CN112979762A - 环肽piz及其用途 - Google Patents
环肽piz及其用途 Download PDFInfo
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- CN112979762A CN112979762A CN202110450974.XA CN202110450974A CN112979762A CN 112979762 A CN112979762 A CN 112979762A CN 202110450974 A CN202110450974 A CN 202110450974A CN 112979762 A CN112979762 A CN 112979762A
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- piz
- cyclic peptide
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- skin
- acne
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Abstract
Description
技术领域
本发明属于生物医药领域,涉及一种环肽PIZ及其用途。本发明合成的环肽具有治疗多种疾病的作用。
背景技术
皮脂膜为覆盖于皮肤表面的一层透明薄膜,主要由皮脂腺分泌的皮脂、角质层细胞崩解产生的脂质与汗腺分泌的汗液乳化形成,呈弱酸性,其主要成分角鲨烯、亚油酸、亚麻酸及脂质成分,具有锁住水分及一定的抗炎作用。"砖墙结构"中的"砖墙"代表角质形成细胞;"灰浆"则指角质细胞间隙中脂质(含神经酰胺、脂肪酸、胆固醇),"砖墙"和"灰浆"使表皮形成牢固的结构,限制水分在细胞内外及细胞间流动,保证不丢失水份,使皮肤维持重要的屏障功能。"三明治"结构存在于角质层中,厚度约为13nm,由三层组成,第一层及第三层由晶状体网格结构组成,中间是液相,由类脂构成,主要含有不饱和脂肪酸及胆固醇,由于存在少量流动的长链饱和烃链,靠近液相的晶状体结构具有缓慢的流动性。层状结构形成过程中,神经酰胺与胆固醇起到很重要的作用,而在其横向堆积中,是脂肪酸在起作用。"三明治"结构在角质层的保湿、保护方面起到了很重要的作用。皮肤屏障广义包括物理屏障、色素屏障、神经屏障、免疫屏障。皮肤屏障狭义主要指物理性屏障,物理性屏障由皮脂膜、角质层角蛋白、脂质、"三明治"结构、砖墙结构、真皮粘多糖类、粘多糖类等共同构成,抵御外界有害、刺激物、日光进入,同时具有保湿及调节抗炎作用。皮肤物理屏障受损将引起皮肤干燥,皮肤老化、色素沉着、异位性皮炎、湿疹、银屑病、鱼鳞病、日光性皮炎等皮肤敏感、刺激性皮炎、激素依赖性皮炎,以及皮脂溢出性疾病,如座疮、酒糟鼻、脂溢性皮炎。皮肤屏障功能的恢复也有利于防治皮肤局部细菌感染。
痤疮(俗称青春豆)是好发于毛囊皮脂腺的慢性炎症性疾病,痤疮的产生与青春期皮肤的生理病理变化密切相关。临床表现主要有粉刺、丘疹、脓疱、结节、囊肿、疤痕等,愈合时间长,给患者的容貌和心理带来严重的影响。痤疮与多个发病机制相关,毛囊口角化异常是本病发病的重要基础,炎症和感染是痤疮的发病因素。痤疮患者的皮脂腺较大,皮脂腺分泌增加,皮脂中亚油酸水平相对减少,影响脂肪的合成,导致滤泡上皮缺乏脂肪酸,从而诱导滤泡过度角化,使上皮细胞不能正常脱落,毛囊皮脂腺口过度变小,皮脂不能顺畅排出,形成粉刺。毛囊皮脂腺口被堵塞而形成毛囊皮脂腺内缺氧的环境,造成厌氧性的痤疮丙酸杆菌大量繁殖,分解皮脂,产生化学趋化因子,白细胞聚集形成丘疹。毛囊皮脂腺内的大量中性粒细胞聚集,吞咽痤疮丙酸杆菌后发生炎症反应,使得大量脓细胞堆积而形成脓疱、囊肿,愈后易形成凹陷性疤痕。当面部、额部、颊部、下颌部、胸部、背部及肩部出现大小不等的结节、囊肿,常继发化脓感染,破溃后常流出带血的胶冻状脓液,以后形成窦道。雄激素水平升高是加速痤疮产生的关键环节,使皮肤角化异常堵塞毛囊皮脂腺导管,导致细菌滞留、繁殖,产生炎症。与痤疮具有类似角化异常机制的疾病包括鱼鳞病、毛周角化病(又名毛发苔藓)、毛囊角化病和汗孔角化症等,毛周角化病见毛囊口扩大,内有角栓,鱼鳞病表现为汗腺和皮脂腺减少,毛囊内出现角质性栓塞。目前临床上消除角栓和粉刺的药物主要是维甲酸类药物。维甲酸类药物可抑制角化,减少皮脂分泌,促进角质形成细胞的正常角化,并具有调节免疫和抗炎作用,从而减少粉刺、丘疹和脓疱的形成。但维甲酸类药物外用对皮肤有刺激,容易导致红肿、刺痛,加重原有皮损,长期外用维甲酸类药物可导致皮肤变薄,光敏和皮肤屏障受损等,而口服维甲酸类药物有肝损和血脂升高等不良反应。
黄褐斑是一种好发于中、青年女性的获得性色素障碍性疾病,其发病机制极为复杂,各种原因所致的皮肤黑色素的沉积是引起黄褐斑直接原因。酪氨酸酶经过系列氧化反应后生成黑色素。酪氨酸在酪氨酸酶的作用下在黑素小体内被氧化成多巴,多巴进一步被多巴氧化酶氧化成多巴醌,多巴醌最终在酪氨酸酶的做一下氧化形成黑色素。在此过程中出现的系列氧化与抗氧化反应紊乱都可能引起和促进黄褐斑的发生和发展,酪氨酸增多是黄褐斑发病的主要物质基础。当系列氧化反应平衡紊乱时,体内生成氧自由基过量,同时超氧化物歧化酶(SOD)等抗氧化酶活性降低,引起膜脂质过氧化,形成过氧化脂质,过氧化脂质不稳定,会迅速分解产生醛类,其终产物丙二醛(MDA)相应增多,并迅速攻击磷脂及蛋白质,导致色素细胞的氧化性损伤,促进了酪氨酸酶的氧化反应,使黑色素增多并沉积于皮肤基底层。因此降低皮肤组织MDA 量,提高抗氧化酶SOD活性,对黄褐斑的预防及治疗有着重要意义。黄褐斑容易反复出现,治疗困难。市场上真正能够解决黄褐斑的产品很少,而且色斑容易复发,因此,需要寻找安全有效的产品来满足广大爱美群体的需求。氢醌是最早并最广泛应用的美白剂,但因皮肤色素分布不均,而且刺激性较强,甚至可能致癌等原因,在美白和黄褐斑的治疗中已被限制应用。相比而言,熊果苷是目前临床应用最为广泛的美白剂之一。
疤痕是物理、生物、化学等因素的损害作用于人体皮肤软组织,导致皮肤软组织的严重损伤而不能完全自行正常修复,转由纤维组织替代修复留下的即影响外观又影响功能的症状。疤痕给患者带来的是巨大的肉体痛苦和精神痛苦。在伤口愈合早期即开始进行干预非常重要,可以有效减少疤痕的形成,改善外观,纠正畸形,恢复功能。目前常用来治疗疤痕方法有:手术治疗、激光治疗、冷冻治疗和药物治疗等。常用的药物主要有:糖皮质激素和维甲酸。糖皮质激素有抗炎、抗病毒、抗休克等功能,并且有明显的抗组织纤维化的效应,但糖皮质激素长期使用毒副作用多。维甲酸是维生素A在体内代谢的中间产物,能减轻局部炎症,促进上皮细胞生长,减少胶原合成,使成纤维细胞的DNA合成减少,抑制细胞生长。但维甲酸疗效有限,系统应用毒副作用也不少,外用对皮肤刺激明显,并随着浓度增加而增加。
银屑病是具有多基因遗传背景,T细胞介导的免疫异常性炎症性疾病,全球发病率约1-3%。病因和发病机制相当复杂,容易反复发作,目前还没有根治方法,需要终生治疗。银屑病根据严重程度又分为轻、中、重度。目前常用来治疗严重银屑病的药物主要有免疫抑制剂和维甲酸类,不良反应常见,包括骨髓抑制、肝肾功能损伤和血脂升高等。随着对其发病机制研究的进展,针对疾病发病机制关键靶位的生物制剂被逐渐用于临床治疗。目前上市应用治疗银屑病的生物制剂主要有针对免疫发病机制通路的靶点TNF-a的单克隆抗体(简称:单抗)类药物,包括英夫利西单抗(商品名:类克)、阿达木单抗注射液(商品名:修美乐)和注射用重组人Ⅱ型肿瘤坏死因子受体抗体融合蛋白(商品名:依赛普)等,以及针对IL-17、IL-12、IL-23单抗等等。然而,约有30%的患者可能表现为对以上药物反应不佳或根本无效,长期使用还具有诱发感染(包括结核)和肿瘤的风险。欧洲药品管理局(EMA)和美国食品药品管理局(FDA)均发现对于那些治疗失败的患者似乎没有更好的治疗方法。占比80%的轻度银屑病患者目前主要采用外用药物进行治疗。
湿疹是一种常见皮肤病,全球发病率约10%,反复发作,严重影响患者的生活质量。临床常用的治疗药物主要是糖皮质激素和免疫抑制剂等,但是这类药物的治疗不良反应大,包括骨髓抑制、肝肾功能损伤、骨质疏松、易诱发感染和肿瘤等。新型生物制剂也具有免疫抑制作用,有诱发感染和肿瘤的风险,而且价格昂贵,限制了其广泛长期应用。对于轻中度湿疹患者,临床上主要使用外用药治疗。他克莫司软膏是目前外用治疗湿疹的非糖皮质激素金标准药,其中0.1%普特彼疗效最佳,不良反应有局部刺激,长期应用有诱发肿瘤风险。
对于上述疾病,目前的治疗方法远不能满足临床需求,需要寻找更多疗效好、副作用少、价格便宜的新药来控制疾病进展,减少复发和并发症。
发明内容
本发明的目的在于提供一种具有药用价值的环肽PIZ。
本发明的另一目的在于提供上述环肽PIZ的制备方法。
本发明的进一步的目的在于提供上述环肽的用途。
为解决上述技术问题,本发明技术方案如下:
一种环肽(简称PIZ)或其衍生物或者它们的可药用盐,具有环肽结构,其特征是:PIZ环肽由谷氨酸-酪氨酸-脯氨酸-酪氨酸-赖氨酸-组氨酸-丝氨酸-甘氨酸-酪氨酸-酪氨酸-组氨酸-精氨酸-丙氨酸-缬氨酸组成,英文名称:cyclo(glu-tyr-pro-tyr-lys-his-ser-gly-tyr-tyr-his-arg-ala-val),结构如式(I)所示:
(I)。
本发明所述的环肽或其衍生物或者它们的可药用盐,其中,衍生物为对于环肽中的氢原子、羟基、羧基、亚氨基用能够取代的公知的取代基取代而成。作为可药用盐,没有特别限定,可列举出例如与无机碱的盐、与有机碱的盐、与无机酸的盐、与有机酸的盐、与碱性、中性或酸性氨基酸的盐等。
本发明所述的环肽cyclo(glu-tyr-pro-tyr-lys-his-ser-gly-tyr-tyr-his-arg-ala-val)的制备方法可以采用现有技术常用的方法,如公知的化学合成法、遗传工程学的合成法等,具体例如包括但不限于以下2种方法:1.从环肽上任一氨基酸开始合成直链肽,然后环合。2.固相法合成环肽,最后脱离固相得到PIZ环肽。
多肽合成专业术语如表1所示:
表1 多肽合成专业术语
本发明还提供一种药物组合物,以本发明的PIZ环肽或其衍生物或者它们的可药用盐为活性成分或主要活性成分,辅以药学上可接受的载体。
本发明还提供此PIZ环肽或其衍生物或者它们的可药用盐,或者本发明所述的药用组合物在制备治疗和/或预防疾病药物中的应用。
本发明还提供此PIZ环肽或其衍生物或者它们的可药用盐,或者本发明所述的药用组合物在制备皮肤屏障修复产品中的应用。
在一些实施例中,本发明提供的PIZ环肽或其衍生物或者它们的可药用盐,或者本发明所述的药用组合物在制备治疗和/或预防痤疮、黄褐斑、疤痕、银屑病、湿疹、激素依耐性皮炎、玫瑰痤疮、脂溢性皮炎、酒糟鼻、化妆品皮炎或日光性皮炎等疾病,以及皮肤屏障修复的产品中的应用。本发明所述的的产品可以包括但不限于药品、医疗器械、保健品或护肤品等。
本发明所述的PIZ环肽可以单独使用也可以联合其他产品使用,为以上疾病的治疗提供了新的产品。
本发明所述的PIZ环肽或组合物可制备为药学上允许的任何剂型,例如为适于外用、口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、吸入、阴道、眼内、局部、皮下、脂肪内、关节内、腹膜内或鞘内任意给药方式的制剂。
在一种优选的实施方式中,本发明所述组合物的剂型为膏剂、搽剂、喷雾剂、凝胶剂、贴剂、水剂、片剂、冲剂、口服液剂、胶囊剂、滴丸剂、灌肠剂、膜剂或注射剂。
本发明所述的环肽(简称PIZ)或其衍生物或者它们的可药用盐,对治疗痤疮、黄褐斑、疤痕、银屑病、湿疹或激素依耐性皮炎、玫瑰痤疮、脂溢性皮炎、酒糟鼻、化妆品皮炎和日光性皮炎等疾病,以及皮肤屏障修复具有显著的疗效,且安全、副作用小。
附图说明
图1 PIZ环肽能够明显减轻小鼠银屑病样炎症反应。
图2 银屑病样炎症模型组小鼠的红斑、鳞屑、浸润及总分(红斑+鳞屑+浸润)均明显高于PIZ环肽治疗组。
图3 湿疹模型组小鼠的耳厚度均明显高于PIZ环肽治疗组。
图4 PIZ环肽能够明显降低湿疹模型组小鼠的血清IL-4水平。
图5 PIZ环肽氢谱分析结果。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到的。
如无特别说明,PIZ环肽制剂配方中的百分比为重量百分比。
实施例1 制备PIZ环肽的方法
1、材料:
选用多肽自动合成仪,3ml反应瓶(0.2mmol),试剂的配制按多肽合成仪说明进行。
2、合成方法:
(1)将Fomc-Glu-OAl(即9-芴基甲氧基羰基谷氨酸烯丙基酯)与PAC(烷氧基苄醇)或PAL(烷氧基苄胺)或其他类型树脂缩合。
键合后的示意图:
(2)用多肽合成仪按照glu-tyr-pro-tyr-lys-his-ser-gly-tyr-tyr-his-arg-ala-val顺序延长肽链。
(3)使用DMSO-THF-0.5N HCl-吗啡啉(2:2:1:0.1)脱去C端烯丙基,用多肽合成仪脱Fmoc程序脱去N端Fmoc保护,用多肽合成仪缩合程序得到连在树脂上的环合产物。
(4)用三氟醋酸:茴香硫醚:2-巯基乙醇:苯甲醚混合试剂从树脂上切下环肽,同时脱去其它侧链保护基,凝胶柱上纯化后,冻干得到PIZ环肽,结构式如下:
PIZ环肽氢谱分析结果如图5所示。
实施例2 PIZ环肽对兔耳痤疮模型的影响
1.实验方法
1.1材料
(1)PIZ环肽乳膏制备方法:赋形剂基质组成成分包括甲基硅油 (15%)、硬脂酸(6%)、白凡士林 (5%)、液体石蜡 (5%)、十八醇 (5%)、甘油 (20%)、烷基芳基聚乙醇醚(1%)、脂肪醇聚氧乙烯醚 (1%)、吐温-807 (1%)、尼泊金乙酯 (0.1%)、蒸馏水 (约31-55%),分别与适量的PIZ环肽液形成不同浓度的混合乳剂。本实施例所用的乳膏基质是指乳膏除去活性成分PIZ环肽的基质成分。
(2)阳性治疗药:0.1%阿达帕林凝胶(商品名:达芙文,法国高德美制药公司生产)
(3)实验动物:普通级新西兰家兔,1.8~ 2.2 kg,雄性,来源于上海斯莱克实验动物有限责任公司。
1.2动物分组与造模
新西兰家兔按体重编号,采用随机排列表法分为模型组(外用乳膏基质)、阳性对照组(外用达芙文)、环肽低剂量组(外用0.05%PIZ环肽乳膏)、环肽中剂量组(外用0.1%PIZ环肽乳膏)、环肽高剂量组(外用0.2%PIZ环肽乳膏),每组各10只。取兔右耳内侧脱毛处理作为观察区,所有家兔左耳内侧作为自身阴性对照,涂抹95%酒精,模型组和治疗组右耳内侧均涂2%煤焦油(Alfa Aesar中国公司,用95%酒精配制成2%的煤焦油溶液),用无菌棉签均匀涂于家兔耳内侧面耳导管开口处约2 cm×2cm 范围,每天1次,每次0.5 mL,并且用温水擦拭前次涂药部位,连续涂14 d,建立痤疮微粉刺模型。肉眼观察局部皮肤的变化,包括耳厚薄、硬度、粗糙程度和毛囊口有无黑色角栓等。末次涂18h后处死取材,使用5 mm 打孔器在涂药部位打孔取皮肤组织,10%甲醛固定,石蜡包埋切片,HE染色后,进行病理组织学观察分析。
1.3观察指标
痤疮模型组织学判定分级标准:按组织学级别为3级。0级“一”为漏斗部仅有松散的角化的细胞,无粉刺生成;1级为兔耳表面皮肤发红,或毛囊漏斗部见少量致密角化物质,漏斗部不扩张“+”;2级为毛囊漏斗部见中等致密角化物质,并向皮脂腺延伸,伴随皮脂腺导管的增生,漏斗扩张“2+”;3级为毛囊内有广泛的角化物质,毛囊中紧密的角质栓塞引起毛囊重度扩张,皮脂腺导管上皮明显增生,皮肤凸起、瘢痕,部分皮脂腺发生退行变“3+”。
在显微镜下观察其组织病理改变情况,并用Biomias99图像分析系统测量一张切片上5处不同表皮的厚度,计算平均值;检测4张切片中位置相同而结构最完整的2个毛囊的面积和4个皮脂腺的直径,计算各自的平均值,然后将各组兔左、右外耳道数据相减,即得各兔的左、右耳表皮厚度差、毛囊面积差和皮脂腺直径差。
1.4统计学处理
用SPSS16软件进行统计分析。自身左右对照采用配对t检验,各组间比较用t检验,P<0.05为差异有统计学意义。
2.实验结果
肉眼观察:涂煤焦油14 d后,所有组兔左耳皮肤柔软,其外耳道毛囊口排列整齐,未见粉刺、丘疹及脓疱等。模型对照组兔右耳涂煤焦油后耳厚度增加、皮肤变硬,表面粗燥,大部分毛囊口见黑头粉刺,毛囊口隆起呈丘疹,触之较硬,部分融合成片。环肽低剂量组右耳表现为皮肤轻度粗燥肥厚,可见少量黑头粉刺。环肽中剂量组和环肽高剂量组均表现为兔右耳大部分毛囊性丘疹消退,皮肤变薄柔软,粉刺明显减少,毛孔明显缩小,无脱屑,基本接近正常兔耳。阳性治疗组兔右耳与左耳相比,皮肤轻度发红,有少许脱屑,可见少量粉刺。
组织切片观察:模型组左耳显示表皮较薄,可见毛囊,真皮与表皮交界清楚。模型组右耳造模后见表皮增厚,角化过度,颗粒层和棘层增厚,有角栓堵塞毛囊口,毛囊扩大,并向皮脂腺延伸,毛囊漏斗部充满角化物质,使毛囊漏斗部扩大呈壶状;真皮浅层毛细血管扩张,毛囊周围散在炎症细胞浸润,有少量中性粒细胞;皮脂腺数量增多,皮脂腺体积增大。
各组镜下实验性粉刺组织学分级(见表2):模型组兔右耳(实验对照)与其左耳(空白对照)比较,差异有统计学意义(P<0.05),说明兔耳痤疮模型造模成功;各治疗组兔右耳与模型组兔右耳进行比较,差异均有统计学意义(P均<0.05),说明阳性对照组、各环肽治疗组均能改善痤疮皮损。
表2 各组痤疮粉刺的组织学分级
如表3所示,模型组兔右耳(实验对照)表皮厚度、毛囊画积和皮脂腺直径与其左耳(空白对照)比较,差异有统计学意义(P<0.05),证明兔耳痤疮模型复制成功;各治疗组兔右耳表皮厚度、毛囊画积和皮脂腺直径与模型组兔右耳进行比较均有减少,差异有统计学意义(P<0.05),提示阳性对照组、各环肽治疗组均能改善痤疮皮肤病理损害。
表3 各组耳表皮厚度、毛囊面积和皮脂腺直径
*为与模型组右耳比较P<0.05
3.实验结论
PIZ环肽能明显减轻煤焦油诱导的兔耳痤疮模型的症状,减少毛孔堵塞和黑头粉刺形成,并对皮肤温和无刺激,显示对痤疮具有治疗作用。
实施例3 PIZ环肽对豚鼠黄褐斑模型的影响
1.实验方法
1.1实验材料
(1)试剂:黄体酮(20 mg/ml)购自上海通用药业股份有限公司,熊果苷软膏购自上海新先锋药业有限公司,酪氨酸、丙二醛(MDA)、超氧化物歧化酶(SOD)试剂盒购自南京建成生物工程研究所。
(2)仪器:DY89-Ⅱ型电动玻璃匀浆机购自宁波新兰生物科技股份有限公司,系统生物显微镜(Image-Pro Plus 6.0)购自美国Media Cybernetics公司。
(3)实验动物:SPF级健康纯系雌性豚鼠,体重(230±31)g,来源于上海斯莱克实验动物技术有限公司。
(4)PIZ环肽乳膏制备方法:赋形剂基质组成成分包括甲基硅油 (15%)、硬脂酸(6%)、白凡士林 (5%)、液体石蜡 (5%)、十八醇 (5%)、甘油 (20%)、烷基芳基聚乙醇醚(1%)、脂肪醇聚氧乙烯醚 (1%)、吐温-807 (1%)、尼泊金乙酯 (0.1%)、蒸馏水 (约31-55%),分别与适量PIZ环肽混匀形成不同浓度的混合乳剂。本实施例所用的乳膏基质是指除去PIZ环肽活性成分的基质成分。
1.2动物分组与造模
按体重编号,采用随机排列表法分为模型对照组(涂抹乳膏基质)、空白对照组(涂抹乳膏基质)、PIZ环肽乳膏组(皮肤涂抹0.25%PIZ环肽乳膏)、PIZ环肽注射组(尾静脉注射PIZ环肽, 1mg/kg.d)、阳性治疗组(皮肤涂抹0.25%熊果苷乳膏),每组6只。除了空白对照组外,其余各组豚鼠均于后腿根部肌内注射20mg/ml黄体酮注射液(7.5mg/kg),每天1 次,连续注射30d建立黄褐斑模型。豚鼠背部模型区域皮肤呈均一稳定、边界清晰的深褐色色斑为模型复制成功。造模后,模型对照组、空白对照组、PIZ环肽乳膏组、阳性治疗组豚鼠背部涂抹相应乳膏进行干预,PIZ环肽注射组经尾静脉注射PIZ环肽注射组(1mg/kg.d)进行干预,每天1次,连续30天。
1.3观察指标
(1)酪氨酸、MDA含量,SOD活性测定
所有豚鼠取备用皮肤组织1块用预冷生理盐水冲洗,除去皮下脂肪及其他结缔组织,每块皮肤组织各切取0.5g,分别放入盛有2.0 ml预冷生理盐水的5根小试管内,高速分散机以10 r/min的速度匀浆,持续10s,重复1次,3500 r/m速度离心15 min后取上清液。酪氨酸测定采用高效液相法,MDA测定用硫代巴比妥酸法,SOD测定用黄嘌呤氧化酶法,按试剂盒说明书检测酪氨酸、MDA含量及SOD活性。
(2)皮肤黑色素细胞的病理形态学观察
所有豚鼠取备用皮肤组织1块,约2 cm×1 cm,10%多聚甲醛固定,病理组织检测,免疫组织化学染色,观察黑色素细胞染色和数目,并根据文献判断阳性细胞:无,0分;<15%,0.5分;<30%,1分;>30%,2分。每张切片分别观察5个视野,找到皮肤表皮和附件上皮细胞胞浆中呈现棕色反应的阳性目标后,用BX50F4北航病理图像分析系统定量分析,得到每只豚鼠5个视野黑色素阳性目标的平均面积、目标与统计场面积之比(面密度)、目标个数与统计场面积之比(数密度)、平均灰度、平均光密度及积分光密度。
1.4统计学方法
采用SPSS16.0软件统计,计量资料以均数±标准差(x±s)表示,多组间比较采用单因素方差分析,组间比较用t检验,P <0.05为差异有统计学意义。
实验结果
(1)各组豚鼠酪氨酸、MDA 含量及SOD 活性
各组豚鼠酪氨酸、MDA 含量及SOD 活性检测结果见表4。模型组豚鼠皮肤酪氨酸、MDA含量均高于空白组,SOD活性低于空白组,说明皮肤黄褐斑模型建立成功;与模型组比较,PIZ环肽乳膏组、PIZ环肽注射组和阳性治疗组皮肤中酪氨酸、MDA含量较低,而SOD活性则升高,差异均有统计学意义(P<0.05)。
表4各组豚鼠酪氨酸、MDA含量及SOD活性比较情况
*为与模型组比较P<0.05
(2)各组豚鼠黑色素细胞的面积、数量及深浅度
各组豚鼠黑色素细胞的面积、数量及深浅度见表5和表6。与空白组比较,模型组豚鼠皮肤黑色素沉着面积增大、黑色素细胞个数增多,光密度变大,着色变深;与模型组比较,PIZ环肽乳膏组、PIZ环肽注射组和阳性治疗组豚鼠皮肤的黑色素沉着面积缩小、黑色素细胞个数减少,光密度变小,着色变浅。
表5各组豚鼠黑色素细胞的面积、数量比较
*为与模型组比较P<0.05
表6各组豚鼠黑色素细胞深浅度比较
*为与模型组比较P<0.05
3.实验结论
PIZ环肽能通过提高皮肤组织中SOD酶活性,降低酪氨酸、MDA的含量,抑制黑色素细胞和黑色素瘤细胞的酪氨酸酶活性,增强皮肤细胞的氧化还原反应,减少自由基产生,抑制黑色素的形成,从而有效治疗黄褐斑。
实施例4 PIZ环肽对大鼠疤痕模型的影响
1.实验方法
1.1 材料:
PIZ环肽乳膏制备方法:基质组成成分包括甲基硅油 (15%)、硬脂酸 (6%)、白凡士林 (5%)、液体石蜡 (5%)、十八醇 (5%)、甘油 (20%)、烷基芳基聚乙醇醚 (1%)、脂肪醇聚氧乙烯醚 (1%)、吐温-807 (1%)、尼泊金乙酯 (0.1%)、蒸馏水 (约31-55%),与适量PIZ环肽溶液混合形成不同浓度的混合乳膏。
1.2实验动物分组与造模:SPF级雄性大鼠6只,体重(210±28)g,来源于南医大动物中心。大鼠用2%戊巴比妥钠(120 mg/kg)腹腔注射麻醉后固定于手术台上,然后在其背部两侧各选择一块4×5cm 的完整皮肤,8%硫化钠脱毛,用组织剪在脱毛处各剪成一直径为2.4cm圆形深达肌筋膜的伤口,破坏部分肌肉表面筋膜。左侧皮肤创面外用0.5%PIZ环肽乳膏,右侧皮肤创面外用0.5%乳膏基质,厚度为薄层覆盖创面,每天2次。动物分笼饲养防止大鼠撕咬、舔蹭。创面每日涂2%碘酊常规消毒,观察大鼠创面愈合情况。
2.实验结果
2 .1 大鼠创面观测结果
创面每天常规消毒,第1d、3d、5d、7d、12d、20d观察大鼠创面。自第5天开始左侧外用PIZ环肽的皮肤伤口恢复速度明显比对右侧快,创面面积逐渐变小。第12天,左侧外用PIZ环肽的皮肤伤口创面已经基本恢复,而右侧外用乳膏基质的皮肤伤口仍有约0.5cm2 大小的创面,到第20天时,两组创面均已经恢复,右侧外用乳膏基质的皮肤伤口留下明显疤痕,左侧外用PIZ环肽的皮肤伤口只留下数量不等的色素沉着。
3.实验结论
PIZ环肽能明显促进皮肤创面愈合,减少疤痕形成。
实施例5 PIZ环肽能抑制小鼠银屑病样炎症反应
1、材料:
阳性药(糖皮质激素药):糠酸莫米松乳膏(艾洛松),上海先灵葆雅制药有限公司产品。
动物:SPF级健康纯系小鼠(C57BL/6);8周龄。
PIZ环肽乳膏制备方法:基质组成成分包括甲基硅油 (15%)、硬脂酸 (6%)、白凡士林 (5%)、液体石蜡 (5%)、十八醇 (5%)、甘油 (20%)、烷基芳基聚乙醇醚 (1%)、脂肪醇聚氧乙烯醚 (1%)、吐温-807 (1%)、尼泊金乙酯 (0.1%)、蒸馏水 (约31-55%),与适量PIZ环肽溶液形成不同浓度的混合乳剂。
本实施例所用的乳膏基质是指环肽乳膏除去活性成分的基质成分。
2、实验方法:
(1)购SPF级雌性C57BL/6小鼠8周龄36只,随机分为空白对照组、模型组、阳性对照组(外用艾洛松乳膏)、低剂量治疗组(外用0.1% PIZ环肽乳膏)、中剂量治疗组(外用0.5%PIZ环肽乳膏)、高剂量治疗组(外用1%PIZ环肽乳膏)各5只。戊巴比妥钠 80 mg /kg腹腔注射麻醉后,背部剃毛,面积约为2cm×3cm,单笼饲养1天。
(2)空白对照组局部涂抹凡士林,模型组、阳性对照组和环肽治疗组背部每日定时涂抹5%咪喹莫特乳膏62.5mg,连续6天,每天拍照,进行PASI评分。
(3)在造模第1天,空白对照组和模型组外用乳膏基质,每天1次,治疗组外用0.1~1% PIZ环肽乳膏,阳性对照组外用艾洛松乳膏,每天1次。
3、实验结果:
(1)连续涂抹5%咪喹莫特乳膏6天后,模型组小鼠的背部涂药区域均出现明显红斑、鳞屑及浸润,而环肽治疗组和激素治疗组小鼠的背部涂药区域的红斑、鳞屑及浸润均明显比模型组轻微,1% 环肽乳膏治疗组的红斑、鳞屑及浸润接近激素阳性药治疗组(图1)。
(2)每天对小鼠背部涂药区域皮损进行评分,模型组小鼠的红斑、鳞屑、浸润及总分(红斑+鳞屑+浸润)均明显高于环肽治疗组(P<0.05)(图2),说明环肽能够明显抑制银屑病样小鼠模型的炎症反应。
实施例6 PIZ环肽对小鼠湿疹模型的影响
1、实验材料:
卵清蛋白(OVA):PBS配成20 g/L,保存于-20℃。
卡泊三醇搽剂(达力士搽剂):丹麦利奥制药有限公司产品。
阳性药(糖皮质激素药):糠酸莫米松乳膏(艾洛松),上海先灵葆雅制药有限公司产品。
PIZ环肽乳膏和基质:制备方法同实施例3。
动物:SPF级健康纯系小鼠(C57BL/6);8周龄。
2、实验方法:
购SPF级雌性C57BL/6小鼠8周龄(0.02kg)30只,随机分为空白对照组(6只)、模型组(6只)、阳性药组(6只)、低剂量治疗组(外用0.1% PIZ环肽乳膏)(各6只)、中剂量治疗组(外用0.25% PIZ环肽乳膏)(各6只)、高剂量治疗组(外用0.5% PIZ环肽乳膏)(各6只)。
造模:正常对照组小鼠两侧耳部涂抹75%乙醇14.3ul,同时模型组、阳性药组和环肽治疗组每日定时先在两侧耳部涂抹1nmoI/L卡泊三醇搽剂14.3ul,风干后涂抹20g/L的OVA 25ul,每日1次,连续涂抹12 d造模。
造模开始后4天起,在空白对照组和模型组小鼠耳部皮肤上涂抹PIZ环肽乳膏基质,阳性药组小鼠耳部皮肤上涂抹艾洛松,环肽治疗组小鼠耳部皮肤上涂抹上诉PIZ环肽乳膏(浓度0.1~0.5%),每天1次,连续10天,每天拍照,进行评分。
分别在造模前和第14天用皮肤测试仪随机检测小鼠背部受试区3处部位,记录经皮水分丢失量(TEWL)值,取平均值。
分别在造模前和第14天用耳厚度测量仪测量记录小鼠耳廓厚度。于第14天测量完毕后脱颈处死小鼠,取血,分离血清。
用兔抗小鼠白介素(IL)-4抗体包被酶标板,4℃过夜,按照ELISA试剂盒说明书操作染色并终止反应,检测血清IL-4水平。ELISA试剂盒均购自美国Raybiotech公司。
3、实验结果:
(1)各组小鼠皮肤经皮水分丢失量(TEWL)比较:造模前,各组间TEWL值差异无统计学意义(P>0.05)。造模14天后,各组小鼠TEWL值见表7。模型组显著高于PIZ环肽低剂量乳膏组、中剂量乳膏组、高剂量乳膏组、阳性药组和空白对照组(P均<0.01),阳性药组与环肽高剂量乳膏组间差异无统计学意义(P>0.05)。
表7 造模后各组小鼠TEWL值
(2)小鼠耳厚度比较:造模前,各组间耳厚度差异无统计学意义(P>0.05)。造模后,各组小鼠耳厚度见表8。模型组显著高于PIZ环肽低剂量乳膏组、中剂量乳膏组、高剂量乳膏组、阳性药组和空白对照组(P均<0.01),阳性药组与环肽高剂量乳膏组间差异无统计学意义(P>0.05)(图3)。
表8 造模后各组小鼠耳厚度
(3)血清IL-4浓度:造模前,各组间血清IL-4浓度差异无统计学意义(P>0.05)。造模后,各组小鼠外周血中血清IL-4水平见表9。模型组显著高于其它各组(P均<0.01),阳性药组与PIZ环肽高剂量乳膏组间差异无统计学意义(P>0.05) (图4)。
表9 造模后各组小鼠外周血中IL-4水平
4. 实验结论
PIZ环肽能通过抑制炎症因子IL-4来减轻湿疹,同时通过减少皮肤经皮水分丢失量(TEWL),修复皮肤屏障。
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