CN114869901B - 马鞭草苷在治疗酒精性肝损伤药物中的应用 - Google Patents
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Abstract
本发明涉及马鞭草苷在治疗酒精性肝损伤药物中的应用。马鞭草苷能够降低ALI小鼠血清的AST、ALT水平，并通过抑制铁死亡对酒精引起的急性肝损伤发挥保护作用，具有发展成为预防和治疗酒精性肝损伤药物的前景。
Description
技术领域
本发明属于药物治疗学技术领域，具体涉及马鞭草苷在预防和/或治疗酒精性肝损伤药物中的应用。
背景技术
酒精性肝损伤是一类由于长期过度饮酒诱发的肝脏损伤，根据其病理特征的不同可由酒精性肝损伤进展为酒精性脂肪肝、酒精性肝炎、酒精性肝纤维化、酒精性肝硬化甚至肝癌等。随着经济的增长，全球酗酒人数在不断增加，因酒精导致的死亡人数也在不断增加，酒精性肝损伤在世界范围内已经成为了不可忽视的问题，以其高发病率和死亡率引起人们的广泛关注。
酒精代谢积累了大量的自由基和活性氧(ROS)，导致氧化还原和抗氧化防御信号如谷胱甘肽(GSH)、超氧化物歧化酶和谷胱甘肽过氧化物酶(GPXs)的不平衡。此外，脂质过氧化会迅速导致细胞死亡。而铁死亡是一种铁依赖性的氧化性细胞死亡，其特征是谷胱甘肽(GSH)耗尽，有害谷胱甘肽过氧化物酶-4(GPX4)氧化还原防御，谷氨酸反向转运蛋白xCT/SCL7A11(系统Xc-)紊乱，以及脂质氢过氧化物水平升高。脂质过氧化物的积累导致细胞死亡是发生致命肝衰竭的一个关键致病因素。
迄今为止ALI尚无任何有效治疗措施，因此，寻找可以减轻组织损伤、促进修复、防止慢性纤维化、肝癌发生的肝脏保护药物具有重要意义。
发明内容
为了解决上述技术问题，本发明提供马鞭草苷在预防和/或治疗酒精性肝损伤药物中的应用。
本发明采用的技术方案如下：
马鞭草苷在预防或治疗酒精性肝损伤药物中的应用，所述马鞭草苷结构式如式(A)所示：
优选的，所述酒精性肝损伤为急性酒精性肝损伤。
优选的，所述药物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂中的任意一种。
本发明还提供一种预防或治疗酒精性肝损伤的药物，其含有药学有效剂量的马鞭草苷，所述马鞭草苷结构式如式(A)所示：
优选的，所述酒精性肝损伤为急性酒精性肝损伤。
优选的，所述药物还包含有药学上可接受的载体。
优选的，所述药学上可接受的载体包括赋形剂、稳定剂、抗氧化剂、着色剂、稀释剂、缓释剂等一种或几种功能的辅料；如淀粉、脂类、蜡、糊精、蔗糖、乳糖、微晶纤维素、明胶、柠檬酸、无机盐类、羟丙基甲基纤维素、羟乙基纤维素等。
优选的，所述药物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂中的任意一种。
本发明的有益效果为：
马鞭草为马鞭草科植物，性寒味苦，归肝，脾经；具有清热解毒，活血散瘀，利水消肿的功效，马鞭草多数生长于原野；原产于欧洲，在中国华东、华南和西南大部地区都有分布。全草供药用，治外感发热，湿热黄疸，水肿，痢疾，疟疾，白喉，喉痹，淋病，经闭，症瘕，痈肿疮毒，牙疳等。广泛地被用于抗炎、抗氧化、促进睡眠、保护脑缺血损伤等方面。马鞭草中有100多种化学成分，马鞭草苷(VE)为其主要活性成分，药理作用广泛，具有抗炎、抗肿瘤等作用。
本发明通过实验在整体动物水平考察马鞭草苷对酒精性急性肝损伤的保护作用，通过动物大体观、肝脏的病理、血清的AST、ALT水平，证明马鞭草苷对酒精引起的急性肝损伤具有保护作用。
本发明通过实验在整体动物水平运用电镜及组织和血清中铁离子的含量变化证明马鞭草苷可通过抑制铁死亡对酒精引起的急性肝损伤发挥保护作用。
本发明通过实验在细胞水平，运用电镜和细胞中铁离子的含量变化证明马鞭草苷可通过抑制铁死亡对酒精引起的急性肝损伤发挥保护作用。
本发明实验证明，马鞭草苷具有发展成为预防和治疗酒精性急性肝损伤药物的前景。
附图说明
图1为马鞭草苷对酒精诱导的ALI小鼠肝脏大体的影响。
图2为马鞭草苷对酒精诱导的ALI小鼠肝脏病理的影响。
图3A马鞭草苷对酒精诱导的小鼠血清ALT的影响，图3B马鞭草苷对酒精诱导的小鼠血清AST的影响。
图4为为马鞭草苷对酒精诱导的ALI小鼠的线粒体影响。
图5为为马鞭草苷对酒精诱导的ALI小鼠血清(图左)和组织(图右)铁死亡的影响。
具体实施方式
除非另有说明，本文中所使用的术语均具有本领域技术人员常规理解的含义。
下面结合实施例对本发明的技术方案做出更为具体的说明：
实施例1
马鞭草苷对酒精诱导的小鼠一般状况与肝脏的影响：
实验设计：
36只雄性C57BL/6J小鼠，体重20±2克，随机分为如下6组(n＝6)：对照组(Vehicle)，对照+马鞭草苷(50mg/kg)组，酒精组，酒精+马鞭草苷(12.5mg/kg)组，酒精+马鞭草苷(25mg/kg)组和酒精+马鞭草苷(50mg/kg)组。
采用慢性长期摄入酒精的方法建立小鼠ALI(酒精诱导的急性肝损伤Alcohol-induced liver injury)模型：适应性饲养一周后，将小鼠随机分为6组，每组6只，对照组(Vehicle)，对照+马鞭草苷(50mg/kg)组，酒精组，酒精+马鞭草苷(12.5mg/kg)组，酒精+马鞭草苷(25mg/kg)组和酒精+马鞭草苷(50mg/kg)组。每笼2只小鼠，建立小鼠酒精性肝损伤模型。
全部分组的小鼠均用对照液体饲料适应性喂养3天，之后酒精组，酒精+马鞭草苷(12.5mg/kg)组，酒精+马鞭草苷(25mg/kg)组和酒精+马鞭草苷(50mg/kg)组均换用乙醇液体饲料慢性乙醇喂养13天，其中包括第四天的1/3酒精量和第五天的2/3酒精量。酒精组，酒精+马鞭草苷(12.5mg/kg)组，酒精+马鞭草苷(25mg/kg)组和酒精+马鞭草苷(50mg/kg)组喂养组小鼠饲喂5％乙醇液体饲料，与此同时连续灌胃给药10天，对照组(Vehicle)，对照+马鞭草苷(50mg/kg)组小鼠饲喂对照液体饲料。液体饲料以0.9％生理盐水配置，其中均加有胆碱和维生素以供小鼠正常生活的营养需要。
在最后一天，用浓度为33％的乙醇(5g/kg)对所有酒精组，酒精+马鞭草苷(12.5mg/kg)组，酒精+马鞭草苷(25mg/kg)组和酒精+马鞭草苷(50mg/kg)小鼠进行灌胃。所有小鼠于末次灌胃后9小时，吸入5％异氟瞇麻醉，收集小鼠的肝脏组织、血液标本并将肝组织冻存或固定，用于石蜡切片和冰冻切片的制备和蛋白及RNA的制备。
观察各组小鼠的一般状况和肝脏组织，结果如下：
与酒精诱导ALI小鼠相比，应用马鞭草苷(12.5、25、50mg/kg)可不同程度改善小鼠一般状态，给药组小鼠状态明显变好。
大体观结果如图1所示，模型组颜色变的深红，与酒精诱导ALI小鼠相比，给药组明显改善，深红有所减退，表明马鞭草苷(12.5、25、50mg/kg)可缓解酒精诱导的ALI小鼠肝脏颜色，对肝脏具有一定的保护作用。
实施例2
马鞭草苷对酒精诱导的小鼠肝脏病理的影响
将实施例1中各组小鼠的肝脏组织固定于福尔马林溶液中24h～48h，样品经过酒精脱水和二甲苯透明后，用石蜡包埋。待包埋好的组织块变硬，用切片机进行切片。染色前，在二甲苯中脱去石蜡切片中的石蜡，经过由高浓度到低浓度的乙醇脱水后，最后用清水(蒸馏水)冲洗即可开始染色。于苏木素染色液中染色5min～15min，用流水稍洗去多余的染色液。在1％盐酸乙醇中作用1～3s，稍水洗后加入蓝液(0.5％淡氨水)返蓝10～30s后，用0.5％伊红染液进行染色1～3min左右。蒸馏水稍洗后，再在由低浓度到高浓度乙醇溶液中进行脱水处理，二甲苯中透明、中性树脂胶封片后在显微镜下观察，分析结果后选取需要的位置拍照。
结果如图2所示，H&E染色检测小鼠肝脏病理发现，与酒精诱导ALI小鼠相比，随着马鞭草苷浓度的升高，治疗作用较明显，马鞭草苷(12.5、25、50mg/kg)可以浓度依赖方式降低肝组织紊乱。给药组脂肪空泡减少，细胞间隙变小，油红染色切片显示模型组脂滴数量多，马鞭草苷给药后脂滴下降，表明马鞭草苷可以减轻诱导的急性肝损伤。
实施例3
马鞭草苷对酒精诱导的小鼠血清ALT与AST的影响
获取实施例1取得的小鼠血液血清作为样品，按照谷丙转氨酶(ALT)试剂盒和谷草转氨酶(AST)试剂盒(微孔96T微板法)(南京建成生物工程研究所)说明书进行操作。
检测血清ALT与AST结果如图3A、图3B所示。与酒精诱导ALI小鼠相比，马鞭草苷(12.5、25、50mg/kg)可明显降低血清ALT与AST水平(p＜0.01)(图3)，提示马鞭草苷对酒精诱导的ALI具有保护作用。
实施例4
马鞭草苷对酒精诱导的小鼠铁死亡的影响
铁死亡是一种铁依赖性的氧化性细胞死亡，铁死亡已成为细胞死亡的中枢性介质，它在形态、生物化学和遗传上都不同于其他类型的细胞调控死亡。铁死亡涉及多个病理过程，包括缺血/再灌注诱导的肾或肝损伤、神经毒性和神经退行性疾病。控制铁死亡对于减轻肝脏组织损伤具有重要意义。
将实施例1中获取的肝脏组织在离体后1～2分钟内取试验样品并放入2.5％戊二醛固定液内，于4℃冰箱内保存固定4h以上。换新鲜配制的2.5％戊二醛PBS溶液固定1h，随后用PBS漂洗15min、3次，1％锇酸固定液固定2h，PBS漂洗15min、3次。依次进行50％乙醇20min，70％乙醇20min，90％乙醇20min，90％乙醇90％丙酮(1:1)20min，90％丙酮20min，100％丙酮20min。依次进行纯丙酮+包埋液(2:1)室温3h；纯丙酮+包埋液(1:2)室温过夜；纯包埋液37℃，2h。依次进行37℃烘箱内过夜；45℃烘箱内12h；60℃烘箱内24h进行固化。LKB-1型超薄切片机切片50-60nm。3％醋酸铀-枸橼酸铅双染色。透射电镜观察线粒体。小鼠血清和组织进行铁离子试剂盒进行含量检测。
检测组织电镜结果如图4、图5所示，与酒精诱导ALI小鼠相比，马鞭草苷(12.5、25、50mg/kg)可明显降低线粒体损伤，血清和组织中铁离子含量降低，减轻铁死亡(p＜0.01)，提示马鞭草苷对酒精诱导ALI具有一定的保护作用。
以上仅为本发明的较佳实用例而已，并不用以限制本发明创造；尽管参照前述实施方式对本发明进行了详细的说明，本领域的普通技术人员应当理解：凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明创造的保护范围之内。
Claims (3)
1.马鞭草苷在制备治疗酒精性肝损伤药物中的应用，所述马鞭草苷结构式如式(A)所示：
2.如权利要求1所述的应用，其特征在于，所述酒精性肝损伤为急性酒精性肝损伤。
3.如权利要求1或2所述的应用，其特征在于，所述药物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂中的任意一种。
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