CN107375373A - 一种微生物发酵组合物及其应用 - Google Patents
一种微生物发酵组合物及其应用 Download PDFInfo
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- CN107375373A CN107375373A CN201710571073.XA CN201710571073A CN107375373A CN 107375373 A CN107375373 A CN 107375373A CN 201710571073 A CN201710571073 A CN 201710571073A CN 107375373 A CN107375373 A CN 107375373A
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- fermentation composition
- microbial fermentation
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- ginseng
- fermentation
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Abstract
本发明公开了一种微生物发酵组合物，所述的组合物选用药食两用真菌姬松茸、香菇、金针菇和大补元气的人参，经提取、酶解后，添加微量元素硒、锌、钼，利用益生菌发酵、转化制得。本发明发酵组合物经过体外抑制HepGII细胞（肝癌细胞）、Hela细胞（宫颈癌细胞）实验表明，经过益生菌发酵发酵组合物对肿瘤细胞的增殖具有明显的抑制作用。发酵组合物与未发酵组合物相比，对实验用肿瘤细胞抑制效果明显增强，差异显著。且发酵组合物对试验用肿瘤细胞的抑制效果，随作用浓度增加而增强。
Description
技术领域
本发明涉及微生物发酵组合物及其应用，尤其涉及一种抗癌的经酶解及微生物发酵、转化的组合物及其应用。
背景技术
现代人由于生活、工作压力紧张，运动量减少，导致身体处于亚健康状态，身体免疫力低下，经常疲劳、感冒、胃肠功能失调，由于机体长期处于免疫力低下状态，癌症的发病几率就会增加。
人参(Panax ginseng C．A．Meyer)为五加科多年生草本植物人参的根，素有“百草之王”的美称，是我国传统名贵中药。在中国、朝鲜、日本乃至亚洲国家被广泛用于滋补保健和医疗。现代药理学研究表明人参具有免疫调节、抗癌、抗脑缺血、治疗糖尿病、预防动脉粥样硬化和抗炎等药理学活性。
药用真菌是指能治疗疾病、具有药用价值的一类真菌，即其菌丝体、子实体、菌核或孢子中能产生氨基酸、蛋白质、维生素、多糖、苷类、生物碱等多种物质， 对人体有保健作用或对疾病有预防、抑制或治疗作用的真菌。其中一些种类不仅具有对人体有保健作用，还可以食用，为药食两用真菌 。我国药食两用真菌资源丰富， 据不完全统计，全球范围内已经记载的此类真菌大约大约 2500 种，中国已报道的近1000 种。药食两用真菌抗肿瘤活性的研究主要集中在对多糖的研究。多糖和蛋白质、核酸、脂类构成生命四大物质，以前人们对多糖活性认识不足，认为多糖只是营养物质。60年代后，人们发现多糖具有多种作用：它能控制细胞分裂、调节细胞生长和衰老、可作为免疫促进剂，对肿瘤、心血管疾病和肝炎具有治疗作用，从而引起人们的重视。多糖的抗肿瘤活性主要为含有β-(1-3)或β-(1-4)主链，侧链为β-(1-6)的葡聚糖。研究表明，药食两用真菌多糖抗肿瘤作用是通过宿主中介作用，它能激活T 淋巴细胞，提高机体细胞免疫功能。例如，云芝多糖能激活B 细胞，香菇多糖能恢复免疫功能下降的T淋巴细胞，裂褶多糖是利用宿主网状内皮细胞，提高宿主非特异防御功能。这些多糖对免疫功能异常的机体起作用。体外试验表明，多糖对细胞本身无直接细胞毒作用。
发明内容
为了解决机体免疫力低下、集体机能下降的问题，本发明提供了一种具有提高免疫力、抗癌作用的微生物发酵组合物。
本发明所述的微生物发酵组合物选用药食两用真菌姬松茸、香菇、金针菇和大补元气的人参，经提取、酶解后，添加微量元素硒、锌、钼，利用益生菌发酵、转化制得；
所述药食两用真菌的重量g/体积mL百分比为：姬松茸1—3%、香菇2-4%、金针菇1-4%；所述人参的重量g/体积mL百分比为：1-3%；所述微量元素含量为：亚硒酸钠30-200µg/100mL、硫酸锌•7H2O 20-85mg/100mL、钼酸钠•2H2O 50-150µg/100mL；
所述的益生菌为双歧杆菌和乳杆菌；
所述的微生物发酵组合物的制备方法如下：
A.发酵底物的提取：将干燥的人参、姬松茸、香菇、金针菇粉碎，过65~80目筛，加入物料重量的30倍饮用水浸泡1小时，加热煮沸1.5小时，温度降至90℃时，调整pH值在5.5-7.0之间，加入高温淀粉酶，加入量为20酶活力单位×物料重量/酶活力，维持温度在80-90℃之间，并搅拌均匀，料液与碘液不再变蓝时结束淀粉酶酶解，将料液温度降至50℃，调整料液pH值为5.0-6.0，加入果胶裂解酶，加入量体积比为料液体积的0.1%，维持温度45-50℃，酶解2小时，结束酶解，煮沸10分钟，灭酶、滤过，取上清液，减压浓缩至姬松茸、香菇、金针菇和人参达到所述浓度，得到发酵底物提取液；
B.配料、灭菌：将发酵底物提取液中加入亚硒酸钠、硫酸锌、钼酸钠，加入0.5%葡萄糖，磷酸二氢钾 100mg/100mL、磷酸氢二钾•3H2O 100mg/100mL，调整料液pH，高压蒸汽灭菌后，即得到继后用于微生物发酵的发酵底物；
C.接种、发酵：将预培养好的双歧杆菌属其中的两株培养液无菌操作接入到步骤B得到的无菌的发酵底物中，38±1℃、兼性厌氧培养2~6小时后，再次接种预培养的至少一种乳杆菌菌液，继续发酵；当发酵液pH值降至4.1时，将温度降至25℃，并再维持24小时，结束发酵；
D.灭活：将发酵完成的发酵液70℃灭活，或者115℃灭活，得到所述的微生物发酵组合物。
本发明中，优选的，所述药食两用真菌的重量g/体积mL百分比为：姬松茸2%、香菇2%、金针菇1%；所述人参的重量g/体积mL百分比为：2%。
本发明中，优选的，所述微量元素及其含量为：亚硒酸钠70µg/100mL、硫酸锌•7H2O50mg/100mL、钼酸钠•2H2O 70µg/100mL。
优选的，制备方法步骤A中，酶解过程中的工艺参数为：将pH值调整为6.0，加入高温淀粉酶，维持温度在85℃，并搅拌均匀；将料液pH值调整为6.0，加入果胶裂解酶，维持温度45℃，酶解2小时，结束酶解。
优选的，制备方法步骤B中，所述的调整料液pH值为7.0±0.1，所述高压蒸汽灭菌的温度为121℃、时间为30分钟。
优选的，制备方法步骤C中所述的双歧杆菌属是指两歧双歧杆菌、短双歧杆菌、青春双歧杆菌、婴儿双歧杆，每株菌接种量体积比均为0.6%，培养时间为6小时；所述的乳杆菌为嗜酸乳杆菌、德氏乳杆菌、鼠李糖乳杆菌、罗伊氏杆菌或植物乳杆菌，每株菌接种量体积比为0.5%，发酵温度为38±1℃。
优选的，制备方法步骤D中所述的灭活温度为115℃,时间为10分钟。
优选的，制备方法步骤B中所述的发酵底物提取液中还加有重量mg/体积mL比为3.0%的蔗糖、30mg/100mL的三氯蔗糖以及5.0mg/100mL的硫酸亚铁•7H2O。
优选的，制备方法步骤C中在发酵结束后，还在无菌条件下，加入事先115℃、40分钟灭菌的低聚木糖浆，加入量为重量mg/体积mL比1.5%。
本发明的另一个目的是提供所述的微生物发酵组合物在制备提高机体免疫力、预防和治疗肿瘤的药物或者保健品中的应用。
人参的主要活性成分为人参皂苷，现已分离并确定结构的单体皂苷成分有50余种。人参皂苷是由苷元和糖相连而成的糖苷类化合物，属于三萜类皂苷。人参皂苷按照苷元的结构不同分为3类：二醇型人参皂苷(PPD)、三醇型人参皂苷(PPT)和齐墩果酸型人参皂苷。PPD和PPT型人参皂苷都属于达玛烷型四环三萜类化合物，在人参皂苷中占大多数，目前认为其是人参的主要活性成分之一。PPD型皂苷如人参皂苷Rbl、Rd、Rh2等，及PPT型皂苷如人参皂苷Re、Rgl、Rg2等，其中人参皂苷Rb1、Rd、Re等含量较高，而人参皂苷Rg3、CompoundK、Rh2等含量极少，在人工栽培的人参中基本不存在，为稀有人参皂苷。
口服人参皂苷或人参提取物后，人参皂苷在酸性胃液环境下水解生成脱糖基代谢产物，在肠道中，亦可由肠道菌群所表达的糖苷水解酶(如β-葡萄糖苷酶，a-鼠李糖苷酶，木糖苷酶等)脱糖基，生成次级代谢产物或苷元，通过跨膜转运等方式吸收进入体循环，进而发挥药效。各种人参皂苷间的差别主要在于苷元，糖基的数目、种类以及糖苷键的位置间的差异。中药皂苷类成分的胃肠道代谢处置，已经被证实是影响其吸收进而发挥药效的重要节点；而肠道菌群所表达的糖苷水解酶系统则是该节点中介导皂苷类成分肠道代谢的关键因素。
金针菇形美、味鲜，因其具有多种药效作用而被广泛用于药膳，是世界上著名的食药两用菌和观赏菌。研究发现在金针菇中存在着丰富的抗肿瘤活性成份，包括多糖、火菇素、构菌素、构菌蛋白等。多糖是金针菇的主要活性成分之一，相关的功能评价显示具有提高免疫力和抗肿瘤的作用。金针菇中含有金针菇素，该物质是一种特殊的碱性蛋白质，能增强机体免疫系统防御功能，对癌细胞有明显的抑制作用。
香菇多糖可增加天然杀伤细胞(NK细胞)活性和淋巴因子激活的杀伤细胞(LAK细胞)的产生，能激活细胞免疫功能和产生肿瘤坏死因子，与化疗药物合用，能明显提高抗肿瘤效果。研究表明，多糖生物活性的高低与其结构有关，化学基团的引入也常常会增强多糖的活性或使多糖产生新的活性，因而对多糖结构进行适当修饰是当前多糖研究领域的重点之一。
姬松茸又名巴西菇，是原产于巴西的珍贵而稀少的富含糖和蛋白质的药食兼用真菌。有研究证明，姬松茸具有调节免疫、抗肿瘤、抗病毒、抗炎、抗疲劳及保肝等作用。
微量元素硒，主要以硒半胱氨酸形式存在于蛋白质中，是人体生命活动所必需的微量元素，具有广泛的生物学功能。大量研究证明：硒具有防癌抗癌作用，是乳腺癌、肝癌、皮肤癌、结肠癌和胃癌等的强有力的抑制剂。能抑制致癌物N一甲基一N´一硝基一N一亚硝基胍(MNNC)诱发的大鼠腺癌胃癌、前胃胃癌；对抗三甲基胆蒽(3一MCA)诱导小鼠肉瘤的发生，降低了肉瘤的发生率。
微量元素锌参与金属硫蛋白的合成，从而抑制自由基的形成，锌的氧化物可以抑制受紫外线A1辐射的人皮肤成纤维细胞DNA单链的破坏。因此，Zn可能与癌症之间呈负相关。
钼是动物与人体必需微量营养元素，是多种种酶组成成分，参与和影响机体内多种物质代谢过程，同时对痛症、肝脏疾病、心脑血管疾病、以及克山病、龋齿、小细胞低色素性贫血和区域性脱发等地方病有很好的防治作。
肠道菌群是人体重要的“微生态器官”，作为与宿主共生的有生系统，参与宿主多项生理过程。而肠道菌群紊乱逐渐被认为是某些代谢性疾病、精神类疾病的重要病理特征，且与此类疾病的发生、发展密切相关。肠道菌群紊乱常加剧疾病症状，疾病进程又可反作用于肠道菌群，加剧肠道菌群紊乱程度。此外，多种外界因素可影响肠道菌群的稳态平衡，如应激、抗生素滥用等，常可导致肠道菌群紊乱。对肠道菌群的组成和功能的系统表征是对肠道菌群进行相关研究的重要手段。现代药物代谢研究表明，许多天然药物口服以后，进入体内，接触到肠道中的微生物菌群，细菌对药物进行代谢转化，将药物的前体物质转化为药物活性成分而发挥作用。
有报道称乳酸菌具有抗癌作用，但其机制却不十分清楚，可能的作用机理有：增强机体免疫系统；调整肠道菌群，阻止肠道内致癌物质的形成；产生抗突变物质；降解或吸附致癌物质等。
当机体摄入过多油腻的食物时，体内油脂增多，其代谢也增多，负责油脂代谢的是肝脏内的胆盐，它通过乳化作用而消化油脂。当胆盐经过机体肠道遇到致病菌时，则会产生致癌物质而引起肠癌。但是，有了益生菌的存在，致病菌则会受到抑制，因此，胆盐的存在也不易产生致癌物质。科学家也通过试验证实了这一点，益生菌类饮品可以降低机体肠道细胞基因受损的可能性，从而预防某些癌症。
乳酸杆菌是女性生殖道的主要益生菌，经热灭活的乳酸杆菌对宫颈癌细胞系HeLa细胞具有较强的黏附性。现已证实提高肿瘤细胞的免疫原性，恢复机体对肿瘤细胞的免疫监视功能是抗肿瘤治疗的重要策略。王红艳等研究发现经热灭活的乳酸杆菌确可提高宫颈癌细胞系HeLa细胞的免疫原性，激活T细胞和NK细胞的抗肿瘤效应，这为益生菌辅助肿瘤免疫治疗提供了新线索。陈玉堂等研究指出，肝癌合并肝硬化患者于介入治疗围手术期口服益生菌制剂，可有效改善患者肠道菌群失调，短期内可降低部分肝硬化并发症的发生率，且无明显的肝功能损害。
与现有技术相比，本发明选用益生菌发酵转化无机微量元素硒、锌、钼等为有机微量元素，减少无机微量元素的蓄积性毒性和致突变性，提高微量元素的生物活性。选用的药食两用真菌和人参富含多糖类成分，经过益生菌发酵，分子量明显减小，提高了真菌多糖的抑瘤效果。
发酵组合物配方中含有人参提取物，其中的人参皂苷在发酵工艺过程中，经益生菌的代谢转化脱糖基，生成次级代谢产物或苷元，通过跨膜转运等方式吸收进入体循环，进而发挥药效。各种人参皂苷间的差别主要在于苷元，发酵组合物中，稀有人参皂苷Rg3含量明显增加。
发酵组合物经过体外抑制HepGII细胞（肝癌细胞）、Hela细胞（宫颈癌细胞）实验表明，经过益生菌发酵发酵组合物对肿瘤细胞的的增殖具有明显的抑制作用。发酵组合物与未发酵组合物相比，对实验用肿瘤细胞抑制效果明显增强，差异显著。且发酵组合物对试验用肿瘤细胞的抑制效果，随作用浓度增加而增强。发酵组合物对小鼠S180实体瘤的体内抑制作用表明，通过本方法制备益生菌发酵的组合物的高、中、低三个剂量组其抑瘤作用明显提高。虽然有关机理尚不明了，但这一研究结果证明，未经益生菌转化的组合物未观察到对肿瘤细胞的抑制作用，人参、姬松茸、香菇、金针菇或其他真菌多糖在肠道有益菌群的体外作用下，经过某些已知或未知的化学修饰或生物转化后，或者益生菌菌体本身及代谢产物对肿瘤细胞具有更高的抑制活性。
具体实施方式
实施例1 益生菌发酵组合物A的制备
发酵组合物组分：微生物发酵组合物包括以下组分组成：其重量/体积百分比为：人参2.0%、姬松茸2.0%、香菇2.0%、金针菇1.0%，亚硒酸钠70µg/100mL、硫酸锌•7H2O 50mg/100mL、钼酸钠•2H2O 70µg/100mL。制备方法如下：
a.发酵底物的提取：将干燥的人参、姬松茸、香菇、金针菇粉碎，过80目筛，加入物料重量的30倍饮用水浸泡1.0小时，加热煮沸1.5小时，温度降至90℃时，调整pH值6.0，加入高温淀粉酶，加入量为20酶活力单位×物料重量/酶活力，维持温度在85℃，并搅拌均匀，料液碘液不再变蓝结束淀粉酶酶解，将料液温度降至50℃，调整料液pH值为6.0，加入果胶裂解酶，加入量为0.1%（酶液体积/料液体积），维持温度45-50℃，酶解2小时，结束酶解，煮沸10分钟，灭酶、滤过，取上清液，减压浓缩至所需体积，得发酵底物提取液。
b.配料、灭菌：将发酵底物提取液中加入亚硒酸钠70µg/100mL、硫酸锌•7H2O50mg/100mL、钼酸钠•2H2O 70µg/100mL，葡萄糖0.5g/100mL，磷酸二氢钾 100mg/100mL、磷酸氢二钾•3H2O 100mg/100mL，蔗糖3.0g/100mL、三氯蔗糖30mg/100mL、硫酸亚铁•7H2O5.0mg/100mL调整料液调整料液pH为7.0±0.1，并高压蒸汽灭菌温度为121℃、30分钟，即得到继后用于微生物发酵底物。
c.接种、发酵：将预培养好两歧双歧杆菌、短双歧杆菌两株菌菌液无菌操作接入到灭菌的温度降至40℃的发酵底物中，接种量均为0.6%（体积/体积）；38±1℃、兼性厌氧培养6小时后，再次接种预培养的嗜酸乳杆菌和植物乳杆菌菌液，接种量均为0.5%（体积/体积）继续发酵；当发酵液pH值降至4.1时，将温度降至25℃，并再维持24小时，结束发酵。
调配：无菌操作，加入事先115℃、40分钟灭菌的低聚木糖浆，加入量为重量/体积比（mg/mL）的1.5%。
d.灭活：将发酵完成的发酵液灭活，温度为115℃,10分钟，得微生物发酵组合物A。
实施例2 益生菌发酵组合物B的制备
发酵组合物组分：微生物发酵组合物包括以下组分组成：其重量/体积百分比为：人参1.5%、姬松茸3.0%、香菇2.5%、金针2.0%，亚硒酸钠100µg/100mL、硫酸锌•7H2O 30mg/100mL、钼酸钠•2H2O 100µg/100mL。
a.发酵底物的提取：将干燥的人参、姬松茸、香菇、金针菇粉碎，过80目筛，加入物料重量的30倍饮用水浸泡1.0小时，加热煮沸1.5小时，温度降至90℃时，调整pH值6.0，加入高温淀粉酶，加入量为20酶活力单位×物料重量/酶活力，维持温度在85℃，并搅拌均匀，料液碘液不再变蓝结束淀粉酶酶解，将料液温度降至50℃，调整料液pH值为6.0，加入果胶裂解酶，加入量为0.1%（酶液体积/料液体积），维持温度45-50℃，酶解2小时，结束酶解，煮沸10分钟，灭酶、滤过，取上清液，减压浓缩至所需体积，得发酵底物提取液。
b.配料、灭菌：将发酵底物提取液中加入亚硒酸钠100µg/100mL、硫酸锌•7H2O30mg/100mL、钼酸钠•2H2O 100µg/100mL，葡萄糖0.5g/100mL，磷酸二氢钾 100mg/100mL、磷酸氢二钾•3H2O 100mg/100mL，蔗糖3.0g/100mL、三氯蔗糖30mg/100mL、硫酸亚铁•7H2O5.0mg/100mL调整料液调整料液pH为7.0±0.1，并高压蒸汽灭菌温度为121℃、30分钟，即得到继后用于微生物发酵底物。
c.接种、发酵：将预培养好的婴儿双歧杆菌、青春歧杆菌两株菌菌液无菌操作接入到灭菌的温度降至40℃的发酵底物中，接种量均为0.6%（体积/体积）；38±1℃兼性厌氧培养6小时后，再次接种预培养的鼠李糖乳杆菌和罗伊氏乳杆菌菌液，接种量均为0.5%（体积/体积）继续发酵。当发酵液pH值降至4.1时，将温度降至25℃，并再维持24小时，结束发酵。
d.灭活：将发酵完成的发酵液灭活，温度为70℃,4小时，得微生物发酵组合物B。
实验例1 微生物发酵组合物与未发酵组合物体外抑制肿瘤细胞增殖试验
选用实施例制备的微生物发酵组合物A和B，并以实施例1组分未经微生物发酵的组合物A1和实施例1不含人参的组分经微生物发酵组合物A2为对照。
取细胞株HepGII和Hela，分别用培养基将肿瘤细胞调整至1×104个/L，在96孔板中每孔加入100ul细胞悬液于37℃、5% CO2下培养过夜。次日每孔加入不同浓度的药物10ul、 20ul 、30ul作为试验组，每组均设4-6个复孔，37℃、5% CO2继续培养。培养至24h、实验终止前1小时加入CCK8试剂10ul培养继续2h后测定A450mm吸光度，然后计算细胞生长的抑制率。实验结果见表1。
实验结果显示，未发酵的组合物A1在实验条件下，各浓度未发现对HepGII细胞株和Hela细胞株有抑制作用。微生物发酵组合物A、B对HepGII细胞株和Hela细胞株有抑制作用，组合物A的抑制作用强于组合物B。不含人参的发酵组合物A2的抑制率相比较于组合物A，抑制率明显降低。由于益生菌的发酵代谢作用，使复合真菌多糖分子量变小，或者是改变了人参皂苷的结构、或者是益生菌菌体本身和代谢产物增强了对肿瘤细胞的抑制作用，使原本体外对HepGII细胞株和Hela细胞株没有抑制作用的组合物产生了较强的抑制作用。
实验例2 微生物发酵组合物与未发酵组合物对小鼠实体瘤的抑制作用比较
1、实验样品：为实施例制备的发酵组合物A、B，以同样浓度的未发酵的组合物A1、B1作为对照。
、器材：BP211D电子分析天平(德国Storis公司)；倒置生物显微镜 LWD200-37T（上海）、注射器、灌胃器、量筒、移液管等。
、动物：清洁级昆明小白鼠 156 只，体重18～22g；购自济南朋悦实验动物繁育有限公司，许可证SCXK（鲁2014-0007）。
、分组：小白鼠156只，随机分为13组，每组12只。分别为：
⑴生理盐水组、⑵发酵组合物A高剂量组、⑶发酵组合物A中剂量组、⑷发酵组合物A低剂量组、⑸发酵组合物B高剂量组、⑹发酵组合物B中剂量组、⑺发酵组合物B低剂量组、⑻未发酵组合物A1高剂量组、⑼未发酵组合物A1中剂量组、⑽未发酵组合物A1低剂量组、⑾未发酵组合物B1高剂量组、⑿未发酵组合物B1中剂量组、⒀未发酵组合物B1低剂量组。
方法:
5．1动物造模、分组及给药
昆明小鼠156只，置于室温、通风的清洁级动物室中自由摄食饮水，适应2天。常规消毒后从S180瘤种小鼠抽取腹水液，用台盼兰染色，显微镜下检测活细胞数达95％后，抽取瘤液用生理盐水稀释至肿瘤细胞数为2×107／mL，给每只小鼠右腋前皮下注射0．2 mL。
接种后24小时随机分为13组。各组动物灌胃给药，连续给药15天。
⑴生理盐水组即正常组，接种后每天给予生理盐水。
⑵⑸⑻⑾高剂量组：高剂量组为人推荐剂量的20倍换算，每日每只口服0.3mL（浓缩2倍，相当于原组合物0.6mL）。
⑶⑹⑼⑿中剂量组：为人推荐剂量的10倍换算，每日每只口服0.3ml。
⑷⑺⑽⒀低剂量组：低剂量组为人推荐剂量的5倍换算，每日每只口服0.3mL，（稀释1倍，相当于原口服液0.15mL）。
．2抑瘤率测定
给药14 d后处死小鼠，剥离瘤体，用电子天平称取瘤重，计算抑瘤率。
抑瘤率(％)=(模型组瘤质量-给药组瘤质量)／模型组瘤质量×100％。
结果:
各实验组与阴性对照组比较，具有显著性差异。并且，发酵的组合物各剂量组与未发酵组合物同浓度比较，具有显著性差异。益生菌发酵转化人参、巴西菇、金针菇、香菇，可以提高抑瘤作用，并且，发酵后可以减低组合物的起效浓度。
实验例3 微生物发酵组合物与未发酵组合物中稀有人参皂苷Rg3含量测定
实验样品：为实施例1制备的发酵组合物A，以同样浓度的未发酵的组合物A1为对照，同时检测只含同样浓度人参的发酵组合物A2中人参皂苷Rg3的含量。
实验方法：采用高效液相色谱法检测样品中Rg3含量。照高效液相色谱法（中国药典一部附录）测定。
试剂、仪器：人参皂苷Rg3 对照品（南京森贝伽生物科技有限公司提供）；乙腈（色谱纯）；甲醇、正丁醇、氨水（分析纯）。
色谱条件：色谱柱Beckman-ODS 柱（4. 6 mm ×250 mm，5 μm），检测波长203 nm，流动相：乙腈-0.05％磷酸（50：50），流速0.8 mL/ min，柱温30 ℃。
对照品溶液的制备：精密称取干燥的Rg3对照品适量，加甲醇溶解，制成每mL含40µg的溶液，即得。
供试品溶液的制备：取测试样品A、A1、A2，摇匀，精密量取25mL，值100mL分液漏斗中，水饱和的正丁醇萃取三次，合并正丁醇液，用20mL氨试液洗涤2次，水浴蒸干正丁醇，残渣用甲醇溶解，并定容至10mL，摇匀、0,45µm膜过滤，即得。
测定法：分别精密吸取对照品溶液与供试品溶液各10µl，注入液相色谱仪，测定，具体结果见表3。
实验结果可以看出，未发酵的组合物中，未检测出人参皂苷Rg3，发酵组合物经过检测，人参皂苷Rg3含量为23µg/mL，只含同浓度人参的发酵组合物A2人参皂苷Rg3含量为10µg/mL。推测巴西菇（姬松茸）、香菇、金针菇可能对益生菌的生长或者糖苷酶的活性有影响，从而在本发明的组合物中，提高了益生菌对人参皂苷的代谢转化能力，经过本方法制备的发酵组合物中产生了较高浓度的稀有人参皂苷Rg3。人参皂苷具明显的生理活性，也是人参成分中最有效的药用成分．目前，已经从人参中分离出约50种人参皂苷成分。药理研究表明，人参皂苷普遍具有抗肿瘤、抗氧化、改善记忆力、抗疲劳、保护神经等药理作用。人参皂苷Rg3最初从红参中分离得到，它主要作用于细胞增殖周期的Ｇ2／Ｍ期，具有诱导肿瘤细胞凋亡，选择性抑制肿瘤细胞黏附和浸润，抑制肿瘤新生血管的形成，增强机体免疫力等作用；但这些皂苷天然含量极低，如Rg3在白参中的含量仅为0.0003%。通过本发明的方法，可以显著的提高组合物中稀有人参皂苷Rg3的含量。
Claims (10)
1.一种微生物发酵组合物，其特征在于，将药食两用真菌姬松茸、香菇、金针菇和人参经提取、酶解后，添加微量元素硒、锌、钼，利用益生菌发酵、转化制得；
所述的药食两用真菌的重量g/体积ml百分比为：姬松茸1—3%、香菇2-4%、金针菇1-4%；所述人参的重量g/体积ml百分比为：1-3%；所述微量元素含量为：亚硒酸钠30-200µg/100mL、硫酸锌•7H2O 20-85mg/100mL、钼酸钠•2H2O 50-150µg/100mL；
所述的益生菌为双歧杆菌和乳杆菌；
所述的微生物发酵组合物的制备方法如下：
A.发酵底物的提取：将干燥的人参、姬松茸、香菇、金针菇粉碎，过65~80目筛，加入物料重量的30倍饮用水浸泡1小时，加热煮沸1.5小时，温度降至90℃时，调整pH值在5.5-7.0之间，加入高温淀粉酶，加入量为20酶活力单位×物料重量/酶活力，维持温度在80-90℃之间，并搅拌均匀，料液与碘液不再变蓝时结束淀粉酶酶解，将料液温度降至50℃，调整料液pH值为5.0-6.0，加入果胶裂解酶，加入量体积比为料液体积的0.1%，维持温度45-50℃，酶解2小时，结束酶解，煮沸10分钟，灭酶、滤过，取上清液，减压浓缩至姬松茸、香菇、金针菇和人参达到所述浓度，得到发酵底物提取液；
B.配料、灭菌：将发酵底物提取液中加入亚硒酸钠、硫酸锌、钼酸钠，加入0.5%葡萄糖，磷酸二氢钾100mg/100mL、磷酸氢二钾•3H2O 100mg/100mL，调整料液pH，高压蒸汽灭菌后，即得到继后用于微生物发酵的发酵底物；
C.接种、发酵：将预培养好的双歧杆菌属其中的两株培养液无菌操作接入到步骤B得到的无菌的发酵底物中，38±1℃、兼性厌氧培养2~6小时后，再次接种预培养的至少一种乳杆菌菌液，继续发酵；当发酵液pH值降至4.1时，将温度降至25℃，并再维持24小时，结束发酵；
D.灭活：将发酵完成的发酵液70℃灭活，或者115℃灭活，得到所述的微生物发酵组合物。
2.根据权利要求1所述的微生物发酵组合物，其特征在于，所述的微生物发酵组合物中各组分的重量g/体积mL百分比为：人参2%、姬松茸2%、香菇2%、金针菇1%。
3.根据权利要求1所述的微生物发酵组合物，其特征在于，所述微量元素及其含量为：亚硒酸钠70µg/100mL、硫酸锌•7H2O 50mg/100mL、钼酸钠•2H2O 70µg/100mL。
4.根据权利要求1所述的微生物发酵组合物，其特征在于，所述制备方法步骤A中，酶解过程中的工艺参数为：将pH值调整为6.0，加入高温淀粉酶，维持温度在85℃，并搅拌均匀；将料液pH值调整为6.0，加入果胶裂解酶，维持温度45℃，酶解2小时，结束酶解。
5.根据权利要求1所述的微生物发酵组合物，其特征在于，所述制备方法步骤B中，所述的调整料液pH值为7.0±0.1，所述高压蒸汽灭菌的温度为121℃、时间为30分钟。
6.根据权利要求1所述的微生物发酵组合物，其特征在于，所述制备方法步骤C中所述的双歧杆菌属是指两歧双歧杆菌、短双歧杆菌、青春双歧杆菌、婴儿双歧杆，每株菌接种量体积比均为0.6%，培养时间为6小时；所述的乳杆菌为嗜酸乳杆菌、德氏乳杆菌、鼠李糖乳杆菌、罗伊氏杆菌或植物乳杆菌，每株菌接种量体积比为0.5%，发酵温度为38±1℃。
7.根据权利要求1所述的微生物发酵组合物，其特征在于，制备方法步骤D中所述的灭活温度为115℃,时间为10分钟。
8.根据权利要求1所述的微生物发酵组合物，其特征在于，制备方法步骤B中所述的发酵底物提取液中还加有重量mg/体积mL比为3.0%的蔗糖、30mg/100mL的三氯蔗糖以及5.0mg/100mL的硫酸亚铁•7H2O。
9.根据权利要求1所述的微生物发酵组合物，其特征在于，制备方法步骤C中在发酵结束后，还在无菌条件下，加入事先115℃、40分钟灭菌的低聚木糖浆，加入量为重量mg/体积mL比1.5%。
10.权利要求1-9任一项所述的微生物发酵组合物在制备提高机体免疫力、预防和治疗肿瘤的药物或者保健品中的应用。
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| CN112957430A (zh) * | 2021-02-06 | 2021-06-15 | 吉林大学 | 生物强化细胞营养素在制备抗肝癌药物中的应用 |
| CN115919961A (zh) * | 2022-11-22 | 2023-04-07 | 常熟雷允上制药有限公司 | 一种天佛参口服液及其制备方法和应用 |
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| CN112691185A (zh) * | 2020-12-30 | 2021-04-23 | 河北巨因生物科技有限公司 | 一种抗肿瘤配方及其提取方法 |
| CN115363155A (zh) * | 2021-05-06 | 2022-11-22 | 江苏恒康生物科技有限公司 | 一种具有缓解体力疲劳的益生菌发酵莲子组合物的制备 |
| CN114304620B (zh) * | 2021-12-30 | 2023-09-19 | 新疆惠泽食品有限责任公司 | 一种复合菌发酵的新疆药桑葚复合酵素及其制备方法 |
| CN114767728B (zh) * | 2022-04-25 | 2023-04-18 | 扬州市职业大学(扬州开放大学) | 一种预防和治疗帕金森氏病的组合物及其制备方法 |
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| WO2019010813A1 (zh) | 2019-01-17 |
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