CN108430486A - 具有保护肝细胞的效果及增加骨密度的效果的含有香豆雌酚的发芽发酵豆提取物及包含其的组合物 - Google Patents
具有保护肝细胞的效果及增加骨密度的效果的含有香豆雌酚的发芽发酵豆提取物及包含其的组合物 Download PDFInfo
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Abstract
本发明涉及含有香豆雌酚的发芽发酵豆提取物、其制备方法及包含所述发芽发酵豆提取物的组合物。对于肝毒性,通过体外(in vitro)抗氧化活性和细胞存活率以及动物模型的血液学检查、测量MDA、GST、GSH、SOD、CAT等,可知本发明的发芽发酵豆提取物有效地保护肝细胞。此外,通过增加骨矿物质含量而显著地增加骨密度,并且具有增加松质骨的厚度和数量的效果。此外,还具有缓解更年期症状的效果。
Description
技术领域
本发明涉及具有保护肝细胞的效果及增加骨密度的效果的含有香豆雌酚的发芽发酵豆提取物及包含其的组合物。更加详细地,利用发芽发酵豆提取物作为在自然食品中具有改善体内脂质及更年期障碍效果的成分,对于更年期障碍时出现的肝毒性,通过体外(in vitro)抗氧化活性和细胞存活率以及动物模型的血液学检查、测量MDA(丙二醛,malone dialdehyde)、GST(谷胱甘肽s-转移酶,glutathione S-transferase)、GSH(还原型谷胱甘肽)、SOD(超氧化物歧化酶,Superoxide dismutase)、过氧化氢酶(Catalase)等来验证保护肝细胞的效果。此外,本发明中将发芽发酵豆提取物作为样品,为了通过体内(invivo)实验来验证改善更年期障碍时出现的骨损失的效果,确认了血液中钙及磷的浓度、骨形成指标ALP(碱性磷酸酶)的活性、骨量(骨矿物质含量,Bone mineral content),并利用显微CT(Micro-CT)测量了松质骨的各种指标。
本发明的发酵发芽豆提取物显著地增加血液中的雌激素和睾酮浓度,因此缓解更年期症状,并且在体外(in vitro)和体内(in vivo)实验中具有保护肝细胞的效果,并通过增加骨矿物质含量而显著地增加骨密度,并且增加松质骨的厚度和数量。
背景技术
豆类的异黄酮中的大豆苷元(daidzein)中含有香豆雌酚成分,其调节雌性激素的均衡及含量,从而预防乳腺癌和子宫癌,并且延迟闭经期或缓解与其相关的各种症状。
全世界范围内的人口老龄化进程非常迅速,尤其,与其他先进国家相比,韩国的老龄化进程速度非常快而成为大的问题。随着经济增长而增进健康的结果引起韩国女性的平均寿命的延长和知识水平的提高等,从而对女性的闭经期和闭经后的生活质量的提高和增进健康的关注也逐渐得到提高。闭经的主要症状中,具有代表性的症状为面部潮红、焦虑、抑郁、神经过敏、心血管疾病、骨质疏松症及记忆力减退等症状,已知出现这些症状的原因为雌激素的产生和分泌的中断。作为预防其的措施提出了激素替代疗法(雌激素替代疗法,estrogen replacement therapy),但是对于使用方法、用量、安全性等尚没有结果。
天然食品中的植物雌激素(Phytoestrogen)为生殖激素的类似物,自从其的预防闭经期症状及骨质疏松症的可能性备受关注开始,有很多研究、报道表明其可以对闭经期之后的女性起到替代雌激素(estrogen)的作用。目前,随着在闭经期症状的治疗中利用合成雌激素(estrogen)替代疗法,大部分的女性正在经历再次月经现象、乳房软化及体重增加等副作用,认为通过摄入天然食品中具有植物雌激素(estrogen)类似物的食品来缓解闭经期症状会非常有助于消除副作用。
植物雌激素包含异黄酮和木脂素,并且是与在豆、水果、蔬菜、花生、谷物等植物中自然产生的雌激素类似的化合物。异黄酮作为与体内的雌激素受体进行弱结合而具有多种生理效果的植物雌激素的一种备受关注。从豆中提取的异黄酮在植物中主要以糖苷(glycoside)存在,被人体吸收时通过糖苷酶(glycosidase)转化为苷元形态的染料木黄酮和大豆苷元,从而具有雌激素性质(estrogenic property)。
对于女性的健康有报道称,与现有的雌激素治疗剂不同,异黄酮的摄入在没有副作用的情况下,缓解闭经期症状,并且在出现血清脂质浓度及高胆固醇血症的女性中减少了心血管系统的危险和血液中的脂质和氧化物。
韩国公开专利公报第10-2014-0053471(包含作为有效成分的含有香豆雌酚的豆提取物的用于预防及治疗更年期症状的组合物)是关于包含作为有效成分的含有香豆雌酚的豆提取物的预防更年期疾病等的组合物的细胞实验(体外(in vitro))的实验结果,本发明的目的在于通过改良及改善的发芽发酵豆提取物获得得到改进的方法和结果,以确认上述的细胞实验,并通过动物实验(体内,in-vivo)确认改善更年期症状及保护肝细胞的效果等。
[先行技术文献]
(专利文献1)韩国专利公开号10-2014-0053471
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发明内容
要解决的技术问题
本发明的目的在于通过利用发酵发芽豆提取物来缓解更年期症状、增加保护肝细胞的效果和骨矿物质含量。
随着经济增长而增进健康的结果而引起韩国女性的平均寿命的延长和知识水平的提高等,从而对女性的闭经期和闭经后的生活质量的提高和促进健康的关注也逐渐得到提高。闭经的主要症状中,具有代表性的症状为面部潮红、焦虑、抑郁、神经过敏、心血管疾病、骨质疏松症及记忆力减退等症状,已知出现这些症状的原因为雌激素的产生和分泌的中断。作为预防其的措施提出了激素替代疗法(雌激素替代疗法,estrogen replacementtherapy),但是对于使用方法、用量、安全性等尚没有结果。尤其,目前的实情是对于闭经期女性缺乏具有保护肝细胞的效果和增加骨密度的效果的合适的药品或健康食品。
技术方案
本发明涉及对闭经期女性具有保护肝细胞及增加骨密度的效果的含有香豆雌酚的发芽发酵豆提取物及包含其的组合物。利用所述含有香豆雌酚的发芽发酵豆提取物,欲验证对闭经期女性的保护肝细胞及增加骨密度的效果。此外,本发明中将发芽发酵豆提取物作为样品,为了通过体内(in vivo)实验来验证更年期障碍时会出现的对闭经期女性的保护肝细胞及改善骨损失的效果,确认了血液中钙及磷的浓度、骨形成指标ALP的活性、骨量(骨矿物质含量,Bone mineral content),并利用显微CT(Micro-CT)测量了松质骨的各种指标。
发明效果
通过显著地增加血液中的雌激素浓度,发芽发酵豆的异黄酮(isoflavone)能够替代雌激素的作用,由此能够期待更年期症状能得到缓解。并确认了与卵巢切除对照组相比,睾酮的浓度是显著(p<0.05)增加的结果。
对更年期障碍时出现的肝毒性,通过体外(in vitro)抗氧化活性和细胞存活率以及动物模型的血液学检查、测量MDA、GST、GSH、SOD、CAT等,可知本发明有效地保护肝细胞。此外,可以确认施用发芽发酵豆能够增加骨矿物质含量。在施用发芽发酵豆的鼠中,骨密度得到显著的增加,这意味着松质骨的厚度和数量得到增加。通过显著地增加血液中的雌激素浓度,发芽发酵豆的异黄酮(isoflavone)能够替代雌激素的作用,由此能够期待更年期症状会得到缓解。尤其,从血液中的中性脂肪的浓度和葡萄糖的浓度减少的倾向可以看出,能预期发芽发酵豆的施用会有助于改善更年期肥胖,并且确认了施用高浓度的发芽发酵豆时具有与施用雌激素相似水平的预防骨质疏松症的效果。对于被指定为人类各种疾病原因的氧化应激的生物体的氧化性损伤需要诸如过氧化氢酶(catalase)、SOD、GSH、GST的抗氧化酶。对此,利用发芽发酵豆对具有人为肝损伤的动物模型测量肝酶的抗氧化活性的结果,与只施用SOD、GSH、GST、MDA等t-BHP的肝损伤模型相比,显示出显著的减少及增加。由此可知发芽发酵豆对氧化应激具有保护肝的效果。
附图说明
图1示出了施用雌激素的组的体重增加量。
图2示出了血清脂质、胆固醇及葡萄糖浓度。
图3示出了激素的变化。
图4示出了骨代谢指标的测量结果。
图5示出了骨盐量的测量结果。
图6示出了骨微细结构的指标。
图7示出了利用显微CT(Micro-CT)拍摄的2D图像。
图8示出了利用sep-pak对70%的乙醇发芽发酵豆的进行分离的过程。
图9示出了发芽发酵豆及70%的乙醇提取物发芽发酵豆的细胞存活率。
图10示出了发芽发酵豆及70%的乙醇提取物发芽发酵豆的t-BHP细胞存活率。
图11示出了发芽发酵豆及70%的乙醇提取物发芽发酵豆的ROS测量结果。
图12示出了动物模型血液学检查AST(GOT)、ALT(GPT)的测量结果。
图13示出了在施用发芽发酵豆后施用t-BHP的组的肝(Liver)中的MDA测量结果。
图14示出了在施用发芽发酵豆后施用t-BHP的组的肝(Liver)中的GST测量结果。
图15示出了在施用发芽发酵豆后施用t-BHP的组的肝(Liver)中的GSH测量结果。
图16示出了在施用发芽发酵豆后施用t-BHP的组的肝(Liver)中的SOD测量结果。
图17示出了在施用发芽发酵豆后施用t-BHP组的肝(Liver)中的CAT测量结果。
具体实施方式
[实施例1]材料及方法
1.1.实验材料
本实验中所使用的发芽发酵豆是从株式会社HUBIO公司获得。将从济州农业技术院(Jeju Agricultural Research and Extension Services)获得的大豆,根据先行研究进行发芽并接种米曲霉(Aspergillus oryzae)进行发酵而获得。经过水洗、精选及利用超声波的提取过程,然后进行干燥并用作试验样品。
1.2.样品的制备
大豆经过水洗、精选、发芽及利用米曲霉(Aspergillus oryzae)的发酵过程并进行过滤后在60℃下进行干燥。在10g的干燥样品中,以7mL/g加入80%的乙醇并进行分解,然后利用超声波进行热水提取。之后,利用离心分离获得发芽发酵豆提取物,用聚四氟乙烯膜(PTFE membrane)对其进行过滤,然后进行干燥而获得样品。将上述样品溶于三蒸水中并用于动物实验。
1.3.实验动物
实验动物为8周龄的斯普拉格-杜勒(Sprague-Dawley)雌白鼠,其购自DaehanBiolink公司(大田),并在本实验中使用固体饲料(普瑞纳公司,Purina)进行饲养,在实验开始前的2周期间使适应于对照组的饲料后,根据动物的体重,使每组的平均体重达到289.72±0.86g,以每组7只分为6组[卵巢切除对照组(阴性对照组,negative control)、非卵巢切除对照组(假手术组,sham)、施用雌激素的组(OVX-雌激素(OVX-estrogen))、施用0.5g/kg的发芽发酵豆提取物的组(OVX-0.5)、施用1.0g/kg的发芽发酵豆提取物的组(OVX-1.0)及施用2.0g/kg的发芽发酵豆提取物的组(OVX-2.0)],并进行了实验6周。使用饲养笼(20×26×13cm),在实验室维持22~24℃的温度、60±5%的湿度且可通过自动调节装置调节日夜周期(12小时光照(light)/12小时黑暗(dark))的高丽大学动物室中对实验动物进行饲养,并取得高丽大学动物实验伦理委员会的批准后,遵循“关于实验动物管理及使用指南(Guide for the care and use of Laboratory Animals,NRC)”进行管理的同时进行了实验。水和饲料为自由供给,实验样品是溶解于三蒸水中,并每天以3ml口服施用,对照组(阴性对照组(Negative-control)、假手术组(sham))每天以同样的用量口服施用三蒸水。
1.4.卵巢切除术
对周围环境适应2周,然后通过随机化完全区组设计(Randomized CompleteBlock Design)根据体重进行分组并实施了卵巢切除术。用异氟烷(isoflurane)进行麻醉后达到深麻醉期时,将背部的侧腹切开并切除卵巢,并缝合切开部位。就非卵巢切除对照组(假手术组,sham)而言,通过相同的方法切除卵巢旁的脂肪并缝合切开部位。在术后经过两周的恢复期之后口服施用样品。
1.5.血清脂质浓度及酶活性的分析
利用FUJI DRI-CHEM 3500测量了分离血清的中性脂肪(TG)、总胆固醇(TCHO)、高密度脂蛋白胆固醇(HDL)、低密度脂蛋白胆固醇(LDL)、葡萄糖(GLU)。利用同样的方法测量了谷氨酸草酰乙酸转氨酶(Glutamate oxaloacetate transaminase(GOT))、谷氨酸丙酮酸转氨酶(Glutamate pyruvate transmaminase(GPT))的活性。
1.6.激素的测量
利用酶联免疫吸附法(ELISA)分别通过大鼠雌二醇酶联免疫试剂盒(ratestradiol Elisa kit)(恩佐生命科学公司(Enzo life science),纽约,美国)和大鼠睾酮酶联免疫试剂盒(rat testosterone Elisa kit)(恩佐生命科学(Enzo life science),纽约,美国)测量了血浆内的雌二醇(estradiol)、睾酮(testosterone)的量。
1.7.骨代谢指标的测量
通过FUJI DRI-CHEM 3500测量了作为骨形成指标的血浆中钙和磷的浓度、血浆中碱性磷酸酶(alkaline phosphatase,ALP)的浓度,并根据先行研究测量了骨碱性磷酸酶(BONE-alkaline phosphatase,BONE-ALP)的浓度。经过干燥、去脂肪等过程对股骨进行灰化,之后测量了股骨的骨盐量。
1.8.骨组织形态的测量:显微CT(Micro-CT)的拍摄
利用显微CT(Micro-CT,Skyscan1072,SKYSCAN公司,安特卫普(Antwerpen),比利时(Belgium))对牺牲的鼠的胫骨中距生长板1mm的部位的2mm高度部分进行拍摄。拍摄的管电压为50kVp,管电流为500μA,并利用了0.5mm的铝过滤,拍摄时间为210ms,像素尺寸(pixel size)为18μm。为了在各个图像中分离骨小梁和骨髓腔,将阈值(threshold value)固定为58,并重建三维图像。使用SkyscanTM CT分析软件(CT-analyzersoftware),由显微CT(Micro-CT)拍摄的图像分析了骨微细结构指标。利用并分析的指标为骨体积分数(Percentbone volume(BV/TV(%))),骨小梁数量(trabecular number(Tb.N())),骨小梁厚度(trabecular thickness(Tb.Th(μm))),骨小梁分离度(trabecular separation(Tb.Sp(μm))),骨小梁模式因子(trabecular pattern factor(Tb.pf()))及结构模型指数(structure model index(SMI))。
1.9.统计处理
使用SPSS(社会科学统计软件包(statistical package for social science),版本(version)12.0)统计软件对通过研究结果得到的资料进行处理。为了查明各组之间显著的差异,对阴性对照组进行了T检验(T-test)。测量值以平均标准误差表示,p<0.05、p<0.01、p<0.001分别以*、**、***表示。
[实施例1]实验结果
2.1.体重变化及饲料摄取量
在进行实验的6周期间,与非卵巢切除对照组相比,所有通过卵巢切除术诱导更年期的组中均确认到体重增加的倾向(图1)。可以确认非卵巢切除对照组的体重增加量为20.4±3.3g,与之相比,卵巢切除对照组、以0.5g/kg、1.0g/kg、2.0g/kg施用发芽发酵豆的组的体重增加量分别为39.8±11.1g、42.2±4.5g、34.0±5.6g、36.8±4.3g。施用雌激素的组的体重增加量为12.1±8.7g,显示出比较减少的倾向,但施用发芽发酵豆的组中并没有显示出显著的差异。饲料摄取量的变化也没有显示出显著的差异。将卵巢切除对照组、非卵巢切除对照组、施用雌激素的组分别以阴性对照组(Neg.C)、假手术组(Sham)、雌激素(Estradiol)来表示,以0.5g/kg、1.0g/kg、2.0g/kg施用发芽发酵豆的组分别以0.5、1.0、2.0表示。数据以平均值±标准误差来表示。
2.2.血清脂质浓度及酶活性的分析
如同女性更年期,进行卵巢切除的组的雌激素分泌急剧减少。这时身体为了加强所减少的雌激素的分泌,会储存很多可以生成雌激素的脂肪细胞,由此会诱导更年期肥胖。作为更年期肥胖的指标确认了血液内的脂质、胆固醇、葡萄糖的浓度,其结果如图2所示。
以0.5g/kg、1.0g/kg、2.0g/kg施用发芽发酵豆的组的中性脂肪数值分别为62.5±21.3mg/dl、59.0±8.5mg/dl、55.8±8.8mg/dl,可以确认与非卵巢切除对照组的66.8±12.6mg/dl相似的数值减少。
就总胆固醇而言,确认了以1.0g/kg、2.0g/kg施用发芽发酵豆时数值分别增加到139.5±9.6mg/dl、136.7±6.5mg/dl。结果,由于胆固醇池(cholesterol pool)增大,因此在高密度脂蛋白胆固醇和低密度脂蛋白胆固醇也显示出相似的效果。
观察图2可以确认,与卵巢切除对照组的血液中葡萄糖浓度162.7±18.6mg/dl相比,所有施用发芽发酵豆的组的血液中葡萄糖的浓度为98.3±16.1mg/dl、123.3±14.4mg/dl、112.8±6.6mg/dl,也显示出减少的倾向。
鉴于血液中的中性脂肪的浓度和葡萄糖的浓度具有减少的倾向,由此预期施用发芽发酵豆有助于改善更年期肥胖。
GOT、GPT是在肝中生成的正常酶。肝脏受到损伤时肝细胞被破坏,从而这些酶会游离到血液中,比正常增加很多,因此这些被用作代表性的肝毒性的指标。如下述表1所示,不同组的血清GOT、GPT活性分析并不具有显著的差异。因此,可知用样品进行处理时并不会显示出肝毒性。
[表1]
2.3.激素的测量
各种更年期症状的原因是卵巢的老化导致的雌激素的生成和分泌的减少。因此,为了观察通过施用发芽发酵豆来缓解更年期症状的效果,确认血液中雌激素浓度的增加是非常重要的。
2.3.1.雌激素
与非卵巢切除对照组的雌激素浓度1020.±63.6pg/ml相比,卵巢切除对照组的雌激素浓度为500.3±27.8pg/ml,由此可以确认通过切除卵巢雌激素浓度显著地(p<0.001)减少。就施用雌激素的组而言,确认了血液中雌激素浓度增加到1134.1±205.8pg/ml,与非卵巢切除对照组相近(图3)。与卵巢切除对照组相比,施用发芽发酵豆的三个组的血液中雌激素浓度分别为1577.1±341.6pg/ml、2358.6±191.8pg/ml、938.5±51.2pg/ml,均得到显著的增加(图3)。通过血液中雌激素浓度的显著的增加,可以期待发芽发酵豆的含有香豆雌酚的提取物可以代替雌激素的作用且由此能够缓解更年期症状。
2.3.2.睾酮
睾酮为典型的同化激素(Anabolic hormone),并且参与肌肉代谢和脂肪代谢。该激素的数值降低时会减少体内肌肉量,从而降低基础代谢量且容易引起肥胖。此外,还会诱导更年期典型的症状之一的皮肤角化。如图3所示,与非卵巢切除对照组相比,所有进行卵巢切除的组的血液中睾酮浓度均减少。其中,可以确认施用雌激素的组和以1.0g/kg施用发芽发酵豆的组的睾酮浓度分别为2797.8±517.3pg/ml、1969.8±164.2pg/ml,与卵巢切除对照组相比,这些组的睾酮浓度是显著(p<0.05)增加的结果。
2.4.骨代谢指标的测量
如图4所示,每组的血液中钙的浓度没有显示出显著的差异,就磷而言,在以1.0g/kg施用发芽发酵豆的组中显示出显著差异(p<0.05)。
碱性磷酸酶(Alkaline phosphatase,ALP)是参与骨代谢的造骨细胞的生物标志物(biomarker)。患有诸如骨质疏松症的骨代谢急剧增加的疾病时,ALP的数值也会增加。与非卵巢切除对照组的血液中ALP的数值340.2±33.31U/L相比,卵巢切除对照组的血液中ALP的数值增加为454.0±69.9U/L。另一方面,与对照组相比,以0.5g/kg施用发芽发酵豆的组为260.0±646.9U/L,显示出显著低的ALP活性(p<0.05)。此外,与卵巢切除对照组相比,以0.5g/kg施用发芽发酵豆的组的骨碱性磷酸酶(Bone-ALP)的数值显示为140.8±58.5U/L,从而可以确认显著地(p<0.05)降低。
如图5所示,进行口服施用6周后,可以确认,与非卵巢切除对照组相比,卵巢切除对照组的骨盐量显著地(p<0.05)降低。以1.0g/kg、2.0g/kg施用发芽发酵豆的组的骨盐量分别显示为61.3±0.36%、60.8±0.31%。与卵巢切除对照组相比,其为骨盐量显著地(p<0.05)增加的数值。由此可以确认施用发芽发酵豆可以增加骨矿物质含量。
2.5.骨组织形态的测量:显微CT(Micro-CT)的拍摄
可以确认,与非卵巢切除组相比,所有进行卵巢切除的组的骨体积分数(Percentbone volume(BV/TV(%)))、骨小梁数量(trabecular number(Tb.N(mm-1)))、骨小梁厚度(trabecular thickness(Tb.Th(μm)))的数值均减少。与卵巢切除对照组相比,施用雌激素的组和以2.0g/kg施用发芽发酵豆的组中,其数值显著地增加。就BV/TV而言,卵巢切除对照组减少到13.7±1.3%,而以2.0g/kg施用发芽发酵豆的组的BT/TV为23.3±1.3%,显示出显著的差异(p<0.01)(图6)。就Tb.N而言,卵巢切除对照组显示出低数值1.17±0.09mm-1,而以2.0g/kg施用发芽发酵豆的组为1.69±0.15mm-1,可以确认增加至与施用雌激素的组相似的数值(p<0.05)。就Tb.Th而言,卵巢切除对照组显示出低数值0.12±0.00mm-1,而施用雌激素和施用所有浓度的发芽发酵豆的组的Tb.Th均显著地增加(图6)。这意味着施用发芽发酵豆的鼠的骨密度显著地增加,并且松质骨的厚度和数量得到增加。
如图6所示,就骨小梁分离度(trabecular separation(Tb.Sp(μm)))、骨小梁模式因子(trabecular pattern factor(Tb.pf(mm-1)))及结构模型指数(structure modelindex(SMI))而言,与非卵巢切除对照组相比,所有进行卵巢切除的组中,其数值均增加。以2.0g/kg施用发芽发酵豆的组的Tb.Sp数值显示为0.70±0.10,显著地减少(p<0.05)。通过其结果可知,与卵巢切除对照组相比,施用发芽发酵豆的组中与骨质疏松症密切相关的松质骨的分散度得到减少。就Tb.pf而言,与卵巢切除对照组相比,施用雌激素的组和以2.0g/kg施用发芽发酵豆的组中显著地(p<0.01、p<0.05)减少。其数值分别显示为0.76±0.48mm-1、0.63±1.25mm-1。最后,就结构模型指数(structure model index(SMI))而言,与卵巢切除对照组相比,施用雌激素的组和以2.0g/kg施用发芽发酵豆的组分别为1.54±0.07、1.53±0.10,显著地(p<0.01)减少。因此,预期以2.0g/kg施用发芽发酵豆与施用雌激素具有相似水平的预防骨质疏松症的效果。
3.肝毒性模型的抗氧化效果
3.1.体外(in vitro)抗氧化活性(DPPH、ABTS、多酚(Polyphenol))的测量结果
如下述表2所示,测量各样品的抗氧化活性的结果,与株式会社HUBIO公司提供的发芽发酵豆相比,利用70%的乙醇(EtOH)提取的发芽发酵豆的抗氧化活性及多酚(Polyphenol)的含量的测量结果更高。
[表2]
3.2.实验材料(发芽发酵大豆,germinated fermented and soybean:GFS)的分离及精制
如图8所示,利用所测量的抗氧化活性高的70%的乙醇(EtOH)提取物,并利用Sep-pak进行物质分离后,测量抗氧化活性的结果,在30%和70%的甲醇(methanol)中显示出高的多酚(Polyphenol)含量。此外,如下述表3所示,抗氧化活性测量方法的ABTS的结果,在70%的甲醇(methanol)中显示出最高的抗氧化活性。下述表3为示出体外(In vitro)抗氧化活性(ABTS IC50值(IC50value),多酚(Polyphenol))的测量结果的表。
[表3]
(抗坏血酸(Ascorbic acid)(IC50μg/ml):2.13±0.06)
3.3.利用HepG2细胞的样品对由t-BHP引起的损伤的保护活性的测量
3.3.1.细胞存活率
MTT法(MTT assay)是一种利用黄色可溶性四唑(tetrazolium)盐通过活细胞线粒体中的琥珀酸脱氢酶(succina dehydrogenase)还原为蓝色不溶性甲瓒(formazan)生成物的原理的实验方法,在540nm的波长下甲瓒(formazan)的吸光度最大。
在该波长下测量的吸光度是反映代谢旺盛的活细胞的浓度,从而用作线粒体活性的指标。MTT为测量线粒体活性的实验,其通过调查细胞毒性程度测量实验物质显示出何种程度的毒性,若实验物质具有毒性而导致线粒体被破坏,则显示出低的吸光度值。
如图9A所示,与没有用样品进行处理的细胞(100%)相比,只用发芽发酵豆样品对HepG2细胞进行处理时,用发芽发酵豆处理的组在0.0312(98.52±3.64)、0.0625(97.08±2.93)、0.125(94.44±1.72)、0.25(96.46±2.86)、0.5(96.19±3.03)mg/mL浓度下显著地显示出弱毒性。
此外,如图9B所示,利用70%的乙醇(EtOH)提取物发芽发酵豆对细胞进行处理时的细胞存活率与没有用样品进行处理的组没有差异。
并且,如图10的A所示,与没有进行任何处理的细胞相比,利用HepG2细胞并用发芽发酵豆和t-BHP进行处理时,只用t-BHP进行处理的细胞显示为约60%,较低,并且与只用t-BHP进行处理的细胞比较时,用发芽发酵豆样品进行处理时与只用t-BHP进行处理的细胞无法看出很大差异。但是,如图10B所示,与只用t-BHP进行处理的细胞(64.67±0.78%)相比,利用70%的乙醇(EtOH)提取物发芽发酵豆进行处理时,根据浓度没有显著差异,但可以确认细胞存活率得到增加。0.0625(80.11±0.90%)、0.125(82.67±0.84%)、0.25(83.52±1.98%)、0.5(82.54±2.58%)mg/mL。
3.4.利用HepG2细胞的活性氧(ROS,reactive oxygen species)的测量
DCFH-DA(二氯荧光素二乙酸酯,dichlorofluorescin diacetate)与细胞内的活性氧(ROS)反应,从而转化为强荧光物质DCF(二氯荧光素,dichlorofluorescein)。因此通过测量DCF的荧光度可以推测ROS的相对量。
为了确认70%的乙醇(EtOH)发芽发酵豆提取物的ROS效果,以没有细胞毒性的浓度培养70%的乙醇(EtOH)发芽发酵豆提取物12小时,然后用1mM的t-BHP处理1小时,从而引发氧化应激。在其中加入25μM的DCFH-DA60分钟后测量了DCF的荧光度。
其结果如图11所示。如图11所示,与正常组(Normal)(100±1.00%)相比,通过t-BHP的处理荧光度增加到(267.62±2.68%),通过70%的乙醇(EtOH)发芽发酵豆提取物的预处理,从最高浓度开始根据浓度而显著地得到抑制,其分别为0.5(195.24±1.95%)、0.25mg/mL(195.24±1.95)、0.125mg/mL(240±2.41)、0.0625mg/mL(252.80±2.53),从而可以确认70%的乙醇(EtOH)发芽发酵豆提取物带来的使活性氧减少的效果。
3.5.利用动物模型的血液学检查
施用发芽发酵豆并施用t-BHP的组的血液生物化学检测结果示于下述表4中。与对照组相比,对总胆固醇(Total Cholestrol)、乳酸脱氢酶(LDH)、总胆红素(TotalBilirubin)、碱性磷酸酶(ALP)、谷氨酸丙酮酸转氨酶(ALT)进行测量的结果显示出显著的差异(表4)。乳酸脱氢酶(LDH)为糖酵解类的酶,广泛分布于体内各组织中,尤其存在于心脏、肝脏、肾脏及肌肉的血清中的LDH在心脏疾病、肝疾病、恶性肿瘤及白血病等中会增加,但其特异性低。在急性肝炎中LDH与AST、ALT相同,从肝细胞中脱离而出,在急性肝炎的初期会增加,在慢性肝炎及肝硬化症中为正常或轻度增加。表示肝障碍的指标之一的AST和ALT显示出显著的差异。
ALT和AST为肝细胞泄漏的酶,随着肝细胞的坏死和肝组织的破坏,酶游离并出现在血液中,从而用于肝毒性的研究。图12为测量ALT和AST活性的结果。就AST而言,发芽发酵豆的浓度为0.5g/kg(83.20±2.86U/L)、1g/kg(81.80±6.72U/L),根据浓度没有显著的变化,但与样品处理组中的只用t-BHP进行处理的组(94.25±7.37U/L)相比,显著地降低。就ALT而言,发芽发酵豆的浓度为0.5g/kg(33.71±5.59U/L)、1g/kg(38.17±4.49U/L),根据浓度没有显著的变化,但与样品处理组中的只用t-BHP进行处理的组(48.25±16.19U/L)相比,显著地降低。
[表4]
处理 | 总胆固醇TCHO(mg/dl) | 乳酸脱氢酶LDH(U/L) | 总胆红素TBIL(mg/dl) |
正常组 | 80.00±7.81abc | 123.33±21.83b | 0.48±0.05ab |
t-BHP对照组 | 85.25±3.77a | 227.0±46.66a | 0.60±0.22a |
水飞蓟素 | 80.8±6.87ab | 141.33±24.34b | 0.54±0.05ab |
0.5g/kg的GFS+t-BHP | 66.29±9.89bc | 127.0±27.38b | 0.49±0.07bc |
1g/kg的GFS+t-BHP | 64.63±7.89c | 102.20±16.83b | 0.41±0.04c |
3.6.利用动物模型的MDA测量结果
脂质过氧化是指通过源自可在体内自然产生的超氧阴离子基团(superoxideanion radical)的各种自由基(free radical),细胞膜的多元不饱和脂肪酸发生过氧化的现象。不饱和脂肪酸通过过氧化过程进行分解而生成MDA,因此将其作为测量脂质过氧化的指标。如图13所示,就肝组织而言,在施用发芽发酵豆后施用t-BHP的组在样品的施用浓度为0.5g/kg(34.25±5.80)、1g/kg(32.68±12.57)时,各个组之间没有显著的差异,但随着浓度的升高而减少,并且与只施用t-BHP的组(44.66±1.94)相比,显示出减少的倾向。
3.7.利用动物模型的GST测量结果
GST存在于身体的几乎所有细胞中,其不仅是参与肝的解毒作用的酶,而且还是参与很多新陈代谢的酶。尤其,GST起到催化将电子亲和性基质结合于GSH的反应的作用。如图14所示,测量GST的结果,与只施用t-BHP的组(25.68±4.28)相比,在施用发芽发酵豆后施用t-BHP的组0.5g/kg、1g/kg中,在样品的施用浓度为0.5g/kg(33.65±12.97)、1g/kg(48.43±8.90)时,随着样品浓度的升高而增加,但是仅在1g/kg时显示出与施用t-BHP的组的显著差异。
3.8.利用动物模型的GSH测量结果
GSH是在体内起到解毒功能、免疫功能、抗氧化功能等核心作用的人体内非常重要的解毒剂且是强力的抗氧化剂。如图13所示,测量GSH的结果,与只施用t-BHP的组21.07±8.33)相比,在施用发芽发酵豆后施用t-BHP的组0.5g/kg、1g/kg中,在样品的施用浓度为0.5g/kg(25.12±2.44)、1g/kg(24.40±2.52)时,随着样品浓度的升高并没有显著的增加。此外,施用t-BHP的组与施用样品的组之间没有显示出显著的差异,但在施用样品的组中显示出略微增加的倾向。
3.9.利用动物模型的SOD测量结果
SOD是具有将超氧阴离子(superoxide anion,O2)还原为H2O2的作用的酶,存在于胞质溶胶(cytosol)和线粒体(mitochondria)中。胞质溶胶(cytosol)中只存在Cu/Zn-SOD,但线粒体(mitochondria)的基质(matrix)中存在Mn-SOD,内膜与外膜之间存在少量的Cu/Zn-SOD。测量SOD的结果(图9),与只施用t-BHP的组(23.11±1.71)相比,在施用发芽发酵豆后施用t-BHP的组0.5g/kg、1g/kg中,在样品的施用浓度为0.5g/kg(27.35±3.32)、1g/kg(25.67±0.02)时,随着样品浓度的升高并没有显著的增加。此外,施用t-BHP的组与施用样品的组之间具有显著的差异。但是,在施用样品的组中并没有显示出浓度依赖性的效果。
3.10.利用动物模型的CAT测量结果
过氧化氢酶(Catalase)是将通过SOD的作用或O2的还原生成的H2O2还原为无毒性的H2O而保护活体免受氧毒的酶,大部分存在于过氧化物酶体(peroxisome),也少量地存在于线粒体(mitochondria)中。测量CAT的结果(图10),与只施用t-BHP的组(182.24±19.29)相比,在施用发芽发酵豆后施用t-BHP的组0.5g/kg、1g/kg中,样品的施用浓度为0.5g/kg(204.49±41.51)、1g/kg(293.19±61.02)时,随着样品浓度的升高而显著地增加。此外,施用t-BHP的组与施用样品的组之间具有显著的差异,并且在施用样品的组中显示出浓度依赖性的效果。
[应用例]
本发明除了发芽发酵豆的提取物之外,还可以包含选自药理学、健康功能食品法、食品卫生法中可接受的赋形剂(崩解剂、粘合剂、润滑剂)、稳定剂、乳化剂、添加剂等中的一种以上。此外,所述组合物可以制备为硬膏剂、颗粒剂、散剂、片剂或胶囊剂等用于口服的剂型来使用。所述组合物的施用量需要根据相关法律中规定的标准(用途、使用目的、患者的状态、年龄、性别、体重、处方药、疾病)进行调整。
[应用例1]制剂
就制剂而言,在发芽发酵豆提取物中混合药事法中可接受的赋形剂或载体,从而作为制剂制备了散剂、片剂、胶囊剂、丸、颗粒。
[散剂]
混合2g的发芽发酵豆提取物及1g的乳糖,并填充于密封袋中,从而制备了散剂。
[片剂]
混合100mg的发芽发酵豆提取物、100mg的玉米淀粉、100mg的乳糖及2mg的硬脂酸镁,然后进行压片,从而制备了片剂。
[胶囊剂]
混合100mg的发芽发酵豆提取物、100mg的玉米淀粉、100mg的乳糖及2mg的硬脂酸镁,然后填充至明胶胶囊而进行制备。
[丸]
混合1g的发芽发酵豆提取物、1.5g的乳糖、1g的甘油、0.5g的木糖醇,然后以4g的大小制备了丸。
[颗粒]
预混合150mg的发芽发酵豆提取物、50mg的大豆提取物、200mg的葡萄糖、600mg的淀粉,然后添加100mg的30%的乙醇溶液,并在60℃下进行干燥,从而形成颗粒后填充到袋中。
[应用例2]食品
就食品而言,在发芽发酵豆提取物中混合食品卫生法或健康功能食品法中可接受的赋形剂或载体,从而制备了健康食品及饮料。
[健康食品]
混合1g的发芽发酵豆提取物、70μg的醋酸维生素A、1.0mg的维生素E、0.13mg的维生素、0.15mg的维生素B2、0.5mg的维生素B6、0.2μg的维生素B12、10mg的维生素C、10μg的生物素、1.7mg的烟酰胺、50μg的叶酸、0.5mg的泛酸钙、适量的无机混合物、1.75mg的硫酸亚铁、0.82mg的氧化锌、25.3mg的碳酸镁、15mg的磷酸二氢钾、55mg的磷酸氢钙、90mg的柠檬酸钾、100mg的碳酸钙、24.8mg的氯化镁,从而制备了健康食品。
上述的发芽发酵豆提取物中所混合的维生素及矿物质的比率可以根据剂型或不同需求者进行多种变形。
[饮料]
将1%的发芽发酵豆提取物、0.5%的液状果糖、2%的低聚糖、2%的白糖、0.5%的食盐及余量的精制水和配料进行调配,并进行杀菌后进行包装,从而制备了饮料。
上述的发芽发酵豆提取物中所混合的糖类、膳食纤维、维生素及矿物质的比率可以根据剂型或不同需求者进行多种变形。
工业实用性
本发明的发芽发酵豆提取物显著地增加血液中雌激素及睾酮的浓度,由此能够缓解更年期症状,并增加骨矿物质含量而显著地增加骨密度,并且增加松质骨的厚度和数量。因此,具有工业实用性。
Claims (10)
1.发芽发酵豆提取物,其含有香豆雌酚。
2.根据权利要求1所述的发芽发酵豆提取物,其特征在于,所述提取物用于保护肝细胞。
3.用于保护肝细胞的组合物,其包含权利要求1所述的发芽发酵豆提取物。
4.根据权利要求1所述的发芽发酵豆提取物,其特征在于,所述提取物用于增加骨密度。
5.用于增加骨密度的组合物,其包含权利要求1所述的发芽发酵豆提取物。
6.根据权利要求3或5所述的组合物,其特征在于,所述组合物为进一步包含药事法中可接受的赋形剂的药学组合物。
7.根据权利要求3或5所述的组合物,其特征在于,所述组合物为进一步包含健康功能食品法中可接受的赋形剂的健康功能食品组合物。
8.根据权利要求3或5所述的组合物,其特征在于,所述组合物为进一步包含食品卫生法中可接受的赋形剂的食品组合物。
9.根据权利要求3至5中任一项所述的组合物,其特征在于,所述组合物的剂型为液剂、颗粒剂、丸剂或胶囊。
10.制备发芽发酵豆提取物的方法,其特征在于,其包括如下步骤:
将大豆进行发芽并接种米曲霉而进行发酵,并进行过滤后进行干燥,从而获得发芽发酵豆;
向所述经过干燥的发芽发酵豆中加入乙醇溶液进行分解,然后通过超声波进行热水提取,从而获得热水提取物;以及
将所述热水提取物进行离心分离而获得的发芽发酵豆提取物进行过滤,然后进行干燥,从而获得发芽发酵豆提取物。
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