CN113318117A - PPD制备预防或治疗TGFβ通路相关疾病的药物的用途 - Google Patents
PPD制备预防或治疗TGFβ通路相关疾病的药物的用途 Download PDFInfo
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- CN113318117A CN113318117A CN202110748858.6A CN202110748858A CN113318117A CN 113318117 A CN113318117 A CN 113318117A CN 202110748858 A CN202110748858 A CN 202110748858A CN 113318117 A CN113318117 A CN 113318117A
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Abstract
本申请提供了20S‑原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在抑制TGFβ通路中的用途,其中所述20S‑原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物结合TGFβR1的胞外域,结合位点包括D57、P59、P64、N78。本申请还提供了20S‑原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在制备预防和/或治疗TGFβ通路相关疾病的药物中的用途,其是通过阻断TGFβ通路,达到治疗疾病的效果。对今后的与TGFβ通路相关的疾病的防治具有重要意义,有望产生可观的社会和经济效益。
Description
技术领域
本申请涉及医药化学领域,涉及一种化合物的新用途,尤其涉及20S-原人参二醇皂苷抑制TGFβ通路相关疾病的用途,其中所述20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物结合TGFβR1的胞外域上的结合位点D57、P59、P64、N78。
背景技术
转化生长因子β (transforming growth factor β, TGFβ)信号通路主要通过调节细胞的生长、增殖、分化、迁移和凋亡等过程,参与介导组织与器官的正常生长和发育、机体的免疫反应等生物过程。TGFβ通路与肝、肺、肾纤维化相关,TGFβ通路诱导星状细胞的激活,纤维蛋白的分泌,纤维化持续导致肝硬化;TGFβ参与肿瘤发生发展过程的多个方面,如TGFβ表达上调会促进血管内皮生长因子A (Vascular Endothelial Growth Factor A,VEGFA)等因子的分泌,刺激新生血管生产,从而为癌细胞的生长和转移提供助力,抑制TGFβ信号传导为治疗肿瘤提供多个研究靶点。
TGFβ信号通路是由活化的TGFβ1与细胞膜上的受体蛋白TGFβR2结合,随后募集TGFβR1受体蛋白,TGFβR2与TGFβR1形成异源四聚体,TGFβR1被TGFβR2激活,活化的TGFβR1磷酸化下游靶标蛋白,包括SMAD2和SMAD3。因此,TGFβR1是TGFβ通路信号从细胞外传递到细胞内的重要环节。
人参是著名的中药材,对记忆障碍、肿瘤等疾病有一定的预防和治疗作用,人参中主要的有效成分是人参皂苷,其中,20S-原人参二醇皂苷(CAS NO.:30636-90-9,分子式:C30H52O3,20(S)-Protopanaxadiol,简称PPD)是其中一种人参皂苷,是一种固醇类化合物。尽管研究发现20S-原人参二醇皂苷具有广泛的生物学活性,但是尚需对其进行更深入的研究,以使其在医药领域得到更好的利用。
发明内容
本申请研究发现,20S-原人参二醇皂苷(PPD)能与TGFβR1结合,有效抑制TGFβ通路,从而通过抑制TGFβ通路达到治疗TGFβ通路相关疾病的目的。
基于此,申请提供了20S-原人参二醇皂苷(PPD)或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在抑制TGFβ通路中的用途,其中所述20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物结合TGFβR1的胞外域。本申请还提供了20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在制备预防和/或治疗TGFβ通路相关疾病的药物、食品或保健品中的用途。
具体来说,一方面,本申请涉及一种预防或治疗TGFβ通路相关疾病的方法,包括给药受试者有效量的20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物。
一方面,本申请涉及抑制TGFβ通路的方法,包括给药受试者有效量的20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物。
在一些实施方案中,所述TGFβ通路相关疾病选自如下的一种或多种:自身免疫性疾病、纤维化疾病、癌症或骨髓发育不良综合征。在一些实施方案中,所述20S-原人参二醇皂苷的衍生物包括通过碳纳米点改构、苷元修饰或化学修饰获得的候选物。在一些实施方案中,所述药物包括以下剂型:液体制剂、颗粒剂、缓释剂、冲剂、片剂、胶丸、洗剂、涂膜剂、软膏剂、透皮贴膏。
一方面,本申请涉及20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在制备预防或治疗TGFβ通路相关疾病的药物、食品或保健品中的用途。
一方面,本申请涉及20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在制备TGFβ通路抑制剂中的用途。
在一些实施方案中,所述TGFβ通路相关疾病选自如下的一种或多种:自身免疫性疾病、纤维化疾病、癌症或骨髓发育不良综合征。在一些实施方案中,所述20S-原人参二醇皂苷的衍生物包括通过碳纳米点改构、苷元修饰或化学修饰获得的候选物。在一些实施方案中,所述药物包括以下剂型:液体制剂、颗粒剂、缓释剂、冲剂、片剂、胶丸、洗剂、涂膜剂、软膏剂、透皮贴膏。
发明效果
本申请的20S-原人参二醇皂苷通过与TGFβR1的胞外域结合,阻断TGFβR2与TGFβR1的结合,有效抑制TGFβ通路,从而有效治疗TGFβ通路相关疾病。
附图说明
图1为PPD对TGFβR1、TGFβR2、麦芽糖结合蛋白(maltose binding protein,MBP)稳定性及亲和力的测定。
(A) PPD与MBP混合,和MBP单独的蛋白稳定性测定,横坐标为温度,纵坐标为350nm荧光吸收与330nm荧光吸收比值的一阶导数,MBP单独和加PPD组的两条曲线重叠,说明PPD不影响MBP蛋白的稳定性;(B) PPD与TGFβR1混合,和MBP单独的蛋白稳定性测定,两条曲线未重叠,说明PPD对TGFβR1的蛋白稳定性有影响;(C) PPD与TGFβR2混合,和TGFβR2单独的蛋白稳定性测定,两条曲线重叠,说明PPD不影响TGFβR2蛋白的稳定性;(D) 不同浓度PPD与荧光标记的MBP蛋白混合后测定荧光强度,结果表明MBP荧光强度的变化不依赖于PPD浓度的变化,因此PPD不与MBP结合;(E) 不同浓度PPD与荧光标记的TGFβR1蛋白混合后测定荧光强度,结果表明随着PPD浓度的增加,TGFβR1荧光强度逐渐降低,因此PPD与TGFβR1结合,解离常数Kd为1.54 μM;(F) 不同浓度PPD与荧光标记的TGFβR2蛋白混合后测定荧光强度,结果表明TGFβR2荧光强度的变化不依赖于PPD浓度的变化,因此PPD不与TGFβR2结合。
图2为PPD与TGFβR1对接及动力学模拟结果。
(A) TGFβR1单独,TGFβR1-PPD复合物模拟200ns过程中,TGFβR1骨架原子的均方根偏差(RMSD),在50ns后,TGFβR1单独或TGFβR1-PPD复合物的均方根偏差趋于稳定,表明体系在50ns后趋于稳定; (B) TGFβR1单独,TGFβR1-PPD复合物模拟200ns过程中,TGFβR1骨架原子的回旋半径(Rg),在50ns后,TGFβR1单独或复合物的回旋半径趋于稳定,再次证明体系在50ns后稳定;(C) TGFβR1-PPD复合物在200ns模拟过程中,小分子PPD与蛋白TGFβR1的均方根偏差(RMSD),表征PPD在模拟过程中与蛋白结合是否稳定,在50ns后,PPD小分子的RMSD在0.6-1nm之间,小分子位置波动较小,说明PPD与TGFβR1结合较稳定;(D) PPD与TGFβR1的反应能,反应能稳定在-100kJ/mol;(E) 200ns模拟过程中,PPD与TGFβR1氢键数量统计;(F)TGFβR1单独,TGFβR1-PPD复合物模拟在200ns模拟过程中,蛋白亲水、疏水表面积平均值计算。
图3为PPD与TGFβR1突变体的亲和力测定。
(A) TGFβR1, TGFβR2, PPD复合物结构,其中TGFβR1-PPD复合物是选取的200ns模拟后的结构,TGFβR2结构从蛋白结构数据库(Protein Data Bank, PDB)得到(PDB: 3KFD),右框展示的是与PPD距离最近的TGFβR1的5个氨基酸;(B) TGFβR1第57位天冬氨酸D突变为丙氨酸A后,与PPD无结合;(C) TGFβR1第58位精氨酸R突变为丙氨酸A后,与PPD的解离常数为4.23 μM;(D) TGFβR1第59位脯氨酸P突变为丙氨酸A后,与PPD的解离常数为14.21 μM;(E) TGFβR1第64位脯氨酸P突变为丙氨酸A后,与PPD的解离常数为1.32 mM;(F) TGFβR1第78位天冬酰胺N突变为丙氨酸A后,与PPD无结合。
具体实施方式
下面结合附图和具体实施例来详细说明本申请。应理解,以下实施例仅用于说明本申请而不用于限制本申请的范围。
本申请一方面提供了20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在抑制TGFβ通路中的用途,其中所述20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物结合TGFβR1的胞外域。
在一个具体的实施方案中,本申请的20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物结合TGFβR1的胞外域上的结合位点D57、P59、P64、N78,阻断TGFβR2与TGFβR1的结合,有效抑制TGFβ通路。
本文所使用的“药学上可接受的盐”指为了增加药物溶解性或为了增强药物的稳定性而将药物制备成的盐,适于药学上使用。例如药学上可接受的盐,包括但不限于:钠、钾、钙等碱金属或碱土金属的盐;氢氟酸、盐酸、氢溴酸或氢碘酸等氢卤酸的盐;硫酸、硝酸、磷酸、高氯酸、碳酸等无机酸的盐;甲酸、乙酸、三氟乙酸、三氯乙酸、羟基乙酸、丙酸、乳酸、柠檬酸、酒石酸、草酸、苯甲酸、扁桃酸、丁酸、富马酸、琥珀酸、马来酸和苹果酸等有机羧酸的盐;天冬氨酸和谷氨酸等酸性氨基酸的盐;甲磺酸、乙磺酸、苯磺酸和甲苯磺酸等磺酸的盐;以及水合物和醇合物等溶剂合物。
本文所使用的“异构体”是指具有相同化学式,有同样的化学键而有不同的原子排列的化合物。本申请的异构体可以以可能的含有不同异构体的混合物的形式存在,也可以以可能的其中一种异构体的形式单独存在,所述的异构体包括几何异构体如Z式与E式、光学异构体如R型与S型,及互变异构体如酮式与烯醇式。本申请的异构体形式包括但不限于,几何异构体如Z式与E式或顺式与反式、光学异构体如R型与S型,及互变异构体如酮式与烯醇式,以及含任意比例的所述异构体的混合物。
本文所使用的“溶剂化物”是指化合物在结晶过程中,与一个或多个溶剂分子缔合而成的聚集体。本申请所述的溶剂化物可以为本领域公知的溶剂化物,所述20S-原人参二醇皂苷的溶剂化物可以为水合物,例如一水合物、乙醇溶剂化物、异丙醇溶剂化物等。溶剂分子可以为水或其它有机溶剂,如乙醇、异丙醇、乙醚、乙酸乙酯、丙酮等。
本文所使用的“前药”是指借助于在体内代谢的方式经过生物体内转化(例如藉由水解、还原或氧化)后才具有药理作用的化合物。前体药物本身没有生物活性或活性很低,经过体内代谢后变为有活性的物质,这一过程的目的在于增加药物的生物利用度,加强靶向性,增加稳定性,降低药物的毒性和副作用,以及改善药物不良反应。例如,可以将所述化合物与酸反应制备成相应的酯。相应的酯即为前药,可以在活体内水解为母体药物。除上述与酸反应形成酯之外,还可以使化合物与醇反应形成酯,或与胺反应形成酰胺,或使用代谢前体等方法制备前药。本申请所述20S-原人参二醇皂苷难溶于水,可以引入亲水性基团,提高其水溶性。
本文所使用的“衍生物”是指通过例如碳纳米点改构、苷元修饰或化学修饰获得的候选物。通过改构或修饰的候选物的生物活性得以维持,同时物理或化学性能得到改善,使药物更稳定、更易递送、半衰期延长或副作用减少。本领域技术人员通过本领域常规技术可以实现上述改造和修饰,从而使20S-原人参二醇皂苷的衍生物具有更稳定、更易递送或半衰期延长等性质。
本文所使用的“TGFβ1相关病症”指其中至少部分发病机制和/或进展可归因于TGFβ1信号传导或其失调的任何疾病或病症。
本申请另一方面提供了20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在制备预防和/或治疗TGFβ通路相关疾病的药物、食品或保健品中的用途。
在一个具体的实施方案中,所述药物、食品或保健品为用于治疗TGFβ通路相关疾病的药物、食品或保健品。所述20S-原人参二醇皂苷的衍生物包括通过碳纳米点改构、苷元修饰、化学修饰获得的候选物。所述TGFβ通路相关疾病包括自身免疫性疾病、纤维化疾病、纤维化进展性疾病、癌症或骨髓发育不良综合征。本申请对所述药物的剂型没有特殊的限定,采用本领域技术人员熟知的剂型即可,在本申请中,所述20S-原人参二醇皂苷的剂型可以为液体剂、颗粒剂、缓释剂、冲剂、片剂、胶丸、洗剂、涂膜剂、软膏剂、透皮贴膏。本申请对上述剂型的辅料没有特殊限定,采用本领域技术人员在药学上可接受的辅料即可。药学上可接受的辅料指在药品制剂中经过合理的安全评价的不包括有效成分或前体的组分,可根据药物的性质加入适宜的辅料,如渗透压调节剂、pH调节剂、增溶剂、助溶剂、抗氧剂、抑菌剂、乳化剂、助悬剂等。本申请对药物剂型的制备方法没有特殊限定,采用本领域技术人员常规制备药物剂型的方法即可。本申请对上述剂型的制备方法没有特殊限定,采用本领域技术人员常规制备上述剂型的方法即可。
本文所使用的“自身免疫性疾病 (autoimlnune disease)”是指以自身免疫应答反应导致组织器官损伤和相应功能障碍为主要发病机制的一类疾病。是临床上常见的一大类疾病,目前已被公认的自身免疫性疾病至少有30多种。根据自身免疫反应对组织器官造成损伤的范围,通常将自身免疫性疾病分为器官特异与非器官特性两大类。
本文所使用的“纤维化”是指器官内成纤维细胞过度增殖,并伴有大量沉积细胞外基质聚集,破坏组织结构。在多种疾病,如病毒性肝炎、慢性肾炎、硬皮病、冠心病等的病程晚期,器官均会发生纤维化,并最终导致器官衰竭。
本文所使用的“纤维化疾病”是指由于TGF-β细胞因子及其信号通路过度激活所导致的。大量研究表明,在纤维化进程中,相关组织内转化生长因子-β,如TGF-β表达量上调。在纤维化进程中,TGF-β可诱导成纤维细胞分化为肌成纤维细胞。而成纤维细胞向肌成纤维细胞的分化在纤维化过程中发挥重要的作用。
本文所使用的“癌症”是指以失调或不受控制的细胞生长为特征的恶性肿瘤。术语“癌症”包括原发性恶性肿瘤(也称为“原发性癌症”,对应于细胞未迁移到对象体内除原始肿瘤部位以外部位的那些)和继发性恶性肿瘤(也称为“继发性癌症”或“转移性癌症”,指由转移引起的,肿瘤细胞迁移到不同于原始肿瘤部位的继发性部位的那些)。TGFβ亚型在癌症中的表达是复杂的并且可变的,其中TGFβ亚型的不同组合在特定癌症中具有不同的作用。TGFβ分子既可以充当肿瘤抑制因子,也可以充当肿瘤促进因子,这表示TGFβ的存在对于预防或减缓肿瘤进展是重要的。
本文所使用的“骨髓发育不良综合征 (MDS)”是造血干细胞恶性病。特征是细胞髓的形态学和成熟受到损害(骨髓发育不良)、外周血血细胞减少和具有发展为急性白血病的可变危险,这是因为血细胞生成失效。
本文所使用的“食品”是指可供人类食用或饮用的物质。在本申请的一个具体实施方案中,食品包括加工食品、半成品和未加工食品。本申请所述的食品含有5~50mg/kg功效成分,所述有效成分为20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物。
本文所使用的“保健品”是指保健食品,是具有保健功能的食品,是食品的一个种类,具有一般食品的共性,能调节人体的机能,适用于特定人群食用,但不以治疗疾病为目的。本申请所述的保健品含有5~50mg/kg功效成分,所述有效成分为20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物。
实施例
以下实施例中所用的试剂均为分析纯级别的试剂,且可从正规渠道商购获得。
本申请对所述PPD的来源没有特殊限定,采用市售产品即可,如吉林萌创生物科技有限公司的GR0515。
本申请中,TGFβR1、TGFβR2胞外域和MBP的生产采用大肠杆菌(E coli.)表达体系,pMal载体,TGFβR1、TGFβR2胞外域因含有his标签,所以上清用镍柱纯化,MBP用MBP柱子纯化,蛋白浓缩后,跑胶确认蛋白纯度。
实施例1 PPD对MBP、TGFβR1、TGFβR2蛋白稳定性的影响
本申请中,为了测定PPD结合TGFβR1、TGFβR2和MBP的稳定性,进行了如下实验:
将1mg/ml的蛋白(TGFβR1、TGFβR2、MBP)分别与400μM PPD(吉林萌创生物科技有限公司,GR0515,以下相同)混合,4℃放置过夜,设置不加PPD的蛋白对照组,每组2个重复,用Prometheus NT.48仪器(德国nanotemper公司)测定蛋白熔解温度Tm值,该仪器原理是测定不同温度下蛋白在350nm吸收与330nm吸收比值的变化,因为色氨酸在350nm时有荧光吸收,色氨酸是疏水性氨基酸,在蛋白结构稳定时,色氨酸位于蛋白内部,350nm荧光吸收与330nm荧光吸收的比值(F350/330)低,当蛋白变性时,色氨酸暴露,F350/330荧光增强,结果如图1,PPD对TGFβR2和MBP的Tm值无影响,而显著改变了TGFβR1的Tm,因此,PPD对TGFβR1的蛋白稳定性有影响。
实施例2 PPD与TGFβR1、TGFβR2和MBP的结合亲和力
为进一步测定PPD与MBP、TGFβR1和TGFβR2的亲和力,我们使用MST-nanotemper仪器(德国nanotemper公司),步骤如下:
100μL 10μM/L 蛋白(TGFβR1、TGFβR2、MBP)分别用荧光染料标记,将PPD从400μM/L梯度两倍稀释,将不同浓度PPD与荧光染料标记后的蛋白混合,上机检测,该仪器原理是样品由红外激光加热产生微观的温度梯度场,再通过共价结合的荧光染料检测和定量分子的定向运动,从而得到PPD-蛋白的结合行为,结果如图1,PPD与TGFβR1的解离常数Kd为1.54μM,PPD不与MBP和TGFβR2结合。
实施例3 动力学模拟PPD与TGFβR1复合物
本申请中,为了得到PPD与TGFβR1的具体结合方式,使用AUTODOCK vina小分子-蛋白(版本1.1.2, http://vina.scripps.edu/)对接软件,和GROMACS(版本2020.5, http://vina.scripps.edu/)复合物模拟软件,首先用AUTODOCK vina将PPD与TGFβR1胞外域结构对接,得到TGFβR1-PPD复合物结构,随后,用GROMACS 2020.5软件,使用Charmm36-mar2019力场,将TGFβR1-PPD置于十二方形盒子,添加TIP3P水分子,体系用Na+和Cl-中和电荷,设置体系水溶液NaCl浓度为0.15M (即生理盐水浓度),先能量最小化,使体系的最大能量小于1000kJ/mol/nm,随后对体系进行两步平衡,使体系温度稳定在300K,压力稳定在1巴,最终进行动力学模拟200ns,结果分析使用GROMACS 2020.5,结果如图2。TGFβR1单独模拟和TGFβR1-PPD复合物模拟均在约50ns时,体系达到平衡,PPD与TGFβR1的距离在50ns以后模拟过程中保持稳定,两者之间的反应能平均值为-103.76kJ/mol,表明两者反应稳定,200ns模拟过程中氢键数目为1或0,TGFβR1的亲水、疏水面积均高于单独的TGFβR1模拟,说明PPD与TGFβR1主要通过疏水作用,PPD的结合对TGFβR1的结构有影响,导致TGFβR1部分亲水、疏水氨基酸暴露。
实施例4 PPD与TGFβR1的结合位点实验验证
本申请为获得PPD与TGFβR1的结合位点,提取模拟后的复合物结构,计算距离PPD小于5埃的氨基酸,得到5个氨基酸与PPD接近,将这5个氨基酸突变为丙氨酸,突变体蛋白表达纯化方法同TGFβR1蛋白表达纯化方法,使用Monolith NT.115仪器测定PPD与突变体的结合亲和力,结果如图3,TGFβR1第58位点突变对解离常数影响较小,第59位突变后解离常数降低约10倍,第64位突变体,解离常数降低约100倍,第57,78位点突变后与PPD不结合。表明D57、P59、P64、N78是与PPD结合的主要位点。
以上结果可知,本申请提供了20S-原人参二醇皂苷可与TGFβR1结合,可达到抑制TGFβ通路的作用,从而有效治疗与TGFβ通路相关的自身免疫性疾病、纤维化疾病、纤维化进展性疾病、癌症或骨髓发育不良综合征。
以上所述仅是本申请的优选实施方案,应当指出,对于本技术领域的普通技术人员来说,在不脱离本申请原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本申请的保护范围。
Claims (11)
1.20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在制备TGFβ通路抑制剂中的用途。
2.如权利要求1所述的用途,其中所述20S-原人参二醇皂苷的衍生物包括通过碳纳米点改构、苷元修饰或化学修饰获得的候选物。
3.如权利要求1或2的用途,其中所述20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物通过抑制TGFβ通路预防或治疗TGFβ通路相关疾病。
4.如权利要求3所述的用途,其中所述TGFβ通路相关疾病选自如下的一种或多种:自身免疫性疾病、纤维化疾病、癌症或骨髓发育不良综合征。
5.20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物在制备预防或治疗TGFβ通路相关疾病的药物、食品或保健品中的用途。
6.如权利要求5所述的用途,其中所述20S-原人参二醇皂苷的衍生物包括通过碳纳米点改构、苷元修饰或化学修饰获得的候选物。
7.如权利要求5或6所述的用途,其中所述TGFβ通路相关疾病选自如下的一种或多种:自身免疫性疾病、纤维化疾病、癌症或骨髓发育不良综合征。
8.如权利要求5或6的用途,其中所述20S-原人参二醇皂苷的衍生物包括通过碳纳米点改构、苷元修饰或化学修饰获得的候选物。
9.如权利要求1或5所述的用途,其中所述药物包括以下剂型:液体制剂、颗粒剂、缓释剂、冲剂、片剂、胶丸、洗剂、涂膜剂、软膏剂、透皮贴膏。
10.如权利要求1或5的用途,其中所述20S-原人参二醇皂苷或其药学上可接受的盐、异构体、溶剂化物、前药或衍生物与一种或多种其他药物联用。
11.如权利要求10的用途,其中所述一种或多种其他药物选自自身免疫性疾病、纤维化疾病、癌症或骨髓发育不良综合征治疗的药物。
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CN114262683A (zh) * | 2022-03-01 | 2022-04-01 | 中国科学院动物研究所 | 一种表达vegfr3 d2多肽的细菌制剂及其构建方法和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104666309A (zh) * | 2013-11-29 | 2015-06-03 | 沈阳药科大学 | 达玛烷型皂苷元抗肝纤维化的医药用途 |
CN105287611A (zh) * | 2014-06-27 | 2016-02-03 | 江苏命码生物科技有限公司 | 人参皂苷Rh2在抑制Treg细胞中的应用 |
-
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- 2021-07-02 CN CN202110748858.6A patent/CN113318117A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104666309A (zh) * | 2013-11-29 | 2015-06-03 | 沈阳药科大学 | 达玛烷型皂苷元抗肝纤维化的医药用途 |
CN105287611A (zh) * | 2014-06-27 | 2016-02-03 | 江苏命码生物科技有限公司 | 人参皂苷Rh2在抑制Treg细胞中的应用 |
Non-Patent Citations (6)
Title |
---|
LEE, HYOUNG-CHEOL等: "Enhanced inhibitory effect of ultra-fine granules of red ginseng on LPS-induced cytokine expression in the monocyte-derived macrophage THP-1 Cells", 《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》 * |
张锐等: "20( S) - 原人参二醇对荷瘤裸鼠化疗的增效减毒作用", 《吉林大学学报(医学版)》 * |
贾辛等: "20( S) - 原人参二醇对肝星状细胞凋亡及激活的作用", 《时珍国医国药》 * |
赵宇青等: "TGF-β1-Smad信号通路与胆管癌细胞发生上皮-间质转化相关性研究", 《黑龙江医学》 * |
马瑞等: "人参皂苷对NLRP3炎性体激活的抑制作用", 《中国药科大学学报》 * |
高春芳: "TGFβ1基因变异与疾病相关性研究展望", 《世界华人消化杂志》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114262683A (zh) * | 2022-03-01 | 2022-04-01 | 中国科学院动物研究所 | 一种表达vegfr3 d2多肽的细菌制剂及其构建方法和应用 |
CN114262683B (zh) * | 2022-03-01 | 2022-06-17 | 中国科学院动物研究所 | 一种表达vegfr3 d2多肽的细菌制剂及其构建方法和应用 |
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