CN117599036A - 隐绿原酸在制备治疗和/或预防非酒精性脂肪肝产品中的用途 - Google Patents
隐绿原酸在制备治疗和/或预防非酒精性脂肪肝产品中的用途 Download PDFInfo
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- CN117599036A CN117599036A CN202311711907.4A CN202311711907A CN117599036A CN 117599036 A CN117599036 A CN 117599036A CN 202311711907 A CN202311711907 A CN 202311711907A CN 117599036 A CN117599036 A CN 117599036A
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Abstract
本发明公开了隐绿原酸在制备治疗和/或预防非酒精性脂肪肝病产品中的用途，所述产品可以为药物、保健品或食品。实验表明，隐绿原酸对于非酒精性脂肪肝病具有显著的治疗效果，能够显著降低体重和肝脏脂肪，减少肝脏脂肪沉积；同时还能降低血清和肝脏ALT、AST水平，降低炎症因子水平，改善肝功能损伤。
Description
技术领域
本发明涉及医药领域，特别是涉及隐绿原酸在制备治疗和/或预防非酒精性脂肪肝产品中的用途。
背景技术
随着人民生活方式和饮食结构的改变，长期高脂饮食极易导致非酒精性脂肪肝病(Non-Alcoholic Fatty Liver Disease，NAFLD)的发生。目前，全球普通人群中非酒精性脂肪肝病患病率高达20％以上，且有低龄化趋势。据估计未来全世界范围内将会有三分之一以上的人患非酒精性脂肪肝病的危险，明显超过乙型肝炎、丙型肝炎及酒精性肝病的发病率，已成为临床最常见的肝病。
非酒精性脂肪肝病按其病理可分为非酒精单纯性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)及相关的肝硬化和肝癌。尽管丙型肝炎、自身免疫性肝病、Wilson病等亦可导致肝脂肪变，但因其病变主体在汇管区，且有特定命名，故不属于普通脂肪性肝病的范畴。脂肪肝的发病机制至今尚未完全清楚。目前认为，“二次打击”学说可能是酒精性脂肪肝和非酒精性脂肪肝共同的发病机制。酒精、肥胖、糖尿病等作为初次打击，通过引起肝细胞内甘油三酯合成和代谢之间失衡导致脂肪贮积形成单纯性脂肪肝；第二次打击是指氧应激相关的脂质过氧化及炎性细胞因子的作用，导致脂肪变的肝细胞发生炎症、坏死和纤维化。不同的是脂肪肝的发生在酒精性主要由乙醇及其代谢产物所致，而在非酒精性则主要与胰岛素抵抗有关。在NAFLD患者中，脂质代谢紊乱比较常见。肝脏在体内脂质代谢过程中发挥着主要的作用，它能够摄入游离脂肪酸，加工、贮存和输出脂质，过程中的任何一环出现问题都可能导致NAFLD的产生。游离脂肪酸在细胞中发挥着重要作用，例如合成细胞膜、作为能量存储以及参与细胞内的信号通路。然而，在很多器官中慢性的游离脂肪酸含量的增加会破坏代谢途径，诱导胰岛素抵抗。肝脏中脂质的积累与限密切相关。脂肪组织胰岛素抵抗能增加脂解并且能增加游离脂肪酸从脂肪组织到肝脏的输入，减少输出。
非酒精性脂肪肝病如不及时治疗，将会转变非酒精性肝硬化并发肝癌，严重影响着人民的生活与健康。减轻体重是预防肥胖者发生NAFLD的基本措施，细胞保护剂、抗氧化剂和降脂药物对NAFLD有一定治疗作用，噻唑脘二酮类(如罗格列酮)的临床治疗研究已取得可喜的疗效。目前已有几种药物被应用于NAFLD和NASH的临床试验中，但是由于出现了与预期不一致的结局和(或)在随机对照试验中缺乏治疗效益，尚未被推荐使用。因此，开发有效的药物进行干预，阻止NAFLD疾病进展就显得尤为重要。
发明内容
隐绿原酸即4-咖啡酰奎宁酸，属于单咖啡酰奎宁酸类化合物，是绿原酸(3-咖啡酰奎宁酸)同分异构体，其结构式如下：
申请人偶然发现，隐绿原酸可显著降低体重、肝脏脂肪，降低ALT、AST水平和抑制炎症因子的表达，具有显著的抗非酒精性脂肪肝病的作用，更令人意料不到的是，其活性显著优于绿原酸，甚至能够在更低的剂量下发挥更高的活性。
因此，本发明提供了隐绿原酸在制备预防和/或治疗非酒精性脂肪肝病产品中的用途。
进一步地，所述的非酒精性脂肪肝病为非酒精单纯性脂肪肝、非酒精性脂肪肝炎或肝硬化。
本发明提供了隐绿原酸在制备预防和/或治疗非酒精性脂肪肝病机体体重和/或肝脏重量增加的产品中的应用。
本发明中，所述产品为调节甘油三酯、总胆固醇、低密度脂蛋白、高密度脂蛋白胆固醇至少一种含量的产品。
在一些具体实施方案中，所述产品为降低甘油三酯、总胆固醇、低密度脂蛋白至少一种含量的产品。
在一些具体实施方案中，所述产品为升高高密度脂蛋白胆固醇含量的产品。
脂肪肝的发生与胆固醇和甘油三酯水平的升高发生有关；正常人肝组织中含有少量的脂肪，如甘油三酯、磷脂、糖脂和胆固醇等，其重量约为肝重量的3％～5％，如果肝内脂肪蓄积太多，超过肝重量的5％或在组织学上肝细胞50％以上有脂肪变性时，就可称为脂肪肝。
本发明提供隐绿原酸在制备预防和/或治疗非酒精性脂肪肝病机体血清和/或肝脏中天冬氨酸氨基转移酶和/或丙氨酸氨基转移酶增加的产品中的应用。
天冬氨酸氨基转移酶(又称谷草转氨酶，AST)、谷丙转氨酶(ALT)主要分布于肝脏组织中；正常时血清中的AST、ALT含量较低，但相应细胞受损时，细胞膜通透性增加，胞浆内的AST、ALT释放入血，故其血清浓度升高，当AST、ALT酶明显升高，提示有肝实质的广泛损害，ALT和AST是急性肝细胞损害的敏感标志。
本发明中，所述产品为降低炎症因子IL-1β、TNF-α或IL-6表达的产品。
本发明中，所述产品为促进抗炎因子表达的产品。
进一步地，所述抗炎因子为IL-10。
本发明还提供了一种护肝产品，包含隐绿原酸。
本发明中，所述产品包括但不限于药物、保健品、化妆品、食品。
进一步地，所述治疗和/或预防飞酒精性脂肪肝病的产品为药物，所述药物中包括隐绿原酸与药学上可接受的辅料。
进一步地，所述治疗和/或预防非酒精性脂肪肝病的药物包括各种可接受的剂型。
本发明中隐绿原酸的剂型没有特殊限制，例如可以是口服剂型或注射剂型。所述口服剂型可以是液体剂型，也可以是固体剂型。所述口服剂型选自硬胶囊、软胶囊、缓控释放胶囊、压片、糖衣片、粉剂、颗粒剂、滴丸、水蜜丸、糖浆或口服液；所述注射剂型选自溶液型、混悬液型、乳浊液型或冻干粉。
所述用于预防和/或治疗酒精性脂肪肝的隐绿原酸的给药方式可以为口服、滴注或注射。
制备口服用固体制剂时，可以在向主药中加入赋形剂以及视需要而定的粘合剂、崩解剂、滑润剂、着色剂、矫味剂等后，按照常规方法制成片剂、包衣片剂、颗粒剂、细粒剂、散剂、胶囊剂等。
作为赋形剂，可选自乳糖、玉米淀粉、葡萄糖、山梨糖醇、结晶纤维素、二氧化硅中的一种或几种。
作为粘合剂，可选自聚乙烯醇、乙基纤维素、甲基纤维素、阿拉伯胶、羟基丙基纤维素、羟基丙基甲基纤维素中的一种或几种。
作为滑润剂，可选自硬脂酸镁、滑石、二氧化硅中的一种或几种。
作为矫味剂，可使用可可粉、薄荷脑、芳香酸、薄荷油、龙脑、桂皮粉中的一种或几种。
当然，也可以在上述片剂、颗粒剂上包覆糖衣、明胶衣、以及其它的必要外衣。
制备注射剂时，可以根据需要向主药中添加pH调节剂、缓冲剂、悬助剂、增溶剂、稳定剂、等渗剂、防腐剂等，再按照常规方法制成静脉、皮下、肌肉内注射剂。此时，也可以根据需要，利用常规方法制成冷冻干燥物。
作为悬助剂，可选自甲基纤维素、吐温80、羟基乙基纤维素、阿拉伯胶、羧甲基纤维素钠、聚氧乙烯山梨糖醇单月桂酸盐中的一种或几种。
作为增溶剂，可选自聚氧化乙烯氢化蓖麻油、吐温80、烟酰胺、聚氧乙烯山梨糖醇单月桂酸盐、聚乙二醇、蓖麻油脂肪酸乙酯中的一种或几种。
另外，作为稳定剂，可选自亚硫酸钠、偏亚硫酸钠中的一种或几种；作为防腐剂，可选自对羟基苯甲酸甲酯、对羟基苯甲酸乙酯、山梨酸、苯酚、甲酚、氯甲酚中的一种或几种。
将本发明的制备得到产品施用于对象，所述对象可以是哺乳动物，例如可以是人、大鼠、兔、羊、猪、牛、猫、狗、猴等，优选为人。
本发明的有益效果是：本发明的实验结果表明隐绿原酸能够显著降低体重、肝脏脂肪；同时还能降低血清和肝脏的ALT、AST、TG水平、降低炎症因子水平，改善肝功能损伤，可用于治疗和/或预防非酒精性脂肪肝病。
以下缩写具有如下含义：
CA表示绿原酸；
CCA隐绿原酸；
TG表示甘油三酯；
TC表示总胆固醇；
LDLC表示低密度脂蛋白胆固醇；
HDLC表示高密度脂蛋白胆固醇；
AST表示天冬氨酸氨基转移酶；
ALT表示丙氨酸氨基转移酶。
附图说明
图1为小鼠解剖图；
图2为肝脏组织油红O染色图；
图3为CCA对血清中TC含量的影响；
图4为CCA对血清中TG含量的影响；
图5为CCA对血清中LDL-C含量的影响；
图6为CCA对血清中HDL-C含量的影响；
图7为CCA对肝脏组织TC含量的影响；
图8为CCA对肝脏组织TG含量的影响；
图9为肝脏组织的H&E染色图。
具体实施方式
下面对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实验材料：高脂饲料(HFD,货号：XT19033)，普通生长饲料(货号：221206474129802)购自江苏省协同医药生物工程有限责任公司。饱和油红O染液(批号：G1015)购自Servicebio。谷丙转氨酶(ALT，批号：C009-2-1)、谷草转氨酶(AST，批号：C010-2-1)、高密度脂蛋白胆固醇(HDL-C，批号：A112-1-1)、低密度脂蛋白胆固醇(LDL-C，批号：A113-1-1)、甘油三酯(TG，批号：A110-1-1)、总胆固醇(TC，批号：A111-1-1)、小鼠肿瘤坏死因子-α(TNF-α，货号：PT512)、小鼠白细胞介素1β(IL-1β，货号：PI301)、小鼠白细胞介素10(IL-10,货号：PI522)测定试剂盒购自碧云天。
实施例1
1、实验方法
50只6-7周龄的雄性C57BL/6小鼠(18±2g)购买于北京华阜康生物科技股份有限公司(SCXK(京)2020-0004)，将其饲养于SPF级动物实验中心，光照昼夜循环12小时。小鼠适应饲养1周后，被随机分为5组(每组n＝10),空白对照组(CON)；模型组(MOD)；阳性药物组(CAH，绿原酸20mg/kg)，CCA治疗组(CCAL，隐绿原酸10mg/kg；CCAH，隐绿原酸20mg/kg)。除空白对照组给予正常高脂饲料外，其余组都喂养高脂饲料(HFD)。饲喂12周后，各给药组每天灌胃一次，连续治疗8周，其余组给予生理盐水，每周记录一次小鼠体重。治疗结束后，隔夜禁食，并称重，收集血液、肝脏、肾脏和附睾脂肪，称重并保存于-80℃储存备用。
2、指标测试
(1)生化指标
血清或肝组织生化指标，包括ALT、AST、HDL-C、LDL-C、TG、TC、NEFA、MDA、SOD、IL-10、IL-1β和TNF-α，按照制造商试剂盒的使用说明进行检测。
(2)细胞和组织染色
H&E染色，选取小鼠肝脏组织，用4％中性多聚甲醛溶液进行固定24小时，然后依次梯度酒精进行脱水，至脱水完全后，接着进行石蜡包埋、切片、脱蜡、复温固定、最后用苏木精-伊红(H&E)溶液进行染色，并根据NAFLD活动评分计算组织病理学评分。
油红O染色，将已固定好的肝脏组织放入到已配好的30％蔗糖水溶液中进行脱水，脱水完全后，选用OTC进行包埋，-80冻存48小时，然后用冰冻切片机将冰冻的肝脏切成10μm的切片，然后根据标准说明书进行油红O染色，细胞核用苏木精染色，最后在光学显微镜下观察并拍照，再用ImageJ进行量化。使用相同的方案对细胞进行油红O染色。
3、结果分析
3.1隐绿原酸对NAFLD小鼠脏器重量的影响
图1～2、表1所示，经12周HFD喂养后，模型组小鼠肝脏呈黑红色，肝脏由于脂质堆积，表面无光泽，小鼠腹部脂肪积累，附睾脂肪大量堆积。肝脏组织油红O染色也显示，模型组肝脏组织中出现大量红色脂滴，脂肪堆积明显。并且，模型组小鼠中AST，ALT水平显著高于对照组，证实NAFLD模型造模成功。经连续给药8周后，检测各组小鼠体重及脏器重量情况，CCA低、高剂量组均能显著降低肥胖小鼠体重，各给药组腹腔脂肪积累显著减少，附睾脂肪明显降低，且其作用效果优于CA组。
表1 CCA对NAFLD小鼠脏器、肝功能的影响
注：CON：空白组，MOD：模型组，CAH：绿原酸高剂量组，CCAL：隐绿原酸低剂量组，CCAH：隐绿原酸高剂量组；与MOD组比较，*p<0.05，**p<0.01，***p<0.001；与CAH组比较，+p<0.05，++p<0.01，+++p<0.001。
3.2隐绿原酸对NAFLD小鼠生化指标及肝脏组织病理的影响
如图3～8所示，与模型组相比，各治疗组均能够显著降低血清和肝脏中的TG、TC、LDL-C的水平，并且能够增加HDL-C的水平。肝脏的油红O染色结果显示(图2)，CCA各剂量组均能够显著降低肝脏组织中的脂肪沉积。说明CCA能够改善由脂肪引起的肝脏脂质积累。并且，从组织切片结果可以看出，CCA高剂量组对高脂饮食引起的脂肪沉积的治疗作用要明显优于阳性药CA。如表1所示，各给药组均能够显著降低AST和ALT的表达，其作用效果明显优于阳性对照组CA。说明隐绿原酸对非酒精性脂肪肝小鼠的肝功能具有很好的保护作用。
3.3隐绿原酸对NAFLD小鼠的肝脏功能及其炎症的影响
如表2所示，CCA给药组能够显著抑制血清和肝脏组织中炎症因子IL-1β和TNF-α的表达，同时显著促进抗炎因子IL-10的表达，说明CCA对肝脏的保护作用不仅与调节脂质代谢相关，也与抑制炎症反应相关。肝脏组织病理切片进一步证实了以上结论。从H&E染色结果可以看出，高脂饲料喂养组的肝脏组织肝细胞排列不规则，出现一定程度的纤维化，并发生气球样变，而CCA各给药组的肝脏组织中细胞纤维化程度改善，恢复到空白组细胞状态，尤其是高剂量组小鼠肝细胞形态与正常组结构相同，并且其作用效果要优于阳性药组。以上结果证实，该组份不仅能够调节脂质代谢也能够通过抑制炎症反应减少肝脏损伤。
表2 CCA对NAFLD小鼠炎症水平的影响
注：CON：空白组，MOD：模型组，CAH：绿原酸高剂量组，CCAL：隐绿原酸低剂量组，CCAH：隐绿原酸高剂量组；与MOD组比较，*p<0.05，**p<0.01，***p<0.001；与CAH组比较，+p<0.05，++p<0.01，+++p<0.001。
综上所述，CCA对脂肪沉积引起的脏器肥大和腹腔中的脂肪堆积有明显的改善作用；同时，CCA能够逆转高脂饲料喂养的小鼠肝脏和血清中TG、TC、HDL、LDL水平的异常，显著减少肝脏组织中脂肪沉积。另外，CCA能够显著改善肝脏功能，显著降低模型小鼠AST、ALT水平。更进一步的，CCA还能够显著调节模型小鼠体内炎症因子IL-1β,TNF-αand IL-10的表达，抑制体内的炎症反应，对肝脏组织的肝纤维化和肝细胞损伤都有很好的保护作用。特别值得关注的是，CCA对抑制肝脏组织中的脂肪沉积和肝脏的保护作用都要明显优于绿原酸。
以上所述仅为本发明的实施例，并非因此限制本发明的专利范围，凡是利用本发明说明书及附图内容所作的等效结构或等效流程变换，或直接或间接运用在其他相关的技术领域，均同理包括在本发明的专利保护范围内。
Claims (10)
1.隐绿原酸在制备预防和/或治疗非酒精性脂肪肝病产品中的用途。
2.根据权利要求1所述的用途，其特征在于，所述的非酒精性脂肪肝病为非酒精单纯性脂肪肝、非酒精性脂肪肝炎或肝硬化。
3.隐绿原酸在制备预防和/或治疗非酒精性脂肪肝病机体体重和/或肝脏重量增加的产品中的用途。
4.根据权利要求1所述的用途，其特征在于，所述产品为调节甘油三酯、总胆固醇、低密度脂蛋白、高密度脂蛋白胆固醇至少一种含量的产品。
5.根据权利要求3所述的用途，其特征在于，所述产品为降低甘油三酯、总胆固醇、低密度脂蛋白至少一种含量的产品。
6.根据权利要求3所述的用途，其特征在于，所述产品为升高高密度脂蛋白胆固醇含量的产品。
7.隐绿原酸在制备预防和/或治疗非酒精性脂肪肝病机体血清和/或肝脏中天冬氨酸氨基转移酶和/或丙氨酸氨基转移酶增加的产品中的应用。
8.根据权利要求1所述的用途，其特征在于，所述产品为降低炎症因子IL-1β、TNF-α或IL-6表达的产品。
9.根据权利要求1所述的用途，其特征在于，所述产品为促进抗炎因子表达的产品；进一步地，所述抗炎因子为IL-10。
10.一种护肝产品，其特征在于，包含隐绿原酸。
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