CN114028377A - 咖啡醇的医药新用途 - Google Patents
咖啡醇的医药新用途 Download PDFInfo
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- CN114028377A CN114028377A CN202111438215.8A CN202111438215A CN114028377A CN 114028377 A CN114028377 A CN 114028377A CN 202111438215 A CN202111438215 A CN 202111438215A CN 114028377 A CN114028377 A CN 114028377A
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- cafestol
- fibrosis
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- kidney
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
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- A—HUMAN NECESSITIES
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Abstract
本发明提供了咖啡醇在制备用于预防和/或治疗肾组织纤维化药物的应用。咖啡醇包括以下应用：a1：制备预防和/或治疗肾组织纤维化的药物；a2：预防和/或治疗肾组织纤维化；a3：抑制Hippo‑YAP信号通路；a4：建立肾组织纤维化动物医学模型。
Description
技术领域
本发明属于天然产物医药技术领域，尤其涉及咖啡醇在制备预防或治疗肾纤维化药物中的应用。
背景技术
慢性肾脏病(chronic kidney disease)在全球患病率为10-12％，且呈逐年上升趋势，慢性肾小球肾炎、高血压肾病、糖尿病肾病、肾间质疾病、肾小管性疾病、先天性获得性肾脏疾病以及不合理服用肾毒性药物等均可引起慢性肾脏病，最终进展至终末期肾衰竭(End-stage renal disease)，成为致死的高危因素。肾脏纤维化(renal fibrosis)是各种原因引起的慢性肾脏病发展到终末期肾衰竭的早期关键的、共同的病理改变，严重影响肾脏功能。肾脏纤维化病因和发病机制非常复杂，目前在预防和治疗上均无有效的方法。因此，寻找理想的能干预、逆转肾纤维化的药物靶点及开发有效的逆转肾纤维化的药物，对在早期阶段预防各种慢性疾病导致的终末期肾衰竭的发生具有重要的意义。
肾脏纤维化的分子机制很复杂，还没有得到很好的阐释。近年来一些研究表明，Hippo信号通路的下游效应子YAP/TAZ在肾组织纤维化的进展中起到了重要作用。在以肾小管间质纤维化为病理特征的IgA肾病或膜性肾病患者的肾脏中，TAZ呈高表达状态。在急性肾损伤后的再生和纤维化阶段，肾小管上皮细胞中的YAP水平升高。在三种不同的小鼠肾病模型(梗阻性、糖尿病和毒素诱导的肾损伤)中，观察到肾小管间质中TAZ核聚集增加。在肾小管上皮细胞中，YAP过表达促进细胞增殖，SAV1缺失引起的YAP/TAZ活化引发EMT样表型改变，促进肾间质纤维化。在腹腔注射嘌呤霉素氨基核苷诱导的肾小球疾病大鼠模型的足细胞中也发现了YAP/TAZ的激活。YAP在足细胞中的过表达增加了几种ECM相关蛋白的水平，如胶原COL6A1、其受体BCAM和基质金属蛋白酶ADAMTS1，从而促进了基底膜的增厚和硬化。体外研究发现，YAP/TAZ可通过机械调节，激活成纤维细胞，并持续诱导ECM的产生。Hippo信号通路可与其它纤维化经典信号相互作用，调节纤维化进程。当Hippo信号激活时，阻止YAP入核，使Smad、β-catenin在核内的积累和转录活性降低，影响TGF-β、Wnt的信号转导。进一步研究表明，Hippo/SAV1通路通过TAZ诱导的TGF-β1和受体II的表达调节肾小管间质纤维化；Wnt5a可能通过上调YAP/TAZ加剧TGF-β1诱导的巨噬细胞M2极化，从而驱动纤维化反应；使用YAP/TAZ抑制剂verteporfin可阻断TGF-β诱导的肾脏成纤维细胞中Smad2/3的信号转导，抑制体内外纤维化发生。Liang等人的研究也证实了抑制YAP/TAZ可以阻断TGF-β1诱导的成纤维细胞转化为肌成纤维细胞(myofibroblast，MF)以及ECM的产生。在UUO小鼠模型中，无论是使用verteporfin抑制还是特异性敲除Gli阳性细胞中的YAP/TAZ，均减轻了肾脏纤维化的发生。此外，他们还发现了大部分激活的YAP(胞核中)位于α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA，MF的标志物)阳性和PDGFR-α阳性的间质细胞中，肾小管细胞的胞质、胞核中也观察到了YAP；其中，大于80％的PDGFR-α阳性或α-SMA阳性细胞都呈YAP阳性。这些结果说明了PDGFR-α+细胞中，Hippo信号通路的确参与了纤维化调控，对YAP的抑制作用改善肾小管间质炎症和纤维化。
咖啡醇是一种有机化合物，分子式为C20H28O3，是咖啡中的一种双萜化合物，目前尚未见有关其抑制肾纤维化作用的报道。
发明内容
本发明的目的之一在于提供一种咖啡醇的应用，为如下a1、a2、a3或a4：
a1：制备预防和/或治疗肾组织纤维化的药物；
a2：预防和/或治疗肾组织纤维化；
a3：抑制Hippo-YAP信号通路；
a4：建立肾组织纤维化动物医学模型。
优选的，所述药物的活性成分包含咖啡醇。
优选的，所述肾组织纤维化的药物为治疗慢性肾脏病的药物。
优选的，抑制Hippo-YAP信号通路。
优选的，所述肾组织纤维化动物医学模型的建立方法包括以下步骤：
S1：分组：将动物分为假手术组和单侧输尿管结扎组；
S2：给予结扎组动物一定剂量的咖啡醇；
S3：造模；
S4：造模后给药7天后取左肾，进行肾脏病理学分析。
应当理解，在步骤S1之前、步骤S1和S2之间、步骤S2和S3之间、步骤S3和S4之间及步骤S4之后还可以包括其他步骤，且均在本发明的保护范围之内。
优选的，根据权利要求4所述的应用，其特征在于，在S3中，单侧输尿管结扎组的处理步骤为：将小鼠适应性喂养7天，于第8天在无菌条件下造模；各模型分别以1％戊巴比妥钠(60mL/kg)腹腔注射麻醉后，剪除左腹部毛，依次用聚维酮碘、75％乙醇消毒手术区皮肤；然后依次切开左腹部皮肤、肌肉，暴露左肾，游离输尿管，分别在肾盂处和输尿管上1/3处用4-0丝线结扎后，剪断输尿管，然后逐层缝合，消毒；假手术组依次行上述步骤，但输尿管只游离不结扎。
优选的，在S2中，咖啡醇的浓度为0.3mg/kg。
应当理解，本发明中的咖啡醇的浓度并不限于以上，本领域技术人员可以根据需要选择任意浓度的咖啡醇，且均在本发明的保护范围之内。
优选的，在S3中，腹部正中切口2cm。
在本发明的一些优选方案中，采用单侧输尿管结扎法建立小鼠肾纤维化模型，实验分为3组：正常对照组、模型组、咖啡醇用药组。
通过Masson染色法检测肾组织纤维化程度及病理改变，Western blot检测肾组织中α-SMA蛋白表达的变化。
在本发明的一些优选方案中，利用TGF-β重组蛋白诱导NIH 3T3小鼠胚胎成纤维细胞形成肌成纤维细胞来模拟组织纤维化过程。
用Western blot检测细胞不同浓度咖啡醇对磷酸化YAP蛋白的表达。
所述四种剂量用药组中咖啡醇用量分别为2.5μM、5μM、10μM、20μM。用In-cellWestern检测TGF-β和咖啡醇处理后YAP/TAZ蛋白表达的变化。
本发明的目的之二在于提供一种预防和/或治疗肾组织纤维化的药物，所述药物的活性成分包含咖啡醇。
优选的，所述药物还包括药学上可接受的赋形剂，所述赋形剂选自粘合剂、填料、增塑剂、助流剂、崩解剂和润滑剂中的一种或者任意组合。
优选的，所述药物为注射剂或口服剂。
在符合本领域常识的基础上，上述各优选条件，可任意组合，而不超出本发明的构思与保护范围。
本发明首次公开了咖啡醇的新用途，为咖啡醇抑制肾纤维化的药理作用提供了理论依据。
附图说明
图1是咖啡醇干预UUO小鼠肾脏Masson染色图(200X)(A:假手术组B:UUO组C:咖啡醇组)；
图2是Western blot检测不同浓度咖啡醇对磷酸化YAP蛋白的表达电泳图(左)及柱状图(右)；
图3是In-cell Western检测TGF-β和咖啡醇处理后YAP/TAZ蛋白的表达免疫荧光图(左)及柱状图(右)。
具体实施方式
为了进一步理解本发明，下面结合实施例对本发明优选实施方案进行描述，但是应当理解，这些描述只是为进一步说明本发明的特征和优点，而不是对本发明权利要求的限制。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。本发明所用试剂和原料均市售可得。
需要注意的是，如未注明具体条件者，均按照常规条件或制造商
建议的条件进行，所用试剂未注明生产厂商者，均为可以通过市场获得的常规产品。
本发明进行了动物实验和细胞实验，经对建立的动物模型和细胞模型，给予咖啡醇进行干预，使用了组织形态学分析，蛋白印迹实验等实验方法。本发明的实施例中，动物实验结果显示，咖啡醇能实现对病理环境诱导的肾纤维化的抑制，减轻纤维化过程中对肾单位的损害；细胞实验结果显示，咖啡醇通过抑制Hippo-YAP信号通路，抑制成纤维细胞向肌成纤维细胞的激活，咖啡醇进一步可用于制备治疗或预防肾纤维化。
本发明实施例中，具体进行了包括以下步骤的干预实验：
(1)小鼠单侧输尿管阻塞手术；(2)组织形态学分析；(3)离体细胞研究；(4)蛋白印迹实验；(5)In-cell Western实验；(6)数据分析：所有数据采用SPSS21.0软件进行统计学处理。计量资料以
表示，组间比较采用单因素方差分析。P<0.05为差异有统计学意义；
实施例1咖啡醇抑制单侧输尿管结扎(unilateral ureteral occlusion,UUO)诱导小鼠肾纤维化
1.动物
SPF级BALB/C雄性小鼠，购于北京维通利华实验动物技术有限公司。
2.实验药品及试剂
咖啡醇(sigma)，苯巴比妥钠(LUPI)，4％多聚甲醛(北京雷根生物科技有限公司)，OCT组织包埋剂(SAKURA)，免疫染色一抗稀释(碧云天)，免疫荧光染色二抗稀释液(碧云天)，改良Masson三色染色液(Solarbio)，中性树胶(北京索莱宝科技有限公司)，RIPA裂解液(中)(碧云天)，磷酸酶抑制剂片(Roche)，蛋白酶抑制剂(康为世纪)，5×SDS-PAGEloading buffer(康润生物科技有限公司)，4×SDS-PAGE分离胶缓冲液(Solarbio)，4×SDS-PAGE浓缩胶缓冲液(Solarbio)，30％丙烯酰胺(29:1)(Solarbio)，PAGE胶促凝剂(Solarbio)，BCA Protein Assay Kit(北京康为世纪生物技术有限公司)，5×Tris-甘氨酸电泳缓冲液(Solarbio)，10×电泳转移缓冲液(转膜液)(Solarbio)，10×TBST buffer(北京酷莱搏科技有限公司)，Western blot一抗稀释液(碧云天生物技术有限公司)，PVDF膜(Millipore)，蛋白Marker(赛默飞世尔科技有限公司)，滤纸(whatman)，脱脂奶粉(BD公司)，鼠抗β-actin单克隆抗体(中杉金桥)，兔抗MTS1多克隆抗体(CST)，兔抗STK3/MST2多克隆抗体(Abcam)，兔抗YAP/TAZ单克隆抗体(CST)。
3.仪器
石蜡切片机(Thermo)，生物组织包埋机(KEDEE)，摊片机(常州市中威电子仪器有限公司)，冷冻切片机(Thermo)，MJ-78A高压灭菌锅(施都凯仪器设备有限公司)，BBXW-20制冰机(北京博翔兴旺科技有限公司)，超声破碎仪(SCIENTZ)，恒温混匀仪(MTHLAB)，D3024R离心机(SCILOGEX)，转移脱色摇床(其林贝尔仪器制造有限公司)，酶标仪(Bio-Rad)，电泳仪(Bio-Rad)，垂直槽隔条玻璃片(Tanon)，垂直槽制胶支架(Tanon)，垂直槽样品梳(Tanon)，Sapphire Biomolecular Imager(Azure Biosystems)，湿式生化分析仪(瑞士罗氏Cobas c501)。
4.实验方法
(1)分组：取8周龄BALB/C雄性小鼠，共12只，体重20～22g，随机分为假手术组(Sham)、UUO组、咖啡醇用药组，每组4只小鼠。饲养于温度(22±2)℃，湿度50％～60％的环境中，光照每12h明暗交替，自由饮水，普通饲料喂养。
(2)造模：将小鼠适应性喂养7d，于第8天在无菌条件下造模。各模型分别以1％戊巴比妥钠(60mL/kg)腹腔注射麻醉后，剪除左腹部毛，依次用聚维酮碘、75％乙醇消毒手术区皮肤。然后依次切开左腹部皮肤、肌肉，暴露左肾，游离输尿管，分别在肾盂处和输尿管上1/3处用4-0丝线结扎后，剪断输尿管，然后逐层缝合。假手术组依次行上述步骤，但输尿管只游离不结扎。在造模中死亡小鼠直接淘汰，并补足数量。
(3)给药及检测：造模后常规饮食喂养3d，观察小鼠状态是否正常，明显异常者淘汰。造模第4天开始，咖啡醇组以0.3mg/只小鼠灌胃，1次/d，连续7d；假手术组及UUO组继续常规饮食并予以1mL/kg蒸馏水灌胃，1次/d，连续7d。之后采用心脏灌注法处死小鼠，解剖获取左侧肾组织。
(4)肾脏病理学指标：用10％福尔马林固定，石蜡包埋，切为4μm厚度的切片，采用马松(Masson)三色染色法(在200倍视野下随机选择10个不重叠视野观察)。
实验结果如图1所示：咖啡醇减轻了肾损伤和肾纤维化，降低了UUO小鼠肾纤维化标志蛋白α-SMA。
实施例2咖啡醇可以显著增加磷酸化YAP的表达，降低YAP/TAZ的量，抑制Hippo-YAP信号通路。
本实施方式中的蛋白免疫印迹法均采用本领域常用的实验步骤进行。
In-cell Western是一种高通量快速检测细胞内蛋白的方法，可直接在细胞培养板上(如96孔板)的细胞上依据抗原抗体结合原理，利用目标蛋白的特异性抗体及近红外荧光标记的二抗，对目标蛋白进行定量分析。
实验步骤如下：
在96孔板完成细胞培养后，倒掉培养液，用PBS洗去残余培养基。4％多聚甲醛固定10min，PBS冲洗3次。0.3％Triton X-100透化处理15min，PBS洗3次。5％BSA封闭30～60min。一抗4孵育过夜(通常1:500稀释，不同种属的目标蛋白抗体和内参抗体混合。之后回收一抗，PBS洗3次，再加入两种荧光标记的二抗(1:1000)室温孵育1h。回收2抗，PBS洗3次，稍晾干后曝光。使用Azure Sport软件对图片进行统计分析。
结果如图2、图3所示：咖啡醇可显著剂量依赖性的增加磷酸化YAP的表达。并可以抑制TGF-β诱导的YAP/TAZ表达。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。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，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。
Claims (9)
1.咖啡醇的应用，为如下a1、a2、a3或a4：
a1：制备预防和/或治疗肾组织纤维化的药物；
a2：预防和/或治疗肾组织纤维化；
a3：抑制Hippo-YAP信号通路；
a4：建立肾组织纤维化动物医学模型。
2.根据权利要求1所述的应用，其特征在于，所述药物的活性成分包含咖啡醇。
3.根据权利要求1所述的应用，其特征在于，所述肾组织纤维化的药物为治疗慢性肾脏病的药物。
4.根据权利要求1所述的应用，其特征在于，所述肾组织纤维化动物医学模型的建立方法包括以下步骤：
S1：分组：将动物分为假手术组和单侧输尿管结扎组；
S2：给予结扎组动物一定剂量的咖啡醇；
S3：造模；
S4：造模后给药7天后取左肾，进行肾脏病理学分析。
5.根据权利要求4所述的应用，其特征在于，在S3中，单侧输尿管结扎组的处理步骤为：将小鼠适应性喂养7天，于第8天在无菌条件下造模；各模型分别以1％戊巴比妥钠(60mL/kg)腹腔注射麻醉后，剪除左腹部毛，依次用聚维酮碘、75％乙醇消毒手术区皮肤；然后依次切开左腹部皮肤、肌肉，暴露左肾，游离输尿管，分别在肾盂处和输尿管上1/3处用4-0丝线结扎后，剪断输尿管，然后逐层缝合，消毒；假手术组依次行上述步骤，但输尿管只游离不结扎。
6.根据权利要求4所述的应用，其特征在于，在S2中，咖啡醇的浓度为0.3mg/kg。
7.一种用于预防和/或治疗肾组织纤维化的药物，其特征在于，所述药物的活性成分包含咖啡醇。
8.根据权利要求7所述的药物，其特征在于，所述药物还包括药学上可接受的赋形剂，所述赋形剂选自粘合剂、填料、增塑剂、助流剂、崩解剂和润滑剂中的一种或者任意组合。
9.根据权利要求7所述的药物，其特征在于，所述药物为口服剂。
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| CN106573063A (zh) * | 2014-05-30 | 2017-04-19 | 奥尔胡斯大学 | 用于治疗糖尿病的咖啡醇 |
| CN108289881A (zh) * | 2015-09-16 | 2018-07-17 | 妥必徕疗治公司 | 用于治疗纤维化的赛尼克韦罗联合疗法 |
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| CN106573063A (zh) * | 2014-05-30 | 2017-04-19 | 奥尔胡斯大学 | 用于治疗糖尿病的咖啡醇 |
| CN108289881A (zh) * | 2015-09-16 | 2018-07-17 | 妥必徕疗治公司 | 用于治疗纤维化的赛尼克韦罗联合疗法 |
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