CN102470155A - 达木林a及达木林b含量增加的新绞股蓝提取物制备方法及利用该提取物制备的代谢疾病治疗用药物组合物 - Google Patents
达木林a及达木林b含量增加的新绞股蓝提取物制备方法及利用该提取物制备的代谢疾病治疗用药物组合物 Download PDFInfo
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Abstract
本发明涉及作为活体内能量传感器及调节脂质代谢和糖代谢的关键酶-蛋白激酶(AMPK)的活化物质在代谢疾病的改善及治疗方面的应用。当AMPK被活化,脂肪合成及胆固醇合成会受到抑制,会促进体内脂肪减少和血糖降低,从而使得肥胖、糖尿病及高血脂症得到改善。本发明涉及作为AMPK的活化物质的新型化合物在改善和治疗包括肥胖、糖尿病及高血脂症的代谢疾病上的应用,所述新型化合物作为具有改善和治疗功效的有效成分使用。所述化合物为被命名为达木林A(DamulinA)的2α,3β,12β-三羟基达马酯-20(2)-E,24-二烯-3-O-[β-D-吡喃葡萄糖基-(1→)-β-D-吡喃葡萄糖]和被命名为达木林B的2α,3β,12β-三羟基达马脂-20,24-二烯-3-O-[β-D-吡喃葡萄糖基-(1→)-β-D-吡喃葡萄糖]。并且,本发明提供通过高温、高压处理绞股蓝(Gynostemma pentaphyllum)提取物,从而提高AMPK活化有效指标物质-达木林A或达木林B含量的方法;同时还提供AMPK活化能力显著增加的新绞股蓝提取物用于改善或治疗肥胖、糖尿病及高血脂症等代谢疾病的技术。
Description
技术领域
本发明涉及具有新组成的绞股蓝提取物的制备方法,其是以高温高压方式处理绞股蓝提取物,提高了蛋白激酶(AMPK)活化有效成分达木林A(Damulin-A)及达木林B(Damulin-B)的含量。
本发明还涉及将达木林A及达木林B含量得到提高的具有新组成的新绞股蓝提取物作为有效治疗及改善代谢疾病的用途使用的方法。所述代谢疾病包括肥胖、糖尿病、高血脂症等。
背景技术
AMPK(蛋白激酶,AMP-activated protein kinase))是由α、β、γ亚单位(Subunit)构成的异三聚体(Heterotrimer)蛋白,肌管细胞中存在较多,还存在于大脑、心脏、脂肪组织及肝,是一种酶。AMPK是感知细胞内能量水平的重要传感器,此外通过上述结果,其对食欲调节、体重调节、血糖调节及血脂代谢调节等起核心作用。
在高强度运动或长时间处于饥饿状态时,由于三磷酸腺苷(ATP)的大量消耗、腺苷酸(AMP)浓度上升,因此AMP与AMPK的γ亚单位结合,从而引发AMPK的活化。实质性的活化由称做LKB1或CaMKK的上位磷酸化酶,通过对AMPKα亚单位苏氨酸(Threonine)(Thr)-172残基的磷酸化来表现。
磷酸化形态的AMPK抑制消耗ATP的生化反应-脂肪酸和胆固醇的合成,与此相反其使得生成ATP的脂肪酸β氧化(β-oxidation)过程和糖酵解作用(glycolysis)得到活化。不仅如此,还增加作为细胞膜葡萄糖吸收通路的葡萄糖转运蛋白4(glucose transporter4,GLUT4)的量。另外,AMPK的活化与胰岛素作用下的PI3K信号传达机制无关,使细胞内的葡萄糖吸收通路GLUT4的细胞膜移动增加。此外,AMPK在磷酸化作用下被活化时,作为另一下位蛋白的胰岛素合成核心酶HMG-CoA还原酶(羟甲基戊二酸-辅酶A还原酶,hydroxymethylglutaryl-CoA reductase)发生磷酸化。结果HMG-CoA还原酶失活(inactivation),胆固醇的合成降低,从而使得血液中的胆固醇减少。
通过磷酸化成为活化形态的AMPK酶使得作为其下位蛋白脂肪酸合成核心酶ACC(乙酰辅酶A羧化酶,acetyl-CoA carboxylase)的丝氨酸(ser)-79残基发生磷酸化,抑制该ACC酶的活性。其结果,AMPK的活化使脂肪酸合成反应中的核心代谢产物-丙二酰基-CoA(Malonyl-CoA)的生成降低,抑制脂肪酸的合成。AMPK活化引起丙二酰基-CoA减少时,向线粒体(mitochondria)内部流入脂肪酸-长链酰基-CoA(Long chain acyl-CoA),促进β氧化。在高浓度丙二酰-CoA存在条件下,将长链酰基-CoA传送到线粒体的CPT1(肉毒碱棕榈酰基-辅酶A转移酶,carnitine palmitoyl-CoA transferase)受到抑制,由于AMPK的活化使丙二酰-CoA的浓度降低,随着这一阻碍作用的消除,使长链酰基-CoA形态的脂肪酸大量流入线粒体内部,增加β氧化,因此体脂肪及血液中性脂质降低。
AMPK的活化引发对PGC-1α(过氧化物酶体增殖子-活化受体γ共激活剂-1α,Peroxisome proliferator-activated receptor gamma coactivator-1α)的磷酸化,此外还活化组蛋白脱乙酰酶(Histone deacetylase)的一种-SIRT1(沉默信息调控T1,Silent Information Regulatory T1)。其结果,在AMPK和SIRT1作用下发生的PGC-1α的磷酸化及去乙酰化,使线粒体代谢活跃,可获得糖尿病及肥胖改善效果(Canto和Auwerx,脂血症新见期刊20,98-105,2009(Canto and Auwerx,Curr.Opin.Lipidol.20,98-105,2009);Canto等,自然(Nature)458,1056-1060,2009)。因此,AMPK的活化可以抑制体内脂肪酸及胆固醇的合成,并促进体脂肪的β氧化及促进血液葡萄糖的细胞吸收等作用。因此,活化AMPK的物质可以有效地用于改善或治疗肥胖、糖尿病及高血脂症。
绞股蓝(Gynostemma pentaphyllum)是属于葫芦科(Cucurbitaceae)的多年生藤本植物。在山地或野外的树丛中自生,根茎向旁伸展,节上长有白毛,互相绞缠生长,,也可以靠卷须攀援生长。干燥绞股蓝叶制备的茶主要也称作绞股蓝茶,可消除圆形脱毛症,恢复各个脏器的功能,维持健康的皮肤。具有调节压力的功效,对迟缓性便秘及痉挛性便秘有抑制效果,有止泻效果,对支气管哮喘,老年性慢性支气管炎有效。另外,具有镇咳、祛痰作用,对应激性溃疡有效,还可预防肝炎、动脉硬化,并具有镇痛等作用。
如韩国公开专利2008-0003931中指出,绞股蓝提取物可增加蛋白激酶(AMP-activated protein kinase)(AMPK)的活性,可改善胰岛素抵抗性、改善包括肥胖以及高血脂症等的代谢疾病。对此,本发明通过分析绞股蓝提取物的成分,发现称做达木林A和达木林B的物质对AMPK的活性产生影响。另外可确认,利用本发明的技术制备的达木林A及达木林B含量增加的具有新组成的新绞股蓝提取物,与现有绞股蓝提取物相比,其AMPK的磷酸化能力及酶活化能力得到增强。
发明内容
本发明要解决的技术问题
本发明的目的在于提供一种含有从绞股蓝提取物分离的新化合物-达木林A或达木林B的具有改善及治疗肥胖、糖尿病及高血脂症等代谢疾病效果的组合物。
本发明的另一目的在于:提供一种达木林A或达木林B含量得到提高,并具有改善及治疗肥胖、糖尿病及高血脂症等代谢疾病效果的新绞股蓝提取物及包括其的医药品、功能保健食品或功能食品。。
解决技术问题的技术手段
本发明利用HPLC及NMR方法,对具有蛋白激酶(AMPK)的酶活化功能的新达玛烷型皂苷物质-被命名为达木林A(damulinA)的2α,3β,12β-三羟基达马脂-20(2)-E,24-二烯-3-O-[β-D-吡喃葡萄糖基-(1→)-β-D-吡喃葡萄糖](2α,3β,12β-trihydroxydammar-20(22)-E,24-diene-3-O-[β-D-glucopyranosyl-(1→)-β-D-glucopyranoside])及被命名为达木林B(damulinA)的2α,3β,12β-三羟基达马脂-20,24-二烯-3-O-[β-D-吡喃葡萄糖基-(1→)-β-D-吡喃葡萄糖](2α,3β,12β-trihydroxydammara-20,24-diene-3-O-[β-D-glucopyranosyl-(1→)-β-D-glucopyranoside]),利用高效液相色谱法(HPLC)及核磁共振法(NMR)进行分离分析,其结构如下列化学式所示。
化学式1
达木林A
达木林B
为了制备分离达木林所需的绞股蓝叶提取物,先把干燥的绞股蓝叶浸泡在10~20倍体积的乙醇水溶液(优选20~80%乙醇水溶液)中,提取后收集1次上清液。再次向绞股蓝叶剩余浸渍物加入6~20倍乙醇水溶液(优选20~80%乙醇水溶液)后,在65~95℃下提取1~8小时,得到2次上清液。混合1次和2次上清液后,利用纱布进行过滤,将获得的液体在800~1,500xG条件下进行离心分离,去除悬浮物。对获得的提取液进行减压浓缩,浓缩成40~70Brix(白利糖度),获得绞股蓝提取物浓缩液(以下称为“TG1022”)。对上述TG1022再次于高温高压条件下进行处理,获得达木林(Damulin)含量提高的新绞股蓝提取物浓缩液(以下称为“TG1022F”)。
为了获得达木林含量得到提高的新绞股蓝提取物(TG1022F),需要维持高温及高压。为此可以利用市场上的普通高温高压或附有高温高压灭菌装置的发酵槽及提取器。
上述新绞股蓝提取物也可以在温度不高的超高压状态下生成,为了维持超高压状态,可以使用市场上销售的超高压反应器。比如,可以使用日本东洋高压公司的DFS-2L等。制备上述新绞股蓝提取物的优选温度是40~125℃,优选压力是1.2~1100大气压。反应时间优选0.1~24小时。此外,作为提高达木林A和达木林B含量的方法,除了高温及高压条件,也可以使用超高频炉(superhigh frequency range)或烘箱(oven)。
达木林A及达木林B的分离及分析可通过如下步骤确认。即,使绞股蓝提取物通过填充有阴离子交换树脂的色谱柱(column)的步骤;以5~15倍纯净水洗涤的步骤;通过5~15倍甲醇进行洗涤的步骤;以5~15倍丙酮、正己烷(n-Hexane)、乙酸乙酯、正丁醇(n-butanol)分步骤进行提取的步骤;利用HPLC从上述各样份提取物中,的AMPK的活性高的提取液分离达木林A及达木林B的步骤。
本发明的对绞股蓝提取物施加高温及高压处理得到的新绞股蓝提取物,其达木林A及达木林B的含量得到增加,其治疗糖尿病、肥胖,减少体脂肪、血液中性脂肪及胆固醇的效果得到显著提高。为了具有针对这些代谢疾病的治疗、改善或预防效果,所需的达木林A及达木林B含量分别是:以干燥重量为标准,本发明新绞股蓝提取物干燥固体粉末中的有效指标成分-达木林A含量范围在0.5%到10%、优选0.7到7%,达木林B的含量范围在0.3%到8%、优选0.5%到6%。
新绞股蓝提取物或粉末化之前的液态物(以固体含量换算达木林A或达木林B分别含有0.5%~10%及0.3%~8%以上)的每天给药量以固体含量为标准1mg~100g为适当,还可与其他添加物及赋形剂一起给药。
本发明的制剂中,含有达木林A或达木林B作为有效成分的绞股蓝提取物含量的范围可以为整个组合物的0.01%~100%。
此外,含本发明组合物的食品,在不妨碍抗肥胖、抗糖尿病以及抗高血脂症效果的组成范围内,可以和任何种类的载体(Carrier)一起使用。本发明的组合物可以添加到温泉水、过滤的水、蒸馏水、碳酸水、果汁(juice)、酸奶、牛奶、食用油、食品添加剂、冰欺凌、汉堡、谷物食品(cereal)、曲奇饼、面包、饼干、加工肉类、豆奶、鲜食(海鲜饭)、营养补品、加工果实、水果汁等,而含有该组合物的食品可以含有增容剂、防腐剂、甜味剂、色素、润湿乳化剂。
根据疾病的临床表现,可选择已公认的多种给药方式。例如可采用口服或非口服给药方式。作为非口服方式有静脉注射、肌肉注射、皮下脂肪注射、鼻腔给药方法,其剂型可以是固体剂型、半固体剂型、液体剂型。另外包括栓剂、膏剂、凝胶(gel)、贴剂、***栓剂、喷雾剂等,可定量给药的所有形式。作为药物组成包含传统的载体及免疫增强剂。本发明的载体,只要是在药理学上得到公认的载体、都可以使用,只要对细胞和哺乳动物无毒害作用即可采用任何赋形剂或稳定剂。药理学上公认的载体包括pH缓冲水溶液、磷酸和柠檬酸,还可以包括抗坏血酸等。水溶性聚合物-聚乙烯吡咯烷酮、甘氨酸、谷氨酸盐、天冬酰胺、精氨酸或赖氨酸等氨基酸,以及葡萄糖、甘露糖、葡聚糖等碳水化合物也能作为载体。EDTA等螯合剂、甘露醇、山梨醇以及非极性表面活性剂吐温(TWEEN)、PEG(聚乙二醇,polyethylene glycol)、以及普朗尼克类(PLURONICS)也可以作为载体使用。作为药理学上得到认证的载体和稀释剂,包括所有种类的溶液、分散剂、抗细菌及抗真菌剂,等渗剂以及吸收延迟剂。这些药理上活性物质相关制剂的利用方法同现有技术中的记载。包括除与药物活性物质不符的制剂之外的所有制剂。该组成中还可加入补充成分。本发明的组合物还可以含有铬、锰、锌、尼克酸、维生素B6、维生素B12等,这里还可以含有对肥胖有疗效的HCA(羟基柠檬酸,hydroxycitric acid)及CLA(共轭亚油酸,conjugated linoleic acid)等。
口服给药时,也可以添加药理上得到认可的无毒害作用的赋形剂。作为赋形剂包括甘露醇、葡聚糖(Polydextrose)、麦芽糊精葡萄糖(Malto dextrose)、淀粉、乳糖、硬脂酸镁、糖精、滑石(talc)、纤维素、葡萄糖、明胶、白糖、碳酸镁等。这种组合可制作成溶液、悬浮液、片剂(tablet)、丸剂、胶囊、粉末等形态,可添加药理上得到认可的无毒赋形剂。
片剂、丸剂、胶囊可以含有如下辅料。即,刺梧桐树胶(TragacanthGum)、洋槐、玉米淀粉、明胶等粘合剂,磷酸钙等赋形剂,玉米淀粉、土豆淀粉及海藻酸(alginic acid)等分解剂,硬脂酸镁等润滑剂,白糖、乳糖等甜味剂,从薄荷、鹿蹄草(wintergreen)、樱桃中提取的芳香剂。如果单位容量采用胶囊形式,则除了上述提示的辅料外,还可以添加液态载体。如果采用糖浆和酏剂(Elixir)形式,则与有效成分一起,可含有白糖等甜味剂和作为防腐剂的木精(methyl)和尼泊金丙酯(Propyl paraben),作为着色剂和芳香剂也可以添加樱桃和橙子芳香剂。配制单位容量时使用的所有辅料应为精制的、无毒的,比如可以添加乳糖、白糖、磷酸钙等稀释剂和硬脂酸镁等润滑剂,淀粉、聚乙烯吡咯烷酮、洋槐树胶、明胶、纤维素等粘合剂。
有益效果
达木林A及达木林B含量得到增加的新绞股蓝提取物与现有的绞股蓝提取物相比,其AMPK的磷酸化能力得到增加,酶活化能力大幅增加。
为AMPK的下游靶蛋白、由于可显著提高生物合成脂肪酸的核心酶ACC(acetyl-CoA carboxylase)的磷酸化,因此这一结果也显示了大幅降低ACC酶活性的作用。与现有的没有增加达木林含量的绞股蓝提取物TG1022相比,达木林含量得到增加的新绞股蓝提取物TG1022F具有体脂肪合成抑制能力、脂肪酸β氧化促进能力、胆固醇生物合成抑制能力、高血脂症的治疗及改善效果、肥胖的治疗及改善效果,并且不依靠胰岛素使细胞葡萄糖转运蛋白GLUT4的细胞膜移动能力大幅提高,可以有效降低糖尿病患者的血糖。
与现有绞股蓝提取物相比,通过本发明的方法制备的达木林A和达木林B含量增加的新绞股蓝提取物,其改善或治疗肥胖、糖尿病、高血脂症等代谢疾病的效果非常显著。
附图说明
图1及图2是从达玛烷型皂苷分离、精制的增加AMPK活性的有效成分-达木林A及达木林B成分的HPLC光谱分析结果示意图。
图3及图4是显示从L6肌管细胞提纯分离的达木林A及达木林B化合物浓度与AMPK(A)及ACC(B)磷酸化能力增加之间的关系示意图。
图5是达木林A及达木林B的脂肪酸β氧化增加效果示意图。
图6是达木林A及达木林B的细胞内葡萄糖吸收增加效果示意图。
图7是达木林A及达木林B的含量分别达到0.89%及0.68%的具有新的组成的的新绞股蓝提取物干燥物TG1022F浓度与AMPK及ACC酶蛋白磷酸化能力增加之间的关系示意图。
图8是达木林A及达木林B含量分别达到0.89%及0.68%的具有组成的新绞股蓝提取物干燥物TG1022F对肥胖小鼠比目鱼肌给药时,肥胖小鼠比目鱼肌中的AMPK及ACC磷酸化增加变化示意图。
图9是绞股蓝提取物及增加了达木林A及达木林B含量的新绞股蓝提取物制备方法流程图。
具体实施方式
下面,详细说明本发明的实施例。但下面的实施例只是用于说明本发明,本发明的内容不受限于下面的实施例。
<实施例1.从绞股蓝提取物分离AMPK活性物质达木林>
将5kg干燥的绞股蓝叶浸泡在50L的50%乙醇中,在90℃下进行6小时1次提取后,收集1次上清液。向剩余的绞股蓝叶浸渍物中再次加入50L的50%乙醇,在90℃下进行6小时2次提取后,获得了2次上清液。混合第1次及第2次上清液后,用纱布过滤,对获得的过滤液在1,000xg下进行离心分离、去除悬浮物。对获得的提取液进行减压浓缩,浓缩成50Brix,将其用于AMPK活性物质-达木林的分离。
为了提纯达木林,使浓缩为50Brix的绞股蓝提取物流过填充有HP-20阴离子交换树脂(三菱化学制品公司,Mitsubishi ChemicalCorporation)的色谱柱(20×65cm)后,先用10L水进行洗涤,接下来使其通过10L的50%甲醇进行洗涤后,再通过10L丙酮后获得丙酮提取液,加以浓缩。向上述浓缩液加1.5L水、制备悬浮液后,再使用1.5L正己烷(n-Hexane)分别提取3次、获得己烷提取液(200g),使用1.5L乙酸乙酯(ethyl acetate)分别提取3次、获得乙酸乙酯提取液(200g),使用1.5L正丁醇(n-butanol)分别提取3次、获得了丁醇提取液(200g)。
其中,在L6肌管细胞(L6myotube cells)中将根据增加AMPK磷酸化增加的活化能力最高的是丁醇分离层。使用硅胶(默克公司)色谱柱(15×65cm;63-200μm粒子大小),以初始溶剂混合比(氯仿∶甲醇∶水=5∶1∶0.1)开始到最终溶剂混合比(氯仿∶甲醇∶水=0∶1∶0.1)的浓度梯度,对丁醇分离层(100g)进行物质分离,获得了共5个样份(B.1-B.5)。
HPLC分析结果,这五个样份中B.3和B.4的所含物质非常相似,因此混合该两个样份制备了新的B34。再次使用ODS-A硅胶(默克公司)色谱柱(6.5×65cm;12nm-150μm粒子大小),使B34通过上述色谱柱,作为分离物质的溶剂使用水和甲醇的混合物、以初始混合比(水∶甲醇=1∶1)开始到最终混合比(水∶甲醇=0∶1),使用分步骤浓度梯度获得了共6个样份(B.34-1到B.34-6)。
其中L6细胞中将根据AMPK磷酸化增加的活化能力最高的是B34-5样份。对该样份利用HPLC方法,使用紫外线检测仪(205mm),再次分离了物质。为此使用了半制备柱(semi-preparative column(半制备色谱柱),RP-C18Package column(填充色谱柱),10×250mm,10particle size(颗粒大小);RS Tech韩国),试料的流速为每分钟2ml,作为溶剂初期使用含有0.1%甲酸(formic acid)的75%甲醇进行75分钟分离后,再次以100%甲醇作为溶剂分离了15分钟,其结果分别分离出14mg达木林A及10mg达木林B。
为了确认分离得到的达木林A及达木林B纯化程度,实施了HPLC分析[设备:吉尔森32泵/GX271液体处理仪(Gilson32Pump/GX271liquid handler),检测器:UV/VIS 155检测器(UV/VIS 155Detector)(205nm),色谱柱:Optimapak C18(250×4.6mm,RS tech),流速:0.8mL/min,溶剂:A-H2O/B-MeCN,溶剂浓度梯度:B20%(0-2分钟)/20-62%(2-33分钟)/62-100%(33-39分钟)/100%(39-48分钟)/100-20%(48-53分钟)20%(53-60分钟)]。为此,达木林A以8mg/ml浓度溶解在甲醇中。然后,在适当的HPLC分析条件下,使用分析用色谱柱,利用紫外线检测仪以205nm对20μl试样进行了吸光度分析。达木林B以4mg/ml浓度溶解在含5%DMSO的甲醇中,对20μl试样,采用同达木林A相同的条件进行了分析。其结果如图1、图2所示,在分离精制的达木林A及达木林B都以单一峰出现,确认了它们的纯度至少达到了97%以上。
<实施例2.分离提纯的Damulin结构的决定>
为了确认化合物达木林的结构,通过快原子轰击质谱法(FABMass)分析,在805.4717(cacld.805.4714)下观察了[M+Na]+峰。测定了1H NMR,13C NMR及HMBC(异核多键相关谱,heteronuclear multiple-bonding correlation)等的光谱(spectrum),确认了分离提纯物的结构。
1H NMR光谱中7个角甲基(angular methyl groups)显示为单一峰,由13C NMR中表现出的具有特征的δC124.4、124.7、132.3、140.5ppm能够确认双键的碳峰。另外,5.08和5.26ppm的质子(proton)峰表明,该化合物结合有两个糖。从1H NMR光谱分析数据中,在δH3.02、3.63、3.75ppm上出现的质子峰和δC68.3、74.1及96.8ppm的碳峰可确认有3个羟基(hydroxyl group)被取代。另外,2号和3号质子耦合常数(proton coupling constant)表明,有两个羟基以2α、3β的双e键取向(diequatorial)形式存在。将各种物理化学特征及13C NMR数据与其他文献比较,鉴定了达木林是新化合物,并为了确定该化合物的构造,检测了HMBC光谱。其结果,以1H与13C NMR的峰连接点可以判断,该化合物的3号位置上结合有两个糖,对各位置的1H,13C NMR结构确认结果,判断为新化合物2α,3β,12β-三羟基达马脂-20(2)-E,24-二烯-3-O-[β-D-吡喃葡萄糖基-(1→)-β-D-吡喃葡萄糖],命名为达木林A。
达木林B是无定形粉末,13C NMR和HR-ESI-MS的实测值为m/z 783.4905([M+H]+计算(calcd).783.4895),分子式被鉴定为C42H70O13。比较达木林A和化合物2的1H和13C NMR光谱可以知道,它们具有相同糖苷配基部分(aglycone moiety)。达木林A与达木林B的主要差异点在于:达木林A的糖苷配基的3级结构(tertiary)CH3基被取代为达木林B的末端(terminal)CH2基。另外,C-22的烯烷基(olefinic methane group)的双键被取代为C-20(δC140.5)的4级结构碳(quaternary carbon)。1H NMR光谱中代替达木林A甲基信号(δ1.63,3H,s),达木林B出现了两个较宽单一峰(δ4.69和4.88,各1H,br,s),而且还有达木林A中没有的典型烯族质子信号(olefinicproton signal)出现在δ5.26(1H,br,t样(like),J=6.9Hz)上。
比较达木林B和达木林A的13C NMR光谱发现,达木林A的烯碳信号(δC 124.7,C-22)与甲基信号(δC 13.1,C-21),在达木林B中分别被亚甲基(methylene)信号(δC 35.1)和末端亚甲基峰(δC 108.7)替代。其他的不同点还有达木林A的4级结构碳(δC 140.5,C-20),在达木林B中向低频磁场(δC 156.3)方向发生化学位移(chemical shift)。对达木林B进行加水分解时,同样生成D葡萄糖(D-Glucose)。通过1H,13C NMR数据(表1)和1H-1H COSY,gHSQC,1H-13C HMBC光谱数据(spectroscopic data)等2维NMR(表1),鉴定了达木林B的两个糖。与达木林A的1H,13C NMR光谱中的化学位移、耦合常数等进行比较发现,达木林B同样存在β-结构(β-configuration)形态的两个葡糖基单位(glucosyl units)。δ4.45(1H,d,J=8.0Hz,glc’的H-1’);δC 105.0(glc’的C-1’)和δ4.75(1H,d,J=8.0Hz,H-1”of glc”);δC 104.5(C-1”of glc”)的端基质子(anomeric proton)支持上述结论。通过HMBC结果(表1)确定了两个糖和糖苷配基的连接部位。以上述结果为基础,达木林B的结构鉴定为2α,3β,12β-三羟基达马脂-20,24-二烯-3-O-[β-D-吡喃葡萄糖基-(1→)-β-D-吡喃葡萄糖]。表1是CD3OD上的达木林A及达木林B的结构分析所需1H(500MHz)及13C(100MHz)NMR结果。
表1
<实施例3.达木林A及达木林B的AMPK和ACC磷酸化增加效果>
由于AMPK的磷酸化引起的活化使ACC和HMG-CoA还原酶的磷酸化增加,其结果抑制ACC和HMG-CoA还原酶的活性(Henin,1995)。因此,AMPK的磷酸化会抑制脂肪酸的生物合成,使线粒体中的β氧化增加,肝组织中的脂肪及胆固醇的合成受到阻碍。AMPK的活性可通过氨基酸172号苏氨酸(Threonine)残基的磷酸化是否得到增加,进行判断。
ACC是在肝和肌肉组织中调节脂质代谢的重要的酶。该酶使乙酰-CoA(acetyl-CoA)羧化(carboxylation),生成丙二酰-CoA(malonyl-CoA)。丙二酰-CoA是在线粒体内调节脂肪酸的β氧化的重要因子,丙二酰-CoA的浓度增加时、线粒体膜的CPT-1(肉毒碱棕榈酰基-辅酶A转移酶,carnitine palmitoyl-CoA transferase)的活性降低,脂肪酸的β氧化被抑制。而丙二酰-CoA的浓度降低时,β氧化会增加,会促进体脂肪的减少。ACC是AMPK活化的下位靶蛋白,AMPK的活化使ACC发生磷酸化,促进ACC酶的失活,降低丙二酰-CoA的浓度,最终使线粒体膜的CPT-1的活性增加,使脂肪酸的β氧化增加。
分离成单一物质的达木林A以10、30、60μg/ml浓度及达木林B以1、5、10μg/ml浓度分别对L6肌管细胞(L6myotube cells)各处理2个小时后,对AMPKα亚单位苏氨酸-172残基及ACC酶蛋白的第79个丝氨酸(Serine)残基的磷酸化增加程度,采用Hwang等(Hwang等、生物化学与生物物理研究通讯(Biochem.Biophys.Res.Commun.)371,289-193,2008)的方法,通过蛋白印迹(western blot)方法进行了确认。其结果,经达木林A及达木林B处理的L6肌管细胞内的AMPK及ACC磷酸化与对照组相比,随浓度的增加而分别得到了增加(请参考图3及图4),并确认了达木林A及达木林B都是可有效使AMPK发生磷酸化、使AMPK活化,使ACC发生磷酸化、抑制ACC活性的有效物质。
<实施例4.达木林A及达木林B通过促进脂肪酸的β氧化降低脂肪的效果>
活化AMPK时ACC的活性降低,使线粒体内的丙二酰-CoA的浓度降低。随之,流入线粒体内的脂肪酸增加,β氧化增加,使体脂肪减少,可得到抑制肥胖的效果。用提纯的达木林A和达木林B处理培养的L6肌管细胞,采用Hwang等的方法(Hwang等、生物化学与生物物理研究通讯(Biochem.Biophys.Res.Commun.)377,1253-1258),调查了脂肪酸的β氧化增进效果。
其结果,观察到达木林A(30μg/ml)及达木林B(5μg/ml)分别让脂肪酸的β氧化增加了1.8倍和2.6倍(图5)。这一结果表明,达木林A及达木林B是可通过减少体脂肪、有效抑制或治疗肥胖的物质。
<实施例5.达木林A及达木林B的细胞内葡萄糖吸收促进效果>
已知AMPK的活化会使向细胞内的葡萄糖吸收增加,有降低血糖效果。(hardie等,FEBS Lett期刊.546,113-120,2003;Carling等,动态生物化学期刊(Trends.Biochem.Sci.)29,18-24,2004;Kahn等,细胞代谢(Cell Metab.)1,15-25,2005;Cool等,细胞代谢(Cell Metab).3.403-416,2006;Lee等,糖尿病(Diabetes),55,2256-2264,2006;Hwang等,生物化学与生物物理研究通讯(Biochem.Biophys.Res.Commun.)371,289-293,2008)。从而,以达木林A和达木林B对L6肌管细胞进行处理,调查了对细胞内葡萄糖吸收能力的影响。
对培养的L6肌管细胞,根据Hwang等的方法(Hwang等、生物化学与生物物理研究通讯(Biochem.Biophys.Res.Commun.)377,1253-1258),添加高浓度葡萄糖的同时加入在细胞内不会发生***的放射线同位素2-DG(2-脱氧-[3H]D-葡萄糖,2-deoxy-[3H]D-glucose)后,调查了由达木林A(30μg/ml)和达木林B(5μg/ml)引起的细胞内2-DG吸收促进程度。其结果,用达木林A处理的细胞糖吸收能力平均提高了42%,用达木林B处理的细胞糖吸收能力平均提高了79%(参考图6)。这一结果表明,达木林A及达木林B都可以降低血糖,具有优异的抗糖尿病效果。
<实施例6.高温及高压处理的达木林含量得到增加的绞股蓝提取物的制备>
如上面的实施例4和5确认,新化合物达木林A和达木林B是可活化AMPK,阻碍ACC活性的有效物质。但现有的单纯绞股蓝提取物(TG1022)所含达木林A及达木林B的含量还没达到显著呈现有效效果的水平。由此,制备了达木林A及达木林B的含量得到增加的具有新组成的新绞股蓝提取物(TG1022F),而且确认了上述新绞股蓝提取物(TG1022F)具有强大的AMPK活化能力。
上述新绞股蓝提取物浓缩液(TG1022F)是对以常温常压下的乙醇提取物(TG1022)施加高温高压反应或超高压反应获得的。
在高温高压反应中,使用一般的高温高压灭菌器(autoclave)或超高压反应器(DFS-2L,东洋高压,日本),从而使30ml绞股蓝单纯提取物浓缩液维持高温高压条件。
对新绞股蓝提取物浓缩液(TG1022F)进行干燥获得的干燥物,对其内的达木林A及达木林B含量,通过HPLC进行了分析。这里,作为标准试样使用了具有图1所示纯度的提纯的达木林A及达木林B,绘制各浓度定量标准曲线后,根据试样各峰面积比、算出了含量。其结果,高温及高压或时间条件变化时,新绞股蓝提取物(TG1022F)中的达木林A和达木林B的含量分别与温度、压力、反应时间成比例增加(表2)。由此,通过本发明的方法,高温高压处理绞股蓝提取物浓缩液,与处理时间成比例地能够制备得到达木林A及达木林B的含量显著增加的新绞股蓝提取物浓缩液(TG1022F)。表2是在高温、高压处理条件下,显示绞股蓝提取物中的达木林的含量增加的表格。
表2
<实施例7.对于达木林含量增加的新绞股蓝提取物的AMPK及ACC磷酸化增加的效果>
利用L6肌管细胞检测了以实施例6的方法制备的达木林A及达木林B含量分别增加到0.89%及0.68%的具有新组成的绞股蓝提取物(TG1022F)对AMPK信号传达器的活化增进能力与浓度关系。结果,如图7所示,当为单纯的绞股蓝提取物TG1022时,即使以120μg/ml浓度进行处理,也几乎与未处理对照组类似,根本没有引起AMPK及ACC的磷酸化。但达木林A及达木林B含量分别增加到0.89%及0.68%的TG1022F在60μg/ml浓度时,大幅促进了AMPK及ACC的磷酸化;把处理浓度增加到90μg/ml及120μg/ml时,随着浓度的增加了AMPK及ACC的磷酸化。特别是,对未以高温、高压处理的单纯绞股蓝乙醇提取物浓缩液TG1022(达木林A含量0.37%、达木林B含量0.28%),与以121℃、1.2气压、1小时反应条件进行高温、高压处理的TG1022F(达木林A含量0.89%、达木林B含量0.68%)以相同的浓度进行处理、比较了两者的效果。其结果发现,与达木林含量没有增加的TG1022相比,达木林含量增加的TG1022F的AMPK及ACC磷酸化能力得到显著提高。
<实施例8.肥胖动物模型中利用新绞股蓝提取物的体重减少效果>
将通过瘦蛋白(leptin)基因变异引起肥胖、高血糖以及抗胰岛素性的b/ob小鼠作为动物模型o,调查了达木林增加的绞股蓝提取物抗肥胖效果。为此,将依照实施例6的方法制备的达木林A及达木林B含量分别增加到0.89%及0.68%的新绞股蓝提取物(TG1022F),以每天150mg/kg和300mg/kg的量,分别以经口方式给药8周。这里,作为对照组使用了给药生理盐水的组,并与每天给药300mg/kg单纯绞股蓝提取物TG1022的情况也做了比较。
作为实验动物,每个测试组使用了8只雄性小鼠。实验结果如表3所示,每天给药150mg/kg和300mg/kg新绞股蓝提取物TG1022F(达木林A含量0.89%,达木林B含量0.68%)的组,在8周后,体重与生理盐水对照组相比、分别降低了2.95g及4.58g(参考表3)。但以300mg/kg给药的TG1022组,与生理盐水对照组相比没有出现显著性体重变化。另外,所有组之间的食物摄取量没有变化,这表明给药达木林A及达木林B含量提高的TG1022F组,其体重下降不是根据食物摄取量减少实现的。(参考表3)
表3为示出了肥胖小鼠(ob/ob)摄取达木林A及达木林B含量增加的具有新组成的新绞股蓝提取物TG1022F(达木林A含量0.89%、达木林B含量0.68%)时,体重降低效果的表。
表3
<实施例9.新绞股蓝提取物对动物肌肉内AMPK及ACC磷酸化增加效果>
为了验证上述实施例8得到的体重减小效果是否是由于AMPK及ACC磷酸化增加带来的结果,分离了给药TG1022F(达木林A及达木林B的含量分别达到0.89%及0.68%的提取物)的小鼠肌肉(比目鱼肌,Soleus muscle),利用蛋白印迹法,检测了AMPK及ACC的磷酸化程度。结果发现,如图8所示,与生理盐水对照组及单纯绞股蓝提取物TG1022相比,达木林A及达木林B含量增加的TG1022F给药组的AMPK及ACC磷酸化非常活跃。这一结果再次确认了上述实施例8表现的达木林含量增加的TG1022F的体重减少效果是由于TG1022F使动物肌肉的AMPK活化及有效引起ACC失活所带来的结果。
<实施例10.新绞股蓝提取物的人体体重及腰围减少效果>
使年龄在21岁到71岁之间的成人男子及女子以口服方式分别以每天300mg的量连续服用12周单纯绞股蓝提取物TG1022,以及达木林A及达木林B含量增加到0.89%及0.68%的TG1022F。这里,TG1022分别向男女各10人为对象以口服方式给药,而TG1022F也分别向男女各10人为对象以口服方式给药。测量体重使用了体重计,腰围是对第十根肋骨下侧和髂骨(iliac crest)之间的中间部位进行了测量。
结果,如表4所示,达木林含量增加的TG1022F给药组中,男子与女子试验组的体重分别平均降低了4.3kg和2.1kg,腰围分别平均降低了5.4cm及5.8cm。而给药TG1022的男子和女子试验组的体重分别平均降低了0.6kg及0.4kg,腰围分别平均降低了0.7cm和0.8cm(表4)。这一结果表明,与单纯绞股蓝提取物TG1022相比,达木林A及达木林B含量增加的具有新组成的TG1022F具有非常显著的体重及体脂肪减少效果。表4是示出了达木林A及达木林B含量增加的新绞股蓝提取物TG1022F的人体体重及腰围减小效果的表。
表4
<实施例11.新绞股蓝提取物的血液脂质降低效果>
为了验证新绞股蓝提取物的血液脂质降低效果,对上述实施例10的被测试者的血液中性脂肪和胆固醇含量变化进行了调查。
调查发现,如表5所示,增加达木林含量的TG1022F给药组中,男子和女子试验组的中性脂质分别平均降低了23.7mg/dl和28.4mg/dl,而总胆固醇分别平均降低了26.3mg/dl和21.5mg/dl。相反,给药单纯绞股蓝提取物TG1022的男子和女子试验组的中性脂质分别平均降低了3.7mg/dl和4.8mg/dl,而总胆固醇分别平均降低了3.1mg/dl和2.5mg/dl(表5)。这一结果表明,与单纯绞股蓝提取物TG1022相比,达木林A及达木林B含量增加的新绞股蓝提取物TG1022F具有非常显著的血液中性脂质及总胆固醇降低效果。表5是在人体内达木林A及达木林B含量增加的新组成的新绞股蓝提取物TG1022F(达木林A含量0.89%、达木林B含量0.68%)的血液中性脂质降低效果的表。
表5
<实施例12.新绞股蓝提取物的血糖降低效果>
为了验证新绞股蓝提取物的血糖降低效果,对上述实施例10的被测试者的空腹血糖变化进行了调查。
调查发现,如表6所示,达木林A及达木林B含量分别增加到0.89%和0.68%的TG1022F给药组中,男子和女子测试组的空腹血糖分别平均降低了26.4mg/dl和21.5mg/dl。相反,给药单纯绞股蓝提取物TG1022的男子和女子试验组的血糖分别平均降低了3.1mg/dl和2.5mg/dl。这一结果表明,与单纯绞股蓝提取物TG1022相比,达木林A及达木林B含量增加的新绞股蓝提取物TG1022F具有非常显著的血糖降低效果。表6是在人体内达木林A及达木林B含量增加的新绞股蓝提取物TG1022F的血糖降低效果的表。
表6
Claims (8)
1.一种绞股蓝提取物的制备方法,其特征在于:其是将绞股蓝叶乙醇提取物浓缩液在40~125℃、1.2~1100气压的高温高压或高压反应条件下,处理0.1~24小时,使绞股蓝叶提取物浓缩液干燥粉末的达木林A含量增加到0.7~7%(w/w)、达木林B含量增加到0.5~6%(w/w)。
2.一种用于改善及治疗如肥胖、糖尿病或高血脂症代谢疾病的绞股蓝提取物,其特征在于:其是将绞股蓝叶乙醇提取物浓缩液在40~125℃、1.2~1100气压下,进行0.1~24小时高温高压反应制得;其含有0.7~7%(w/w)达木林A,0.5~6%(w/w)达木林B作为有效成分。
3.一种用于改善如肥胖、糖尿病或高脂血症代谢疾病的功能食品,其特征在于:其含有权利要求2所述的绞股蓝提取物。
4.根据权利要求3所述的功能食品,其特征在于:所述功能食品含有作为载体的温泉水、过滤水、蒸馏水、碳酸水、果汁、酸奶、牛奶、食用油。
5.一种用于改善及治疗如肥胖、糖尿病或高血脂症代谢疾病的药物组合物,其特征在于:其含有权利要求2所述的绞股蓝提取物。
6.根据权利要求5所述的用于改善及治疗如肥胖、糖尿病或高血脂症等代谢疾病的药物组合物,其特征在于:所述药物组合物提高蛋白激酶的活性。
8.根据权利要求7所述的用于改善及治疗如肥胖、糖尿病或高脂血症代谢疾病的药物组合物,其特征在于:所述药物组合物提高蛋白激酶的活性。
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Family Cites Families (7)
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KR101102480B1 (ko) * | 2004-04-27 | 2012-01-05 | 노부유키 하야시 | 가압 열매체를 이용한 추출방법 및 그 장치 |
JP2006124355A (ja) * | 2004-11-01 | 2006-05-18 | Ichimaru Pharcos Co Ltd | ファゴサイトーシス抑制剤 |
JP2006241097A (ja) * | 2005-03-04 | 2006-09-14 | Kaneka Corp | Pparリガンド剤であるアマチャヅル疎水性抽出物 |
WO2006114775A2 (en) * | 2005-04-27 | 2006-11-02 | Tg Biotech | Treatment of insulin resistance syndrome |
KR100856083B1 (ko) * | 2007-03-15 | 2008-09-03 | (주)뉴트리 | 홍삼 특이 사포닌 고함유 인삼엑기스의 효율적인 제조방법 |
KR100886743B1 (ko) * | 2007-03-19 | 2009-03-04 | 바이오스펙트럼 주식회사 | 지페노사이드를 포함하는 피부 미백제 또는 발모제 |
JP5175072B2 (ja) * | 2007-08-10 | 2013-04-03 | 株式会社ミゾタ | 有用物質の抽出装置 |
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2009
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- 2009-12-22 DE DE112009005072T patent/DE112009005072T5/de not_active Withdrawn
- 2009-12-22 CN CN200980160081.9A patent/CN102470155B/zh active Active
- 2009-12-22 WO PCT/KR2009/007668 patent/WO2011007943A1/ko active Application Filing
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2010
- 2010-01-27 JP JP2010015020A patent/JP5550365B2/ja active Active
- 2010-01-29 US US12/696,362 patent/US8357786B2/en active Active
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN108178778A (zh) * | 2018-03-23 | 2018-06-19 | 娄志春 | 一种制备达木林b的方法 |
CN112321666A (zh) * | 2020-11-16 | 2021-02-05 | 中国药科大学 | 一种降低肝细胞分泌pcsk9的天然药物及其应用 |
CN112321666B (zh) * | 2020-11-16 | 2022-02-22 | 中国药科大学 | 一种降低肝细胞分泌pcsk9的天然药物及其应用 |
CN114907432A (zh) * | 2021-02-10 | 2022-08-16 | 遵义医科大学 | 达玛烷型三萜及其制备方法与用途 |
CN114907432B (zh) * | 2021-02-10 | 2023-08-22 | 遵义医科大学 | 达玛烷型三萜及其制备方法与用途 |
Also Published As
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US20110015142A1 (en) | 2011-01-20 |
JP5550365B2 (ja) | 2014-07-16 |
US8357786B2 (en) | 2013-01-22 |
CN102470155B (zh) | 2014-10-08 |
JP2011020995A (ja) | 2011-02-03 |
WO2011007943A1 (ko) | 2011-01-20 |
DE112009005072T5 (de) | 2012-11-08 |
KR100930580B1 (ko) | 2009-12-09 |
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