CN112156118A - 文王一支笔提取物在制备抗肾脏纤维化药物中的应用 - Google Patents
文王一支笔提取物在制备抗肾脏纤维化药物中的应用 Download PDFInfo
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Abstract
本发明公开了文王一支笔提取物在制备抗肾脏纤维化药物中的应用，其中文王一支笔提取物为水提取物或者水提醇沉部位提取物。文王一支笔的水提醇沉提取物（BPP）能抑制UUO诱导小鼠肾脏间质损伤及其纤维化；对UUO诱导小鼠肾脏功能具有一定的保护作用。进一步研究表明BPP通过抑制Collagen I、Collagen III及Collagen IV的表达而抑制肾脏纤维化；采用水提醇沉提取物（BPP）在动物实验过程中，未发现小鼠死亡，也没有观察到小鼠明显的肝肾功能异常，这表明其具有较好的安全性。文王一支笔水提醇沉部位提取物，可应用于制备抗肾脏纤维化药物及药物组合物。
Description
技术领域
本发明涉及药物领域，具体涉及一种文王一支笔提取物在制备抗肾脏纤维化药物中的应用。
背景技术
慢性肾功能衰竭(CRF)已成为影响全球人类公共卫生健康的重大疾病之一。肾间质纤维化是CRF的主要病理特征之一，是各种肾脏疾病发展到终末期肾病的共同通路，是CRF的必经途径。目前认为，终末期肾脏病的病理改变是不可逆的；因此，防治肾纤维化的发生发展至关重要，是防治CRF的关键。肾纤维化的发病机制及其复杂，是多因素、多环节相互作用的缓慢过程，其机制主要涉及肌成纤维细胞的活化、细胞外基质的合成与降解失衡、上皮间质转化(EMT)及炎症等。长期以来，临床上对肾纤维化的治疗主要包括：原发病的治疗(如梗阻性肾病等)、相关危险因素的消除和干预(如感染、药物等)及针对发病机制的治疗(如非甾体类抗炎药物、降压药物等)。然而，目前临床上针对抑制肾脏纤维化过程的药物很少，尚缺乏真正有效用于临床治疗的药物。
基于对肾脏纤维化发病机制的认识，以及治疗学的角度，阻断肾素－血管紧张素－醛固酮系统(RAAS)激活是目前唯一有证据支持可延缓肾脏纤维化进展的临床治疗手段。目前应用于临床的RAAS系统阻断药物主要包括血管紧张素转化酶抑制剂(ACEI)与血管紧张素II受体阻断剂(ARB)，二者均是合并蛋白尿的慢性肾脏病患者的一线推荐用药。然而，ACEI与ARB的使用在慢性肾脏病患者中后期患者中容易导致高钾血症及急性肾功能衰竭，在孕妇、肾动脉狭窄、非高血压人群中存在使用限制，并且仅能部分延缓肾纤维化进展。随着近年来CRF患病率的快速增长，发展更加安全有效的抗肾纤维化药物尤为迫切。
中医学认为肾纤维化是一个正气耗损，邪毒滞盛，长期正邪相争，邪盛正虚的过程。中医学治疗肾纤维化，主要以活血化瘀、清热解毒、补益脾肾为主，从多环节、多方位、多靶点干预用药。近年来，有关单味中药，部分中药有效成分及中药复方在抗肾间质纤维化领域的研究取得了令人瞩目的成果，目前已有报道具有抗肾纤维化作用的中药包括冬虫夏草、黄芪、三七等。针对肾纤维化的产生是一个多环节、多途径作用过程的特点，中医药治疗CRF和防治肾脏纤维化的优势主要体现在多成分、多途径，多靶点的综合药理作用。借助现代医学的研究成果，深入系统研究中草药防治肾纤维化的作用机制和作用环节，有望从中研发出具有抗肾纤维化的新型、特效药物应用于临床。
发明内容
本发明提供一种文王一支笔提取物在制备抗肾脏纤维化药物中的应用，该文王一支笔提取物对肾脏纤维化具有良好的抑制作用，可用于制备抗肾脏纤维化药物。
本发明提供文王一支笔提取物在制备抗肾脏纤维化药物中的应用。
进一步地，所述的文王一支笔提取物为水提取物。
更进一步地，所述的文王一支笔提取物为水提醇沉部位提取物。
进一步地，该药物中包含水提醇沉提取物，质量浓度在5％以上。
进一步地，该药物中包含水提醇沉提取物的精制成分，且药物中精制成分质量浓度在1％以上。
进一步地，所述精制成分用水提醇沉提取物经过脱色、精制后得到的，主要包括鞣质类和多糖类成分，其中多糖含量在50％以上。
进一步地，该药物的剂型为混悬液、胶囊、片剂、丸剂、滴丸剂、粉剂、注射液或者其他药学上可接受的剂型。
文王一支笔作用于肾脏纤维化、肾炎等方面鲜有实验报道或临床观察。为了试验并明确文王一支笔的抗肾脏纤维化作用，我们初期对文王一支笔按传统水煎煮获得水提取物，通过以单侧输尿管梗阻(unilateral urethral obstruction,UUO)造成小鼠单侧输尿管梗阻法肾小管间质纤维化模型进行观察，结果表明文王一支笔水提物对UUO诱导的小鼠肾脏纤维化表现出一定的抑制作用。随后进一步发现，文王一支笔水提醇沉部位是文王一支笔抗肾脏纤维化作用的主要有效部位。最终经过药效学反复验证，以及相关作用机制研究后发现，文王一支笔水提醇沉部位具有确切的抗肾脏纤维化作用，其作用机制与其抑制Hedgehog信号通路有关。民间应用基础及相关科学实验研究还表明，文王一支笔具有较好安全性。基于此，我们认为，文王一支笔提取物，尤其是从中制备得到的水提醇沉部位提取物，可应用于制备抗肾脏纤维化药物及药物组合物。
文王一支笔的水提醇沉提取物(BPP)能抑制UUO诱导小鼠肾脏间质损伤及其纤维化；对UUO诱导小鼠肾脏功能具有一定的保护作用。进一步地研究证明，BPP通过抑制Collagen I、Collagen III及Collagen IV的表达而抑制肾脏纤维化；低、高剂量BPP给药组能显著降低UUO小鼠肾脏组织中Fibronectin及α-SMA的蛋白及mRNA的表达，使小鼠肾脏组织中MMP2、MMP9 mRNA及蛋白的表达显著增加，TIMP1、TIMP2 mRNA及蛋白的表达显著降低。采用水提醇沉提取物(BPP)在动物实验过程中，没有发现小鼠死亡，也没有观察到小鼠明显的肝肾功能异常，这表明其具有较好的安全性。
附图说明
图1是文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾功能的影响。
图2为文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾间质损伤及其纤维化的影响。
图3为文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾脏Collagen I,CollagenIII,Collagen IV表达的影响。
图4为文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾脏Fibronectin及α-SMA表达的影响，其中A为Fibronectin及α-SMA的免疫组织化学结果；B为Fibronectin及α-SMA的免疫组织化学阳性区域比分的统计分析；C为Fibronectin及α-SMA的mRNA表达。
上述图中*p<0.05为与Sham组比较；#p<0.05为与UUO组比较；n＝5；BPP-L为BPP低剂量组(150mg/kg.d)；BPP-H为BPP高剂量组(450mg/kg.d)；CPN为阳性对照组。
图5为文王一支笔水提醇沉部位提取物(BPP)经多种脱色剂处理后的脱色效果图。
其中1-1:脱色1组原液(10mg/ml)；1-2：脱色1组活性炭法；1-3：脱色1组双氧水法；1-4：脱色1组离子树脂法；2-1:脱色2组原液(2mg/ml)；2-2：脱色1组活性炭法；2-3：脱色1组双氧水法；2-4：脱色1组离子树脂法。
具体实施方式
下面结合实施例，进一步阐明本发明。
实施例：
1、药物来源
本发明中的药物来源，与ZL201710972233.1“文王一支笔提取物及其在制备抗癌药物中的应用”中的药物来源一致。
2、药物制备及特征图谱研究
本发明中的文王一支笔水提醇沉部位提取物(BPP)的提取与制备方法，与专利“文王一支笔提取物及其在制备抗癌药物中的应用”(专利号ZL201710972233.1)中的方法一致，具体为该专利中的FrP；其特征图谱与专利“文王一支笔提取物及其在制备抗癌药物中的应用”(专利号ZL201710972233.1)中相应部位提取物的特征图谱一致。
水提醇沉部位提取物进一步经过脱色、精制后得到精制成分。在脱色工艺研究中，考察了D941型阴离子交换树脂、活性炭和双氧水等脱色剂对文王一支笔水提醇沉部位提取物(BPP)的脱色除杂效果，主要操作步骤：取文王一支笔水提醇沉部位提取物适量，加水溶解，配制成两种浓度的脱色原液(10mg/ml和2mg/ml)；活性炭和双氧水脱色组分别加入相应脱色剂，加入量分别为1.5％(m/v)和10％(v/v)，然后置于60℃水浴中1.0h，时时振摇；树脂脱色组取处理好的D941型湿树脂，按20g/30ml原液的比例，静态吸附过夜；脱色处理后的溶液过滤后，与原液比较，观察脱色效果，结果如图5所示。各组脱色后溶液经冷冻干燥得到精制提取物，随后参照《中草药有效成分提取与分离》(第二版)(中国科学院上海药物研究所编著)所载方法进行化学成分预试验研究，结果显示Molish反应、FeCl3反应以及FeCl3-K3[Fe(CN)6]反应为阳性，其余皆为阴性或弱阳性，表明该精制提取物中主要含有多糖和鞣质类成分。进一步以苯酚-硫酸法测定各组精制提取物中的多糖含量，结果见表1。
表1文王一支笔水提醇沉部位提取物(BPP)及其精制提取物的多糖含量(n＝6)
3、文王一支笔水提醇沉部位提取物(BPP)的抗肾脏纤维化作用研究
3.1材料及方法
3.1.1动物实验
雄性C57BL/6小鼠50只，SPF级，体质量18～22g，购自北京维通利华实验动物技术有限公司，动物合格证号：SCXK(京)2016—0006。饲养于三峡大学实验动物中心，环境温度为18～22℃，相对湿度为50～60％，所有动物实验前适应性饲养1周。小鼠自由活动及摄食饮水。动物实验依据“三峡大学实验动物护理和使用指南”进行，并经动物实验伦理委员会批准，实验单位使用许可证号为SYXK(鄂)2017-0061。
将50只小鼠随机分为5组，每组10只，即假手术组(Sham组)，模型组(UUO组)，BPP低剂量组(UUO+BPP-L)、BPP高剂量组(UUO+BPP-H)及阳性对照(UUO+CPN)组。UUO组其他用药组小鼠在无菌条件下进行左侧输尿管结扎；Sham组除不结扎外其余操作均与UUO组相同。术后第1天开始，UUO+BPP-L组、UUO+BPP-H组分别灌胃给予BPP(150mg/kg.d及450mg/kg.d)；UUO+CPN组灌胃给予cyclopamine(CPN，5mg/kg.d)，用作阳性对照组；同时，Sham组和UUO组灌胃等体积的0.5％C8H15NaO8[Sodium carboxyl methyl cellulose(CMC solution)]，每天一次。术后第14天，眼眶静脉取血，静置1h后3000r/min离心10min，收集血清，-20℃保存，用于血清Creatinine、BUN、β2MG、Cys C含量测定。窒息处死小鼠，切取左肾，一部分置于4％的多聚甲醛中固定，用于HE和Masson染色；一部分-80℃保存，用于肾组织mRNA及蛋白表达水平的检测。
3.1.2组织学检查
肾脏组织用4％的多聚甲醛固定后，常规石蜡包埋。4微米的石蜡切片用二甲苯脱蜡、梯度乙醇脱水，经苏木精和伊红染色(H&E)后，光学显微镜下观察肾脏病理改变(Olympus,BX61,Japan)。
3.1.3 Masson's染色
石蜡包埋的肾脏组织切片进行Masson's trichrome染色，分析肾脏中胶原沉积情况。操作按照Masson's trichrome试剂盒(碧云天生物技术有限公司，中国)说明书进行。染色采用Image Pro Plus 6.0图像软件进行定量分析。每张切片随机选取20个不同视野，呈现蓝色的纤维区域为阳性，以阳性面积与整个视野总面积的比值作为肾脏纤维化指数。
3.1.4酶联免疫吸附实验(ELISA)检测
收集每组小鼠血样本，在4℃离心后，血清样本在-80℃冻存直至检测。血清creatinine、BUN、β2微球蛋白(β2MG)、胱蛋白酶抑制剂C(Cys C)水平通过ELISA试剂盒检测，操作按试剂盒说明书进行。小鼠ELISA试剂盒购自上海双赢生物科技有限公司。
3.1.5免疫组织化学检测
石蜡包埋的肾脏组织切片用于免疫组织化学染色分析。所有肾脏组织切片(4μm)经二甲苯脱蜡、梯度乙醇水化、抗原修复(0.01M柠檬酸盐缓冲液，PH 6.0)；用3％过氧化氢封闭内源性过氧化氢酶，5％BSA室温封闭。切片用α-SMA(Santa Cruz Biotechnology,Sc-53142,1:500)及Fibronectin(Santa Cruz Biotechnology,Sc-29011,1:500)一抗4℃孵育过夜。切片用PBS缓冲液冲洗后，室温下孵育相应二抗1h。滴加新鲜配制的DAB显色剂，苏木精复染，盐酸酒精分化，梯度乙醇脱水干燥，二甲苯透明，封片后显微镜下观察棕褐色为阳性表达。每张切片选取10个不同视野，用Image Pro Plus 6.0软件分析阳性表达的相对面积。
3.1.6 Real time PCR检测相关基因mRNA的表达
用Trizol试剂(Invitrogen,USA)提取上述药物处理的HK-2细胞或UUO小鼠肾脏组织总RNA(按试剂说明书进行操作)；经DNase处理后，用1.2％琼脂糖凝胶电泳检测RNA完整性；用紫外分光光度计在波长260nm检测RNA浓度。用2微克总RNA逆转录得到模板cDNA。PCR反应按以下进行：1μl cDNA(diluted 1:5)，特异性引物1μl，SYBR Green PCR Master Mix10μl，最终体积20μl。起始反应在95℃ 10min,紧接着用95℃15sec及60℃1min进行40循环。基因表达水平用2-ΔΔCt方法分析，GAPDH用作内参。
3.1.7 Western blot检测相关蛋白的表达
用RIPA buffer(RIPA裂解液：PMSF：蛋白磷酸酶抑制剂＝100:1:1)匀浆上述处理的HK-2细胞或UUO小鼠肾组织，匀浆物于4℃12000rpm离心15min后取上清，用BCA方法测定蛋白浓度。50微克蛋白样品用5×上样缓冲液稀释，并100℃加热5分钟后，在SDS-PAGE胶中电泳，随后转移到PVDF膜上，用5％牛奶封闭1h，4℃相应一抗孵育过夜，TBST缓冲液洗膜3次后室温下孵育相应二抗1h，洗膜后用ECL化学发光液显影,用Image-Pro Plus 6.0软件对图像进行分析。
3.1.8统计学处理
实验结果以均数±标准差
表示，使用统计软件SPSS 11.5进行分析，多组间用单因素方差分析(One Way ANOVA)，以p<0.05为差异有显著性。
4、研究结果
4.1文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾脏功能影响
取各组小鼠血清样本，根据ELISA试剂盒说明书检测小鼠血清creatinine、BUN、β2MG、Cys C的含量。结果(图1)表明：与假手术组比较，模型组的creatinine、BUN、β2MG、CysC的含量均显著升高，差异有统计学意义(p<0.05)；低、高剂量BPP给药组能显著降低UUO小鼠纤维化肾的creatinine、BUN、β2MG、Cys C的水平(p<0.05)，表明文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾脏功能有一定的保护作用。
4.2文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾脏间质损伤及其纤维化的影响
HE及Masson染色结果(图2)显示，Sham组肾脏形态结构基本正常，肾小管之间仅见少量蓝色胶原纤维蛋白的阳性染色；UUO组中结扎侧肾小管间质苯胺蓝染色物质明显增多，肾盂扩张，肾小管出现严重的变性坏死，肾间质纤维化区域明显增宽伴随大量炎性细胞浸涧，肾间质纤维化区域显著增多，肾间质损伤比分明显升高，与Sham组比较，差异有统计学意义(p<0.05)。与UUO组比较，低、高剂量BPP给药组能显著降低UUO小鼠肾小管间质损伤比分及减少其苯胺蓝染色物质，差异有统计学意义(p<0.05)，表明文王一支笔水提醇沉提取物(BPP)能显著减轻UUO小鼠肾脏间质损伤及其纤维化作用。
4.3文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾脏组织中CollagenⅠ、CollagenIII及CollagenⅣ表达的影响
上述Masson染色结果显示BPP能明显抑制UUO小鼠肾脏纤维化；而细胞外基质(ECM)沉积是肾脏纤维化的主要特征。Collagen I、Collagen III及Collagen IV是ECM的主要成分，因此，我们检测BPP对Collagen I、Collagen III及Collagen IV表达的影响。结果(图3)显示，与Sham组相比，UUO模型组小鼠肾脏组织中Collagen I、Collagen III、Collagen IV mRNA及蛋白表达明显升高(p<0.05)，而低、高剂量BPP给药组能显著降低小鼠肾脏组织中相应基因mRNA及蛋白的表达(p<0.05)，表明BPP抑制UUO小鼠肾脏纤维化主要是通过抑制Collagen I、Collagen III及Collagen IV的表达而实现。
4.4文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾脏组织中Fibronectin及α-SMA表达的影响
肾间质中的成纤维细胞被认为是Collagen I、Collagen III及Collagen IV的主要来源，而Fibronectin及α-SMA是成纤维细胞激活的主要标志。因此，接下来检查BPP对UUO小鼠肾脏组织中Fibronectin及α-SMA表达的影响。图4结果显示：与Sham组相比，UUO模型组小鼠肾脏组织中Fibronectin及α-SMA的蛋白及mRNA表达明显升高(p<0.05)，而低、高剂量BPP给药组能显著降低小鼠肾脏组织中Fibronectin及α-SMA的蛋白及mRNA的表达(p<0.05)，表明文王一支笔水提醇沉提取物(BPP)能显著抑制UUO小鼠肾间质成纤维细胞的激活。
4.5文王一支笔水提醇沉提取物(BPP)对UUO小鼠肾脏组织中MMP2、MMP9及TIMP1、TIMP2表达的影响
MMPs催化ECM的降解，特别地，MMP2及MMP9与肾纤维化密切相关。MMPs的活性主要被TIMPs抑制，在TIMPs家族中，TIMP1及TIMP2能抑制MMPs的活性，在维持ECM平衡中发挥重要作用。上述结果显示BPP能抑制ECM沉积，接下来，检测BPP对UUO小鼠肾脏组织中MMP2、MMP9及TIMP1、TIMP2表达的影响。结果如图5所示：与Sham组相比，UUO模型组小鼠肾脏组织中MMP2、MMP9 mRNA及蛋白的表达显著降低，而TIMP1、TIMP2 mRNA及蛋白的表达显著增加(p<0.05)；而低、高剂量BPP给药组能使小鼠肾脏组织中MMP2、MMP9 mRNA及蛋白的表达显著增加，TIMP1、TIMP2 mRNA及蛋白的表达显著降低(p<0.05)，表明文王一支笔水提醇沉提取物(BPP)抑制ECM沉积主要是通过显著增加MMP2、MMP9 mRNA及蛋白的表达，并明显降低TIMP1、TIMP2 mRNA及蛋白的表达而实现。
本发明证明文王一支笔提取物具有确切的抗纤维化活性，可用于制备抗纤维化药物，尤其是制备抗肾脏纤维化的药物。
Claims (7)
1.文王一支笔提取物在制备抗肾脏纤维化药物中的应用。
2.根据权利要求1所述的应用，其特征在于：所述的文王一支笔提取物为水提取物。
3.根据权利要求1所述的应用，其特征在于：所述的文王一支笔提取物为水提醇沉部位提取物，具体是水提取物经醇沉处理后得到的沉淀物。
4.根据权利要求3所述的应用，其特征在于：该药物中包含水提醇沉提取物，质量浓度在5%以上。
5.根据权利要求3所述的应用，其特征在于：该药物中包含水提醇沉提取物的精制成分，且药物中精制成分质量浓度在1%以上。
6.根据权利要求5所述的应用，其特征在于：所述精制成分用水提醇沉提取物经过脱色、精制后得到的，主要包括鞣质类和多糖类成分，其中多糖含量在50%以上。
7.根据权利要求1-6任意一项所述的应用，其特征在于：该药物的剂型为混悬液、胶囊、片剂、丸剂、滴丸剂、粉剂、注射液或者其他药学上可接受的剂型。
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