CN115581697A - 尼古丁及衍生物作为FXR-meglin/cublin调节剂在制备利胆产品中的应用 - Google Patents
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Abstract
本发明公开了一种尼古丁及衍生物作为FXR‑meglin/cublin调节剂在制备利胆产品中的应用，所述利胆产品为抗胆汁淤积或抗胆囊结石的产品。本申请中，尼古丁及器衍生物通过抑制FXR‑megalin/cublin在胆囊的表达与功能，用于有效治疗胆汁淤积和胆结石，其具有作用靶点新颖，疗效可靠，无毒副作用、资源丰富、价格低廉等优点。
Description
技术领域
本发明涉及医药技术领域，特别涉及一种尼古丁及衍生物作为FXR-meglin/cublin调节剂在制备利胆产品中的应用。
背景技术
胆结石病是世界范围内最普遍和最昂贵的胃肠道疾病之一。胆固醇胆结石是所有发达国家的主要公共卫生问题。胆结石的形成受多种因素影响，包括吸烟。然而，一些研究表明，吸烟不是胆结石的危险因素，甚至会产生相反的效果。与不吸烟者相比，大半辈子吸烟的老年吸烟者患胆结石病的风险较低。鉴于此，从烟草中开发新型有效药物，改变胆囊或胆汁成分中胆结石相关蛋白的水平，从而影响胆结石的形成，对于胆囊结石的预防和治疗具有积极意义。
胆结石是由胆汁中的胆固醇分泌物在胆道系统中形成的，其是由于胆固醇过多或/和胆盐缺乏所致。已经发现了诸多基因同胆结石的形成相关，它们参与调节了胆汁中的胆固醇过饱和、结晶成核、脂质代谢异常、胆汁成分异常、胆囊功能障碍以及胆囊内壁黏膜吸收功能异常等因素，进而影响了胆固醇/胆汁酸代谢，诱导胆固醇从胆汁中过饱和，形成结石。因此，调控参与胆固醇/胆汁酸代谢相关基因的表达可能与结石形成相关。
目前，临床上使用的口服胆结石药物主要有鹅去氧胆酸(CDCA)和熊去氧胆酸(VDCA)。这两种药物通过降低胆汁胆固醇的分泌使胆汁去饱和，不饱和胆汁则具有溶解胆固醇的作用，使胆石表面的胆固醇分子不断地被溶解，胆石体积逐渐缩小以至完全溶解。然而，研究显示，这些结石治疗药物仅适用于胆结石直径在2cm以下病症。此外，结石治疗的药物价值昂贵，且有一定的副作用和毒性反应(主要包括胃肠道、肝胆功能紊乱以及过敏反应)，又必须终生服药，如停药后3个月，胆汁中胆固醇又将重新变为过饱和状态，结石便将复发，据统计3年复发率可达25％。因此，急需寻找基于新型作用靶点的高效低毒的药物，用于临床上胆结石的治疗。
尼古丁，俗称烟碱，是一种发现于茄科植物的强效拟副交感神经生物碱，是香烟的主要化学成分和主要致瘾成分，属于兴奋剂的一种。尼古丁是一种烟碱型乙酰胆碱受体激动剂，而在nAChRα9和nAChRα10上作为受体拮抗剂。多项权威证据表明，尼古丁能用于治疗抑郁症、帕金森等多种疾病。同时尼古丁本身具有抗炎症作用，因此，对溃疡性结肠炎有益。但对于胆结石的影响还尚未见报道。
发明内容
本发明所要解决的技术问题是提供尼古丁及衍生物作为FXR-meglin/cublin调节剂在制备利胆产品中的应用，尼古丁及其衍生物作为FXR新型调节剂，通过抑制FXR-meglin/cublin在胆囊的表达与功能，调节胆汁胆固醇代谢，有效抑制胆结石的形成。
本发明所要解决的技术问题是通过以下技术方案来实现的：
尼古丁及衍生物作为FXR-megalin/cublin调节剂在制备利胆产品中的应用。
优选地，所述利胆产品为抗胆汁淤积或抗胆囊结石的产品。
优选地，所述尼古丁提取自烟草，所述衍生物为(1'S.2'S)-尼古丁1'-氧化物。当然，尼古丁也可是纯品或其他途径获得的产品，本申请并不以此为限。
优选地，所述尼古丁通过调节胆囊上皮细胞中的胆固醇代谢来影响胆囊结石的形成。
优选地，所述利胆产品为药物或保健品。
一种包含尼古丁及衍生物的药物组合物。
优选地，所述组合物通过静脉注射或口服给药。
优选地，所述药物组合物为片剂、颗粒剂、胶囊、悬浮液或冻干剂。
优选地，所述药物组合物还包括医学上能接受的辅料。
本发明上述技术方案，具有如下有益效果：
本发明提供了尼古丁及其衍生物通过FXR-meglin/cublin在拮抗胆囊结石形成中的应用，尼古丁及其衍生物作为FXR-megalin/cublin调节剂，通过抑制FXR-megalin/cublin在胆囊的表达与功能，用于有效治疗胆汁淤积和胆结石，其具有作用靶点新颖，疗效可靠，无毒副作用、资源丰富、价格低廉等优点。
此外，尼古丁及其衍生物具有抑制FXR-megalin/cublin的表达活性，可用于制备利胆的药物或保健品，用于制备治疗胆汁淤积或胆结石的药物。
本申请阐明了尼古丁在胆囊结石形成和胆固醇/胆汁酸平衡之间的调节机制，为开发相应疾病的预防药物提供了理论基础。
附图说明
被结合在说明书中并构成说明书的一部分的附图示出了本发明的实施例，并且连同其说明一起用于解释本发明的原理。
图1为本申请的尼古丁对小鼠胆结石的治疗作用(其中：A为不同组别的小鼠中胆囊结石的形成情况，B为不同组别的小鼠胆囊重量柱状图)。
图2为本申请的尼古丁对胆汁代谢的调控作用(其中：A为不同组别的小鼠胆固醇的水平，B为不同组别的小鼠磷脂的水平，C为不同组别的小鼠胆盐的水平，D为不同组别的小鼠甘油三酯的水平，E为不同组别的小鼠总胆固醇的水平，F为不同组别的小鼠胆汁中低密度脂蛋白的水平，G为不同组别的小鼠高密度脂蛋白的水平，H为不同组别的小鼠总胆汁酸的水平)。
图3为本申请的尼古丁对小鼠胆囊FXR-megalin/cublin的调节作用(其中：A为荧光定量检测胆汁酸代谢相关因子的mRNA水平，B为蛋白免疫印迹检测的FXR、Megalin和Cubilin的蛋白水平，C为免疫组化染色检测FXR、Megalin的表达情况)。
具体实施方式
现在将参照附图来详细描述本发明的各种示例性实施例。应注意到：除非另外具体说明，否则在这些实施例中阐述的部件和步骤的相对布置、数字表达式和数值不限制本发明的范围。
实施例1尼古丁对小鼠胆囊结石的治疗作用
实验材料：
野生C57小鼠，8周龄，雄性。随机分为5组：正常饮食组(ND)，正常饮食+尼古丁组(ND+nicotine(H))，成石饮食组(LD)、成石饮食+低剂量尼古丁组(LD+nicotine(L))，成石饮食+高剂量尼古丁组(LD+nicotine(H))。
实验方法：
(1)第1周正常饮食，从第2周开始更换高胆盐饮食(1.25％胆固醇+0.5％胆酸)。正常饮食组给予生理盐水，正常饮食+尼古丁组，成石饮食组、成石饮食+低剂量尼古丁组，成石饮食+高剂量尼古丁组从第5周开始给予尼古丁(1.1mg/kg的低剂量和6.6mg/kg的高剂量)，腹腔注射给药，每2天一次，第10周结束。
(2)第10周，小鼠处死后开腹，观察胆囊结石情况，拍照，结扎胆总管，取胆囊，取出结石称重。
实验结果：
结果表明，成石饮食后，小鼠胆囊结石形成率较高。尼古丁给药下，胆囊重量比成石饮食组均显著降低了，胆汁体积增加，说明尼古丁具有治疗胆结石和胆汁淤积的作用，见图1。
实施例2体内尼古丁对胆汁代谢的影响
实验材料：
野生C57小鼠，8周龄，雄性，随机分为5组：正常饮食组(ND)，正常饮食+尼古丁组(ND+nicotine(H))，成石饮食组(LD)、成石饮食+低剂量尼古丁组(LD+nicotine(L))，成石饮食+高剂量尼古丁组(LD+nicotine(H))。
实验方法：
(1)第1周正常饮食，从第2周开始更换高胆盐饮食(1.25％胆固醇+0.5％胆酸)。正常饮食组给予生理盐水，正常饮食+尼古丁组，成石饮食组、成石饮食+低剂量尼古丁组，成石饮食+高剂量尼古丁组从第5周开始给予尼古丁(1.1mg/kg的低剂量和6.6mg/kg的高剂量)，腹腔注射给药，每2天一次，第10周结束。
(2)第10周，小鼠35mg/kg的无巴比妥钠麻醉，进行收集胆囊胆汁，静脉收集血液。生化分析仪对胆固醇、磷脂、胆汁盐、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL-C)、高密度脂蛋白(HDL-C)、总胆汁酸(TBA)进行检测。取肝脏组织，qPCR测定胆汁代谢相关mRNA表达水平，包括FXR、Cyp7A1、Cyp7B1、Cyp8B1、Cyp27A1、BSEP、NTCP、OATP1、OSTα、OSTβ、MRP2、MRP3和MRP4。
实验结果：
结果表明，与LD组相比，LD+nicotine(H)组胆囊胆汁中的胆固醇水平显着降低。与LD组相比，LD+nicotine(L)组的胆固醇水平没有显着降低。与LD组相比，实验组胆汁中的磷脂和胆汁盐没有明显差异。与ND组相比，LD组血清TG、TC、LDL-C水平显着升高，而HDL-C和TBA显着降低。经过低浓度尼古丁处理后，这些指标的水平没有变化。与LD组相比，LD+nicotine(H)组小鼠血清TG、TC、LDL-C显着降低，而HDL-C、TBA水平升高。与LD组相比，尼古丁处理组的Cyp7A1、NTCP、OSTβmRNAs显着上调；FXR和Cyp7B1 mRNA下调。说明尼古丁具有调节胆汁胆固醇的作用，见图2。
实施例3尼古丁对FXR-megalin/cublin的抑制活性及其对代谢基因的影响
实验材料：
野生C57小鼠，8周龄，雄性，随机分为5组：正常饮食组(ND)，正常饮食+尼古丁组(ND+nicotine(H))，成石饮食组(LD)、成石饮食+低剂量尼古丁组(LD+nicotine(L))，成石饮食+高剂量尼古丁组(LD+nicotine(H))。第1周正常饮食，从第2周开始更换高胆盐饮食(1.25％胆固醇+0.5％胆酸)。
实验方法：
(1)正常饮食组给予生理盐水，正常饮食+尼古丁组，成石饮食组、成石饮食+低剂量尼古丁组，成石饮食+高剂量尼古丁组从第5周开始给予尼古丁(1.1mg/kg的低剂量和6.6mg/kg的高剂量)，腹腔注射给药，每2天一次，第10周结束。
(2)第10周，小鼠35mg/kg的戊巴比妥钠麻醉处死。取胆囊组织，qPCR测定FXR-megalin/cublin信号通路相关mRNA表达水平；蛋白免疫印迹检测FXR-megalin/cublin的蛋白表达水平；免疫组化检测FXR-megalin的表达情况4。
实验结果：
结果表明，与ND组相比，LD组NPC1L1和megalin的表达水平显着降低，而ABCG5/G8和SR-BI的表达水平升高。低浓度和高浓度的尼古丁可以减弱它们的表达水平。免疫蛋白印迹和免疫组化结果显示，尼古丁不会改变cubilin蛋白水平，但会恢复LD下调的FXR和megalin水平。说明尼古丁可以通过调节胆囊上皮细胞中的胆固醇代谢来影响胆囊结石的形成过程，见图3。
本申请中，尼古丁及其衍生物作为FXR新型调节剂，可以通过抑制FXR-meglin/cublin信号通路表达的方式，调节胆汁胆固醇代谢，有效抑制胆结石的形成；具有疗效可靠，价格低廉等优点。
虽然本发明已以实施例公开如上，然其并非用于限定本发明，任何本领域技术人员，在不脱离本发明的精神和范围内，均可作各种不同的选择和修改，因此本发明的保护范围由权利要求书及其等同形式所限定。
Claims (9)
1.尼古丁及衍生物作为FXR-megalin/cublin调节剂在制备利胆产品中的应用。
2.根据权利要求1所述的应用，所述利胆产品为抗胆汁淤积或抗胆囊结石的产品。
3.根据权利要求1所述的应用，所述尼古丁提取自烟草，所述衍生物为(1'S.2'S)-尼古丁1'-氧化物。
4.根据权利要求1所述的应用，所述尼古丁通过调节胆囊上皮细胞中的胆固醇代谢来影响胆囊结石的形成。
5.根据权利要求1所述的应用，所述利胆产品为药品或保健品。
6.一种包含权利要求1-5任一所述的尼古丁及衍生物的药物组合物。
7.根据权利要求6所述的药物组合物，其特征在于，所述组合物通过静脉注射或口服给药。
8.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物为片剂、颗粒剂、胶囊、悬浮液或冻干剂。
9.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物还包括医学上能接受的辅料。
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997034605A1 (en) * | 1996-03-21 | 1997-09-25 | Mayo Foundation For Medical Education And Research | Use of nicotine to treat liver disease |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997034605A1 (en) * | 1996-03-21 | 1997-09-25 | Mayo Foundation For Medical Education And Research | Use of nicotine to treat liver disease |
Non-Patent Citations (3)
| Title |
|---|
| KERSHBAUM A, BELLET S, KHORSANDIAN R.: "Elevation of serum cholesterol after administration of nicotine", AMERICAN HEART JOURNAL, vol. 69 * |
| LATHA M S, VIJAYAMMAL P L, KURUP P A: "Effect of nicotine administration on lipid metabolism in rats", THE INDIAN JOURNAL OF MEDICAL RESEARCH, vol. 98 * |
| RHODES M, ZIJLASTRA F J, BRADBURN D M, 等: "Effect of nicotine on gallbladder bile", 《 CANADIAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY 》, vol. 8, pages 2 - 3 * |
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