CN102099049B - 3-脱氧葡糖醛酮的天然产物抑制剂 - Google Patents
3-脱氧葡糖醛酮的天然产物抑制剂 Download PDFInfo
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Abstract
本发明公开了组合物,其具有抑制果糖赖氨酸酶催产生3-脱氧葡糖醛酮(3DG)的抑制剂和/或3DG失活剂作为其组分,并且其可有效用于治疗或预防通过抑制这种3DG产生可减轻的病症或疾病状态。还公开了这种组合物的使用方法,例如,改善衰老皮肤的外观、质地和/或弹性。
Description
发明人:
Annette Tobia
Alice Marcy
Bangying Su
Takeshi Niwa
相关申请的交叉引用
本申请要求美国临时专利申请61/057,398(2008年5月30日申请)的权益,本文结合其全部公开内容作为参考。
背景
氨基酸赖氨酸是哺乳动物中必需的氨基酸,并且存在回收赖氨酸并因此其可被重复利用的生物化学途径。美国专利6,004,958(Brown等人)公开了由果糖赖氨酸(FL)酶催回收赖氨酸的Amadori途径,同时伴随产生3-脱氧葡糖醛酮(3DG)。正如在国际公开WO 03/089601所公开的那样,在皮肤中也发现了3DG和该酶。由于在葡萄糖和含有赖氨酸的蛋白的ε-NH2基团之间的可逆反应,赖氨酸在身体内被糖化。这种方法通过希夫碱中间体来进行,该中间体重排变成更稳定的FL,一种“Amadori产物”。通过饮食引进的熟的动物产品也可以提供糖化蛋白。糖化蛋白最终降解产生FL。果糖胺-3-激酶(F3K)在FL的3'-OH上将其磷酸化,形成果糖赖氨酸-3磷酸(FL3P),然后其自发地分解为赖氨酸、Pi和3DG。由此,F3K可以使身体回收赖氨酸,然而,这种方法产生3DG,其是高度反应性的二醛分子。已经证明,在初期不可逆转的步骤中,在形成蛋白交叉连接基(其是晚期糖化最终产物(AGEs)的特征)的过程中,3DG化学上可以与蛋白赖氨酸残基相互作用。
美国专利6,004,958(Brown等人)和国际申请公开WO 03/089601描述了一类化合物,其可以抑制FL酶转化为FL3P,抑制由FL的去醣化而形成赖氨酸,抑制3DG的形成,以及提供了3DG的失活作用和3DG的解毒作用。也已经对代表该类别的具体化合物进行了描述(Brown等人,国际公开WO 98/33492)。例如,人们发现,尿或血浆3DG可以被葡甲胺、山梨糖醇赖氨酸、甘露糖醇赖氨酸和半乳糖醇赖氨酸还原。在同一文献中,还发现,糖化蛋白含量高的饮食对肾有害,并且导致出生率降低。在同一文献中,还公开的是,FL途径与肾脏致癌作用有关。在同一文献中,进一步的,先前的研究表明,饮食和3DG可以在与这种途径有关的致癌作用中起一定作用(参见国际公开WO 00/24405;WO 00/62626;WO 98/33492)。
3DG是高度反应性的分子,可以通过至少两种途径将其在身体内解毒。在一种途径中,3DG被醛还原酶还原成3-脱氧果糖(3DF),然后3DF可有效地通过尿排泄(Takahashi等人1995, Biochemistry 34:1433-8)。另一个解毒反应是通过氧醛脱氢酶将3DG氧化为3-脱氧-2-酮葡糖酸(DGA)(Fujii等人1995, Biochem. Biophys. Res. Commun. 210:852-7)。
迄今为止的研究结果表明,这些酶中的一种(醛还原酶)对糖尿病产生不利影响。当从患有糖尿病的大鼠肝脏中分离这种酶时,这种酶在赖氨酸的67、84和140位置上被糖化,并且与正常未改性的酶相比较,具有催化作用降低的效果(Takahashi等人1995, Biochemistry 34:1433-8)。由于糖尿病患者比血糖正常个体具有更高比例的糖化蛋白,所以他们具有更高水平的3DG,其立刻趋向于使醛还原酶失活,并且降低该酶通过还原成3DF来解毒这种反应性分子的能力。有支持性的证据表明,在糖尿病人中,3DG至3DF的这种解毒作用受到削弱,这是由于糖尿病人的尿和血浆3DG解毒为3DF的比例显著地不同于非糖尿病个体(Lal等人1997, Arch. Biochem. Biophys. 342:254-60)。醛还原酶的超表达保护PC12细胞免于丙酮醛或3DG的细胞毒素效果(Suzuki等人1998, J. Biochem. 123:353-7)。
已经研究了醛还原酶的工作机理。这些研究表明,这种重要的解毒酶被醛糖还原酶抑制剂(ARIs)所抑制(Barski等人1995, Biochemistry 34:11264-75)。ARIs目前处于临床研究中,研究其降低某些糖尿病并发症的潜力。已经证明这些化合物(作为一类)对短期糖尿病并发症具有一些效果,但它们对长期糖尿病并发症缺乏临床效果,并且它们使饲喂高蛋白食物的大鼠的肾脏功能变差。这种发现与新发现的赖氨酸回收的代谢途径一致。
氨基胍(AG),其是通过形成快速排泄的共价衍生物而将3DG进行药理学解毒的药剂,(Hirsch等人1992, Carbohydr. Res. 232:125-30),可以在动物模型中降低AGEs相关的视网膜、神经、动脉和肾病变(Brownlee, 1994, Diabetes 43:836-41; Brownlee等人1986, Science 232:1629-32; 等人1991, Metabolism 40:1016-9; Soulis-Liparota等人1991, Diabetes 40:1328-34, 和Edelstein等人1992, Diabetologia 35:96-7)。
过去的研究集中于3DG在糖尿病中的作用。与非糖尿病个体相比较,糖尿病人的血浆中(Niwa等人1993, Biochem. Biophys. Res. Commun. 196:837-43; Wells-Knecht等人1994, Diabetes 43:1152-6)和尿中(Wells-Knecht等人1994, Diabetes 43:1152-6)的3DG和3DF(3DG的解毒产物)的水平提高。此外,与非糖尿病患者相比,发现患有肾病的糖尿病患者的血浆3DG水平提高(Niwa等人1993, Biochem. Biophys. Res. Commun. 196:837-43)。
最近的研究(比较患有胰岛素依赖性糖尿病(IDDM)和非胰岛素依赖性糖尿病(NIDDM)的患者)证明,两种类型病人的血液和尿中的3DG和3DF水平都提高。由此,在糖尿病人中,还原解毒3DG(转化为3DF)的正常途径受到削弱(Lal等人1995, Arch. Biochem. Biophys. 318:191-9)。甚至表明,在生理条件下体外培养葡萄糖和蛋白可以产生3DG。
继而,已经表明3DG使蛋白糖化和交联,形成可检测出的AGE产物(Baynes等人1984, Methods Enzymol. 106:88-98; Dyer等人1991, J. Biol. Chem. 266:11654-60)。
此外,与对照大鼠的肾相比,在糖尿病大鼠的肾中已经发现了3DG改性的蛋白的水平提高(Niwa等人1997, J. Clin. Invest. 99:1272-80)。3DG具有使酶(例如谷胱甘肽还原酶,中心抗氧化酶)失活的能力。还已经表明,糖尿病个体中的血色素-AGE水平提高(Makita等人1992, Science 258:651-3),并且在实验模型中已经显示其它AGE蛋白随时间而聚集,在糖尿病大鼠的视网膜、晶状体和肾皮质中,经过5-20周的周期,提高5-50倍(Brownlee, 1994, Diabetes 43:836-41)。另外,在糖尿病的胚胎病中,3DG是导致胚胎畸形的致畸因子(Eriksson等人1998, Diabetes 47:1960-6)。这看起来是由3DG的积聚所引起,其导致过氧化物介导的胚胎病。
无酶催化的糖化(其中还原糖与自由氨基共价连接、并且最终形成AGEs)在自然老化期间发生,并且在糖尿病中得到促进(Bierhaus等人1998, Cardiovasc. Res. 37:586-600)。蛋白的交联和随后AGEs的形成是不可逆过程,其改变蛋白、脂质组分和核苷酸的结构和功能性质(Bierhaus等人1998, Cardiovasc. Res. 37:586-600)。人们相信这些过程有助于一些糖尿病并发症的发展,包括肾病、视网膜病和神经病(Rahbar等人1999, Biochem. Biophys. Res. Commun. 262:651-6)。
在糖尿病大鼠中,抑制AGE的形成降低了肾病的程度(Ninomiya等人2001, Diabetes 50:A178-179)。因此,抑制AGE形成和/或氧化应激的物质似乎限制了糖尿病并发症的发展,并且可以在糖尿病的治疗中为治疗干预提供新的方法(Thornalley, 1996, Endocrinol. Metab. 3:149-166; Bierhaus等人1998, Cardiovasc. Res. 37:586-600)。
糖尿病个体中的血色素-AGE水平提高(Makita等人1992, Science 258:651-3),并且在实验模型中已经显示其它AGE蛋白随时间而聚集,在糖尿病大鼠的视网膜、晶状体和肾皮质中,经过5-20周的周期,提高5-50倍(Brownlee, 1994, Diabetes 43:836-41)。
3DG在人脐静脉内皮细胞中诱导反应性的氧物种,导致氧化性DNA损伤(Shimoi等人2001, Mutat. Res. 480-481:371-8)。另外,3DG诱导的反应性氧物种有助于糖尿病并发症的发展(araki, 1997, Nippon Ronen Igakkai Zasshi 34:716-20)。具体地说,3DG诱导肝素-结合表皮生长因子,其是在动脉粥样硬化斑块中大量存在的平滑肌分裂素。这说明3DG的提高可以在糖尿病中引发动脉粥样化形成(Taniguchi等人1996, Diabetes 45 Suppl. 3:S81-3; Che等人1997, J. Biol. Chem. 272:18453-9)。
最后,已经表明,糖尿病中的3DG血清水平和糖尿病并发症发展的危险之间具有直接联系(Kusunoki等人2003, Diabetes Care 26:1889-94)。结果表明,在糖尿病患者中,空腹血清3DG水平提高,并且具有相对更高的3DG水平的患者倾向于患有更严重的并发症,这表明3DG与糖尿病性微血管病变可能有关联。
3DG还产生与糖尿病无关的有害影响。例如,据证实,3DG在巨噬细胞衍生的细胞系中诱导细胞程序死亡(Okado等人1996, Biochem. Biophys. Res. Commun. 225:219-24),并且对培养的皮层神经元(Kikuchi等人1999, J. Neurosci. Res. 57:280-9)和PC12细胞(Suzuki等人1998, J. Biochem. 123:353-7)具有毒性。最近,对肌萎缩侧索硬化(运动神经元病的一种形式)的病因的研究已经说明,3DG的积聚可以由于形成ROS而导致神经毒性 (Shinpo等人2000, Brain Res. 861:151-9)。
先前的研究表明,3DG使蛋白糖化和交联,产生被称为AGEs的化合物的复杂混合物(Baynes等人1984, Methods Enzymol. 106: 88-98; Dyer等人1991, J. Biol. Chem. 266:11654-60)。AGEs与大部分炎症性疾病例如动脉粥样硬化和智力衰退以及糖尿病有关。它们最通常在长时间生存的结构蛋白例如胶原上形成。
AGEs具有特定的细胞受体,通常称为RAGE。细胞RAGE在内皮、单核吞噬细胞和胸腺依赖性细胞上的活化引发自由基的形成和炎症基因介质的表达(Hofmann等人1999, Cell 97:889-901)。这种提高的氧化应激导致转录因子NF-kB的活化,并且促进与动脉粥样硬化有关的NF-kB基因的表达(Bierhaus等人1998, Cardiovasc. Res. 37:586-600)。
在与癌的关系中,RAGE活化的阻断可以抑制与肿瘤增殖和肿瘤细胞的跨内皮迁移有关系的一些机理。这还会降低自发性和植入性肿瘤两者的生长和转移病变(Taguchi等人2000, Nature 405:354-60)。
AGEs由正常代谢作用产生,并且是非还原糖与蛋白、脂质或核酸的氨基的反应产物。AGEs可以通过各种成分组合与烹调而被引进到食品中。AGEs含量高的食品包括在高温下(例如焙、烤、油炸和烘)烹调的那些食品。(Goldberg等人2004, J Am Diet Assoc 104:1287-1291)。一部分摄食的AGEs被吸收,并且出现在循环中(Koschinsky等人1997, Proc Natl Acad Sci USA 94:6474-6497)。少量的AGE改性的肽可以通过肠内的上皮细胞(Huebschmann等人2006, Diabetes Care 29:1420-1432)。富含糖化蛋白的饮食导致循环AGE产物的提高(Uribarri等人2005. Ann NY Acad Sci 1043:461-466)。
循环AGEs水平还依赖于环境因素和生理状态。在患有糖尿病的人中,血浆AGE水平由于葡萄糖水平提高而提高,或在患有肾衰竭的患者中,血浆AGE水平由于肾的廓清率降低而提高(Odani等人1999, J. Chromatogr B 731:131-140; Odani等人Biochem Biophys res Commun 256:89-93)。吸烟者具有更高循环水平的AGEs(Cerami等人1997. Proc Natl Acad Sci USA 94:13915-20)。
饮食AGEs的摄入与循环AGEs有关,并且继而这些又与炎症和氧化应激的标记物有关(Koschinsky等人1997, Proc Natl Acad Sci USA 94:6474-6497; Vlassara等人2002, Proc Natl Acad Sci USA 99:15596-15601; Uribarri等人2007. J. Gerontol A Biol Sci Med Sci 62:427)。保持低AGE饮食的小鼠显示了AGE积聚降低、氧化应激降低和寿命提高(Cai等人2000, Am J Pathol 170:1893)。摄食高AGE膳食的糖尿病患者显示血清AGE的水平提高、氧化应激提高和血管功能的削弱(Negrean等人2007. Am J Clin Nutr 85:1236-43)。与低AGE饮食的动物相比,摄食高AGE饮食的糖尿病小鼠显示了削弱的创伤愈合能力(Peppa等人2003. .Diabetes 52:2805-13)。通过口腔吸附剂AST-120来吸收一种AGE产物,羧甲基赖氨酸,在患有慢性肾衰竭的非糖尿病患者中降低了AGE水平(Ueda等人2006. Mol Med 12:180-184)。
由于循环3DG的不利影响,合乎需要的是,通过使从食品或营养增补剂中摄入的3DG最小化,降低3DG接触量。由于3DG对皮肤细胞具有不利影响,因此,还合乎需要的是,通过降低局部制剂或化妆品中的3DG浓度来减少3DG对皮肤的接触量。3DG可以被醛还原酶酶催还原成3DF(Kato等人1990, Biochim Biophys Acta 1035:71-76; Liang等人1991, Eur J Biochem 197:373-379; Knecht等人1992, Arch Biochem Biophys294:130-137; Niwa 1999, J Chromatog B Biomed Sci Appl 731:23-36)。然后3DF可以有效地在尿中排泄 (Takahashi等人1995, Biochemistry 34:1433-8)。可以用氨基胍、半胱氨酸或吡哆醛5'-磷酸使3DG化学失活(Nakamura和Niwa, 2005, J Am Soc Nephrol, 16:144-150; Igaki等人1990, Clin Chem 36:631-634)。
已经注意到,具有F3K抑制活性的某些药剂还可以有效治疗或预防被称为“干眼症”(干性角膜炎)的病症。参见美国临时申请61/043,162(2008年4月8日申请)。干眼症是角膜和结膜表面的慢性干燥,并且由产生的泪水组分减少或湿润眼睛的泪膜的个别油、水和粘液组分的比例发生改变所引起。该病症显现各种症状,包括眼睛发红、眼疮、眼睛灼痛和眼睛发痒、畏光、视力模糊、异物感和接触眼镜不耐受。人们相信,上述药剂可以促进角膜和结膜表面的湿润,这是由于杯状细胞(其是分泌粘蛋白的主要渠道)增加而增加了粘液产生。由于杯状细胞存在于其它组织(消化道和呼吸上皮)中,所以,增加粘蛋白产生的药剂可以在治疗病症例如口干燥(口干症)和便秘方面具有附加的用途。
本发明概述
如上所述,如先前报道的,F3K在赖氨酸回收途径中的作用可导致高度反应性的3DG的产生,其在AGEs的形成过程中具有主要的作用。
按照本发明,现在发现,很多种天然产物包含一或多种可抑制FL酶转化成为FL3P和/或使3DG失活的组分。这种发现可以用下面的方式来付诸实际使用:
- 治疗或预防需要这种治疗或预防的患者的病症或疾病状态的方法,这种病症或疾病状态是通过抑制FL酶转化成为FL3P来减轻的,该方法是给予患者至少一种天然产物,该天然产物具有FL至FL3P酶转化的抑制剂作为其组分,以有效抑制这种转化的数量给予;
- 预防、改善和/或逆转内在和/或外在皮肤衰老的方法,该方法是给衰老皮肤局部施加包含至少一种天然产物的组合物,该天然产物具有FL至FL3P酶转化的抑制剂作为其组分,以有效抑制这种转化的数量施加;
- 改善衰老皮肤的外观、质地或弹性的方法,该方法是给衰老皮肤局部施加包含至少一种天然产物的组合物,该天然产物具有FL至FL3P酶转化的抑制剂作为其组分,以有效抑制这种转化的数量施加;或
- 治疗由于氧化应激和/或产生AGEs所造成的皮肤损伤的方法,该方法是给损伤皮肤局部施加包含天然产物的组合物,该天然产物具有FL至FL3P酶转化的抑制剂作为其组分,以有效抑制这种转化的数量施加。
按照本发明,还已经发现,许多天然产物含有不同数量的3DG,在某些实例中,其可以对使用它们的患者(人和动物)造成健康危险。当用作食品、化妆品、药物或营养增补剂成分时,可以通过降低3DG含量来提高这种含有3DG物质的纯度(健康危险的可能性相应地降低),例如,与3DG失活试剂混合。在下面的详细说明中,鉴定为此目的的合适失活试剂。
本发明的详细说明
含有F3K酶的抑制剂和/或3DG失活剂的天然产物可以有利地用于治疗或预防与3DG(以F3K活性的副产物形式产生)有关的病症或疾病状态。可以用本发明方法治疗或预防的疾病状态包括炎症性病症,糖尿病的并发症,衰老疾病,高血压症,中风,神经变性病症,循环疾病,动脉粥样硬化,骨关节炎和白内障。本文所描述的方法还可以用于治疗或预防皮肤病症,尤其是与内在或外在的衰老有关的那些皮肤病症。皮肤的内在衰老是由自然老化过程引起的逐渐退化,这种过程引起蛋白的化学结构发生变化,包括胶原和弹性蛋白,部分地是由于形成AGEs所造成的。许多外因,常常与自然老化过程结合起作用,致使皮肤的过早衰老。绝大部分外在的衰老是由日光照射或“光老化”引起的;然而,其它因素,例如,重复的面部表情和吸烟可以促进这种过早衰老。
各种不同的天然产物可以用于治疗或预防病症或疾病状态,这种病症或疾病状态可以通过抑制果糖赖氨酸至果糖赖氨酸-3-磷酸的酶转化和/或通过3DG的体内失活而得到减轻。本文使用的术语“天然产物”是指自然界中发现的化学物质,例如,从陆生植物、海洋动物或植物及其它生物机体的组织中获得的物质,以及这种物质的衍生物。可以用于本发明实践的天然产物(和其提取物)的代表性的例子包括:来自植物和动物源的材料,多肽,寡肽,维生素,前维生素等等。天然产物提取物可从各种渠道商购,并且可以使用一般性地描述在美国专利6,485,756(Aust和Wilmott)中的提取方法来制备。
适合于实践本发明的天然产物可以使用下文所描述的F3K试验来鉴别。对多种天然产物进行该试验的结果列在下面的表1和1A中。通过直接测定果糖赖氨酸-3-磷酸产生来测定F3K抑制活性的替代性试验描述在上述美国专利6,004,958中。
如果需要的话,可以与本文所描述的天然产物结合给予辅助活性剂。合适的辅助活性剂包括,例如,麻醉剂,抗生素,抗过敏剂,抗霉菌剂,杀菌剂,抗刺激剂,消炎剂,抗微生物剂,镇痛剂和抗高血压剂,例如ACE抑制剂。
本文所描述的天然产物以及任何辅助活性剂可以使用有效抑制酶催3DG产生的任何数量和任何给药途径来给予。所给予的确切数量可以根据患者的种类、年龄和一般条件、所治疗病症或疾病状态的性质、使用的具体天然产物和其给药模式来变化。本文使用的术语“患者”是指动物,包括哺乳动物,优选人和家畜。
通过供给患者(人或动物)富含糖化赖氨酸残基或FL的食品,并且测定供给食品前后的患者尿中的3DG和3DF数量,可以评价给予患者的天然产物数量的效果。与在给予天然产物之前相同患者的分泌水平相比较,在系统中具有有效抑制数量的F3K抑制剂的患者显示出3DG和/或3DF的分泌减少和FL的尿分泌增加。用于本发明实践的天然产物通常以粉末形式获得。因此,可以容易地将它们配制为局部或口服形式给药,优选局部给药形式。
包括任何各种皮肤可接受的赋形剂的局部制剂可以以下列形式制备:乳剂,膏剂,香脂,光泽剂,洗剂,油膏剂,屏蔽剂,乳浆剂,调色剂,软膏剂,油剂,摩丝,凝胶剂,油脂剂,溶液剂,液体喷雾剂,基于蜡的条状物或小毛巾。这种制剂可以有利地包括通常在化妆品领域使用的任何成分。这些成分包括:防腐剂,液相增稠剂,脂肪相增稠剂,香料,亲水性的和亲脂性的活性剂,以及色素,填料,油,一或多种蜡或胶,或任何上述成分的混合物。
另外,上述制剂可以包括下列中的一或多种:皮肤渗透增强剂,表皮输送系统,柔软剂,皮肤除酸剂,光学扩散剂,防晒剂,表皮脱落促进剂和抗氧化剂。除了别的以外,表皮输送系统可以是脂质体,纳米物质(nanosomes),基于磷脂的非脂质体组合物(例如,选择的脂质双层卷(cochleates))。关于这些及其它合适化妆品成分的详细内容可以在下列中得到:International Cosmetic Ingredient Dictionary and Handbook(ICID), 10th ed., Cosmetic, Toiletry and Fragrance Association, at 2177-2299(2004)。
这些天然产物还可以结合进透皮贴片或类似的递送系统中。透皮贴片可以是常规类型的结构,例如,用于递送持续剂量的雌激素、硝化甘油、芬大尼等等的类型。
在本发明的其它实施方案中,用作食品、化妆品、药物或规定食物的增补剂成分的含有3DG的天然产物的益处,可以通过降低其3DG含量的纯化或精制过程而得到提高。可以使用下面实施例2所描述的测定技术来测定天然产物的3DG浓度。
本发明所涉及的纯化或精制过程包括:使天然产物与至少一种3DG失活剂混合。合适的3DG失活剂的代表性例子列于下面表3中。精氨酸是实践本发明的该实施方案所使用的优选的3DG失活剂。
考虑到3DG对健康的潜在有害效果,将用作食品、化妆品、药物或规定食物的增补剂成分的天然产物的3DG含量的任何可测量的降低都会提供益处。
可以使用同样的方法以降低食品、食品添加剂或饮料中的3DG含量,饮料例如碳酸饮料,其可以是发酵的(例如啤酒,麦芽酒等等)或未发酵的碳酸饮料(例如可乐),以及非碳酸饮料,其可以是发酵的(例如酒)或未发酵的(例如果汁,果汁喷趣饮料,蔬菜汁或茶)。
提供下列方法和试验数据,以便进一步详细地描述本发明的各种实施方案。提供这些方法和数据仅仅是为了说明的目的,决不应该将其理解为对本发明的限制。
F3K试验
果糖胺-3-激酶(F3K)将果糖赖氨酸磷酸化,形成果糖赖氨酸-3-P,其自发地分解得到赖氨酸、Pi和3DG。该试验是在96孔平皿中进行的,每个孔含有100μl的50 mM Hepes,pH8.0,1mM Mg-ATP和0.20 mM果糖赖氨酸(Dynamis Therapeutics)。加入5μl试验抑制剂样品,用120 nM人重组F3K酶(Dynamis Therapeutics)来起始反应。在37℃将该平皿培养24小时,使F3K产生FL3P,而后分解释放Pi和3DG。按照实施例2测定3DG。
天然产物和化学制品
用各种商购的天然产物制备含水提取物。下面给出了所得到的提取物的浓度,基于重量/重量,除非另有陈述。LFK提取物和粉末得自于溶解的粪肠球菌FK-23。用榨汁机(Juiceman自动榨汁机)制备新鲜水果和蔬菜提取物。类似地制备草莓叶提取物(50% w/w,在水中)。使样品沉积或离心(12,000 x g,10 min),而后取出上清液的等分样品,用于分析。
实施例1
F3K抑制作用
使用上述试验,在各种天然产物的存在下测定F3K活性。抑制百分比示于表1和1A中。栗子皮、荔枝核、葡萄种子、醋栗、花生皮、猫爪藤和玫瑰的提取物抑制超过90%的F3K活性。
表1
在天然产物提取物的存在下的F3K活性
表1A
利用新鲜水果和蔬菜提取物、草药(herb)和茶来抑制F3K酶活性
样品 | 试验浓度(%) | 抑制(%) |
西红柿 | 5 | 73 |
洋蓟 | 5 | 92 |
洋蓟 | 0.5 | 61 |
椰菜 | 5 | 99 |
胡萝卜 | 5 | 88 |
黄瓜果肉 | 5 | 78 |
黄瓜皮 | 5 | 36 |
大蒜 | 5 | 66 |
青豆 | 5 | 30 |
青南瓜 | 5 | 62 |
苦瓜 | 5 | 90 |
李子 | 5 | 96 |
李子 | 0.5 | 87 |
红葡萄 | 5 | 91 |
绿葡萄 | 5 | 68 |
越桔(蓝莓) | 5 | 55 |
黑莓 | 5 | 76 |
覆盆子 | 5 | 74 |
草莓 | 5 | 86 |
薄荷叶 | 0.25 | 98 |
薄荷叶 | 0.025 | 90 |
玫瑰花 | 0.25 | 98 |
玫瑰花 | 0.025 | 77 |
草莓叶 | 0.25 | 96 |
草莓叶 | 0.025 | 75 |
银杏叶 | 0.25 | 84 |
银杏叶 | 0.025 | 42 |
咖啡 | 0.25 | 73 |
KeT Chi | 0.25 | 16 |
菊花 | 0.25 | 34 |
绿茶#1 | 0.12 | 89 |
绿茶#2 | 0.12 | 56 |
红茶 | 0.12 | 61 |
人参茶 | 0.12 | 81 |
有机绿茶 | 0.12 | 61 |
酸果蔓(cranberry)粉 | 0.25 | 92 |
野樱皮粉 | 0.25 | 94 |
猫爪草粉 | 0.25 | 95 |
紫草根粉 | 0.25 | 82 |
没药树胶粉 | 0.25 | 56 |
番茄粉 | 0.25 | 73 |
黑莓叶 | 0.25 | 32 |
桦树叶 | 0.25 | 3 |
桦树皮 | 0.25 | 15 |
罗勒叶 | 0.25 | 60 |
洋蓟叶 | 0.25 | 41 |
全燕麦 | 0.25 | 7 |
槲寄生 | 0.25 | 45 |
毒参茄/鬼臼根 | 0.25 | 71 |
蜜蜂花(Lemon Balm)草 | 0.25 | 55 |
蓝籽类叶牡丹(Blue Cohosh) | 0.25 | 25 |
草莓叶 | 0.25 | 14 |
绿薄荷叶 | 0.25 | 39 |
圣约翰草 | 0.25 | 35 |
覆盆子叶 | 0.25 | 36 |
薄荷叶 | 0.25 | 63 |
银柳皮粉 | 0.025 | 74 |
甘草粉 | 0.025 | 47 |
芥菜籽粉 | 0.025 | 43 |
银杏叶粉 | 0.025 | 31 |
爱尔兰藓粉 | 0.025 | 29 |
实施例2
天然产物和化学样品中的内原性的3DG浓度
使用下列技术,测定F3K试验样品和各种天然产物(在PBS中制备)中的3DG水平。
3DG的测定
试剂
50mM磷酸盐缓冲液,pH7.2(PBS)(Sigma)
乙酸乙酯(Fisher)
N-甲基-N-(三甲基甲硅烷基)-三氟乙酰胺(MSTFA)(Acros Organics)
2,3-二氨基萘(DAN)Sigma
10uM U-13C-3-脱氧葡糖醛酮(3DG)作为内标
试剂准备
试剂1:50mM磷酸盐缓冲液,pH7.2(PBS)
试剂2:0.1g DAN至1%(在100mL PBS中)
试剂3:10uM U-13C-3DG
试剂4:乙酸乙酯
试剂5:N-甲基-N-(三甲基甲硅烷基)-三氟乙酰胺(MSTFA)
设备
GC-MS: 6850自动液体取样器/G2570A 6850 GC/MSD系统/G1701 DA GC/MSD Chem Station Agilent
分析设定
1. 将样品(100uL-1mL)与试剂1合并,达总共1mL。
2. 加入1mL试剂2和20 uL试剂3。
3. 涡旋,并在室温下静置10小时。
4. 加入1 mL试剂4,涡旋。
5. 静置5分钟,并再加入1mL试剂4。
6. 离心大约10分钟。
7. 将上层移至另一个管中,在Speed-Vac中真空离心大约30分钟。
8. 加入200uL试剂4,涡旋。
9. 转移到另一个用于GC-MS的管中。
10. 在Speed-Vac中真空离心大约15分钟。
11. 加入100μL试剂5。
12. 在封闭加热器中,在50℃加热大约60分钟。
13. 利用GC-MS分析I295(12C-3DG)和I299(U-13C-3DG)。
结果示于表2中。一些天然产物提取物和氨基葡糖-盐酸盐含有>100μM的3DG。
表2
各种组合物中的3DG的水平
样品 | 浓度 | 3DG浓度(uM) |
栗子皮 | 0.1% * | 16.30 |
玫瑰提取物#1 | 5% * | 33.36 |
玫瑰提取物#2 | 5% * | 309.91 |
LFK提取物 | 10% * | 20.75 |
LFK粉 | 10% * | 20.06 |
植物提取物 | 10% * | 247.99 |
葡萄种子提取物 | 10% * | 11.63 |
荔枝核提取物 | 10% * | 26.50 |
氨基葡糖HCl | 100mM | 1011.94 |
凝血酸 | 100mM | 54.69 |
椰菜苗提取物 | 5% * | 23.13 |
椰菜提取物 | 5% * | 272.32 |
椰菜苗提取物 | 5% * | 53.71 |
花生皮提取物 | 5% * | 29.31 |
草药混合物 | 5% * | 255.57 |
醋栗提取物 | 5% * | 14.58 |
罗布麻提取物 | 5% * | 649.01 |
猫爪藤提取物 | 5% * | 54.98 |
* 表示含有不溶性物质的样品。
实施例3
3DG失活试验
下列试验用于测定3DG的失活(利用各种天然产物和化学制品)。
3DG结合试验
试剂
试剂1:50mM磷酸盐缓冲液,pH7.2(PBS)
试剂6:620μM 12C-3DG
培养设定
1. 用试剂1将样品稀释至1.9 ml体积,并加入100 uL试剂6,达总共2mL。
2. 在培养之前,从每个溶液取样600μL(作为第0天的样品)。
3. 使其在37℃静置24小时和72小时,并在第1天和第3天取出600μL样品。
4. 按照实施例2测定3DG水平。
表3中列出了结果。一些化学制品和天然产物提取物显示了3DG失活活性。3DG失活活性数量最多的样品是精氨酸,蛤蜊提取物,栗子皮提取物,猪和鱼胶原,吡哆醛-5'-磷酸,葡萄种子提取物,荔枝核提取物,花生皮提取物和猫爪藤提取物。大部分栗子皮3DG失活活性是在离心之后的上清液中。一些样品显示了3DG的高度内在水平,包括壳聚糖L,氨基葡糖,罗布麻提取物,椰菜提取物和草药混合物。
表3
实施例4
饮料和食品中的3DG水平
测定各种商品名饮料和食品中的3DG水平;结果示于表4中。日本豆酱汤、酱油和所有非酒精性饮料(食用苏打除外)和一种商标的绿茶含有高水平的3DG(>50μM)。所有的啤酒含有>300μM 3DG,黑啤酒含有最高水平的3DG(>600μM)。梅酒含有高水平的3DG,红葡萄酒具有相对低水平的3DG。
表4
样品 | 原产国 | μM 3DG |
苏打可乐A | 日本 | 286.59 |
苏打可乐B | 美国 | 491.58 |
苏打可乐C | 美国 | 550.28 |
无糖(diet)苏打可乐A | 美国 | 6.62 |
无糖(diet)苏打可乐B | 美国 | 10.64 |
柠檬莱姆饮料 | 美国 | 159.81 |
果汁宾治(Punch)饮料 | 美国 | 55.71 |
柠檬水 | 美国 | 499.06 |
橘子汁 | 美国 | 87.14 |
葡萄汁 | 美国 | 701.54 |
蔬菜汁 | 美国 | 321.51 |
绿茶A | 美国 | 608.88 |
绿茶B | 美国 | 246.68 |
绿茶C | 日本 | 1.14 |
啤酒A | 日本 | 420.47 |
啤酒B | 日本 | 329.46 |
啤酒C | 日本 | 529.46 |
啤酒D | 日本 | 463.94 |
啤酒E | 美国 | 370.06 |
啤酒F | 美国 | 759.09 |
啤酒G | 美国 | 322.48 |
啤酒H | 德国 | 360.79 |
黑啤酒A | 日本 | 757.37 |
黑啤酒B | 爱尔兰 | 646.63 |
红葡萄酒 | 美国 | 125.98 |
日本烧酒(Syotyu) | 日本 | 2.84 |
梅酒 | 日本 | 1582.25 |
酱油 | 日本 | 979.35 |
日本豆酱(5%溶液) | 日本 | 745.65 |
为了描述本发明所涉及的现有技术状态,在上述说明书中列举了许多专利和非专利出版物。本文结合这些出版物中的每一个的全部公开内容作为参考。
尽管上面已经描述了本发明的某些优选实施方案并且进行了具体举例说明,但本发明不限于这种实施方案。在没有背离下面权利要求所列出的本发明的范围和精神的条件下,可以对本发明进行各种修改。此外,过渡性术语“包括”、“基本上由...组成”和“由...组成”以原始和修正形式定义了后附的权利要求的范围,对于未叙述的其它权利要求要素或步骤,如果有的话,被从权利要求的范围中排除。术语“包括”是指包括在内或末端开放的,和不排除额外的、未叙述的要素、方法步骤或材料。措词“由...组成”除权利要求中具体说明的以外,排除任何其他要素、步骤或材料,且,在后者的实例中,杂质通常与明确说明的材料有关。措词“基本上由...组成”将权利要求的范围限制到具体的要素、步骤或材料,以及不实质上影响所请求权项的发明的基本的和新的特征的那些。本文中确定的所有的组合物或制剂,在可替换的实施方案中,更具体地由过渡性措词“包括”,“基本上由...组成”和“由...组成”的任何一项所定义。
Claims (18)
1.提高制剂的纯度的方法,该制剂含有作为食品、化妆品、药物或营养增补剂成份的氨基葡糖和其可药用盐和衍生物,所述方法包括:通过与3DG失活剂混合降低其3-脱氧葡糖醛酮(3DG)含量,所述3DG失活剂选自下面一组:栗子皮提取物,胶原,吡哆醛-5'-磷酸,玫瑰提取物,溶解的粪肠球菌FK-23提取物,溶解的粪肠球菌FK-23粉,葡萄种子提取物,荔枝核提取物,花生皮提取物,罗布麻提取物和猫爪藤提取物。
2.精制含有3DG的天然产物的方法,该天然产物作为食品、化妆品、药物或营养增补剂成分,所述方法包括:通过与3DG失活剂混合降低所述天然产物的3DG含量,所述3DG失活剂选自下面一组:栗子皮提取物,胶原,吡哆醛-5'-磷酸,玫瑰提取物,溶解的粪肠球菌FK-23提取物,溶解的粪肠球菌FK-23粉,葡萄种子提取物,荔枝核提取物,花生皮提取物,罗布麻提取物和猫爪藤提取物。
3.降低含有3DG的饮料、食品或食品添加剂的3-脱氧葡糖醛酮(3DG)含量的方法,所述方法包括:使3DG失活剂与所述饮料、食品或食品添加剂混合,所述3DG失活剂选自下面一组:栗子皮提取物,胶原,吡哆醛-5'-磷酸,玫瑰提取物,溶解的粪肠球菌FK-23提取物,溶解的粪肠球菌FK-23粉,葡萄种子提取物,荔枝核提取物,花生皮提取物,罗布麻提取物和猫爪藤提取物。
4.权利要求3的方法,其中所述3DG失活剂与碳酸饮料混合。
5.权利要求4的方法,其中所述碳酸饮料是发酵饮料。
6.权利要求3的方法,其中所述3DG失活剂与非碳酸饮料混合。
7.权利要求6的方法,其中所述饮料是发酵饮料。
8.权利要求6的方法,其中所述饮料是果汁、果汁宾治、蔬菜汁或茶。
9.可提高杯状细胞增殖的天然产物用于制备用于治疗或预防干燥粘膜病症的药物中的用途,其中所述天然产物选自栗子皮提取物,胶原,吡哆醛-5'-磷酸,玫瑰提取物,溶解的粪肠球菌FK-23提取物,溶解的粪肠球菌FK-23粉,葡萄种子提取物,荔枝核提取物,花生皮提取物,罗布麻提取物和猫爪藤提取物。
10.权利要求9的用途,其中所述病症选自下面一组:干眼症、口干燥和便秘。
11.一种局部组合物,其包含至少一种天然产物和至少一种皮肤可接受的赋形剂,其中该天然产物包含能够起到抑制由果糖赖氨酸酶催产生3-脱氧葡糖醛酮的作用的试剂,所述能够起到抑制由果糖赖氨酸酶催产生3-脱氧葡糖醛酮的作用的试剂选自栗子皮提取物,胶原,吡哆醛-5'-磷酸,玫瑰提取物,溶解的粪肠球菌FK-23提取物,溶解的粪肠球菌FK-23粉,葡萄种子提取物,荔枝核提取物,花生皮提取物,罗布麻提取物和猫爪藤提取物。
12.权利要求11的组合物,进一步包含下列中的至少一种:皮肤渗透增强剂,柔软剂,皮肤除酸剂,光学扩散剂,防晒剂,表皮脱落促进剂和抗氧化剂。
13.权利要求11的组合物,其中所述赋形剂是包含至少一种脂质体、纳米物质(nanosomes)和基于磷脂的非脂质体制剂的递送赋形剂。
14.制品,其包含结合进透皮贴片中的权利要求11的组合物。
15.局部组合物,其包含至少一种天然产物和至少一种皮肤可接受的赋形剂,其中该天然产物包含3-脱氧葡糖醛酮的失活剂,所述失活剂选自栗子皮提取物,胶原,吡哆醛-5'-磷酸,玫瑰提取物,溶解的粪肠球菌FK-23提取物,溶解的粪肠球菌FK-23粉,葡萄种子提取物,荔枝核提取物,花生皮提取物,罗布麻提取物和猫爪藤提取物。
16.权利要求15的组合物,其中所述赋形剂选自下面一组:皮肤渗透增强剂,柔软剂,皮肤除酸剂,光学扩散剂,防晒剂,表皮脱落促进剂和抗氧化剂。
17.权利要求15的组合物,其包括递送赋形剂,其中递送赋形剂包含脂质体、纳米物质和基于磷脂的非脂质体制剂。
18.制品,其包含结合进透皮贴片中的权利要求15的组合物。
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2009
- 2009-05-29 US US12/474,904 patent/US20100068259A1/en not_active Abandoned
- 2009-05-29 CN CN201410250459.7A patent/CN104173392A/zh active Pending
- 2009-05-29 WO PCT/US2009/045641 patent/WO2009155097A1/en active Application Filing
- 2009-05-29 CN CN200980128105.2A patent/CN102099049B/zh not_active Expired - Fee Related
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2011
- 2011-09-02 HK HK11109315.6A patent/HK1155074A1/zh not_active IP Right Cessation
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2012
- 2012-05-24 US US13/479,419 patent/US20120231071A1/en not_active Abandoned
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2013
- 2013-06-03 US US13/908,248 patent/US20130266638A1/en not_active Abandoned
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2016
- 2016-07-25 US US15/218,347 patent/US20160331798A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
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WO2009155097A1 (en) | 2009-12-23 |
US20130266638A1 (en) | 2013-10-10 |
US20160331798A1 (en) | 2016-11-17 |
CN102099049A (zh) | 2011-06-15 |
CN104173392A (zh) | 2014-12-03 |
US20120231071A1 (en) | 2012-09-13 |
HK1155074A1 (zh) | 2012-05-11 |
US20100068259A1 (en) | 2010-03-18 |
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