引文
1. Bran GM, Goessler UR, Hormann K, et al. Keloids: current concepts of pathogenesis(review). Int J Mol Med,2009,24(3):283-293.
2. De Felice B, Garbi C, Santoriello M, et al. Differential apoptosis markers in humankeloids and hypertrophic scars fibroblasts. Mol Cell Biochem,2009,327(1-2):191-201.
3. Fujiwara M, Muragaki Y, Ooshima A. Keloid-derived fibroblasts show increasedsecretion of factors involved in collagen turnover and depend on matrixmetalloproteinase for migration. Br J Dermatol,2005,153(2):295-300.
4. Zhang GY, Yi CG, Li X, et al. Inhibition of vascular endothelial growth factorexpression in keloid fibroblasts by vector-mediated vascular endothelial growth factorshRNA: a therapeutic potential strategy for keloid. Arch Dermatol Res,2008,300(4):177-184.
5. Song B, Zhang W, Guo S, et al. Adenovirus-mediated METH1gene expressioninhibits hypertrophic scarring in a rabbit ear model. Wound Repair Regen,2009,17(4):559-568.
6. Berman B, Flores F. The treatment of hypertrophic scars and keloids. Eur J Dermatol,1998,8(8):591-595.
7.鲍卫汉,徐少骏.激素治疗瘢痕的机理研究.中华外科杂志,2000,38(5):378-381.
8. Rombouts K, Niki T, Greenwel P, et al. Trichostatin A, a histone deacetylase inhibitor,suppresses collagen synthesis and prevents TGF-beta(1)-induced fibrogenesis in skinfibroblasts. Exp Cell Res,2002,278(2):184-197.
9. Ghosh AK, Mori Y, Dowling E, et al. Trichostatin A blocks TGF-beta-inducedcollagen gene expression in skin fibroblasts: involvement of Sp1. Biochem BiophysRes Commun,2007,354(2):420-426.
10. Venugopal B, Evans TR. Developing histone deacetylase inhibitors as anti-cancertherapeutics. Curr Med Chem,2011,18(11):1658-1671.
11. Thurn KT, Thomas S, Moore A, et al. Rational therapeutic combinations with histonedeacetylase inhibitors for the treatment of cancer. Future Oncol,2011,7(2):263-283.
12. O'Connor EJ, Badshah II, Addae LY,et al.Histone deacetylase2is upregulated innormal and keloid scars. J Invest Dermatol,2012,132(4):1293-1296.
13. Arima J, Ogawa R, Iimura T, et al. Relationship between Keloid and Hypertension. JNippon Med Sch,2012,79(6):494-495.
14. Xi-Qiao W, Ying-Kai L, Chun Q, et al. Hyperactivity of fibroblasts and functionalregression of endothelial cells contribute to microvessel occlusion in hypertrophicscarring. Microvasc Res,2009,77(2):204-211.
15. Staton CA, Valluru M, Hoh L, et al. Angiopoietin-1, angiopoietin-2and Tie-2receptorexpression in human dermal wound repair and scarring. Br J Dermatol,2010,163(5):920-927.
16. Gira AK, Brown LF, Washington CV, et al. Keloids demonstrate high-level epidermalexpression of vascular endothelial growth factor. J Am Acad Dermatol,2004,50(6):850-853.
17. Wilgus TA, Ferreira AM, Oberyszyn TM, et al. Regulation of scar formation byvascular endothelial growth factor. Lab Invest,2008,88(6):579-590.
18. Le AD, Zhang Q, Wu Y, et a1. Elevated vascular endothelial growth factor in keloids:relevance to tissue fibrosis. Cells Tissues Organs,2004,176(1-3):87-94.
19. Hill LM, Gavala ML, Lenertz LY, et al. Extracellular ATP may contribute to tissuerepair by rapidly stimulating purinergic receptor X7-dependent vascular endothelialgrowth factor release from primary human monocytes. J Immunol,2010,185(5):3028-3034.
20. Ehrlich HP, Desmoulière A, Diegelmann RF, et a1. Morphological andimmunochemical differences between keloid and hypertrophic scar. Am J Pathol,1994,145(1):105-113.
21. Wu Y, Zhang Q, Ann DK, et al. Increased vascular endothelial growth factor mayaccount for elevated level of plasminogen activator inhibitor-1via activating ERK1/2in keloid fibroblasts. Am J Physiol Cell Physiol,2004,286(4):C905-912.
22. Wu WS, Wang FS, Yang KD, et al. Dexamethasone induction of keloid regressionthrough effective suppression of VEGF expression and keloid fibroblast proliferation.J Invest Dermatol,2006,126(6):1264-1271.
23. Nissen NN, Polverini PJ, Koch AE, et al. Vascular endothelial growth factor mediatesangiogenic activity during the proliferative phase of wound healing. Am J Pathol,1998,152(6):1445-1452.
24. Brown LF, Yeo KT, Berse B, et al. Expression of vascular permeability factor(vascular endothelial growth factor) by epidermal keratinocytes during wound healing.J Exp Med,1992,176(5):1375-1379.
25. Steinbrech DS, Mehrara BJ, Chau D, et al. Hypoxia upregulates VEGF production inkeloid fibroblasts. Ann Plast Surg,1999,42(5):514-519.
26. YUE Yi-gang, JIANG Chang-wen, LI Pei-ying, et al. A study on endothelialcell-targeted therapy with VEGF antibody for the cure of hypertrophic scar in nudemice. Chinese J Pract Aesth Plast Surg,2006,17(1):68-71.
27. Adhami VM, Syed DN, Khan N, et al. Dietary flavonoid fisetin: a novel dual inhibitorof PI3K/Akt and mTOR for prostate cancer management. Biochem Pharmacol,2012,84(10):1277-1281.
28. Ge Y, Chen J. Mammalian target of rapamycin (mTOR) signaling network in skeletalmyogenesis. J Biol Chem,2012,287(52):43928-43935.
29. Yang Z, Ming XF. mTOR signalling: the molecular interface connecting metabolicstress, aging and cardiovascular diseases. Obes Rev,2012,13Suppl2:58-68.
30. Shegogue D, Trojanowska M. Mammalian target of rapamycin positively regulatescollagen type I production via a phosphatidylinositol3-kinase-independent pathway. JBiol Chem,2004,279(22):23166-23175.
31. Ong CT, Khoo YT, Mukhopadhyay A, et al. mTOR as a potential therapeutic targetfor treatment of keloids and excessive scars. Exp Dermatol,2007,16(5):394-404.
32. Syed F, Sanganee HJ, Bahl A, et al. Potent dual inhibitors of TORC1and TORC2complexes (KU-0063794and KU-0068650) demonstrate in vitro and ex vivoanti-keloid scar activity. J Invest Dermatol,2013Jan10. doi:10.1038/jid.2012.483.
33. Syed F, Sherris D, Paus R, et al. Keloid disease can be inhibited by antagonizingexcessive mTOR signaling with a novel dual TORC1/2inhibitor.Am J Pathol,2012,181(5):1642-1658.
34. Szatmary Z. Molecular biology of toll-like receptors. Gen Physiol Biophys,2012,31(4):357-366.
35. Gosu V, Basith S, Kwon OP, et al. Molecules,2012,17(11):13503-13529.
36. Bai T, Lian LH, Wu YL, et al. Thymoquinone attenuates liver fibrosis via PI3K andTLR4signaling pathways in activated hepatic stellate cells. Int Immunopharmacol,2013, pii: S1567-5769(12)00398-0.
37. Bhattacharyya S, Kelley K, Melichian DS, et al. Toll-Like Receptor4SignalingAugments Transforming Growth Factor-β Responses: A Novel Mechanism forMaintaining and Amplifying Fibrosis in Scleroderma.Am J Pathol,2013,182(1):192-205.
38. Chen J, Zeng B, Yao H, et al. The effect of TLR4/7on the TGF-β-induced Smadsignal transduction pathway in human keloid.Burns,2012, pii: S0305-4179(12)00238-0.
39. Bagabir RA, Syed F, Rautemaa R, et al. Upregulation of Toll-like receptors (TLRs)6,7, and8in keloid scars.J Invest Dermatol,2011,131(10):2128-2130.
40. Koch U, Lehal R, Radtke F. Stem cells living with a Notch. Development,2013,140(4):689-704.
41. Rota R, Ciarapica R, Miele L, et al. Notch signaling in pediatric soft tissue sarcomas.BMC Med,2012,10:141.
42. Cheng F, Pekkonen P, Ojala PM. Instigation of Notch signaling in the pathogenesis ofKaposi's sarcoma-associated herpesvirus and other human tumor viruses. FutureMicrobiol,2012,7(10):1191-1205.
43.李冰,夏炜. Notch信号在表皮及皮肤疾病中的研究进展.中国美容医学,2010,19(10)：1565-1569.
44.夏炜,潘宝华,刘宾,等. Notch信号在增生性瘢痕表皮中的表达.中华整形外科杂志,2009(1):41-45.
45.李冰,刁建升,楚菲菲,等.阻断Notch信号抑制角质形成细胞的分泌功能的研究.中国美容医学,2012,21(4):576-579.
46.刁建升,张曦,任静,等.阻断Notch信号对兔耳增生性瘢痕形成的影响及作用机制.中华医学杂志,2009,89(16):1088-1092.
47. Syed F, Bayat A. Notch signaling pathway in keloid disease: enhanced fibroblastactivity in a Jagged-1peptide-dependent manner in lesional vs. extralesionalfibroblasts. Wound Repair Regen,2012,20(5):688-706.
48. Dees C, Tomcik M, Zerr P, et al. Notch signalling regulates fibroblast activation andcollagen release in systemic sclerosis. Ann Rheum Dis,2011,70(7):1304-1310.
49. Maas C, Kane MA, Bucay VW, at al. Current aesthetic use of abobotulinumtoxinA inclinical practice: an evidence-based consensus review. Aesthet Surg J,2012,32(1Suppl):8S-29S.
50. Won CH, Lee HM, Lee WS, at al. Efficacy and safety of a novel botulinum toxin typeA product for the treatment of moderate to severe glabellar lines: a randomized,double-blind, active-controlled multicenter study. Dermatol Surg,2013,39(1Pt2):171-178.
51.王琳,邰宁正,傅敏刚,等. A型肉毒素注射治疗瘢痕疙瘩顽固性痛痒的临床研究.组织工程与重建外科,2009,5:286-288.
52. Uyesugi B, Lippincott B, Dave S. Treatment of a painful keloid with botulinum toxintype A. Am J Phys Med Rehabil,2010,89(2):153-155.
53.王琳,邰宁正,范志宏. A型肉毒毒素局部应用对兔耳增生性瘢痕创面愈合和瘢痕增生的影响.中华整形外科杂志,2009,7(4):284-287.
54. Xiao Z, Qu G. Effects of botulinum toxin type a on collagen deposition inhypertrophic scars.Molecules,2012,17(2):2169-2177.
55. Zhibo X, Miaobo Z. Botulinum Toxin Type A affects cell cycle distribution offibroblasts derived from hypertrophic scar. J Plast Reconstr Aesthet Surg,2008,61(9):1128-1129.
56. Xiao Z, Zhang M, Liu Y, et al. Botulinum toxin type a inhibits connective tissuegrowth factor expression in fibroblasts derived from hypertrophic scar. Aesthetic PlastSurg,2011,35(5):802-807.
57. Zhibo X, Miaobo Z. Intralesional botulinum toxin type A injection as a new treatmentmeasure for keloids. Plast Reconstr Surg,2009,124(5):275e-277e.
58. Robinson AJ, Khadim MF, Khan K. Keloid scars and treatment with Botulinum ToxinType A: The Belfast experience. J Plast Reconstr Aesthet Surg,2013,66(3):439-440.
59. Rodríguez-Perálvarez M, Germani G, Darius T, et al. Tacrolimus trough levels,rejection and renal impairment in liver transplantation: a systematic review andmeta-analysis. Am J Transplant,2012,12(10):2797-2814.
60.韩晓霞,曾海峰,刁建升,等.他克莫司预防兔耳瘢痕增生的实验研究.中国美容医学,2011,20(5):756-759.
61.曾海峰,韩晓霞,刘蓓,等.他克莫司抑制兔耳瘢痕增生的作用及其机制研究.中国美容医学,2011,20(1):68-70.
62. Gisquet H, Liu H, Blondel WC, et al. Intradermal tacrolimus prevent scar hypertrophyin a rabbit ear model: a clinical, histological and spectroscopical analysis. Skin ResTechnol,2011,17(2):160-166.
63. Wu CS, Wu PH, Fang AH, et al. FK506inhibits the enhancing effects of transforminggrowth factor (TGF)-β1on collagen expression and TGF-β/Smad signalling in keloidfibroblasts: implication for new therapeutic approach. Br J Dermatol,2012,167(3):532-541.
64. Kahmann L, Beyer U, Mehlhorn G, et al. Mitomycin C in patients with gynecologicalmalignancies. Onkologie,2010,33(10):547-557.
65. Volpe A, Racioppi M, D'Agostino D, et al. Mitomycin C for the treatment of bladdercancer. Minerva Urol Nefrol,2010,62(2):133-144.
66. Simman R, Alani H, Williams F. Effect of mitomycin C on keloid fibroblasts: an invitro study. Ann Plast Surg,2003,50(1):71-76.
67. Talmi YP, Orenstein A, Wolf M, et al. Use of mitomycin C for treatment of keloid: apreliminary report. Otolaryngol Head Neck Surg,2005,132(4):598-601.
68. Stewart CE4th, Kim JY. Application of mitomycin-C for head and neck keloids.Otolaryngol Head Neck Surg,2006,135(6):946-950.
69. Gupta M, Narang T. Role of mitomycin C in reducing keloid recurrence: patient seriesand literature review. J Laryngol Otol,2011,125(3):297-300.
70. Elliott WJ, Ram CV. Calcium channel blockers. J Clin Hypertens (Greenwich),2011,13(9):687-689.
71. Giugliano G, Pasquali D, Notaro A, et al. Verapamil inhibits interleukin-6andvascular endothelial growth factor production in primary cultures of keloid fibroblasts.Br J Plast Surg,2003,56(8):804-809.
72. Margaret Shanthi FX, Ernest K. Comparison of intralesional verapamil withintralesional triamcinolone in the treatment of hypertrophic scars and keloids. Indian JDermatol Venereol Leprol,2008,74(4):343-348.
73. Skaria AM. Prevention and treatment of keloids with intralesional verapamil.Dermatology,2004,209(1):71.
74. Copcu E, Sivrioglu N, Oztan Y. Combination of surgery and intralesional verapamilinjection in the treatment of the keloid. J Burn Care Rehabil,2004,25(1):1-7.
75. D'Andrea F, Brongo S, Ferraro G, et al. Prevention and treatment of keloids withintralesional verapamil. Dermatology,2002,204(1):60-62.
76. Lawrence WT. Treatment of earlobe keloids with surgery plus adjuvant intralesionalverapamil and pressure earrings. Ann Plast Surg,1996,37(2):167-169.
77. Binkhorst L, van Gelder T, Mathijssen RH. Individualization of tamoxifen treatmentfor breast carcinoma. Clin Pharmacol Ther,2012,92(4):431-433.
78. Kiyotani K, Mushiroda T, Nakamura Y, et al. Pharmacogenomics of tamoxifen: rolesof drug metabolizing enzymes and transporters. Drug Metab Pharmacokinet,2012,27(1):122-131.
79. Chau D, Mancoll JS, Lee S, et al. Tamoxifen downregulates TGF-beta production inkeloid fibroblasts. Ann Plast Surg,1998,40(5):490-493.
80. Bayat A, Bock O, Mrowietz U, et al. Genetic susceptibility to keloid disease andtransforming growth factor beta2polymorphisms. Br J Plast Surg,2002,55(4):283-286.
81. Mikulec AA, Hanasono MM, Lum J, et al. Effect of tamoxifen on transforminggrowth factor beta1production by keloid and fetal fibroblasts. Arch Facial Plast Surg,2001,3(2):111-114.
82. Liu Y, Xiao Z, Yang D, et al. Effects of the cyclin-dependent kinase10(CDK10) onthe tamoxifen sensitivity of keloid samples. Molecules,2012,17(2):1307-1318.
83. Ruffy MB, Kunnavatana SS, Koch RJ. Effects of tamoxifen on normal human dermalfibroblasts. Arch Facial Plast Surg,2006,8(5):329-332.
84. Ferrari A, Fiorino E, Giudici M, et al. Linking epigenetics to lipid metabolism: focuson histone deacetylases. Mol Membr Biol,2012,29(7):257-266.
85. Gr ff J, Tsai LH. Histone acetylation: molecular mnemonics on the chromatin. NatRev Neurosci,2013,14(2):97-111.
86. Kim M, Thompson LA, Wenger SD, et al. Romidepsin: a histone deacetylase inhibitorfor refractory cutaneous T-cell lymphoma. Ann Pharmacother,2012,46(10):1340-1348.
87. Lai F, Jin L, Gallagher S, et al. Histone deacetylases (HDACs) as mediators ofresistance to apoptosis in melanoma and as targets for combination therapy withselective BRAF inhibitors. Adv Pharmacol,2012,65:27-43.
88. Vanden Berghe W, Haegeman G. Epigenetic remedies by dietary phytochemicalsagainst inflammatory skin disorders: myth or reality? Curr Drug Metab,2010,11(5):436-450.
89. Matthews GM, Newbold A, Johnstone RW. Intrinsic and extrinsic apoptotic pathwaysignaling as determinants of histone deacetylase inhibitor antitumor activity. AdvCancer Res,2012,116:165-197.
90. Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene,2007,26(37):5420-5432.
91. Weichert W, R ske A, Niesporek S, et al. Class I histone deacetylase expression hasindependent prognostic impact in human colorectal cancer：specific role of class Ihistone deacetylases in vitro and in vivo. Clin Cancer Res,2008,14(6):1669-1677．
92. Giannini G, Cabri W, Fattorusso C, et al. Histone deacetylase inhibitors in thetreatment of cancer: overview and perspectives. Future Med Chem,2012,4(11):1439-1460.
93. Kloster MM, Naderi EH, Haaland I, et al. cAMP signalling inhibits p53acetylationand apoptosis via HDAC and SIRT deacetylases. Int J Oncol,2013,42(5):1815-1821.
94. Liu H, Wu H, Wang Y, et al. Inhibition of class II histone deacetylase blocksproliferation and promotes neuronal differentiation of the embryonic rat neuralprogenitor cells. Acta Neurobiol Exp (Wars),2012,72(4):365-376.
95. Shakespear MR, Halili MA, Irvine KM, et al. Histone deacetylases as regulators ofinflammation and immunity. Trends Immunol,2011,32(7):335-343.
96. Simboeck E, Di Croce L. HDAC1, a novel marker for benign teratomas. EMBO J,2010,29(23):3893-3895.
97. Glaser KB, Li J, Staver MJ, et al. Role of class I and class II histone deacetylases incarcinoma cells using siRNA.Biochem Biophys Res Commun,2003,310(2):529-536.
98. Mehnert JM, Kelly WK. Histone deacetylase inhibitors: biology and mechanism ofaction. Cancer J,2007,13(1):23-29.
99. Hosseinkhani M, Hasegawa K, Ono K, et al. Trichostatin A induces myocardialdifferentiation of monkey ES cells. Biochem Biophys Res Commun,2007,356(2):386-391.
100.Cohen LA, Amin S, Marks PA, et al. Chemoprevention of carcinogen-inducedmammary tumorigenesis by the hybrid polar cytodifferentiation agent,suberanilohydroxamic acid (SAHA). Anticancer Res,1999,19(6B):4999-5005.
101.Mann BS, Johnson JR, He K, et al. Vorinostat for treatment of cutaneousmanifestations of advanced primary cutaneous T-cell lymphoma. Clin Cancer Res,2007,13(8):2318-2322.
102.Gui CY, Ngo L, Xu WS, et al. Histone deacetylase (HDAC) inhibitor activation ofp21WAF1involves changes in promoter-associated proteins, including HDAC1. ProcNatl Acad Sci U S A,2004,101(5):1241-1246.
103.Mayo C, Lloreta J, Real FX, et al. In vitro differentiation of HT-29M6mucus-secreting colon cancer cells involves a trychostatin A and p27(KIP1)-inducibletranscriptional program of gene expression. J Cell Physiol,2007,212(1):42-50.
104.Hsia DA, Tepper CG, Pochampalli MR, et al. KDM8, a H3K36me2histonedemethylase that acts in the cyclin A1coding region to regulate cancer cellproliferation. Proc Natl Acad Sci U S A,2010,107(21):9671-9676.
105.Jin JS, Tsao TY, Sun PC, et al. SAHA inhibits the growth of colon tumors bydecreasing histone deacetylase and the expression of cyclin D1and survivin. PatholOncol Res,2012,18(3):713-720.
106.Kitamura T, Connolly K, Ruffino L, et al. The therapeutic effect of histonedeacetylase inhibitor PCI-24781on gallbladder carcinoma in BK5.erbB2mice. JHepatol,2012,57(1):84-91.
107.Buglio D, Georgakis GV, Hanabuchi S, et al. Vorinostat inhibits STAT6-mediatedTH2cytokine and TARC production and induces cell death in Hodgkin lymphomacell lines. Blood.2008Aug15;112(4):1424-1433.
108.Noro R, Miyanaga A, Minegishi Y, et al. Histone deacetylase inhibitor enhancessensitivity of non-small-cell lung cancer cells to5-FU/S-1via down-regulation ofthymidylate synthase expression and up-regulation of p21(waf1/cip1) expression.Cancer Sci,2010,101(6):1424-1430.
109.Butler LM, Zhou X, Xu WS, et al. The histone deacetylase inhibitor SAHA arrestscancer cell growth, up-regulates thioredoxin-binding protein-2, and down-regulatesthioredoxin. Proc Natl Acad Sci U S A,2002,99(18):11700-11705.
110.Wallace DM, Donovan M, Cotter TG. Histone deacetylase activity regulates apaf-1and caspase3expression in the developing mouse retina. Invest Ophthalmol Vis Sci,2006,47(7):2765-2772.
111.Sutheesophon K, Kobayashi Y, Takatoku MA, et al. Histone deacetylase inhibitordepsipeptide (FK228) induces apoptosis in leukemic cells by facilitatingmitochondrial translocation of Bax, which is enhanced by the proteasome inhibitorbortezomib. Acta Haematol,2006,115(1-2):78-90.
112.Strait KA, Warnick CT, Ford CD, et al. Histone deacetylase inhibitors induceG2-checkpoint arrest and apoptosis in cisplatinum-resistant ovarian cancer cellsassociated with overexpression of the Bcl-2-related protein Bad. Mol Cancer Ther,2005,4(4):603-611.
113.Yang Y, Zhao Y, Liao W, et al. Acetylation of FoxO1activates Bim expression toinduce apoptosis in response to histone deacetylase inhibitor depsipeptide treatment.Neoplasia,2009,11(4):313-324.
114.Miller CP, Ban K, Dujka ME, et al. NPI-0052, a novel proteasome inhibitor, inducescaspase-8and ROS-dependent apoptosis alone and in combination with HDACinhibitors in leukemia cells. Blood,2007,110(1):267-277.
115.Chen S, Dai Y, Pei XY, et al. Bim upregulation by histone deacetylase inhibitorsmediates interactions with the Bcl-2antagonist ABT-737: evidence for distinct rolesfor Bcl-2, Bcl-xL, and Mcl-1. Mol Cell Biol,2009,29(23):6149-6169.
116.Hwang JJ, Kim YS, Kim T, et al. A novel histone deacetylase inhibitor, CG200745,potentiates anticancer effect of docetaxel in prostate cancer via decreasing Mcl-1andBcl-XL. Invest New Drugs,2012,30(4):1434-1442.
117.Rosato R, Hock S, Dent P, et al. LBH-589(panobinostat) potentiates fludarabineanti-leukemic activity through a JNK-and XIAP-dependent mechanism. Leuk Res,2012,36(4):491-498.
118.Fandy TE, Shankar S, Ross DD, et al. Interactive effects of HDAC inhibitors andTRAIL on apoptosis are associated with changes in mitochondrial functions andexpressions of cell cycle regulatory genes in multiple myeloma. Neoplasia,2005,7(7):646-657.
119.Zhang XD, Gillespie SK, Borrow JM, et al. The histone deacetylase inhibitor subericbishydroxamate: a potential sensitizer of melanoma to TNF-related apoptosis-inducing ligand (TRAIL) induced apoptosis. Biochem Pharmacol,2003,66(8):1537-1545.
120.Imai T, Adachi S, Nishijo K, et al. FR901228induces tumor regression associatedwith induction of Fas ligand and activation of Fas signaling in human osteosarcomacells. Oncogene,2003,22(58):9231-9242.
121.Shultz M, Fan J, Chen C, et al. The design, synthesis and structure-activityrelationships of novel isoindoline-based histone deacetylase inhibitors. Bioorg MedChem Lett,2011,21(16):4909-4912.
122.Xu WS, Parmigian RB, Marks PA. Histone deacetylase inhibitors： molecularmechanisms of action. Oncogene,2007,26(37):5541-5552.
123.Camphausen K, Tofilon PJ. Inhibition of histone deacetylation: a strategy for tumorradiosensitization. J Clin Oncol,2007,25(26):4051-4056.
124.Fakih MG, Groman A, McMahon J, et al. A randomized phase II study of two doses ofvorinostat in combination with5-FU/LV in patients with refractory colorectal cancer.Cancer Chemother Pharmacol,2012,69(3):743-751.
125.Jeon HG, Yoon CY, Yu JH, et al. Induction of caspase mediated apoptosis anddown-regulation of nuclear factor-κB and Akt signaling are involved in the synergisticantitumor effect of gemcitabine and the histone deacetylase inhibitor trichostatin A inhuman bladder cancer cells. J Urol,2011,186(5):2084-2093.
126.Zhang QC, Jiang SJ, Zhang S, et al. Histone deacetylase inhibitor trichostatin Aenhances anti-tumor effects of docetaxel or erlotinib in A549cell line. Asian Pac JCancer Prev,2012,13(7):3471-3476.
127.Zuco V, De Cesare M, Cincinelli R, et al. Synergistic antitumor effects of novelHDAC inhibitors and paclitaxel in vitro and in vivo. PLoS One,2011,6(12):e29085.
128.Fuino L, Bali P, Wittmann S, et al. Histone deacetylase inhibitor LAQ824down-regulates Her-2and sensitizes human breast cancer cells to trastuzumab,taxotere, gemcitabine, and epothilone B. Mol Cancer Ther,2003,2(10):971-984.
129.Tarasenko N, Cutts SM, Phillips DR, et al. Disparate impact of butyroyloxymethyldiethylphosphate (AN-7), a histone deacetylase inhibitor, and doxorubicin in micebearing a mammary tumor. PLoS One,2012,7(2):e31393.
130.Munster P, Marchion D, Bicaku E, et al. Clinical and biological effects of valproicacid as a histone deacetylase inhibitor on tumor and surrogate tissues: phase I/II trialof valproic acid and epirubicin/FEC. Clin Cancer Res,2009,15(7):2488-2496.
131.Groh T, Hrabeta J, Poljakova J, et al. Impact of histone deacetylase inhibitor valproicacid on the anticancer effect of etoposide on neuroblastoma cells. Neuro EndocrinolLett,2012,33Suppl3:16-24.
132.Poljakova J, Hrebackova J, Dvorakova M, et al. Anticancer agent ellipticine combinedwith histone deacetylase inhibitors, valproic acid and trichostatin A, is an effectiveDNA damage strategy in human neuroblastoma. Neuro Endocrinol Lett,2011,32Suppl1:101-116.
133.Eriksson I, Joosten M, Roberg K, et al. The histone deacetylase inhibitor trichostatinA reduces lysosomal pH and enhances cisplatin-induced apoptosis. Exp Cell Res,2013,319(1):12-20.
134.Yang Y, Rao R, Shen J, et al. Role of acetylation and extracellular location of heatshock protein90alpha in tumor cell invasion. Cancer Res,2008,68(12):4833-4842.
135.Shimizu R, Kikuchi J, Wada T, et al. HDAC inhibitors augment cytotoxic activity ofrituximab by upregulating CD20expression on lymphoma cells. Leukemia,2010,24(10):1760-1768.
136.Huang X, Wang S, Lee CK, et al. HDAC inhibitor SNDX-275enhances efficacy oftrastuzumab in erbB2-overexpressing breast cancer cells and exhibits potential toovercome trastuzumab resistance. Cancer Lett,2011,307(1):72-79.
137.Kurtze I, Sonnemann J, Beck JF. KRAS-mutated non-small cell lung cancer cells areresponsive to either co-treatment with erlotinib or gefitinib and histone deacetylaseinhibitors or single treatment with lapatinib. Oncol Rep,2011,25(4):1021-1029.
138.Feng D, Cao Z, Li C, et al. Combination of valproic acid and ATRA restores RARβ2expression and induces differentiation in cervical cancer through the PI3K/Aktpathway. Curr Mol Med,2012,12(3):342-354.
139.Chu BF, Karpenko MJ, Liu Z, et al. Phase I study of5-aza-2'-deoxycytidine incombination with valproic acid in non-small-cell lung cancer. Cancer ChemotherPharmacol,2013,71(1):115-121.
140.Cervera E, Candelaria M, López-Navarro O, et al. Epigenetic therapy withhydralazine and magnesium valproate reverses imatinib resistance in patients withchronic myeloid leukemia. Clin Lymphoma Myeloma Leuk,2012,12(3):207-212.
141.Musumeci F, Radi M, Brullo C, et al. Vascular endothelial growth factor (VEGF)receptors: drugs and new inhibitors. J Med Chem,2012,55(24):10797-10822.
142.Lejay A, Georg Y, Dieval F, et al. Properties and challenges in materials used asvascular and endovascular devices. J Cardiovasc Surg (Torino),2013,54(1Suppl1):167-182.
143.Park JH, Kim SH, Choi MC, et a1. Class II histone deacetylases play pivotal roles inheat shock protein90-mediated proteasomal degradation of vascular endothelialgrowth factor receptors. Bioehem Biophys Res Commun,2008,368(2):318-322
144.Liang D, Kong X, Sang N. Effects of histone deacetylase inhibitors on HIF-1. CellCycle,2006,5(21):2430-2435.
145.Ellis L, Hammers H, Pili R. Targeting tumor angiogenesis with histone deacetylaseinhibitors. Cancer Lett,2009,280(2):145-153.
146.Jeong JW, Bae MK, Ahn MY, et al. Regulation and destabilization of HIF-1alpha byARD1-mediated acetylation. Cell,2002,111(5):709-720.
147.Kong X, Lin Z, Liang D, et al. Histone deacetylase inhibitors induce VHL andubiquitin-independent proteasomal degradation of hypoxia-inducible factor1alpha.Mol Cell Biol,2006,26(6):2019-2028.
148.Qian DZ, Kachhap SK, Collis SJ, et al. Class II histone deacetylases are associatedwith VHL-independent regulation of hypoxia-inducible factor1alpha. Cancer Res,2006,66(17):8814-8821.
149.Naldini A, Filippi I, Cini E, et al. Downregulation of hypoxia-related responses bynovel antitumor histone deacetylase inhibitors in MDAMB231breast cancer cells.Anticancer Agents Med Chem,2012,12(4):407-413.
150.Pang M, Zhuang S. Histone deacetylase: a potential therapeutic target for fibroticdisorders. J Pharmacol Exp Ther,2010,335(2):266-272.
151.Marumo T, Hishikawa K, Yoshikawa M, et al. Histone deacetylase modulates theproinflammatory and fibrotic changes in tubulointerstitial injury. Am J Physiol RenalPhysiol,2010,298(1):F133-141.
152.Hu J, Colburn NH. Histone deacetylase inhibition down-regulates cyclin D1transcription by inhibiting nuclear factor-kappaB/p65DNA binding. Mol Cancer Res,2005,3(2):100-109.
153.Pang M, Kothapally J, Mao H, et al. Inhibition of histone deacetylase activityattenuates renal fibroblast activation and interstitial fibrosis in obstructivenephropathy. Am J Physiol Renal Physiol,2009,297(4):F996-1005.
154.Noh H, Oh EY, Seo JY, et al. Histone deacetylase-2is a key regulator of diabetes-andtransforming growth factor-beta1-induced renal injury. Am J Physiol Renal Physiol,2009,297(3):F729-739.
155.Kee HJ, Sohn IS, Nam KI, et al. Inhibition of histone deacetylation blocks cardiachypertrophy induced by angiotensin II infusion and aortic banding. Circulation,2006,113(1):51-59.
156.Guo W, Shan B, Klingsberg RC, et al. Abrogation of TGF-beta1-inducedfibroblast-myofibroblast differentiation by histone deacetylase inhibition. Am JPhysiol Lung Cell Mol Physiol,2009,297(5):L864-870.
157.Coward WR, Watts K, Feghali-Bostwick CA, et al. Defective histone acetylation isresponsible for the diminished expression of cyclooxygenase2in idiopathicpulmonary fibrosis. Mol Cell Biol,2009,29(15):4325-4339.
158.Huber LC, Distler JH, Moritz F, et al. Trichostatin A prevents the accumulation ofextracellular matrix in a mouse model of bleomycin-induced skin fibrosis. ArthritisRheum,2007,56(8):2755-2764.
159.Rubenstein RC, Egan ME, Zeitlin PL. In vitro pharmacologic restoration ofCFTR-mediated chloride transport with sodium4-phenylbutyrate in cystic fibrosisepithelial cells containing delta F508-CFTR. J Clin Invest,1997,100(10):2457-2465.
160.Rubenstein RC, Zeitlin PL. Sodium4-phenylbutyrate downregulates Hsc70:implications for intracellular trafficking of DeltaF508-CFTR. Am J Physiol CellPhysiol,2000,278(2):C259-267.
161.Sharma A, Mehan MM, Sinha S, et al. Trichostatin a inhibits corneal haze in vitro andin vivo. Invest Ophthalmol Vis Sci,2009,50(6):2695-2701.
162.Bidic SM, Dauwe PB, Heller J, at al. Reconstructing large keloids with neodermis: asystematic review. Plast Reconstr Surg,2012,129(2):380e-382e.
163.Willis-Martinez D, Richards HW, Timchenko NA, et al. Role of HDAC1insenescence, aging, and cancer. Exp Gerontol,2010,45(4):279-285.
164.Park JJ, Kim YE, Pham HT, et al. Functional interaction of the humancytomegalovirus IE2protein with histone deacetylase2in infected human fibroblasts.J Gen Virol,2007,88(Pt12):3214-3223.
165.Zhou R, Han L, Li G, et al. Senescence delay and repression of p16INK4a by Lsh viarecruitment of histone deacetylases in human diploid fibroblasts. Nucleic Acids Res,2009,37(15):5183-5196.
166.Hu E, Dul E, Sung CM, at al. Identification of novel isoform-selective inhibitorswithin class I histone deacetylases. J Pharmacol Exp Ther,2003,307(2):720-728.
167.Choi HS, Lee JH, Park JG, at al. Trichostatin A, a histone deacetylase inhibitor,activates the IGFBP-3promoter by upregulating Sp1activity in hepatoma cells:alteration of the Sp1/Sp3/HDAC1multiprotein complex. Biochem Biophys ResCommun,2002,296(4):1005-1012.
168.Han Y, Zhang Y, Yang LH, et al. X-radiation inhibits histone deacetylase1and2,upregulates Axin expression and induces apoptosis in non-small cell lung cancer.Radiat Oncol,2012,7:183.
169.Yang PM, Lin PJ, Chen CC. CD1d induction in solid tumor cells by histonedeacetylase inhibitors through inhibition of HDAC1/2and activation of Sp1.Epigenetics,2012,7(4):390-399.
170.Bran GM, Sommer UJ, Goessler UR, et al. TGF-1antisense impacts the SMADsignalling system in fibroblasts from keloid scars. Anticancer Res,2010,30(9):3459-3463.
171.Sandulache VC, Parekh A, Li-Korotky H, et al. Prostaglandin E2inhibition of keloidfibroblast migration, contraction, and transforming growth factor(TGF)-beta1-induced collagen synthesis. Wound Repair Regen,2007,15(1):122-133.
172.Gragnani A, Warde M, Furtado F, et al. Topical tamoxifen therapy in hypertrophicscars or keloids in burns. Arch Dermatol Res,2010,302(1):1-4.
173.Hsu YC, Chen MJ, Yu YM, et al. Suppression of TGF-β1/SMAD pathway andextracellular matrix production in primary keloid fibroblasts by curcuminoids: itspotential therapeutic use in the chemoprevention of keloid. Arch Dermatol Res,2010,302(10):717-724.
174.Phan TT, Lim IJ, Chan SY, et al. Suppression of transforming growth factor beta/smadsignaling in keloid-derived fibroblasts by quercetin: implications for the treatment ofexcessive scars. J Trauma,2004,57(5):1032-1037.
175.Kashiyama K, Mitsutake N, Matsuse M, et al. miR-196a downregulation increases theexpression of type I and III collagens in keloid fibroblasts. J Invest Dermatol,2012,132(6):1597-1604.
176.Chua AW, Gan SU, Ting Y, et al. Keloid fibroblasts are more sensitive to Wnt3atreatment in terms of elevated cellular growth and fibronectin expression. J DermatolSci,2011,64(3):199-209.
177.Sidgwick GP, Bayat A. Extracellular matrix molecules implicated in hypertrophic andkeloid scarring. J Eur Acad Dermatol Venereol,2012,26(2):141-152.
178.Barter MJ, Pybus L, Litherland GJ, et al. HDAC-mediated control of ERK-andPI3K-dependent TGF-β-induced extracellular matrix-regulating genes. Matrix Biol,2010,29(7):602-612.
179.Morris DE, Wu I, Zhao LL, et al. Acute and chronic animal models for excessivedermal scarring: quantitative studies. Plast Reconstr Surg,1997(3),100:674-681.
180.李荟元,刘建波,兰海.建立增生性瘢痕动物实验模型.第四军医大学学报,1998,19(06):655-657.
181.Tandon A, Tovey JC, Waggoner MR, et al. Vorinostat: a potent agent to prevent andtreat laser-induced corneal haze. J Refract Surg,2012,28(4):285-290.
182.R ssig L, Li H, Fisslthaler B, et al. Inhibitors of histone deacetylation downregulatethe expression of endothelial nitric oxide synthase and compromise endothelial cellfunction in vasorelaxation and angiogenesis. Circ Res,2002,91(9):837-844.
183.Deroanne CF, Bonjean K, Servotte S, et al. Histone deacetylases inhibitors asanti-angiogenic agents altering vascular endothelial growth factor signaling.Oncogene,2002,21(3):427-436.
184.Dulmovits BM, Herman IM. Microvascular remodeling and wound healing: a role forpericytes. Int J Biochem Cell Biol,2012,44(11):1800-1812.
185.Chen CW, Corselli M, Péault B, et al. Human blood-vessel-derived stem cells fortissue repair and regeneration. J Biomed Biotechnol,2012,2012:597439.