CN104487069A - 抑制shc-1/p66以对抗老化相关疾病的方法 - Google Patents
抑制shc-1/p66以对抗老化相关疾病的方法 Download PDFInfo
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Abstract
本发明涉及治疗SHC-1/p66相关疾病的一种或一种以上症状的方法、抑制ROS产生的方法、或制备用于上述治疗的医药的方法。
Description
技术领域
本申请涉及抑制SHC-1/p66以对抗老化相关疾病的方法。
背景技术
世界人口的平均年龄因为***症而下降以及因二十世纪下半叶平均寿命延长20年的因素而增加(Centers for Disease Control and Prevention,Morbidity and Mortality Weekly Report,February 13,2003,52(06):101-106)。这些因素加上二次世界大战后的二十年间许多国家的生殖率的提高(即“婴儿潮”)，将使得2010年至2030年间年龄高于65岁的人口增加。预期全世界人口的平均寿命还会再增加至下一个十年至2050年。老年人口的增加使得对公共卫生***及医疗与社会福利的需求也会增加。严重影响老人的慢性疾病会造成残障、生活品质的下降及看护与长期照护成本的增加。
为确定老化症状及其生化学与神经学的关系已进行了研究。特别是已有多条生物学路径被确认可延长寿命及防止多种老化相关的疾病(Trinei et al.,“P66Shc Signals to Age”Aging(2009)v.1(6)pages 503-510)。
本申请所述的方法涉及老化症状的生化学及神经学基础。特别是本申请所述的方法在SHC-1/p66路径、活性氧化物(reactive oxygen species；ROS)的数目及其所产生的氧化应激(oxidative stress)、肝功能与病理、及运动控制(motor control)方面，呈现正面效果。
SHC-1/p66与老化
已有报导显示，缺乏SHC(Src同源域胶原蛋白(Src Homology andCollagen))蛋白质家族中66kD异构体的小鼠，较正常表现p66的手足，寿命延长30％。剔除p66的小鼠(p66KO mice)寿命延长，而且表型正常、具有生殖力及健康(Migliaccio et al.,“The p66shc adaptor protein controls oxidativestress response and the life span in mammals.Nature.1999；402:309-313；Alamet al.,Endocr.Relat Cancer.2009 March；16(1):1.)。SHC蛋白已知为转接分子(adapter molecules)，即传递(signaling)与位于活化生长因子受体(growth factorreceptors)下游的具有巨观研究前景的分子复合体的聚集有关的成分(RTKs)。SHC在胰岛素传递中的角色也已被报导(Giorgetti et al.“Involvement of Srchomology/collagen(SHC)proteins in signaling through the insulin receptor andthe insulin-like-growth-factor-I-receptor.”Eur.J.Biochem.1994；223:195-202)。因此，剔除p66的小鼠(p66KO mice)是藉由基因调节胰岛素与IGF的讯息传递所形成的具有寿命延长的哺乳动物实验例。
然而，p66与长寿之间的关联性目前具有多种理论，而成为支持Harman的“老化的自由基理论”中最强烈的论据之一(Harman,D.,“A biologic clock:the mitochondria？”Journal of the American Geriatrics Society 1972；20:145-147.)。事实上，p66基因剔除鼠(p66-deficient mice)及细胞实验显示显著减少细胞中的ROS浓度会增强对抗氧化应激。
p66shc与其他的SHC蛋白质异构体有完全不同的功能，在对氧化促进物质(prooxidant)及细胞死亡物质(apoptogenic)刺激的反应中，p66shc会转位至线粒体(mitochondria)，并在线粒体中直接产生活性氧化物。
在分子层面上，SHC、p66Shc、p52Shc及p46Shc异构体普遍在C端具有相同的氨基酸序列，其C端包含Src同源二域(homologous type twodomain)(SH2)、负责与磷酸化酪胺酸(phosphorylated tyrosine)结合的磷酸酪胺酸结合域(PTB)以及因与胶原蛋白同源而被称为胶原同源(collagenhomologous)(CH1)域的高度富含甘氨酸与脯氨酸的区域(Pelicci,G.et al.,“Afamily of Shc related proteins with conserved PTB,CH1and SH2regions.Oncogene.1996；13:633-41)。p66Shc的特质在于，在N端具有一个额外的CH区域(CH2)(Pelicci,G.et al.,“A novel transforming protein(SHC)with anSH2 domain is implicated in mitogenic signal transduction.”Cell.1992；70:93-104.Migliaccio,E.et al.,“Opposite effects on the p52shc/p46shc andp66shc splicing isoforms on the EGF receptor-MAP kinase-fos signaling pathway.EMBO J.1997；16:706-716)。
活性氧化物、细胞压力及老化
活性氧化物(ROS)的超氧化物及过氧化物在许多生理及病理过程中进行重要的讯息传递功能，包括细胞衰老(cell senescence)及生物体器官老化(organismal age)(Afanas’ev,Igor,Oxidative Medicine and Cellular Longevity,V.3(2010),Issue 2,pages 77-85)。ROS为有效的细胞死亡诱导物，并执行细胞死亡过程(Giorgio et al.“Electron Transfer between Cytochrome c andp66Shc Generates Reactive Oxygen Species that Trigger MitochondrialApoptosis,”Cell Vol.122,221-233,July 29,2005)。
特别是通过ROS讯息传递来刺激SHC-1/p66。相反地，ROS藉由SHC-1/p66而产生。
因此，藉由许多结果可推论SHC-1/p66涉及糖尿病诱导的氧化应激及氧化剂依存性的肾病变引起的分子机制(Menini et al.,Diabetes 55:1642-1657(2006))。同时可知SHC-1/p66涉及与糖尿病相关的症状，例如高葡萄糖浓度相关的内皮功能障碍、动脉粥状硬化生成、糖尿病肾病变、及心肌病变等(Francia et al.,J.Mol.Med.(2009)87:885-891 and Berniakovich et al.JBC Vol.283 No.49,pp.34283-34293,December 5,2008)。
老化与肝脏
相较于年轻肝脏，老化的肝脏呈现增加的细胞性退化。具体地说，老化的肝脏细胞呈现代谢减弱并影响线粒体的功能与型态的改变(Sastre et al.“Aging of the Liver:Age-Associated Mitrochondrial Damage in IntactHepatocytes,”Hepatology November.(1996)pp.1199-1205 and Koch et al.,“Role of the life span determinant P66shcA in ethanol-induced liver damage,”Laboratory investigation(2008)88,750-760)。例如，糖质新生作用(gluconeogenesis)及酮体生成作用(ketogenesis)可能降低，但线粒体体积却可能增加。通过膨胀或“泡沫状”的细胞或脂肪变性(又称为脂肪改变、脂肪退化或脂肪细胞退化)可对肝细胞的退化进行病理性地检测。
膨胀的细胞通常为相邻肝细胞体积的二至三倍，且其特征为H&E染色切片上细束状清晰的细胞质。根据细胞质与细胞核，可区别膨胀细胞与类似脂肪细胞的细胞。膨胀细胞的细胞核位于细胞中央(类似脂肪细胞的细胞核则位于细胞周围)。而且，膨胀细胞具有(小的)绉缩的细胞核(pyknotic nuclei)或正在进行核碎裂(karyorrhexis)(即正在崩解)的细胞核。膨胀退化的细胞其细胞质则类似小束状或蜘蛛网状，而类似脂肪细胞的细胞则具有清楚的细胞质或有液泡的细胞质。
脂肪变性(steatosis)表示细胞中脂质被不正常的保留。这反应出三酸甘油酯的合成及去除的正常过程受到损坏。脂肪变性被认为与氧自由基造成肝细胞肿大有关(Del Monte,“Swelling of hepatocytes injured by oxidative stresssuggests pathological changes related to macromolecular crowding”MedicalHypotheses(2005)64,818-825)。
老化对运动技能与运动缺陷的影响
随着逐渐老化，感觉运动控制(sensory motor control)与功能也会逐渐地衰退。对细动作的控制、步态及平衡的衰退会影响老年人日常活动及其生活独立性(Yankner BA,Lu T,Loerch P.The aging brain.Annu Rev Pathol2008；3:41–66.；Twohing,J.P.et al.,“Age-dependent maintenance of motorcontrol and corticostriatal innervation by death receptor 3.”J.Neurosci.2010.30:3782-3792.)。运动缺陷(motor deficits)的原因是多因素的，且感觉受体、肌肉与周边神经的改变会影响中枢神经***的衰退。
对老年人而言，动作表现缺陷(Motor performance deficits)显然是因为中枢与周边神经***以及神经肌肉***的功能障碍(Seidler,R.et al.,“Motorcontrol and aging:Links to age-related brain structural,functional,andbiochemical effects.”Neuroscience and Biobehavioral Reviews 30(2010)721-733)。动作表现缺陷，相较于年轻人而言，在老年人发生包括肢体协调困难(Seidler,RD et al.,.“Changes in multi-joint performance with age.”MotorControl.2002；6(1):19–31.)、增加运动变异性(Contreras-Vidal et al.,“Elderlysubjects are impaired in spatial coordination in fine motor control,”Acta Psychol(Amst).1998 Nov；100(1-2):25-35；Darling et al.,”Control of simple armmovements in elderly humans.”Neurobiol Aging,1989 Mar-Apr；10(2):149-57)、动作缓慢(Diggles-Buckles V.“Age-related slowing.In:Stelmach GE,HombergV,editors.”Sensorimotor impairment in the elderly.Norwell,MA:KluwerAcademic；1993.)、步态及平衡困难等(Tang PF,Woollacott MH.“Balancecontrol in the elderly.”In:Bronstein AM,Brandt T,Woollacott MH,editors.Clinical disorders of balance,posture and gait.London:Arnold；1996.)。
这些缺陷负面影响老年人进行日常功能性活动的能力。步态及平衡的问题特别受到注意，其是老年人受伤及生病的主要原因，跌倒的老年人有20～30％会受到中度至重度的伤害，进而限制其活动及降低生活品质。因此随年龄增长而显著地延长运动的持续时间有多种的因素。随着年龄增加，运动会减慢约15～30％(cf.Diggles-Buckles,1993)。老年人在运动时会以强调动作的正确性但却会减缓运动速度作为运动的策略。缓慢的信息处理也会影响非特异性表现，如全球性的神经噪音(neural noise)或其他突触(synaptic)变化等。
而且，步态模式与老化之间的关联性连结已被描述，尤其在老化族群中，其步态的缩短与变慢(Wolfson,L.,et al.,(1990)“Gait assessment in the elderly:A gait abnormality rating scale and its relation to falls.”J.Gerontol.45:M12-19)。这种人类中可被辨识步态的改变已被认定与嚙齿类动物的老化依赖性性的步态变化有直接相关性(Klapdor,K.et al.,(1997)“A low-costmethod to analyze footprint patterns.”J.of Neuroscience Methods.75:49-54 andHilber et al.,(2001)“Motor skills and motor learning in lurcher mutant miceduring aging.”Neuroscience.102:615-623)。
发明内容
本申请涉及治疗SHC-1/p66相关疾病的一种或一种以上症状的方法、抑制ROS产生的方法、或制备用于上述治疗的医药的方法。在本申请的一实施例，本发明包括通过向所需哺乳动物给药含有具下式I所示的单体单元、和/或其可药用的盐类、溶剂化物、或前驱药物的聚合组合物来治疗SHC-1/p66相关疾病的一种或一种以上症状的方法:
其中，在式I中，R1和R2各自独立为氢、烷基或酰基；R3、R4、R5、R6和R7各自独立为氢、羟基、烷氧基、或酰基；以及R8为氢或糖基配体(saccharidemoiety)，并且其中上述单体的聚合度为2～30，该聚合物的平均分子量为600～10,000。
在本申请的一实施例，本发明包括聚合组合物用于制备治疗选自老化、糖尿病、及缺血后再灌流伤害(reperfusion injuries after ischemia)的SHC-1/p66相关性疾病的一种或一种以上症状的药物的用途，其中该聚合组合物包含具有式I所示的单体单元、和/或其可药用的盐类、溶剂化物、或前驱药物。
在本申请的一实施例，上述方法涉及治疗因SHC-1/p66表达(expression)或活性而影响的疾病的一种或一种以上症状。在一项特别的实施例中，“SHC-1/p66相关疾病”表示藉由降低SHC-1/p66的表达或活性而改善症状的疾病。此种疾病包括老化、糖尿病、及缺血后再灌流伤害等。本申请的方法涉及治疗老化的一种或一种以上的症状，例如细胞退化、肝细胞肿大、线粒体功能障碍、年龄相关的动作缺陷、和/或步态宽度的减少；涉及治疗糖尿病的一种或一种以上的症状，例如高葡萄糖浓度相关的内皮功能障碍、动脉粥状硬化形成、肾病变、和/或心肌病变；以及涉及治疗缺血后再灌流伤害的一种或一种以上的症状，其包括活性氧化物的增加及细胞死亡。
在一实施例中，本申请的方法包括给药含BEL-X和/或其可药用的盐类、溶剂化物、或前驱药物的组合物。在一实施例中，上述组合物的给药剂量为每公斤每日50～1,500mg。
本申请的详细说明及其特定实施例，参照图式记载、说明如下。
附图说明
图1:根据一实施例对老年小鼠的肝脏进行中草药BEL-X的治疗。
图1A～图1C为以***(formalin)固定、石蜡包埋后的肝脏样本经切片以苏木精(hemotoxylin)与嗜伊红(eosin)染色的结果，图1A为年轻小鼠(二月龄)的肝脏切片样本，图1B为老年、未处理的小鼠(20月龄)的肝脏切片样本，图1C为老年小鼠(20月龄)以口服给药1000mg/kg/日的BEL-X药物后的肝脏切片样本。
图2:以RT-qPCR检测SHC-1/p66表达。图中显示，根据一实施例，BEL-X降低了SHC-1/p66的表达。
图3:根据一实施例，使用西方点渍法(Western blotting)检测SHC-1/p66蛋白在小鼠肝脏中的含量。
图4:根据一实施例，检测经BEL-X药物处理后，对细胞中ROS产生量的影响。
人类肝癌细胞株Huh7以H2O2处理从而诱导ROS的产生(图4A及图4C)。此细胞在经H2O2诱导后再以BEL-X药物处理(图4B及图4D)。图4A及图4C显示在显微镜观察下的细胞，每一玻片上的细胞数量相近。这些细胞在图4B中以免疫荧光观察显示，H2O2诱导大量的ROS产生，然而在经BEL-X药物处理的细胞中则显示ROS产生量显著减少，表示BEL-X可减少ROS的产生以避免细胞癌化(图4D)。
图5:根据一实施例检测细胞中ROS的减少。对于包括人类肝癌细胞株Huh7、人类直肠癌细胞株HRT-18及人类正常皮肤细胞株WS1的多种细胞型态进行检测。所有被检测的细胞都显示，经BEL-X处理后的细胞显著地减少由H2O2诱导后产生的ROS。
图6A-图6C:显示根据一实施例，纯化自山苎麻(Boehmeria nivea(L.)Gaud)的原花青素(proanthocyanidins)的13C核磁共振光谱结果以获得BEL-X。
图7A-图7B:显示根据一实施例，原花青素(proanthocyanidins)的两个单体之间的键结关系。
具体实施方式
为了进一步解释，以下内容详细记载数种特定型态以提供对所揭示的实施例有完整的了解。然而无需这些特定的详细内容也可实施这些实施例中的一种或多种。另一方面，绘制习知结构与装置以简化图式的表现。
本申请的实施例包含式I所示的单体、或其可药用的盐类、溶剂化物(solvates)、或前驱药物(prodrugs):
其中，R1和R2各自独立为氢、烷基或酰基；R3、R4、R5、R6和R7各自独立为氢、羟基、烷氧基、或酰基；R8为氢或糖基配体(saccharide moiety)。
在一实施例中，本申请包含营养品、营养制剂、健康食品或补充品形式的组合物，其包括含有具下式I所示的单体单元的聚合组合物。
上述式中，该聚合化合物中的单体可具有一个或多个的下列特征:R1及R2独立为氢；R3和R7各自独立为氢；R4、R5和R6各自独立为羟基或烷氧基；以及R8为氢。
此聚合化合物中，藉由不同的单体单元的任意两个原子间的键结，例如C4-C8键结(即一个单体单元的C4碳原子与另一个单体单元的C8键结碳原子)、C4-C6键结(即一个单体单元的C4碳原子与另一个单体单元的C6碳原子键结)、或C2-O7键结(即一个单体单元的C4碳原子与另一个单体单元的O7氧原子键结)，单体单元彼此可共价连接。一实施例中，藉由C4-C8键结，所有的单体单元彼此共价键结。另一实施例中，藉由C4-C6键结，所有的单体单元彼此共价键结。应注意的是，环状化合物的原子以周知且惯用于化学结构命名规则的方式编号。以下显示式I聚合化合物的核心结构的原子编号:
一实施例中，本申请的组合物包含式I所示化合物的低寡聚物，如二聚体(dimer)、三聚体(trimer)及四聚体(tetramer)。于其他实施例中，此纯化的组合物包含式I所示的单体单元以不同聚合度所得的聚合化合物的混合物。
该单体单元的聚合度可在2～30的范围，优选在3～20的范围。平均分子量优选在600～10,000的范围。
一实施例中，本申请的组合物(包含BEL-X)可包含一种以上的式I单体单元的混合物。一实施例中，该聚合物可为均聚物(homopolymers)。一实施例中，该组合物可包含不同均聚物的混合物。于一实施例中，该聚合物可为包含复数种如式I所示的不同单体化合物的异聚物(heteropolymer)。
所述“经分离的制剂”(“isolated preparation”)表示含有如上述聚合化合物的一种或以上的组合物，该聚合化合物已分离(partition)自天然资源或合成的混合物。
术语“烷基”表示含有1～10个碳原子的直链或支链的烃类(hydrocarbon)。烷基的例子包含但不限于：甲基、乙基、正丙基、异丙基、正丁基、异丁基、和叔丁基。术语“酰基”表示-C(O)-烷基或-C(O)-芳基。酰基的例子包含但不限于：-C(O)-CH3或-C(O)-ph。术语“烷氧基”表示-O-烷基。烷氧基的例子包含但不限于-OCH3或-OC2CH3。
此处所提到的烷基可为经取代或未经取代的烷基。取代基的例子包含但不限于：卤素、羟基、氨基(amino)、氰基、硝基、巯基(mercapto)、烷氧基羰基(alkoxycarbonyl)、酰氨基(amido)、羧基、烷磺酰基(alkanesulfonyl)、烷基羰基、脲基(carbamido)、氨基甲酰基(carbamyl)、羧基、硫脲基(thioureido)、氰硫基(thiocyanato)、磺酰胺基(sulfonamido)、烷基、烯基、炔基、烷氧基、芳基、杂芳基、环基、杂环基，其中，烷基、烯基、炔基、烷氧基、芳基、杂芳基、环基和杂环基可选择性地以烷基、芳基、杂芳基、卤素、羟基、氨基、巯基、氰基或硝基所取代。
术语“糖基配体”表示碳水化合物基团。可为单糖(如阿洛糖(allose)、阿卓糖(altrose)、葡萄糖、甘露糖、古洛糖(gulose)、艾度糖(idose)、半乳糖、太洛糖(talose)、核酮糖(ribuose)、阿罗酮糖(psicose)、果糖、山梨糖(sorbose)、或塔格糖(tagatose))、二糖(如蔗糖、乳酮糖(lactulose)、乳糖、麦芽糖、海藻糖(trehalose)或纤维二糖(cellobiose))、寡糖(含3-10个单糖)、或多醣(含10个以上的单糖)的基团。
再者，式I所示单体可包含类黄酮(flavonoid)。类黄酮(flavonoid)可包含儿茶素(catechin)、表儿茶素(epicatechin)、表阿夫儿茶素(epiafzetechin)、没食子儿茶素(gallocatechin)、没食子表儿茶素(galloepicatechin)、表没食子儿茶素(epigallocatechin)、酯型儿茶素(gallates)、类黄酮(flavonols)、黄酮醇(flavandiols)、矢车菊素(leucocyanidins)、或前花青素(procynidins)。一实施例中，式I所示单体可包含黄烷-3-醇(flavan-3-ol)或黄烷酮衍生物(flavanonesderivatives)。具体例子分别包含：3-黄烷醇(3-flavanol)、3,4-黄烷醇(3,4-flavanol)、儿茶素((2R,3S)及(2S,3R))以及表儿茶素((2S,3S)及(2R,3R))。
上述聚合化合物包含上述单体或聚合的化合物，以及可实施的盐类、前驱药物及溶剂化物。盐类，例如形成于聚合化合物的阴离子与带正电荷的基团(如铵离子)之间。合适的阴离子包括氯离子、溴离子、碘离子、硫酸根离子、硝酸根离子、磷酸根离子、柠檬酸根离子、甲烷磺酸根离子、三氟乙酸根离子、乙酸根离子、琥珀酸根离子、苹果酸根离子、甲苯磺酸根离子、酒石酸根离子、富马酸根离子、谷氨酸根离子、葡萄糖醛糖酸根离子(glucuronate)、乳酸根离子、戊二酸根离子、及马来酸根离子。类似地，盐也可形成于聚合化合物上的阳离子与带负电荷的基团(如酚基或羧基)之间。合适的阳离子包括钠离子、钾离子、镁离子、钙离子、及铵离子。化合物也可为前驱药物(prodrug)及溶剂化物(solvate)的形式。前驱药物的例子包括酯类及其他可药用的衍生物，其在于个体(subject)给药时能够提供活性化合物。溶剂化物表示活性化合物与可药用的溶剂所形成的复合物。可药用的溶剂的例包括水、乙醇、异丙醇、乙酸乙酯、乙酸或乙醇胺。
该聚合化合物的单体包含非对称中心。因此可出现外消旋体(racemates)及外消旋混合物、单一的对映异构体(single enantiomers)、个别的非对映异构体(individual diastereomers)、及非对映异构体混合物。此述的异构体形式皆被考虑。一实施例中，该单体包含在C4位置上的(R)或(S)光学异构体。
本申请另一方面涉及抑制SHC-1表达、抑制肝细胞肿大、抑制ROS产生的方法、或涉及通过向所需个体给药由混合来自上述经分离的制剂与可药用的载体而得的医药组合物来减少老年运动缺陷(age-related motor deficits)的发生或严重度的方法。
在一实施例，本申请包括聚合组合物用于制备抑制SHC-1表达、抑制肝细胞肿大、抑制ROS产生或减少老年运动缺陷(age-related motor deficits)的发生或严重度的药物的用途，其中该聚合组合物包含具有式I所示的单体单元、和/或其可药用的盐类、溶剂化物、或前驱药物。
上述经分离的制剂用于治疗SHC-1/p66相关疾病的方法，或者用于制备上述改善、治疗、促进的医药的用途也落在本发明的范畴之内。
另一方面，本申请的组合物可于食品，如营养品、营养制剂、健康食品或补充品中而给药于个体。
本申请的多种实施例详细记载如下。从说明书和权利要求书中，本申请的其它特征，目的和优点将是显而易见的。
式I所示的聚合化合物，如上所述，可给药于所需个体以治疗SHC-1/p66相关疾病及抑制ROS的产生。
本申请的组合物可萃取自植物或以人工方法改良或合成。一实施例中，该植物可包括属于豆科(Leguminosae)、景天科(Crassulaceae)、使君子科(Combretaceae)、萝藦科(Asclepiadaceae)、蔷薇科(Rosaceae)、唇形花科(Lamiaceae)、蓼科(Polygonaceae)、杜鹃花科(Ericaceae)、松科(Pinaceae)、葡萄科(Vitaceae)或荨麻科(Urticaceae)的植物，优选为荨麻科(Urticaceae)的山苎麻(Boehmeria nivea(L.)Gaud)。可萃取的植物部分可包含根、茎、叶和/或果实部分。
萃取方法已记载于美国专利公开案US 2010/0168221及US2011/0158933中，全文在此并入作为参考资料。萃取物可进一步视需要进行部分纯化或完全纯化。
术语“减轻”或“抑制”包括减轻症状的严重程度或发生。一实施例中，减轻或抑制由与年龄相当的未处理对照组和/或未处理的年轻对照组比较所得的百分比而测得。在一实施例中，与年龄相当的对照组相比，症状的发生可被减少至少25％、50％或75％。在一实施例中，特定症状的严重度可被减少至少25％、50％或75％～99％。100％的症状严重度的减少表示该症状不再存在或可被检测到。一实施例中，“减轻或抑制”可由相对于年轻小鼠该症状的发生或严重度的”倍数”增加而测得。优选状况为，相对于年轻小鼠，该症状的发生或严重度的倍数增加为至少25％。
术语“显著”为一般统计学的显著数值。统计学上的显著可由一般周知方法确认。
术语“显著”表示使用统计方法比较处理群与未处理群或不同年龄群。
术语“治疗SHC-1/p66相关疾病”可表示治疗由SHC-1/p66的表达或活性影响的疾病的一种或一种以上的症状。尤其是，“SHC-1/p66相关疾病”是其症状会因减少SHC-1/p66的表达或活性而减轻的疾病。此疾病包括老化、糖尿病及缺血后再灌注损伤。
尤其是，本申请涉及治疗老化的一种或一种以上的症状，例如细胞性退化(cellular degeneration)、肝细胞肿大(hepatocyte swelling)、线粒体功能障碍(mitochondrial dysfunction)、老化性运动缺陷(age-related motor deficits)和/或步态宽步的减少(reduced stride length)等；涉及治疗糖尿病的一种或一种以上的症状，例如高葡萄糖浓度相关的内皮功能障碍(high glucose associatedendothelial dysfunction)、动脉粥状硬化(atherogenesis)、肾病变(nephropathy)和/或心肌病变(cardiomyopathy)等；以及涉及治疗缺血后再灌注损伤的一种或一种以上的症状，包括活性氧化物的增加及细胞死亡。
术语“老化性运动缺陷”可包括活动力的速度降低、步态宽度的减少、或活动力范围的减少。老化性运动缺陷的减少可表示延迟老化性运动缺陷的发生或者降低老化性运动缺陷的严重性。在一实施例中，人类老化性运动缺陷的发生可被延迟至少5年、10年、20年、30年、40年或50年。在一实施例中，老化性运动缺陷的严重性的降低可为，相较于未经处理、年龄相当的对照组的运动缺陷的严重性，在活动力速度和/或活动力范围方面改善至少50％～100％(包含该数值)。
个体可为动物，更具体为哺乳类动物，更具体为小鼠、大鼠、兔、羊或人。
剂型
为了实施本申请的方法，含有上述一种或多种聚合化合物的组合物或其构成单体可经胃肠外(parenterally)、口服(例如p.o.)、鼻腔、直肠、局部、或***(buccally)给药。本文的术语“非肠胃道”表示皮下、皮内、静脉内、肌肉内、关节内、动脉内、滑膜内、胸骨内、骨髓内(intrathecal)、病灶内或颅内注射以及任何合适的注射技术。
无菌注射组合物可为无毒的肠胃外可接受的稀释剂或溶剂中的溶液或悬浮液，例如于1,3-丁二醇中的溶液。可接受的容许载剂及溶剂为甘露醇及水。而且，通常采用固定油(fixed oil)作为溶剂或悬浮媒介(例如合成的单-或双-甘油酯)。例如为油酸及其甘油衍生物的脂肪酸可用于注射剂的制备，天然的可药用的油类，例如橄榄油或篦麻油，特别是其聚氧乙烯(polyoxyethylated)的形式。这些油溶液或悬浮液也可包含长链醇稀释剂或分散剂、羧甲基纤维素、或类似的分散剂。其他惯用于制备可药用的固体、液体或其他剂型的表面活性剂(例如Tween或Spans)或其他类似的乳化剂或生物活性促进剂也可于配方中使用。
口服给药的组合物可为任何口服可接受的剂型，包括胶囊、锭剂、乳状液或水溶性悬浮液、分散液及溶液。为锭剂时，通常使用的载剂包括乳糖及玉米淀粉。通常也会加入润滑剂例如硬脂酸镁。口服胶囊的有效稀释剂包括乳糖及干燥的玉米淀粉。为口服的水溶性悬浮液或乳状液时，活性成分可悬浮或溶解于油相而与乳化剂或悬浮剂结合。如果需要，也可加入甜味剂、调味剂、或着色剂。
鼻用气化喷雾或吸入组合物可根据习知医药调配技术制备。例如，可制备如溶液于生理食盐水中，加入苯甲醇或其他合适的防腐剂、吸收促进剂以增进生物有效性，如氟烃、和/或其他本领域习知的助溶剂或分散剂。具有一种或多种活性化合物的组合物也可以栓剂形式经直肠给药。
本申请的组合物的给药剂量为每日50～1,500mg/kg。在一实施例中，本申请组合物的给药剂量为每日250～1,000mg/kg。
增加步态宽度的优选剂量范围为每日50～1000mg/kg。
减少肝细胞肿大的优选剂量范围为每日100～1000mg/kg。
该医药组合物中的载剂必须为”可接受的”，这表示其必须与该组合物中的活性成分相容(优选为可稳定该活性成分)且无害于接受治疗的个体。一种或多种的助溶剂可为医药赋形剂(excipients)以递送活性化合物。其他载剂的例子包括胶体二氧化硅、硬脂酸镁、纤维素、月桂酸硫酸钠、D&C Yellow#10。
另一方面，本组合物可于食品中食用，例如营养品、营养制剂、健康食品或补充品。
化合物的效力可由体外(in vitro)或体内(in vivo)分析法的测试而得知。例如本申请的化合物可初步以体外(in vitro)分析法筛选，测试该化合物与氧化应激(oxidative stress)相关的生物活性。经初步筛选证实具有高效力的化合物可进一步地以本领域习知的体内(in vivo)分析法评估，以评估该化合物减轻或抑制老化基因(例如SHC-1/p66)的表达或转录的活性。
下述特定实施例仅用于说明，非用于限制本申请。无须进一步地阐述，相信此技术领域的人士可基于此述的说明利用本申请发明至最大程度。此引述的公开文献皆全文并入本文作为参考。
实施例
实施例1:BEL-X的制造及特征
含有原花青素(Proanthocyanidins)的山苎麻(Boehmeria nivea(L.)Gaud)萃取物的制备
方法1
清洗山苎麻(Boehmeria nivea(L.)Gaud)的根与茎并于自然环境下干燥。干燥的山苎麻切成5mm厚的薄片，于4℃的温度下储存。之后借由研磨机将储存的山苎麻磨粉，再使用20网目(mesh)的筛过筛。收集过筛的粉末，加入95％乙醇(1:10w/v)，加热回流2小时(进行两次)，之后冷却至室温。将经由加热、冷却至室温所得的萃取溶液放入离心袋(centrifuge bag)中以通过离心来过滤。通过真空蒸发器于低于40℃的温度浓缩过滤后的溶液，再经冷冻干燥机冷冻干燥。冷冻干燥后的萃取物为含有原花青素(proanthocyanidins)成分的医药组合物。
方法2
如方法1借由研磨机将于4℃的温度储存的山苎麻磨粉，再使用20网目(mesh)的筛过筛。收集过筛的粉末，加入RO水(1:10w/v)，加热回流2小时(进行两次)，之后冷却至室温。将经由加热、冷却至室温所得的萃取溶液加入乙醇水溶液(95-50％)并混合。待此萃取溶液冷却、沉淀后，将上层溶液加入离心袋中以通过离心来过滤。通过真空蒸发器于低于40℃的温度浓缩过滤后的溶液，再经冷冻干燥机冷冻干燥。冷冻干燥后的萃取物为含有原花青素(proanthocyanidins)成分的医药组合物。
山苎麻萃取物的纯化
方法1
溶剂萃取-1
将含有原花青素的山苎麻萃取物加入己烷(1:10w/v)，加热回流6小时以移除萃取液中的脂质。将固态的萃取物溶于70％甲醇水溶液和/或0.3％维生素C溶液，并通过真空蒸发器于低于40℃的温度将其浓缩以移除溶剂。之后将萃取物加入氯仿(萃取物:氯仿＝1:1v/v)，震荡30分钟(进行数次萃取)。将所得水层加入乙酸乙酯(萃取物:乙酸乙酯＝1:1,v/v)，震荡30分钟(进行数个萃取物)。通过真空蒸发器于低于40℃的温度浓缩将所得水层，再经冷冻干燥机冷冻干燥。
方法2
溶剂萃取-2
将含有原花青素的山苎麻萃取物溶于水/乙醇溶液，通过真空蒸发器于低于40℃的温度去除乙醇，加入己烷(1:10v/v)震荡30分钟(进行数次萃取)以移除萃取物中的脂质。将所得水层加入乙酸乙酯(水层:乙酸乙酯＝1:1,v/v)，并震荡30分钟(此步骤进行多次萃取)。将所得水层加入1-丁醇(1:1,v/v)，震荡30分钟(此步骤进行多次萃取)。通过真空蒸发器于低于40℃的温度浓缩所得水层，再经冷冻干燥机冷冻干燥。
方法3
凝胶渗透色谱分析(Gel Permeation Chromatography)
借由凝胶渗透色谱(gel permeation chromatography)(4cm直径x 45cm长的Sephadex LH-20)将方法1中部分纯化的含有原花青素的山苎麻萃取物分离，并使用具有不同极性比例的溶剂进行洗脱并移除杂质。将2.5g的部分纯化的山苎麻溶于0.5ml的95％乙醇，并将其加入凝胶渗透色谱柱再连续以一系列溶剂洗脱。收集以不同溶剂洗脱的洗脱液。该溶剂分别为300ml的95％乙醇、300ml的95％乙醇/甲醇(1/1,v/v)、300ml甲醇、300ml的50％甲醇水溶液及300ml的50％丙酮水溶液、300ml丙酮。除了洗脱液以300ml的95％乙醇洗脱外，所有其他的洗脱液通过真空蒸发器于低于40℃的温度浓缩，再经冷冻干燥机冷冻干燥。冷冻干燥的物质储存于-20℃以待后用。分析该具有部分纯化和/或纯化的原花青素的经冷冻干燥的山苎麻萃取物的物理化学性质。经冷冻干燥的洗脱物质具有部分纯化和/或纯化的原花青素成分。
13C及1H核磁共振光谱
纯化的原花青素样本以13C核磁共振光谱及1H核磁共振光谱检测。13C核磁共振光谱如图6A～图6C所示，其中，只有在145.2-145.7ppm处有双峰。因此该单体具有花青素，但无飞燕草素(delphindin)，亦即B环有3个OH基，此结果与EGA/MS分析结果相符。图6中，R1＝H或OH，R2＝H、OH或OCH。
根据13C核磁共振光谱及1H核磁共振光谱结果，原花青素的相邻单体间的键结主要发生在C4、C8碳–碳键之间。C4、C6碳–碳键及C2、C7氧键单元如图7A、图7B所示。
实施例2BEL-X的效果
实验动物群:使用C57BL/6种(C57BL/6 strain mice)的雄、雌鼠分为4群:(1)未处理的雄鼠(对照)；(2)9-20月龄经BEL-X处理的雄鼠；(3)未处理的雌鼠(对照)；(4)9-20月龄经BEL-X处理的雌鼠。
组合物的制备及剂量:将上述方法3得到的BEL-X溶于蒸馏水，使用管喂(feeding needle)经口服(p.o.administration)每日递送小鼠1000mg/kg。
至20月龄牺牲小鼠。收集肝组织及血清进行病理及生化活性分析。
A.Bel-X对老化肝脏的影响
小鼠牺牲时测量其体重及肝脏重量。收集肝脏，以***固定，石蜡包埋。肝脏切片以苏木精(hemotoxylin)与嗜伊红(eosin)染色。在显微镜下观察并对经固定与染色的肝切片进行组织病理评估，评估肝细胞的肿大病变。
结果如图1A、图1B、图1C所示。比较年轻小鼠(2月龄)与老年小鼠(20月龄)的肝脏，老年小鼠的肝脏确认有肝细胞肿大的现象(比较图1A、图1B)。再比较年轻小鼠与经过BEL-X处理的老年小鼠的肝细胞肿大现象，经BEL-X处理组显示出少量或几乎没有肝细胞肿大的现象，类似年轻小鼠的肝脏(图1C)。详细结果如下表1所示：
表1
具体地说，对于雄小鼠的对照组(未给药)而言，评估12只老年小鼠，其中有9只显示肝细胞肿大及退化。因此，所谓“肝异常比例”是显示肝细胞肿大的小鼠数目在进行评估的小鼠总数中的百分比。根据此数据发现，肝异常比例愈高，呈现肝细胞肿大现象者愈多。
表1证实在雄鼠及雌鼠群中，BEL-X给药显著减少肝细胞肿大的发生约50～75％。
B.以RT-qPCR检测SHC-1/p66
实时RT-PCR:根据Trizol RNA分离流程(Trizol RNA isolationprotocol)，对冷冻的小鼠肝脏进行总RNA的提取。使用随机引子(randomprimers)及SuperScript II试剂盒(SuperScript II kit)进行cDNA的合成。针对对目标基因SHC1异构体p66的无盐顺向引子(salt-free forward primer)为5’-CGGAATGAGTCTCTGTCATCGCTGGA(SEQ ID NO:1)；反向引子为5’-CGCCGCCTCCACTCAGCTTGTT(SEQ ID NO:2)。针对对内因性控制的家管基因(internal control house-keeping gene)GAPDH的顺向引子为5’-GAAGGTGAAGGTCGGAGT(SEQ ID NO:3)；反向引子为r5’-GAAGATGGTGATGGGATTTC(SEQ ID NO:4)。为了检测不同肝组织中目标基因的表达程度，于玻璃毛细管中将1μl的总cDNA加入9ml的实时PCR混合试剂(Roche Molecular Biochemicals)。使用四步骤的实验进行流程:(i)变性步骤(95℃、20秒)；(ii)扩增及定量步骤，对SHC-1/p66重复循环60次，对GAPDH重复循环40次(95℃、20秒；对SHC-1/p66为62℃、20秒，对GAPDH为60℃、20秒；72℃、20秒；对SHC-1/p66及GAPDH为82℃、20秒；使用单荧光测量)；(iii)解链曲线步骤(melting curve program)(以0.1℃/sec的加热速度升温60-95℃，以及连续荧光测量)；(iv)冷却步骤，降至40℃。
使用LightCycler软件3.5(Roche Molecular Biochemicals)计算RT-PCR产物的CT值。GAPDH基因用作参照。相关的SHC-1/p66表达程度以比较CT法来分析(Schmittgen,T.D.&K.J.Livak.(2008)“Analyzing real-time PCRdata by the comparative CT method.”Nature Protocol.3:1101-1108.)。
结果:如图2所示，在与未给药BEL-X的小鼠中SHC-1/p66的表达相比，BEL-X显著地减少了SHC-1/p66的表达。由于缺乏p66的小鼠及细胞会呈现ROS浓度降低及对氧化应激的抗性增加，因此SHC-1/p66表达的降低可减少ROS的产生进而降低氧化应激。
C.老化及BEL-X对SHC-1/p66蛋白的影响
西方点渍法:肝组织中加入10倍体积的RIPA缓冲液，均质化后离心移除组织碎片，以SDS-PAGE分离该溶液中的蛋白质。将SDS-PAGE中的蛋白转印至PVDF膜(Millipore)，并分别与特异性的抗SHC-1/p66抗体及抗GAPDH抗体培养。使用UVP生物光谱仪检测及分析特定的蛋白表达。
结果:如图3所示，图3证实SHC-1/p66在老年小鼠体内的蛋白浓度约为年轻小鼠体内的蛋白浓度的约两倍。但是，经过BEL-X处理的老年小鼠其肝脏中SHC1/p66蛋白表现量显著减少(蛋白浓度仅增加约64％)。
实施例3动作技能的评估
动物:使用C57BL/6种的雄、雌鼠。分为4群:(1)未给药的雄鼠(对照)；(2)12-20月龄经BEL-X处理的雄鼠；(3)未处理的雌鼠(对照)；(4)12-20月龄经BEL-X处理的雌鼠。将BEL-X溶于蒸馏水，使用管喂(feeding needle)经口服(p.o.administration)每日给药小鼠250mg/kg。
运动技能测试:已有研究比较嚙齿类动物的步态模式依赖年龄的变化与老年人行走模式的变化(Wolfson L,Whipple R,Amerman P,Tobin JN.(1990)Gait assessment in the elderly:A gait abnormality rating scale and its relation tofalls.J Gerontol.45:M12–19.)。因此，使用改良的步态测试法(Klapdor,K.et al.,(1997)A low-cost method to analyze footprint patterns.Journal of Neurosciencemethods.75:49-54；Hilber,P.and J.Caston.(2001)Motor skills and motorlearning in lurcher mutant mice during aging.Neuroscience.102:615-623.)测量不同年龄小鼠的步态宽度。以足染料染色小鼠脚爪，并于40×10cm纸上评估脚印。分析每只小鼠的步态宽度至少3次。
结果:如表2所示，不论雄鼠、雌鼠，老年小鼠的步态明显较年轻小鼠短。但是，经喂食BEL-X的年老小鼠具有与年轻小鼠几乎相同的步态宽度。因此每日250mg/kg的BEL-X处理可协助老年者维持其步态宽度。
表2动作技能测试
| 实验群 | 年龄(月数) | 性别 | 小鼠数 | 步态宽度(cm) |
| 对照组(Mock) | 5 | 雄 | 16 | 3.1±0.1 |
| 对照组 | 20 | 雄 | 16 | 2.6±0.1* |
| BEL-X喂食组 | 20 | 雄 | 16 | 3.2±0.1## |
| 对照组 | 5 | 雌 | 14 | 3.0±0.1 |
| 对照组 | 20 | 雌 | 15 | 2.6±0.1* |
| BEL-X喂食组 | 20 | 雌 | 16 | 3.1±0.1## |
*p<0.01，相较于C57BL/6J对照组5月龄；#p<0.01，##p<0.001，相较于C57BL/6J对照组20月龄。
比较小鼠与人类寿命，显然小鼠寿命短于人类。根据The JacksonLaboratory的报告，3～6月龄小鼠可相当于人类20～30岁，而16～24月龄小鼠则可相当于人类56～69岁。因此，根据上述实验数据，BEL-X的处理可使56～69岁的老人具有与20～30岁年轻人相当的步态宽度。
实施例4 BEL-X处理对ROS生成的影响
细胞培养:将人类肝癌细胞(Huh7)在MEM中培养，人类直肠腺癌细胞(HRT-18)及人类皮肤细胞(WS1)分别在DMEM中培养。该培养基添加1％盘尼西林(Penicillin)/链霉素(Streptomycin)混合物及1％非必须氨基酸、1％GlutaMAX-I、1Mm丙酮酸钠及10％胎牛血清。细胞在37℃、5％CO2培养箱中培养。
ROS诱导:将该细胞接种至24孔盘，培养24小时，之后加入800M的H2O2，培养1小时以诱导细胞中ROS的产生。
BEL-X处理:在上述H2O2诱导后，以BEL-X处理上述细胞24小时以测试BEL-X对ROS的影响。
检测ROS的产生:于上述细胞中加入10mM的CM-H2DCFDA，于37℃培养45分钟。使用荧光探针培养后，以PBS清洗细胞两次，直接于荧光显微镜下观察ROS的产生，或者以裂解的细胞(lysed cells)及分光光度计测量荧光强度，得到ROS的产生情形。
结果:如图4B～图4D所示，以H2O2诱导而诱发ROS产生的人类肝癌细胞Huh7，显示大量的ROS产生(如图4B的绿色荧光处)。但是，同时以BEL-X处理的诱发ROS产生的细胞则显示几乎无ROS的产生(如图4D的绿色荧光处)。
而且，如图5所示，在三种细胞型态(人类肝癌细胞Huh7、人类直肠腺癌细胞HRT-18、人类皮肤细胞WS1)中，BEL-X显著地降低因H2O2诱导的ROS的产生(*p<0.05)。因此，比较这些试验结果及先前的评估，显示BEL-X影响SHC-1，而SHC-1后续受到氧化应激路径的影响。因此，BEL-X可降低各种细胞类型，例如肝细胞、大肠细胞及皮肤细胞中的氧化应激。
对于本领域的技术人员而言，显然对此揭露的实施例可有多种修饰改良及变异。此目的为说明书和实施例被认为仅是示例性的真正范围，由所附权利要求及其等同物所指示的披露。
Claims (9)
1.聚合组合物用于制备治疗SHC-1/p66相关疾病的一种或一种以上的症状的药物的用途，其中该SHC-1/p66相关疾病为选自由老化、糖尿病及缺血后再灌注损伤所构成的群组，
其中，该聚合组合物包含具有下式I所示的单体、和/或其可药用的盐类、溶剂化物、或前驱药物:
式I中，R1及R2各自独立为氢、烷基或酰基；R3、R4、R5、R6和R7各自独立为氢、羟基、烷氧基、或酰基；R8为氢或糖基配体，
其中，上述单体的聚合度为2～30，并且该聚合物的平均分子量为600～10,000。
2.如权利要求1所述的用途，其中该SHC-1/p66相关疾病的一种或一种以上的症状为选自由下列所构成的群组:细胞性退化、肝细胞肿大、线粒体功能障碍、老化的运动缺陷、步态宽度减少、高葡萄糖浓度相关的内皮功能障碍、动脉粥状硬化、肾病变及心肌病变。
3.如权利要求1所述的用途，其中该聚合物包括BEL-X。
4.聚合组合物用于制备抑制肝细胞肿大的药物的用途，其中，该聚合组合物包含具有下式I所示的单体、和/或其可药用的盐类、溶剂化物、或前驱药物:
式I中，R1和R2各自独立为氢、烷基或酰基；R3、R4、R5、R6和R7各自独立为氢、羟基、烷氧基、或酰基；R8为氢或糖基配体，
其中，上述单体的聚合度为2～30，该聚合物的平均分子量为600～10,000。
5.聚合组合物用于制备抑制活性氧化物(ROS)产生的药物的用途，其中，该聚合组合物包含具有下式I所示的单体、和/或其可药用的盐类、溶剂化物、或前驱药物:
式I中，R1和R2各自独立为氢、烷基或酰基；R3、R4、R5、R6和R7各自独立为氢、羟基、烷氧基、或酰基；R8为氢或糖基配体，
其中，上述单体的聚合度为2～30，该聚合物的平均分子量为600～10,000。
6.如权利要求1～6任一项所述的用途，其中该方法包括经胃肠外、口服、鼻腔、直肠、局部、或***的方式给药该组合物。
7.如权利要求1～6任一项所述的用途，其中该组合物的给药剂量为每公斤每日50～1,500mg。
8.如权利要求7所述的用途，其中该聚合物为营养品、营养制剂、健康食品或补充品的形式。
9.营养品、营养制剂、健康食品或补充品型态的包含聚合组合物的组合物，该聚合组合物包括具有下式I所示的单体:
式I中，R1和R2各自独立为氢、烷基或酰基；R3、R4、R5、R6和R7各自独立为氢、羟基、烷氧基、或酰基；R8为氢或糖基配体，
其中，上述单体的聚合度为2～30，为营养品、营养制剂、健康食品或补充品型态。
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| PCT/CN2013/075599 WO2014101366A1 (en) | 2012-12-26 | 2013-05-14 | Methods for inhibition of shc-1/p66 to combat aging-related diseases |
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