CN117750950A - 作为预防或治疗代谢性疾病的活性成分的含苄基乙醇胺衍生物的组合物 - Google Patents
作为预防或治疗代谢性疾病的活性成分的含苄基乙醇胺衍生物的组合物 Download PDFInfo
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- CN117750950A CN117750950A CN202280053402.0A CN202280053402A CN117750950A CN 117750950 A CN117750950 A CN 117750950A CN 202280053402 A CN202280053402 A CN 202280053402A CN 117750950 A CN117750950 A CN 117750950A
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Abstract
本发明涉及一种用于预防或治疗代谢疾病的药物组合物和功能性食品组合物,其含有苄基乙醇胺衍生物作为活性成分。本发明的组合物显示细胞毒性很低或没有,即使在长期给药时也副作用也很少,同时通过显著抑制脂肪细胞分化和脂质累积而显著降低代谢疾病指标,因此是代谢疾病的有效治疗剂。
Description
技术领域
本发明涉及一种预防或治疗代谢性疾病的组合物,其包括的活性成分是USP25和USP28抑制剂的苄基乙醇胺衍生物。
背景技术
代谢综合征包括糖尿病、高血压、脂质代谢异常、胰岛素抵抗等,其发病率高,已成为威胁人类健康的一大类疾病。在发达国家如美国和欧洲,代谢综合征已被视为威胁国家竞争力的严重健康问题,并投入了大量人力和物力来解决这一问题。归类为代谢综合征的疾病是一组常见疾病,他们增加相互发生的风险,并与多种代谢变化有关,如衰老、压力和免疫功能下降。
根据OCED(经济合作与发展组织)2017年的统计,在韩国,严重肥胖人口约占总人口的5.3%,与OCED统计的平均肥胖率相比并不高,但男性儿童和青少年肥胖率(26%,包括超重)高于OCED统计的平均水平(25.6%),肥胖率呈逐年上升趋势,预计到2030年严重肥胖人口将翻一番。此外,因肥胖造成的社会经济损失在过去十年里翻了一番,在2015年达到9.2万亿韩元,而且由于老龄化等原因,预计还会进一步增加。
同时,泛素(ubiquitin,Ub)是由76个氨基酸组成的蛋白质,在大多数真核生物或细胞中参与多种细胞内功能,如蛋白质的选择性降解和细胞分裂的调节,在人类中其由四个基因编码:UBB、UBC、UBA52和RPS27A。泛素化是指通过泛素活化酶(E1)、泛素偶联酶(E2)、泛素偶联酶(E3)的顺序作用,使泛素与底物蛋白共价结合,而将泛素从底物蛋白中去除的可逆泛素化过程称为去泛素化。
去泛素酶(deubiquitinases,DUBs)是一种可引发去泛素化的酶,可分为5个家族:USP(Ub-特异性加工蛋白酶)、UCH(UbC-末端水解酶)、Otubain(OUT-结构域Ub-醛-结合蛋白)、MJD(Machado-Joseph病)和JAMM(Jab1/Pad1/MPN结构域金属酶)。其中,USP是最大的家族,其除了含有半胱氨酸盒和组氨酸盒等激活结构域外,还含有许多功能未知的结构域。特别是,除部分亚型外,USP与代谢性疾病的相关性研究较少。
整个说明书中参考和引用了许多出版物和专利文献。所引用出版物和专利文件的公开内容全部以引用方式并入本文中,以更清楚地描述相关技术的状态和本发明。
公开内容
技术问题
本发明人致力于开发一种高效的治疗组合物,该组合物即使长期服用也几乎没有副作用,同时对代谢疾病(包括肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征)具有良好的治疗活性,因此适用于慢性疾病的治疗。因此,本发明人发现了一种结构如式1所示的苄基乙醇胺衍生物,所述化合物将在后面描述,其显著抑制脂肪细胞的分化,显著减少脂质蓄积量,同时细胞毒性很小,从而显著降低代谢疾病指标。基于这一发现,完成了本发明。
因此,本发明的目的是提供一种用于预防或治疗代谢疾病的药物组合物或功能性食品组合物。
本发明的另一个目的是提供一种筛选预防或治疗代谢疾病的药物组合物的方法。
本发明的其他目的和优点会在后续发明详述、所附权利要求和附图中更加明显。
技术方案
根据本发明的一个方面,本发明提供了一种用于预防或治疗代谢疾病的药物组合物,其中所述代谢疾病选自下组:肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征,所述药物组合物包括如下式1所示的化合物或其药学上可接受的盐作为活性成分:
式1
其中R1和R2各自独立为氢或卤素,R3为氢、卤素、或未取代或被卤素取代的C1-C3烷基,X为卤素。
本发明人经过广泛而深入的研究来开发一种有效的治疗组合物,该组合物即使在长期给药时也几乎没有副作用,同时对包括肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征的代谢疾病具有优异的治疗活性,因此适合于治疗慢性疾病。因此,本发明专利人发现,具有式1结构的苄基乙醇胺衍生物显著抑制脂肪细胞分化,显著减少脂质累积量,同时细胞毒性很小,从而显著降低代谢疾病指标,表明所述化合物可制备有效治疗脂质代谢异常引起的代谢疾病的组合物。
在本说明书中,术语“代谢疾病”是指将由代谢异常引起的各种心血管疾病和2型糖尿病的危险因素聚集在一起的现象概念化定义的一组疾病,并且该术语意在包括胰岛素抵抗和各种复杂多样的代谢异常以及与之相关的临床方面。
在本说明书中,术语“肥胖”是指在很长一段时间内能量摄入超过能量消耗,多余的能量作为脂肪储存,这种水平的脂肪组织在体内变得过量的情况。一般来说,当身体质量指数(=体重(kg)/[身高(m)]2)大于25时,临床定义为肥胖。
在本说明书中,术语“糖尿病”是指以胰岛素的相对或绝对缺乏为特征的慢性疾病,导致葡萄糖不耐受。应用本发明组合物治疗或预防的糖尿病包括所有类型的糖尿病,例如1型糖尿病、2型糖尿病和遗传性糖尿病。1型糖尿病是胰岛素依赖型糖尿病,主要由β细胞破坏引起。2型糖尿病是非胰岛素依赖型糖尿病,是由餐后胰岛素分泌不足或胰岛素抵抗引起的。
在本说明书中,术语“血脂异常”是指血液中的脂肪浓度超出正常范围的病理状态。血脂异常的例子包括高胆固醇血症、高甘油三酯血症、低高密度脂蛋白胆固醇血症和高低密度脂蛋白胆固醇血症,以及所有由脂蛋白代谢异常引起的异常脂质状况。
在本说明书中,术语“脂肪肝”是指由于肝脏中的脂肪代谢紊乱而过量脂质在肝细胞中累积的病况。脂肪肝是多种疾病如心绞痛、心肌梗塞、中风、动脉硬化、脂肪肝、胰腺炎等的诱因。
在本说明书中,术语“胰岛素抵抗”是指因为降低血糖水平的胰岛素功能下降所以细胞不能有效地燃烧葡萄糖的状况。如果胰岛素抵抗高,人体会产生过多的胰岛素,从而导致高血压或血脂异常,以及心脏病和糖尿病。特别是在2型糖尿病患者中,肌肉和脂肪组织无法识别胰岛素的增加,因此胰岛素不会起效。“胰岛素抵抗综合征”是由胰岛素抵抗引起的疾病的总称,是指以细胞抵抗胰岛素作用、高胰岛素血症、极低密度脂蛋白(VLDL)和甘油三酯升高、高密度脂蛋白(HDL)降低和高血压为特征的疾病,胰岛素抵抗综合征通常被认为是心血管疾病和2型糖尿病的危险因素[瑞文(Reaven)GM,糖尿病,37:1595-607,(1988)]。
在本说明书中,术语“烷基”是指直链或支链饱和烃基团,包括如甲基、乙基、丙基、异丙基等。术语“C1-C3烷基”是指具有1-3个碳原子的烷基单元的烷基,并且当C1-C3烷基被取代时,不包括取代基的碳原子数。
在本说明书中,术语“卤素”是指卤素族元素,包括如氟、氯、溴和碘。
根据本发明的具体实施例,在式1中,R1为氢,R2为氟,R3为被卤素取代的C1-C3烷基,X为溴。
更具体地说,R3是三氟甲基。
R1为氢,R2为氟,R3为三氟甲基,X为溴的式1化合物,是具有IUPAC名称“2-(5-溴-2-(4-氟-3-(三氟甲基)苄氧基)苄胺)乙醇”的化合物(CAS号:2165322-94-9),也称为“AZ1”。已知该化合物对泛素特异性蛋白酶(USP)25和USP 28具有双重抑制活性,因此被认为对几种癌症类型具有治疗作用,但其与代谢疾病的关系完全未知。
在本说明书中,术语“药学上可接受的盐”包括衍生自药学上可接受的无机酸、有机酸或碱的盐。适用的酸的例子包括盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、甲苯-对磺酸、酒石酸、乙酸、三氟乙酸、柠檬酸、甲磺酸、甲酸、苯甲酸、丙二酸、萘-2-磺酸、苯磺酸等。适用碱衍生的盐包括例如钠的碱金属盐,如镁、铵等的碱土金属盐。
根据本发明的具体实施例,所述血脂异常是高脂血症。
如本说明书中所用的术语“高脂血症”是指当诸如甘油三酯和胆固醇等脂肪代谢不良并且血液中的脂质水平维持在高水平时发生的疾病。更具体地说,高脂血症是指血液中的脂质成分如甘油三酯、低密度脂蛋白胆固醇、磷脂和游离脂肪酸增加的一种状态。高脂血症包括高胆固醇血症或高甘油三酯血症,发病率高。
根据本发明的具体实施例,所述脂肪肝为非酒精性脂肪肝。
在本说明书中,术语“非酒精性脂肪肝(NAFL)”是指不论是否摄取酒精,肝脏细胞内脂肪过量累积的疾病,并且包括单纯性脂肪肝(脂肪变性)和非酒精性脂肪性肝炎(NASH)。单纯性脂肪肝临床预后良好,但NASH是一种进行性肝病,常伴有炎症或纤维化,被公认为肝硬化或肝癌的诱发疾病。肥胖和胰岛素抵抗是非酒精性脂肪肝的代表性危险因素。肝纤维化恶化的危险因素包括肥胖(BMI>30)、血清肝功能指标比值(AST/ALT>1)和糖尿病。特别是,当丙型肝炎携带者患有非酒精性脂肪肝时,非酒精性脂肪肝可发展为肝癌。69~100%的非酒精性脂肪性肝病患者为肥胖,20~40%的肥胖患者为非酒精性脂肪性肝病。特别是,在欧洲、美国和亚洲,10%~77%的肥胖儿童患有非酒精性脂肪肝病变,因为肥胖是非酒精性肝病最重要的危险因素。
在本说明书中,术语“预防”是指抑制所述紊乱或疾病在未被诊断患有所述紊乱或疾病,但易患所述紊乱或疾病的受试者中发生。
在本说明书中,术语“治疗”是指(a)延缓紊乱、疾病或症状的进展;(b)减轻紊乱、疾病或症状;或(c)消除紊乱、疾病或症状。当本发明组合物给药于受试者时,其直接与TUFM结合,从而起激活自噬的内流并诱导脂肪分解的作用,从而抑制由于脂肪过度积累而产生的代谢疾病症状的发展,或消除或减轻代谢疾病症状。因此,本发明所述组合物可以单独作为该疾病的治疗组合物,或者可以与其他药理学成分联合用药并作为该疾病的治疗辅助物施用。因此,如在本说明书中使用的,术语“治疗”或“治疗剂”包括“治疗助剂”或“治疗助剂”。
在本说明书中,术语“施用”或“给药”是指将治疗有效量的本发明所述组合物直接施用于受试者,以便在受试者体内形成相同的量。
在本说明书中,术语“治疗有效量”是指足够向施用本发明所述药物组合物的受试者提供治疗或预防作用的药理学成分的量。因此,术语“治疗有效量”包括“预防有效量”。
在本说明书中,术语“受试者”包括但不限于人、小鼠、大鼠、豚鼠、狗、猫、马、牛、猪、猴、黑猩猩、狒狒或恒河猴。具体地说,本发明的受试者是人。
当本发明所述组合物制备为药物组合物时,本发明所述药物组合物包含药学上可接受的载体。
本发明所述药物组合物所含的药学上可接受的载体的例子包括但不限于:乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、淀粉、金合子胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡罗烷酮、纤维素、水、糖浆、甲基纤维素、甲基羟基苯甲酸甲酯、丙基羟基苯甲酸酯、滑石粉、硬脂酸镁和矿物油;这些都是配方中常用的。除上述成分外,本发明的药物组合物还可以包括润滑剂、润湿剂、甜味剂、调味剂、乳化剂、悬浮剂、防腐剂等。合适的药学上可接受的载体和制剂在雷明顿的《药学科学》(第19版,1995年)中有详细的描述。
本发明所述药物组合物可口服或胃肠外给药。具体来说,可胃肠外给药。更具体地说,可皮下或透皮给药
本发明所述药物组合物的适当剂量可因配制方法、给药方式、患者年龄、体重、性别、病理状况、饮食、给药时间、给药途径、排泄率和反应敏感性等各种因素而变化。对于成人,本发明所述药物组合物的优选剂量在0.001~100mg/kg范围内。
本发明所述药物组合物可以制备成单位剂量形式,或者按照本领域技术人员易于实施的方法,与药学上可接受的载体和/或赋形剂配制而制备成包含在多剂量容器中。在此,所述药物组合物的制剂可以是所述药物组合物在油或含水介质中的溶液、悬浮液、糖浆或乳剂,也可以是含有所述药物组合物的提取物、粉末、颗粒、片剂或胶囊,并且还可以包括分散剂或稳定剂。
根据本发明的另一个方面,本发明提供了一种用于改善或减轻代谢疾病的食品组合物,其中代谢疾病选自下组:肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征,所述食品组合物包括如下式1所示的化合物或其可食用的盐作为活性成分:
式1
其中R1和R2各自独立为氢或卤素,R3为氢、卤素、未取代或被卤素取代的C1-C3烷基,X为卤素。
由于本发明中所述的式1化合物和使用该化合物改善的肝脏疾病已在上文描述,因此将省略其描述以避免过度重叠
在本说明书中,术语“可食用的盐”是指在通过静电吸引结合在一起的阳离子和阴离子组成的盐之间,可用于食品组合物的形式的盐,其具体示例包括上述“药学上可接受的盐”的示例。
当本发明所述组合物制备为食品组合物时,它不仅可以包含作为活性成分的本发明所述化合物,还可以包含在食品制备中通常会添加的碳水化合物、调味剂和调味剂。碳水化合物的实例包括,但不限于,单糖如葡萄糖和果糖,双糖如麦芽糖和蔗糖,多糖如糊精和环糊精,糖醇如木糖醇、山梨醇和赤藓糖醇。调味剂的例子包括天然调味剂[鲜奶素,甜叶菊提取物(例如,雷博地苷A,甘草酸苷等)]和合成调味剂(糖精,阿斯巴甜等)。例如,当本发明所述食品组合物制备成饮料时,除了作为本发明活性成分的松皮提取物外,它还可以包括柠檬酸、液体果糖、糖、葡萄糖、醋酸、苹果酸、果汁、杜仲提取物、枣提取物、甘草提取物等。
根据本发明的另一个方面,本发明提供了一种用于预防或治疗代谢疾病的方法,所述代谢疾病选自下组:肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征,所述方法包括步骤:向受试者施用含有如下式1所示的化合物或其药学上可接受的盐作为活性成分的药物组合物。
式1
由于本发明中所述的式1化合物和使用该化合物改善的肝脏疾病已在上文描述,因此将省略其描述以避免过度重叠。
根据本发明的另一个方面,本发明提供了一种用于改善或减轻代谢疾病的方法,所述代谢疾病选自下组:肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征,所述方法包括步骤:向受试者施用含有如下式1所示的化合物或其可食用的盐作为活性成分的食品组合物。
式1
其中R1和R2各自独立为氢或卤素,R3为氢、卤素、未取代或被卤素取代的C1-C3烷基,X为卤素。
由于本发明中所述的式1化合物和使用该化合物改善的肝脏疾病已在上文描述,因此将省略其描述以避免过度重叠
根据本发明的另一个方面,本发明提供了一种筛选用于预防或治疗代谢疾病的药物组合物的方法,所述代谢疾病选自下组:肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征,所述方法包括以下步骤:
(1)将测试物质与含有表达去泛素酶细胞的生物样品接触,其中去泛素酶选自下组:泛素特异性蛋白酶(USP)25、USP28或其组合;和
(2)测量样品中去泛素酶的活性或表达水平,
其中,当去泛素酶的活性或表达水平降低时,确定测试物质为用于预防或治疗代谢紊乱的组合物。
由脂质代谢异常(如肥胖)引起的代谢疾病与USP25或USP28酶之间的相关性尚不清楚。根据本发明,本发明人通过观察本发明所述化合物(已报道可抑制USP25和USP28活性)抑制脂肪细胞分化和减少脂质积累,首次提出USP25和USP28酶可作为代谢疾病的治疗靶点。
在提及本发明所述筛选方法时使用的术语“测试物质”是指用于筛选以检查其是否在基因或蛋白质水平上影响USP25/28的活性或表达水平的未知物质。测试物质的示例包括但不限于化合物、核苷酸、抗体、反义RNA、小干扰RNA(siRNA)和天然产物提取物。随后,测量用测试物质处理的生物样品中USP25和/或USP28的表达水平或活性。表达水平的测量可通过本领域已知的各种免疫测定方法或各种基因检测方法进行,基因检测中采用针对序列已知基因的专门设计的引物或探针。作为测量的结果,当USP25和/或USP28的表达水平或活性降低时,可将测试物质确定为用于预防或治疗代谢紊乱的组合物。
在本说明书中,术语“表达水平或活性降低”是指USP25和/或USP28的表达水平或独特的体内功能降低到一定程度,各种脂质代谢指标,包括体重、体脂肪质量、肝脂质重量和白色脂肪重量降低到可测量的水平。活性降低不仅包括简单的功能下降,还包括由于稳定性下降而导致的活性最终降低。具体而言,术语“表达水平或活性降低”可指与对照组相比,活性或表达水平降低至少20%,更具体地说是至少40%,甚至更具体地说是至少60%的状态。
有利效果
本发明的特点和优点总结如下:
(a)本发明提供了一种用于预防或治疗代谢疾病的药物组合物和功能性食品组合物,其包括苄基乙醇胺衍生物作为活性成分。
(b)本发明的组合物细胞毒性很低或没有,同时通过显著抑制脂肪细胞分化和脂质积累来降低代谢疾病指标,因此可作为代谢疾病的有效治疗剂,即使长期服药时副作用也很少。
附图简述
图1显示了0、0.1、1、5、10和25μM AZ1化合物处理的3T3-L1细胞和未处理对照细胞的活力分析结果。
图2为AZ1化合物处理3T3-L1细胞后,通过Oil-Red-O染色观察脂肪细胞分化(图2a)和测量脂肪累积量(图2b)的结果。
图3为AZ1化合物处理3T3-L1细胞后,测量与脂肪细胞分化和脂质累积有关的因子PPARg、C/EBPa和FASN的蛋白表达水平(图3a)和mRNA表达水平(图3b)的结果。
发明方式
以下,本发明将参考实施例更为详细地描述。这些实施例只是为了更详细地解释本发明,对于本领域技术人员来说,显而易见的是本发明的范围根据本发明的主题不受这些实施例的限制。
实施例
实验方法
细胞毒性测定
3T3-l1细胞接种于含有10%牛血清(Gibco)和1%青霉素-链霉素(Gibco)的DMEM(Welgene)的96孔板中,在37℃、5% CO2条件下培养24小时。然后用浓度分别为0、0.1、1、5、10和25μM的AZ1化合物处理细胞。48h后,在每个细胞培养液中加入10μL EZ-Cytox,孵育30min,用酶标仪测定450nm处吸光度。
脂肪细胞分化研究
3T3-l1细胞以6×104个细胞/孔的细胞密度接种于含有10%牛血清(Gibco)和1%青霉素-链霉素(Gibco)的DMEM(Welgene)的6孔板中,在37℃、5% CO2条件下培养48小时。当细胞融合度达到100%时,去除原有培养基,加入新鲜的DMEM(10%牛血清,1%青霉素-链霉素),再培养48小时。然后,再次取出现有培养基,用含有诱导分化物质(胰岛素、地塞米松、3-异丁基-1-甲基黄嘌呤)和AZ1(0、0.1、1、5、10、25μM)的DMEM(10%胎牛血清和1%链霉素)处理细胞。48小时后,用含有胰岛素和AZ1(0、0.1、1、5、10和25μM)的DMEM(10%胎牛血清(Gibco)和1%链霉素)替代培养基。48小时后,再次用含有AZ1(0、0.1、1、5、10和25μM)的DMEM(10%胎牛血清(Gibco)和1%链霉素)替换培养基。48小时后,当分化完成时,收集细胞,用于基因和蛋白表达分析。
脂肪细胞染色和脂质累积测定
分化完成后,去除3T3-L1细胞的培养基,PBS洗涤细胞,10%福尔马林固定20分钟。去除福尔马林后,用蒸馏水清洗,然后干燥。将油-红-O(Sigma)溶于100%异丙醇中,制备100%油-红-O原液,再与蒸馏水混合,制备60%油-红-O溶液。用60%的油-红-O溶液处理细胞,孵育30分钟。染色完成后,用蒸馏水洗涤细胞三次。然后,用100%异丙醇处理细胞,使油-红-O染料溶解,然后用微孔板仪测定500nm处的吸光度。
基因表达水平测定
分化完成后,3T3-L1细胞用1mL易蓝(内含子)处理,然后用匀浆机切碎。加入200μL氯仿,与细胞混合均匀,孵育3分钟后,在4℃下,13200rpm离心15分钟。离心后,仅将上清液转移至新鲜管中,加入等量异丙醇,与之混合均匀。孵育10分钟后,在4℃下,13200rpm离心10分钟。去除上清后,用70%乙醇洗涤RNA小球,在4℃下13200rpm离心5分钟。去除上清,将RNA颗粒干燥10分钟后,将RNA颗粒溶解在不含RNA酶的水中。
用逆转录酶RT混合物(ReverTraAce RT master mix,TOYOBO)将提取的RNA合成cDNA,然后用实时PCR系统(ABI)检测基因表达变化。所使用的引物组总结如下表1所示。
表1
基因 | 方向 | 引物序列 |
PPARg | 正向 | 5’-AGGGCGATCTTGACAGGAAA-3’ |
PPARg | 反向 | 5’-CGAAACTGGCACCCTTGAAA-3’ |
C/EBPa | 正向 | 5’-GTGACTTTGACTACCCGGGA-3’ |
C/EBPa | 反向 | 5’-GGGGCTCTTGTTTGATCACC-3’ |
FASN | 正向 | 5’-TGGGTTCTAGCCAGCAGAGT-3’ |
FASN | 反向 | 5’-ACCACCAGAGACCGTTATGC-3’ |
蛋白表达水平测定
分化完成后,将3T3-L1细胞加入RIPA缓冲液(Biosesang)中,1.5mL EP管收集,然后裂解。将细胞裂解液在冰上孵育20分钟,然后在4℃下以13200rpm离心25分钟。离心后,将上清液转移到新鲜EP管中,用考马斯亮蓝Bradford试剂(赛默飞世尔科技,Thermo FisherScientific)定量上清液中所含蛋白质的量。将等量的蛋白放入新鲜EP管中,加入5X SDS样品缓冲液,在100℃下加热5分钟,制备样品用于蛋白质印迹(Western blotting)。蛋白质样品在SDS聚丙烯酰胺凝胶上电泳,然后转移到PVDF膜(默克)。将PVDF膜用5%脱脂牛奶阻断1小时,将一抗(Santacruz)加入5% BSA溶液中,倒在膜上,在4℃下进行O/N反应。用PBST洗涤3次,每次10分钟后,加入含二抗(Bethyl)的5%脱脂牛奶,孵育1小时。然后,用PBST洗涤3次,每次10分钟,然后用ECL溶液(Bio-Rad)孵育膜,用LAS(Vilber)检测蛋白。
实验结果
细胞毒性测定(WST分析)
用0、0.1、1、5、10和25μM AZ1化合物处理的细胞与未处理的细胞之间的活力没有显著差异(图1)。因此,证实AZ1在所有处理浓度下都没有表现出细胞毒性。
脂肪细胞染色和脂质累积测定
通过对3T3-L1细胞的油-红-O染色证实,与未处理的细胞相比,5μM及以上AZ1处理的细胞的脂肪细胞分化明显降低(图2a)。此外,在5μM或更高的浓度下,AZ1呈浓度依赖性减少脂质积累(图2b)。
基因和蛋白质表达水平测定
研究证实,与未添加AZ1的对照组相比,添加5μM及以上AZ1处理的3T3-L1细胞中与脂肪细胞分化和脂质积累相关的PPARg、C/EBPa和FASN的所有蛋白表达水平(图3a)和mRNA表达水平(图3b)均呈浓度依赖性显著降低。
尽管本发明已经参照具体特征进行了详细描述,但是对于本领域技术人员来说,显而易见的是,该描述仅是其优选实施例,并且不限制本发明的范围。因此,本发明的实质范围将由所附权利要求书及其等同物界定。
Claims (10)
1.一种用于预防或治疗代谢疾病的药物组合物,其中所述代谢疾病选自下组:肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征,所述药物组合物包括如下式1所示的化合物或其药学上可接受的盐作为活性成分:
式1
其中R1和R2各自独立为氢或卤素,R3为氢、卤素、或未取代或被卤素取代的C1-C3烷基,X为卤素。
2.如权利要求1所述的组合物,其中,在式1中,R1是氢,R2是氟,R3是被卤素取代的C1-C3烷基,X为溴。
3.如权利要求2所述的组合物,其中,R3是三氟甲基。
4.如权利要求1所述的组合物,其中,血脂异常是高脂血症。
5.如权利要求1所述的组合物,其中,脂肪肝是非酒精性脂肪肝。
6.一种用于改善或减轻代谢疾病的食品组合物,其中代谢疾病选自下组:肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征,所述食品组合物包括如下式1所示的化合物或其可食用的盐作为活性成分:
式1
其中R1和R2各自独立为氢或卤素,R3为氢、卤素、未取代或被卤素取代的C1-C3烷基,X为卤素。
7.如权利要求6所述的组合物,其中,在式1中,R1是氢,R2是氟,R3是被卤素取代的C1-C3烷基,X为溴。
8.如权利要求6所述的组合物,其中,R3是三氟甲基。
9.一种筛选用于预防或治疗代谢疾病的药物化合物的方法,所述代谢疾病选自下组:肥胖、糖尿病、血脂异常、脂肪肝和胰岛素抵抗综合征,所述方法包括以下步骤:
(1)将测试物质与含有表达去泛素酶细胞的生物样品接触,其中去泛素酶选自下组:泛素特异性蛋白酶(USP)25、USP28或其组合;和
(2)测量样品中去泛素酶的活性或表达水平,
其中,当去泛素酶的活性或表达水平降低时,确定测试物质为用于预防或治疗代谢疾病的组合物。
10.如权利要求9所述的组合物,其中生物样品含有脂肪细胞或其培养物。
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