CN110859932B - 抗肾纤维化的药物及其制备方法 - Google Patents
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Abstract
本发明涉及中药技术领域，尤其涉及治疗肾纤维化的药物及其制备方法。本发明提供的31种中药材皆具有抗肾纤维化、抗心肾综合征、抗心力衰竭、抗肾病综合征和/或抗肾衰竭的药物的作用，其中由白术、马勃、石吊兰、蝉蜕组成的组合物能够抑制肾小管细胞上皮‑间质转化、抑制关键基因的转录水平，因此能够有效治疗肾纤维化、心肾综合征、心力衰竭、肾病综合征、肾衰竭。
Description
技术领域
本发明涉及中药技术领域，尤其涉及治疗肾纤维化的药物及其制备方法。
背景技术
肾纤维化是各种肾脏疾病发展到终末期肾脏衰竭的共同病理基础，是心肾综合征和心力衰竭的重要病理过程。开发新型治疗肾纤维化的新疗法对于肾衰和心肾综合征具有重要意义。肾纤维化与多种基因表达失调有关，其中人纤溶酶原激活物抑制剂1基因(SERPINE1)、Ⅰ型胶原α1基因(COL1A1)、人白介素13受体α1(IL13RA1)、内皮素受体B(EDNRB)和SMAD4为影响肾纤维的关键基因。抑制肾纤维化的关键基因能够有效抑制肾纤维化的病理进程，阻止细胞外基质的聚集，逆转肾小管细胞的上皮-间质转化。
目前，抗肾纤维化作用的西药专一性不强，疗效欠佳。而肾纤维化的中医病机为本虚标实，本虚主要为肾气亏虚，标实主要为指血瘀、湿热、水泛，中药治疗肾纤维化具有独特的临床优势，但目前仍未有特效的中药组合物能够有效的治疗肾纤维化。
发明内容
有鉴于此，本发明要解决的技术问题在于提供治疗肾纤维化的药物及其制备方法，本发明所述的药物为中药材或其组合物，能够有效抑制肾纤维的关键基因，抑制肾小管细胞上皮-间质转化。
本发明提供了中药在制备抗肾纤维化药物中的应用；
所述中药选自白术、马勃、石吊兰、蝉蜕、杜仲叶、蛇床子、甘草、徐长卿、枇杷叶、杜仲、滇鸡血藤、筋骨草、桃枝、皂角刺、射干、蛇蜕、翼首草、浮萍、升麻、白及、苦楝皮、淡竹叶、通草、常山、红花龙胆、女贞子、四季青、马钱子、山柰、藕节、三颗针中至少一种。
本发明所述抗肾纤维化包括抑制关键基因转录水平和/或抑制肾小管细胞上皮-间质转化。
本发明所述关键基因为SERPINE1、COL1A1、SMAD4、IL13RA1或EDNRB。
本发明利用35种中药(即白术、马勃、石吊兰、蝉蜕、杜仲叶、蛇床子、甘草、徐长卿、枇杷叶、杜仲、滇鸡血藤、筋骨草、桃枝、皂角刺、射干、蛇蜕、翼首草、浮萍、升麻、白及、苦楝皮、淡竹叶、通草、常山、红花龙胆、女贞子、四季青、马钱子、山柰、藕节、三颗针、牡丹皮、益母草、人参和黄芪)的乙醇提取物验证了它们对于SERPINE1、COL1A1、SMAD4、IL13RA1和EDNRB基因转录的调控作用。结果表明，其中31种中药材能够对几种关键基因中的至少一种起到抑制作用，而由于SERPINE1、COL1A1、SMAD4、IL13RA1或EDNRB基因是肾纤维化、心肾综合征、心力衰竭、肾病综合征、肾衰竭的关键基因，特别是肾纤维化的关键基因，因此，上述中药组合物能够用于治疗肾纤维化。
其中，白术、马勃、石吊兰、蛇蜕、射干、桃枝、翼首草、浮萍、升麻、白及、筋骨草、皂角刺、苦楝皮、淡竹叶、通草、常山、红花龙胆、徐长卿、女贞子、四季青、滇鸡血藤、马钱子能够用于抑制SERPINE1基因的转录水平。
射干、桃枝、筋骨草、皂角刺、徐长卿、滇鸡血藤、杜仲、枇杷叶、蛇床子、甘草、杜仲叶能够用于抑制COL1A1基因的转录水平。
蝉蜕、藕节、三颗针、山柰能够用于抑制SMAD4基因的转录水平。
石吊兰、马勃能够用于抑制IL13RA1基因的转录水平。
白术、石吊兰能够用于抑制EDNRB基因的转录水平。
本发明还提供了一种中药组合物，其由白术、马勃、石吊兰和组分A组成；
所述组分A选自蝉蜕、杜仲叶、蛇床子、甘草、徐长卿、枇杷叶、杜仲、滇鸡血藤、筋骨草、桃枝、皂角刺、射干、蛇蜕、翼首草、浮萍、升麻、白及、苦楝皮、淡竹叶、通草、常山、红花龙胆、女贞子、四季青、马钱子、山柰、藕节、三颗针中至少一种。
例如，本发明提供的组合物包括白术、马勃、石吊兰和蝉蜕。
或所述组合物包括白术、马勃、石吊兰和蛇蜕。
或所述组合物包括白术、马勃、石吊兰和射干。
或所述组合物包括白术、马勃、石吊兰和桃枝。
或所述组合物包括白术、马勃、石吊兰和翼首草。
或所述组合物包括白术、马勃、石吊兰和浮萍。
或所述组合物包括白术、马勃、石吊兰和升麻。
或所述组合物包括白术、马勃、石吊兰和白芨。
或所述组合物包括白术、马勃、石吊兰和筋骨草。
或所述组合物包括白术、马勃、石吊兰和皂角刺。
或所述组合物包括白术、马勃、石吊兰和苦楝皮。
或所述组合物包括白术、马勃、石吊兰和淡竹叶。
或所述组合物包括白术、马勃、石吊兰和通草。
或所述组合物包括白术、马勃、石吊兰和常山。
或所述组合物包括白术、马勃、石吊兰和红花龙胆。
或所述组合物包括白术、马勃、石吊兰和徐长卿。
或所述组合物包括白术、马勃、石吊兰和女贞子。
或所述组合物包括白术、马勃、石吊兰和四季青。
或所述组合物包括白术、马勃、石吊兰和滇鸡血藤。
或所述组合物包括白术、马勃、石吊兰和马钱子。
或所述组合物包括白术、马勃、石吊兰和藕节。
或所述组合物包括白术、马勃、石吊兰和三颗针。
或所述组合物包括白术、马勃、石吊兰和山奈。
或所述组合物包括白术、马勃、石吊兰和杜仲。
或所述组合物包括白术、马勃、石吊兰和枇杷叶。
或所述组合物包括白术、马勃、石吊兰和甘草。
或所述组合物包括白术、马勃、石吊兰和蛇床子。
或所述组合物包括白术、马勃、石吊兰和杜仲叶。
一些实施例中，所述中药组合物由白术、马勃、石吊兰和蝉蜕组成；所述白术、马勃、石吊兰和蝉蜕的质量比为(2～30)：(2～50)：(2～100)：(2～50)。
一些具体实施例中，所述中药组合物由白术、马勃、石吊兰和蝉蜕组成；所述白术、马勃、石吊兰和蝉蜕的质量比为2.5：2.5：2.5：2.5。
本发明以由白术、马勃、石吊兰和蝉蜕组成的中药组合物验证功效，结果表明，该组合物的乙醇提取物能够抑制TGFβ诱导的人肾小管上皮细胞HK2的纤维化基因Ⅰ型胶原α1(COL1A1)和人纤溶酶原激活物抑制剂1基因(SERPINE1)表达，从而发挥抗肾纤维化的作用。
本发明还提供了一种中药提取物，其由本发明所述的中药组合物提取获得。
本发明所述中药提取物的制备方法，包括：将本发明所述的中药组合物，粉碎后，以乙醇水溶液进行标准索氏回流提取，所得提取液经浓缩、冻干制得中药提取物。
一些实施例中，所述粉碎至粒度为80～100目。
一些实施例中，所述乙醇水溶液中乙醇的体积分数为90％，所述中药组合物与乙醇水溶液的质量-体积比为1:15。
一些实施例中，所述标准索氏回流提取的时长为3h。
一些实施例中，所述浓缩，每10g药材的提取液浓缩至2mL。
所述冻干为减压冻干，冻干24h。
一些具体实施例中，本发明所述重要提取物的制备方法为，将白术、马勃、石吊兰和蝉蜕粉碎至80～100目，加入加15倍体积的90％乙醇，标准索氏回流提取3h，提取液浓缩20min，减压冻干24h制成提取物。
本发明所述的中药组合物、中药提取物或所述制备方法制得的提取物，在制备抗肾纤维化的药物中的应用。
本发明中所述抗肾纤维化包括抑制关键基因的转录水平和/或抑制肾小管细胞上皮-间质转化。
本发明中，所述关键基因为SERPINE1、COL1A1、SMAD4、IL13RA1或EDNRB。一些实施例中，所述关键基因为SERPINE1和COL1A1。
本发明还提供了一种抗肾纤维化的药物，其包括本发明所述的中药组合物、中药提取物或所述制备方法制得的提取物。
本发明所述的药物中，还包括药学上可接受的辅料。
在本发明提供的一些实施例中，药学上可接受的辅料为食用香精、甜味剂、酸味剂、填充剂、润滑剂、防腐剂、助悬剂、食用色素、稀释剂、乳化剂、崩解剂或增塑剂中的一种或两者以上的混合物。
作为优选，所述药物的剂型为注射剂、片剂、丸剂、口服液剂、胶囊剂、糖浆剂、滴丸剂或颗粒剂。
在本发明提供的一些实施例中，胶囊剂为硬胶囊剂或软胶囊剂。
在本发明提供的一些实施例中，片剂为口服片剂或口腔片剂。
口服片剂指供口服的片剂，多数此类片剂中的药物是经胃肠道吸收而发挥作用，也有的片剂中的药物是在胃肠道局部发挥作用。在本发明提供的一些实施例中，口服片剂为普通压制片、分散片、泡腾片、咀嚼片、包衣片或缓控释片。
本发明还提供了一种抗肾纤维化的方法，其为给予本发明所述的药物。
本发明提供的31种中药材皆具有抗肾纤维化、抗心肾综合征、抗心力衰竭、抗肾病综合征和/或抗肾衰竭的药物的作用，其中由白术、马勃、石吊兰、蝉蜕组成的组合物能够抑制肾小管细胞上皮-间质转化、抑制关键基因的转录水平，因此能够有效治疗抗肾纤维化、心肾综合征、心力衰竭、肾病综合征、肾衰竭。
附图说明
图1示35种中药在肾小管上皮细胞的肾纤维化特征基因表达谱；
图2示中药组合物提取物对HK2的上皮-间质转化的影响；
图3示中药组合物提取物对Ⅰ型胶原α1(COL1A1)和人纤溶酶原激活物抑制剂1基因(SERPINE1)表达的调控。
具体实施方式
本发明提供了治疗肾纤维化的药物及其制备方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
本发明采用的仪器皆为普通市售品，皆可于市场购得。
下面结合实施例，进一步阐述本发明：
实施例1
利用基于高通量测序技术，检测35种中药乙醇提取物对人肾小管上皮细胞HK2的五个肾纤维化关键基因的调控。
1、35种中药材的单一药味提取物制备：
白术、马勃、石吊兰、蝉蜕、蛇蜕、射干、桃枝、翼首草、浮萍、升麻、白及、筋骨草、皂角刺、苦楝皮、淡竹叶、通草、常山、红花龙胆、徐长卿、女贞子、四季青、滇鸡血藤、马钱子、藕节、三颗针、山柰、杜仲、枇杷叶、蛇床子、甘草、杜仲叶、黄芪、人参、益母草、牡丹皮。
分别取以上中药材，粉碎成80-100目粉末，分别加15倍体积的90％乙醇，标准索氏回流提取3h，每10g药材的提取液浓缩20min至体积为2mL，利用冻干机减压冻干24h制成提取物冻干粉，称取一定质量冻干粉，溶于DMSO(二甲基亚砜)中制成提取物母液，-20℃保存。
2、以上述制备的35种单一药味的提取物，同时进行五个肾纤维化关键基因的表达调控检测，其实验方案参考文献(Versatile pathway-centric approach based on high-throughput sequencing to anticancer drug discovery)，具体实验过程为：
2.1利用35种中药乙醇提取物处理HK2细胞(肾小管上皮细胞)24小时。
2.2细胞裂解，加入基因特异性探针结合mRNA，并利用DNA连接酶将结合成功的一对探针连接。
2.3.将连接成功的探针洗脱，利用PCR技术进行扩增、建库、二代测序。
2.4.数据处理：以溶剂对照DMSO处理组为对照组，药物处理组的基因变化倍数≥1.5倍，p值<0.05定义为基因表达显著上调或下调。结果如图1所示，其中数据展示了35种中药在肾小管上皮细胞种对五个关键基因的表达影响情况，包括SERPINE1、COL1A1、IL13RA1、EDNRB和SMAD4，红色表示该基因表达上调，蓝色表示下调，白色表示无显著影响。
基因表达结果显示中药组合物中白术能显著下调纤维化相关基因SERPINE1和EDNRB，石吊兰能下调基因SERPINE1、IL13RA1和EDNRB，马勃能下调基因SERPINE1和IL13RA1，三个中药对肾纤维基因具有显著的调控作用，可作为方剂的基本组成单元。其他28种中药(包括蝉蜕)可显著降低SERPINE1或COL1A1或SMAD4，从而起到抗肾纤维化的作用，可作为方剂加减的补充药物。而作为对照的4种中药，即牡丹皮、益母草、人参和黄芪，均不能显著降低肾纤维化的关键基因。
实施例2
以组合物白术2.5g、马勃2.5g、石吊兰2.5g、蝉蜕2.5g为例验证中药组合物的功效：
1、组合物的提取：
将配方粉碎称80-100目粉末，按配比称量后混合，加15倍体积的90％乙醇，标准索氏回流提取3h，提取液浓缩20min至体积为2mL，利用冻干机减压冻干24h制成提取物冻干粉，称取一定质量冻干粉，溶于DMSO中制成提取物母液，-20℃保存。
2、提取物对人肾小管细胞上皮-间质转化的调控
2.1HK2细胞以8万/孔铺于12孔板中，过夜后，血清饥饿24h，随后加入10ng/mL TGFβ处理细胞48h。
2.2.分别加入终浓度为50和100μg/mL的上述中药组合物提取物，同时设置DMSO溶剂对照组，共处理细胞48h；
2.3. PBS清洗细胞两次，在倒置荧光显微镜下，白光明场拍摄细胞形态。
2.4.利用显微镜明场成像与细胞形态学分析(图2)，结果表明，中药组合物提取物具有抑制TGFβ诱导的人肾小管上皮细胞HK2的上皮-间质转化的表型，从而起到抗肾纤维化的作用。
3、利用qPCR技术，检测中药组合物的提取物对COL1A1和SERPINE1基因的表达影响，具体实验过程为：
3.1 HK2细胞以8万/孔铺于12孔板中，过夜后，血清饥饿24h，随后加入10ng/mLTGFβ处理细胞48h。
3.2加入终浓度为50和100μg/mL的中药组合物提取物，同时设置溶剂对照组，共处理细胞48h；
3.3 PBS清洗细胞两次，利用试剂盒提取RNA并反转为cDNA。
3.4qPCR反应，程序：95℃，3min；(95℃，3s；60℃，30s)40个循环。
其中，引物序列为：
| Gene name | Forward primer | Reverse primer |
| COL1A1 | GAGGGCCAAGACGAAGACATC | CAGATCACGTCATCGCACAAC |
| SERPINE1 | AGTGGACTTTTCAGAGGTGGA | GCCGTTGAAGTAGAGGGCATT |
3.5数据处理：以空白对照组的基因表达量为1，药物处理组基因表达量大于1为基因表达上调，小于1为下调，结果如图3。
结果表明，由白术、马勃、石吊兰、蝉蜕组成的中药组合物提取物，能够抑制TGFβ诱导的人肾小管上皮细胞HK2的纤维化基因Ⅰ型胶原α1(COL1A1)和人纤溶酶原激活物抑制剂1基因(SERPINE1)表达，从而发挥抗肾纤维的作用。
以上仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.白术、马勃、石吊兰和蝉蜕在制备治疗抗肾纤维化的药物中的应用，所述白术、马勃、石吊兰和蝉蜕的质量比为（2~30）：（2~50）：（2~100）：（2~50）。
2.根据权利要求1所述的应用，其特征在于，所述抗肾纤维化包括抑制关键基因转录水平和/或抑制肾小管细胞上皮-间质转化；所述关键基因为SERPINE1、COL1A1、SMAD4、IL13RA1或EDNRB。
3.一种抗肾纤维化的中药组合物，其特征在于，由白术、马勃、石吊兰和蝉蜕组成；所述白术、马勃、石吊兰和蝉蜕的质量比为（2~30）：（2~50）：（2~100）：（2~50）。
4.一种抗肾纤维化的中药提取物，其特征在于，由权利要求3所述的中药组合物提取获得；其制备方法包括：将权利要求3所述的中药组合物，粉碎后，以乙醇水溶液进行标准索氏回流提取，所得提取液经浓缩、冻干制得中药提取物；
所述乙醇水溶液中乙醇的体积分数为90%，所述中药组合物与乙醇水溶液的质量-体积比为1:15；所述标准索氏回流提取的时长为3h。
5.权利要求4所述的抗肾纤维化的中药提取物的制备方法，其特征在于，包括：将权利要求3所述的中药组合物，粉碎后，以乙醇水溶液进行标准索氏回流提取，所得提取液经浓缩、冻干制得中药提取物；
所述乙醇水溶液中乙醇的体积分数为90%，所述中药组合物与乙醇水溶液的质量-体积比为1:15；所述标准索氏回流提取的时长为3h。
6.一种抗肾纤维化的药物，其特征在于，包括权利要求3所述的中药组合物、权利要求4所述的中药提取物或权利要求5所述制备方法制得的提取物；
其还包括药学上可接受的辅料；
所述药学上可接受的辅料为食用香精、甜味剂、酸味剂、填充剂、润滑剂、防腐剂、助悬剂、食用色素、乳化剂、崩解剂或增塑剂中的一种或两者以上的混合物；
所述药物的剂型为注射剂、片剂、丸剂、口服液剂、胶囊剂、糖浆剂或颗粒剂。
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