CN112971121A - 一种增加骨密度、调节肠道菌群的功能食品组合物及其制备方法 - Google Patents
一种增加骨密度、调节肠道菌群的功能食品组合物及其制备方法 Download PDFInfo
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Abstract
本发明属于保健品技术领域,更具体地,涉及一种增加骨密度、调节肠道菌群的功能食品组合物及其制备方法。该功能食品组合物,由如下重量份数的各组分组成:葛根20~25份、覆盆子8~20份、黄精8~15份、芡实4~6份、山药4~6份、大枣4~6份、黑芝麻2~4份、龙眼肉2~4份、牡蛎2~4份、茯苓2~4份、乌梅1~3份、甘草1~3份、芹菜粉1~3份、大豆膳食纤维1~2份。本发明的原药材均为药食两用,对动物进行抗骨质疏松试验取得显著疗效,与临床应用的雌激素类药物相比,有着相似的药效,肝肾等不良反应显著降低。同具有时调节肠道菌群的功能。
Description
技术领域
本发明属于保健品技术领域,更具体地,涉及一种增加骨密度、调节肠道菌群的功能食品组合物及其制备方法。
背景技术
骨质疏松症(Osteopomsis,OP)以骨量减少、骨强度降低导致骨折,以及由骨折引起的局限性疼痛、骨骼变形等临床综合症。骨质疏松症分为三种类型,包括原发性骨质疏松症、继发性骨质疏松症及特发性骨质疏松症,其中原发性骨质疏松症约占90%左右。骨质疏松起病比较隐袭,多发展到一定程度才被发现,而且骨量丢失及骨折发生概率均随年龄增加而明显增加。目前我国是全球骨质疏松(OP)患者最多的国家已达9000万,而我国骨质疏松患者在1988-2018这30年间增加了300%,在60岁以上人群中发病率为56%,预计到2020年,我国将有超过2亿人受到OP和骨量减少的影响。老年、妇女绝经、疾病、药物和营养缺乏等均可引起骨骼矿物质的丢失,骨密度降低,出现腰酸背、驼背、最终导致骨质疏松,重者可造成骨折、致残、终身卧床。骨折为骨质疏松最严重的后果,骨折可发生在任何部位,以椎骨、腕部和髋部多见,而其中髋部骨折最为严重,而且患者死亡率均会由于伴随的高血压、心血管、糖尿病和慢性呼吸道疾病而相对增加。全世界范围内,每3s会发生1例骨质疏松性骨折。国际骨质疏松基金会(IOF) 的数据显示,有20%~24%的患者在发生髋部骨折1年内死亡,一半的患者生活不能自理,生活质量相应降低,从而给患者和家庭带来极大的经济负担及精神压力。因此,关注骨健康,预防骨质疏松,刻不容缓!
骨质疏松症当属目前世界上生命危害性和医疗保健消耗较大的疾病之一。因此,寻找有效的防止骨质疏松药物已成为国内医学界研究的热点。目前治疗骨质疏松的药物主要有降钙素、双膦酸盐、氟化物、维生素D、钙剂和雌激素替代等,但疗效均存在一定争议。特别是雌激素替代疗法一直是绝经后骨质疏松症的首选,但随着年龄增长,雌激素替代疗法的治疗作用减弱,而且长期使用雌激素可引起子宫内膜和乳腺增生、增加子宫内膜癌、乳腺癌和卵巢癌发生的危险性、提升深静脉血栓形成和肺栓塞发生率,使其在临床上的应用受到了严格限制。所以寻找到高效低毒的药物来治疗骨质疏松成为当务之急。
很多人认为:人到老年,腰背疼,腿脚疼,是“缺钙” 造成的!一般来说,骨质疏松症一旦出现明显的疼痛症状时,骨骼中的骨量已经丢失30%~50%以上了。骨质疏松的原因不仅是缺钙,更关键的是骨代谢异常。骨质疏松会导致肠道菌群紊乱,肠道菌群失调引起的炎症状态、自身免疫改变会导致骨质流失,骨形成减少。肠道微生态系统是人体最大的微生态系统,栖息着大约1014数量级的细菌,其基因组的基因数约为人类基因组基因总数的150倍。肠道菌群与人体相互依存,影响着人体肠道内分泌系统、肠道神经系统、肠道通透性以及免疫系统等的功能。研究表明,特定的肠道菌群可通过免疫系统影响宿主的健康状态,具有调节免疫、提高防御功能、抑制肿瘤形成、促进正常的细胞代谢、促进骨质健康、抑制骨钙流失、延缓衰老等作用。肠道菌群失调可直接导致炎症性肠病、糖尿病或肥胖,也可通过引起的炎症状态、自身免疫改变导致骨质流失,骨形成减少。研究表明,肠道菌群还具有促进氨基酸、蛋白质、骨代谢的作用,有利于蛋白质的生物固氮能力、非蛋白的氮合成氨基酸能力、骨钙的合成及延缓骨质流失,提示肠道菌群与骨质疏松的发生具有密切关系。因此,从药食两用的药材中找到一种增加骨密度、调节肠道菌群的功能食品组合物及其制备方法是行之有效的途径。
骨质疏松症在历代中医学记载归属为中医学中“骨痿”、“骨痹”、“骨折”、“绝经前后诸症”、“虚劳”等范畴。《内经》曰:“病在骨,骨重不可举,骨髓酸痛,寒气至,名曰骨痹。”《素问·痿论篇》曰:“肾气热,则腰脊不举,骨枯而髓减,发为骨痿。”肾主骨生髓,肾气盛衰是骨枯荣之根本,脾胃虚损,骨络空虚、瘀痹,肝失疏泄是骨质疏松病发的重要因素。中医学理论认为骨质疏松多因先天之精无后天滋养,肾不足而脾不健,肾脾虚弱致正气亏虚,外邪深侵入骨所致;又因气血运行不畅导致瘀滞脉络,终使骨失所养。因此防治骨质疏松症多以补肾益精为主,辅以健脾补气养血、活血祛瘀,起强筋壮骨之效。
在传统中医药中,食品是重要的组成部分,一些传统食品可作为药物来治疗疾病,而一些常用于防治疾病的中药也逐渐在人们的日常饮食中出现,这些食品或中药被统称为药食同源中药。我国中医药治疗骨质疏松症的历史悠久,拥有丰富的药食同源的植物资源,毒副作用小,多成分多靶点共同调节机体的平衡,同时改善多方面的代谢。随着国内外对骨质疏松症实验研究的不断深入,利用中药现代化技术从传统中药寻找新的高效低毒药物治疗骨质疏松症是药物发展的一种必然趋势。随着社会发展节奏的加快,各方面的压力使得人们大多处于亚健康状态;另外,环境恶化、食品安全事件频发、化工产品带来的负效应,都给健康造成威胁。因此,更加安全、有效的药食同源中药及以其为原料开发出来的一系列产品受到越来越多的关注。
发明内容
针对上述现有技术中的不足,本发明提供了一种增加骨密度、调节肠道菌群的功能食品组合物及其制备方法,制备工艺简单,疗效好,安全无副作用。
本发明的上述目的是通过以下技术方案予以实现的。
一种增加骨密度的多功能食品组合物,由如下重量份数的各组分组成:葛根20~25份、覆盆子8~20份、黄精8~15份、芡实4~6份、山药4~6份、大枣4~6份、黑芝麻2~4份、龙眼肉2~4份、牡蛎2~4份、茯苓2~4份、乌梅1~3份、甘草1~3份、芹菜粉1~3份、大豆膳食纤维1~2份。
其中,各组分的质量份优选如下:
(1)葛根20份、覆盆子20份、黄精12份、芡实5份、山药5份、大枣5份、黑芝麻3份、龙眼肉2份、牡蛎4份、茯苓3份、乌梅1份、甘草1份、芹菜粉3份、大豆膳食纤维1份。
(2)葛根25份、覆盆子15份、黄精10份、芡实6份、山药10份、大枣6份、黑芝麻2份、龙眼肉4份、牡蛎2份、茯苓3份、乌梅3份、甘草3份、芹菜粉2份、大豆膳食纤维2份。
(3)葛根24份、覆盆子8份、黄精8份、芡实4份、山药4份、大枣4份、黑芝麻4份、龙眼肉2份、牡蛎2份、茯苓2份、乌梅2份、甘草2份、芹菜粉1份、大豆膳食纤维1份。
进一步的,本发明提供了所述保健食品组合物可加入辅料制备的制剂,优选的,本发明的保健食品组合物可以根据需要制备成任何适宜的口服制剂,包括片剂,胶囊剂,散剂,颗粒剂,冲剂,泡腾剂或袋泡剂等,所加入的辅料为药学上可接受的辅料。
本发明还可应用到不同食品中。
本发明还提供了一种增加骨密度的功能食品组合物的制备方法,包括以下步骤:
S1 .将所述各组分原料除杂、净化、晾干后备用;
S2 .将葛根、黄精、芡实、山药、茯苓、甘草于100 ℃蒸锅中蒸1h,蒸熟后在80℃的烘箱中烘干5h,再粉碎,过100目筛,得到细粉混合物A;
S3 .将覆盆子、大枣、黑芝麻、龙眼肉、乌梅在80℃的烘箱中烘干5h,再粉碎,过120目筛,得到细粉混合物B;
S4 .牡蛎直接粉碎,合并大豆膳食纤维和芹菜粉过100目筛,得到细粉混合物C;
S5 .将步骤S2的混合物A、步骤S3的混合B与步骤S4的混合物C均匀混合后,制得所需剂型。
所述增加骨密度的功能食品组合物作为制备增加骨密度的保健品中的用途。
本发明各组分功效如下:
葛根,本品为豆科葛属植物野葛Pueraria lobate (Willd.) Ohwi的干燥根。味甘、辛,凉。归脾、胃、肺经。解肌退热,生津止渴,透疹,升阳止泻,通经活络,解酒毒。
覆盆子,为蔷薇科植物华东覆盆子chingii Hu的干燥果实。味甘、酸,性温。归肝、肾、膀胱经。益肾固精缩尿,养肝明目。覆盆子果实含有相当丰富的维生素A、维生素C、钙、钾、镁等营养元素以及大量纤维。覆盆子果实酸甜可口,“黄金水果”的美誉。
黄精,为百合科植物滇黄精Polygonatum kingianum Coll.et Hemsl、黄精Polygonatum sibiricum Red. 或多花黄精Polygonatum cyrtonema Hua的干燥根茎。味甘、性平, 具有补中益气、润心肺、补肾益精、强筋骨、安五脏、止寒热、填精髓等功效。
芡实,为睡莲科植物芡Euryale ferox Salisb.的干燥成熟种仁。味甘、涩,性平。归脾、肾经。益肾固精,补脾止泻,除湿止带。常用于遗精滑精,遗尿尿频,脾虚久泻,白浊,带下。
山药,为薯蓣科植物山药Dioscorea opposite Thumb.干燥根茎。味甘,性平。归肺经、脾经、肾经。山药又称薯蓣、土薯、山薯蓣、怀山药、淮山、白山药,是《中华本草》收载的草药,具有滋养强壮,补益脾胃,益肺滋肾,敛虚汗,止泻之功效。
大枣,为鼠李科植物物枣Ziziphus jujuba Mill.的干燥成熟果实。味甘,性温,补中益气,养血安神。自古以来就被列为“五果”(栗、桃、李、杏、枣)之一。红枣富含蛋白质、脂肪、糖类、胡萝卜素、B族维生素、维生素C、维生素P以及钙、磷、铁和环磷酸腺苷等营养成分。
黑芝麻,为脂麻科植物脂麻Sesamum indicum L .的干燥成熟熟种子。味甘,性平,归肝、肾、大肠经,补肝肾,益精血,润肠燥。黑芝麻含有大量的脂肪和蛋白质,还含有糖类、维生素A、维生素E、卵磷脂、钙、铁、铬等营养成分,是补钙的圣品。
牡蛎,为牡蟠科动物长牡蝠 Ostrea gigas Thimberg、大连湾牡蛎 Ostrea talienwhanensis Crosse 或近江牡賴 Ostrearivularis Gould 的贝壳。味咸,性微寒。归肝、胆、肾经,重镇安神,潜阳补阴,软坚散结,牡蛎壳含有大量的钙与丰富的微量元素及多种氨基酸。
茯苓,为多孔菌科真菌茯苓 Poria cocos (Schw.)Wolf的干燥菌核。性甘、淡,平。归心、肺、脾、肾经。利水渗湿,健脾宁心。用于水肿尿少,痰饮眩悸,脾虚食少,便溏泄泻,心神不安,惊悸失眠,利水渗湿,健脾化痰,宁心安神;补脾,运化营养物质入血,补血不足,助消化;运化水液,消除痰湿之邪,性平寒热均可。
乌梅,为蓄薇科植物梅Prunus mume (Sieb.) Sieb. Et Zucc的干燥近成熟果实。性酸、涩,味平。归肝、脾、肺、大肠经。具有敛肺,涩肠,生津,安蛔之功效,具有调味作用。
甘草, 为豆科植物甘草 Glycyrrhiza uralensis Fisch.、胀果甘草Glycyrrhiza inflata Bat. 或光果甘草 Glycyrrhiza glabra L. 的干燥根和根茎。性甘、平,归心、肺、脾、胃经,补脾益气,淸热解毒,祛痰止咳,缓急止痛,调和诸药。
芹菜,属伞形科植物,品种繁多,在我国有着悠久的种植历史和大范围的种植面积,是中国人常吃的蔬菜之一,其富含蛋白质、碳水化合物、胡萝卜素、B族维生素、钙、磷、铁、钠等,同时,具有平肝清热、祛风利湿、除烦消肿、凉血止血、解毒宣肺、健胃利血、清肠利便、润肺止咳、降低血压、健脑镇静的功效。
本发明与现有技术相比,具有如下优点:
葛根、覆盆子、黄精、芡实、山药、大枣、黑芝麻、龙眼肉、牡蛎、茯苓、乌梅、甘草、芹菜粉、大豆膳食纤维14味药材组合在一起,在改善骨微结构、调理性补钙方面的协同作用,达到增加骨密度的效果的保健食品还未见报道。本发明的14味中药材均选自国家卫计委2017年发布文件《按照传统既是食品又是中药材物质目录管理办法》征求意见稿的102种药食同源的药材,天然无害,适合长期服用。整体性味甘平,不会产生寒凉刺激,归经上五脏六腑均能兼顾。
除了参考药典、古籍、报导文献等资料,本发明还利用TCMSP、DAVID等在线数据库的生物信息学分析手段对组合物主药材的成分、靶点进行了筛选和富集分析以支持本发明组方的合理性和全面性。
本发明作为一种组合物的保健品,其中葛根为野葛富含大量的异黄酮类成分,芡实为麸炒芡实,牡蛎为牡蛎壳,富含碳酸钙。
本发明的组方原则:本发明以中医药组方理论为指导,采用抗骨质疏松药效学参数为验证指标,筛选验证组方的合理性,疗效较佳的抗绝经后骨质疏松配方,按照传统的补肾壮骨中医理论以及中药系统药理学大数据分析得到治疗骨质疏松的组方,根据君臣佐使及药物配伍规律进行组方及拆方研究,并通过现代生物化学的手段进行验证,具有非常显著的增加骨密度的作用。在现有技术中没有利用本配方治疗骨质疏松的相关报道。配方中的各药物成分协同起效,滋补肝肾,活血通络,强筋壮骨,是通过疾病-机体-中药三者关系的辨证施治,实现标本兼顾的机体整体状态改善,通过调节肠道菌群和调理性补钙增加骨密度。葛根中含有的异黄酮类成分具有雌激素样作用,对绝经后骨质疏松症有治疗作用。黄精具有补肾阳、强筋骨功效,通过补肾促进骨折的愈合,防止骨质疏松,减少骨的病变。覆盆子、龙眼肉和黑芝麻能益精填髓,滋阴补血,修复骨质结构,增加骨质密度,提高体内钙、磷含量,调节骨代谢,调整骨质成分构成比例的平衡。大枣有具补血益气之功效。山药、芡实和茯苓具有滋养强壮,助消化,敛虚汗,补脾虚之功效。甘草具有补脾益气, 清热解毒, 调和诸药的功效。乌梅有舒筋、活络、健脾开胃之功效,富含大量的氨基酸和维生素。芹菜粉其富含蛋白质、碳水化合物、胡萝卜素、B族维生素、钙、磷、铁。牡蛎,含碳酸钙量高达94%,副作用小,生物利用度较高,是中国营养学会首推补钙剂,可以降低老年的骨质疏松。本发明补肾健脾,活血通络,标本兼顾,即脾健肾精充足,络通而气血旺,致精血充沛,则筋骨强健。
附图说明
图1为本发明8味主药葛根、黄精、覆盆子、芡实、山药、大枣、黑芝麻、茯苓根据成分、靶点富集到的与骨质疏松疾病相关的通路排名前15的高级气泡图。
图2为本发明对去卵巢大鼠血清中CTX、BLAP、TRACP5b、OPG骨代谢生化指的影响。
图3为本发明对去卵巢大鼠骨密度、骨体积分数(BV/TV)、骨小梁厚度(TB.Th)和骨小梁间距(TB.Sp)的影响。
图4为本发明对股骨远心端骨小梁的影响2D图。
图5本发明对肠组织HE染色切片的影响。
图6为本发明对肠道菌群物种差异分析科水平的影响。
图7为本发明对差异菌种胃瘤球菌科、毛螺菌科、普雷沃氏菌科、乳杆菌科、理研菌科、肠杆菌的影响。
图8为本发明对纲、目、科、属物种丰度热图分析的影响。
图9为本发明对Lefse物种差异分析实验结果的影响(假手术组Vs模型组)。
图10为本发明对Lefse物种差异分析实验结果的影响(模型组Vs中剂量组)。
图11为本发明对Lefse物种差异分析实验结果的影响(假手术组Vs中剂量组)。
图12为本发明对粪便中乙酸、丙酸、异丁酸、丁酸、异戊酸、戊酸、总短链脂肪酸的含量的影响。
图13为本发明对体重和子宫指数的影响。
图14本发明对子宫组织HE染色切片的影响。
图15本发明对血清中肝功指标ALB、TP、ALT和 ALP浓度的影响。
图16为本发明对去卵巢大鼠脏器指数的影响。
图17为本发明对肝脏组织HE染色切片的影响。
图18为本发明对血清中肾功指标UREA、UA和CRA浓度的影响。
图19为本发明对肾脏组织HE染色切片的影响。
图20为本发明对全血中WBC(白细胞计数)、lym(淋巴细胞计数)、Gran(中性粒细胞)和Momo(单核细胞计数)浓度的影响。
图21为本发明对全血中RBC(红细胞计数)、HGB(血红蛋白)和PTL(血小板计数)浓度的影响。
其中,Sham:假手术组,OVX:造模组,Sham+L:低剂量;Sham+M:中剂量组;Sham+H:高剂量组;Sham+P:己烯雌酚;Sham+M: 假手术+中剂量组。
具体实施方式
以下通过实施例形式,对本发明的上述内容再作进一步的详细说明,但不应将此理解为本发明上述主题的范围仅限于以下的实例,凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1:称取葛根20份、覆盆子20份、黄精12份、芡实5份、山药5份、大枣5份、黑芝麻3份、龙眼肉2份、牡蛎4份、茯苓3份、乌梅1份、甘草1份、芹菜粉3份、大豆膳食纤维1份,然后按照如下方法制备实施例1的保健食品:S1将所述各组分原料除杂、净化、晾干后备用;S2将葛根、黄精、芡实、山药、茯苓、甘草于100 ℃蒸锅中蒸1h,蒸熟后在80℃的烘箱中烘干5h,再粉碎,过100目筛,得到细粉混合物A;S3覆盆子、大枣、黑芝麻、龙眼肉、乌梅在80℃的烘箱中烘干4-5 h,再粉碎,过100目筛,得到细粉混合物B;S4牡蛎直接粉碎,合并大豆膳食纤维和芹菜粉过100目筛,得到细粉混合物C;S5将步骤S2的混合物A、步骤S3的混合B与步骤S4的混合物C均匀混合。
实施例2:称取葛根25份、覆盆子15份、黄精10份、芡实6份、山药10份、大枣6份、黑芝麻2份、龙眼肉4份、牡蛎2份、茯苓3份、乌梅3份、甘草3份、芹菜粉2份、大豆膳食纤维2份;然后按照与实施例1相同的制备方法制备实施例2的保健食品。
实施例3:称取葛根24份、覆盆子8份、黄精8份、芡实4份、山药4份、大枣4份、黑芝麻4份、龙眼肉2份、牡蛎2份、茯苓2份、乌梅2份、甘草2份、芹菜粉1份、大豆膳食纤维1份;然后按照与实施例1相同的制备方法制备实施例3的保健食品。
实施例4:称取覆盆子8份、黄精8份、芡实4份、山药4份、大枣4份、黑芝麻4份、龙眼肉2份、牡蛎2份、茯苓2份、乌梅2份、甘草2份、芹菜粉1份、大豆膳食纤维1份;然后按照与实施例1相同的制备方法制备实施例4的保健食品。
实施例5:称取葛根24份、黄精8份、芡实4份、山药4份、大枣4份、黑芝麻4份、龙眼肉2份、牡蛎2份、茯苓2份、乌梅2份、甘草2份、芹菜粉1份、大豆膳食纤维1份;然后按照与实施例1相同的制备方法制备实施例5的保健食品。
实施例6:称取葛根24份、覆盆子8份、芡实4份、山药4份、大枣4份、黑芝麻4份、龙眼肉2份、牡蛎2份、茯苓2份、乌梅2份、甘草2份、芹菜粉1份、大豆膳食纤维1份;然后按照与实施例1相同的制备方法制备实施例6的保健食品。
实施例7:称取葛根24份、覆盆子8份、黄精8份、山药4份、大枣4份、黑芝麻4份、龙眼肉2份、牡蛎2份、茯苓2份、乌梅2份、甘草2份、芹菜粉1份、大豆膳食纤维1份;然后按照与实施例1相同的制备方法制备实施例7的保健食品。
实施例8:称取葛根24份、覆盆子8份、黄精8份、芡实4份、山药4份、黑芝麻4份、龙眼肉2份、牡蛎2份、茯苓2份、乌梅2份、甘草2份、芹菜粉1份、大豆膳食纤维1份;然后按照与
实施例9.通过文献检索及利用网络药理学大数据分析进行组方合理性验证
首先利用文献挖掘从古代方剂和国产保健食品数据库检索抗骨质疏松应用频次较多的中药材,从中选取药食两用的单味药:葛根、覆盆子、黄精、芡实、山药、大枣、黑芝麻、龙眼肉、牡蛎、茯苓、乌梅、甘草、芹菜粉。
通过以下数据库Tcm SP 数据库(http://sm.nwsuaf.edu.cn/lsp/tcmsp.php);TCMID 数据库(http://www.megabionet.org/tcmid/);TCM Database@Taiwan 数据库(http://tcm.cmu.edu.tw/);搜集各原料药的成分(OB>20%, DL>0.18),建立成分-靶点的网络图,每一味药材含有大量的成分,每一个成分又作用于很多靶点,不同单味药材所含成分几乎没有交叉,而不同药材所含成分涉及的靶点有很多共同靶点,说明每一味药材都对组方有贡献,不同的成分共同作用于同一靶点,同一成分也作用于不同靶点,体现了中药复方多成分-多靶点共同作用。
应用生物信息学方法对本发明组合物中8味主药材的成分、靶点进行筛选和富集分析
(1)将8味中药材分别输入到TCMSP(http://lsp.nwu.edu.cn/tcmspsearch.php)数据库中,将所有成分按照药代动力学参数,口服生物利用度OB≥20%、类药性DL≥0.18的条件进行筛选。
(2)将所筛选的成分,对应数据库中的靶点。
(3)将筛选到的靶点输入到Uniprot数据库中规范靶点名称,对应其基因名称。
(4)将所有靶点的基因名称上传至DAVID数据库,进行GO-BP的生物过程和KEGG的通路富集分析,筛选出与骨质疏松发生发展相关的靶点基因。
(5)应用Cytoscape3.2.1软件将入选的成分、靶点进行成分-靶点的网络构建,绘制骨代谢相关的生物过程或者通路高级气泡图。
表1 气泡图中与骨质疏松相关通路的条目名称
本发明的8味主要原料中药材共筛选出91个潜在活性成分,225个靶点,其中所富集到的与骨质疏松相关的靶点共计71个,占到筛选靶点的1/3以上。排名前15的通路都与钙的吸收、骨代谢和脂代谢过程息息相关,从大数据生物信息学分析的角度,充分说明本发明组方的合理性和具有增加骨密度改善骨质疏松功能性的潜在性(表1,图1)。
实施例10方剂的筛选实验
通过网络药理学的预测和传统中医理论组方,确定了组方中的几味君药和臣药为葛根、覆盆子、黄精、芡实、山药、大枣,然后按不同的配比进行组方的优选,即实施例1-3,;对组方中的几味主药进行拆方,验证组方的合理性,减少方中葛根即实施例4,减少方中覆盆子即实施例5,减少方中黄精即实施例6,减少方中芡实即实施例7,减少方中大枣即实施例8。然后进行去势大鼠的灌胃给药,三个月后测量大鼠的骨密度。
【造模】大鼠腹腔注射30mg/kg 戊巴比妥钠溶液麻醉,腹位固定后于腹中线距离阴道口3—4cm处去毛,分别用碘酒和酒精消毒,待稍干后切开皮肤和腹肌约2—3cm,切口视野可见白色脂肪,拨开脂肪层找到子宫后,轻轻将一侧子宫角拉出,在其末端可见被脂肪团包裹的卵巢。分离脂肪团,便可见粉红色或黄色的卵巢,以止血钳夹住卵巢,然后将卵巢下输卵管用线结扎,剪出卵巢,顺势将子宫角送回腹腔中,同法剪除另一侧卵巢。腹肌和皮肤分层缝合后,再次消毒。最后经后肢肌肉注射2万U青霉素。
【动物分组与给药】大鼠经适应性饲养后分组,按照发明组合物实施例1-7配置混悬液(按大鼠体重每kg等计量的生药材给药),实验动物按体重随机分组为切除卵巢+实施例1、切除卵巢+实施例2、切除卵巢+实施例3、切除卵巢+实施例4、切除卵巢+实施例5、切除卵巢+实施例6、切除卵巢+实施例7、切除卵巢+实施例8、切除卵巢组+溶剂组、假手术组。每组动物10只。每周称取体重,并按新体重调整灌胃剂量,给药3个月,各组大鼠自由饮水、摄食。
【数据分析】所有实验数据以平均数±标准差表示,用SPSS16.0进行t检验分析。
10.1 测定指标
骨骼标本:采血后脱颈处死大鼠,完整分离大鼠的左右两侧股骨,剔除所有附着的肌肉和结缔组织,每只以10%甲醛溶液固定,进行病理学检查;一只用生理盐水浸泡的纱布包裹,保存于-80℃保存,分别测定股骨的骨密度。
用双能X射线骨密度仪测定股骨中点的骨密度。将待测骨放置于测量台上与骨密度仪探测头移动方向垂直;移动待测骨,令其待测点标记线与探测头移动轨迹于测量台上的垂直投影重合。开始测量股骨中点骨密度。
10.2 实验结果
不同组大鼠股骨分别测定骨密度(表2),模型组股骨中点骨密度降低,提示去卵巢后大鼠股骨的骨密度明显降低;实施例1、2、3不同程度地提高了骨密度,其中实施例3改善的最为明显;实施例4、5、6、7、8与造模组相比无显著性差异,提示拆掉主药中的任何一味药重新组方改善骨密度的药效都不如本发明组方好,证实了组方的合理性。
表2 对去卵巢大鼠骨密度(g/cm2)的影响(`X±S,n=10)
注:与模型组比较 “*”P<0.05,“**”P<0.01,与假手术组比较“#”P<0.05(下同)
实施例11本发明抗骨质疏松的药效学评价
【造模】与实施例10相同的造模方法。
【动物分组与给药】大鼠经适应性饲养后分组,按照发明组合物(实施例1)配置成低、中、高三种混悬液,实验动物按体重随机分组为切除卵巢+低剂量、切除卵巢+中剂量、切除卵巢+高剂量、切除卵巢组+溶剂组、切除卵巢+阳性对照组(己烯雌酚)、假手术组+中剂量、假手术组。每组动物10只。每周称取体重,并按新体重调整灌胃剂量,给药3个月,各组大鼠自由饮水、摄食。
【数据分析】
所有实验数据以平均数±标准差表示,用SPSS16.0进行t检验分析。
11.1 本发明抗骨质疏松的作用。
11.1.1 测定指标
骨代谢生化指标:大鼠酒石酸酸性磷酸酶5b(TRACP5b),骨源性碱性磷酸酶(BALP),I性胶原羧基末端肽(CTX), 骨保护素(OPG)。
骨骼标本:采血后脱颈处死大鼠,完整分离大鼠的左右两侧股骨,剔除所有辐照的肌肉和结缔组织,一只以10%甲醛溶液固定,进行病理学检查;一只用生理盐水浸泡的纱布包裹,保存于-80℃保存,分别测定股骨的皮质骨骨密度、骨小梁3D结构。
将大鼠右侧股骨从软组织中取材,清洗,固定在4%多聚甲醛中。采用Quantum GX型号微计算机断层扫描(μ-CT)系统(PerkinElmer micro-CT, USA)对其进行研究。使用30μm体素尺寸、90 kv扫描股骨远端。对于小梁骨,在股骨远端2 mm3的干骺端海绵区进行μ-CT评估。这些区域位于股骨生长板上方0.8 mm处。使用Quantum GX 3.1.4软件对图像进行三维重建和可视化。三维重建后,使用Accuct Microct Analysis 12.0软件进行骨分析。计算或直接测量骨密度(BMD)、骨体积分数(BV/TV)、骨小梁厚度(TB.Th)和骨小梁间距(TB.Sp)的指标。
子宫标本:充分暴露并剥离取出子宫,电子天平称重,计算子宫指数。子宫指数=(子宫重量÷体重)×100%
在骨、子宫、肠、肝脏、肾脏组织学和组织形态学分析中,我们使用石蜡切片。首先将大鼠左股骨、子宫、肠、肝脏、肾脏组织固定在4%多聚甲醛(PFA)中,按照方案依次脱钙脱水,然后将其嵌入石蜡中,切片成4μm厚的切片。切片用苏木精和伊红(H&E)染色,光镜下观察组织结构。
将新鲜粪便样本(n=5只/组)收集在无菌管并储存在液氮中。采用粪便提纯DNA试剂盒,根据制造商的说明书提取粪便样品DNA,并通过凝胶电泳检测细菌基因组DNA。采用16S rRNA基因分析法对4组肠道细菌组成进行分析,将样本DNA扩增,用带有条形码的特定引物16S v3–v4 rDNA区域。引物序列为341F: CCTACGGGNGCWGCAG;806R:GGACTACHVGGTATCTAAT。利用QuantiFluor TM Qubit 3.0和ABI Steponeplus实时PCR系统回收并定量PCR扩增产物。将纯化的扩增产物等量混合,连接到测序适配器上构建测序库。最后,利用PE250平台在hiseq2500系统上对库进行排序,生成250 bp的成对端读。使用qiime(v1.9.1)软件包(微生物生态学定量分析)分析序列。首先,读取被qiime质量过滤器过滤。接下来,我们为每个OTU(操作分类单元)选择代表性序列,并使用RDP(核糖体数据库项目)分类器(版本2.2)对每个代表性序列的分类信息进行注释。按大小降序排列的分类等级有域、门、类、目、科、属和种。鉴定了两组样品的属间差异。
11.1.2 实验结果
(1) 对血清CTX, BALP,TRACP5b,OPG骨代谢生化指标的检测。
酶联免疫吸附剂测定血清中的大鼠酒石酸酸性磷酸酶5b(TRACP5b),骨源性碱性磷酸酶(BALP),I性胶原羧基末端肽(CTX)和骨保护素(OPG)水平,CTX、 BALP和TRACP5b含量显著升高与骨质疏松症有关,骨保护素是骨形成的标志物。结果如表3,图2所示。模型组大鼠血清中四种成分的含量,与假手术对照组比较具有显著性差异,提示造骨质疏松模型成立;本发明各剂量组不同程度降低了血清中CTX、 BALP和TRACP5b三种成分的含量,而提高了OPG的含量,提示本发明对骨质疏松有治疗作用;假手术组给本发明组合物后三种成分的含量也略有下降,骨保护素显著升高,说明本发明对正常机体也有改善骨质疏松的作用。
表3 本发明对去卵巢大鼠血清CTX, BALP,TRACP5b和OPG骨代谢生化指标的影响(`X±S,n=10)
(2) 对去势大鼠股骨骨密度的影响。
不同组大鼠股骨骨密度和Micro-CT测试参数骨体积分数(BV/TV)、骨小梁厚度(TB.Th)和骨小梁间距(TB.Sp)如表4,图3。实验结果表明:与正常组相比,骨质疏松模型组骨密度下降,骨小梁厚度变薄,骨体积分数下降,骨小梁分离度增加,本发明不同程度改善造模引起的骨质疏松,提高了骨密度,增加骨小梁厚度,增加了骨体积分数,减少骨小梁之间的距离;与假手术组相比,假手术组给本发明组合物后骨密度也有一定提升,提示本发明也可改善正常机体的骨密度。
表4 本发明对去卵巢大鼠骨密度(g/cm2)、骨小梁厚度(TB.Th)、骨小梁间距(TB.Sp)和骨体积分数(BV/TV)的影响(`X±S,n=10)
(3) 对去卵巢大鼠骨组织病理学的影响
通过Micro-CT对大鼠左侧股骨进行扫描,病理诊断结果如图4所示。
空白组:该组股骨骨小梁排列密集,互相连接呈网状结构,骨小梁密度大,间距减小。
模型组:骨小梁明显变细,数量明显减少,断裂增多,骨小梁密度明显减小,髓腔扩大,皮质骨变薄。与空白组比较骨小梁髓腔间距增大,造成了骨质疏松。
己烯雌酚组:与模型组比较骨小梁变得规则,数目增多,断裂减少,髓腔间隙变小,但骨小梁密度仍小于空白组。
中剂量:给本发明组合物后,骨小梁数量增多,密度明显增高,髓腔间隙变小,皮质骨变厚,提示本发明对正常机体的骨质有改善。
本发明低、中、高剂量组:与造模组相比,本发明各组不同程度地改善了骨小梁的密度,提示本发明可以有效提高骨小梁密度,对骨质疏松有治疗作用。
(4)对肠道菌群的影响
骨质疏松会导致肠道菌群紊乱,肠道菌群失调引起的炎症状态、自身免疫改变会导致骨质流失,骨形成减少。通过HE染色切片观察到(图5),骨质疏松后小肠绒毛结构破坏,出现局灶性浅表固有层水肿,轻度炎症增加,上皮细胞损伤或丢失,杯状细胞形态不规则,而本发明能够明显调节这种紊乱,使其恢复至正常水平,从而增加骨密度,改善骨质疏松。与假手术相比,模型组在科水平,胃瘤球菌科、毛螺菌科、肠杆菌科、理研菌科的丰度异常升高,而普雷沃氏菌科、乳杆菌科的比例异常降低,而在给药中剂量组,这些异常升高的菌科水平明显降低,乳杆菌科水平完全升高至正常水平,整体物种组成比例恢复至正常水平(图6,7)。提示去势造模会导致大鼠肠道菌群紊乱,而本发明能够明显调节这种紊乱,使其恢复至正常水平。同样,通过热图分析(图8),假手术组和中剂量组菌群分布接近,提示去势造模会导致大鼠肠道菌群紊乱,而本发明能够明显调节这种紊乱,使其恢复至正常水平。
Lefse分析表明(图9-11),造模组较中剂量组和假手术组明显增多的物种有很多重叠,以条件致病菌为主,提示服用本发明改善去势大鼠肠道菌群失调的状态。而中剂量组较造模组明显增多的则是乳杆菌属,是动物及人体的益生菌,从而增加骨密度,改善骨质疏松。
短链脂肪酸是肠道菌群的重要代谢产物,模型组粪便中乙酸、丙酸、异丁酸、丁酸、异戊酸、戊酸含量均下降(图12),服用中剂量组合物后,短链脂肪酸含量显著提高,特别是乙酸和丁酸含量显著增加。结合已有研究报道SCFA通过调节免疫相关的炎性因子或者直接作用于破骨细胞,可以发挥改善骨质疏松的作用。
11.2 本发明安全性评价
11.2.1 对去势大鼠体重及子宫指数的影响
连续给药三个月后,分别观察各组大鼠体重,结果如表5,图13所示。本发明可以平稳地降低体重,其中本发明高剂量组与模型组有非常显著的统计学差异,低剂量和中剂量作用也较明显,但阳性药己烯雌酚组体重急剧下降;由于造模后子宫没有激素的支持就会萎缩,与模型组相比假手术组和己烯雌酚组子宫指数有显著性差异;而发明组合物具有雌激素样作用会改善子宫萎缩,提示本发明不会对子宫产生影响;但阳性药会过度作用于子宫引起子宫肿大(图14),子宫增生,可能导致子宫内膜癌、宫颈癌等。
表5 本发明对去卵巢大鼠体重,子宫指数的影响(`X±S,n=10)
11.2.2 对去势大鼠肝功和肾功的影响
(1)血生化指标:给药三个月后,仰卧位固定大鼠,取静脉血,3000r/min 离心15min,分离血清,肾功三项(UREA,UA,CRA),肝功五项(ALB,TP,ALT,ALP)
脏器标本:充分暴露并剥离取出肝脏、肾脏、脾脏,电子天平称重,计算脏器指数脏器指数=(脏器重量÷体重)×100%
(2)肝功四项:结果如表6,图15所示,总蛋白(TP)和白蛋白(ALB)含量各组均无明显差异,阳性药略高;谷丙转氨酶(ALT)与正常组比造模组显著降低,可能与肝萎缩有关,本发明各组可以不同程度地将其改善至正常值,提示本发明不会增加肝脏的负担;而阳性药转氨酶显著高于正常组,提示己烯雌酚引起肝细胞损伤。
结果如表7,图16所示,肝脏指数中与造模组相比,正常组有显著性增高,说明摘除卵巢后大鼠肝萎缩;与正常组相比阳性药的肝指数显著增大,结合前面的肝功生化指标检测提示阳性药有很大的肝毒性。结合HE染色的结果(图17)可以发现阳性药使肝组织中的肝小叶结构不清晰,肝门静脉周围细胞呈弥散样病变,肝细胞损伤明显。
表6 本发明对血清中ALB、TP、ALT和 ALP浓度的影响(`X±S,n=10)
表7 本发明对去卵巢大鼠脏器指数的影响(`X±S,n=10)
(3)肾功三项:结果如表8,图18所示。尿素氮(UREA)、尿酸(UA)、肌酐(CRA)各组均无显著性差异,本发明不会增加肾脏负担。但阳性药尿素氮和肌酐均偏高,同时结合肾脏组织HE染色结果(图19),肾小球萎缩,提示:肾小球的滤过率下降,容易引起肾衰。
表8 本发明对血清中UREA、UA和CRA浓度的影响(`X±S,n=10)
11.2.3 对去势大鼠空腹血糖和血常规的影响
(1)实验内容
血常规:给药三个月后,仰卧位固定大鼠,取静脉血1ml到装有抗凝剂的离心管中,用全自动动物血液细胞分析仪进行测定血常规分析。
空腹血糖的测定:将大鼠禁食4h后,尾静脉取血,用血糖测试仪测试血糖值。
(2)测定空腹血糖:结果如表9所示,空腹血糖值无显著性差异,提示本发明不会引起血糖升高。
表9 本发明对空腹血糖浓度的影响
(3)血常规:白细胞的数值都在正常范围内,组间差异较大,可能与大鼠个体差异有关,提示:本发明对白细胞无影响,结果如表10,图20所示。
表10 本发明对全血中WBC(白细胞计数)、lym(淋巴细胞计数)、Gran(中性粒细胞)和Momo(单核细胞计数)浓度的影响(`X±S,n=10)
各组红细胞计数和血红蛋白无显著性差异,除阳性药组都在正常范围内,提示:本发明对红细胞无影响,阳性药可能引起轻度贫血,结果如表11,图21所示。
表12 本发明对全血中RBC(红细胞计数)、HGB(血红蛋白)和PTL(血小板计数)浓度的影响(`X±S,n=10)
各组血小板计数均无显著性差异,只有阳性药数值略低,提示:本发明对血小板无影响。
Claims (10)
1.一种增加骨密度、调节肠道菌群的功能食品组合物,其特征在于,该食品组合物由如下重量份数的组分组成:葛根20~25份、覆盆子8~20份、黄精8~15份、芡实4~6份、山药4~6份、大枣4~6份、黑芝麻2~4份、龙眼肉2~4份、牡蛎2~4份、茯苓2~4份、乌梅1~3份、甘草1~3份、芹菜粉1~3份、大豆膳食纤维1~2份。
2.根据权利要求1所述的一种增加骨密度、调节肠道菌群的功能食品组合物,其特征在于,该食品组合物由如下重量份数的组分组成:葛根24份、覆盆子8份、黄精8份、芡实4份、山药4份、大枣4份、黑芝麻4份、龙眼肉2份、牡蛎2份、茯苓2份、乌梅2份、甘草2份、芹菜粉1份、大豆膳食纤维1份。
3.一种增加骨密度、调节肠道菌群的功能食品组合物的制备方法,其特征在于,该制备方法包括以下步骤:
S1 .将所述各组分原料除杂、净化、晾干后备用;
S2 .将葛根、黄精、芡实、山药、茯苓、甘草于100 ℃蒸锅中蒸1h,蒸熟后在80℃的烘箱中烘干5h,再粉碎,过100目筛,得到细粉混合物A;
S3 .将覆盆子、大枣、黑芝麻、龙眼肉、乌梅在80℃的烘箱中烘干5h,再粉碎,过120目筛,得到细粉混合物B;
S4 .牡蛎直接粉碎,合并大豆膳食纤维和芹菜粉过100目筛,得到细粉混合物C;
S5 .将步骤S2的混合物A、步骤S3的混合B与步骤S4的混合物C均匀混合后制得所需剂型。
4.如权利要求1所述的一种增加骨密度、调节肠道菌群的功能食品组合物作为制备增加骨密度、改善肠道菌群的保健食品中的用途。
5.如权利要求1所述的一种增加骨密度、调节肠道菌群的功能食品组合物作为制备增加骨密度、改善肠道菌群的药物的用途。
6.如权利要求5所述的用途,其特征在于,所述食品组合物能够根据需要加入辅料制备成任何适宜的药物口服制剂。
7.如权利要求4-5任一所述的用途,其特征在于,所述药物的口服剂型为颗粒剂、片剂、胶囊剂、袋泡剂、泡腾剂、散剂、口服液、丸剂等,优选为颗粒剂、片剂、胶囊剂和袋泡剂。
8.如权利要求1所述的增加骨密度、调节肠道菌群的功能食品组合物作为功能性食品的用途。
9.如权利要求4所述用于功能性食品的用途,其特征在于,所述功能性食品是饮料或食品。
10.如权利要求4-5所述的增加骨密度、调节肠道菌群的功能食品组合物,其特征在于,所述辅料为一般药学上可接受的辅料。
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