CN113662951A - 一种环烯醚萜苷化合物的医药用途 - Google Patents
一种环烯醚萜苷化合物的医药用途 Download PDFInfo
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Abstract
本发明公开一种环烯醚萜苷化合物的医药用途,具体涉及京尼平1‑β‑D龙胆双糖苷的用途。京尼平1‑β‑D龙胆双糖苷在体外细胞上显著降低甘油三酯TG及炎症相关基因TNF‑α和IL‑6的表达;在高脂高糖诱导的非酒精性脂肪肝模型小鼠上降低动物血清ALT和肝脏TG含量;且在体内外均能抑制NLRP3相关基因表达。因此,京尼平1‑β‑D龙胆双糖苷能够用于制备预防和治疗非酒精性脂肪性肝病药物及其他产品。
Description
技术领域
本发明属于医药及保健品领域,具体涉及京尼平1-β-D龙胆双糖苷在制备预防和治疗非酒精性脂肪性肝病(NAFLD)药物、保健品及其他产品中的应用。
背景技术
非酒精性脂肪性肝病((Nonalcoholic Fatty Liver Disease,NAFLD)是指除外酒精和其他明确的损肝因素所致的肝细胞内脂肪过度沉积为主要特征的代谢性疾病。全世界约有1/4的人口患有NAFLD,NAFLD也将成为我国第一大慢性肝病。但NAFLD的防治尚缺乏理想的治疗药物,美国FDA尚未批准任何一个专门治疗NAFLD的新药上市。目前,NAFLD的具体发病机制尚未明确,研究发现其与胰岛素抵抗、氧化应激、脂质代谢紊乱、遗传因素等多种因素相关。长期以来,中药在预防和治疗综合性代谢性疾病中发挥着独特的作用。从近年中药药理研究显示,中药在改善胰岛素抵抗、抑制脂质过氧化、减少氧化应激、抑制炎症因子释放等方面有较好效果,具有多途径、多靶点的优势。因此,从中药中寻找具有抗NAFLD的单体小分子具有重要的临床意义。
栀子(Gardenia jasminoides Ellis.)是茜草科(Rubiaceae)栀子属常绿灌木栀子的干燥成熟果实,具有泻火除烦、清热解毒的功效。栀子的主要化学成分有环烯醚萜、有机酸、黄酮、香豆素、挥发油、皂苷等其他类化合物,具有保肝利胆、抗炎、抗菌、镇定、安神等方面作用。
京尼平1-β-D-龙胆双糖苷双糖苷(genipin-1-β-D-gentiobioside),是中药栀子果实的主要化学成分。京尼平1-β-D-龙胆双糖苷双糖苷可以通过增加心肌收缩力、降低心脏的负荷来抗戊巴比妥钠诱导的心力衰竭(Chen,L.;Luo,Z.;Peng,G.;Li,X.;Liu,L.;Sheng,X.;Wang,Z.,The cardiac systolic and diastolic effects of genipin-1-beta-D-gentiobioside in the experimental heart failure.Pharmacology andClinics of Chinese Materia Medic,2013,29(2),39-41);减轻B16小鼠黑色素瘤细胞系的黑素合成(kihisa,T.;Watanabe,K.;Yamamoto,A.;Zhang,J.;Matsumoto,M.;Fukatsu,M.,Melanogenesis Inhibitory Activity of Monoterpene Glycosides from GardeniaeFructus.Chemistry&Biodiversity 2012,9(8),1490-1499.);此外它被发现能通过增加脑内乙酰胆碱水平对记忆障碍小鼠模型发挥治疗效果(Kwak,J.H.;Lee,D.-U.,Structure&ndash;Antiamnesic Activity Relationship of Iridoid Glycosides from GardeniaFruits.Chemistry Letters 2015,44(6),837-839.)。但是目前尚未有文献报道关于京尼平1-β-D-龙胆双糖苷有抗非酒精性脂肪肝的作用。
中国专利申请CN104510747A公布了京尼平1-β-D-龙胆双糖苷及其他成分配伍形成的组合物用于制备抗病毒、抗菌、退热、抗炎、抗氧化等新用途。临床上可用于治疗急性呼吸道感染、流感、肺炎、乙型病毒性感性、带状疱疹等病毒及细菌性感染疾病。中国专利申请CN102000102A公布了京尼平龙胆双糖苷在制备和治疗心力衰竭疾病药物中的应用。中国专利申请CN106309462.A公布了京尼平1-β-D-龙胆双糖苷及组合物在体内外对脑缺血损伤模型均具有明显的治疗作用,且小鼠急性和大鼠长期毒性试验表明京尼平1-β-D-龙胆双糖苷具有较好的安全性。但是目前尚未有专利公布关于京尼平1-β-D-龙胆双糖苷有抗非酒精性脂肪肝的治疗作用。
发明内容
本发明的目的在于提供一种环烯醚萜苷化合物的医药用途,具体涉及京尼平1-β-D龙胆双糖苷的用途。
本发明的第一方面,提供一种式I化合物,或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物的用途,用于制备预防或治疗非酒精性脂肪性肝病的药物或保健品或功能食品、用于制备炎性小体NLRP3的抑制剂、或用作炎性小体NLRP3的抑制剂,
R1为双糖基或多糖基,
R2为氢、C1-C4烷基、取代的C1-C4烷基、C2-C4烯基、取代的C2-C4烯基、C2-C4炔基、取代的C2-C4炔基、C6-C10芳基、取代的C6-C10芳基、3-8元杂芳基、取代的3-8元杂芳基、单糖基、双糖基或者多糖基,
R3为COOR4或者CONHR4,R4为氢、C1-C4烷基、取代的C1-C4烷基、C2-C4烯基、取代的C2-C4烯基、C2-C4炔基、取代的C2-C4炔基、C6-C10芳基、取代的C6-C10芳基、3-8元杂芳基、取代的3-8元杂芳基、杂环基、取代的杂环基。
在另一优选例中,所述式I化合物具有式2所示的结构,
R5为双糖基。
在另一优选例中,所述式I化合物具有式2所示的结构,
在另一优选例中,所述式I化合物为式4所示的京尼平1-β-D龙胆双糖苷,
在另一优选例中,所述非酒精性脂肪性肝病选自:非酒精性脂肪肝、非酒精性脂肪肝炎、脂肪性肝纤维化、脂肪性肝硬化、肝癌。
在另一优选例中,所述式I化合物降低非酒精性脂肪性肝病患病机体的肝脏甘油三脂水平。
在另一优选例中,所述式I化合物抑制或改善非酒精性脂肪性肝病患病机体肝脏炎症。
在另一优选例中,所述式I化合物降低非酒精性脂肪性肝病患病机体肝脏内脂质沉积或降低肝脏脂肪活性。
在另一优选例中,所述式I化合物降低降低非酒精性脂肪性肝病患病机体谷丙转氨酶水平。
本发明的第二方面,提供一种药物组合物或保健品或功能食品,其包含第一方面所述的式I化合物,或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物作为活性成分。
在另一优选例中,所述药物组合物或保健品或功能食品用于治疗和/或预防非酒精性脂肪性肝病,选自:非酒精性脂肪肝、非酒精性脂肪肝炎、脂肪性肝纤维化、脂肪性肝硬化、肝癌。
在另一优选例中,所述药物组合物或保健品或功能食品包含药学上或食品上可接受的载体。
在另一优选例中,所述式I化合物具有如上所述的式2、式3或式4所示的结构。
在另一优选例中,所述药物组合物或保健品或功能食品不包含栀子苷和京尼平。
本发明的第三方面,提供一种包含式I化合物、或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物的组合物的应用,用于制备预防或治疗非酒精性脂肪性肝病的药物或保健品或功能食品。
在另一优选例中,所述非酒精性脂肪性肝病选自:非酒精性脂肪肝、非酒精性脂肪肝炎、脂肪性肝纤维化、脂肪性肝硬化、肝癌。
在另一优选例中,所述组合物、药物或保健品或功能食品不包含栀子苷和京尼平。
在另一优选例中,所述式I化合物具有如上所述的式2、式3或式4所示的结构。
京尼平1-β-D龙胆双糖苷在体外细胞上可显著降低甘油三酯(TG)及炎症相关基因TNF-α和IL-6的表达;京尼平1-β-D龙胆双糖苷在高脂高糖诱导的非酒精性脂肪肝模型小鼠可降低动物血清ALT和肝脏TG含量;京尼平1-β-D龙胆双糖苷体内外可抑制NLRP3相关基因表达,能够用于制备预防或治疗非酒精性脂肪性肝病的药物或保健品或功能食品及其他产品。此外,京尼平1-β-D龙胆双糖苷能够抑制炎性小体NLRP3,用作炎性小体NLRP3的抑制剂。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。说明书中所揭示的各个特征,可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅,在此不再一一累述。
附图说明
图1是实施例1中,各组HepG2细胞TG含量、TNF-αmRNA和IL-6mRNA表达量柱形图。
图2是实施例1各组HepG2细胞油红染色图结果图。
图3是实施例2中各组小鼠实验后血清ALT水平和肝脏TG含量图。
图4:是实施例2中各组小鼠肝脏油红染色情况图。
图5是实施例3中京尼平1-β-D龙胆双糖苷对游离脂肪酸诱导肝细胞AML-12和高脂高糖诱导的模型小鼠肝脏中炎性小体NLPR3mRNA和蛋白表达的影响图。
图6是实施例4中京尼平1-β-D龙胆双糖苷、栀子苷和京尼平对HepG2细胞活力的影响图。
具体实施方式
本申请的发明人经过广泛而深入地研究,发现京尼平1-β-D龙胆双糖苷能够降低非酒精性脂肪性肝病患病机体肝脏甘油三脂(TG)含量;改善非酒精性脂肪性肝病患病机体肝脏炎症;降低非酒精性脂肪性肝病患病机体肝脏内脂质沉积;降低非酒精性脂肪性肝病患病机体肝功能损伤指标-谷丙转氨酶(ALT),能够用于治疗非酒精性脂肪性肝病。在此基础上,完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“C1-C4”是指具有1、2、3或4个碳原子。“3-8元”是指具有3-8个环原子,依此类推。
在本发明中,术语“烷基”表示饱和的线性或支链烃部分,例如术语“C1-C4烷基”是指具有1至4个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
在本发明中,术语“烯基”表示包含至少一个双键的直链或支链烃基部分,例如术语“C2-C4烯基”是指具有2至4个碳原子的含有一个双键的直链或支链烯基,非限制性地包括乙烯基、丙烯基、正丁烯基、异丁烯基。
在本发明中,术语“炔基”是指含有一个三键的直链或支链炔基,非限制性地包括乙炔基、丙炔基、丁炔基、异丁炔基等。
在本发明中,术语“芳基”表示包含一个或多个芳环的烃基部分。例如术语“C6-C10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基,如苯基、萘基等。
除非另外说明,本文所述的烷基、烯基、炔基、杂芳基和芳基为取代的和未取代的基团,可能的取代基包括,但不限于:羟基、氨基、硝基、腈基、卤素、C1-C6烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C6烷氧基、芳基、杂芳基、杂芳氧基、C1-C10烷基氨基、C1-C20二烷基氨基、芳基氨基、二芳基氨基、C1-C10烷基氨磺酰基、芳基氨磺酰基、C1-C10烷基亚氨基、C1-C10烷基磺基亚氨基、芳基磺基亚氨基、巯基、C1-C10烷硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨酰基、氨基硫代酰基、胍基、脲基、氰基、酰基、硫代酰基、酰氧基、羧基和羧酸酯基。
本发明中,所述取代为单取代或多取代,所述多取代为二取代、三取代、四取代、或五取代。所述二取代就是指具有两个取代基,依此类推。
本发明所述药学上可接受的盐可以是阴离子与式I化合物上带正电荷的基团形成的盐。合适的阴离子为氯离子、溴离子、碘离子、硫酸根、硝酸根、磷酸根、柠檬酸根、甲基磺酸根、三氟乙酸根、乙酸根、苹果酸根、甲苯磺酸根、酒石酸根、富马酸根、谷氨酸根、葡糖醛酸根、乳酸根、戊二酸根或马来酸根。类似地,可以由阳离子与式I化合物上的带负电荷的基团形成盐。合适的阳离子包括钠离子、钾离子、镁离子、钙离子和铵离子,例如四甲基铵离子。
在另一优选例中,“药学上可接受的盐”是指式I化合物同选自下组的酸形成的盐类:氢氟酸、盐酸、氢溴酸、磷酸、乙酸、草酸、硫酸、硝酸、甲磺酸、胺基磺酸、水杨酸、三氟甲磺酸、萘磺酸、马来酸、柠檬酸、醋酸、乳酸、酒石酸、琥珀酸、酢浆草酸、丙酮酸、苹果酸、谷氨酸、对甲苯磺酸、萘磺酸、乙磺酸、萘二磺酸、丙二酸、富马酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者式I化合物与无机碱形成的钠盐、钾盐、钙盐、铝盐或铵盐;或者通式I化合物与有机碱形成的甲胺盐、乙胺盐或乙醇胺盐。
京尼平1-β-D龙胆双糖苷及其应用
本发明涉及环烯醚萜苷化合物的医药用途,具体涉及京尼平1-β-D龙胆双糖苷的用途。
京尼平1-β-D龙胆双糖苷是从从栀子(Gardenia jasminoides Ellis),美洲格尼帕树(Genipaamericana)等植物中提取的一种环烯醚萜苷,也可采用人工合成或生物合成等,具有以下结构:
经研究发现,京尼平1-β-D龙胆双糖苷能够用于治疗非酒精性脂肪性肝病。京尼平1-β-D龙胆双糖苷能够降低非酒精性脂肪性肝病患病机体肝脏甘油三脂(TG)含量;改善非酒精性脂肪性肝病患病机体肝脏炎症;降低非酒精性脂肪性肝病患病机体肝脏内脂质沉积;降低非酒精性脂肪性肝病患病机体肝功能损伤指标-谷丙转氨酶(ALT)。
具体地京尼平1-β-D龙胆双糖苷在体外细胞上可显著降低甘油三酯(TG)及炎症相关基因TNF-α和IL-6和表达;京尼平1-β-D龙胆双糖苷在高脂高糖诱导的非酒精性脂肪肝模型小鼠可降低动物血清ALT和肝脏TG含量,且存在剂量依赖关系;京尼平1-β-D龙胆双糖苷体内外可抑制NLRP3相关基因表达,改善肝脏炎症。
栀子苷和京尼平也是中药栀子中典型的环烯醚萜苷类化合物,目前,有文献报道京尼平和栀子苷具有一定治疗非酒精性脂肪肝的作用。但是研究发现京尼平在HepG2细胞上具有明显的肝毒性,(IC50为0.216mM),与文献报道京尼平在肝细胞上有肝毒性的现象一致(Khanal T,Kim HG,Choi JH,Do MT,Kong MJ,Kang MJ,et al.Biotransformation ofgeniposide by human intestinal microflora on cytotoxicity against HepG2cells.Toxicol.Lett.2012;209:246-54.),京尼平1-β-D-龙胆双糖苷在最大给药剂量2mM仍能维持良好的细胞活力。此外,在体内等剂量的京尼平1-β-D龙胆双糖苷降非酒精性脂肪肝模型动物血清ALT和肝脏TG能力优于等剂量的栀子苷;因此,认为京尼平1-β-D-龙胆双糖苷比栀子苷和京尼平具有更好的治疗非酒精性脂肪性肝病的成药潜力。
综上,京尼平1-β-D龙胆双糖苷对非酒精性脂肪性肝病具有治疗和预防作用。通过体外细胞和体内模型动物实验发现,京尼平1-β-D龙胆双糖苷具有降脂、抗炎、保肝的作用,其抗炎机制与抑制肝脏炎性小体NLRP3有关。
药物组合物
本发明还提供一种药物组合物,用于制备预防或治疗非酒精性脂肪性肝病的药物或保健品或功能食品,其包含的活性成分为京尼平1-β-D龙胆双糖苷。
本发明还提供了一种药物组合物,它包含安全有效量范围内的活性成分京尼平1-β-D龙胆双糖苷,以及药学上可接受的载体,较佳地,本发明的药物组合物不包含栀子苷和京尼平。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和,而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的活性成分或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、直肠、肠胃外(静脉内、肌肉内或皮下)等。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件(如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1:
京尼平1-β-D-龙胆双糖苷体外抗炎、降脂实验
1.实验及方法
1.1细胞培养及给药方法
人肝癌细胞株HepG2用含10%胎牛血清DMEM培养基按接种到6孔板中(密度约1X105个/ml),置于37℃、5%CO2、95%湿度的培养箱中培养24h后,分为正常对照组、模型组和京尼平1-β-D龙胆双糖苷组,每组4孔。正常对照组给予DMEM培养基,模型组在DMEM培养基中加入FFA(油酸0.3mM:棕榈酸0.15mM);京尼平1-β-D龙胆双糖苷组培养基中加入FFA(油酸0.3mM:棕榈酸0.15mM)及京尼平1-β-D龙胆双糖苷(100μM)共同孵育,孵育24h后,收集细胞。
1.2TG的测定
吸弃12孔板培养基,(0.5ml/每孔)PBS清洗,(200μl/每孔)胰酶消化3min;用PBS稀释至800μl/每孔,每孔吹打,然后吸取液体至EP管内,
离心3000rpm,6min,留沉淀,加入(0.5ml/每孔)异丙醇,插入冰盒,然后调AMPL15%,超声破碎细胞,离心3000rpm 15min取上清加入玻璃管,留沉淀于冰盒用皮筋将玻璃管三三捆住,放入烧杯隔水加热,直至完全蒸发异丙醇。取出后迅速插入冰盒,使用TG试剂盒检测TG。
1.3RNA样品的制备及质量分析
①孵育结束后弃去上清液,用PBS将细胞洗涤两次,洗去残留培养基后,各孔加入1ml Trizol,静置5-10min,反复吹打至均匀,分别转移至新1.5mL离心管中。
②每管加入400μL氯仿剧烈振荡混匀30s,静置3min后离心,离心条件为4℃、12000rpm、10min。
③吸取上层水相200μL转移至新1.5mL管,加入1/2体积无水乙醇,混匀。
④将吸附柱放入收集管,用移液枪将液体转移至吸附柱中,静置2min,离心12000rpm、3min,倒掉收集管废液。
⑤将吸附柱放回收集管中,加入500μLRPE Solution,静置2min,1000rpm离心30s,倒掉收集管中废液。
⑥重复步骤⑤一次。
⑦将吸附柱放回收集管中,10000rpm离心2min。
⑧将吸附柱放入新的一套1.5ml的离心管中,在吸附膜中央加入60μl DEPC-treated ddH2O,静置5min,12000rpm离心2min,将所得到的RNA溶液应用酶标仪测定浓度并校正。
1.4.逆转录
使用Bio-RAD公司的反转录试剂盒进行操作。每管取600ngRNA进行逆转录,构建20μL反应体系。其中包括5×iScript Reaction Mix 4μL,iScript Reverse Transcriptase1μL,Nuclease-free water 5μL,RNAtemplate 10μL。逆转录条件为25℃5min(priming),46℃20min(Reversetranscription),95℃1min(RT inactivation),4℃保存。
1.5.Real time PCR
引物由bioTNT公司合成提供,具体引物序列如下:
β-actin基因:
正向引物为5’-CATGTACGTTGCTATCCAGGC-3’
反向引物为5’-CTCCTTAATGTCACGCACGAT-3’
TNF-α基因:
正向引物为5’-GAGGCCAAGCCCTGGTATG-3’
反向引物为5’-CGGGCCGATTGATCTCAGC-3’
IL-6基因:
正向引物为5’-ACTCACCTCTTCAGAACGAATTG-3’
反向引物为5’-CCATCTTTGGAAGGTTCAGGTTG-3’
按照下表配制PCR反应体系,其中SYBR Green购自TAKARA。
试剂 | 使用量 |
SYBRPremix Ex Taq | 10μL |
PCRForward Primer | 2μL |
PCR ReversePrimer | 2μL |
ROX Reference Dye II | 0.4μL |
DNA模板 | 4μL |
DEPC水 | 1.6μL |
将加样好的PCR板放入Ab applied Biosystems的PCR仪器,设置反应条件:95℃30s,(95℃5s,60℃32s)×50个循环,95℃15s,60℃1min,95℃15s。利用ΔΔCT法进行相对定量。数据采用GraphPad Prism7.00软件进行方差分析。
2.实验结果
与正常对照组相比,模型组细胞内TG的含量(P<0.001),TNF-αmRNA表达量(P<0.001)和IL-6mRNA(P<0.01)表达量均显著上升。与模型组相比,京尼平1-β-D-龙胆双糖给药组细胞内的TG含量(P<0.001),TNF-αmRNA表达量(P<0.01)和IL-6mRNA表达量(P<0.001)显均著降低,如图1所示。
油红O染色结果显示:正常组肝细胞无红色脂滴,胞质见淡蓝色半透明状,细胞核深染;模型组细胞胞质内见富含被红染的脂滴,且有部分红色脂滴连接成片。较模型组相比,京尼平1-β-D-龙胆双糖苷组细胞内红色脂滴显著减少,如图2所示。
以上结果证明京尼平1-β-D龙胆双糖苷具有降肝脂、抗炎和改善肝脏脂质沉积作用。
实施例2
京尼平1-β-D龙胆双糖苷及栀子苷抗非酒精性脂肪肝体内药效实验
1.实验方法
1.1.实验材料
50只雄性4周龄C57小鼠购于上海斯莱克实验动物中心,于上海中医药大学实验动物中心SPF级饲养室饲养;高脂饲料及其对照饲料购于RESEARCH DIEATS公司,货号为D12331和D12328,果糖和蔗糖购于南通特洛菲公司,均附辐照证明。京尼平1-β-D龙胆双糖苷由中国科学院上海药物研究所从栀子中分离提纯所得,其纯度>98%。当飞利肝宁购于四川美大康药业股份有限公司,批号为国药准字Z51020085。
1.2.动物造模、分组及给药
模型:雄性4周龄C57小鼠,按照体重随机分组为正常组和模型组,正常组给予对照饲料(,模型组予以高脂饲料高糖(42g/L,45%蔗糖,55%果糖)饮食造模4周,监测饮水量和饮食量。
动物分组及给药:造模4周后,将模型组按照体重随机分组为模型组、京尼平1-β-D-龙胆双糖苷低剂量(60mg/kg)组、京尼平1-β-D-龙胆双糖苷中剂量(120mg/kg)组、京尼平1-β-D-龙胆双糖苷中高剂量(240mg/kg)组、栀子苷(120mg/kg)组,连续给药4周(n=10)。正常组、模型组给予相应量0.3%CMC-Na灌胃。连续给药四周后,禁食12小时摘眼球取血,血液常温放置后离心取上清,取整个肝脏去掉胆囊,以上样品均保存于-80℃。
1.3肝组织TG含量的测定
向已标记号的2ml EP管中加入750μl丙酮及750μl无水乙醇备用,将冻存在-70℃冰箱里的肝组织取出置于-20℃冰箱备用。称取100mg左右的肝组织放入已加好丙酮及无水乙醇的2ml EP管中,使组织与试剂充分接触后置于冰上,剩下的肝组织迅速放入液氮中,全部称取完毕后放入-70℃冰箱冻存。在每一管加好肝组织样本及试剂的2ml EP管中加入2颗小磁珠,放入匀浆机的模块中固定,开机后设定匀浆机参数:65HZ,60s,匀浆好后放置于4℃冰箱,静置过夜。
静置过夜后的肝组织匀浆常温离心,3000rpm,15min。吸取9μl上清至1.5ml EP管,吸取试剂盒(浙江东瓯诊断产品有限公司)中标准品至标准管,再加入900μl试剂盒中试剂分别加入样品管及标准品管,混匀后吸取200μl至96孔板中,置于37℃水浴锅中水浴5min,以空白管校零,使用多功能酶标仪在546nm波长下比色读取各管吸光度值。肝组织TG含量(mg/g)测算公式为:(测定管数值-空白管数值)/标准管*200*3/20。
1.4.血清中ALT的测定
血清ALT活性的测定按照试剂盒说明书(南京建成生物工程研究所)先加样测标准曲线,再使用多功能酶标仪读取吸光值后代入相应的标准曲线进行数值计算。ALT活性检测使用微板法。
1.5.肝组织油红O染色
在冷冻切片机开启24小时后,将-80℃冰箱中的冷冻OCT凝胶冷冻组织块置于-20℃冰箱中进行切片。将粘合剂载玻片自然粘附到切片上并置于4℃的冰箱中进行染色,用准备好的稀释剂按照储备溶液:稀释剂=5:2的比例稀释试剂盒中的储备溶液,用0.22μm滤纸过滤三次后放于一边。将水性固封剂置于-60℃水浴锅中加热至液态,在薄膜密封时使用。将待染色的冰冻切片置于室温15分钟,置于稀释和过滤的储备溶液中20分钟,然后用双蒸水37℃洗涤10秒,洗涤后,在复染溶液中染色5分钟,仍用双蒸水37℃洗涤40秒。最后用水性固封剂滴加到载玻片上,待薄膜密封上后用显微镜检查观察。
2.实验结果
与正常大鼠相比,高脂饲料诱导的NAFLD模型小鼠血清ALT(P<0.05)和肝脏TG含量(P<0.01)显著上升。与模型组相比,阳性药当飞利肝宁可以显著下降模型小鼠血清ALT(P<0.05),但是对肝脏TG含量没显著性影响。
低(60mg/kg)、中(120mg/kg)、高(240mg/kg)剂量的京尼平1-β-D龙胆双糖苷分别可显著降低模型小鼠血清ALT水平的38%(P<0.05),58%(P<0.01),62%(P<0.01);中剂量(120mg/kg)、高(240mg/kg)剂量的的京尼平1-β-D龙胆双糖苷可分别显著降低模型小鼠肝脏TG含量的31%(P<0.05)和40%(P<0.001),低剂量(60mg/kg)的京尼平1-β-D龙胆双糖苷对模型小鼠肝脏TG含量无显著影响。如图3所示。
动物口服等剂量的京尼平1-β-D龙胆双糖苷和栀子苷后,发现京尼平1-β-D龙胆双糖苷(120mg/kg)可显著降低模型动物血清ALT水平(P<0.01)和肝脏TG含量(P<0.05),而等剂量栀子苷(120mg/kg)仅显著降低模型动物血清ALT水平(P<0.05),对模型动物肝脏TG含量无显著影响(P>0.05)。以上结果表明京尼平1-β-D龙胆双糖苷对模型动物降血清ALT和肝脏TG能力均优于等剂量的栀子苷。
油红染色结果显示:正常组肝小叶仅有少量散在的红染的脂滴;模型组可见存在大量的红色脂滴,部分融合成片。较模型组相比,低、中、高剂量京尼平1-β-D-龙胆双糖苷组脂滴红染面积较模型组均明显减少,其中高剂量减少最为显著。如图4所示。
实施例3:
京尼平1-β-D-龙胆双糖苷体内及体外抑制NLRP3的效应实验
1.实验及方法
(体内前期实验动物及造模同上)
1.1细胞培养及给药方法
小鼠正常肝细胞株AML-12用含10%胎牛血的DMEM/F-12培养基按接种到6孔板中(密度约1X105个/ml),置于37℃、5%CO2、95%湿度的培养箱中培养24h后,分为正常对照组(Con),模型组(FFA)和京尼平1-β-D龙胆双糖苷组(FFA+GG),每组4孔。正常对照组给予DMEM培养基,模型组在DMEM培养基中加入FFA(油酸0.3mM:棕榈酸0.15mM);京尼平1-β-D龙胆双糖苷组培养基中加入FFA(油酸0.3mM:棕榈酸0.15mM)及京尼平1-β-D龙胆双糖苷(100μM)共同孵育,孵育24h后,收集细胞。
1.2RNA样品的制备及质量分析
①孵育结束后弃去上清液,用PBS将细胞洗涤两次,洗去残留培养基后,各孔加入1ml Trizol,静置5-10min,反复吹打至均匀,分别转移至新1.5mL离心管中。
②每管加入400μL氯仿剧烈振荡混匀30s,静置3min后离心,离心条件为4℃、12000rpm、10min。
③吸取上层水相200μL转移至新1.5mL管,加入1/2体积无水乙醇,混匀。
④将吸附柱放入收集管,用移液枪将液体转移至吸附柱中,静置2min,离心12000rpm、3min,倒掉收集管废液。
⑤将吸附柱放回收集管中,加入500μLRPE Solution,静置2min,1000rpm离心30s,倒掉收集管中废液。
⑥重复步骤⑤一次。
⑦将吸附柱放回收集管中,10000rpm离心2min。
⑧将吸附柱放入新的一套1.5ml的离心管中,在吸附膜中央加入60μl DEPC-treated ddH2O,静置5min,12000rpm离心2min,将所得到的RNA溶液应用酶标仪测定浓度并校正。
1.3.逆转录
使用Bio-RAD公司的反转录试剂盒进行操作。每管取600ngRNA进行逆转录,构建20μL反应体系。其中包括5×iScript Reaction Mix 4μL,iScript Reverse Transcriptase1μL,Nuclease-free water 5μL,RNAtemplate 10μL。逆转录条件为25℃5min(priming),46℃20min(Reversetranscription),95℃1min(RT inactivation),4℃保存。
1.4.Real time PCR
引物由bioTNT公司合成提供,具体引物序列如下:
β-actin基因:
正向引物为5’-CATGTACGTTGCTATCCAGGC-3’
反向引物为5’-CTCCTTAATGTCACGCACGAT-3’
NLRP3基因:
正向引物为5'AACGACCCCTTCATTGAC3'
反向引物为5'GAGGAAGAGGAGGAAGGACA3'
按照下表配制PCR反应体系,其中SYBR Green购自TAKARA。
试剂 | 使用量 |
SYBRPremix Ex Taq | 10μL |
PCRForward Primer | 2μL |
PCR ReversePrimer | 2μL |
ROX Reference Dye II | 0.4μL |
DNA模板 | 4μL |
DEPC水 | 1.6μL |
将加样好的PCR板放入Ab applied Biosystems的PCR仪器,设置反应条件:95℃30s,(95℃5s,60℃32s)×50个循环,95℃15s,60℃1min,95℃15s。利用ΔΔCT法进行相对定量。数据采用GraphPad Prism7.00软件进行方差分析。
1.5.蛋白样品的制备
组织蛋白样品的制备:混合中强度RIPA、100X蛋白酶抑制剂和100X磷酸酶抑制剂配制裂解液,向标记好的1.5mlEP管中加入600ul裂解液和3颗小钢珠。取用-80℃冰箱内称量好的100mg肝组织分别加入对应EP管,使用匀浆机以60Hz速率匀浆120s,待组织匀浆液呈现无明显组织块混悬液后,置于-80℃?冰箱过夜,第二天4℃,12000rpm,离心。第三天重复第二天步骤,将上清即蛋白原液吸取至洁净1.5mlEP管,-80℃冰箱储存备用。
细胞蛋白样品的制备:细胞于6cm小培养皿中培养,待细胞长满皿底90%面积左右,弃去培养基,预冷PBS漂洗细胞2次。提前融化蛋白酶抑制剂和磷酸酶抑制剂,将RIPA和它们按50:1:1的比例配置细胞裂解液。将小皿转移至冰面操作,每皿细胞内加入100μl细胞裂解液,静置15min使其充分裂解。使用细胞刮刀轻而充分的将细胞刮至皿一侧,收集细胞裂解液于1.5ml洁净EP管内。将EP管插于冰上,静置20min。然后使用漩涡振荡仪震荡EP管30使其充分裂解。提前预冷离心机4℃,以12000rpm离心10分钟,收集上清于新的洁净1.5mlEP管内,-80℃冰箱保存备用。
蛋白浓度的测定:取2ul的蛋白样品稀释20倍,按照试剂盒的说明书以A液:B液=50:1的配比配制BCA检测试剂,向96孔板中每孔加入20ul待检样品和200ulBCA检测试剂,同时蛋白标准品倍比稀释绘制标准蛋白曲线,37℃恒温箱孵育30分钟,多功能酶标仪波长562nm处检测每孔吸光度值。按照标准曲线公式换算待检样品的蛋白浓度。以最低蛋白浓度的样品为基线,加入Loading Buffer和RIPA校正其余样品蛋白浓度至统一水平。将所有蛋白样品放入100℃恒温加热器中变性10min,变性三次,分装后放入-80℃冰箱。
1.6.Westernblot实验过程:
①提前按Tris 5.8g+甘氨酸2.6g+甲醇200ml+双蒸水800ml的比例配制转膜液,混匀后4℃冰箱过夜保存。按TBS(20X)50ml+双蒸水950ml+Tween-20 1ml配制TBST溶液。
②按照雅酶试剂盒说明书,先后配制分离胶及浓缩胶于洁净玻璃板内,室温凝胶30分钟。
③按照Tris 3g+甘氨酸14.4g+SDS1g+双蒸水1L的比例配制电泳液混匀备用。
④在电泳槽内固定好玻璃板,倒入电泳液,小心缓慢拔出梳子,向孔内加样,Marker加6ul,样本每孔15ul,避免样本从孔内溢出,加满电泳液至划线处后进行电泳。设定电压180V,时间60分钟,待目的蛋白跑入相应条带间(实验记录)修改结束电泳。
⑤按6.0cm*8.0cm大小裁剪PVDF膜,甲醇激活2分钟备用。用转膜液浸泡两张厚滤纸,按照滤纸1、PVDF膜、胶、滤纸2的顺序在转膜仪上依次铺开,小心避免中间各层气泡,设置转膜仪电压12V,时间80分钟。
⑥转膜结束后,取出PVDF膜,放于8ml左右的TBST中洗涤3次,每次6分钟。
⑦封闭液封闭1.5小时,结束后加入目的蛋白对应一抗,4℃冰箱摇床过夜。
⑧第二天回收一抗,放于4℃冰箱保存。TBST洗膜3次,每次6分钟,紧接着加入辣根过氧化物酶标记的生物二抗,避光摇床孵育1小时。
⑨二抗结束后,TBST洗膜,每张膜加入显影液4ml(A液:B液=1:1),使用ECL成像仪显影,再进行统计分析。
2.实验结果
肝组织:与正常对照组(NC)相比,模型组肝组织NLRP3 mRNA(P<0.01)表达量显著上升。与模型组(HFHC)相比,京尼平1-β-D-龙胆双糖给药组肝组织内的mRNANLRP3表达量(P<0.01)显著降低,如图5中A所示。
Westernblot结果显示:与正常对照组相比,模型组肝组织NLRP3蛋白(P<0.01)表达量均显著上升。与模型组相比,京尼平1-β-D-龙胆双糖给药组肝组织内的NLRP3蛋白表达量(P<0.01)显著降低,如图5中A所示。
肝细胞:与正常对照组(Con)相比,模型组(FFA)细胞NLRP3 mRNA(P<0.01)表达量显著上升。与模型组相比,京尼平1-β-D-龙胆双糖给药组细胞内的NLRP3mRNA表达量(P<0.01)显著降低,如图5中B所示。
Westernblot结果显示:与正常对照组相比,模型组细胞NLRP3蛋白(P<0.01)表达量显著上升。与模型组相比,京尼平1-β-D-龙胆双糖给药组细胞内的NLRP3蛋白表达量(P<0.01)显著降低,如图5中B所示。
以上结果证明京尼平1-β-D龙胆双糖苷体内外可抑制肝脏NLRP3相关基因表达,认为是京尼平1-β-D龙胆双糖苷发挥抗肝脏炎症的机制之一。
实施例4:
京尼平1-β-D-龙胆双糖苷、栀子苷和京尼平肝毒性比较
1.实验及方法
1.1实验材料
人肝癌细胞株HepG2,购于ATCC细胞库。DMEM细胞培养基,胎牛血清均购于Gibco公司;双抗,0.25%胰酶购于Corning Cellgro公司,CCK-8试剂盒购于上海博古生物科技有限公司
1.2实验方法
取生长状态较好的一皿细胞,吸弃培养基,胰酶消化3分钟,加入2ml培养基使用移液枪将皿底细胞吹打细胞至悬浮状。将皿内细胞悬液转移至15mlEP管内,以1000rpm离心5分钟。弃去上层培养基,留底部细胞沉淀,再次加入2ml培养基多次吹打使其充分混匀,取10μl细胞悬液至显微镜下计数。以5000/孔的细胞密度,将细胞均匀种于96孔板内,100μl培养基/孔,细胞贴壁24小时后,弃去培养上清,随后更换含有0、25、50、100、200、400、800μM G01的DMEM培养基培养24小时,每组药物各设6孔。24小时后弃去上清,按照100μl DMEM培养基+10μlCCK8的比例配制含有CCK8试剂的培养基,每孔加入100μl,随后放入37℃细胞培养箱中孵育。在0.5h,1h,2h分别将96孔板放入多功能酶标仪内读取波长为490nm处的吸光度值,进行统计分析。
2.实验结果
京尼平1-β-D-龙胆双糖苷和栀子苷在最大给药浓度2mM时对HepG2细胞活力无影响,但是京尼平会对导致HepG2细胞活力下降,其IC50为0.216mM,如图6所示。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
序列表
<110> 中国科学院上海药物研究所
上海中医药大学附属曙光医院
<120> 一种环烯醚萜苷化合物的医药用途
<130> P2020-0786
<160> 10
<170> SIPOSequenceListing 1.0
<210> 1
<211> 21
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 1
catgtacgtt gctatccagg c 21
<210> 2
<211> 21
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 2
ctccttaatg tcacgcacga t 21
<210> 3
<211> 19
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 3
gaggccaagc cctggtatg 19
<210> 4
<211> 19
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 4
cgggccgatt gatctcagc 19
<210> 5
<211> 23
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 5
actcacctct tcagaacgaa ttg 23
<210> 6
<211> 23
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 6
ccatctttgg aaggttcagg ttg 23
<210> 7
<211> 21
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 7
catgtacgtt gctatccagg c 21
<210> 8
<211> 21
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 8
ctccttaatg tcacgcacga t 21
<210> 9
<211> 18
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 9
aacgacccct tcattgac 18
<210> 10
<211> 20
<212> DNA
<213> 人工序列(Artificial sequence)
<400> 10
gaggaagagg aggaaggaca 20
Claims (10)
1.一种式I化合物,或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物的用途,用于制备预防或治疗非酒精性脂肪性肝病的药物或保健品或功能食品、用于制备炎性小体NLRP3的抑制剂、或用作炎性小体NLRP3的抑制剂,
R1为双糖基或多糖基,
R2为氢、C1-C4烷基、取代的C1-C4烷基、C2-C4烯基、取代的C2-C4烯基、C2-C4炔基、取代的C2-C4炔基、C6-C10芳基、取代的C6-C10芳基、3-8元杂芳基、取代的3-8元杂芳基、单糖基、双糖基或者多糖基,
R3为COOR4或者CONHR4,R4为氢、C1-C4烷基、取代的C1-C4烷基、C2-C4烯基、取代的C2-C4烯基、C2-C4炔基、取代的C2-C4炔基、C6-C10芳基、取代的C6-C10芳基、3-8元杂芳基、取代的3-8元杂芳基、杂环基、取代的杂环基。
5.根据权利要求1-4任一项所述的用途,其特征在于,所述非酒精性脂肪性肝病选自:非酒精性脂肪肝、非酒精性脂肪肝炎、脂肪性肝纤维化、脂肪性肝硬化、肝癌。
6.根据权利要求1-4任一项所述的用途,其特征在于,所述式I化合物降低非酒精性脂肪性肝病患病机体的肝脏甘油三脂水平。
7.根据权利要求1-4任一项所述的用途,其特征在于,所述式I化合物抑制或改善非酒精性脂肪性肝病患病机体肝脏炎症。
8.根据权利要求1-4任一项所述的用途,其特征在于,所述式I化合物降低非酒精性脂肪性肝病患病机体肝脏内脂质沉积或降低肝脏脂肪活性。
9.根据权利要求1-4任一项所述的用途,其特征在于,所述式I化合物降低降低非酒精性脂肪性肝病患病机体谷丙转氨酶水平。
10.一种包含式I化合物,或其药学上可接受的盐、溶剂化物、光学纯异构体、立体异构体或它们的混合物的组合物的应用,用于制备预防或治疗非酒精性脂肪性肝病的药物或保健品或功能食品。
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