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摘要: 随着人口老龄化和社会经济的发展，慢性创面发病率日益增高，同时烧创伤发病率仍处于较高水平，使得创面修复成为临床日益关注的领域。胸腺素β4是一种体内天然存在的小分子蛋白，其广泛分布于多种体液和细胞内，尤其是血小板中。胸腺素β4具有促进血管生成、抗炎、抗凋亡及抗纤维化的生物活性，在创面修复方面有许多重要的功能。目前已经在烧伤、糖尿病溃疡、压疮等多种创面中观察到胸腺素β4具有促进愈合的作用。该文将从胸腺素β4的分子结构、促创面愈合作用机制、药代动力学及临床应用方面进行综述，旨在介绍该因子在创面治疗中的潜力和当前研究的不足之处。Abstract: With the aging of population and the development of social economy, the incidence of chronic wounds is increasing day by day, while the incidence of burns and trauma remains at a high level, making wound repair an increasingly concerned area in clinical practice. Thymosin β4 is a naturally occurring small molecule protein in vivo, which is widely distributed in a variety of body fluids and cells, especially in platelets. Thymosin β4 has biological activities of promoting angiogenesis, anti-inflammation, anti-apoptosis, and anti-fibrosis, and has many important functions in wound repair. Thymosin β4 has been observed to promote the healing of various wounds, such as burns, diabetic ulcers, pressure ulcers. This paper will review the molecular structure, mechanism of wound healing promotion, pharmacokinetics, and clinical application of thymosin β4, aiming to introduce its potential in wound treatment and the shortcomings of current researches.
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Key words:
- Wound healing /
- Thymosin /
- Mechanism of action /
- Clinical application
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参考文献
(47) [1] FuX,ShengZ,CherryGW,et al.Epidemiological study of chronic dermal ulcers in China[J].Wound Repair Regen,1998,6(1):21-27.DOI: 10.1046/j.1524-475x.1998.60105.x. [2] JiangY,HuangS,FuX,et al.Epidemiology of chronic cutaneous wounds in China[J].Wound Repair Regen,2011,19(2):181-188.DOI: 10.1111/j.1524-475X.2010.00666.x. [3] ChengB,JiangY,FuX,et al.Epidemiological characteristics and clinical analyses of chronic cutaneous wounds of inpatients in China: prevention and control[J].Wound Repair Regen,2020,28(5):623-630.DOI: 10.1111/wrr.12825. [4] HaagsmaJA,GraetzN,BolligerI,et al.The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the Global Burden of Disease study 2013[J].Inj Prev,2016,22(1):3-18.DOI: 10.1136/injuryprev-2015-041616. [5] 张忠胜,刘双凤,黄四春.胸腺素β4对大鼠皮质神经细胞氧糖剥夺-复氧损伤的保护作用研究[J].中国脑血管病杂志,2019,16(6):296-302.DOI: 10.3969/j.issn.1672-5921.2019.06.003. [6] VasilopoulouE,RileyPR,LongDA.Thymosin-β4: a key modifier of renal disease[J].Expert Opin Biol Ther,2018,18 (Suppl 1):S185-192.DOI: 10.1080/14712598.2018.1473371. [7] PohKK,LeePSS,DjohanAH,et al.Transplantation of endothelial progenitor cells in obese diabetic rats following myocardial infarction: role of thymosin beta-4[J].Cells,2020,9(4):949.DOI: 10.3390/cells9040949. [8] SosneG,QiuP,GoldsteinAL,et al.Biological activities of thymosin beta4 defined by active sites in short peptide sequences[J].FASEB J,2010,24(7):2144-2151.DOI: 10.1096/fj.09-142307. [9] 王姗,张巧丹,李世峰,等.Ac-SDKP调节Rac1信号抑制皮肤肌成纤维细胞的转化和迁移[J].福建医科大学学报,2019,53(1):9-12,22. [10] ZhangY,YangF,LiuY,et al.Influence of the interaction between Ac-SDKP and Ang Ⅱ on the pathogenesis and development of silicotic fibrosis[J].Mol Med Rep,2018,17(6):7467-7476.DOI: 10.3892/mmr.2018.8824. [11] 刘瑞姣,AmerAAA,高兴华,等.肌动蛋白结构与生物学功能的研究进展[J].中国细胞生物学学报,2020,42(10):1870-1875.DOI: 10.11844/cjcb.2020.10.0019. [12] HinkelR,KlettK,BährA,et al.Thymosin β4-mediated protective effects in the heart[J].Expert Opin Biol Ther,2018,18 (Suppl 1):S121-129.DOI: 10.1080/14712598.2018.1490409. [13] GoldsteinAL,KleinmanHK.Advances in the basic and clinical applications of thymosin β4[J].Expert Opin Biol Ther,2015,15 Suppl 1:S139-145.DOI: 10.1517/14712598.2015.1011617. [14] JingJ,SunX,ZhouC,et al.Cloning, expression and effects of P. americana thymosin on wound healing[J].Int J Mol Sci,2019,20(19):4932.DOI: 10.3390/ijms20194932. [15] YangWS,KangS,SungJ,et al.Thymosin β4: potential to treat epidermolysis bullosa and other severe dermal injuries[J].Eur J Dermatol,2019,29(5):459-467.DOI: 10.1684/ejd.2019.3642. [16] RoyP,RajfurZ,JonesD,et al.Local photorelease of caged thymosin beta4 in locomoting keratocytes causes cell turning[J].J Cell Biol,2001,153(5):1035-1048.DOI: 10.1083/jcb.153.5.1035. [17] LvS,CaiH,XuY,et al.Thymosin-β 4 induces angiogenesis in critical limb ischemia mice via regulating Notch/NF-κB pathway[J].Int J Mol Med,2020,46(4):1347-1358.DOI: 10.3892/ijmm.2020.4701. [18] QiuF,SongJ,BiX,et al.Thymosin β4 promotes glucose-impaired endothelial progenitor cell function via Akt/endothelial nitric oxide synthesis signaling pathway[J].Exp Ther Med,2018,16(4):3439-3444.DOI: 10.3892/etm.2018.6593. [19] KleinmanHK,SosneG.Thymosin β4 promotes dermal healing[J].Vitam Horm,2016,102:251-275.DOI: 10.1016/bs.vh.2016.04.005. [20] KassemKM,VaidS,PengH,et al.Tβ4-Ac-SDKP pathway: any relevance for the cardiovascular system?[J].Can J Physiol Pharmacol,2019,97(7):589-599.DOI: 10.1139/cjpp-2018-0570. [21] 翟晓梅,聂兴举,秦泽莲,等.胸腺素β4基因片断mRNA在人瘢痕及皮肤组织中的表达定位[J].中国微创外科杂志,2007,7(12):1217-1220.DOI: 10.3969/j.issn.1009-6604.2007.12.040. [22] 曲亚平,穆大力,栾杰.胸腺素β4的机制研究及应用进展[J]. 中国美容整形外科杂志,2017,28(7):444-445,后插1.DOI: 10.3969/j.issn.1673-7040.2017.07.022. [23] 杨尚青,杨东亮,刘嘉.基质金属蛋白酶2/9在慢性肝脏疾病发生发展中的作用[J].临床肝胆病杂志,2020,36(10):2364-2369.DOI: 10.3969/j.issn.1001-5256.2020.10.045. [24] CrockfordD,TurjmanN,AllanC,et al.Thymosin beta4: structure, function, and biological properties supporting current and future clinical applications[J].Ann N Y Acad Sci,2010,1194:179-189.DOI: 10.1111/j.1749-6632.2010.05492.x. [25] 马素永 重组甘氨酸—胸腺素β4生产工艺研究 天津 天津大学 2011 DOI: 10.7666/d.y2081115 马素永.重组甘氨酸—胸腺素β4生产工艺研究[D].天津:天津大学,2011. DOI:10.7666/d.y2081115.
[26] 潘锋君,林丽君.胸腺素注射用灭菌粉末的稳定性实验[J].医药导报,2007,26(6):674-675.DOI: 10.3870/j.issn.1004-0781.2007.06.045. [27] RuffD,CrockfordD,GirardiG,et al.A randomized, placebo-controlled, single and multiple dose study of intravenous thymosin beta4 in healthy volunteers[J].Ann N Y Acad Sci,2010,1194:223-229.DOI: 10.1111/j.1749-6632.2010.05474.x. [28] FinkK,KobakK,KaszturaM,et al.Synthesis and biological activity of thymosin β4-anionic boron cluster conjugates[J].Bioconjug Chem,2018,29(11):3509-3515.DOI: 10.1021/acs.bioconjchem.8b00646. [29] TiD,HaoH,XiaL,et al.Controlled release of thymosin beta 4 using a collagen-chitosan sponge scaffold augments cutaneous wound healing and increases angiogenesis in diabetic rats with hindlimb ischemia[J].Tissue Eng Part A,2015,21(3/4):541-549.DOI: 10.1089/ten.TEA.2013.0750. [30] FuX,ShiY,WangH,et al.Ethosomal gel for improving transdermal delivery of thymosin β-4[J].Int J Nanomedicine,2019,14:9275-9284.DOI: 10.2147/IJN.S228863. [31] TreadwellT,KleinmanHK,CrockfordD,et al.The regenerative peptide thymosin β4 accelerates the rate of dermal healing in preclinical animal models and in patients[J].Ann N Y Acad Sci,2012,1270:37-44.DOI: 10.1111/j.1749-6632.2012.06717.x. [32] MorrisDC,CuiY,CheungWL,et al.A dose-response study of thymosin β4 for the treatment of acute stroke[J].J Neurol Sci,2014,345(1/2):61-67.DOI: 10.1016/j.jns.2014.07.006. [33] 李树松,马滢,吴晓明,等.胸腺素β4联合外源性bFGF对深Ⅱ度烫伤大鼠创面愈合的影响及机制研究[J].西部医学,2020,32(2):203-209.DOI: 10.3969/j.issn.1672-3511.2020.02.010. [34] 李树松,马滢,吴晓明,等.胸腺素β4对深Ⅱ°烫伤创面愈合的影响及机制研究[J].解放军预防医学杂志,2018,36(11):1409-1411,1453. [35] KimS,KwonJ.Thymosin β4 has a major role in dermal burn wound healing that involves actin cytoskeletal remodelling via heat-shock protein 70[J].J Tissue Eng Regen Med,2017,11(4):1262-1273.DOI: 10.1002/term.2028. [36] PhilpD,BadamchianM,ScheremetaB,et al.Thymosin beta 4 and a synthetic peptide containing its actin-binding domain promote dermal wound repair in db/db diabetic mice and in aged mice[J].Wound Repair Regen,2003,11(1):19-24.DOI: 10.1046/j.1524-475x.2003.11105.x. [37] 于虎,马瑞珏,张朔杨,等.胸腺素β4调节血管内皮生长因子、层粘连蛋白5表达,促进糖尿病大鼠皮肤损伤愈合[J].中国糖尿病杂志,2011,19(1):60-63.DOI: 10.3969/j.issn.1006-6187.2011.01.016. [38] GuarneraG,DeRosaA,CameriniR,et al.The effect of thymosin treatment of venous ulcers[J].Ann N Y Acad Sci,2010,1194:207-212.DOI: 10.1111/j.1749-6632.2010.05490.x. [39] 杨敏烈,周小金,朱宇刚,等.不同模式持续负压伤口疗法对下肢静脉性溃疡创面的临床疗效及其影响因素前瞻性随机对照研究[J].中华烧伤杂志,2020,36(12):1149-1158.DOI: 10.3760/cma.j.cn501120-20200316-00173. [40] 于灵,冯素英.先天性大疱性表皮松解症诊断及治疗进展[J].中华皮肤科杂志,2016,49(7):516-519.DOI: 10.3760/cma.j.issn.0412-4030.2016.07.019. [41] 于越乾,暴芳芳,刘红.遗传性大疱性表皮松解症致病基因研究进展[J].中国麻风皮肤病杂志,2019,35(6):380-384. [42] 中华人民共和国国家卫生健康委员会.遗传性大疱性表皮松解症诊治指南[J].中国实用乡村医生杂志,2019,26(5):16-18.DOI: 10.3969/j.issn.1672-7185.2019.05.007. [43] BiopharmaceuticalsRegeneRx, Inc. A phase 2 study on effect of thymosin beta 4 on wound healing in patients with epidermolysis bullosa[DB/OL].[S.l.]:[s.n.].2006(2014-05-12)[2021-02-21].https://clinicaltrials.gov/ct2/show/NCT00311766. https://clinicaltrials.gov/ct2/show/NCT00311766 [44] 李鹏宇,贾克荣.Tβ4关于促进毛发生长的研究进展[J/CD].临床医药文献电子杂志,2017,4(22):4351.DOI: 10.3877/j.issn.2095-8242.2017.22.154. [45] 马丽,石荣珍,邓九零,等.胸腺素β4和β10表达促进小鼠乳腺癌细胞转移[J].中国药理学与毒理学杂志,2018,32(7):565-572.DOI: 10.3867/j.issn.1000-3002.2018.07.008. [46] 程飚,付小兵.微环境控制是实现创面完美修复的必由之路[J].中华烧伤杂志,2020,36(11):1003-1008.DOI: 10.3760/cma.j.cn501120-20201009-00429. [47] DwivediC,PandeyH,PandeyAC,et al.In vivo biocompatibility of electrospun biodegradable dual carrier (antibiotic + growth factor) in a mouse model-implications for rapid wound healing[J]. Pharmaceutics,2019,11(4):180.DOI: 10.3390/pharmaceutics11040180. -
1 胸腺素β4的氨基酸序列示意图
注：图中S、D、K、P等小球分别代表丝氨酸、天冬氨酸、赖氨酸、脯氨酸等氨基酸；从最左S开始，已知的胸腺素β4的4个生物活性位点位于第1~4位氨基酸、第1~15位氨基酸、第17~23位氨基酸、最末4位氨基酸
2 胸腺素β4在创面凝血、炎症、增生阶段的作用机制
注：IL-1为白细胞介素1，TNF-α为肿瘤坏死因子α，Bcl-2为B淋巴细胞瘤-2，Bax为Bcl-2相关X蛋白，iNOS为诱导型一氧化氮合酶
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