CN112138026A - 一种熊胆粉在抗醉酒及预防急性酒精性脂肪肝药物中的应用 - Google Patents
一种熊胆粉在抗醉酒及预防急性酒精性脂肪肝药物中的应用 Download PDFInfo
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Abstract
本发明涉及动物有效成分的医药用途技术领域，具体涉及一种熊胆粉在抗醉酒及预防急性酒精性脂肪肝药物中的应用。急性酒精性脂肪肝（AFL）是酒精性肝损伤(ALD)病程中的初期阶段，严重的ALD会导致肝功能衰竭，目前为止临床上并没有针对ALD治疗的特效药，更没有专门针对病程中出现的AFL的特效药，基于此，本申请研究了熊胆粉（PFU）在抗醉酒及预防AFL药物中的应用，并且运用了创新性的体内小鼠模型，翻正反射小鼠抗醉酒等一系列体内实验，结果也充分证明了PFU是抗醉酒及预防急性酒精性脂肪肝的有效补充药物。
Description
技术领域
本发明涉及动物有效成分的医药用途技术领域，具体涉及一种熊胆粉在抗醉酒及预防急性酒精性脂肪肝药物中的应用。
背景技术
肝损伤长久以来都是危害人类健康的基本疾病之一，然而随着生活水平的日益提升，饮酒已经成为生活中不可缺少的部分，伴随着酒精而来的是各种危害健康的疾病，其中酒精性肝病(Alcoholic Liver Disease,ALD)是最为主要且不可忽视的严重疾病。酒精性肝病指的是长期以及过度摄入乙醇所导致的肝脏疾病，其中，在疾病初期，通常会表现酒精性脂肪肝(Alcoholic Fatty Liver,AFL)，进一步才会发展为酒精性肝炎、酒精性肝纤维化和酒精性肝硬化，严重者酒精中毒可能会导致广泛的肝细胞坏死，最终诱发肝功能的衰竭。目前为止临床上并没有针对ALD治疗的特效药，更没有专门针对病程中出现的AFL的特效药，治疗ALD的最有效办法依然是戒酒，对症以及支持性治疗。本申请的药物主要针对AFL起保护和预防的作用，其机制可能是减轻肝脏在乙醇刺激下的氧化应激和炎症以及抑制CYP2E1的活性有关。
古代获得熊胆的方法是猎杀黑熊后取其胆囊，而上世纪八十年代开始，我国采用无管造瘘引流法引流熊胆汁，干燥后得到熊胆粉，这目前也是提供熊胆到市场的唯一途径。熊胆的化学成分主要是胆汁酸类，其中以牛磺熊去氧胆酸(TUDCA)，牛磺鹅去氧胆酸(TCDCA)为主，具有清热解毒，利胆溶石的功效。基于以上，本申请主要研究了熊胆粉在抗醉酒及预防AFL药物中的应用，为熊胆粉作为保肝药对抗AFL的临床应用中提供理论依据。
现有技术中尚未见相关报道，本申请将填补这一空白。
发明内容
针对现有技术中存在的不足，本发明的目的在于提供一种熊胆粉在抗醉酒、解酒和/或预防急性酒精性脂肪肝的药物中的应用。
与现有技术相比，本发明具有以下优点和效果：
1、本申请首次发现熊胆粉(Pulvis Fellis Ursi,PFU)具有抗醉解酒的功效。
2、本申请改进了ALD的造模方法，保证既测得小鼠解酒实验的同时，又可以成功造出AFL的小鼠模型。
3、本申请首次发现PFU可以以剂量依赖性的方式显著降低急性AFL昆明小鼠体内的丙氨酸转氨酶(ALT)、门冬氨酸转氨酶(AST)、甘油三酯(TG)以及胆固醇(TC)的值，由此表明PFU可以拮抗急性乙醇暴露导致的小鼠肝内脂肪蓄积。
4、本申请预防和保护AFL小鼠的作用机制与其抑制CYP2E1活性进而减少肝脏氧化应激有关。
附图说明
图1为PFU对急性酒精性脂肪肝小鼠肝脏的组织病理学变化。
图2为PFU对急性酒精性脂肪肝小鼠细胞凋亡的影响。
图3为PFU对急性酒精性脂肪肝小鼠肝脏中CYP2E1表达的影响。
图4为PFU对急性酒精性脂肪肝小鼠抗氧化蛋白表达的影响。
具体实施方式
下面申请人将结合具体的实施例对本发明的技术方案做进一步的详细说明。应理解，以下内容不应以任何方式解释为对本发明权利要求书请求保护范围的限制。
实施例1熊胆粉(PFU)的抗醉酒和急性酒精性脂肪肝的保护作用
1.实验动物和试剂
SPF级雄性昆明小鼠50只，体质量18～22g，购自湖北省实验动物研究中心。小鼠适应性喂养3天后开始实验。
熊胆粉来自资溪康仁堂生物开发有限公司，生产批号：20190835C。
无水乙醇购自成都科隆化学品有限公司，丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、甘油三酯(TG)、胆固醇(TC)、还原型谷胱甘肽(GSH)、超氧化物歧化酶(SOD)和丙二醛(MDA)含量测定试剂盒购于南京建成生物研究所；肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)、白细胞介素-6(IL-6)含量测定试剂盒购自上海源叶生物科技公司。GCLC、HO-1和β-actin购自武汉三鹰生物技术有限公司，Nrf2、CYP2E1购自武汉爱博泰克生物科技有限公司，Hoechst 33258、4',6-二脒基-2-苯基吲哚(DAPI)、辣根过氧化物酶标记山羊抗兔IgG(H+L)和辣根过氧化物酶标记山羊抗小鼠IgG(H+L)购自碧云天生物技术研究所。
2.方法
2.1动物实验方案
取昆明小鼠50只，随机分为空白组、模型组、熊胆粉(PFU)低、中、高剂量组(剂量分别为100、300、600mg/kg，溶于生理盐水)，每组10只。空白组和模型组小鼠每天灌胃生理盐水(0.1mL/g)，PFU三组每天灌胃相应剂量溶液，连续8天。第8天末次给药30min后，模型组和药物组同时以灌胃的方法给予50％(体积百分比，下同)乙醇溶液(10mL/kg)，每12h一次，共6次，第1次给予50％乙醇溶液后观察并记录各组小鼠醉酒醒酒的情况，末次给予50％乙醇溶液4小时后，将小鼠摘眼球取血于离心管，室温放置1h后，离心机3000r/min，离心15min，离心后吸取上清液保存于-20℃冰箱，用于后续生化基本指标的检测。小鼠采用颈椎脱臼方法处死，剖取肝脏称重并记录，肝脏指数(mg/g)％＝肝脏重量/体重×100％。取一部分肝小叶于4％甲醛溶液固定，剩余组织立即放入-80℃冰箱保存。
2.2小鼠行为观察
比较给予50％乙醇溶液后各组小鼠的活动变化，观察各组小鼠翻正反射的消失与恢复的时间，记录小鼠的醉酒时间和醒酒时间，即：醉酒时间＝小鼠翻正反射消失时间-给予50％乙醇溶液的时间；醒酒时间＝小鼠翻正反射恢复时间-小鼠翻正反射消失时间。
2.3生化指标和氧化应激指标的测定
小鼠血清按照试剂盒说明书检测如下肝功能指标：转氨酶(ALT、AST)、甘油三酯(TG)、胆固醇(TC)、还原型谷胱甘肽(GSH)、超氧化物歧化酶(SOD)和丙二醛(MDA)。
2.4炎症因子TNF-α，IL-6和IL-1β含量的测定
根据ELISA试剂盒说明书，测定肝组织中TNF-α，IL-6和IL-1β含量，并在450nm处测量。
2.5组织病理学分析
将肝组织包埋在石蜡中并切成5μm厚的切片。在HE染色后，随后在光学显微镜下观察切片的组织病理学变化。组织病理学特征是用于评估肝细胞脂肪性病变的情况。
2.6 Hoechst 33258染色
将5μm厚的石蜡包埋切片脱蜡，水合，并用Hoechst 33258染色。用PBS洗涤3次后，观察染色的细胞核并用荧光显微镜拍照。
2.7免疫荧光分析
免疫荧光染色用于检测CYP2E1的表达。将5μm厚的切片脱石蜡，水合后用高压热的方式进行抗原修复。然后将切片与阻断血清分离，在4℃下使用CYP2E1和一抗稀释剂(1：100)温育过夜，并用二抗(兔抗)孵育12h。DAPI用于核染色，在荧光显微镜下观察并拍照。
2.8 Western-blot分析
用玻璃匀浆器在裂解液中匀化冷冻的肝脏组织，测定蛋白质浓度。通过十二烷基硫酸钠—聚丙烯酰胺凝胶电泳(SDS-PAGE)分离蛋白质，然后将蛋白转移到PVDF膜上，将膜与不同的一抗(GCLC、HO-1、β-actin和Nrf2)在4℃下孵育过夜，然后与对应的二抗(兔或鼠)在室温下孵育2h，用超敏ECL化学发光试剂盒显色。
2.9统计分析
所有实验数据均以mean±SD表示，使用GraphPad Prism 5.0(GraphPadSoftware，La Jolla，CA，USA)制作得到统计图。通过单因素方差分析(ANOVA)进行统计学分析，P<0.05说明差异具有统计学意义。Image-Pro plus 6.0用于量化免疫荧光强度和Western-bolt灰度值。
3.实验结果
3.1 PFU对醉酒小鼠的解酒抗醉作用
空白组小鼠行为敏捷，活动自由且步态稳定，无任何异常状态，与空白组小鼠相比，模型组小鼠在给予50％的乙醇后，小鼠逐渐出现走路摇晃，方向感差且攀爬能力下降，反应力明显减弱，小鼠心率加快，呼吸急促，部分小鼠出现大小便失禁的情况。此时观察小鼠的翻正反射情况，正常小鼠轻轻用手将其侧卧或者仰卧后立即翻正，翻正反射的消失即小鼠可一直保持背部朝下的状态持续1min，可证明此时小鼠已呈现醉酒状态。处于醉酒状态的小鼠在一段时间后会恢复清醒，自主运动正常进而回归正常体位，小鼠翻正反射恢复则证明小鼠清醒。
如下表1显示，PFU各组的醉酒时间均晚于模型组，高剂量组小鼠醉酒状态明显延迟，且小鼠醉酒时间长短与PFU呈剂量依赖性延长，以上表明PFU有很好的抗醉作用。表2为各组小鼠的醒酒时间，实验结果表明PFU各组小鼠的醒酒时间都短于模型组，高剂量组小鼠清醒最快，这说明了PFU同时也是有效的解酒剂。
表1小鼠醉酒时间结果
与模型组比较*P<0.05，**P<0.01
表2小鼠醒酒时间结果
与模型组比较*P<0.05，**P<0.01
3.2 PFU对小鼠血清生化指标和氧化应激指标的影响
小鼠血清中的ALT、AST、TG和TC能直接反映小鼠的肝损伤和脂肪肝程度。如表3所示，经50％乙醇灌胃后，模型组小鼠血清中的ALT、AST显著上升，小鼠的肝指数也有显著升高，这指示肝脏组织的水肿和肝功能异常，TG和TC可显示小鼠的血脂含量，模型组小鼠TC和TG含量均增高明显，说明50％乙醇溶液所致小鼠急性脂肪肝模型造模成功。与模型组相比，PFU给药组小鼠血清中ALT，AST水平和肝指数均有不同程度的下降，且结果呈剂量依赖性。说明PFU可以剂量依赖性地改善50％乙醇溶液诱导肝损伤小鼠的肝功能异常和肝水肿。同样地，PFU给药组小鼠的TG和TC的值也呈现剂量依赖性降低，由此证明PFU有很好的改善急性酒精性脂肪肝炎的效果。
表3小鼠ALT、AST、TC、TG和肝指数
与正常组比较#P<0.05，##P<0.01；与模型组比较*P<0.05，**P<0.01.
抗氧化因子T-SOD、GSH以及氧化应激标志物MDA反映机体氧化应激状态。如表4所示，当50％乙醇溶液诱导小鼠肝损伤后，其组织中的GSH和SOD的水平较空白组均显著降低，而MDA水平显著升高，说明50％乙醇溶液诱导小鼠脂肪肝与氧化应激相关。与模型组相比，高剂量组中MDA显著下降，而GSH和T-SOD显著上升(P<0.05)。说明PFU可以减轻50％酒精溶液诱导的脂肪肝小鼠氧化应激状态。
表4小鼠氧化应激指标
与正常组比较#P<0.05，##P<0.01；与模型组比较*P<0.05，**P<0.01.
3.3 PFU对急性酒精性脂肪肝小鼠炎症反应的影响
研究表明，炎症因子与急性酒精性脂肪肝具有密切的关系。如表5所示，与空白组相比，模型组肝组织中TNF-α、IL-6和IL-1β水平显著上升，而PFU的治疗可以显著抑制其过量产生。
表5小鼠炎症因子TNF-α、IL-6和IL-1β
与正常组比较#P<0.05，##P<0.01；与模型组比较*P<0.05，**P<0.01.
3.4 PFU对急性酒精性脂肪肝小鼠肝脏病理学形态的影响
肝脏的病理学形态是评价肝脏损伤情况以及药物对损伤保护作用的最直观指标。如附图1所示，病理组织检查发现，正常组小鼠肝脏细胞大小均一，排列整齐，结构完整，细胞核位于肝细胞中央。模型组肝细胞变性出现炎性细胞浸润和脂肪空泡，经PFU给药后，小鼠肝细胞间隙减小，高剂量组脂肪病变和炎性细胞浸润状况显著改善，趋近于恢复正常。说明PFU能剂量依赖性地缓解50％酒精溶液诱导的肝脏病理学变化。
3.5 PFU对急性酒精性脂肪肝小鼠肝细胞凋亡的影响
Hoechst 33258荧光染色是评估细胞凋亡形态的经典方法。本申请用Hoechst33258染色法研究PFU预处理对肝细胞核凋亡的影响，如图2所示，酒精模型组中的肝细胞显示出显著的核碎裂和缩合，表明细胞凋亡。然而，在PFU预处理组的大多数细胞核中显示出规则的均匀荧光强度和正常轮廓。
3.6 PFU对急性酒精性脂肪肝小鼠CYP2E1表达的影响
现有研究表明，参与乙醇代谢的细胞色素P4502E1(CYP2E1)在酒精性脂肪肝中扮演重要作用，CYP2E1可被乙醇活化，机制可能为乙醇会抑制CYP2E1的降解并且上调其mRNA水平的转录，因此PFU对CYP2E1表达水平的影响是肝保护的重要指标。如图3所示，与正常组相比，模型组CYP2E1的表达显著增强，而PFU组可以显著降低由50％乙醇溶液诱导的小鼠体内CYP2E1的过表达，且显示出剂量依赖性。
3.7 PFU对急性酒精性脂肪肝小鼠抗氧化作用的影响
为了研究PFU在急性酒精性脂肪肝小鼠中起到保护作用的具体机制，本申请深入研究了Nrf2及其下游的抗氧化通路。采用Western-blot分析了Nrf2及其下游GCLC和HO-1的表达情况。如图4所示，模型组中Nrf2、GCLC和HO-1的表达下调，而PFU剂量依赖性的改善了这种下调，并且显著提高了下游蛋白GCLC和HO-1的表达，这说明PFU对急性酒精性脂肪肝小鼠的保护作用可能是由Nrf2及其下游介导的。
4.讨论
用50％乙醇溶液处理小鼠会增加机体内的氧化应激，炎症和肝细胞凋亡。而AFL是以过量乙醇摄入后引起肝脏内脂质过度积聚为特征的疾病，其发病机制复杂，在此本申请从氧化应激的分子机制出发，讨论了熊胆粉的保护作用。
通过翻正反射实验可以看出，有PFU保护的小鼠相比较模型组小鼠来说更抗醉且醒酒更快，由此证明PFU有很好的抗醉醒酒作用，且呈剂量依赖性。
血清中ALT、AST水平，是检测肝功能的有效指标。结果显示，50％乙醇溶液给药后，血清ALT和AST水平显着增加。然而PFU的处理基本上防止了这些升高，表明PFU不仅保护了肝细胞膜的结构和功能的完整性，而且还保护肝组织免受50％乙醇溶液的毒性作用。TG和TC是反应脂肪肝程度的重要指标，PFU保护组的小鼠TG和TC的含量大大降低，表明PFU有很好的降脂作用。组织病理学检查为PFU的肝脏保护作用提供了直观证据，表现为对组织形态学变化的恢复。
氧化应激是急性酒精性肝损伤的主要因素之一。MDA水平被广泛用作自由基介导的脂质过氧化(LPO)损伤的标志物。我们的结果清楚地表明，在50％乙醇溶液处理后，MDA水平显着增加并且GSH水平显着降低，然而PFU的预处理有效地缓解了这些改变并逆转了氧化应激水平。
乙醇的代谢是由细胞色素酶P450介导的，尤其是CYP2E1。值得注意的是，本申请中PFU能剂量依赖性地抑制50％乙醇溶液介导的CYP2E1的过表达。
细胞凋亡是细胞死亡的一种重要形式，细胞凋亡的特征在于维持生物体基本的生理平衡。通过Hoechst 33258染色观察凋亡的肝细胞，结果表明，PFU处理组细胞凋亡明显减少，肝损伤得到有效改善，证实PFU可以预防50％乙醇溶液诱导的肝细胞凋亡。
在氧化应激下，为了维持细胞氧化还原平衡，人体的抗氧化防御系统经常被激活以对抗氧化损伤。Nrf2是一种重要的抗氧化转录因子，它积极参与由50％乙醇溶液诱导的氧化应激介导的肝毒性。典型的受Nrf2调控的下游基因包括HO-1和GCLC等。本申请结果表明，PFU预处理组上调了Nrf2蛋白的表达，进而上调HO-1和GCLC表达。这表明PFU可以激活Nrf2途径来增强肝脏防御。
乙醇可以激活NF-κB蛋白，促进一系列促炎细胞因子如TNF-α、IL-1β和IL-6的表达，并调节细胞反应，包括促凋亡。TNF-α可促进炎症细胞向中央静脉的迁移和浸润，并引发活性氧的产生。本申请结果表明，PFU可能通过抑制炎症反应而对50％乙醇溶液诱导的脂肪肝具有预防和治疗效果。
综上所述，PFU是抗醉酒及预防急性酒精性脂肪肝的有效补充药物。
Claims (1)
1.熊胆粉在制备抗醉酒、解酒和/或预防急性酒精性脂肪肝的药物中的应用。
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| CN115337312A (zh) * | 2022-08-19 | 2022-11-15 | 金熊药业(珠海横琴)有限公司 | 胆酸复合物及其制备方法和应用 |
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| CN101065110A (zh) * | 2004-11-24 | 2007-10-31 | 柳署弘 | 水溶胆汁酸制剂的干燥形式：制备及其用途 |
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| CN115337312A (zh) * | 2022-08-19 | 2022-11-15 | 金熊药业(珠海横琴)有限公司 | 胆酸复合物及其制备方法和应用 |
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