CN112826935B - 包含乳酸菌及益生元的更年期症状的预防、缓解或治疗用组合物 - Google Patents
包含乳酸菌及益生元的更年期症状的预防、缓解或治疗用组合物 Download PDFInfo
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Abstract
本发明涉及包含乳酸菌及益生元的更年期症状的预防、缓解或治疗用组合物。本发明的乳酸菌具有β‑葡萄糖苷酶活性,从异黄酮变为雌马酚(equol)化合物的转换能力非常优秀,可通过与肠道微生物群之间的协同增效作用来呈现出雌激素活性(estrogen activity),从而可有效地用于女性的更年期或绝经期症状的预防、缓解以及治疗。
Description
技术领域
本发明涉及包含乳酸菌及益生元的更年期症状的预防、缓解或治疗用组合物。
背景技术
女性的绝经(menopause)是指出生后长达约50年的遗传方面决定的卵巢功能衰竭所致的无月经状态,意味着再无生育能力,属于生理变化,而不是疾病现象。当前,韩国女性的平均寿命为81.2岁(2011年,统计厅),若将大韩妇产科学会规定的韩国女性的平均绝经年龄假设成50岁,则意味着女性一生当中的约1/3以上的时间将会以女性荷尔蒙枯竭的状态度过。女性更年期(climacteric periods)是指绝经前后的女性生育能力减退、消失的转变时期,属于在身体和精神上非常不稳定的时期。将绝经前后3~5年的约10年左右的时间称为更年期,大概是在46~55岁期间。而且,完全停经并经过1年时间之后的时期开始被定义为绝经。因而,女性将在绝经前、绝经期进行期、绝经、绝经后等阶段产生身体上、精神上的变化。
近来,随着发表关于反对荷尔蒙疗法的多种研究,荷尔蒙疗法是否具有有效性受到很大挑战。其中,最具代表性的是通过美国国立卫生研究院(NIH)的支援来在2002年发表的妇女健康倡议(WHI)研究。自1993年起研究了荷尔蒙疗法对原发性冠状动脉疾病、乳腺癌、直肠癌、继发性骨折有怎样的影响。妇女健康倡议研究原计划进行8年零六个月,但在经过5年零两个月左右的时间后,发现荷尔蒙治疗组中的乳腺癌风险显著增加,在荷尔蒙用药组中的心血管疾病的发生显著增加,因而提前终止。
植物性雌激素为植物中存在的物质,是指在结构上、功能上与17-β-雌二醇(estradiol)有关或呈现出雌激素效果的物质,大致分为如下的4种。包括:(i)石榴或枣椰树等的类固醇类;(ii)红参等的含皂苷(saponin)物质;(iii)黄酮类化合物类等的酚类;(iv)升麻或甘草等的萜类(terpenoid),其中,黄酮类化合物类划分为大豆及红三叶草等的异黄酮(isoflavone)类、亚麻子及蓝莓等的木脂素(lignan)类、葵花籽油及红车轴草等的香豆素(coumestan)类。
源自大豆(soy)的异黄酮大多为糖苷缀合物(glycoside conjugates)(大豆苷(daidzin)、染料木苷(genistin)、黄豆黄素苷(glycitin))形态,这是生物体利用能力及雌激素活性低的形态。为了提高对其的吸收力及活性,需要分解有糖苷的异黄酮苷元(isoflavone aglycone)(黄豆苷元(daidzein)、染料木素(genistein)、黄豆黄素(glycitein)),这通过肠道微生物群(gut microbiota)的β-葡萄糖苷酶生成。并且,通过肠道微生物群最终变为雌马酚(equol)形态并形成植物性雌激素(phyto-estrogen)形态。通过肠道微生物群生成的雌马酚在东西方呈现出不同的生成量。在豆的平时摄入量大的亚洲人群中,有50%是通过豆的射入来生成雌马酚,但在豆摄入量少的西方人群中,只有20~30%能够生成雌马酚。
在异黄酮中,雌马酚呈现出最强的雌激素反应。雌马酚和雌激素的分子结构非常相似。雌马酚通过与雌激素受体(estrogen receptor、ERα、ERβ)相结合来呈现出通过雌激素表达的活性,尤其对于ERβ呈现出高亲和度。黄豆苷元也呈现出雌激素受体(ER)结合亲和度,但雌马酚呈现出更高的ER结合亲和度。
在本说明书中提及的专利文献及参照文献以与各个文献通过参照来单独地、明确地特定的部分相同的程度插入为本说明书的参照文献。
现有技术文献
专利文献
专利文献1:韩国公开专利第2019-0014056号
专利文献2:韩国公开专利第2014-0131881号
专利文献3:韩国公开专利第2015-0007851号
发明内容
要解决的问题
本发明者致力于研究开发可适用于女性更年期或绝经期症状的预防、缓解、治疗的益生菌乳酸菌菌株。最终,开发了β-葡萄糖苷酶活性高、能够以高效率将异黄酮类转换成雌马酚化合物的乳酸菌,通过实验证明及确认该乳酸菌在细胞实验及更年期动物模型中呈现出雌激素活性(estrogen activity),从而完成了本发明。
因此,本发明的一目的在于提供包含益生元组合物的更年期或绝经期症状的预防或改善用食品组合物,上述益生元组合物包含乳酸菌及异黄酮。
本发明的再一目的在于提供包含益生元组合物的更年期或绝经期症状的预防或治疗用药学组合物,上述益生元组合物包含乳酸菌及异黄酮。
本发明的其他目的及技术特征可通过以下的本发明的详细说明、发明要求保护范围及附图来具体阐述。
解决问题的方案
根据本发明的一实施方式,本发明提供更年期或绝经期症状的预防或改善用食品组合物,上述更年期或绝经期症状的预防或改善用食品组合物包含:(i)选自由双歧杆菌(Bifidobacterium)属乳酸菌、乳杆菌(Lactobacillus)属乳酸菌以及乳球菌(Lactococcus)属乳酸菌组成的组中的一种以上的乳酸菌;以及(ii)包含异黄酮(isoflavone)及大豆胚芽提取物(soybean germ extract)的益生元组合物。
从在给药到体内的情况下停留在肠道并与肠道微生物群(gut microbiota)一同起到有益的协同增效作用的含义上出发,本发明的乳酸菌可以为益生菌(probiotics)乳酸菌。
在本发明中使用的乳酸菌为选自由双歧杆菌属乳酸菌、乳杆菌属乳酸菌以及乳球菌属乳酸菌组成的组中的一种以上的乳酸菌。
在本发明的一实例中,上述双歧杆菌属乳酸菌为选自由乳双歧杆菌(Bifidobacterium lactis)、短双歧杆菌(Bifidobacterium breve)、长双歧杆菌(Bifidobacterium longum)以及婴儿双歧杆菌(Bifidobacterium infantis)组成的组中的一种以上的乳酸菌。
在本发明的再一实例中,上述乳杆菌属乳酸菌为鼠李糖乳杆菌(Lactobacillusrhamnosus)、格氏乳杆菌(Lactobacillus gasseri)以及瑞士乳杆菌(Lactobacillushelveticus)组成的组中的一种以上的乳酸菌。
在本发明的另一实例中,上述乳球菌属乳酸菌为乳酸乳球菌(Lactococcuslactis)。
在本发明的还有一实例中,上述乳酸菌可以为选自由乳双歧杆菌(Bifidobacterium lactis)、婴儿双歧杆菌(Bifidobacterium infantis)、格氏乳杆菌(Lactobacillus gasseri)以及瑞士乳杆菌(Lactobacillus helveticus)组成的组中的一种以上的乳酸菌。
在本发明的又一实例中,上述乳酸菌可以为选自由乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌以及瑞士乳杆菌组成的组中的两种以上的复合乳酸菌。
在本发明的又一实例中,上述乳酸菌可以为选自由乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌以及瑞士乳杆菌组成的组中的4种复合乳酸菌。
本发明的食品组合物包含益生元(prebiotics)组合物,上述益生元组合物包含异黄酮及大豆胚芽提取物。
在本发明中,术语“益生元”意味着通过对以上说明的本发明的乳酸菌起到基质(substrate)作用来促进乳酸菌的生长或有益的活性的多个化合物。
在本发明中,益生元成分促进本发明的乳酸菌的生长,将通过本发明的乳酸菌转换成雌马酚(equol)化合物。
在本发明的一实例中,相对于上述益生元组合物,包含1~50重量%的上述异黄酮,优选地包含5~45重量%的上述异黄酮,更优选地包含10~40重量%的上述异黄酮。
本发明的乳酸菌呈现出非常高的β-葡萄糖苷酶(glucosidase)活性。
在本发明中,术语“更年期症状”或“绝经期症状”意味着因女性卵巢功能逐渐消失而在女性荷尔蒙的生成及活性下降的绝经期间出现的症状。例如,在上述更年期期间,活性和生产出现减少的女性荷尔蒙有雌激素。上述雌激素为雌酮(estrone)、雌二醇(estradiol)、雌三醇(estriol)的荷尔蒙的总称,其中,雌二醇为最强的女性荷尔蒙。
在本发明中,例如,上述更年期或绝经期症状可以为面部红潮、夜间发汗、经期不规律、性欲减退、阴道干燥、疲劳、脱发、睡眠障碍、注意力障碍、记忆力减退、眩晕症、体重增加、尿失禁、腹部膨胀感、过敏、指甲易断、体味变化、心律不齐、抑郁症、不安、焦躁、惊恐障碍症状、骨质疏松症、骨密度减少症、高血脂或血脂异常症,但并不限定于此。
本发明的食品组合物可由功能性食品(functional food)、营养增补剂(nutritional supplement)、健康食品(health food)或食品添加剂(food additives)来制作,但并不限定于此。
本发明的食品组合物可根据该领域公知的常规方法来以多种形态制作,例如,能够以发酵奶等的饮料或粉末形态制作。
本发明的食品组合物不仅包含如上所述的本发明的有效成分,还包含制作食品时通常添加的成分,例如,包含蛋白质、碳水化合物、脂肪、营养素、调味剂以及香味剂。例如,上述碳水化合物为单糖、二塘、多糖等的常规的糖以及糖醇,上述单糖有葡萄糖、果糖等,上述二塘有麦芽糖、蔗糖、低聚糖等,上述多糖有糊精、环糊精等,上述糖醇为木糖醇、山梨糖醇、赤藓糖醇等。香味剂可使用天然香味剂(索马甜、甜菊糖提取物(例如,瑞鲍迪甙A、甘草素等))以及合成香味剂(糖精、阿斯巴甜等)。
在以饮料形态制作本发明的食品组合物的情况下,除了本发明的有效成分之外,还可包含柠檬酸、液态果糖、白糖、葡萄糖、醋酸、苹果酸、果汁、杜仲提取物、大枣提取物、甘草提取物等。
根据本发明的其他实施方式,本发明提供一种更年期或绝经期症状的预防或治疗用药学组合物,包含:(i)选自由双歧杆菌属乳酸菌、乳杆菌属乳酸菌以及乳球菌属乳酸菌组成的组中的一种以上的乳酸菌;(ii)包含异黄酮及大豆胚芽提取物的益生元组合物;以及(iii)药学上可接受的载体。
在本发明的药学组合物中,与乳酸菌及益生元组合物相关的内容与以上说明的作为本发明的一实施方式的更年期或绝经期症状的预防或改善用食品组合物中说明的内容相同,因而进行引用,不进行重复说明。
在本发明中,术语“预防”意味着虽然并未诊断为患上疾患、疾病或疾患引起的症状,但在具有易患上疾患、疾病或症状的倾向的动物中抑制疾患、疾病或症状的发生。
在本发明中,术语“治疗”意味着(i)抑制疾患、疾病或症状的发展,(ii)减轻疾患、疾病或症状,或者(iii)消除疾患、疾病或症状。
本发明的药学组合物中所包含的药学上可接受的载体为制剂时通常利用的,包括碳水化合物类化合物(例:乳糖、直链淀粉、右旋糖、蔗糖、山梨糖醇、甘露醇、淀粉、纤维素等)、阿拉伯树橡胶、磷酸钙、海藻酸钠盐、明胶、硅酸钙、微细结晶性纤维素、聚乙烯吡咯烷酮、纤维素、水、糖汁、盐溶液、乙醇、阿拉伯树胶、植物性油(例如:玉米油、棉花籽油、豆油、橄榄油、椰子油)、聚乙二醇、甲基纤维素、对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、滑石、硬脂酸镁以及矿物油等,但并不限定于此。
除了上述成分之外,本发明的药学组合物还可包含润滑剂、湿润剂、甜味剂、香味剂、乳化剂、悬浮剂、保存剂等。适当的药剂学上可接受的载体及制剂在雷明顿药学(Remington′s Pharmaceutical Sciences,19th ed.,1995)。
本发明的药学组合物的适当用量可根据制剂化方法、用药方式、患者的年龄、体重、性别、病情、饮食、用药时间、用药途径、排泄速度以及反应灵敏性等来有多种处方形式。另一方面,本发明的药学组合物的径口用量优选为每天0.001~1000mg/kg(体重)。
本发明的药学组合物可通过可由本发明所属技术领域的普通技术人员轻松实施的方法来利用药学上可接受的载体和/或成型添加剂进行制剂化,从而按单位容量形态进行制作或内入于多容量容器内来制作。在此情况下,剂型可以为油或水性介质中的溶液、悬浮液或乳化液,还可以为浓缩剂、粉末剂、冲剂、片剂或胶囊剂形态,还可包括分散剂或稳定剂。
发明的效果
如上所述,本发明的乳酸菌具有β-葡萄糖苷酶活性,从异黄酮变为雌马酚化合物的转换能力非常优秀,可通过与肠道微生物群之间的协同增效作用来呈现出雌激素活性(estrogen activity),从而可有效地用于女性的更年期或绝经期症状的预防、缓解以及治疗。
附图说明
图1a及图1b为在大豆胚芽提取物中测定的益生菌乳酸菌菌株的雌马酚生成能力的结果。
图2a及图2b为在大豆胚芽提取物中测定的益生菌乳酸菌菌株的β-葡萄糖苷酶活性的结果。
图3a为在MCF-7细胞中测定S30及在S30培养益生菌乳酸菌菌株(B.lactis、B.infantis、L.gasseri、L.helveticus)的培养液处理对雌激素相关基因ESR1、ESR2及pS2的信使核糖核酸(mRNA)表达水平产生的影响的结果。
图3b为在MG-63细胞中测定S30及在S30培养益生菌乳酸菌菌株(B.1actis、B.infantis、L.gasseri、L.helveticus)的培养液处理对ESR1、ESR2、Osteocalcin、Osteoprotegerin的信使核糖核酸表达水平产生影响的结果。
图3c为在MG-63细胞中测定S30及在S30培养益生菌乳酸菌菌株(B.lactis、B.infantis、L.gasseri、L.helveticus)的培养液处理对Alkaline phosphatase、COL1A1、BMP-2、BMP-4的信使核糖核酸表达水平产生的影响的结果。
图4为在去卵巢(OVX,ovariectomized)大鼠中测定的各个实验组(Sham、OVX、OVX+E2、OVX+PRO、OVX+S30、OVX+S30+PRO)的17β-雌二醇及雌马酚的血液(serum)浓度测定结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2 group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30group。
图5为在去卵巢大鼠中测定的各个实验组(Sham、OVX、OVX+E2、OVX+PRO、OVX+S30、OVX+S30+PRO)的体重变化的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2 group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30 group。
图6a及图6b为在去卵巢大鼠中测定的各个实验组的基于体重的腹部脂肪体积的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、comparedto OVX+S30 group。
图7a及图7b为在去卵巢大鼠中测定的各个实验组的血液指标的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2 group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30group。
图8a为在去卵巢大鼠中测定的各个实验组的阴道上皮组织的厚度的结果。
图8b为在去卵巢大鼠中测定的各个实验组的子宫组织的重量的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2 group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30group。
图9a至图9c为在去卵巢大鼠中测定各个实验组的骨指标的结果。
图10为在去卵巢大鼠中测定各个实验组的血中血清素及肾上腺素的浓度的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2 group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30group。
图11a为在去卵巢大鼠中测定各个实验组的血中骨形成标记Osteocalcin及B-ALP的浓度的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Shamgroup.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared toOVX+E2group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30 group。
图11b为在去卵巢大鼠中测定各个实验组的血中骨吸收标记Deoxypyridinoline、Pyridinoline、Type 1 Collagen cross-linked telopeptide(NTX、CTX)的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2 group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30 group。
图12为在去卵巢大鼠中测定各个实验组的血管稳态血液标记、皮内素-1(Endothelin-1)、一氧化氮(NO,Nitric Oxide)、内皮型一氧化氮合酶(eNOS,endothelialNitric Oxide Synthase)的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2 group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30 group。
图13为在去卵巢大鼠中测定各个实验组的血中促卵胞成熟荷尔蒙(folliclestimulating hormone、FSH)和促黄体荷尔蒙(luteinizing hormone,LH)的浓度的结果。测定值以平均±SD来表示。ap<0.05.bp<0.01、compared to Sham group.cp<0.05.dp<0.01、compared to OVX group.ep<0.05.fp<0.01、compared to OVX+E2 group.gp<0.05.hp<0.01、compared to OVX+PRO group.ip<0.05.jp<0.01、compared to OVX+S30group。
具体实施方式
在本说明书中说明的具体实施例意味着本发明的优选实施例或例示,本发明的范围并不受此限制。本发明的变形实施方式和其他用途不脱离在本说明书的发明要求保护范围中所记载的本发明的范围,这对本发明所属技术领域的普通技术人员而言是不言而喻的。
实施例
实验方法
实验例1:具有从异黄酮转换成雌马酚的转换能力的益生菌的筛选
筛选了具有可从包含30重量百分比的异黄酮的大豆胚芽提取物S30生成雌马酚的能力的益生菌菌株。
首先,使用包含30重量百分比的异黄酮的大豆胚芽提取物S30(Seorim Bio制造)和40g/L的杀菌水来制备了大豆胚芽提取物。使用5M的NaOH来将pH调节成6.7。在121℃的温度下对整个大豆胚芽提取物进行15分钟的高压灭菌,从而进行了灭菌。在重修微生物的MRS(Mann Rogosa Sharpe)肉汤(De Mann et al.1960)中以37℃的温度进行了20个小时的活性化,使用5%(v/v)的接种水平来在灭菌的大豆胚芽提取物中进行了4次活性化。对于40~400mL的灭菌大豆胚芽提取物接种活性化培养物(5%v/v),为了水解异黄酮糖苷,在37℃的温度下进行了24小时的接种。在大豆胚芽提取物中使用了活性化状态的菌株。
在初期筛选步骤中,在大豆胚芽提取物中培养了48个小时,从而调查了是否从大豆胚芽提取物生成雌马酚。并且,随着时间流逝来以规定时间间隔提取了样本并确认了β-葡萄糖苷酶活性。β-葡萄糖苷酶活性度测定利用了pNPG(p-nitrophenyl-β-D-glucopyranoside)方法。灵活地决定了上述筛选步骤中的优选顺序。即,在先筛选生成雌马酚的菌株之后,测定了β-葡萄糖苷酶活性,或在先筛选具有高β-葡萄糖苷酶活性的菌株之后,确认了是否生成雌马酚。通过在单一菌株或符合菌株中测定雌马酚生成能力及β-葡萄糖苷酶活性来进行了筛选。
实验例2:体外(in vitro)细胞分析
通过体外细胞实验,调查了通过益生菌生成的雌马酚的雌激素相关效果及雌激素相关标记表达水平。在MG-63细胞(Homo sapiens bone osteosarcoma,造骨细胞)和MCF-7细胞(human breast adenocarcinoma,乳腺癌细胞)中调查了雌激素相关标记的表达水平。使用以雌马酚形成及β-葡萄糖苷酶活性为基准筛选的益生菌菌株的大豆胚芽提取物培养液来对上述细胞株进行了处理,以实时聚合酶链式反应(PCR)分析了信使核糖核酸水平下的生物标记的表达量(表1)。
表1
2-1.雌激素受体(ER)-α、β活性化及蛋白质表达水平测定细胞实验使用了分布有很多雌激素受体的组织的确立的细胞株MCF-7细胞(乳腺癌细胞株)、Ishikawa细胞(子宫内膜癌细胞)SaOS-2细胞(骨癌)。通过用实验物质对这些细胞进行处理来确认了是否使受体活性化,由此评价了基因转录活性。并且,在细胞实验或动物样本中利用蛋白质印迹法(Western blotting)来测定了ERα(ESR1)、ERβ(ESR2)的蛋白质表达水平以及通过逆转录聚合酶链反应(RT-PCR,reverse transcription polymerase chain reaction)来测定了信使核糖核酸水平。
2-2.测定ESR1及pS2信使核糖核酸表达水平
ESR1、pS2为通过雌激素受体增加表达的雌激素反应基因(estrogen-responsivegene),在用试验物质对MCF-7细胞(乳腺癌细胞株)进行处理之后,通过分析上述基因的信使核糖核酸水平变化来评价了试验物质是否呈现出雌激素活性(estrogenic activity)。
2-3.在造骨细胞测定骨密度相关表达量
作为骨形成指标,测定了骨保护素(OPG,osteoprotegerin)、骨形成蛋白-2(BMP-2,Bone morphogenetic protein 2)、骨形成蛋白-4(BMP-4,Bone morphogenetic protein4)、骨钙素(Osteocalcin)、碱性磷酸酶(Alkaline phosphatase)等的表达水平。骨形成蛋白-4为骨形成蛋白质,骨诱导能力高,骨形成蛋白-2为促进骨形成的基因,若表达增加,则促进骨形成,I型胶原A1(COL1A1,Collagen type Iα1)为结合组织、软骨等的主要结构要素,使第1型胶原的生成活性化。并且,骨保护素为在形成骨骼的造骨细胞中生成的蛋白质,其抑制破骨细胞的作用。
实验例3:动物实验测试
在更年期样本实验动物中,对于最终筛选的益生菌菌株,评价了更年期症状抑制活性。
3-1.实验设计
在实验动物方面,按6大鼠/组的方式使用了雌性斯泼累格·多雷(FemaleSprague-Dawley)大鼠(初始体重:150~180g/大鼠)。实验期间为10周(1周:适应期;1周:去卵巢后恢复期;8周:实验物质给药期间)。给药了雌激素E2(17β-雌二醇)、大豆胚芽提取物(异黄酮30%,S30)、益生菌(BL+BT+LGA+LH,Pro)、饲料(AIN-93G,将豆油(Soybean Oil)更换成玉米油(Corn Oil))。以10μg/kg的容量每周给药3次雌激素E2(17β-雌二醇),S30每天给药10mg/kg,以1×107CFU/head的容量每天给药益生菌。表2中示出了动物实验计划。
表2
3-2.测定实验
每周测定了各个实验组的体重。给药8周之后,在各个实验组的血液中测定了血中雌激素以及雌马酚含量。给药8周之后,通过微型电子计算机断层扫描(Micro-CT)测定了各个个体的腹部组织的脂肪分布及定量。
通过阴道上皮细胞的H&E染色来测定了阴道上皮细胞的厚度。通过测定子宫重量来确认了因去卵巢而使子宫重量减少并很好地诱导了更年期样本,确认了给药物质是否对子宫的内皮产生影响。
作为血液分析,通过测定中性脂肪、总胆固醇、低密度脂蛋白(LDL)胆固醇、高密度脂蛋白(HDL)胆固醇、游离脂肪酸水平来测定了血中脂质水平。并且,测定了血管松弛。雌激素起到使血管松弛并减少血中脂质的作用,更年期女性的心血管类疾病发病率的增加与雌激素水平的减少相关。由此,作为测定更年期女性的心血管健康的指标,测定了血中总胆固醇(total cholesterol)、高密度脂蛋白胆固醇、极低密度脂蛋白(VLDL)胆固醇、低密度脂蛋白胆固醇、中性脂肪水平,测定了皮内素-1(Endothelin-1)、一氧化氮(nitric oxide,NO)、内皮型一氧化氮合酶(eNOS,endothelial nitric oxide synthase)等的血管收缩及松弛指标。
测定了骨密度(BMD,Bone mineral density)及骨矿物质浓度(BMC,Bone mineralconcentration)。通过在更年期动物样本(OVX)中测定骨密度,来评价了是否能够通过给药物质来调停因缺乏雌激素而导致骨密度下降的情况。测定了造骨细胞的骨密度相关表达量。对于更年期女性而言,通常会使骨吸收指标高于骨形成指标。骨吸收指标为破骨细胞噬骨时呈现的指标,有D-焦谷氨酸(Deoxypyridinoline)、Pyridinoline、1型胶原交联末端肽(Type 1 collagen cross-linked telopeptide(NTX、CTX))等。作为骨形成指标,测定了骨钙素(Osteocalcin)、碱性磷酸酶(Alkaline phosphatase)等。表3中示出了更年期效果相关测定标记(marker)。
表3
实验结果
实施例1:基于益生菌测定雌马酚生成浓度
将细胞生物科技有限公司(Cell Biotech Co.,Ltd.)的菌株(CBT 19个菌株)接种到含有30%的异黄酮的大豆胚芽提取物S30并在37℃的温度下培养48个小时后判断了是否在上清液形成雌马酚并测定了浓度。在所测定的菌株中的8个菌株(乳双歧杆菌、短双歧杆菌、长双歧杆菌、婴儿双歧杆菌、鼠李糖乳杆菌、格氏乳杆菌、瑞士乳杆菌、乳酸乳球菌)中,在培养上清液形成了雌马酚,测定到值得留意的浓度。尤其,在双歧杆菌类菌株中形成了大量的雌马酚(图1a)。并且,在雌马酚生成能力高的4个菌株的混合体(四种益生菌(Fourstrains of probiotics)、乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌、瑞士乳杆菌)中呈现出了比各个单一菌株更高的雌马酚形成能力(图1b)。
实施例2:测定益生菌的β-葡萄糖苷酶活性
异黄酮以结合有糖的糖苷缀合物形式(glycoside conjugates form)存在。为了形成雌马酚,首先需分解与异黄酮相结合的糖苷(glycoside)来形成非缀合物形式。这种反应通过肠道微生物群(gut microbiota)的β-葡萄糖苷酶进行。在形成雌马酚的8个菌株中,在相同条件下,通过测定β-葡萄糖苷酶活性来筛选了效率性高的菌株。在初期反应时间(1h~2h)中,β-葡萄糖苷酶活性相对高的菌株为乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌、瑞士乳杆菌,并且与总共反应48个小时(48h)的其他菌株相比,维持了高β-葡萄糖苷酶活性(图2a)。并且,在4个菌株的混合体(乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌、瑞士乳杆菌)中,与其他单一菌株相比维持了高β-葡萄糖苷酶活性(图2b)。在给药后在肠道内与大豆胚芽提取物S30产生反应来形成了高浓度的雌马酚,选定了呈现出高β-葡萄糖苷酶活性的4种益生菌,即,乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌、瑞士乳杆菌,将这些用到了体内(in vivo)测试。
实施例3:在乳腺癌细胞及造骨细胞中测定雌激素相关基因表达
在MCF-7细胞(human breast adenocarcinoma,乳腺癌细胞)及MG-63细胞(Homosapiens bone osteosarcoma,造骨细胞)用S30进行处理或用在S30培养益生菌菌株乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌、瑞士乳杆菌的滤液进行处理,从而测定了雌激素相关基因的表达量。测定结果,虽然在用S30单独处理的细胞中与对照组相比未呈现出显著性差异,但在使用在S30中培养各个益生菌菌株而得到的滤液进行处理的细胞中,在基因的表达量方面呈现出了显著性差异,整体上,与对照组及S30处理组相比,雌激素相关基因的表达量显著增加(图3a~图3c)。
实施例4:在去卵巢大鼠中测定17β-雌二醇及雌马酚的血中浓度
在各个实验组的血液(serum)中测定17β-雌二醇(E2)的结果,虽然在OVX中显著减少,但通过给药17β-雌二醇,确认到维持到Sham数值。通过向去卵巢个体给药Probiotics、S30、S30+Probiotics来使17β-雌二醇的数值并未显著增加。对于雌马酚而言,在各个实验组的血液中进行测定的结果,Sham、OVX、OVX+E2、OVX+Probiotics并未呈现出显著性差异,通过给药30或S30+Probiotics来确认到雌马酚显著增加。在OVX+S30实验组中,判断为雌马酚的增加是因个体的肠道微生物群(gut microbiota)而生成。因给药S30+Proiotics而使得血液内的雌马酚浓度显著增加,这被判断为通过向个体的肠道微生物群给药益生菌来与从S30形成雌马酚产生协同效果(synergy effect)(图4)。
实施例5:在去卵巢大鼠中测定体重变化
由于即使绝经之后也需要维持一定水平的雌激素,因而在绝经后主要在腹部脂肪组织的脂肪细胞和肌肉细胞中将雌激素前体转换成雌激素,在缓解因绝经引起的雌激素骤减的过程中,脂肪细胞将被活性化,将成为肥胖的原因。在去卵巢后测定了8周的体重。在给药之前(0week),各个实验组的体重没有显著性差异,呈现出了相似的值。从给药第一周开始,实验组之间开始呈现出显著性差异。与Sham组相比,因去卵巢而开始引起体重增加,尤其,在S30+Probioics实验组中,体重增加量显著减少。并且,因给药Probiotic而引起的效果也开始显现。从给药的第3周开始,与Sham组相比,在S30+Probioics实验组中,开始不出现明显的体重之差,在给药的第4周,与E2(17β-雌二醇、雌激素)给药组相比,体重增加量减少了。在给药的第8周(结束给药)开始的时间点,与Sham组及Probiotics给药组相比,S30+Probiotics实验组并未呈现出显著性差异,但与OVX实验组、E2实验组及S30实验组相比,体重增加量显著减少。在去卵巢后,确认到8周之内个体的体重增加,并且,确认到,因给药E2而使得体重增加量显著减少。这种效果在Probiotics给药组、S30+Probiotics给药组中也出现,但仅给药S30就不会显现(图5)。
实施例6:在去卵巢大鼠中测定腹部脂肪体积
在去卵巢大鼠中测定了以各个实验组的体重为基础的腹部脂肪体积并进行了比较(图6a及图6b)。
总腹部体积(Total abdominal volume)测定结果,基于去卵巢及单独给药S30而形成的腹部体积与Sham组相比显著增加。给药E2、Probiotics并未与OVX组相比呈现出显著性差异,但给药S30+Probiotics与OVX组相比呈现出显著减少的效果。
并且,测定总腹部脂肪体积、腹部内脏脂肪体积+腹部皮下脂肪体积(TotalAbdominal Fat volume)的结果,呈现出与总腹部体积测定中相同样态的结果。并且,测定腹部内脏脂肪体积(Abdominal Visceral Fat volume)的结果,与Sham组相比,在OVX组及S30单独给药组中显著增加。由于给药E2、Probiotics,与OVX组相比,呈现出显著减少的样态。与OVX组及S30给药组相比,S30+Probiotics给药组显著减少。
测定腹部皮下脂肪体积(Abdominal Subcutaneous Fat volume)的结果,与Sham组相比,因去卵巢而显著增加。在其他实验组中,并未产生与OVX组明显不同的之处,与OVX组相比,S30+Probiotics给药组呈现出显著减少的效果。
总腹部脂肪比例(Total Abdominal Fat ratio、Total Abdominal Fat volume/Total abdominal volume,%):与Sham组相比,在OVX组及S30单独给药组中显著增加。与Sham组相比,S30+Probiotics给药组并没有明显不同之处,与E2给药组、Probiotics给药组及S30给药组相比,呈现出显著减少的效果。
在测定腹部内脏脂肪比例(Abdominal Visceral Fat ratio、AbdominalVisceral Fat volume/Total Abdominal Fat volume,%)的结果,实验组之间没有显著性差异。
在测定腹部皮下脂肪比例(Abdominal Subcutaneous Fat ratio、AbdominalSubcutaneous Fat volume/Total Abdominal Fat volume,%)的结果,实验组之间没有显著性差异。
实施例7:在去卵巢大鼠中测定血液学指标
在去卵巢大鼠中测定了各个实验组的血液学指标并进行了分析(图7a及图7b)。
白蛋白(Albumin)作为多种荷尔蒙的搬运体,与Ca、P、sulfur(S)等的电介质及甲状腺荷尔蒙相结合来起到搬运作用。若白蛋白的浓度下降,则基础功能将下降。由于去卵巢而使得白蛋白的数值下降,但因给药Probiotics或S30+Probiotics,使得白蛋白数值显著增加。
血中钙浓度(calcium)的变化将受到骨中钙含量的影响,因去卵巢而引起的骨胶着率的增加将导致骨质减少,会引起血中钙浓度上升,因而钙浓度的变化与骨吸收有关。虽然因去卵巢而使血中钙浓度增加,但因给药E2而减少。并且,因给药S30、Probiotics、S30+Probiotics,与Sham组及E2给药组相比,钙浓度显著减少。
若雌激素的分泌减少,则抑制脂蛋白脂肪酶(Lipoprotein lipase)活性的功能下降,因而脂肪将过度堆积,将出现高血脂。因去卵巢,与Sham组相比,胆固醇(cholestrol)、中性脂肪(triglyceride)、LDL显著增加,HDL显著减少。S30、Probiotics、S30+Probiotics的给药整体上呈现出明显的高血脂改善效果,尤其,与其他给药组相比,S30+Probiotics的给药会在血中LDL的减少及HDL的增加方面呈现出很显著的效果。
因去卵巢,与Sham组相比,在肝数值方面,谷草转氨酶(AST,Aspartateransaminase)、谷丙转氨酶(ALT,Alanine transaminase)显著增加。仅给药Probiotics就能够呈现出明显的减少效果,与单独给药S30的情况相比,S30+Probiotics给药组将呈现出更好的效果。
实施例8:在去卵巢大鼠中测定子宫阴道内膜的厚度
8-1.在各个实验组中测定阴道上皮组织厚度(vaginal epithelial height)
在更年期及绝经期之后减少的血中雌激素浓度还会对泌尿生殖器产生影响,将引起阴道粘膜的红肿、失去弹性、失去褶皱、细胞结构的变化、阴道内酸度增加等的泌尿生殖器退化。由于阴道上皮的厚度和血液流量减少,会导致干燥、变薄、苍白、阴道上皮的成熟度下降,因而未成熟的细胞将变多。因去卵巢而使得阴道上皮组织的厚度比Sham组显著减少,因给药E2,与OVX组相比,显著增加。与Sham及E2给药组相比,Probiotics或S30的单独给药将使阴道上皮组织的厚度显著减少,与OVX组相比,并未呈现出显著性差异。但是,在阴道上皮组织的厚度方面,与Sham实验组及E2实验组相比,S30+Probiotics给药组呈现出显著性差异,与OVX实验组、Probiotics实验组或S30实验组相比,显著增加。这在因雌激素减少而呈现的阴道组织的变化方面解释成因给药S30+Probiotics而呈现出明显的改善效果(图8a)。
8-2.在各个实验组中测定子宫组织重量
若去卵巢,则因使子宫内膜生长的雌激素减少而导致子宫重量减少。因去卵巢,子宫组织的重量比Sham组显著减少,因给药E2而与OVX组相比显著增加。因单独给药Probiotics或S30,与Sham及E2的给药组相比,子宫组织重量显著减少,与OVX组相比,并未呈现出显著性差异。但是,通过给药S30+Probiotics,与Sham实验组及E2实验组相比,子宫组织的重量显著减少,但与OVX实验组、Probiotics实验组或S30实验组相比,显著增加。这是S30+Probiotics的给药在因雌激素的减少而产生的子宫组织变化方面呈现出明显的改善效果的结果(相对于每100g的个体重量,子宫组织重量也呈现出相同的趋势)(图8b)。
实施例9:在去卵巢大鼠中测定骨指标
在去卵巢大鼠中测定了各个实验组的骨指标并进行了分析(图9a~图9c)。在骨密度方面,因去卵巢而显著减少。Probiotics、S30给药组虽然并未呈现出与OVX之间的显著性差异,但因给药E2或S30+Probiotics,骨密度显著增加。尤其,与Probiotics给药组、S30给药组相比,S30+Probiotics给药组的骨密度显著增加。总体积(TV,Total volum)在所有实验组均相同,并未因去卵巢而在总体积方面产生变化。因去卵巢,骨体积(BV,Bonevolume)、骨体积/总体积(BV/TV)、骨表面(BS,Bone surface)显著减少。与OVX组相比,Probiotics给药组、S30给药组并不产生显著性差异,但在E2给药组或S30+Probiotics给药组在骨体积/总体积(BV/TV)、骨表面(BS,Bone surface)方面显著增加。因去卵巢,骨表面/骨体积(BS/BV)、骨小梁厚度(Tb.Th,Trabecular Thickness)显著减少,因给药E2及S30+Probiotics,显著增加。骨小梁数目(Tb.N,Trabecular Number)、骨小梁间距(Tb.Sp,Trabecular Separation)在执行去卵巢的所有实验组显著增加,但在实验组之间并未产生显著性差异。
实施例10:在去卵巢大鼠中测定血中血清素及肾上腺素浓度
血清素(serotonin)为大脑、内脏组织、血小板、肥胖细胞等中的神经传递物质,其中因微生物菌群(microbiome)的影响而在肠道组织生成的血清素(Peripheralserotonin)将抑制造骨细胞(osteoblast)的分化。众所周知,雌激素将增加肾上腺素的浓度和神经传递物质的受体,雌激素的减少有可能在更年期引起肾上腺素的减少。测定血中(serum)血清素(serotonin)的浓度的结果,因去卵巢,与Sham组相比显著增加,但因给药E2、probiotics或S30+Probiotics而显著减少。S30实验组、S30+Probiotics实验组之间未呈现出显著性差异。测定血中肾上腺素浓度的结果,因去卵巢,与Sham组相比显著减少,因给药E2、probiotics、S30、S30+Probiotics,因而显著增加。尤其,在S30+Probiotics给药组中,呈现出显著增加的最高浓度(图10)。
实施例11:在去卵巢大鼠中测定血中骨形成标记及骨吸收标记浓度
雌激素将起到抑制骨吸收的作用,若雌激素分泌在更年期出现减少,则股损失将增加。对于更年期女性而言,通常骨吸收指标比骨形成指标显著增加。骨吸收指标为当破骨细胞分解骨骼时生成的指标,测定了D-焦谷氨酸、Pyridinoline、1型胶原交联末端肽(NTX、CTX),作为骨形成指标,测定了骨钙素、骨碱性磷酸酶(Bone Alkaline phosphatase,B-ALP)等。测定骨形成(Bone formation)标记的结果,因去卵巢,骨钙素、骨碱性磷酸酶显著减少,但因给药E2、probiotics、S30,与OVX组相比显著增加,尤其,因给药S30+Probiotics,与E2给药组、probiotics给药组、S30给药组相比显著增加(图11a)。测定骨吸收(Boneresorption)标记的结果,因去卵巢,在Deoxypyridinoline、Pyridinoline、NTX、CTX等方面整体上呈现出增加趋势,因给药E2、probiotics、S30,与OVX组相比显著减少,尤其,因给药S30+Probiotics,呈现出显著减少的趋势,类似于E2组(图11b)。
实施例12:测定血管稳态血液标记
众所周知,雌激素会使血管松弛,更年期女性的心血管类疾病发病率的增加与雌激素水平的减少有关。因此,作为测定更年期女性心血管健康的指标,测定了作为血管收缩指标的皮内素-1、作为血管松弛指标的一氧化氮、内皮型一氧化氮合酶。皮内素-1的测定结果,因去卵巢而显著增加,因给药E2、probiotics、S30+probiotics而与OVX组相比显著减少。尤其,S30+Probiotics给药组与Sham组相似,与S30给药组相比,显著减少。一氧化氮会因去卵巢而显著减少,但因给药E2、S30+probiotics而与OVX组相比显著增加,probiotics、S30的给药与OVX组没有明显不同之处。在内皮型一氧化氮合酶方面,Sham组与OVX组之间没有明显不同之处,因给药E2而显著增加,因给药S30+Probiotics而与OVX组相比显著增加。Probiotics、S30的给药与Sham组、OVX组相比没有明显不同之处(图12)。
实施例13:测定促卵胞成熟荷尔蒙、促黄体荷尔蒙的血中水平
在更年期,由于卵巢中缺少卵泡,将使雌激素的分泌减少,因此,因下丘脑视神经轴的负反馈(negative feedback)机制,促卵胞成熟荷尔蒙和促黄体荷尔蒙的分泌将增加。促卵胞成熟荷尔蒙会因去卵巢而显著增加。因给药E2、S30+probiotics而比OVX组显著减少。尤其,S30+Probiotics给药组与Sham给药组及E2给药组相似,与Probiotics给药组、S30给药组相比,显著减少。促黄体荷尔蒙(LH,luteinizing hormone)呈现出与促卵胞成熟荷尔蒙(FSH)相似的趋势,因给药S30+Probiotics而呈现出与E2给药组相似的效果(图13)。
以上,详细记述了本发明的特定部分,而对于本发明所属技术领域的普通技术人员而言,这种具体技术仅属于优选的实例,本发明的范围并不限定于此,这是明确无误的。因此,本发明的实际范围由本发明的发明要求保护范围和其等同技术方案来定义。
Claims (4)
1.一种更年期或绝经期症状的预防或改善用食品组合物,其特征在于,包含:
(i)由乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌和瑞士乳杆菌的组合组成的乳酸菌;以及
(ii)包含异黄酮及大豆胚芽提取物的益生元组合物,
其中相对于上述益生元组合物,包含1~50重量百分比的上述异黄酮。
2.根据权利要求1所述的更年期或绝经期症状的预防或改善用食品组合物,其特征在于,上述更年期或绝经期症状为面部红潮、夜间发汗、经期不规律、性欲减退、阴道干燥、疲劳、脱发、睡眠障碍、注意力障碍、记忆力减退、眩晕症、体重增加、尿失禁、腹部膨胀感、过敏、指甲易断、体味变化、心律不齐、抑郁症、不安、焦躁、惊恐障碍症状、骨质疏松症、骨密度减少症、高血脂或血脂异常症。
3.一种更年期或绝经期症状的预防或治疗用药学组合物,其特征在于,包含:
(i)由乳双歧杆菌、婴儿双歧杆菌、格氏乳杆菌和瑞士乳杆菌的组合组成的乳酸菌;
(ii)包含异黄酮及大豆胚芽提取物的益生元组合物;以及
(iii)药学上可接受的载体,
其中相对于上述益生元组合物,包含1~50重量百分比的上述异黄酮。
4.根据权利要求3所述的更年期或绝经期症状的预防或治疗用药学组合物,其特征在于,上述更年期或绝经期症状为面部红潮、夜间发汗、经期不规律、性欲减退、阴道干燥、疲劳、脱发、睡眠障碍、注意力障碍、记忆力减退、眩晕症、体重增加、尿失禁、腹部膨胀感、过敏、指甲易断、体味变化、心律不齐、抑郁症、不安、焦躁、惊恐障碍症状、骨质疏松症、骨密度减少症、高血脂或血脂异常症。
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US11805799B2 (en) | 2023-11-07 |
EP3824743A1 (en) | 2021-05-26 |
CN112826935A (zh) | 2021-05-25 |
KR102362968B1 (ko) | 2022-02-17 |
US20210204583A1 (en) | 2021-07-08 |
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