CN105744934B - 用于预防或治疗血脂异常的化合物和包含这类化合物的组合物 - Google Patents
用于预防或治疗血脂异常的化合物和包含这类化合物的组合物 Download PDFInfo
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Abstract
本发明涉及医学领域。更具体来说,本发明涉及化合物在预防和/或治疗对象中的血脂异常中的用途,所述血脂异常通常与脂肪酸、尤其是饱和长链脂肪酸和/或固醇在生物膜中、包括在非脂肪细胞的生物膜中的过量存在相关联。本发明还涉及包含这类化合物的组合物、特别是药物组合物和食品增补剂或补充剂,以及所述组合物在预防和/或治疗血脂异常中的用途。本发明的化合物和组合物尤其可以被有利地用于预防和/或治疗选自代谢综合征和/或代谢综合征特有的症状或异常的病理状态,优选被用于预防或治疗2型糖尿病或脂肪肝。
Description
技术领域
本发明涉及医学领域。更具体来说,本发明涉及化合物在预防和/或治疗对象中的血脂异常中的用途,无论所述血脂异常是食物来源的还是与细胞缺氧相关的,所述血脂异常通常与脂肪酸、尤其是饱和长链脂肪酸和/或固醇在生物膜中、包括在非脂肪细胞的生物膜中的过量存在相关联。本发明还涉及包含这类化合物的组合物、特别是药物组合物和食品增补剂或补充剂,以及所述组合物在预防和/或治疗血脂异常中的用途。本发明的化合物和组合物尤其可以被有利地用于预防和/或治疗选自代谢综合征和/或代谢综合征特有的症状或异常的病理状态,优选被用于预防和/或治疗2型糖尿病(T2DM)或脂肪肝。
背景技术
胰岛素抗性、胰岛素缺乏、高血糖症、高胆固醇血症、特别是以低HDL胆固醇浓度为特征的高胆固醇血症、高甘油三酯血症、高血压、心力衰竭和脂肪肝属于代谢综合征特有的症状或异常。
代谢综合征(在不存在治疗的情况下)被具体并典型地定义为出现下述5种异常中的至少3种:腹部肥胖,高甘油三酯血症(TG≥约1.7mM),低HDL胆固醇浓度(对男性来说HDLc<约1mM,对女性来说<约1.3mM),高血压(BP≥约130/85mm Hg)和禁食血糖≥约5.5mM(参见“Syndrome métabolique et diabète chez l’homme.Composition lipidique etoxidation des lipoprotéines de basse densité(DL)plasmatiques en relation avecl’activation des plaquettes sanguine”-Romain Colas的论文稿件-2010年12月10日答辩)。血脂异常参与代谢综合征的发生,这已经知道几十年了。
血脂异常通常被定义为脂类、通常为游离或非酯化脂肪酸、固醇(例如胆固醇)、甘油三酯或磷脂的异常高或低的血液浓度。大多数血脂异常表现为这些要素的水平提高,降低要罕见得多。
非酯化脂肪酸(NEFA)或游离脂肪酸(FFA)是生物体的重要能量组分。它们由双键数目和构成烃链的碳原子数目不同的脂肪酸的复杂混合物构成。内源起源的这些脂肪酸通过细胞质内的生物合成来形成,并在脂肪组织和肝脏中以乙酰CoA的形式用于甘油三酯的合成,或者被细胞氧化。它们也进入构成生物膜的结构性脂类例如磷脂和鞘脂的组成。在细胞质中发现了占NEFA的85%的主要4种脂肪酸:油酸,棕榈酸,亚油酸和硬脂酸。大多数NEFA结合于白蛋白。它们来自于脂肪组织的甘油三酯,所述甘油三酯在禁食期间,在组织和血液中的脂蛋白脂肪酶的作用下被水解成甘油和脂肪酸。它们的浓度随着年龄、食物摄入和体育锻炼而以大比例变化。一般来说,在餐后时间段,它们的释放被抑制。
固醇是具有甾烷核的脂类,所述甾烷核的3位碳带有羟基。固醇被视为甾类化合物的一个亚类。胆固醇,最常见和广泛的固醇之一,对细胞功能来说是至关重要的,并且是维生素和脂溶性甾类激素的前体。
通常,血液中异常高的脂类浓度对应于生物膜中异常高的脂类浓度(“细胞性血脂异常”)。例如,血液中异常高的饱和游离脂肪酸(NEFA)浓度对应于生物膜的磷脂中异常高的饱和酯化脂肪酸(EFA)浓度。这些脂类总是与特定蛋白质相结合存在,以便形成脂蛋白。血脂异常起因于脂类动态平衡的调节障碍。
已确立,过度富含动物脂肪的饮食尤其导致饱和脂肪酸(SFA)在生物膜中的积累(脂中毒),并且这在细胞水平上引起膜的可塑性的整体破坏,然后引起细胞的代谢失活,并从长远来看引起细胞凋亡(图1)。
迄今为止,已知只有不饱和脂肪酸(UFA)、特别是油酸(橄榄油)能够反击与SFA积累相关的毒性的有害效果(Cunha等,2008;Diakogiannaki等,2008;Katsoulieris等,2009;Pineau等,2009;Stein等,1997;Wei等,2006;Deguil等,2011)。然而,它们作为功能食品和/或药物的用途遇到两个主要限制。首先,UFA具有本质上预防性特性,因此在治疗已确立的脂中毒、即造成所有膜机制的破坏(可以在蛋白质分泌途径的每一步中检测到)的脂中毒的背景中重要性有限。事实上,UFA通过在摄入食物时与SFA在膜磷脂(PL)的合成中直接竞争而起作用。第二,对于不能转化(缓冲)过量游离脂肪酸、尤其是UFA并在之后将其储存在中性脂类、通常为甘油三酯(TG)和/或酯化的固醇中的细胞来说,显示出UFA毒性。对于例如由于不存在4个乙酰基转移酶Lro1p、Dga1p、Are1p和Are2p而在其中观察到中性脂类合成的调节障碍的酵母菌株来说,情况正是如此。当将这种突变菌株暴露于外源UFA源时,脂类调节障碍表现为细胞内膜的大量增生,并最终表现为通过不依赖于未折叠蛋白质响应(UPR;参见下文)的过程而出现的细胞死亡(Kohlwein&Petschnigg,2007;Petschnigg等,2011)。有趣的是,在哺乳动物细胞中可以观察到一致的现象(Listenberger等,2003)。这解释了为何不饱和脂肪酸在脂中毒条件下,在细胞将不饱和脂肪酸作为中性脂类储存的能力被超过这样一种状态(所谓的“代谢失活的”脂中毒的细胞)之前变得对所述细胞有毒,或者在正常条件下对具有非常弱的合成TG的能力的细胞例如胰腺非β细胞变得有毒(Cnop M等,2001)。因此,在人类中,除了脂肪细胞(单独地能够合成并储存中性脂类)之外的所有细胞类型都可能被脂中毒光顾。尤其是,已知与SFA积累相关联的破坏导致负责胰岛素合成的胰腺β–细胞(Butler等,2003)或肝细胞(Egnatchik等,2014)的凋亡。
在2型糖尿病(T2DM)的情形中,SFA积累的影响出现在各种不同器官中,并且尤其表现为胰腺中的胰岛素缺乏(与上面描述的胰腺β–细胞凋亡相关),但是也表现为肝脏和肌肉中的胰岛素抗性。
目前,据估计全世界有3亿8千2百万糖尿病个体。尽管几十年前就已确立脂类动态平衡调节障碍的参与,但大多数当前疗法聚焦于胰岛素分泌水平或血糖水平。具体来说,几种分子被用于治疗2型糖尿病。对每位患者测试这些分子,然后如果它们被证明无效,依次用新的分子(根据它们对体重的影响和其他潜在副作用)代替。按照法国药物安全管理局(French drug safety agency)AFSSAPS 2006年的推荐,首先和首要地使用甲福明(一种双胍)以便降低胰岛素抗性而不引起低血糖症。其次,可以使用胰岛素分泌药剂例如基于磺胺的降血糖药或美格替奈类药物。此外,自从2008年起,DPP–4抑制剂(gliptins)和其他GLP–1类似物(肠降血糖素模拟物)也已出现在可用于校正血糖而在血脂异常的背景中没有利益的产品的范围内。最后,作为最终手段,开出胰岛素注射剂处方。
所提到的策略都不能从根本上恢复脂中毒的细胞和器官的功能性,因此不能干预在代谢综合征或2型糖尿病中遇到的一系列有害效应中通常在由现有治疗所靶向的每个步骤上游的早期步骤。旨在刺激“患病”器官的生理功能的当代治疗方法甚至可能事与愿违地造成它们的弱化,并且解释了在许多患者中使用的药物的无效性和抗性现象随时间的出现。
本发明人现在描述了通过作用于在所有脂中毒的组织中常常改变的现象——膜的可塑性而用于预防在生物膜中出现血脂异常、通常为脂肪酸、尤其是饱和脂肪酸和/或固醇的细胞积累,或用于治疗已确立的血脂异常的分子或化合物,以及包含这类分子或化合物的组合物。
发明内容
本发明涉及用于预防或治疗与由脂肪酸、通常为饱和脂肪酸(SFA)和/或固醇、尤其是饱和长链脂肪酸和/或反式脂肪酸引起的脂中毒相关的疾病的一类新的分子。长链脂肪酸通常是指碳链包含至少14个碳原子,通常为14至24个之间的碳原子,例如至少16或至少18个碳原子,通常为14至22个之间或14至18个之间的碳原子的脂肪酸。
脂中毒可以显示为生物膜中存在的磷脂(PL)中饱和脂肪酸/不饱和脂肪酸(SFA/UFA)的比例倒转,SFA变得占优势,甚至完全代替UFA。因此,本发明的分子通常用于预防或治疗血脂异常、代谢综合征、代谢综合征特有的症状或异常,优选地用于预防或治疗2型糖尿病或脂肪肝。
与现有技术中用于补偿饱和脂肪酸(SFA)过量的不饱和脂肪酸(UFA)、特别是油酸相比,本发明的分子(或化合物)的相当大的优点在于与前者不同,它们不引起任何细胞毒性,特别是对不能合成中性脂类的细胞、通常为非脂肪细胞例如胰腺细胞的任何毒性。本发明的分子的另一个主要优点在于,与在现有技术中预防性使用的UFA不同,由于它们通过例如作用于膜的可塑性而恢复细胞功能性的能力,它们也可以治疗性使用。因此,它们可以有利地用于治疗已确立的血脂异常,即造成可检测的细胞功能障碍、通常为细胞执行其天然功能的能力的改变、甚至是失能(代谢失活)的血脂异常。
因此,本发明的特定目的涉及一种用于预防或治疗对象中的血脂异常的化合物,所述化合物包含具有至少一个羟基基团的极性头部,所述极性头部上接枝有包含16至24个之间、例如16至22或16至20个之间的碳原子并具有1至6个、例如3个处于顺式构型的不饱和键的单个不饱和脂肪酸。血脂异常通常影响生物膜,包括非脂肪细胞的生物膜。它通常与饱和脂肪酸、更具体为饱和长链脂肪酸和/或固醇在所述生物膜中的过量存在有关联。当例如饱和脂肪酸和/或固醇通过降低膜的可塑性而引起细胞功能障碍时,它的量尤其被视为过量。在本发明的优选实施方式中,所述化合物i)不允许在被治疗细胞的膜中产生双不饱和磷脂,尤其是不造成在所述膜中引入双不饱和磷脂,通常不在被治疗细胞中恢复与相应的未脂中毒的细胞的膜磷脂的脂肪酸组成可比的膜磷脂脂肪酸组成,ii)对于被治疗细胞来说不是油酸的来源,通常不是能够恢复被治疗细胞的膜的可塑性的油酸的来源,并且优选地iii)不诱导细胞内钙动员和/或不被脂肪酶降解。
本发明的另一个目的涉及一种用于预防或治疗对象中的血脂异常、通常为如上所定义的血脂异常的化合物,所述化合物的极性头部是式(I)的结构:
其中:
-A是氮或氧原子,优选为氧原子,
-n等于2或3,优选地n等于2,并且
-R是任何化学基团。
本发明的i)不允许在被治疗细胞的膜中产生双不饱和磷脂或不造成在所述膜中引入这类磷脂,通常不在被治疗细胞中恢复与相应的未脂中毒的细胞的膜磷脂的脂肪酸组成可比的膜磷脂脂肪酸组成,以及ii)对于被治疗细胞来说不构成油酸的来源,通常不构成能够恢复被治疗细胞的膜的可塑性的油酸的来源的优选化合物的实例,选自二缩甘露醇单油酸酯、3–羟基–2,2–双(羟甲基)丙基油酸酯和N,N–二乙醇油酰胺(与例如1–油酰基溶血磷脂酸或LPA不同)。
本发明的不诱导细胞内钙动员的优选化合物的实例是二缩甘露醇单油酸酯和3–羟基–2,2–双(羟甲基)丙基油酸酯。与用于诱导细胞钙动员的参比分子OAG(Marin&Cooper,2006)或1–油酰基甘油和2–油酰基甘油(Iwasaki等,2008)不同,这些化合物的特别有利之处在于它们具有由细胞内钙依赖性有害过程例如增殖或凋亡引起的毒性的较低风险(Stutzmann GE等,2011)。
本发明的抵抗脂肪酶的降解作用的优选化合物的实例是N,N–二乙醇油酰胺。
本发明还涉及本文中所描述的化合物,其用于预防或治疗代谢综合征,通常为代谢综合征特有的至少一种症状或异常,优选地至少两种或三种症状,所述症状选自胰岛素抗性、胰岛素缺乏、高血糖症(通常禁食血糖≥约5.5mM)、高胆固醇血症、尤其是以低HDL胆固醇浓度(通常对于男性来说<约1mM,对于女性来说<约1.3mM)为特征的高胆固醇血症、高甘油三酯血症(通常TG≥约1.7mM)、高血压(通常血压(BP)≥约130/820mm Hg)、心力衰竭和脂肪肝,优选地选自胰岛素抗性、高血糖症(通常禁食血糖≥约5.5mM)、高胆固醇血症、尤其是以低HDL胆固醇浓度(通常对于男性来说<约1mM,对于女性来说<约1.3mM)为特征的高胆固醇血症、高甘油三酯血症(通常TG≥约1.7mM)、高血压(通常血压(BP)≥约130/820mmHg)、心力衰竭和脂肪肝。具体目的涉及本发明的用于预防或治疗2型糖尿病的化合物。
本发明的特别优选的化合物是二缩甘露醇单油酸酯,其发明人已使用通过饱和脂肪酸进行脂中毒的哺乳动物胰腺β–细胞显示,所述化合物通过在患有脂中毒和/或2型糖尿病的对象中促进胰岛素原向胰岛素的成熟,能够有利地提高所述对象中的胰岛素分泌。
本发明还涉及包含至少一种本发明的化合物的组合物,其为药物组合物、功能食品或食品增补剂的形式。具体目的通常涉及一种药物组合物,其除了包含所述至少一种本发明的化合物之外,还包含至少一种具有治疗活性(并且被本领域技术人员公认如此)的其他化合物(不同于本发明的化合物)。
本发明还涉及这类组合物在预防或治疗对象中的血脂异常中的用途,所述血脂异常通常为生物膜、包括非脂肪细胞的生物膜中的血脂异常,尤其是与脂肪酸、更具体为饱和长链和/或反式脂肪酸和/或固醇在所述生物膜中的过量存在相关联的血脂异常。本发明还涉及这类组合物在预防或治疗对象中的代谢综合征、优选地在预防或治疗2型糖尿病中的用途,所述代谢综合征通常为代谢综合征特有的至少一种症状或异常,优选为几种症状(例如2、3、4或5种)。所描述的用途也可以有利地与至少一种其他治疗活性化合物(被本领域技术人员公认为具有治疗活性并且不同于本发明的化合物)相组合来执行,特别是用于治疗代谢综合征,通常为代谢综合征特有的至少一种症状或异常和/或2型糖尿病。
详细描述
本发明人显示,来自于外源来源(饮食)或内源来源(缺氧或由突变引起的脂肪酸去饱和步骤的改变)的SFA积累在构成细胞膜的磷脂中,因此通过改变介入蛋白质分泌途径的细胞内细胞器的功能性而破坏大量过程(参见图1)。
为了提供这个证明,本发明人开发了一种简单的单细胞模型(从baker的酿酒酵母(Saccharomyces cerevisiae)精心设计的hem1Δ菌株),其重现了在哺乳动物细胞中观察到的SFA和胆固醇的所有效应,尤其是参与代谢综合征的发生的所有异常(Pineau等,2008和Pineau等,2009)。
在YPG培养基(即既不含麦角固醇(Erg)也不含油酸(Ole)的培养基)中,hem1Δ菌株在其磷脂、尤其是磷脂酰胆碱(PC)中积累饱和脂肪酸(尤其是棕榈酸,C16:0)。应该指出,麦角固醇是酵母中存在的主要固醇,因此它在酵母中等同于人类中的胆固醇。
其中负责甘油三酯和固醇酯合成的酶的编码基因被缺失的四倍体突变(QM)菌株(Petschnigg等,2009)进而不能将外源供应的油酸C18:1类型的游离脂肪酸转化成中性酯类,使得这种供应由于它所产生的膜可塑性平衡的破坏而引起有害胁迫。特别是,QM菌株的使用能够使本发明人执行清楚地显示出油酸在这种环境中的毒性的毒性试验(参见图4)。
更确切来说,本发明人在hem1Δ菌株上观察到细胞内细胞器膜中带有饱和链的磷脂(饱和PL)和胆固醇的积累对分泌囊泡形成的负面影响。这种脂中毒(内源性的,因为hem1Δ菌株的细胞体系仅仅合成SFA)破坏内质网(ER)膜的脂类环境,在所述ER中改变蛋白质折叠过程(错误折叠),然后引发复杂的响应,这种响应被称为未折叠蛋白质响应(UPR)。这种后备系统的饱和引起凋亡性细胞死亡。并行地,本发明人能够观察到高尔基体囊泡化的破坏和参比蛋白(ex.:Fur4p)在高尔基体与质膜之间的运输的改变。具体来说,本发明人观察到由脂中毒造成的整个分泌途径的改变。换句话说,hem1Δ酵母菌株使他们能够证实SFA对ER胁迫和蛋白质向质膜的运输的影响两者。
内质网(ER)参与几种基本细胞过程,包括脂类合成、钙动态平衡的调节以及旨在用于各种不同细胞器和细胞表面的蛋白质(例如膜蛋白例如离子通道和转运蛋白)的合成。ER也是膜或分泌蛋白被组装和折叠的位点。因此,UPR通过使ER能够管控错误折叠的蛋白质的积累,在维持该细胞器的完整性和功能性方面发挥必不可少的作用(Kincaid&Cooper,2007;Zhang&Kaufman,2006)。应该指出,在胰腺β–细胞(在哺乳动物中负责胰岛素合成)中,SFA毒性与未折叠蛋白质响应的诱导相关(Cunha等,2008;Diakogiannaki&Morgan,2008;Laybutt等,2007)。Alkhateeb等(2007)和Kato等(2008)进一步观察到SFA积累改变胰岛素受体和葡萄糖转运蛋白Glut4在肌肉细胞表面上的寻址。
Schneider等(1999)观察到内质网(ER)和高尔基体的膜绝大部分由不饱和磷脂(PL)构成,但是在分泌途径中最远端的区室中饱和PL的水平逐渐增加,并在质膜中达到其最大值。高的不饱和PL水平表现为高的膜流动性,这对召集某些对囊泡形成来说必不可少的蛋白质而言是关键参数。典型实例由Arf–GAP1家族的蛋白质提供,一种是酵母中的Gcs1p。已显示,Gcs1p是高尔基体与ER之间以及ER与质膜之间的囊泡转运两者的介导物(Robinson等,2006)。有趣的是,GCS1基因的缺失引起高尔基体的破碎和后高尔基体囊泡运输的破坏(Poon等,2001),本发明人自身在hem1Δ酵母模型中,即在SFA积累条件下能够观察到同样多的这些现象(参见Payet等,2013)。
Arf–GAP1家族的蛋白质通过经由被称为ArfGAP1脂质堆积传感器(ALPS;(Bigay等,2005))的特定基序被吸附在膜表面上,而对膜的曲度做出响应。具体来说,ALPS基序不识别膜曲度本身,即弯曲的几何形状,而是识别作为膜曲度的结果的磷脂极性头部的松散堆积(松散脂质堆积)(Bigay等,2005)。本发明人成功地显示,在脂中毒条件下高的饱和PL水平与膜脂质堆积的提高有关(Deguil等,2011),并且这种提高改变了Gcs1p被高尔基体从细胞质的召集(Payet等,2013)。更通常地,他们显示,脂肪酸、尤其是SFA在生物膜中的积累引起细胞内细胞器(包括高尔基体和内质网(ER))的功能性调节障碍,尤其是较低的囊泡化程度,所述较低的囊泡化程度造成某些膜转运蛋白和受体在细胞表面上的易位减少。
由本发明人引起的细胞脂中毒起因于在体外暴露于专一地采取饱和形式的脂肪酸的外源来源(“外源”脂中毒),或起因于细胞固有地不能产生不饱和形式的脂肪酸(“内源”脂中毒)。
使用他们的hem1Δ酵母模型,本发明人显示,油酸(Ole)通过被代谢成磷脂(PL)(参见图1,属于SFA的PL的减少,有利于属于UFA的PL),恢复了事先被SFA脂中毒的膜的可塑性。他们还使用QM酵母菌株显示,观察到的有益效应限于能够缓冲中性脂类形式的过量外源UFA的细胞。在不具有这种能力的细胞中,过剩的外源油酸最终引起细胞内膜的异常增生,其通过胁迫细胞而触发细胞的凋亡。
本发明人使用他们的hem1Δ酵母模型和QM菌株来筛选可能阻止或限制这种现象,理想地对抗过量存在和/或代谢(即酯化)不良的脂肪酸的有毒效应并校正所有被破坏的现象的目标分子。因此,他们发现了具体来说能够将细胞功能恢复(例如通过恢复膜的流动性)到与非病理状态下所遇到的相当的水平的分子。
然后,本发明人在哺乳动物胰腺β–细胞、特别是大鼠胰腺β–细胞(BRIN–BD11细胞系)中测试并显示了由本发明人预先选择的分子的有效性,即它们即使在已确立的血脂异常的情况下将细胞功能恢复到与非病理状态下所遇到的相当的水平的能力。此外,本发明人能够证实,目标化合物对负责诱导细胞增殖和凋亡的细胞现象例如钙动员具有非常有限的影响。因此,它们与相反地诱导或促进这种细胞钙动员的化合物例如OAG相比毒性更低。同样地,某些化合物显示出在哺乳动物胰腺β–细胞、尤其是小鼠胰腺β–细胞(MIN6细胞系)中,在恢复胰岛素原向胰岛素的转化方面特别有效。
因此,本发明涉及一种用于预防或治疗对象中的血脂异常的化合物,所述化合物包含具有至少一个羟基基团的极性头部,所述极性头部上接枝有包含16至24个之间、例如16至20个之间、通常为18个碳原子并具有1至6个、例如3个处于顺式构型的不饱和键的单个不饱和脂肪酸(在本文中被鉴定为“目标化合物”)。
所关注的对象是动物,通常为哺乳动物,例如选自小鼠、大鼠、猪和人类的哺乳动物。所关注的对象优选为人类。
在本说明书的上下文中,寻求预防或治疗的血脂异常通常影响生物膜,尤其是非脂肪细胞的生物膜。它通常与脂肪酸、更具体为饱和长链和/或反式脂肪酸和/或固醇在所述生物膜中的过量存在相关联。血脂异常通常通过降低甚至抑制非脂肪细胞的质膜和/或其细胞器膜的流动性,在所述细胞的功能障碍或凋亡的源头处造成所述细胞的中毒(脂中毒)。
在本发明的特定实施方式中,血脂异常与所述对象中代谢综合征、通常为代谢综合征的至少一种症状、优选为至少两种或三种症状的存在相关,所述症状选自胰岛素抗性、胰岛素缺乏、高血糖症(通常禁食血糖≥约5.5mM)、高胆固醇血症、尤其是以低的HDL胆固醇浓度(通常对于男性来说<约1mM,对于女性来说<约1.3mM)为特征的高胆固醇血症、高甘油三酯血症(通常TG≥约1.7mM)、高血压(通常血压(BP)≥约130/820mm Hg)、心力衰竭和脂肪肝,优选地选自胰岛素抗性、高血糖症(通常禁食血糖≥约5.5mM)、高胆固醇血症、尤其是以低的HDL胆固醇浓度(通常对于男性来说<约1mM,对于女性来说<约1.3mM)为特征的高胆固醇血症、高甘油三酯血症(通常TG≥约1.7mM)、高血压(通常血压(BP)≥约130/820mm Hg)、心力衰竭和脂肪肝。
正如可以从本说明书看到的,脂肪酸、尤其是SFA和/或固醇的“过量存在”的表述,与“脂中毒”例如外源脂中毒或内源脂中毒(例如缺氧)同义,并且是指非脂肪细胞中存在的尤其是饱和和/或反式脂肪酸和/或固醇的量足以破坏上面描述的分泌途径,并因此改变细胞功能(通常为蛋白质分泌途径以及因此所述蛋白质的功能),或者作为结果在更高水平上改变相应器官的功能。
例如,当饱和脂肪酸、尤其是饱和长链脂肪酸储存在肾脏和近曲小管的细胞中时,出现肾脏脂中毒。这种储存引起小管间质炎症和纤维化,甚至引起肾衰竭,并且在最严重的病例中引起所关注对象的死亡。作为另一个实例,胰腺的脂中毒通常通过饱和脂肪酸、尤其是饱和长链脂肪酸在胰腺β–细胞的膜磷脂中的储存来诊断。
在细胞尺度上,脂中毒通常通过检测生物膜的磷脂(PL)(特别是磷脂酰胆碱(PC)的磷脂物质)的脂肪酸含量变化来诊断,具体来说,通过属于UFA的PL形式的消耗以有利于属于SFA的PL来诊断。在本说明书的实验部分中所描述的程序的图片中,在提取总细胞脂类,纯化它们的磷脂并对后者进行质谱分析后,可以显示出这种脂类组学特征(Deguil等,2011)。
此外,这种细胞脂中毒可以因未折叠蛋白质响应(UPR)的诱导而出现。如实验部分中所示,通过分析在启动子序列中含有特异性针对在所述响应触发期间特征性诱导的基因、例如选自CHOP、BiP、GRP78和ATF4的基因(Laybutt等,2007)的一个或多个、例如4个UPR元件(UPRE)的报告基因(例如编码酶活性可以被定量的β–半乳糖苷酶的lacZ基因)的表达,可以在体外检测和测量该UPR。或者,UPR对脂中毒做出响应的触发,可以通过定量该细胞事件级联中某些关键蛋白质的活性形式的比例来检测和测量。eIF2α蛋白的情况就是如此,其磷酸化的活性形式的丰度与UPR活化状态成比例。正如在实验部分中解释的,磷酸化活性形式的量可以通过在western印迹后获得的图像的密度测量来评估(Dhayal&Morgan,2011)。
在本发明的情形中,可以通过检测或测量如上解释的参与UPR的基因的表达或蛋白质的活性,有利地检测或测量UPR。
特定目标化合物是如上所定义的化合物,其极性头部是式(I)的结构:
其中:
A通常是氧原子或NR1基团,其中R1=H或任选被OH取代的C1–C6烷基,并且A优选为氧原子或NH或NCH3或NCH2CH2OH,更优选地A是氧原子,
n=2或3,优选地n=2,并且
R是任何化学基团,并且在不同(CHR)基团之间可以不同。
在式(I)中,由锯齿线打断的键代表极性头部与不饱和脂肪酸的碳链之间的键,式(I)的C=O基团是不饱和脂肪酸的C=O。
优选地,R是只包含碳、氢和氧原子的基团。
优选地,R是只包含碳、氢和氧原子的饱和基团。
优选地,(CHR)n-OH基团是甘油、赤藓糖醇或单糖例如甘露糖的衍生物。
在本发明中,每个羟基基团可以被独立地磷酸化。
可以在本发明的背景中用于预防或治疗血脂异常的目标化合物的实例被鉴定如下:
1–油酰基–2–乙酰基–sn–甘油(OAG),
1–油酰基–sn–甘油–3–磷酸酯(1–油酰基溶血磷脂酸或LPA),
2–花生四烯酰甘油(2–AG),
二缩甘露醇单油酸酯,
3–羟基–2,2–双(羟甲基)丙基油酸酯,
N,N–二乙醇油酰胺,
丙二醇单油酸酯,
1–油酰基甘油,
2–油酰基甘油,
与三甘油的油酸单酯,
(Z)–9–十八烯酸–(2,2–二甲基–1,3–二氧戊环–4–基)甲基酯,
二乙二醇单油酸酯。
可以在本发明的背景中用于预防或治疗血脂异常的目标化合物选自例如1–油酰基–2–乙酰基–sn–甘油(OAG)、1–油酰基–sn–甘油–3–磷酸酯(1–油酰基溶血磷脂酸或LPA)、2–花生四烯酰甘油(2–AG)、二缩甘露醇单油酸酯、3–羟基–2,2–双(羟甲基)丙基油酸酯、N,N–二乙醇油酰胺、丙二醇单油酸酯、与三甘油的油酸单酯和(Z)–9–十八烯酸–(2,2–二甲基–1,3–二氧戊环–4–基)甲基酯。
优选地,可以在本发明的背景中用于预防或治疗血脂异常、特别是与代谢疾病例如2型糖尿病相关的脂中毒和/或缺氧性脂中毒的目标化合物,选自二缩甘露醇单油酸酯、3–羟基–2,2–双(羟甲基)丙基油酸酯和N,N–二乙醇油酰胺。
用于预防或治疗血脂异常、尤其是在代谢疾病和/或代谢综合征特有的症状或异常、优选为2型糖尿病的预防和/或治疗的背景中,特别优选的目标化合物是二缩甘露醇单油酸酯。
在本发明的背景中,目标化合物通常通过恢复生物膜的流动性,用于预防或治疗血脂异常。这些化合物的有利特点在于,与在现有技术中使用的不饱和脂肪酸不同,它们对不能合成中性脂类、通常为甘油三酯和/或酯化的固醇的细胞无毒。特别是,这些化合物对胰腺细胞(胰腺β–细胞和胰腺α–细胞)无毒。优选地,它们也对肾脏、肝脏、心脏和肌肉细胞无毒。此外,优选地,它们有利地能够恢复脂中毒的细胞以及如果需要、相关器官的功能。
本发明的典型目标化合物具有下述特性:
(i)它恢复酿酒酵母(Saccharomyces cerevisiae)的脂中毒的hem1Δ突变株的生长,
(ii)它降低或抑制未折叠蛋白质响应(UPR),
(iii)它对酿酒酵母(Saccharomyces cerevisiae)的四倍体突变株(QM)无毒性,和/或
(iv)它减少或抑制脂中毒的哺乳动物细胞的凋亡性死亡。
在本发明的背景中使用的特定化合物能够恢复酿酒酵母(Saccharomycescerevisiae)的脂中毒的hem1Δ突变株的生长和/或降低或抑制未折叠蛋白质响应(UPR),通常为由脂中毒诱导的UPR(不论所述脂中毒在本质上是内源还是外源的)。
在本发明的背景中使用的特定化合物对QM株酵母无毒性。
在本发明的背景中使用的特定化合物能够减少或抑制脂中毒的哺乳动物细胞的凋亡性死亡。
在所描述的可以在本发明的背景中使用的化合物中,一些化合物直接作用于脂类内含物,即作用于细胞膜中存在的磷脂的脂肪酸组成。这样的化合物的实例是1–油酰基–sn–甘油–3–磷酸酯(1–油酰基溶血磷脂酸或LPA)和丙二醇单油酸酯。
可以在本发明的背景中使用的其他化合物恢复膜的流动性并因此恢复膜的功能,而不恢复细胞膜中正常的双不饱和磷脂的组成。这类化合物的优选实例是1–油酰基–2–乙酰基–sn–甘油(OAG)。更优选的实例是二缩甘露醇单油酸酯、3–羟基–2,2–双(羟甲基)丙基油酸酯和N,N–二乙醇油酰胺。
在本发明的优选实施方式中,目标化合物被用于预防和/或治疗选自代谢综合征和/或代谢综合征特有的症状或异常的病理状态,优选地用于预防或治疗2型糖尿病。
在本发明的特定实施方式中,目标化合物被用于预防和/或治疗代谢综合征,通常为代谢综合征的至少一种症状,优选为至少两种或三种症状,所述症状选自胰岛素抗性、胰岛素缺乏、高血糖症(通常禁食血糖≥约5.5mM)、高胆固醇血症、尤其是以低的HDL胆固醇浓度(通常对于男性来说<约1mM,对于女性来说<约1.3mM)为特征的高胆固醇血症、高甘油三酯血症(通常TG≥约1.7mM)、高血压(通常血压(BP)≥约130/820mm Hg)、心力衰竭和脂肪肝,优选地选自胰岛素抗性、高血糖症(通常禁食血糖≥约5.5mM)、高胆固醇血症、尤其是以低的HDL胆固醇浓度(通常对于男性来说<约1mM,对于女性来说<约1.3mM)为特征的高胆固醇血症、高甘油三酯血症(通常TG≥约1.7mM)、高血压(通常血压(BP)≥约130/820mm Hg)、心力衰竭和脂肪肝。
正如上面解释的,对于2型糖尿病来说,当前的治疗方法靶向在最初的血脂异常下游介入的参数。尽管在实验室中在生理背景中得到验证,但这些治疗苦于缺乏有效性,这是由于在已确立的脂中毒的情况下提到的膜机制的整体破坏,特别是表现为改变或无效的膜流动性(其中所涉及的细胞不再有功能)。具体来说,目前不存在用于治疗影响不能合成中性脂类的细胞、尤其是非脂肪细胞的血脂异常的分子或化合物。
在本发明的优选实施方式中,本文中所描述的至少一种目标化合物被用于预防和/或治疗2型糖尿病。二缩甘露醇单油酸酯是优选地用于预防和/或治疗2型糖尿病的目标化合物的实例。
在本发明的特定实施方式中,该至少一种目标化合物可以与本领域技术人员已知且传统上用于2型糖尿病的预防或治疗的不同化合物相组合使用,所述不同化合物优选地选自双胍、格列酮、基于磺胺的降血糖药、格列奈、DPP–4抑制剂、肠降血糖素模拟物和α–葡萄糖苷酶抑制剂。
本发明的另一个目的还涉及一种药物组合物、功能食品、食品增补剂或补充剂形式的组合物,其包含至少一种本发明的目标化合物(在本文中被鉴定为“目标组合物”)。
特定目标通常涉及一种药物组合物,其除了包含所述至少一种本发明的目标化合物之外,还包含具有治疗活性(并被本领域技术人员公认如此)的至少一种其他化合物(不同于在本发明的背景中用于预防或治疗血脂异常而不在非脂肪细胞中引起毒性的目标化合物),尤其是在代谢综合征特有的症状或异常和/或2型糖尿病的预防或治疗中有活性的化合物(例如,如本文中所描述的)。
本发明还涉及一种本文中所描述的组合物,其用于预防或治疗血脂异常,通常为选自代谢综合征和/或代谢综合征特有的症状或异常的病理状态,优选地用于预防或治疗2型糖尿病。
术语“治疗”是指治愈性、症状性或预防性治疗。因此,本发明的化合物可用于患有所宣称的疾病的对象(例如哺乳动物,尤其是人类)。本发明的化合物也可用于延迟或减缓所述疾病的发展或阻止所述疾病的进一步发展,因此改善对象的状况。最后,本发明的化合物可以被预防性给药到尚未患病但通常情况下可能发生疾病或处于发生疾病的高风险中的对象。
本发明的目标化合物或组合物可以以各种不同方式和各种不同形式给药。
因此,在典型的实施方式中,将目标化合物一起或分开地给药到对象,并且本发明的目标化合物或组合物在整个治疗期间,即在被治疗的疾病的症状改善、优选地所有或一部分所述症状消失之前,被连续或顺序给药,每日一次或多次(每日给药),每周一次或多次(每周给药)或每月一次或多次(每月给药)给药。
如有必要,每日剂量可以例如以每日2、3、4、5、6或更多剂给药,或者在一日中经适合的间隔以多个子剂量给药。
所述化合物或组合物可以例如被全身性、经口、肠胃外、通过吸入或通过注射例如静脉内、腹膜内、肌内、皮下、透皮、动脉内注射等给药。作为长期治疗,优选的给药途径是舌下、经口、腹膜内或经皮。
所述组合物可以被配制成可注射悬液、油、栓剂、硬壳胶囊、软壳胶囊、气溶胶等,任选地利用盖伦形式或装置提供延长和/或延迟释放。对于注射剂来说,所述化合物一般被包装成液体悬液,其可以利用例如注射器或灌注来注射。
应该理解,流速和/或注射剂量可以由专业技术人员根据患者、疾病、给药方式等改变。一般来说,化合物的每日剂量是获得治疗效果所需的最小量。治疗性组合物中存在的所述化合物的量可以被调整,以便获得对于特定患者、组合物、给药方式来说获得所需治疗效果并且优选地对患者无毒性所需的活性成分循环水平。所选的量取决于多种因素,尤其是给药途径、给药持续时间、给药时间点、化合物的消除速率、与化合物组合使用的各种不同产品、患者的年龄、体重、身体状况和医疗史,以及医学中已知的任何其他信息。
通常,被给药的化合物的剂量在每次给药1μg至2g之间,优选地在每次给药0.1mg至1g之间变化。此外,本发明的组合物可以进一步包含如上解释的其他药剂或活性成分。本发明的组合物也可以包含一种或多种可药用赋形剂或载体。可以提到的是例如与制药用途相容并且为专业技术人员所知的盐水、生理溶液、等渗溶液和缓冲溶液等。所述组合物可以含有选自分散剂、增溶剂、稳定剂、防腐剂等的一种或多种药剂或载体。
本发明还涉及用于预防或治疗对象中的血脂异常的方法,所述方法包括向患有血脂异常或可能发生血脂异常的对象给药本文中所描述的用于预防或治疗所述血脂异常的目标化合物或组合物。
本发明还涉及用于在对象中预防或在患病对象中治疗选自代谢综合征、代谢综合征特有的症状或异常和2型糖尿病的病理状态的方法。这些方法都包括向患有这类病理状态或可能发生这类病理状态的对象给药本文中所描述的用于预防或治疗所述疾病的目标化合物或组合物的步骤。
下面的图和实施例说明本发明但不限制其范围。
附图说明
图1:分泌途径和膜的可塑性
在合成后,膜或分泌的蛋白质(细胞的分子“工具”)必须在细胞内部经历成熟步骤。这个被称为“分泌途径”的过程的每个步骤发生在特定的亚细胞区室(尤其是内质网(ER)和高尔基体)中。因此,为了获得成熟蛋白质,需要各种不同内膜系统之间的功能性细胞内转运。除了其他方面之外,这种流通受到细胞内区室膜的可塑性影响,所述膜的可塑性本身直接与构成膜的磷脂(PL)的本性相关。特别是,已确认PL中饱和脂肪酸(SFA)的存在降低膜的流动性,而带有不饱和脂肪酸(UFA)的PL形成流动性更高的膜。
在具有缓冲中性脂类(以脂类小滴(LD)形式储存的甘油三酯(TG)或酯化的固醇(ES))形式的过量外源UFA的能力的细胞中,观察带油酸(Ole)的有益效果。在不具有这种能力的细胞中,过剩的外源油酸酯最终导致细胞内膜的增生,其通过引起细胞胁迫而触发凋亡。
图2:高等真核生物中的UPR途径(Pineau&Ferreira,2010)。
图3:油酸、OAG和LPA恢复脂中毒的酵母的生长。
A)油酸、OAG和LPA的分子结构。B)在浓度逐渐增加的油酸、OAG和LPA存在下,在SFA积累条件下生长的hem1Δ酵母的生长的恢复(3天后)。
图4:OAG和LPA对不合成甘油三酯的细胞无毒。
将OAG、LPA或油酸的液滴(5μl)从所指明浓度的储用溶液沉积在事先铺有QM菌株的琼脂培养基的表面上。3天后,在油酸的情况下可以观察到生长抑制晕圈(不存在菌落)。然而,在LPA或OAG存在下没有观察到这些晕圈。
图5:OAG和LPA在脂中毒的酵母中降低未折叠蛋白质响应(UPR)。
如Pineau等,(2009)所述,将带有融合基因的质粒构建物导入到hem1Δ酵母菌株中,所述融合基因对应于置于含有4个UPR元件(UPRE)的人工启动子控制之下的lacZ基因的编码序列。在UPR诱导期间,转录因子Hac1p/XBP1p被激活并结合于融合基因的UPRE,导致lacZ基因的转录。由于lacZ编码β–半乳糖苷酶,因此UPR诱导水平通过检测相应的酶活性来测量。hem1Δ酵母菌株生长在诱导SFA积累并且没有其他添加物的液体培养基或如所示增补有200μM油酸、OAG或LPA的同样培养基中。
图6:在饱和脂肪酸存在下,OAG通过降低UPR诱导水平来阻止胰腺β–细胞的凋亡。
如Dhayal&Morgan(2011)所述,在对照条件下或在饱和脂肪酸的外源来源(200μM棕榈酸)存在下生长胰腺β–细胞BRIN–BD11,以便在添加或不添加OAG情况下产生脂中毒状况。A)对于浓度逐渐提高的OAG,在不存在(对照)或存在棕榈酸的情况下估算死细胞的比例。B)在存在或不存在OAG的情况下,还通过western印迹在各种不同条件下分析了eIF2α的磷酸化水平,并将其归一化到总eIF2α。由于磷酸化水平与UPR强度相关,因此这个实验显示OAG降低由棕榈酸积累诱导的UPR。
图7:3–羟基–2,2–双(羟甲基)丙基油酸酯和二缩甘露醇单油酸酯不诱导钙动员。
将人上皮细胞CFBE用荧光钙探针进行装载,然后暴露于100μM OAG、3–羟基–2,2–双(羟甲基)丙基油酸酯、二缩甘露醇单油酸酯或N,N–二乙醇油酰胺。然后记录与细胞内钙移动相关的荧光强度的变化(参见Vachel等,2013)。获得的结果表明,3–羟基–2,2–双(羟甲基)丙基油酸酯和二缩甘露醇单油酸酯与OAG相比对细胞钙储存的消耗具有非常弱的影响(即它们不诱导细胞的钙动员),因此这些化合物具有非常有限的细胞毒性的风险。
图8:在饱和脂肪酸存在下,3–羟基–2,2–双(羟甲基)丙基油酸酯、二缩甘露醇单油酸酯和N,N–二乙醇油酰胺阻止胰腺β–细胞的凋亡。
如Dhayal&Morgan(2011)所述,在饱和脂肪酸的外源来源(200μM棕榈酸)存在下生长胰腺β–细胞BRIN–BD11,以便产生脂中毒状况,然后添加3–羟基–2,2–双(羟甲基)丙基油酸酯、二缩甘露醇单油酸酯或N,N–二乙醇油酰胺。与图6的数据合在一起,这些结果表明三种目标化合物阻止脂中毒诱导的胰腺β–细胞的死亡。
图9:在哺乳动物胰腺β–细胞中,在脂中毒状况下二缩甘露醇单油酸酯恢复胰岛素原的成熟。
如Boslem等(2011)所述,在对照条件下或在400μM棕榈酸的外源来源存在下(P)将胰腺β–细胞MIN6生长48小时,以便产生脂中毒状况。在生长的最后24小时期间,如所述添加或不添加200μM OAG、LPA或二缩甘露醇单油酸酯。在这些条件下,对蛋白质样品进行western印迹,得到的结果表明在脂中毒状况下,只有二缩甘露醇单油酸酯恢复胰岛素原向胰岛素的成熟。
图10:N,N–二乙醇油酰胺抵抗脂肪酶的水解活性。
将OAG(15μmol)和N,N–二乙醇油酰胺进行(+)或不进行(–)在37℃下暴露于10U脂肪酶30分钟。在温育后,从样品提取脂类物质,然后通过薄层层析进行分离。目标分子物质被注明,并且结果表明与OAG不同,N,N–二乙醇油酰胺抵抗脂肪酶的水解。
实施例
A/酵母菌株和哺乳动物细胞系
表1中列出的酿酒酵母(Saccharomyces cerevisiae)菌株被用于生长恢复的各个不同试验,用于证实毒性,用于细胞磷脂的脂肪酸含量分析,并用于未折叠蛋白质响应(UPR)触发的试验。
也在大鼠胰腺β–细胞系BRIN–BD11中分析UPR的活化状态和脂中毒诱导的细胞死亡。
此外,钙动员试验在人上皮细胞CFBE上进行,胰岛素成熟实验在小鼠胰腺β–细胞系MIN6上进行。
表1:所使用的酵母菌株
B/hem1Δ酵母的脂中毒
将带有hem1Δ突变的菌株在好氧条件下,在振摇和28℃下生长在液体YPGA培养基(增补有80μg/mlδ–氨基乙酰丙酸(ALA)的YPG(1%酵母提取物(w/v),1%蛋白胨(w/v)和2%葡萄糖(w/v)))中。通过转移到YPG+培养基(增补有80μg/ml麦角固醇的YPG,以补偿在这种条件下获得的固醇消耗),通过其合成依赖于血红素(特别是Ole1p酶的辅基)的存在的不饱和脂肪酸(UFA)的消耗,造成由饱和脂肪酸(SFA)引起的脂中毒。脂中毒可以在固体YPG+培养基+2%琼脂(w/v)上通过每cm2转移3500个细胞(来自于YPGA中的预培养物的hem1Δ),或在液体培养基中通过接种2·106个细胞/ml YPG+来诱导。典型情况下,在转移到YPG+培养基后7小时分析SFA脂中毒的效应。进而在用细胞接种后,在YPG+转移培养基上(或其中)添加化合物后,相继评估该化合物对抗SFA脂中毒的有害效应的能力。
C/由棕榈酸引起的大鼠胰腺β–细胞的脂中毒
1)脂类试剂的制备:
将脂类物质制备在乙醇中,然后与牛血清白蛋白(BSA,首先剥除脂肪酸)通过在37℃温育1小时进行复合。通过添加一倍体积乙醇,然后将整体加热至70℃进行均质化,获得棕榈酸储用溶液。在室温下在100%乙醇中制备OAG和LPA溶液。对于哺乳动物细胞的温育来说,培养基中最终的BSA和乙醇浓度分别保持在1%和0.5%(w/v)。
2)细胞存活性试验:
将大鼠胰腺β–细胞系(BRIN–BD11)生长在含有11mM葡萄糖并增补有10%(v/v)胎牛血清(FCS)、2mM L–谷氨酰胺、100U/ml青霉素和100μg/ml链霉素的完全RPMI–1640培养基中。对于每个实验,首先将细胞以0.5·105个细胞/ml的密度接种在6孔板中24小时。然后,将完全培养基用缺少FCS但含有所需浓度的与BSA复合的目标脂类试剂的等同物替换。然后,在对照条件下,使用相同量的BSA和乙醇。在温育结束时,将所有细胞(死的和活的)收集并以300g离心5分钟。然后将细胞团块重悬浮在200μl培养基中,然后通过添加200μl20μg/ml的碘化丙啶(PI)在FACS缓冲液(磷酸盐缓冲盐水(PBS),2%(v/v)FCS,10mM叠氮钠)中的溶液,用PI对死细胞(已失去其质膜完整性)的DNA进行染色。在冰上温育10分钟后,通过流式细胞术分析由此获得的样品。使用Beckman Coulter EPICS XL MCL进行定量,使用FL3通道检测嵌入到DNA中的PI的发射,并且使用EXPO32 ADC软件(Applied Cytometry Systems,V 1.1 build 207)来进行分析。
3)Western印迹分析:
将BRIN–BD11细胞以0.5·105个细胞/ml的密度接种在T25培养瓶中24小时。正如上面指明的,然后将完全培养基用缺少FCS但含有目标脂类试剂的等同物替换。在温育6小时后,使用含有蛋白酶和磷酸酶抑制剂的裂解缓冲液(20mM Tris,150mM NaCl,1mM EDTA和1%(v/v)Triton–X)提取总蛋白。然后将这些蛋白质在12% Bis–TrisGels(Invitrogen)丙烯酰胺凝胶上进行电泳,随后转移到PVDF膜,然后使用稀释到1/1000的抗磷酸化eIF2α抗体(Cell Signaling(New England Biolabs))探测。接下来,将膜用缓冲液Re–Blot Plus–Strong(Millipore)剥脱,然后用稀释至1/1000的抗总eIF2α抗体(CellSignaling(New England Biolabs))第二次探测。使用与Quantify One软件相组合的Fluor–S MultiImager分析系统(Biorad UK Ltd),进行磷酸化或未磷酸化形式的eIF2α蛋白的相对丰度的密度测量分析。
D/胰岛素成熟的监测(参见图9)
以上面对BRIN–BD11细胞的脂中毒所描述的方式,将MIN6细胞系生长在增补有10%(v/v)胎牛血清(FCS)、15mM HEPES、100U/ml青霉素和100μg/ml链霉素的完全DMEM–高葡萄糖培养基(6mM)中,并通过暴露于400μM与BSA(终浓度0.92%(w/v))偶联的棕榈酸48小时,在添加或不添加目标化合物的情况下诱导脂中毒(参见Boslem等,2011)。然后收集细胞并如上所述使用抗胰岛素抗体进行western印迹,以便追踪胰岛素原向胰岛素的成熟。
E/钙动员试验(参见图7)
将人上皮细胞系CFBE在玻璃底培养皿上生长在增补有10%胎牛血清(FCS)、100IU/ml青霉素、100μg/ml链霉素和0.5μg/ml嘌呤霉素的MEM+GlutaMAXTM–1培养基(αMEM;Invitrogen)中。首先将细胞用3μM荧光钙探针Fluo–4–乙酰氧基甲基酯在室温下装载20分钟。然后利用Zeiss Axio Observer Z1倒置显微镜,使用250ms的激光刺激序列共4分钟,通过获取目标区域的荧光强度的变化来记录钙动员。然后使用Carl ZeissAxioVision Release 4.8.2软件和相关的生理获取模块来解释收集的数据。最后,通过用时间t时每个像素的强度(F)除以刺激之前所述像素的荧光强度(F0),将强度曲线归一化。由此获得的图像((F–F0)/F0)使得可以获得在整个记录期间钙强度/动员的曲线(参见Vachel等,2013)。
F/生长的恢复
1)化合物筛选:在诱导SFA脂中毒后(对于生长在固体培养基上的hem1Δ来说),将10mM的各种不同化合物在二甲基亚砜(DMSO)或乙醇(EtOH)中的溶液的5μl液滴沉积在琼脂表面上。在28℃培养3天后,通过在所述化合物沉积位点处hem1Δ菌落晕圈的出现,来估算化合物对抗脂类诱导的细胞生长的停止的能力(参见Deguil等,2011)。
2)增殖动力学:与SFA脂中毒的诱导联合(对于液体培养基中的hem1Δ来说),以200μM的初始浓度向培养物加入各种不同化合物。通过细胞密度的分光光度计测量,以定期的时间间隔(在观察期间每小时)监测增殖。在600nm波长处,1个光密度单位(OD600nm)对应于2·107个细胞/ml。
G/毒性试验
在好氧条件下,在振摇和28℃下,将野生型(WT)和四倍体突变(QM)菌株平行地生长在液体YPG培养基中,然后以每cm2 3500个细胞的密度接种YPG+2%琼脂(w/v)。在如此转移至固体培养基后,将1、10和100mM的各种不同化合物在DMSO或EtOH中的溶液的1μl液滴沉积在琼脂表面上。也分开地沉积DMSO和EtOH以便评估这两种溶剂的固有毒性。在28℃培养3天后,通过将沉积纯溶剂所获得的生长抑制晕圈直径与沉积各种不同浓度的测试化合物获得的生长抑制晕圈直径进行比较,来评估测试的化合物的毒性。与WT菌株不同,QM菌株不能缓冲脂类小液滴中中性脂类(甘油三酯(TG)或酯化的固醇(ES))形式的过量外源油酸。因此,在对于WT菌株来说不存在毒性的情况下,对于QM菌株来说观察到化合物的毒性表明该化合物被酵母视为游离脂肪酸的来源。
H/总脂类提取
从2·106个细胞/ml的初始细胞密度,将hem1Δ菌株在好氧条件下,在振摇和28℃下在液体培养基(YPGA、YPG+或YPG++200μM待测试化合物)中生长7小时。在培养结束时,收集108个细胞以便进行总脂类提取。在将细胞在4℃下悬浮在1ml蒸馏水中之后,加入500μl玻璃珠(0.6mm),然后使整体在摇床中经历3段20秒在5000rpm下的振摇(在3段中的每段之间将管保持在冰上)。向由此获得的细胞裂解物补充珠子洗涤溶液(1ml),然后转移到40ml玻璃管(CorexTM),随后使用2:1(v/v)的甲醇:氯仿比例进行脂类提取。首先加入6ml甲醇,并将整体涡旋振荡30秒,然后在65℃温育15分钟。一旦混合物冷却至室温,加入3ml氯仿,然后将整体再次涡旋振荡30秒,随后允许提取进行16小时。然后,将样品以10000g离心12分钟,随后将上清液转移到新的CorexTM管。在加入2ml氯仿、然后加入4ml蒸馏水后,将整体涡旋振荡30秒,然后以3000g离心8分钟。在除去得到的上层相后,将下层有机相收集在玻璃溶血管中。最后,在80℃和氮气流下蒸发溶剂,以便获得总细胞脂类样品。
I/磷脂纯化和质谱分析
将总细胞脂类样品重悬浮在1ml二氯甲烷中,同时涡旋振荡30秒。将整体沉积在用3ml甲醇、随后用2ml二氯甲烷相继预调制的二氧化硅柱(BOND ELUT–SI,100mg 1ml)上。然后,用2ml二氯甲烷,随后用3ml丙酮相继洗涤被柱保留的级分。最后,将2ml 50:45:5(v/v/v)的氯仿/甲醇/水混合物沉积在柱上,并将由此洗脱的磷脂收集在玻璃溶血管中。在80℃和氮气下蒸发溶剂,以便获得细胞磷脂样品。
在100μl混合物Mix-(2:1:1(v/v/v)的异丙醇/乙腈/水+1%(v/v)三乙胺)或混合物Mix+(2:1:1(v/v/v)的异丙醇/乙腈/水+1%(v/v)甲酸)中重悬浮后,通过电喷雾电离质谱术(ESI–MS)分别以负或正模式分析样品,并使用得到的结果分析各种不同磷脂物质的脂肪酸含量。
J/UPR触发试验
从2·106个细胞/ml的初始细胞密度,将用质粒pPW344[2μURA3 4×UPRE–lacZ(Patil等,2004)]转化的hem1Δ菌株在好氧条件下,在振摇和28℃下在液体培养基(YPGA、YPG或YPG+200μM待测试化合物)中生长7小时。在培养结束时,收集108个细胞以便定量由lacZ转入基因的表达(在UPR激活的情况下)产生的β–半乳糖苷酶(β–gal)活性。首先,将细胞重悬浮在1.5ml Z–缓冲液(60mM Na2HPO4,40mM NaH2PO4,10mM KCl,1mM MgSO4和50mMβ–巯基乙醇;溶液处于pH 7下)中,然后使用1/15的该悬液进行OD600nm测量。其次,向悬液增补100μl 0.1%(v/v)十二烷基硫酸钠(SDS)和200μl氯仿,然后在两个相继的30秒时间段中进行涡旋振荡。在倾析后,将400μl(体积V)由此获得的溶液转移到玻璃溶血管,然后增补600μlZ–缓冲液。然后加入200微升底物邻硝基苯基–β–半乳糖苷(ONPG)在Z–缓冲液中的4mg/ml溶液,随后将整体用涡旋振荡器均质化,然后在30℃水浴中温育以便起始反应。当整体具有浅黄色色彩时,在室温下通过加入500μl 1M Na2CO3将反应淬灭(在时间t时)。最后,在将样品以800g离心5分钟、然后将上清液收集在新的玻璃溶血管中之后,通过光谱测定法分别在420nm和550nm处测定反应产物(邻硝基苯酚)和细胞碎片。对于每个样品来说,使用公式U=(1000×[OD420nm–(1.75×OD550nm)])/(t×V×OD600nm)计算β–gal活性(U),其被表示为任意单位。
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Claims (9)
1.选自二缩甘露醇单油酸酯、3–羟基–2,2–双(羟甲基)丙基油酸酯和N,N–二乙醇油酰胺的化合物在制备用于预防或治疗对象中的代谢综合征的组合物中的应用。
2.选自二缩甘露醇单油酸酯、3–羟基–2,2–双(羟甲基)丙基油酸酯和N,N–二乙醇油酰胺的化合物在制备用于预防或治疗对象中的2型糖尿病或脂肪肝的组合物中的应用。
3.选自二缩甘露醇单油酸酯、3–羟基–2,2–双(羟甲基)丙基油酸酯和N,N–二乙醇油酰胺的化合物在制备用于预防或治疗胰岛素抗性、高血糖症、高胆固醇血症、高甘油三酯血症、高血压或心力衰竭的组合物中的应用。
4.选自二缩甘露醇单油酸酯、3–羟基–2,2–双(羟甲基)丙基油酸酯和N,N–二乙醇油酰胺的化合物在制备用于预防或治疗2型糖尿病的组合物中的应用,其中所述化合物与经典用于2型糖尿病的预防或治疗的不同化合物相结合使用。
5.权利要求4的应用,其中所述不同化合物选自双胍、格列酮、基于磺胺的降血糖药、格列奈、DPP–4抑制剂、肠降血糖素模拟物和α–葡萄糖苷酶抑制剂。
6.权利要求1至5任一项的应用,其中所述对象是动物。
7.权利要求1至5任一项的应用,其中所述对象为哺乳动物。
8.权利要求1至5任一项的应用,其中所述对象为人类。
9.权利要求1至5任一项的应用,其中所述组合物为药物组合物。
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- 2014-10-08 WO PCT/FR2014/052546 patent/WO2015052433A1/fr active Application Filing
- 2014-10-08 BR BR112016007536-6A patent/BR112016007536B1/pt active IP Right Grant
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- 2014-10-08 AU AU2014333636A patent/AU2014333636B2/en active Active
- 2014-10-08 CA CA2926582A patent/CA2926582C/fr active Active
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Patent Citations (1)
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WO2002083059A2 (en) * | 2001-04-11 | 2002-10-24 | Yeda Research And Development Co. Ltd. | Use of esters of long-chain fatty acids for treatment of autoimmune diseases |
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JP2016535727A (ja) | 2016-11-17 |
EP3065733A1 (fr) | 2016-09-14 |
US9821000B2 (en) | 2017-11-21 |
CA2926582A1 (fr) | 2015-04-16 |
JP6594866B2 (ja) | 2019-10-23 |
AU2014333636A1 (en) | 2016-05-05 |
CA2926582C (fr) | 2023-07-25 |
ES2682973T3 (es) | 2018-09-24 |
ES2674869T3 (es) | 2018-07-04 |
EP3065732A1 (fr) | 2016-09-14 |
JP2016535725A (ja) | 2016-11-17 |
US20160256429A1 (en) | 2016-09-08 |
BR112016007536A2 (pt) | 2017-09-26 |
AU2014333853A1 (en) | 2016-05-12 |
CN105828814A (zh) | 2016-08-03 |
WO2015052237A1 (fr) | 2015-04-16 |
FR3011467B1 (fr) | 2016-02-12 |
EP3065733B1 (fr) | 2018-05-30 |
PL3065732T3 (pl) | 2019-03-29 |
CN105828814B (zh) | 2019-04-19 |
CA2927951A1 (en) | 2015-04-16 |
WO2015052433A1 (fr) | 2015-04-16 |
CA2927951C (en) | 2022-08-30 |
EP3065732B1 (fr) | 2018-04-11 |
FR3011467A1 (fr) | 2015-04-10 |
JP6502335B2 (ja) | 2019-04-17 |
US20160287542A1 (en) | 2016-10-06 |
AU2014333636B2 (en) | 2019-12-05 |
CN105744934A (zh) | 2016-07-06 |
BR112016007536A8 (pt) | 2018-01-30 |
BR112016007536B1 (pt) | 2020-10-13 |
US10231985B2 (en) | 2019-03-19 |
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