CN104244938A - 4-氧代-2-戊烯酸和肝脏病症 - Google Patents
4-氧代-2-戊烯酸和肝脏病症 Download PDFInfo
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- CN104244938A CN104244938A CN201380018462.XA CN201380018462A CN104244938A CN 104244938 A CN104244938 A CN 104244938A CN 201380018462 A CN201380018462 A CN 201380018462A CN 104244938 A CN104244938 A CN 104244938A
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Abstract
本发明一般涉及具有健康益处的组合物。特别而言,本发明涉及治疗或预防肝脏病症。本发明的主题是用于治疗或预防肝脏病症的包含4-氧代-2-戊烯酸的组合物。本发明的另一主题是用于治疗或预防与肝脏中的II期酶活性不足有关的病症、包含4-氧代-2-戊烯酸的组合物。
Description
描述
本发明一般涉及具有健康益处的组合物。特别而言,本发明涉及治疗或预防肝脏病症。本发明的主题是用于治疗或预防肝脏病症的包含4-氧代-2-戊烯酸的组合物。本发明的另一主题是用于治疗或预防与肝脏中的II相酶活性不足有关的病症的包含4-氧代-2-戊烯酸的组合物。
肝脏是体内的最大器官。其充当体内化学工厂,执行很多生命机能–从调控化学物质在体内的水平到生产制备血凝块的物质。由于其在如此多的体内过程中的关键作用,与肝脏功能相关的病症是不健康的主要原因。根据British Liver Trust,肝脏疾病是在英格兰和威尔士中排在心脏、癌症、中风和呼吸疾病后的第五大“杀手”(http://www.britishlivertrust.org.uk,于2011年11月1日检索)。由于人们可在70%肝脏损伤下存活,所以存在来自肝脏疾病的患病率的巨大负担和来自肝相关的不健康的巨大的经济和人成本。
肝脏是负责异源性物质的生物转化和随后的解毒的主要器官。异源性物质是存在于体内但通常不被产生或不预期存在于其中的化学物质。术语异源性物质还是指以高于平常浓度存在的物质。为了在尿液中排泄亲脂性异源性物质,它们必须被制成水溶性的。亲脂性化合物至水溶性化合物的生物转化通常在体内以两个阶段发生:官能化,然后缀合。官能化使用氧以形成反应性位点并且被称为I期解毒。缀合导致将水溶性基团添加至反应性位点并且被称为II期解毒。存在许多催化II期解毒的酶,例如血红素氧合酶1、NAD(P)H脱氢酶醌1、谷胱甘肽还原酶、谷氨酸半胱氨酸连接酶、谷胱甘肽S-转移酶和UDP-葡萄醛酸基转移酶。因为肝脏的解毒中的主要作用,故肝脏中这些II期酶的活性特别重要。
用于治疗肝脏病症的现有治疗性干预是非常有限的。当病因可被鉴定时,那么去除该病因在预防和/或治疗中起重要作用。例如,当该病症归因于过度酒精消耗或肥胖时,那么戒酒或适当的生活方式和饮食变化是重要的。同样应建议人们采取预防措施以避免被病毒性肝炎感染。
氧化应激和炎症在肝脏疾病的发病机理中起关键作用,故已提出靶向这些疾病的化合物用于治疗或预防肝脏病症。例如,已显示奥替普拉(4-甲基-5-(2-吡嗪基)-3-二硫杂环戊二烯硫酮(dithiolethione))使小鼠肝脏免遭α-萘基异硫氰酸酯(ANIT)-诱导的胆汁郁积以及降低大鼠中黄曲毒素-诱导的肝癌发生。合成三萜系化合物2-氰基-3,12-二氧代齐墩果-1,9-二烯-28-酸(CDDO)可与相应的甲基(CDDO-Me)和咪唑(CDDO-Im)酯(C.D.Klaassen等人,Toxicology and Applied Pharmacology,244,57-65(2010))一起产生保肝作用。然而,这些化合物还可以产生不希望的作用;例如,奥替普拉的临床试验已显示显著副作用(Y.Zhang等人,Molecular CancerTherapeutics 3,885-893(2004))。因此具有可用于治疗或预防肝脏病症且没有现有技术中所述那些组合物的缺点的另外组合物将是可取的。特别而言,发现其活性成分从天然来源获得的有效组合物是高度可取的。
因此,本发明的目的是改良技术状态,特别而言是提供可用于治疗或预防肝脏病症的替代组合物。发明人惊讶地看到,可由独立权利要求的主题实现本发明的目的。从属权利要求进一步开发本发明的理念。
因此,本发明提供用于治疗或预防肝脏病症的包含4-氧代-2-戊烯酸的组合物。
本发明还提供4-氧代-2-戊烯酸在制备用于治疗或预防肝脏病症的组合物中的用途。
在本发明的范围内的“治疗”是指减少、抑制、减轻或改善。
4-氧代-2-戊烯酸具有CAS号4743-82-2和下列式
发明人惊讶地发现4-氧代-2-戊烯酸激活Nrf2。Nrf2(核因子(红细胞源性2)-样2)是细胞中抗氧化剂响应的主要调控因子。Nrf2在肝脏中的显著性是公认的,因为无Nrf2的小鼠的肝脏比野生型小鼠更易受各种氧化/亲电子应激-诱导的病理学影响(C.D.Klaassen等人,Toxicology and AppliedPharmacology,244,57-65(2010))。转录因子Nrf2在细胞的细胞溶质中发现并且结合于抑制剂Keap1。当结合于Keap1时,Nrf2还被蛋白酶体快速降解,因此其基底浓度低。在氧化应激发生时,从Keap1释放Nrf2。Nrf2浓度增加并且其易位到细胞核中。其刺激编码解毒酶的基因和抗氧化剂蛋白的表达,从而增加对氧化应激和亲电子剂的抗性。
反应性氧种类和氧化应激在发展肝病中起重要的作用(Y.-P.Wang等人,World Chinese Journal of Digestology,18,1907-1911(2010))。已知肝脏中Nrf2的激活治疗或预防肝脏病症。例如,Aleksunes(L.M.Aleksunes等人,Toxicologic Pathology,35,459-473(2007))和Klaassen(C.D.Klaassen等人,Toxicology and Applied Pharmacology,244,57-65(2010))的现有综述已将Nrf2激活与病症的治疗相关联。包括胆汁郁积性肝脏疾病、炎症性肝损伤、扑热息痛肝脏毒性、黄曲毒素-诱导的癌、化学物质-诱导的癌发生、乙醇-介导的肝脏毒性、肝纤维化、肝细胞细胞凋亡和重金属毒性,以及预防高脂肪饮食-诱导的体重、脂肪质量和肝脂质蓄积的增加。
Nrf2的激活可通过药理学方法来实现。例如奥替普拉、CDDO、CDDO-Me和CDDO-Im(上文论述的)导致经由Nrf2激活的保肝作用(C.D.Klaassen等人,Toxicology and Applied Pharmacology,244,57-65(2010))。
已描述存在于食物中的Nrf2激活化合物。这些化合物包括姜黄素(姜黄的一种主要组分)(US2009/0042980);于葡萄中发现的白藜芦醇(Chen CY等人,Biochem Biophys Res Commun 2005年6月17日;331(4):993-1000);于花椰菜中发现的莱服硫烷(F.Elbarbry等人,Journal of Medical PlantsResearch,5,473-484,(2011));于苹果中发现的槲皮素(Tanigawa S等人,Free Radic Biol Med 2007年6月1日;42(11):1690-703)和于大豆和咖啡中发现的染料木黄酮;于羽衣甘蓝(kale)中发现的山柰酚(kaempferol);于草莓和覆盆子(raspberry)中发现的鞣花酸(ellagic acid);以及绿茶中发现的表儿茶素类黄酮(B.H.J.Juurlink,Canadian Journal of Pharmacology,79,266-282(2001))。如同激活Nrf2,已均报道它们诱导II期酶。然而,Nrf2激活化合物以低水平存在于这些食物中,故将需要大量天然来源物质提取显著量的Nrf2激活化合物。姜黄素、白藜芦醇、莱服硫烷和槲皮素的非常低的水溶解度影响其生物利用度。因此,仍需要鉴定激活Nrf2的其它化合物,特别而言可从天然来源以显著量获得的化合物和具有良好的水溶解度的化合物。
已知Nrf2介导II期酶的诱导。因此,发明人调查了4-氧代-2-戊烯酸是否刺激编码II期酶的基因在肝脏中的表达。发明人发现4-氧代-2-戊烯酸激活在肝脏细胞(肝细胞)中下列II期酶的基因表达:血红素氧合酶1、NAD(P)H脱氢酶醌1、谷胱甘肽还原酶、谷氨酸半胱氨酸连接酶、谷胱甘肽S-转移酶和UDP-葡萄醛酸基转移酶。
肝脏中II期酶的活性不足已与如环境敏感性、药物不耐受性、肝脏的病理学解毒、慢性疲劳综合征和纤维肌痛的病症相关。包含4-氧代-2-戊烯酸的组合物提供治疗这些病症的方法。
已显示核转录因子κB(NF-κB)的抑制预防急性和慢性肝损伤(P.Muriel,Journal of Applied Toxicology,29,91–100(2009))。NF-κB是慢性免疫响应和炎症性疾病中的关键转录因子(P.J.Barnes等人,The NewEngland Journal of Medicine,336,1066-1078(1997))。NF-κB被多种刺激物激活,包括细胞因子、蛋白激酶C活化剂、病毒、免疫刺激物和尤其是反应性氧种类(F.Luft,Current Hypertension Reports,3,61-67(2001))。NF-κB由Rel蛋白的同二聚体和异二聚体组成。NF-κB的主要反式激活形式由p65和p50异二聚体组成。NF-kB的激活涉及通过特异性IκB激酶使抑制性蛋白IκB磷酸化和随后蛋白质降解。游离NF-κB传入细胞核,在那里它结合于在炎症中涉及的许多基因的启动子区中的κB位点。
已鉴定NF-κB抑制剂,如糖皮质激素(Adcock等人,American JournalPhysiology-Cell Physiology,268,C331-C338(1995)),但是当全身给予时糖皮质激素具有内分泌和代谢副作用。也已报道肝素抑制NF-κB(WO200119376),但是其具有潜在副作用,导致肝素诱导的血小板减少。
发明人调查了4-氧代-2-戊烯酸是否抑制NF-κB激活。使用暴露于促炎症性应激(LPS和rhTNF-α)的人结肠细胞和人单核细胞/巨噬细胞,他们发现4-氧代-2-戊烯酸抑制NF-κB激活。
发明人惊讶地发现4-氧代-2-戊烯酸可由天然来源获得,例如获自一些经过热处理的细菌株。例如,当在90℃加热6小时时短双岐杆菌CNCMI-3865和短双岐杆菌ATCC 15700TM的细菌制品均产生4-氧代-2-戊烯酸。发现在离心并过滤经过热处理的细菌制品后,4-氧代-2-戊烯酸存在于可溶性部分中。
短双岐杆菌CNCM I-3865于2007年11月15日保藏于COLLECTIONNATIONALE DE CULTURES DE MICROORGANISMES(CNCM),INSTITUT PASTEUR,25rue du Docteur Roux,F-75724PARIS Cedex 15,France。
短双岐杆菌ATCC 15700TM可商业获得,例如以ATCC 15700的商标获自美国典型培养物保藏中心(American type Culture Collection)(ATCC),Manassas,Virginia,USA。
因此,本发明部分涉及用于治疗或预防肝脏病症的包含4-氧代-2-戊烯酸的组合物,其中组合物不用作药剂。药剂是在药房中制备或分发且在医学治疗中使用的药物或药品(<URL:www.thefreedictionary.com/pharmaceutical/>[于2012年07月17检索])。本发明可以是用于治疗或预防肝脏病症的包含4-氧代-2-戊烯酸的食品组合物。肝脏病症可选自下组:肝炎;肝纤维化;胆汁郁积性肝脏疾病;炎症性肝损伤;生物异源物质毒性,包括药物-诱导的肝脏毒性和乙醇-介导的肝脏毒性;肝性脑病;脂肪肝脏疾病;缺血再灌注肝损伤;肝衰竭;1型遗传性酪氨酸血症;肝细胞癌,包括由肝炎、黄曲毒素和化学毒素诱导的那些;环境敏感性、药物不耐受性、慢性疲劳综合征和纤维肌痛,归因于过量负载毒素进入I期和低效II期途径;肝脏的病理学解毒及其组合。这些病症均具有氧化应激组分并且可通过肝脏中的Nrf2激活(常常与NF-κB抑制组合)来治疗。例如,包含4-氧代-2-戊烯酸的组合物可用于治疗或预防可通过肝脏中Nrf2激活治疗的病症。
肝炎是肝脏的炎症。一组被称为肝炎病毒的病毒引起全世界大多数情况的肝炎,但是其还可以归因于毒素、其它感染和自身免疫性疾病。
肝纤维化是指坚韧的纤维癜痕组织在肝脏中的蓄积并且是对肝脏的炎症或直接毒性损害的一个结果。
胆汁郁积是一种其中胆汁不能从肝脏流向十二指肠的疾患。其可作为很多药物的副作用获得。已显示Nrf2活化剂可用于治疗胆汁郁积性肝脏疾病,这不仅通过降低由胆酸积聚引起的氧化应激,而且通过调节Bsep(胆汁盐流出泵)蛋白来动员和分泌毒性胆酸。
肝细胞死亡可触发炎症性响应。这种炎症性响应的关键是促进反应性氧种类(ROS)形成。炎症是固有免疫响应于微生物感染和组织创伤的关键部分。然而,过度炎症性响应可导致炎症性肝损伤。
许多化合物可证实对肝有毒性并且导致肝脏病症。此类肝脏毒素的实例包括脂多糖;药物如扑热息痛(对乙酰氨基酚)合成代谢类固醇、一些抗生素和糖皮质激素;乙醇;溴苯;四氯化碳;硫代乙酰胺;呋塞米;鬼笔环肽;砷;五氯苯酚(PCB);吡唑;马来酸二乙酯;百草枯(paraquat);秋水仙碱;和过量的所谓的“重金属”如铁、锰、铝、汞、镉、铍和砷。
肝性脑病是通常由肝移除的毒性物质在血流中蓄积造成的意识模糊、改变意识水平或昏迷的发生。
脂肪肝脏疾病是其中甘油三酯脂肪的大液泡经由脂肪变性的过程于肝细胞中蓄积(肝脏脂质蓄积)的疾患。尽管具有多种原因,但是脂肪肝可被认为是在世界范围内在过度饮酒的人和肥胖的人(具有或没有胰岛素抗性的作用)中发生的单一疾病。脂肪的蓄积还可以伴有肝的进展性炎症。取决于酒精的贡献,脂肪肝可被称为酒精或非酒精脂肪肝脏疾病(或酒精或非酒精脂肪变性)。
再灌注损伤是在缺血或缺氧的时期后在血液供给返回组织时造成的组织损伤。缺血再灌注肝损伤在许多临床环境中发生,包括肝手术、移植、和随后流体复苏的出血性休克,导致显著性患病率和死亡率。其特征在于伴有内源性抗氧化剂耗竭的显著性氧化应激。
肝细胞癌(也称为恶性肝细胞瘤)是最常见类型的肝癌。大多数情况的肝细胞癌继发于病毒感染或肝硬化。肝细胞癌可以通过暴露于黄曲毒素而造成,黄曲毒素是遍及经济发展中国家的人类食物供给的普遍存在的污染物。黄曲毒素暴露使肝癌在被肝炎乙型病毒慢性感染的人中的风险成倍数增加。肝细胞癌还可以被化学毒素如除草剂、氯乙烯和砷所诱导。尽管化学癌发生是多因子的时,但是氧化应激是用于细胞转化的关键组分。
肝衰竭是肝不能执行其正常合成和代谢功能作为正常生理学的部分。
1型酪氨酸血症,也称为肝肾酪氨酸血症,由缺少延胡索酰乙酰乙酸水解酶而造成。
肝脏的病理性解毒是指一种其中I期和II解毒途径未处于平衡且I期相对于II期增加的疾患。环境敏感性、药物不耐受性、慢性疲劳综合征和纤维肌痛可归因于过量负载的毒素进入I期且II期途径低效。环境敏感性或多发性化学敏感性是由于人们不能耐受环境化学物质或一类生物异源化学物质而造成的慢性复发疾病。慢性疲劳综合征是一种或一组明显使人衰弱的医学病症,通常由持续疲劳伴有其它具体症状至少6个月而定义的病症,并非归因于持续劳累,并非通过休息来显著缓解,也不是由其它医学疾患引起。该病症还可以被称为肌痛性脑脊髓炎(myalgicencephalomyelitis)、病毒后疲劳综合征或慢性疲劳免疫机能紊乱综合征。纤维肌痛是特征在于慢性广泛疼痛和触诱发痛(一种对压力强烈且痛苦的响应)的医学病症。提供用于治疗或预防上文所述所有肝脏病症的组合物是有利的。
本发明提供用于治疗或预防与肝脏中II期酶活性不足相关的病症、包含4-氧代-2-戊烯酸的组合物。在本发明的范围内的“II期酶活性不足”包括活性不足以实现或保持II期解毒途径的正常健康的运行;活性不足以正确地平衡或补偿I期解毒途径的被干扰水平;和/或活性不足以通过处理异源性物质、包括药物、前药和毒素来控制、减少或预防慢性疾病。
II期酶可选自下组:血红素氧合酶1、NAD(P)H脱氢酶醌1、谷胱甘肽还原酶、谷氨酸半胱氨酸连接酶、谷胱甘肽S-转移酶、UDP-葡萄醛酸基转移酶及其组合。能够治疗或预防与这些II期酶的活性不足相关的病症是有利的。
血红素(heme)氧合酶或血红素(haem)氧合酶是催化血红素降解的酶。这产生胆绿素、铁和一氧化碳。有三种已知血红素氧合酶同工型。血红素氧合酶1(HO-1)是响应于如氧化应激、低氧、重金属和细胞因子的应激的可诱导同工型。NAD(P)H脱氢酶醌1(Nqo1)是胞质黄素蛋白。其催化内源性和生物异源化学物质的两个电子还原性代谢和解毒以及通过清除超氧化物来防御胞内氧化应激。谷胱甘肽还原酶(Gsr)是还原谷胱甘肽二硫化物为谷胱甘肽的酶,其是重要的细胞抗氧化剂。谷氨酸半胱氨酸连接酶(GCL)是谷胱甘肽生物合成途径的第一酶。GCL执行在谷胱甘肽合成中的限速步骤。GCL是由两种蛋白质组成的异二聚体酶:具有所有催化性质的谷氨酸半胱氨酸连接酶催化亚单位(Gclc),和增加Gclc的催化效率的谷氨酸半胱氨酸连接酶调节剂亚单位(Gclm)。谷胱甘肽S-转移酶(Gst)家族的酶由很多胞质、线粒体和微粒体蛋白质组成。Gst酶催化化学物质和亲电子种类与谷胱甘肽的缀合。这些缀合物随后被降解为巯基尿酸盐(mercapturates)并从体内排泄。UDP-葡萄醛酸基转移酶(UGT)催化生物异源和内源性化学物质与葡糖醛酸(II期解毒途径的主要部分)的缀合。
有利的是,可以向肝脏中I期酶的活性增加和/或肝脏中II期酶活性减少的对象施用本发明的组合物。I期酶和II期酶的活性应通常处于平衡,其中I期酶产生II期酶缀合并去除的反应性中间体。I期酶的活性增加且II期酶的活性没有相应增加、或II期酶的活性减少将破坏这个平衡并且产生较高水平的反应性中间体,后者可对DNA、RNA和蛋白质产生损伤。I期酶活性增加可例如由来自香烟烟雾的多环烃和来自在高温炙烤的肉的芳基胺引起。这些诱导Cyp1A1和Cyp1A2酶,导致I期活性大幅增加且II期酶未受或受极少诱导。抑制II期酶的常用机制是耗竭必要的辅因子。在人类中,硫酸化尤其易受由于受损的辅因子状态造成的抑制。硫酸储备必须通过饮食摄入含硫氨基酸或无机硫酸盐来保持。I期和II期酶活性之间的失衡可通过施用激活II期酶途径的组合物来弥补。
肝脏中的毒性负载增加可通过简单压制该系统并竞争解毒酶活性而导致解毒抑制。如果I期和II解毒途径变得过度负载,则毒素将在体内累积。这些毒素中的很多种是脂溶性的并且变得掺入体内的脂肪部分,它们可在体内存在数年。脑和内分泌腺是脂肪器官并且是脂溶性毒素蓄积的常见位点。这可产生脑功能障碍的症状和激素失调。因此,有利的是,本发明还提供向需要肝解毒的对象施用的包含4-氧代-2-戊烯酸的组合物。
过重或肥胖是熟知的病症,目前在我们社会中是个很大的负担。“过重”对于成年人被定义为具有体重指数(BMI)介于25至30之间。“体重指数”计算为重量(以kg计)除以身高(以米计)的比率的平方。
“肥胖症”是一种其中在贮存于动物、特别是人和其它哺乳动物脂肪组织中的天然能量储备增加至与某些健康状况或增加的死亡率相关的点的疾患。“肥胖”对于成年人被定义为具有大于30的BMI。
脂肪肝脏疾病作为与人口中的肥胖症和2型糖尿病的发病率增加相关的慢性肝脏疾病的最重要病因出现。非脂肪组织具有有限的供三酰甘油储存的容量,并且在营养过度的情况下,过量脂质蓄积,确定高水平的饱和脂肪酸,其可触发细胞功能障碍和/或细胞死亡,即为一种称为脂毒性的响应。该现象涉及反应性氧种类水平的升高。尤其,这种氧化还原失衡的特征在于谷胱甘肽显著耗竭(L.A.Videl等人,Trends in Molecular Medicine,12,555-558(2006))。谷胱甘肽的形成通过激活II期酶来促成,并且已知Nrf2活化剂减少高脂肪饮食-诱导的肝脏脂质蓄积增加(S.Shin等人,EuropeanJournal of Pharmacology 620,138-144(2009))。因此,有利的是,本发明还提供向过重和/或患有2型糖尿病的对象施用的包含4-氧代-2-戊烯酸的组合物。
在本发明中,4-氧代-2-戊烯酸是可获得的,例如获自天然来源。很多人关心在工业上由化工原料合成的材料的安全性,尤其在将摄入这些材料的情况下,并且优选获自天然来源的材料。
令人惊讶的是,发明人发现,一些菌株提供4-氧代-2-戊烯酸的天然来源。特别而言,发明人已发现4-氧代-2-戊烯酸可获自短双岐杆菌CNCMI-3865或短双岐杆菌ATCC 15700TM(短双岐杆菌的模式株)。将细菌用作4-氧代-2-戊烯酸的来源是尤其有利的,因为例如通过使用生物反应器可以生产大量4-氧代-2-戊烯酸。因此,在本发明中4-氧代-2-戊烯酸可以获得,例如获自短双岐杆菌CNCM I-3865或短双岐杆菌ATCC 15700TM。
该细菌可以在商业生产过程中在约60-180℃、优选在约80-160℃、例如在约110-150℃进行热处理。发明人发现,在这些温度的热处理在可接受的时间内提供令人满意的4-氧代-2-戊烯酸收率。不希望受理论束缚,应理解,热处理的温度越高4-氧代-2-戊烯酸形成速率增加,而且使其降解速率增加。因此,这些温度在4-氧代-2-戊烯酸的形成速率与其降解之间给出良好平衡。
包含4-氧代-2-戊烯酸的典型组合物可以包含至少1mg/kg组合物的量的4-氧代-2-戊烯酸。一般而言,如果组合物包含至少10mg/kg组合物、例如在50mg至50g/kg组合物之间的量的4-氧代-2-戊烯酸,则是优选的。
待施用的最佳量的4-氧代-2-戊烯酸可以由熟练技术人员容易地确定。
在治疗性应用中,以足以至少部分治愈或阻止病症和/或其并发症的症状的量施用组合物。足以完成此的量被定义为“治疗性有效剂量”。对于此目的有效的量将取决于本领域技术人员已知的许多因素,如病症的严重性以及患者的重量和一般状况。在预防性应用中,向易受特定病症影响或另外处于特定病症风险的患者施用足以至少部分减少发展病症的风险的量的根据本发明的组合物。此类量被定义为“预防性有效剂量”。而且,精确量取决于许多患者特异性因素如患者的健康状况和重量。
在本发明的框架中,4-氧代-2-戊烯酸可以以治疗性有效剂量和/或以预防性有效剂量施用。本发明的组合物可以以对应于2μg至20mg 4-氧代-2-戊烯酸/kg体重、优选20μg至2mg 4-氧代-2-戊烯酸/kg体重、例如40μg至1mg 4-氧代-2-戊烯酸/kg体重的日剂量施用。
肝脏病症可影响动物和人,例如肝炎是动物中的常见肝脏疾病。猫中最常见肝脏病症之一是猫肝脏脂质沉积症,也称为猫脂肪肝综合征。小玩具狗也可易受肝脏脂质沉积症影响。脂肪肝脏疾病还常见于例如奶牛和小鸡的家畜中。以与人类似的方法,存在很多可损害动物肝脏的毒素,包括药物如扑热息痛、阿司匹林、合成代谢类固醇、化学疗法药物、一些抗生素、糖皮质激素、麻醉剂、寄生虫防治药物和保泰松。物种之间存在代谢机制的差异,导致对一些肝脏病症的特定易感性。例如,因为猫缺少II期酶葡萄醛酸基转移酶,所以它们缀合化合物如吗啡和苯酚的能力受到影响。狗对糖皮质激素药物特别敏感并且将在多剂疗法后在肝脏中形成典型的病变。
因此,提供向人、宠物或家畜施用的组合物是有利的。在伴侣动物的情况下,此类治疗改良动物的整体生活质量,改良主人满意度并且改良主人与伴侣动物之间的联系。本发明的实施方案提供向人、宠物或家畜施用的组合物。
组合物的性质并不特别受限。其可以是用于口服或肠道施用的组合物。组合物可以是例如选自下组:食品组合物、食品添加剂、营养品(nutraceutical)、饮料、营养配方、管饲配方、在乳或水中重构的粉状组合物、和宠物食品组合物。
根据本发明的食品组合物具有不同特征,例如:乳、酸奶、奶酪、发酵乳、乳基发酵产品、冰淇淋、基于谷物的产品或发酵的基于谷物的产品、乳基粉末、冷冻的或耐贮藏的饮料、糖果、动物饲料,特别对于家畜。
食品组合物还可以进一步包含蛋白源、碳水化合物源、脂质源、矿物源和/或维生素源。蛋白质、碳水化合物、脂质、矿物和/或维生素的存在可具有数种优势。这些化合物通常促成最终产品的味道和口感。它们还为身体提供当其受肝脏病症影响时可急需的营养物。它们还允许将本发明的组合物配制成完整营养配方,以使无需另外的营养。
溶于水中的化合物具有以多种方式、包括作为溶液口服来方便施用的优势。包含4-氧代-2-戊烯酸的组合物可以是水基的,例如组合物可以包含溶解于水中的4-氧代-2-戊烯酸。
本领域技术人员应理解,他们可自由地组合本文公开的本发明的所有特征。特别而言,可以组合对于本发明的不同实施方案所述的特征。本发明的另外的优势和特征根据下列附图和非限制性实例是明显的。
图1示出短双岐杆菌ATCC 15700TM的粗制品(OD 50,在90℃加热6小时)的标准化荧光素酶活性。结果在y-轴上被表示成技术上一式三份的平均±SD。x-轴值为样品的最终稀释度。
图2示出短双岐杆菌CNCM I-3865的粗制品(OD 50,在90℃加热6小时)的标准化荧光素酶活性。结果在y-轴上被表示成技术上一式三份的平均±SD。x-轴值为样品的最终稀释度。
图3示出用0至200μM的剂量范围的4-氧代-2-戊烯酸温育的AREc32细胞的Nrf2诱导倍数(棒)和细胞活力百分比(线)。Nrf2倍数诱导为在4-氧代-2-戊烯酸存在下AREc32细胞的荧光素酶活性(RLU)与未暴露细胞的基底荧光素酶活性之间的比率。通过ATP定量测量的细胞活力表示为对照(未治疗)细胞的相对百分比。结果被表示为技术上一式三份的平均±SD并且代表四个独立实验。
图4示出用2.5至50%v/v的剂量范围的短双岐杆菌CNCM I-3865的“纯制品”温育的AREc32细胞的Nrf2诱导倍数(棒)和细胞活力百分比(线)。其它细节如图3所示。
图5示出与一定剂量范围的4-氧代-2-戊烯酸温育24h的肝细胞中II期酶的基因的mRNA表达谱。结果代表以技术上一式两份执行的两个实验并且表示为平均±SD。
图6示出通过用LPS刺激的HT-29克隆34细胞的上清液中测量SEAP(实心棒)和IL-8(条纹棒)的产生而估算的NF-κB活性。细胞活力用线示出。将细胞暴露于一定剂量范围的4-氧代-2-戊烯酸。结果被表示为两个以技术上一式三份执行的独立实验的平均±SD。
图7示出在一定剂量范围的4-氧代-2-戊烯酸存在下LPS刺激24h的(0.5μg/ml)THP-1蓝细胞的NF-κB活性(棒)和细胞活力(线)。结果被表示为两个以技术上一式三份执行的独立实验的平均±SD。
图8示出溶解于水中的4-氧代-2-戊烯酸标准品的典型色谱图。较高的SRM与m/z 113→69的跃迁反应相关联,而较低的SRM对应于m/z113→41的跃迁反应。保留时间以分钟(x-轴)表示。信号强度(y-轴)以Cps表示。
图9示出使用HPLC-ESI-MS/MS、在90℃(以圆形○表示)、120℃(以三角形△表示)和140℃(以正方形□表示)加热2、15、30和60分钟的短双岐杆菌CNCM I-3865(OD 40)的粗制品中的4-氧代-2-戊烯酸定量。
实施例1:通过4-氧代-2-戊烯酸和细菌部分的Nrf2激活
Nrf2报告基因测定:
使用Nrf2报告基因测定测量Nrf2的激活。该测定基于来自CRX生物科学(Dundee,Scotland)的AREc32细胞系,一种在ARE控制下含有荧光素酶基因构建体的稳定转染MCF7(乳腺癌)的细胞系。荧光素酶是消化荧光素并且产生荧光的酶。抗氧化分子如叔丁基氢醌(TBHQ)经由结合于ARE的Nrf2激活而诱导荧光素酶转录。荧光素酶活性使用荧光素酶试剂盒形式Promega(Madison,WI)来确定。荧光素酶活性与Nrf2激活成比例。
通过细菌部分的Nrf2激活:
使用三种细菌株来调查通过微生物的Nrf2激活:短双岐杆菌CNCMI-3865(NCC2950)、短双岐杆菌CNCM I-3914(NCC466)和短双岐杆菌ATCC 15700TM(NCC2791)。短双岐杆菌CNCM I-3914于2008年2月5日保藏于COLLECTION NATIONALE DE CULTURES DEMICROORGANISMES(CNCM),INSTITUT PASTEUR,25rue duDocteur Roux,F-75724PARIS Cedex 15,France。
对于各株,将10ml含有0.05%半胱氨酸的MRS琼脂用20μl甘油储液接种并在37℃在厌氧条件中温育过夜以形成预培养物。然后通过用预培养物接种10ml含有0.05%半胱氨酸的MRS制备另外的培养物(最终OD600调节为0.1)。将培养物在37℃在厌氧条件中温育16小时以形成P2培养物。将200ml含有0.05%半胱氨酸的MRS用P2培养物接种(最终OD600调节为0.1)且将瓶在37℃在厌氧条件中温育16小时。
测量OD600,将培养物以3300g离心10min且将细菌沉淀物用冷1XPBS(磷酸盐缓冲液盐水)洗涤两次且用1X PBS标准化至OD 50。
对于各细菌株,用两种方法获得细菌部分;“粗制品”和“纯制品”。
如下获得细菌“粗制品”。将5ml OD 50细菌制品在90℃于加热块(来自Techne,Staffordshire,United Kingdom的Dri-Block DB-3加热块)中加热6小时。将经过加热的细菌制品在+4℃以3300g离心10min,将上清液使用0.22μm注射器滤器过滤且在+4℃贮藏直至进一步分析。
如下获得细菌“纯制品”。将5ml OD 50细菌制品在+4℃以3300g离心10min且将细菌沉淀物用5ml水重悬浮。在冷藏室中使用迷你珠敲打(MBB)装置破坏细菌细胞(6个循环,以最大速度各90秒,每个循环之间停顿10min)。将经破坏的细胞在+4℃以3300g离心1h,将沉淀物用5ml 1XPBS重悬浮并且于加热块中在90℃加热6小时。将经过加热的制品在+4℃以3300g离心10min。将上清液使用0.22μm注射器滤器过滤并在+4℃储存直至进一步分析。
通过使用斑点法铺板来确定“OD 50悬液”的活菌计数,并使用具有下列设置的卤素水分分析仪(Metler-Toledo,Greifensee,Switzerland)确定干重:干燥温度为160℃且激活步阶干燥。
为了确定Nrf2激活,将样品在AREc32细胞(于96孔板中接种)中使用10个独立稀释(1/2、1/4、1/6、1/10、1/15、1/20、1/25、1/30、1/40和1/50)测试且于5%CO2/空气孵育箱中在37℃温育24小时。使用荧光素酶和来自Promega的Cell Titer-Glo试剂盒确定荧光素酶活性和细胞活力(ATP测量)。
对于每次运行,用所有板中仅细胞的荧光素酶活性的平均值将所有孔的以相对光单位(RLU)测量的荧光素酶活性标准化。在测试的所有样品中,发现标准化程序不影响数据,这种观察允许不同运行中测量的样品的比较。
对于每个样品,如下计算Nrf2激活:
1)Nrf2倍数诱导:
Nrf2倍数诱导对于筛选目的是非常有用的。然而,Nrf2倍数诱导仅仅是定性测量,因为该计算不考虑样品稀释。
2)每个样品的荧光素酶含量:
“每个样品的荧光素酶含量”还反映Nrf2激活,但可区分两个以类似Nrf2倍数诱导激活Nrf2的样品,因为该计算考虑样品稀释。
每个样品的荧光素酶含量通过反映Nrf2激活分子的量而允许Nrf2激活的半定量。
表A:标准化荧光素酶活性和短双岐杆菌ATCC 15700TM的粗制品(OD50,在90℃加热6小时)的“每个样品的荧光素酶含量”的计算
每个样品的荧光素酶含量=9.37E5x 2=1.87E6
(科学符号9.4E5等于9.4x 105)
表B:标准化荧光素酶活性和短双岐杆菌CNCM I-3865的粗制品(OD50,在90℃加热6小时)的“每个样品的荧光素酶含量”的计算
每个样品的荧光素酶含量=1.04E+06x 25=2.60E+07
如表A和B中图示,两个粗制品短双岐杆菌ATCC 15700TM和短双岐杆菌CNCM I-3865具有类似的最大Nrf2诱导,但是具有不同荧光素酶含量/样品值。每个样品的荧光素酶含量值的差异反映它们相应的Nrf2激活模式(参见图1和2)。
相比之下,短双岐杆菌CNCM I-3914并未显著地激活Nrf2,参见比较表C。
表C:来自三种不同短双岐杆菌株–粗制品的比较结果
表D:来自三种不同短双岐杆菌株–纯制品的比较结果
通过4-氧代-2-戊烯酸的Nrf2激活
将4-氧代-2-戊烯酸(Alfa Aesar-参考号L02185)在Nrf2报告基因测定中测试。将不同剂量的4-氧代-2-戊烯酸应用于AREc32细胞上24小时,然后如上所述定量荧光素酶活性。还使用细胞Titer-Glo试剂盒(ATP定量)测量细胞活力。
如图3中所示,发现4-氧代-2-戊烯酸分子以剂量依赖性方式强烈激活Nrf2。AREc32细胞的活力不受低于70μM剂量的4-氧代-2-戊烯酸影响。Nrf2激活的最佳剂量为约40-50μM。为了比较,图4示出,短双岐杆菌CNCM I-3865的细菌部分以类似方式激活Nrf2。
实施例2:刺激编码肝脏中II期酶的基因的表达
肝细胞通过肝灌注自Sprague-Dawley雄性大鼠(190-240g)分离。将细胞以2500000个细胞/皿(6cm)接种于2.5ml补充有2mM L-谷氨酰胺、10mM Hepes(Sigma)、1%ITS+、1%青霉素/链霉素(Sigma)和25nM地塞米松(Sigma)的Williams'E培养基中。在过夜温育后,去除培养基并且加入2.5ml含有测试物质的新鲜培养基。将皿在37℃于5%CO2/空气孵育箱中温育24h。
在温育结束时,收集细胞上清液用于LDH(乳酸脱氢酶)测量,其是细胞活力指示剂。将细胞用2.5ml冷PBS 1X洗涤1次,然后通过刮擦从Petri培养皿分离。然后将细胞转移至1.5ml Eppendorf管,将这些管在4℃以7000g离心1min。
通过将400μl RNA裂解缓冲液(含有1%v/vβ-巯基乙醇的RA-1)加入至细胞且剧烈混合(涡旋),获得用于RNA提取的细胞裂解液。根据具有细微改变(20min DNASE处理和60μl洗脱体积)的制造商说明(NucleospinRNA2试剂盒,Macherey-Nagel,Düren,Germany),从细胞裂解液提取总RNA。
总RNA使用Ribogren试剂盒(分子探针)来定量并且质量通过毛细管电泳、使用Bionalyzer(Agilent)来评价。
在随机六聚体引物(来自Applied Biosystems的逆转录试剂)存在下,用Multiscribe逆转录酶执行逆转录反应。基因表达定量使用预设计的TaqMan探针(Applied Biosystems)来执行。以技术上一式两份对50ngcDNA进行各qPCR反应。两个管家基因(GAPDH和β-肌动蛋白)的算术平均值用于标准化。
mRNA基因表达计算基于ΔΔCt法:
标准化mRNA表达=2-ΔCt x F
Ct=Ct(goi)–平均CT(hk)
F=1000000(用于获得合理数字的固定因子)
goi=所关注的基因
hk=管家基因
表F:在Nrf2控制下基因的TaqMan探针
TaqMan ID | 基因名称 | 基因别名 |
Rn99999916_s1 | GAPDH | GAPDH |
Rn00667869-m1 | β-肌动蛋白 | Actb |
Rn00563101-m1 | 谷氨酸半胱氨酸连接酶,催化亚单位 | Gclc |
Rn00588153_m1 | 谷胱甘肽还原酶 | Gsr |
Rn00561387_m1 | 血红素氧合酶1 | HO-1 |
Rn00566528_m1 | NAD(P)H脱氢酶醌 | Nqo1 |
Rn00564188_m1 | 谷胱甘肽合酶 | Gss |
Rn00821792_g1 | 谷胱甘肽-S-转移酶,pi 1 | Gstp1 |
Rn00821927_g1 | UDP-葡萄醛酸基转移酶(UGT) | LOC286989 |
Rn00577994_g1 | 谷胱甘肽过氧化物酶1 | Gpx1 |
Rn00822100_gH | 谷胱甘肽过氧化物酶2 | Gpx2 |
如可在图5中可见,4-氧代-2-戊烯酸增加肝脏中的II期酶基因:血红素氧合酶1、NAD(P)H脱氢酶醌、谷胱甘肽合酶、谷氨酸半胱氨酸连接酶催化亚单位、谷胱甘肽-S-转移酶和UDP-葡萄醛酸基转移酶(UGT)。谷胱甘肽过氧化物酶1、谷胱甘肽过氧化物酶2和谷胱甘肽合酶的表达水平不受4-氧代-2-戊烯酸存在的影响。LDH测量显示细胞活力未受影响。
因此,所呈示的数据允许我们得出结论,4-氧代-2-戊烯酸可用于治疗或预防与肝脏中II期酶活性不足有关的病症。
实施例3:通过4-氧代-2-戊烯酸抑制NF-κB激活(抗炎症效应)
发明人评价了4-氧代-2-戊烯酸在促炎症性应激(LPS和rhTNF-α)下抑制NF-κB激活的能力。使用两个体外系统:人结肠细胞(HT-29克隆34)和人单核细胞/巨噬细胞(THP-1蓝细胞)。
HT-29克隆34
人结肠腺癌HT-29克隆34细胞系(第42-50代)为用NF-κB/SEAP报告基因质粒稳定转染的粘附细胞。将它们在37℃于5%CO2/空气孵育箱中、在含有1%稳定的L-谷氨酰胺且补充有10%热灭活的(在56℃,1小时)胎牛血清(FCS)(Bioconcept,Allschwil,Switzerland)、1%青霉素/链霉素(Sigma)和500μg/ml遗传霉素(PAA,Pasching,Austria)的DMEM高葡萄糖(4.5g/L)(Invitrogen)中培养。每两天更换培养基直至细胞单层达到~90%汇合。使用1X胰蛋白酶/EDTA(Sigma)对细胞继代培养。
在平底白边96孔板(Greiner Bio One,Kremsmuenster,Austria)中将10000个细胞/孔于200μl培养基中接种。3-4天培养后(即细胞达到~70-80%汇合),去除培养基,将180μl含有(或不含)剂量范围的4-氧代-2-戊烯酸(3至400μM)的实验培养基(补充有50mM HEPES和5%人乳(HM)的DMEM高葡萄糖,作为CD14和LPS结合蛋白(LBP)的来源,仅用于LPS刺激)加至细胞中,并将板在37℃于5%CO2/空气孵育箱中预温育4小时。加入20μl含有(或不含)LPS 055:B5或rhTNF-α(最终分别为100和10ng/ml)的实验培养基,并将板在37℃于5%CO2/空气孵育箱中温育24小时。
然后,收集细胞培养物上清液用于测量NF-κB活性(确定分泌的碱性磷酸酶和IL-8产生),分别使用Phosphalight(Applied Biosystems)和IL-8singleplex(Meso Scale,Gaithersburg,Maryland)试剂盒。
细胞活力通过使用细胞Titer-Glo试剂盒(Promega)测量ATP来确定。简言之,在室温在水平振摇(250rpm)下将剩余的附着HT-29克隆34细胞与120μl Cell Titer-Glo试剂(于1X PBS中预稀释两次)温育10min,使用增益值设定为3500的Polarstar微板读数器(BMG,Offenburg,Germany)测量发光1000ms。
在缺少LPS下,以所测试剂量的4-氧代-2-戊烯酸温育的HT-29克隆34细胞的细胞培养物上清液中,观察到无NF-κB活性(基于SEAP或IL-8检测)。
HT-29克隆34细胞的细胞活力的测量结果显示,在高于~50μM的4-氧代-2-戊烯酸剂量下细胞活力下降(图6)。
当炎症响应由LPS触发,4-氧代-2-戊烯酸以剂量依赖性方式抑制NF-κB活性(图6)。4-氧代-2-戊烯酸对SEAP和IL-8分泌两者产生影响,最好的抑制为使用50μM 4-氧代-2-戊烯酸)。尽管不太明显,在用rhTNF-α刺激的细胞下观察到类似的结果。
THP-1蓝
在37℃于5%CO2/空气孵育箱中将人单核细胞/巨噬细胞THP-1蓝细胞(第16-20代)(Invivogen,Toulouse,France)在含有1mM丙酮酸钠、2mML-谷氨酰胺、4.5g/L葡萄糖和10mM HEPES且补充有10%热灭活的FCS(Bioconcept)、1%青霉素/链霉素(Sigma)和500μg/ml博来霉素(Invivogen)的改性RPMI培养基(ATCC,Manassas,VA)中培养。
在96孔平底透明板中将200000个细胞/孔接种于100μl培养基中。在37℃于5%CO2/空气孵育箱中温育24小时后,将80μl含有(或不含)剂量范围的4-氧代-2-戊烯酸(5至200μM)的培养基加至细胞并在37℃预温育5小时。加入20μl含有(或不含)LPS 055:B5(Sigma)(最终为100ng/ml)的培养基并将板在37℃于5%CO2/空气孵育箱中温育16小时。
将细胞培养物上清液小心转移至96孔板用于NF-κB活性测量,其与分泌的碱性磷酸酶的水平成比例。简言之,将100μl上清液与150μlQuantiBlue(Invivogen)在37℃温育3h的96孔板中混合,然后用Sunrise微板读数器(Tecan,Mannedorf,Switzerland)在620nm进行OD测量。细胞活力使用如上所述的Cell Titer-Glo试剂盒来确定。
当用LPS刺激时,响应于约40至75μM剂量的4-氧代-2-戊烯酸,获得强NF-κB抑制。4-氧代-2-戊烯酸在高于75μM的剂量下对细胞有毒性(图7)。
用HT-29克隆34细胞和THP-1蓝细胞产生的数据指示,4-氧代-2-戊烯酸在促炎症性应激下抑制NF-κB激活。
实施例4:HPLC-MS/MS对4-氧代-2-戊烯酸的定量
为了定量4-氧代-2-戊烯酸,开发了涉及将高性能液相色谱与电喷雾离子化串联质谱法(HPLC-ESI-MS/MS)耦合的高通量分析法。
方法学
4-氧代-2-戊烯酸标准品购自Alfa Aesar(Ward Hill,USA)。HPLC级水、甲醇和乙酸均购自Lichrosolv(Merck,Darmstadt,Germany)。HPLC小瓶和2mm插入物均购自Agilent(Santa Clara,CA)。发现4-氧代-2-戊烯酸可溶于水中以达到至少20mg/ml。将4-氧代-2-戊烯酸标准品化合物溶解于水中以达到10mg/ml的最终储备溶液,并进一步稀释于水中以建立校准曲线。
在与3200Q TRAP质谱仪(Applied Biosystems)耦合的湍流色谱(TFC)系统(Thermo Fisher,Waltham,MA)上进行HPLC-ESI-MS/MS分析。使用的分析柱为购自Thermo Fisher(Waltham,MA)的Hypersil Gold AQ(3x50mm,5μm),其在室温和恒定流速600μl/min下运行。流动相由溶剂A-含有0.05%乙酸的水和B-含有0.05%乙酸的甲醇构成。梯度程序为:0min0%B,以0%B保持40秒(0-0.67min),在180秒内升至50%B(0.67-3.67min),在10秒内从50%B升至90%B(3.67-3.83min),以90%B保持120秒(5.83min),之后回到0%B且保持另外的300秒(5.83-10.83min)。注射体积为5μl。
以电喷雾负电离模式实现MS数据采集。使用T型接头,以流速10μl/min注入与由溶剂A和B的HPLC流(80/20,v:v;0.6ml/min)混合的4-氧代-2-戊烯酸标准品(5μg/ml于水中)的溶液来执行MS调节。氮气用于喷雾器和气帘气体。激活接口加热器且用设定在-4.5kV的毛细管电压将块源温度保持在700℃。氮气还用作在中压选择下的碰撞气体。使用选择的反应监测(SRM)采集模式实现MS/MS检测。使用恒定停留时间50ms(总扫描时间110ms),通过扫描m/z 113→69(碰撞能量11eV)和m/z 113→41(碰撞能量26eV)选择两个最强片段离子。去簇电压设定为-29V。使用最强SRM信号执行定量分析,而基于由标准溶液计算的适当面积比,第二跃迁用于分析物确认。使用Analyst 1.5.1软件(Applied Biosystems)执行数据处理。
通过HPLC-MS/MS检测PBS和水中的4-氧代-2-戊烯酸
将4-氧代-2-戊烯酸溶解于1X PBS或水中,如前述章节中所述,执行HPLC-MS/MS的检测。与跃迁反应m/z 113→69相关的SRM揭示,其与保留时间1.25min处的跃迁m/z 113→41相关联的SRM相比,信号更强。观察到两种转变的保留时间类似,确认分析的正确性(图8)。在1X PBS(数据未示出)和水(图8)中成功地检测到分子4-氧代-2-戊烯酸。
建立4-氧代-2-戊烯酸标准曲线:
为了准确定量细菌部分中4-氧代-2-戊烯酸的量,在简单基质如1X PBS或HPLC级水中建立4-氧代-2-戊烯酸的标准曲线。将商购4-氧代-2-戊烯酸以不同剂量悬浮于1X PBS和水中。然后将HPLC-ESI-MS/MS方法用于定量所估计剂量的4-氧代-2-戊烯酸。在1X PBS和HPLC级水中,均观察到4-氧代-2-戊烯酸的量(从0.1至25μg/ml)和所得强度(以cps表示)之间存在良好线性。
定量细菌部分中的4-氧代-2-戊烯酸:
在来自实施例1的经过热处理的细菌制品中定量4-氧代-2-戊烯酸。在HPLC-ESI-MS/MS分析之前将所有样品在HPLC级水(3次稀释/样品)中稀释。结果概述于表E中。
表E:来自实施例1的经过加热的粗和纯细菌制品(OD 50)(在90℃加热6小时)中4-氧代-2-戊烯酸的浓度(μg/ml)。N.D表示“不可检测的”,低于方法的检测限。
实施例5:加热温度和时间对4-氧代-2-戊烯酸从短双岐杆菌CNCM
I-3865的产生的影响
为了表征在热处理后4-氧代-2-戊烯酸从短双岐杆菌CNCM I-3865的产生,使用不同温度执行动力学实验。在厌氧和pH控制条件下,用于该实验的生物质的“主原料(master stock)”在生物反应器中在37℃用MRS培养基产生。在生长培养(16h)后,去除培养基且将细胞用1X PBS洗涤两次,于含有10%甘油的1X PBS中浓缩至OD 134(1.5E+10cfu/ml),然后在-80℃以50ml等分试样储存。
然后如下由生物质主原料制备短双岐杆菌CNCM I-3865的“工作生物质”:将生物质用1X PBS洗涤两次且于1X PBS中调节至OD 40。
使用温度加热装置(THA)来调查不同加热时间和温度的作用。该系统为在生产环境中发现的典型装置的小规模形式。使用蒸汽加热含有生物质套筒的保持管。将90℃、120℃和140℃的样品温度应用多达60分钟的时间。然后将5ml各经热处理的生物质以5000g离心10min且过滤上清液(0.2μm),通过HPLC-ESI-MS/MS定量4-氧代-2-戊烯酸含量。产生的4-氧代-2-戊烯酸的量示于图9中。
Claims (15)
1.用于治疗或预防肝脏病症的包含4-氧代-2-戊烯酸的组合物,其中所述组合物不用作药剂。
2.根据权利要求1使用的组合物,其中所述肝脏病症选自下组:肝炎;肝纤维化;胆汁郁积性肝脏疾病;炎症性肝损伤;生物异源物质毒性,包括药物-诱导的肝脏毒性和乙醇-介导的肝脏毒性;肝性脑病;脂肪肝脏疾病;缺血再灌注肝损伤;肝衰竭;1型遗传性酪氨酸血症;肝细胞癌,包括由肝炎、黄曲毒素和化学毒素诱导的那些;环境敏感性、药物不耐受性、慢性疲劳综合征和纤维肌痛,归因于过量负载的毒素进入I期且II期途径低效;肝脏的病理性解毒及其组合。
3.根据权利要求1使用的组合物,其中所述病症与肝脏中的II期酶活性不足有关。
4.根据权利要求1使用的组合物,其中所述II期酶选自下组:血红素氧合酶1、NAD(P)H脱氢酶醌1、谷胱甘肽还原酶、谷氨酸半胱氨酸连接酶、谷胱甘肽S-转移酶、UDP-葡萄醛酸基转移酶及其组合。
5.根据前述权利要求中一项使用的组合物,其向肝脏中的I期酶的活性增加和/或肝脏中的II期酶的活性减少的对象施用。
6.根据前述权利要求中一项使用的组合物,其向需要肝脏解毒的对象施用。
7.根据前述权利要求中一项使用的组合物,其向过重和/或患有2型糖尿病的对象施用。
8.根据前述权利要求中一项使用的组合物,其中4-氧代-2-戊烯酸获自天然来源。
9.根据前述权利要求中一项使用的组合物,其中4-氧代-2-戊烯酸可获自短双岐杆菌CNCM I-3865或短双岐杆菌ATCC 15700。
10.根据权利要求9使用的组合物,其中所述短双岐杆菌CNCMI-3865或短双岐杆菌ATCC 15700在约60-180℃、优选在约80-160℃进行热处理。
11.根据前述权利要求中一项使用的组合物,其包含至少1mg/kg组合物、优选至少10mg/kg组合物、例如50mg至50g/kg组合物的量的4-氧代-2-戊烯酸。
12.根据前述权利要求中一项使用的组合物,其以对应于2μg至20mg4-氧代-2-戊烯酸/kg体重、优选20μg至2mg 4-氧代-2-戊烯酸/kg体重、例如40μg至1mg 4-氧代-2-戊烯酸/kg体重的日剂量施用。
13.根据前述权利要求中一项使用的组合物,其口服或肠内施用。
14.根据前述权利要求中一项使用的组合物,其向人、宠物或家畜施用。
15.根据前述权利要求中一项使用的组合物,其中所述组合物选自下组:食品组合物、食品添加剂、营养品、饮料、营养配方、管饲配方、在乳或水中重构的粉状组合物、和宠物食品组合物。
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WO2022213353A1 (en) * | 2021-04-09 | 2022-10-13 | Peking University | Sirna, medical compositions, and methods for treating diabetes using the same |
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