CN115531501A - 金鳝消渴复方制剂在制备治疗非酒精性脂肪肝药物的应用 - Google Patents
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Abstract
本发明公开了金鳝消渴复方制剂治疗非酒精性脂肪性肝病的应用。其以熟地黄为君药活血化瘀、滋肾、护肝健脾，以麦冬和地黄为臣药养阴生津、清热凉血，以丹参、山药为佐药活血祛瘀，消肿止血，以鳝鱼、郁金、麦芽、泽泻、甘草为使药行气化瘀，清湿热解毒，诸药合用协同起效，针对NAFLD关键环节进行多途径、多靶点调控。药理实验证明金鳝消渴复方制剂通过改善胰岛素抵抗、调整脂质代谢异常、降低炎症因子IL‑6和TNF‑α含量、提高抗氧化酶含量、抑制小鼠肠道微生物紊乱有效调控NAFLD病程的发生发展；同时也克服了西药联合治疗费用昂贵和药物不良反应的不足，使用方便，安全有效，为治疗NAFLD的临床用药提供了新选择。
Description
技术领域
本发明属于中药新用途领域，具体涉及金鳝消渴复方制剂在治疗非酒精性脂肪肝病的应用。
背景技术
非酒精性脂肪性肝病(Non-alcoholic Fatty Liver Disease，NAFLD)是除酒精和其他明确的肝损伤因素所致，由代谢应激引起的以肝脏脂肪沉积为特征的获得性代谢性疾病，现已超过病毒性肝炎成为世界范围内的第一大肝病。如不加以控制NAFLD可进一步发展成为非酒精性脂肪肝炎、肝硬化、肝纤维化及肝癌。同时，NAFLD已经成为世界范围诱发心脑血管疾病、糖尿病、心脏疾病、慢性肾脏病等相关疾病的主要原因之一。近年来，随着人们生活水平的提高及生活方式的改变，NAFLD疾病的发病率呈现逐年上升且年轻化的趋势。据统计，当前全球NAFLD的患病率约为25.24％，其中我国患病率达到32.9％，每年NAFLD及其相关疾病治疗费用高达上千亿美元。由于发病率高及治疗药物的缺乏，NAFLD已经成为当前全球激增的经济负担，严重干扰了人们的健康生活。因此，开发治疗NAFLD的药物具有重要的社会意义和医学研究价值。
目前尚无治疗NAFLD的特效药物。以往NAFLD的治疗措施主要分为4类：①运动疗法，缺点在于难以坚持，且不能完全控制病情的发展；②外科治疗(减肥手术和肝脏移植)，缺点在于费用高，复发率高；③饮食疗法，缺点在于没有确切的NAFLD饮食治疗方案，治疗效果在临床实际中并不容易得到重复；④药物治疗，降脂和抑炎的药物(如二甲双胍、他汀类、噻唑烷二酮类、熊去氧胆酸、维生素E等)只能在一定程度上缓解NAFLD症状，但是其有效性和安全性仍缺少临床考证。因此寻找一种有效、安全的非酒精性脂肪肝的治疗药物已成为当务之急。NAFLD是遗传、环境、代谢、应激相关性疾病，其发病机制较为复杂，至今尚未完全阐明。影响NAFLD的发病因素并不是独立存在的，而是互为因果、相互促进、相互合作的关系促进NAFLD的发生发展。目前，“二次打击”学说常用来解释NAFLD的发病机制：肝脏脂肪的积累，即肝脏脂肪变性(hepatic steatosis)，是第一次打击，导致肝脏脂质代谢紊乱，更易受到进一步损伤；第二次打击是指炎症因子、脂肪因子、氧化应激、线粒体功能损伤等，引起肝脏损伤，并逐渐导致脂肪肝炎(NASH)和肝纤维化。然而，近年来“肝-肠轴”研究发现高脂饮食诱导肠道菌群失调导致的胰岛素抵抗、肝脏炎症及脂质代谢紊乱与NAFLD 的发生发展密切相关。因此，肠道菌群紊乱和肝脏脂质代谢失调是NAFLD形成的重要因素。由于NAFLD的发病是多种信号通路同时异常引起的，靶向单一信号通路的药物难以有效根治，而且容易出现耐药。因此，开发高效低毒的创新药物以调节脂质代谢异常、消除炎症促使肝脏恢复正常功能势在必行。
非酒精性脂肪性肝病是现代医学针对该病发病机制、病位及病理改变综合定义而命名的。中医学中无此病名，但从症状表现或病因病机论述与非酒精性脂肪性肝病相似者，早有记载。如《素问·奇病论》中说：“肥者令人内热，甘者令人中满”，是指过食肥甘厚味，可损伤脾胃，湿热内生，淤积肝经，导致肝失疏泄。《太平圣惠方卷四十八》记载“治肥气在左胁下，似覆杯。咽酸吐水，面目萎黄，胸膈不利”，也描述了本病的症状表现。《金匿翼·胁痛统论》中有记载：“肝郁胁痛者，悲哀恼怒，郁伤肝气”，指出情志失调，长期忧郁或恼怒，气机郁结，进而影响水液的输布运化，日久成湿成痰，导致肝郁脾虚，最终形成该病。《景岳全书·痰饮》：“五脏之病……肾主水，水泛亦为痰……而痰之本无不在肾”和《医宗必读·积聚》：“积之成也，正气不足，而后邪气居之”，揭示肝肾同源，肾虚则肝不调，痰湿瘀滞留滞肝脏则致该病。《古今医鉴·胁痛》中说：“胁痛者……或痰积流注于血，与血相搏”，指出痰湿阻滞，血脉运行不畅，终导致瘀血阻络，痰湿聚结，最终形成本病。尤在径《金医要略心典》中说：“食积太阴，敦阜之气，抑遏肝气，故病在胁下……”。过食肥甘厚味可以直接损伤脾胃，脾气虚无以运化和敷布水谷精微，反化为痰、湿、浊、脂堆积体内，阻碍气机升降；同时脾失健运，湿浊等病理产物内生，中焦气机不畅，影响肝之疏泄，各种病理产物聚阻于肝脏则形成NAFLD。结合上述理论和中医临床实践，可以认为该病主要由饮食不当、情志失调等引起肝失疏泄，脾失健运，导致痰湿瘀阻互结，瘀血阻络，痰湿聚集而成。因此，疏肝、健脾、解郁、清热祛湿是治疗该病的关键。
NAFLD的发病机制涉及到多种复杂因素，因此治疗靶点单一的西医学难以有效治疗该病。中医在整体观念、辨证论治理论指导下，通过多途径、多靶点、整体调节等特点，临床上对 NAFLD的治疗效果显著、不良反应少、价格低廉、不容易出现耐药等明显的优势，已成为治疗该病的重要手段，也为研发防治非酒精性脂肪性肝病的新药提供了新方向。
发明内容
本发明的目的是针对现有方法和技术针对NAFLD的治疗无确切药物的不足，提供金鳝消渴复方制剂的应用，具有治疗NAFLD的功能，能有效抑制NAFLD患者糖脂代谢紊乱、改善胰岛素抵抗及减轻脂质过氧化造成的损伤。
为达到上述目的，本发明的技术方案为：
金鳝消渴复方制剂在制备治疗非酒精性脂肪性肝病药物中的应用，原料药以重量份计，由以下组分制成，鳝鱼20-60份、丹参25-60份、熟地黄15-40份、麦冬15-40份、地黄20-50 份、郁金20-50份、麦芽10-40份和泽泻5-30份、甘草10-20份、山药10-20份。
前述金鳝消渴复方制剂的应用，所述原料药以重量份计，鳝鱼40-60份、丹参40-60份、熟地黄20-40份、麦冬20-40份、地黄30-50份、郁金30-50份、麦芽15-30份和泽泻10-15份、甘草15-20份、山药15-20份。
前述金鳝消渴复方制剂的应用，所述原料药以重量份计，鳝鱼50份、丹参50份、熟地黄30份、麦冬30份、地黄40份、郁金40份、麦芽20份和泽泻15份、甘草15份、山药 15份。
前述金鳝消渴复方制剂的应用，所述组合物的制备方法，包括以下步骤：
分别取鳝鱼、丹参、熟地黄、麦冬、地黄、郁金、麦芽、泽泻、甘草、山药，以上述药物组合物总重量为基准，每次加入5-15重量倍量50％-80％的乙醇水溶液，提取50-80℃回流提取1-4次，每次0.5-3h，过滤，合并滤液，将滤液浓缩至40℃-80℃相对密度为1.13-1.30的浸膏，干燥，即得。
前述金鳝消渴复方制剂的应用，所述组合物的制备方法，包括以下步骤：
分别取鳝鱼、丹参、熟地黄、麦冬、地黄、郁金、麦芽、泽泻、甘草、山药，以上述药物组合物总重量为基准，每次加入7-13重量倍量的50％-70％乙醇，回流提取1-3次，每次 1-3h，过滤，合并滤液，将滤液浓缩至40℃-70℃相对密度为1.25-1.30的浸膏，干燥，即得。
前述金鳝消渴复方制剂的应用，所述组合物的制备方法，包括以下步骤：
分别取鳝鱼、丹参、熟地黄、麦冬、地黄、郁金、麦芽、泽泻、甘草、山药，，以上述药物组合物总重量为基准，每次加入10重量倍量60％乙醇，回流提取2次，每次2h，过滤，合并滤液，将滤液浓缩至50℃相对密度为1.13-1.15的浸膏，干燥，即得。
前述金鳝消渴复方制剂的应用，所述组合物的制备方法，包括以下步骤：
所述金鳝消渴复方制剂加入药学上可接受的辅料，按照常规工艺，制成口服液、片剂、散剂、颗粒剂、胶囊、丸剂、缓释制剂、控释制剂、靶向制剂、糖浆剂或合剂。
本发明中各主要原料药的功效活性：
熟地黄(君药)：味甘、性微温；入肝、肾经。具有滋肾水，封填骨髓，利血脉，补益真阴，补脾，止久泻等功效，可用于治疗用于血虚萎黄，心悸怔忡，月经不调，崩漏下血，肝肾阴虚，腰膝酸软，骨蒸潮热，盗汗遗精，内热消渴，眩晕，耳鸣，颏发早白等症。
丹参(佐药)：味苦，性微寒；归心、肝经。具有活血祛瘀，消肿止血，消炎止痛，降低血压，降血糖，安神静心，通经止痛，清心除烦，凉血消痈的功效；用于治疗胸痹心痛，脘腹胁痛，症瘕积聚，热痹疼痛，心烦不眠，月经不调，痛经经闭，疮疡肿痛，肝脾肿大。
鳝鱼(使药)：味甘，性温；入肝、脾、肾经。具有补虚损，除风湿，强筋骨的功效；用于治疗风寒湿痹，血气不调，止血，补气。
麦冬(臣药)：味甘，味苦，性微寒；归心、肺、胃经。具有养阴生津，润肺清心之功效；可用于虚痨咳嗽，津伤口渴，心烦失眠，内热消渴，肠燥便秘的治疗。
地黄(臣药)：味甘、苦，性寒，归脾、胃、肝经。具有清热生津，凉血，止血的功效；用于热病伤阴，舌绛烦渴，温毒发斑，吐血，衄血，咽喉肿痛等病症的治疗。
郁金(使药)：味辛、苦，性寒，味辛。归肝、心、肺经。具有行气化瘀，清心解郁，凉血破瘀，疏肝利胆的功效；用于治疗主胸腹胁肋诸痛，妇女痛经，经闭，症瘕结块，热病神昏，癫狂，惊痫，吐血，衄备，血淋，砂淋，黄疸等症。
麦芽(使药)：味甘，性平；归脾、胃经。有行气消食，健脾开胃，退乳消胀之功效；用于治疗食积不消，脘腹胀痛，脾虚食少，乳汁郁积，乳房胀痛，妇女断乳等症。
泽泻(使药)：味甘，性寒；归肾、膀胱经。具有利小便，清湿热的功效；用于治疗小便不利，水肿胀满，泄泻尿少，痰饮眩晕，热淋涩痛，高血脂等病症。
甘草(使药)：味甘，性平；归心、肺、脾、胃经。具有补脾益气，清热解毒，祛痰止咳，缓急止痛，调和诸药之功效；用于脾胃虚弱，倦怠乏力，心悸气短，咳嗽痰多，脘腹、四肢挛急疼痛，痈肿疮毒，缓解药物毒性、烈性等症的治疗。
山药(佐药)：味甘，性平；入肺、脾、肾经。有治脾虚泄泻，久痢，虚劳咳嗽，消渴，补脾养胃，生津益肺，补肾涩精之功效。用于治疗脾虚食少、久泻不止、肺虚喘咳、肾虚遗精、带下、尿频、虚热消渴等症。
相对于现有技术，本发明的有益效果为：
本发明金鳝消渴复方制剂来源于贵州苗族地区的民间中医经验方，由鳝鱼、丹参、熟地黄、麦冬、地黄、郁金、麦芽、泽泻、甘草、山药等10味药组成，该方剂具有活血化瘀、行气止痛、消食化滞、护肝健脾的功效。方中以熟地黄为君药起到活血化瘀、滋肾、护肝健脾的作用，以麦冬和地黄为臣药起到养阴生津、清热凉血的作用；以丹参、山药为佐药，起到活血祛瘀，消肿止血，消炎止痛，降血糖，清热利湿、疏肝解郁、补脾养胃，生津益肺，补肾涩精的作用；以鳝鱼、郁金、麦芽、泽泻、甘草为使药起到行气化瘀，清心解郁，疏肝利胆，消食，健脾，清湿热解毒的作用。诸药合用协同起效，针对NAFLD关键环节进行多途径、多靶点调控，通过改善胰岛素抵抗、调控脂质代谢异常通路、降低炎症因子IL-6和TNF- α含量、提高抗氧化酶含量、抑制小鼠肠道微生物紊乱来有效调控NAFLD病程的发生发展；同时也克服了西药联合治疗带来费用昂贵和药物不良反应的不足，使用方便，安全有效，为治疗NAFLD疾病的临床用药提供了新的选择。
附图说明
图1为小鼠血糖含量测定，其中A：小鼠空腹血糖含量测定；B：小鼠葡萄糖耐量测定； C：口服葡萄糖耐受；D：血糖曲线下面积；JS为金鳝消渴复方制剂处理组，MET为二甲双胍处理组，M为NAFLD模型组，CN为正常组；###：M组与CN组相比p＜0.001；*：JS组与M 组相比p＜0.05；**：MET、JS组与M组相比p＜0.01；
图2为小鼠体重及腹部脂肪重量分析，其中A：小鼠形态对比；B：小鼠体重分析；JS为金鳝消渴复方制剂处理组，MET为二甲双胍处理组，M为NAFLD模型组，CN为正常组；
图3为小鼠肝组织病理分析，其中A：小鼠肝脏H&E和油红0染色；B：小鼠肝脏形态观察；C：小鼠肝脏重量变化；JS为金鳝消渴复方制剂处理组，MET为二甲双胍处理组，M为NAFLD模型组，CN为正常组
图4为小鼠血清生化指标确定，其中A、B、C、D：小鼠血清中ALT、AST、TG、TC含量测定；JS为金鳝消渴复方制剂处理组，MET为二甲双胍处理组，M为NAFLD模型组，CN为正常组
图5为ELISA测定小鼠血清中IL-6、TNF-α和胰岛素的含量，其中A：小鼠血清中IL-6含量；B：小鼠血清中TNF-α含量；C：小鼠血清中胰岛素含量；JS为金鳝消渴复方制剂处理组，MET为二甲双胍处理组，M为NAFLD模型组，CN为正常组
图6为小鼠血清低密度脂蛋白含量(LDL-C)和高密度脂蛋白含量(HDL-C)变化；JS为金鳝消渴复方制剂处理组，MET为二甲双胍处理组，M为NAFLD模型组，CN为正常组
图7为小鼠肠道菌群16S测序；JS为金鳝消渴复方制剂处理组，MET为二甲双胍处理组， M为NAFLD模型组，CN为正常组
图8为JS处理组小鼠肝脏代谢通路KEGG pathway和GO富集分析；JS为金鳝消渴复方制剂处理组，M为NAFLD模型组，CN为正常组。
具体实施方式
本发明实施例1：金鳝消渴复方制剂的应用：
取鳝鱼50份、丹参50份、熟地黄30份、麦冬30份、地黄40份、郁金40份、麦芽20 份和泽泻15份、甘草15份、山药15份。每次加入10重量倍量60％乙醇，回流提取2次，每次2h，过滤，合并滤液，将滤液浓缩至50℃相对密度为1.18-1.21的清膏，再喷雾干燥，装胶囊制成胶囊剂。
所得胶囊剂可直接用于治疗非酒精性脂肪性肝病。用法用量：口服，一次3-5粒，一日 3次。
实施例2：金鳝消渴复方制剂的应用：
取鳝鱼40份、丹参40份、熟地黄30份、麦冬30份、地黄30份、郁金35份、麦30 份、泽泻15份、甘草20份、山药15份。每次加入7重量倍量60％乙醇，回流提取3次，每次1h，过滤，合并滤液，将滤液减压浓缩，得浓缩液，备用。将浓缩液加入蒸馏水溶解，加入适量的矫味剂和防腐剂后过滤，调节pH值，制成口服液。
所得口服液直接用于非酒精性脂肪性肝病。用法用量：口服，一次30-50g，一日3次。
实施例3：金鳝消渴复方制剂的应用：
取鳝鱼30份、丹参30份、熟地黄20份、麦冬20份、地黄25份、郁金25份、麦20 份、泽泻10份、甘草15份、山药15份。加入13重量倍量70％乙醇，回流提取2h，过滤，合并滤液，将滤液浓缩至60℃相对密度为1.13-1.15的清膏，再加入适量淀粉和木糖醇，混合均匀，整粒，干燥，制成颗粒剂。
所得颗粒剂剂直接用于非酒精性脂肪性肝病。用法用量：口服，一次15-25g，一日3次。
实施例4：金鳝消渴复方制剂的应用：
取鳝鱼20份、丹参60份、熟地黄15份、麦冬15份、地黄20份、郁金50份、麦芽40 份和泽泻5份、甘草10份、山药10份。每次加入5重量倍量80％乙醇，回流提取4次，每次0.5h，过滤，合并滤液，将滤液浓缩至40℃相对密度为1.25-1.30的清膏，再加入适量乙基纤维素乙醇，混合均匀，干燥，制成缓释制剂。
所得缓释制剂可直接用于治疗非酒精性脂肪性肝病。用法用量：口服，一次3-5g，一日 2-3次。
实施例5：金鳝消渴复方制剂的应用：
取鳝鱼60份、丹参25份、熟地黄40份、麦冬40份、地黄50份、郁金20份、麦芽10 份和泽泻30份、甘草20份、山药20份。加入15重量倍量50％乙醇，回流提取3h，过滤，合并滤液，将滤液浓缩至80℃相对密度为1.15-1.20的清膏，再加入适量聚乙二醇，混合均匀，干燥，制成靶向制剂。
所得靶向制剂可直接用于治疗非酒精性脂肪性肝病。用法用量：口服，一次1.5-3g，一日3次。
实施例6：金鳝消渴复方制剂的应用：
市售金鳝消渴复方制剂，可直接用于治疗非酒精性脂肪性肝病。用法用量：口服，一次 4g，一日2-3次。
实施例7：金鳝消渴复方制剂的应用：
将实施例1-6所得降脂消渴组合物任意配合使用，直接用于治疗非酒精性脂肪性肝病。用法用量为2-4g，一日3次。
实验例：
以下通过试验例具体说明本发明的有益效果
1.实验材料
1.1材料及方法
SPF级C57/6小鼠，雄鼠，6周龄，体重20±2g，共50只，均购自南京模式动物研究所。小鼠饲喂生长繁殖饲料和高脂饲料，大鼠饲喂生长繁殖饲料，均由上海华雅思创生物公司生产，饮用水为灭菌自来水，试验期间动物自由采食饮水，实验室温度21±2℃，湿度40-70％，实验室许可证号：SYXK(黔)2018-0001。
1.2仪器
台式离心机(Beckman)，生物安全柜(Thermo Scientific)，细胞培养箱(ThermoScientific)，荧光倒置显微镜(Olympus)，恒温水浴锅(Grant)，高压蒸汽灭菌锅(Shenan)，Milli-Q制水机(BioGen)，多功能酶标仪(Bio tek)，实时定量PCR(Bio Rad)。
1.3分组及建立NAFLD模型
动物购进适应一周后，进入实验状态。将50只小鼠，随机分为5组，每组10只，分别为：对照组、模型组、阳性对照组、实验组低剂量组、实验组高剂量组。除对照组给予正常饲料和灭菌自来水外，其余组全部给予高脂饲料，饮用10％果糖水，持续饲喂12周。
1.4分组给药
实验造模第4周开始灌胃给药。本发明药物组合物中剂量组给予本发明药物组合实例3的制剂1.8g生药/kg灌胃给药，阳性药组给予二甲双胍10mg/kg。正常及模型对照组灌胃等体积的生理盐水，每日一次，连续给药8周。给药期间，除正常组外，各组小鼠均继续造模。小鼠每周称一次体重，按体重变化给药量。
1.5实验动物处理
第12周末，给药结束后动物禁食不禁水12h，称重。各组小鼠以10％水合氯醛麻醉后，脱臼处死小鼠，眼眶取血。将血清放置冰上静置1-2h，3000rpm离心15min，取血清放置 -20℃保存待用。同时取小鼠肝脏、小鼠粪便，冻存于-80℃冰箱中进行后续分析检测。
小鼠肠道菌群16S测序：
a.实例3药物处理NAFLD小鼠12周后，脱臼处死小鼠，利用75％酒精对死亡小鼠尸体进行表面消毒。随后用无菌解剖刀，在无菌状态下取出整个肠道，无菌生理盐水清洗肠道外表面后，切取所需肠段(在无菌操作台进行)。
b.用无菌手术刀挖取内容物，装入无菌2.0mL离心管中，每管取约50～100mg到无菌的2.0mL离心管中，每个样本取3-5管备份。
c.将样本进行液氮速冻后，转移到-80℃冰箱保存。
d.将小鼠粪便样品用干冰寄送至中国华大基因公司，委托其对小鼠粪便样品进行16s 测序分析。
1.6检测指标
1.6.1小鼠空腹血糖及葡萄糖耐受测定
小鼠在给药结束之后，禁食不禁水12h后，取小鼠尾静脉血液用罗氏血糖仪检测血糖含量。葡萄糖耐受测定：空腹血糖测定后，腹腔注射葡萄糖(剂量1.5g/kg)，取小鼠尾静脉血液用罗氏血糖仪分别测定腹腔注射葡萄糖不同时间段(0min、15min、30min、60min、120min)的血糖含量。
1.6.2肝脏样品
给药结束后取小鼠部分肝脏样品和粪便样品送华大基因做转录组测序分析；给药结束后取小鼠肝脏部分样品送至武汉赛维尔生物科技有限公司，进行肝脏组织病理分析(H&E染色和油红0染色)。
1.6.3酶标仪检测各组小鼠血清样品中谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三脂(TG)、总胆固醇(TC)、糖化血红蛋白(HbAlc)、超氧化物歧化酶(SOD)、丙二醛 (MDA)、谷胱甘肽过氧化物酶(GPx)、高密度脂蛋白(HDL-C)、低密度脂蛋白(LDL-C) 含量
小鼠血液生化指标的检测，用1.5制备好的小鼠血清样本采用南京检测生物制品有限公司生产的试剂盒通过酶标仪来检测ALT、AST、TG、TC、HDL-C、LDL-C、HbAlc、MDA、SOD、GPx等指标含量。
1.6.4酶联免疫吸附剂术(ELISA)检测各组小鼠血清中IL-6、TNF-α、胰岛素含量
小鼠血液生化指标的检测，用1.5制备好的小鼠血清样本采用ELISA试剂盒通过酶标仪来检测IL-6、TNF-α、胰岛素等指标。
1.6.5肠道菌群分析
肠道菌群16S测序分析，用1.5制备好的小鼠粪便样本送至华大基因做肠道菌群16S测序分析。
1.7统计方法
实验结果采用SPSS 22.0统计软件，所有数据采用均数±标准差表示，两两比较采用t检验p＜0.05为差异有统计学意义。
2实验结果
2.1小鼠空腹血糖及葡萄糖耐受结果
实验结果如图1A所示，模型组小鼠空腹血糖(M)含量显著高于对照组(CN)组(p＜0.001)，本发明中的金鳝消渴复方制剂(JS)组小鼠血糖含量显著低于M组(p＜0.05)，而阳性药二甲双胍处理组(MET)对NAFLD小鼠血清中血糖含量无明显影响。从图1C中我们可发现，将 1.5g/kg的葡萄糖通过腹腔注射到小鼠体内15min后，随着时间的增加MET和JS组小鼠血糖含量呈现显著下降的趋势，这说明MET和JS处理后均显著增强了小鼠对葡糖糖的耐受能力。结合上述结果我们发现，MET和JS处理后均降低了小鼠血糖含量，同时增加了小鼠对葡萄糖的耐受能力。另外，值得注意的是，通过对比小鼠空腹血糖含量及葡糖糖耐受结果，可以看到，本发明金鳝消渴复方制剂处理后对小鼠血糖含量及增加小鼠葡糖糖耐受的结果均优于阳性药 MET。
2.2小鼠体重及脂肪含量变化
如图2A和B所示，M组小鼠的体重显著高于CN组(p＜0.001)；与M组相比，本发明金鳝消渴复方制剂处理显著降低了小鼠的体重(p＜0.01)，而MET组小鼠体重与M组无明显差异 (p＞0.05)。上述实验结果还显示，所述药物组合物对小鼠体重增长的抑制效果明显优于阳性药二甲双胍。
2.3小鼠肝脏切片分析
H&E染上显示高脂诱导的NAFLD模型小鼠均有点状坏死及炎细胞浸润出现及不同程度的脂肪变性及空泡样变，同时NAFLD模型组小鼠肝脏明显大于JS方剂组及二甲双胍(MET)组(图 3C)，且其肝呈现不同程度的乳白色(图3B)。油红0染色结果显示，高脂诱导的NAFLD模型小鼠肝脏中脂肪含量明显增加(图3A)。本发明金鳝消渴复方制剂(JS)处理后明显改善了小鼠肝脏脂肪变性、空泡样变及脂质蓄积，同时小鼠肝脏形态与正常组趋于一致(图3A)。
2.4小鼠血清生化指标分析
与正常组相比，高脂饮食诱导的NAFLD组，小鼠LDL-C、TG、TC均显著升高(p＜0.01，p＜0.001)，HDL-C显著降低(p＜0.05)；本发明金鳝消渴复方制剂JS组显著下调了饮食诱导的NAFLD模型小鼠血清中LDL-C、TG、TC含量(p＜0.05，p＜0.01)，HDL-C显著升高(p＜0.001)；且本发明金鳝消渴复方制剂的作用效果显著优于二甲双胍处理组(图4)。
2.5酶联免疫吸附剂术(ELISA)检测各组小鼠血清中IL-6、TNF-α和胰岛素含量
给药结束后，通过ELISA试剂盒测定小鼠各组血清中IL-6、TNF-α和胰岛素的含量。与正常组相比(图5)，高脂饮食诱导的NAFLD模型小鼠血清中炎症因子IL-6、TNF-α和胰岛素的含量显著高于CN组(p＜0.001)；MET组血清中IL-6、TNF-α和胰岛素的含量与M组相比显著降低(p＜0.01，p＜0.05)；而与M组相比，本发明金鳝消渴复方制剂处理后NAFLD小鼠血清中IL-6和TNF-α的含量显著降低(p＜0.01，p＜0.05)，JS处理组小鼠血清胰岛素含量无明显差异(p＞0.05)。上述研究结果说明，本发明金鳝消渴复方制剂抑制了NAFLD模型组小鼠体内炎症因子的表达。
2.6小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)、超氧化物歧化酶(SOD)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GPx)、糖化血红蛋白(HbAlc)含量的变化
为进一步分析本发明金鳝消渴复方制剂对NAFLD小鼠的治疗效果，实验还测定了各组小鼠血清中ALT、AST、GPx、MDA、SOD等生化指标含量。如图6所示，相比正常组，本发明金鳝消渴复方制剂降低了小鼠血清中谷草转氨酶(AST)、丙二醛(MDA)、谷胱甘肽过氧化物酶(GPx)、糖化血红蛋白(HbA1c)含量(p＜0.05，p＜0.01，p＜0.001)。上述结果说明本发明金鳝消渴复方制剂可降低脂质过度蓄积及脂质过氧化对肝细胞是损伤，且效果优于阳性药MET组。
2.7肠道菌群分析
近年来研究发现，肠道微生物紊乱与NAFLD的发生和发展密切相关。肠道菌群紊乱产生的代谢产物脂多糖(LPS)通过肠道上皮细胞吸收进入肝脏与脂质过氧化产生的ROS一起激活 NF-κB信号通路，诱发炎症反应的发生和发展。与模型组相比，JS处理组显著降低了NAFLD 小鼠肠道厚壁菌门的比例，增加了拟杆菌门的比例促使肠道微生态平衡，且对肠道菌群的有益调节作用优于MET组(图7)。
2.8小鼠肝脏转录组分析
小鼠肝脏转录组学数据显示，JS处理组主要调控涉及小鼠能量代谢通路的945个基因(图 8A)，这些基因参与的代谢通路主要由脂肪酸氧化、脂肪酸合成、酮体代谢途径等(图8B)。本发明金鳝消渴复方制剂主要通过调节小鼠能量代谢通路来改善或治疗NAFLD。
上述动物实验研究结果显示，本发明金鳝消渴复方制剂可通过调节脂质代谢和炎症反应异常信号通路及抑制肠道微生态紊乱进而达到治疗NAFLD小鼠的目的。为进一步揭示本发明金鳝消渴复方制剂对人NAFLD细胞模型中脂质蓄积的影响，实验通过金鳝消渴复方制剂大鼠含药血清处理人NAFLD肝细胞模型，分析其对人NAFLD肝细胞模型中脂质代谢的影响。
Claims (7)
1.金鳝消渴复方制剂在制备治疗非酒精性脂肪性肝病药物中的应用，其特征在于：原料药以重量份计，由以下组分制成，鳝鱼20-60份、丹参25-60份、熟地黄15-40份、麦冬15-40份、地黄20-50份、郁金20-50份、麦芽10-40份和泽泻5-30份、甘草10-20份、山药10-20份。
2.根据权利要求1所述金鳝消渴复方制剂的应用，其特征在于：所述原料药以重量份计，鳝鱼40-60份、丹参40-60份、熟地黄20-40份、麦冬20-40份、地黄30-50份、郁金30-50份、麦芽15-30份和泽泻10-15份、甘草15-20份、山药15-20份。
3.根据权利要求2所述金鳝消渴复方制剂的应用，其特征在于：所述原料药以重量份计，鳝鱼50份、丹参50份、熟地黄30份、麦冬30份、地黄40份、郁金40份、麦芽20份和泽泻15份、甘草15份、山药15份。
4.根据权利1-3所述金鳝消渴复方制剂的应用，其特征在于，所述组合物的制备方法，包括以下步骤：
分别取鳝鱼、丹参、熟地黄、麦冬、地黄、郁金、麦芽、泽泻、甘草、山药，以上述药物组合物总重量为基准，每次加入5-15重量倍量50％-80％的乙醇水溶液，提取50-80℃回流提取1-4次，每次0.5-3h，过滤，合并滤液，将滤液浓缩至40℃-80℃相对密度为1.13-1.30的浸膏，干燥，即得。
5.根据权利4要求所述金鳝消渴复方制剂的应用，其特征在于，所述组合物的制备方法，包括以下步骤：
分别取鳝鱼、丹参、熟地黄、麦冬、地黄、郁金、麦芽、泽泻、甘草、山药，以上述药物组合物总重量为基准，每次加入7-13重量倍量的50％-70％乙醇，回流提取1-3次，每次1-3h，过滤，合并滤液，将滤液浓缩至40℃2-70℃相对密度为1.25-1.30的浸膏，干燥，即得。
6.根据权利5所述金鳝消渴复方制剂的应用，其特征在于，所述组合物的制备方法，包括以下步骤：
分别取鳝鱼、丹参、熟地黄、麦冬、地黄、郁金、麦芽、泽泻、甘草、山药，以上述药物组合物总重量为基准，加入10重量倍量60％乙醇，回流提取2h，过滤，合并滤液，将滤液浓缩至50℃相对密度为1.13-1.15的浸膏，干燥，即得。
7.根据权利6所述金鳝消渴复方制剂的应用，其特征在于，所述组合物的制备方法，包括以下步骤：
所述金鳝消渴复方制剂加入药学上可接受的辅料，按照常规工艺，制成口服液、片剂、散剂、颗粒剂、胶囊、丸剂、缓释制剂、控释制剂、靶向制剂或糖浆剂。
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