CN116744916A - 抗衰老治疗物质 - Google Patents
抗衰老治疗物质 Download PDFInfo
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- CN116744916A CN116744916A CN202180089914.8A CN202180089914A CN116744916A CN 116744916 A CN116744916 A CN 116744916A CN 202180089914 A CN202180089914 A CN 202180089914A CN 116744916 A CN116744916 A CN 116744916A
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Abstract
提供了一种抗衰老治疗物质,其特征在于包含黄酮类化合物、脂肪酸,并且优选包含酚酸和/或维生素。
Description
技术领域
本发明涉及第一权利要求前序中指定类型的抗衰老治疗(senotherapeutic)物质。
背景技术
目前已知用于特殊医疗用途的物质,特别是食品。这些是专门配制的食品,旨在用于对仅靠正常饮食无法满足营养需求的疾病进行饮食管理。
此外,最近还发现了衰老细胞的存在以及随后发展出一类被称为抗衰老治疗的药物,特别是senolytic、或senostatic或senomorphic。例如,senolytics是当使用者服用时,选择性杀死人体或动物体内衰老细胞的物质。
衰老细胞是指不再能够分裂和繁殖的细胞。它们还经受生理功能丧失、抵抗细胞凋亡和各种细胞变化。
此外,衰老细胞促成衰老表型,包括衰弱综合征(frailty syndrome)、肌少症(sarcopenia)和与衰老相关的疾病。衰老的星形胶质细胞和小胶质细胞促成神经退行性病变(neurodegeneration)。
因此,抗衰老治疗(并且特别是senolytics)的目标是通过尽可能选择性地清除衰老细胞来延缓、预防、缓解或逆转与年龄相关的疾病。
例如,Mayo医学教育和研究基金会(Mayo Foundation for Medical Educationand Research)(美国明尼苏达州)已经例如在专利申请WO2015116735A1、WO2019183282A1和US2015296755A1中研究了抗衰老化合物。其他抗衰老化合物已经由UnityBiotechnology公司(美国加利福尼亚州)开发,例如在专利申请WO2019241567A1、US2019330199A1和CA3043103A1中。
然而,对更精确、更有效或更便宜的抗衰老治疗,并且特别是对senolytics的需求总是更大。
发明内容
在这种情况下,本发明的技术任务是设计能够基本上消除至少部分上述缺点的抗衰老治疗物质。
在所述技术任务的范围内,本发明的重要目的是获得选择性地对衰老细胞起作用的抗衰老治疗物质。
另一项重要的技术任务是制造一种抗衰老治疗物质,其生产是经济实惠的。
该技术任务和特定目的通过所附权利要求1所要求保护的抗衰老治疗物质来实现。
在从属权利要求中描述了优选实施例的示例。
附图说明
本发明的特征和优点在下文中通过参考附图对本发明的优选实施例的详细描述来阐明,其中:
图1示出了用根据本发明的物质获得的结果的第一张图。
具体实施方式
在本文件中,当与像“约”这样的词或其他类似术语(如“近似”或“基本上”)相关联时,测量结果、数值、形状和几何参照(如垂直度和平行度)应被视为除了由于生产和/或制造误差而导致的测量误差或不准确性之外,以及,最重要的是,除了与数值、测量值、形状或与其相关的几何参照有轻微偏差。例如,如果这些术语与数值相关联,则优选地指示不超过该值的10%的偏差。
此外,在使用时,例如“第一”、“第二”、“更高”、“更低”、“主要”和“次要”的术语并不一定确定顺序、关系的优先级或相对位置,而是可以简单地用于明确区分它们的不同组分。
除非另有指示,否则应考虑本文本中报告的测量值和数据,如在国际民航组织标准大气(ICAO International Standard Atmosphere)(ISO 2533)中进行。
根据本发明的抗衰老治疗物质用于医学目的,优选地尽可能选择性地用于衰老细胞的治疗。
该抗衰老治疗物质优选具有抗衰老作用(senolytic action),因此是抗衰老食品。抗衰老物质用于优选选择性地清除衰老细胞。
或者,抗衰老治疗物质可以具有senostatic作用,即阻断衰老过程的作用。
或者,该抗衰老治疗物质还可以具有senomorphic作用,即对衰老细胞的分泌产生作用。
sinotherapeutic是专门特异性靶向细胞的治疗剂和方法,其包括它们的分子和细胞内过程,以及它们释放的分泌物质。衰老细胞表现出独特且改变的细胞表型,这种表型出现在生物体(包括人类)的所有组织中,是许多生物应激源的结果。除其他外,细胞衰老可能与衰老和与年龄相关的疾病有关。
sinotherapeutic可以进一步分为至少两大类:
-senolytics:特异性清除衰老细胞的药物。senolytics可以通过诱导特定的细胞死亡机制来清除衰老细胞,包括细胞凋亡、细胞自噬、细胞坏死(necrosis)、坏死性凋亡(necroptosis)或其他形式的非凋亡程序性细胞死亡(如铁死亡、细胞焦亡等)。在某些配置中,senolytics可以靶向衰老细胞中的生存和抗凋亡通路,即衰老细胞抗凋亡通路(SCAP)。
-senomorphic:特异性抑制衰老细胞表型的药物,不一定能清除或杀死衰老细胞。senomorphic调节衰老细胞的功能和形态,从而潜在地延迟/阻止/抑制其形成、积聚和病理作用。在一些配置中,senomorphic包括衰老相关分泌表型(SASP)的抑制剂和特异性防止细胞衰老的药物。
该物质在以下列表中所示的领域中可能具有更具体的优点和相应的用途,并且更优选地用于治疗病症,该病症可以是病理学或美学病症或其他优选与衰老相关的病症,以下用任何语言的技术人员都清楚的英语科学术语表示:
·特发性肺纤维化(IPF)、慢性阻塞性肺病(COPD)、哮喘、囊性纤维化、肺气肿、支气管扩张和与年龄相关的肺功能丧失;
·慢性肾脏疾病(CKD)、间质性肾炎、肾小球硬化/肾小球肾炎、急性肾脏病(AKD)、肾衰竭;
·肝纤维化、慢性肝炎、非酒精性脂肪肝病(NAFLD);
·胰腺纤维化、慢性胰腺炎;
·心肌纤维化、梗死;
·口腔黏膜下层纤维化;
·神经退行性疾病,如阿尔茨海默病、帕金森病、多发性硬化症、轻度认知障碍、运动神经元功能障碍、亨廷顿病、痴呆症等;
·神经精神障碍;
·化学治疗、放射治疗或任何其他医疗程序(例如用于治疗、诊断和美容目的)引起的毒性或炎症;
·急性和慢性病毒性疾病,如HIV、Covid-19等;
·骨质疏松症、骨关节炎、炎症性肠病(IBD)、炎症性肠综合征(IBS)、类风湿性关节炎、口腔黏膜炎、脊柱后凸、椎间盘退变、椎间盘突出;
·脂肪萎缩;
·肌少症、衰老导致的肌肉/活动能力丧失、肌肉疲劳;
·动脉粥样硬化、心绞痛、心律失常、心肌病、心肌细胞肥大、充血性心力衰竭、冠状动脉疾病、颈动脉疾病、心内膜炎、冠状动脉血栓形成、心肌梗死、高血压、主动脉瘤、心脏舒张功能障碍、高胆固醇血症、高脂血症、二尖瓣脱垂、外周血管疾病、心脏应激抵抗、心脏纤维化、脑动脉瘤和中风;
·与老化和衰老相关的罕见疾病,如:再生障碍性贫血、先天性角化不良、瑞氏综合征(Revetz syndrome)、Hoyeraal-Hreidarsson综合征、路易体痴呆症(Lewy bodydementia,LBD)、淀粉样变性、派杰氏病(Paget's disease)、弥漫性特发性骨质增生症(DISH)、多系统萎缩(MSA)等;
·糖尿病(2型、1型)、糖尿病溃疡、肥胖症、代谢综合征;
·伤口愈合;
·衰弱;
·青光眼、黄斑变性、白内障、老花眼和视力丧失;
·听力损失;
·衰老导致的免疫功能下降(免疫衰老);
·脱发症(Alopecia)、掉发;
·黄褐斑、皮肤变色、湿疹、银屑病、色素沉着、痣、皮疹、特应性皮炎、荨麻疹、与光敏性或光老化有关的疾病和病症、皱纹、瘙痒症(pruritis)、感觉障碍(dysesthesia)、湿疹样皮疹、嗜酸性皮肤病、反应性嗜中性皮肤病、类天疱疮皮肤病、皮肤纤维组织细胞增殖、皮肤淋巴瘤和皮肤狼疮;
·与肾、肝、肺、心脏、胰腺或其他器官以及干细胞或其他细胞移植相关的疾病或病理改变或灌注病况。
所述抗衰老治疗物质可以单独使用,或者与其他已知的食品和选自以下类型的药物组合使用:senolytics、senomorphic、senostatic、抗衰老治疗、细胞衰老促进剂和保持组织完整性的化合物。
根据本发明的抗衰老治疗物质优选包括黄酮类化合物(flavonoids)、脂肪酸和任选的酚酸和/或维生素。所述组分可以与其他组分一起存在或者不存在其他组分。
抗衰老治疗物质优选由固体食品或液体食品组成,或者再次,可替代地,由局部使用的物质或乳膏和可吸入的气雾剂(aeriform)或其他方式(例如,但不限于,通过注射给药)组成。
优选地,黄酮类化合物以黄酮的形式存在,更优选地,黄酮类化合物选自槲皮素、非瑟酮(fisetin)、芹菜素和木犀草素中的一种或多种。例如,类似的物质由Fluorochem有限公司(英国)以047268Quercetin商标销售。
此外,黄酮类化合物可包括以下物质中的一种或多种:芦丁、异槲皮素、槲皮素、绣线菊甙、橙皮甙、橙皮素、地奥司明、白藜芦醇、羟基酪醇、酪醇、儿茶素、表型儿茶素、杨梅素、表没食子儿茶素没食子酸酯(epigallocatechin gallate)、鞣花酸、姜黄素、silystein、叶黄素、荜茇酰胺(piperlongumine)、iuglanin、黑麦草内酯、bromheolin、木瓜蛋白酶、大蒜素、番茄红素、chemferol、柚皮苷、芝麻素、二氢槲皮素、金丝桃甙。
黄酮类化合物优选以重量计包括在1dg至1g之间的量存在,更优选在2dg至6dg之间。这些量优选地对应于每日要摄取的量。
脂肪酸优选以重量计相对于黄酮类化合物重量包括在1/50至25倍之间的量存在,更优选所述量包括在1至10倍之间,更优选在3至8倍之间。
优选地,脂肪酸以在2cg至5g的范围内的量存在,更优选在1dg至10dg之间。这些量优选地对应于每日要摄取的量。
优选地,脂肪酸以棕榈酸的形式存在。可替代地或另外地,它们可以选自以下的一种或多种:酰基乙醇胺、氧化脂质、脂氧素及其各种技术制剂。优选但非详尽的示例包括:油酸、亚麻酸、共轭亚麻酸、亚油酸、共轭亚油酸、大麻素、棕榈酰乙醇胺(PEA)、花生四烯酸、二十碳五烯酸、二十二碳六烯酸、二十二烷酸、硫辛酸。类似的物质例如由TCI Europe NV以P0002棕榈酸的商标销售。
酚酸优选以重量计相对于黄酮类化合物重量包括在1/100至4倍之间的量存在,更优选所述量包括在30%至100%之间,更优选在40%至80%之间。
优选地,酚酸以在1cg至8dg的范围内的量存在,更优选在1dg至5dg之间。这些量优选地对应于每日要摄取的量。
优选地,酚酸以没食子酸的形式存在。可替代地或另外地,它们可以选自以下的一种或多种:香草酸、羟基苯甲酸、香豆酸、阿魏酸、咖啡酸、羟基肉桂酸。类似的物质例如由TCI Europe NV以G0011 Gallic Acid Hydrate的商标销售。
维生素优选以重量计相对于黄酮类化合物重量包括在1/20至5倍之间的量存在,更优选所述量包括在50%至150%之间,更优选在80%至120%之间。
优选地,维生素以在1cg至1g的范围内的量存在,更优选在5cg至5dg之间。这些量优选地对应于每日要摄取的量。
优选地,维生素以维生素C的形式存在。可替代地或另外地,它们可以选自维生素D、维生素A、维生素B、维生素E中的一种或多种。类似的物质例如由TCI Europe NV以A0537L-抗坏血酸的商标销售。
所公开的抗衰老治疗物质可以单独使用,也可以与其他补充剂、局部乳膏、吸入式气雾剂、特殊医学用途的食品、营养原理、必需矿物质或已知的食品抗氧化剂组合使用。这些非详尽的示例是:肌肽、激动素(kinetine)、GAL-倍癌霉素(GAL-duocarmicine)、精胺、亚精胺、玉米黄素、地高辛、哇巴因(ouabain)、阿南酰胺-C(avenanthramide C)、尿石素、氨基葡萄糖、肉毒碱、菠萝蛋白酶(bromelain)、木瓜蛋白酶、岩藻聚糖、锌、锂、锰、镁、铁、钙、硒、铬、磷。
所述的抗衰老治疗物质也可以单独使用或与选自以下类型的其他已知药物组合使用:senolytics、senomorphic、senostatic、抗衰老治疗、细胞衰老促进剂和保持组织完整性的化合物。
因此,本发明还限定了一种用于通过采用所述食品或物质来消除衰老细胞或解决与衰老相关的问题的新方法,以及一种用于制备用于治疗上述问题的物质或食品的新方法。
在申请人的实验之后,其中将包括上述各种组分的以重量计的量的抗衰老治疗物质施用于来自患者的细胞,观察到了重要的抗衰老活性。
特别地,根据本发明实现的抗衰老治疗物质,在人类乳腺的衰老上皮细胞中显示出显著的抗衰老活性,其包括3种黄酮类化合物(非瑟酮、木犀草素和芹菜素)、维生素C和棕榈酸(图1)。简言之,在体外通过用非凋亡浓度(200nM)的阿霉素处理(24小时)诱导MCF7人乳腺上皮细胞(人乳腺腺癌细胞,HTB-22TM)的衰老,随后细胞恢复(在最佳培养基中,没有处理)10天。形态学变化(扁平化和细胞增大)和溶酶体β-半乳糖苷酶(β-GAL)阳性证实了成功转化为衰老细胞表型。使用SA-β-GAL染色试剂盒(马萨诸塞州丹佛斯细胞信号技术有限公司(Cell Signaling Technology,Inc.))进行SA-β-GAL(衰老相关β-GAL)衰老试验。在这种情况下,在室温下用20%甲醛固定15分钟后,通过用相差显微镜EVOS XL细胞成像系统(Thermo Fisher;物镜,40X)检查每孔≥200个细胞,计算培养物中存在的SA-β-GAL阳性细胞(蓝色)的百分比来对衰老细胞进行定量。
用载体(DMSO;阴性对照)、槲皮素(Q,5μM;对照阳性)或根据本发明的包括非瑟酮(F,5μM)+木犀草素(L,5μM)+芹菜素(A,5μM)的组合的抗衰老治疗物质单独使用或在棕榈酸(AP,以3种不同浓度使用:低,10μM;中,30μM和高,60μM)和/或维生素C(VC,5μM)的存在下处理(72小时)后,来评估(在96孔板中)的衰老MCF7细胞的抗衰老活性(图1)。在处理结束时,通过结晶紫染色来定量细胞存活率。在这种情况下,用PBS中的多聚甲醛(4%)固定细胞20分钟,洗涤(在蒸馏水中2X),并用1%结晶紫染色(20分钟)。用水(3X)进一步洗涤后,每孔加入100μl乙酸(10%),并用Synergy分光光度计(AHSI)测量吸光度(λ=590nm)。实验一式四份进行,并在三个不同的日子里重复三次。抗衰老活性以相对于对照条件(DMSO)消除的衰老细胞的%表示。结果以平均值±SEM(平均值的标准误差)表示,并使用6.0软件(加利福尼亚州,美国)进行相关分析。
与槲皮素相比,所检测的所有根据本发明的抗衰老治疗组合对人MCF7衰老细胞表现出显著更高的抑制活性(图1)。事实上,单独使用非瑟酮-木犀草素-芹菜素组合或在维生素C存在的情况下使用的抗衰老功效(≥100%)高于槲皮素的,学生t检验(Student's t-test)证实了显著性(*,p<0.05)(图1)。值得注意的是,将棕榈酸添加到抗衰老治疗组合中进一步增加了本发明物质的抗衰老功效,其剂量依赖性协同作用显著高于槲皮素(**,p<0.01和***,p<0.001,用学生t检验),并且在浓度≥30μM时具有最大强度的剂量依赖性协同作用(~80%的衰老细胞裂解(senolysis))(图1)。在这些研究中所述的构成本发明的抗衰老治疗物质的化学组分(非瑟酮+木犀草素+芹菜素+维生素C+棕榈酸)的生物协同作用通过单独给药(在所研究的相同剂量下)对维生素C和棕榈酸没有显著的抗衰老作用而得到证实。因此,这些结果表明,抗衰老治疗食品具有特异性、重要性和非常有前景的抗衰老活性,表明它们可以被开发为用于人的新的抗衰老治疗物质,特别是senolytics。
Claims (13)
1.一种抗衰老治疗物质,其特征在于,包括黄酮类化合物和脂肪酸。
2.根据前述权利要求中任一项所述的抗衰老治疗物质,其中所述黄酮类化合物以重量计在1dg至1g之间的量存在。
3.根据前述权利要求中任一项所述的抗衰老治疗物质,其中所述黄酮类化合物选自槲皮素、非瑟酮、芹菜素和木犀草素中的一种或多种。
4.根据前述权利要求中任一项所述的抗衰老治疗物质,其中所述脂肪酸以重量计相对于所述黄酮类化合物重量在1至10倍的范围内的量存在。
5.根据前述权利要求中任一项所述的抗衰老治疗物质,其中所述脂肪酸以棕榈酸的形式存在。
6.根据权利要求1所述的抗衰老治疗物质,其进一步包含酚酸。
7.根据前述权利要求中任一项所述的抗衰老治疗物质,其中所述酚酸以重量计相对于所述黄酮类化合物重量在30%至100%的范围内的量存在。
8.根据权利要求4或5所述的抗衰老治疗物质,其中所述酚酸以没食子酸的形式存在。
9.根据前述权利要求中任一项所述的抗衰老治疗物质,其进一步包含维生素。
10.根据前述权利要求中任一项所述的抗衰老治疗物质,其由固体或液体食品组成。
11.根据前述权利要求中任一项所述的抗衰老治疗物质,其由局部使用的物质或乳膏或待吸入的气雾剂组成。
12.根据一项或多项前述权利要求所述的治疗物质,用于治疗一种或多种以下病症:特发性肺纤维化(IPF)、慢性阻塞性肺病(COPD)、哮喘、囊性纤维化、肺气肿、支气管扩张和与年龄相关的肺功能丧失;慢性肾脏疾病(CKD)、间质性肾炎、肾小球硬化/肾小球肾炎、急性肾脏病(AKD)、肾衰竭;肝纤维化、慢性肝炎、非酒精性脂肪肝病(NASH);胰腺纤维化、慢性胰腺炎;心肌纤维化、梗死;口腔黏膜下层纤维化;神经退行性疾病:阿尔茨海默病、帕金森病、多发性硬化症、轻度认知障碍、运动神经元功能障碍、亨廷顿病、痴呆症等;神经精神障碍;毒性或炎症,其由化学治疗、放射治疗或任何其他医疗程序例如用于治疗、诊断和美容目的引起的;急性和慢性病毒性疾病,如HIV、Covid-19等;骨质疏松症、骨关节炎、炎症性肠病(IBD)、炎症性肠综合征(IBS)、类风湿性关节炎、口腔黏膜炎、脊柱后凸、椎间盘退变、椎间盘突出;脂肪萎缩;肌少症、衰老导致的肌肉/活动能力丧失、肌肉疲劳;动脉粥样硬化、心绞痛、心律失常、心肌病、心肌细胞肥大、充血性心力衰竭、冠状动脉疾病、颈动脉疾病、心内膜炎、冠状动脉血栓形成、心肌梗死、高血压、主动脉瘤、心脏舒张功能障碍、高胆固醇血症、高脂血症、二尖瓣脱垂、外周血管疾病、心脏应激抵抗、心脏纤维化、脑动脉瘤和中风;与老化和衰老相关的罕见疾病,如:再生障碍性贫血、先天性角化不良、瑞氏综合征、Hoyeraal-Hreidarsson综合征、路易体痴呆症(LBD)、淀粉样变性、派杰氏病、弥漫性特发性骨质增生症(DISH)、多系统萎缩(MSA)等;糖尿病(2型、1型)、糖尿病溃疡、肥胖症、代谢综合征;伤口愈合;衰弱;青光眼、黄斑变性、白内障、老花眼和视力丧失;听力损失;衰老导致的免疫功能下降(免疫衰老);脱发症、掉发;黄褐斑、皮肤变色、湿疹、银屑病、色素沉着、痣、皮疹、特应性皮炎、荨麻疹、与光敏性或光老化有关的疾病和病症、皱纹、瘙痒症、感觉障碍、湿疹样皮疹、嗜酸性皮肤病、反应性嗜中性皮肤病、天疱疮、类天疱疮、大疱性皮肤病、皮肤纤维组织细胞增殖、皮肤淋巴瘤和皮肤狼疮;与肾、肝、肺、心脏、胰腺或其他器官以及干细胞或其他细胞移植相关的疾病或病理改变或灌注病况。
13.根据前述权利要求中任一项所述的物质在制备用于抗衰老治疗用途的药物中的用途。
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