CN1767837A - 用于免疫活性或防治癌症的包含从酿酒酵母is2中得到的可溶性葡聚糖低聚物的组合物及其制备方法 - Google Patents
用于免疫活性或防治癌症的包含从酿酒酵母is2中得到的可溶性葡聚糖低聚物的组合物及其制备方法 Download PDFInfo
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Abstract
本发明涉及M.W.范围为1,000到10,000的可溶性葡聚糖低聚物,该低聚物通过用商业可得的β-葡聚糖水解酶处理由分离出的酵母变异IS2细胞壁得到的不溶性β-葡聚糖来制备。该可溶性葡聚糖低聚物在促进免疫活性和抑制癌细胞生长方面显示强大效力,因此可用作治疗或保健食品来治疗和预防免疫缺陷和癌症疾病。
Description
技术领域
本发明涉及包含从酿酒酵母IS2中分离得到的可溶性葡聚糖低聚物的组合物及其制备方法,该组合物可用于免疫活性或者防治癌症。
背景技术
β-葡聚糖可以从各种来源如酵母菌、微生物、蘑菇、谷物和藻类中分离得到。到目前为止,已对β-葡聚糖进行了研究并以各种形式的产品加以应用。特别是对从酵母菌细胞壁得到的β-葡聚糖进行了研究,具有很深的了解。
酵母菌是一种微生物,FDA将其分类为GRAS(食品安全规范),该菌用于包括食品领域在内的各种领域,其内层细胞膜包括作为主要成份的1,3-和1,6-葡聚糖,还有少量的甲壳质和甘露蛋白质;然而其外层细胞膜包括连接甘露聚糖的甘露蛋白质。
β-葡聚糖是酵母菌细胞壁的主要成份。据报道,β-葡聚糖能够通过激活和激增巨噬细胞来增加Ag-特异性免疫反应,能提高对病原体如真菌、细菌、病毒等的抵抗力,能抑制外伤中出现的免疫消弱和能增加宿主对癌症和癌症转移的抵抗力。(Abel,G.and Czop,J.K.,INT.J.Immunophamacol.,14,pp1363-1373,1992;Babineau,et al.,
220(5),pp601-609,1994;Benach J.L.,et al.,Infection and Immunity,35(3),pp947-951,1982;Di Renzo,L.,et al.,Eur.J.Immunol.,21,pp1755-1758,1991;Fukase,S.,et al.,Cancer Res.,47,pp4842-4847,1987;Janusz,M.J.,etal.,J.Immun.,142,pp959-965,1989;Olsen,E,J.,et al.,J.Immun.,64,pp3548-3554,1996,Sakurai,T.,et al.,Int.J.Immunopharmacol.,14,pp821-830,1992;Czop,J.K.,et al.,Prog.Clin.Biol.Res.,297,pp287-296,1989)。
因为酵母菌的β-葡聚糖是水不溶性多糖,所以到目前为止,已经发展出许多制备高溶解性β-葡聚糖的方法,如下所述。
美国专利No.5,576,015公开了细微粒形式的β-葡聚糖的制备方法以提高其吸收率;美国专利No.4,877,777公开了向葡聚糖上引入化学式以提高其溶解性的方法;美国专利No.5,037,972和美国专利No.6,143,883公开了制备可溶性葡聚糖颗粒的方法,该方法包括用有机溶剂提取葡聚糖,然后用β-葡聚糖酶或者纤维素酶处理该葡聚糖,这些酶能降解葡聚糖的基本结构β-1,3-D-葡萄糖链。
然而,上述引用文献中并未报道或公开从酵母变异菌株IS2(KCTC0959BP)分离得到的特定可溶性葡聚糖低聚物及该葡聚糖低聚物对癌症疾病的治疗效果,这些公开在此并入作为参考。
本发明的发明人致力于研究从特定的酵母变异菌株中找到具有药学活性的β-葡聚糖并最终完成本发明,确认通过提取酵母菌突变体IS2细胞壁所得到的M.W.小于50,000D的可溶性葡聚糖低聚物显示了强大的对免疫系统刺激活性和对癌细胞增殖的抑制活性。
对本发明公开的以下详细描述会使本发明的上述目的和其它目的显而易见。
发明内容
根据本发明的一个方面,本发明提供了源自酵母菌变异菌株IS2的可溶性葡聚糖低聚物及其制备方法。
另外,本发明提供了用于提高免疫力和抗癌活性的包含利用本发明方法制备的可溶性葡聚糖低聚物的药物组合物。
相应地,本发明的目的是提供具有免疫提高活性和癌细胞增殖抑制活性的可溶性葡聚糖低聚物,该可溶性葡聚糖低聚物源自酵母菌变异菌株(KCTC 0959BP)细胞壁,通过用酶处理不溶性β-葡聚糖得到。
本发明的另一个目的是提供制备可溶性葡聚糖低聚物的方法,该方法包括以下步骤:(a)在培养基中培养酵母菌(酿酒酵母)变异IS2用于接种;(b)将上述酵母菌培养溶液接种到培养基中,培养并离心得到酵母菌;(c)向其中加入NaOH以从酵母菌细胞壁中提取β-葡聚糖;(d)将提取的β-葡聚糖与水解酶反应,然后经过滤得到可溶性葡聚糖低聚物;和(e)最后冷冻干燥以得到本发明的可溶性葡聚糖低聚物。
上述酵母变异IS2的特征是具有提高免疫力活性。
通过上述步骤制备的可溶性葡聚糖低聚物包括分子量小于50,000,优选范围1,000-10,000的葡聚糖低聚物。
本发明的又一目的是提供可作为有效成份的、以有效剂量治疗或预防免疫缺陷疾病或癌症的药物组合物及其药学可接受载体,该药物组合物包括通过上述步骤获得的源自酵母菌变异菌株(KCTC 0959BP)细胞壁的可溶性葡聚糖低聚物。
可根据下述优选的实施方案制备该具有创造性的可溶性葡聚糖低聚物。
对于本发明,上述可溶性葡聚糖低聚物可通过以下步骤制备;
(a)第一步,培养酵母菌IS2(KCTC0959BP)的步骤,包括在含有0.5-10w/v%葡萄糖、0.1-5w/v%酵母菌提取物和0.1-10w/v%蛋白胨(pepton)的液态培养介质中培养酵母菌IS2(KCTC0959BP);
(b)第二步,从酵母菌培养介质中得到酵母菌的步骤,包括将第一步制备的数量范围为0.1-10v/v%的酵母菌培养介质接种到PH范围为5.0-6.0的含0.5-10w/v%葡萄糖、0.1-5w/v%酵母菌提取物、0.01-2w/v%硫酸铵、0.001-1w/v%磷酸钾和0.001-1w/v%的硫酸镁的初级液态培养介质中,在速度范围100-400rpm下培养12-48小时,通气量范围从0.3-3vvm,生长介质的温度范围为20-40℃,然后经离心以得到酵母菌;
(c)第三步,从酵母菌细胞壁中提取湿的β-葡聚糖的步骤,包括向酵母菌中加入1-10%的氢氧化钠溶液,分散,在70-100℃温度范围内反应30分钟到5小时,然后经离心就得到干燥的酵母菌细胞群,该过程可重复数次并合并,用强酸如盐酸或硫酸将细胞群的PH滴定到4.0-5.0范围内,重新分散在氢氧化钠溶液中,在75℃下进一步反应1小时,经离心分离氢氧化钠溶液和固体成份;最后,洗涤并纯化该固体成份以得到湿的β-葡聚糖;
(d)第四步,得到葡聚糖低聚物液态相的步骤,包括向上述所得物中加入数量等于葡聚糖体积(v/v%)1-10倍的蒸馏水和等于葡聚糖(v/w%)1/20到1/5量的β-葡聚糖水解酶,在30-80℃温度范围内反应6-24小时,淬灭反应后经离心回收上清液,用超滤膜过滤上清液以得到分子量小于50,000的具有发明性质的可溶性葡聚糖低聚物
(e)第五步,得到最终可溶性葡聚糖低聚物干燥粉末形式的步骤,包括将第四步所制备的低聚物在低于-70℃下单独放置12-48小时,然后经冷冻干燥以得到本发明的可溶性葡聚糖低聚物干燥粉末形式。
本发明的另一目的是提供制备上述可溶性葡聚糖低聚物的方法。
本发明的又一目的是提供采用上述方法制备的、源自酵母菌变异菌株IS2(KCTC 0959BP)的可溶性葡聚糖低聚物,另外,本发明的目的还包括提供可作为有效成份的、以有效剂量治疗或预防免疫缺陷疾病或癌症的药物组合物及其药学可接受载体,该药物组合物包括通过上述步骤获得的源自酵母菌变异菌株(KCTC 0959BP)细胞壁的可溶性葡聚糖低聚物。
本发明的组合物可用于加强或激活免疫系统。
上面提到的免疫缺陷疾病包括由各种细菌或病毒引起的传染疾病。
上面提到的癌症疾病包括各种疾病如肺癌、砷细胞(arsenic cellular)肺癌、结肠癌、骨癌、胰腺癌、皮肤癌、脑或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、胃癌、肛周癌、结肠癌、乳腺癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌(vulvul carcinoma)、何杰金淋巴瘤、食道癌、肠癌、内分泌腺癌、甲状腺癌、甲状旁腺癌、肾上腺癌、平滑组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞瘤、膀胱癌、肾癌、输尿管癌、肾细胞癌、肾骨盆癌、CNS肿瘤、原发性CNS淋巴瘤、脊髓瘤、脑干神经胶质瘤和垂体腺瘤。
本发明的另一方面还提供了药物结合物,该结合物可适当地加入或除去另一种免疫增强剂或癌症药物,也可在保持它们药效的限度内增加或减少药物的组合物比率。
本发明的目的之一为提供包括源自酵母菌变异菌株IS2(KCTC0959BP)的可溶性葡聚糖低聚物的药物组合物在制备治疗性药物方面的用途,该治疗性药物主要用于治疗或预防人体或哺乳动物的免疫缺陷和癌症疾病。
本发明的目的之一为提供治疗或预防哺乳动物免疫缺陷和癌症疾病的方法,包括将包含源自酵母菌变异菌株IS2(KCTC 0959BP)的可溶性葡聚糖低聚物的组合物及其药学可接受载体以有效剂量给药到所述哺乳动物这一步骤。
根据所使用的方法,该发明性组合物可另外包括常规的载体、辅料或稀释剂。根据用途和应用方法,所述载体优选地用作合适物质,但这并不是限制性的。合适的稀释剂列于《雷氏药学大全》(MackPublishing co,Easton PA)的书面文本中。
以下所述的配制方法和赋形剂仅仅是示例性的,而决不是对本发明的限制。
本发明的组合物可以药物组合物的形式给出,包括药学可接受载体、辅料或稀释剂,如乳糖、葡萄糖、蔗糖、山梨醇糖、甘露醇、木糖醇、赤藓醇、麦芽糖醇、淀粉、金合欢橡胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油。配制中可另外包括填料、抗粘合剂、润滑剂、润湿剂、调味剂、乳化剂和防腐剂等。通过采用本领域熟知的任何操作来配制本发明的组合物,使其在对病人给药后,有效成份能够快速、持续或延迟释放。
例如,本发明的组合物可溶解在油类、丙二醇或其它通常用来生产注射剂的溶剂中。合适的载体例子包括生理盐水、丙二醇、乙醇、植物油、肉豆蔻酸异丙酯等,但并不限于这些。对于局部给药,本发明的提取物可配制成软膏和乳膏的形式。
包括原料药组合物的药学配制剂可以制备成任何形式,如口服剂量形式(粉末、片剂、胶囊、软胶囊、水性药物、糖浆、酏丸剂、粉末、小药囊、粒剂)或局部制剂(乳膏、软膏、洗剂、凝胶、香膏、贴片、泥膏剂、喷雾溶液、气雾剂等等)、栓剂或无菌可注射制剂(溶液、悬浮剂、乳剂)。
以药学剂量形式存在的本发明组合物可以以它们药学可接受的盐的形式使用,也可单独或适当结合,及与其它药学活性成份组合使用。
该发明性组合物所需的剂量随被治疗者的身体状况和体重、严重程度、剂型、给药途径和给药期的变化而变化,可由本领域的技术人员选择。然而,为了获得所需效果,通常建议本发明的发明性组合物的给药量范围为0.01-10g/kg,优选0.1-1g/kg体重/天。这些剂量可以每天以一次或可多次给药形式给药。
本发明的组合物可以通过各种途径给药到接受治疗的动物如哺乳动物(大鼠、小鼠、家畜或人)上。所有的给药方式都考虑到了,例如,可以口服、直肠或者静脉的、肌内的、皮下的、皮内的、鞘内的、硬膜外的或脑室内注射给药。
本发明的另一个目的也是提供用于预防和改善免疫缺陷和癌症疾病的保健食品,该保健食品包括如下的组合物和饮食学可接受的添加剂,其中所述组合物不可缺少地包含源自酵母菌变异菌株IS2(KCTC0959BP)的可溶性葡聚糖低聚物。
以组合物的总重量记,用于预防和改善免疫缺陷和癌症疾病的保健食品应包含大约0.01-80w/w%,优选1-50w/w%的本发明上述源自酵母菌变异菌株IS2(KCTC 0959BP)的可溶性葡聚糖低聚物。
本发明提供了用于预防和改善免疫缺陷和癌症疾病的包括源自酵母菌变异菌株IS2(KCTC 0959BP)的可溶性葡聚糖低聚物的保健食品饮料组合物。
上述发明性低聚物组合物可加到食品和饮料中,用于预防和改善免疫缺陷和癌症疾病。
为了发展保健食品,包括上述低聚物组合物的可加入食品的例子如,各种食品、饮料、面包、饼干、果酱、糖果、口香糖、茶、乳酪、维生素络合物、康复食品及类似物,可以以粉末、颗粒、片剂、咀嚼片、胶囊或饮料等加以使用。
本发明的发明性组合物没有毒性和副作用,因此可安全使用。
上面提到的组合物可加到食品、添加剂或饮料中,其中上述低聚物在食品或饮料中的量,对于保健食品来说,以食品的总重量计,可大体上从约0.01到80w/w%;对于100ml健康饮料组合物来说,为0.02-30g,优选是0.3-5g。
在本发明的健康饮料组合物以所示比率包含作为必要成份的上述低聚物的前提下,对其它液态成份没有特别限制,其中,其它成份可以是各种芳香剂或天然糖类等,如常规饮料。前面提到的天然糖类的例子是单糖如葡萄糖、果糖等;二糖如麦芽糖、蔗糖等;常规糖类如糊精、环糊精;糖醇如木糖醇和赤藓醇等。除了前面提到的那些芳香剂,天然芳香剂如taumatin,甜菊提取物如levaudiosideA、甘草甜素等和合成芳香剂如糖精、阿巴斯甜等可优先适用。上述天然糖类的量通常是100ml本发明饮料组合物用约1g到20g,优选5到12g。
上面提到的组合物的其它组份是各种营养素、维生素、矿物质或电介质、合成调味剂、着色剂和在乳酪巧克力等中使用的改善剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶态粘合剂、PH控制剂、稳定剂、防腐剂、甘油、醇、在碳酸酯饮料中使用的碳化剂等。除了前面提到的那些,其它组份还可以是制备天然果汁所用的果汁、果汁饮料和蔬菜饮料。
该发明性组合物可作为混合剂用于乳酸菌配制的饮料或酱等等中。
上述提到的组份可单独使用,也可组合使用。
本发明提供的保健食品除了包括本发明组合物外,还包括约0.01到30w/w%的维生素、寡糖和可食用成份。
这些成份的比例不是严格的,但是通常范围为每100w/w%本发明组合物包含0.01到30w/w%。包括上述提取物的可加入食品的例子是各种食品、饮料、口香糖、维生素复合物、康复食品等。
该发明性组合物可另外包括一种或多种有机酸如柠檬酸、反丁烯二酸、脂肪酸、苹果酸、磷酸盐如磷酸盐,磷酸钠,磷酸钾、焦磷酸盐、缩聚磷酸盐;天然抗氧化剂如多元酚、儿茶酚、α-生育酚、迷迷香提取物、维生素C、干草根提取物、壳聚糖、鞣酸、植酸。
在不背离本发明思想和范围的条件下可以对本发明组合物、用途和制备做各种修改和变动,这一点对于本领域的技术人员来说是显而易见的。
附图说明
通过下面的详细说明并结合附图可更清楚地了解本发明的上述和其它目的、特征及优点。其中;
图1显示了腹腔注射后,可溶性葡聚糖低聚物对小鼠淋巴细胞NO生成的影响;
图2显示了腹腔注射后,可溶性葡聚糖低聚物对小鼠脾细胞IL-2生成的影响;
图3显示了可溶性葡聚糖低聚物对小鼠骨髓IL-3依赖的LyD9细胞系增殖的抑制效果;
图4显示了可溶性葡聚糖低聚物对Raw264.7细胞系、小鼠巨噬细胞系增殖的抑制效果;
图5显示了可溶性葡聚糖低聚物对EL4细胞系、小鼠T淋巴细胞系增殖的抑制效果;
图6显示了可溶性葡聚糖低聚物对Jurkat细胞系、人T淋巴细胞系增殖的抑制效果;
图7显示了可溶性葡聚糖低聚物对HeLa细胞系、人子宫颈癌细胞系增殖的抑制效果;
图8显示了可溶性葡聚糖低聚物对KAT03细胞系、人胃癌细胞系增殖的抑制效果;
下面,通过以下实施例对本发明进行更明确的解释。然而,从任何意义上来说,不应理解为本发明限于这些实施例。
最佳方式
下列实施例和实验实施例用于解释本发明,而没有限制其范围。
实施例1.酵母菌变异IS2的培养和采收
将含有10g/L葡萄糖、6g/L酵母菌提取物、3g/L硫酸铵((NH4)2SO4)、1.5g/L磷酸钾(K2PO4)、0.5g/L硫酸镁(MgSO4·7H2O)的液态介质作为原介质。
液态YPD介质(葡萄糖20g/L、酵母菌提取物10g/L、蛋白胨20g/L)用于接种和生长培养基,该生长培养基包含400g/L葡萄糖、30g/L酵母菌提取物、40g/L硫酸铵((NH4)2SO4)、15g/L磷酸钾(K2PO4)和5.7g/L硫酸镁(MgSO4·7H2O)。
生长培养基用高压灭菌后,将100ml培养的酵母菌变异菌株IS2(KCTC 0959BP)播种到其上,并在旋转速度300rpm、通气量1vvm、温度30℃、PH5.5条件下培养,最终通过分批次培养系统得到50-55g/L干燥细胞群(DCW)。
实施例2.从酵母菌变异IS2中提取β-葡聚糖
将上面实施例1中制备的80g酵母菌DCW悬浮在1,000ml 4%的氢氧化钠(NaOH)溶液中,然后在95℃下培养1小时。该培养的悬浮液在2,000rpm速度下离心15分钟以分离成氢氧化钠溶液部分和固体部分。
将分离得到的固体部分重新悬浮在2,000ml 3%的氢氧化钠(NaOH)溶液中,在75℃下培养3小时,然后在2,000rpm速度下离心15分钟再次分离成氢氧化钠溶液部分和固体部分。
将收集的固体部分用HCl调节到pH4.5并分散到最终体积为2,000ml的程度,然后在75℃下培养1小时。该培养的悬浮液在2,000rpm速度下离心15分钟以分离成氢氧化钠溶液部分和固体部分。
所得固体用蒸馏水洗涤三次,得到160g来自酵母菌变异细胞壁的湿β-葡聚糖。
实施例3.源自酵母菌变异IS2β-葡聚糖的可溶性葡聚糖低聚物的制备将实施例2制备的160g湿β-葡聚糖、480ml蒸馏水和等于葡聚糖1/10量的ββ-葡聚糖(v/w)加到1,000ml烧瓶中,在40℃下培养15小时。
停止反应后,反应混合物在7,000rpm下离心15分钟,收集上清液。用超滤膜(Filtron Co.,MWCO 10K)过滤收集的上清液以除去未反应的酶,就得到了含有分子量小于10,000道尔顿的葡聚糖低聚物的溶液。该溶液在-74℃下单独放置过夜后,经冷冻干燥得到5.8g粉末形式的可溶性葡聚糖低聚物。
实验实施例1.可溶性葡聚糖低聚物对NO(氧化氮)生成的影响
实施例3制备的可溶性葡聚糖低聚物溶解在浓度为5mg/ml磷酸盐缓冲的盐水中(PBS,2.56g/L NaH2PO4·H2O,22.5g/L Na2HPO4·7H2O,87.9g/L NaCl,PH7.2),将0.2ml所得可溶性葡聚糖低聚物溶液腹腔注射到5-6周大的雄性C57BL/6小鼠(Biolink CO.)体内。
作为本实验的对照组,源自野生型酵母菌(KCTC7911)菌株的可溶性葡聚糖低聚物根据上面实施例1和实施例3所描述的方法制备,并以与上述所描述的方法相同的方式给药。
给药3天后,使用灭菌筛和汉克斯(Hank’s)平衡盐溶液(0.185g/LCaCl2·2H2O,0.09767g/L无水MgSO4,0.4g/L KCl,0.06g/L无水磷酸钾单碱,0.8g/L氯化钠,0.04788g/L无水磷酸氢二钠,1.0g/LD-葡萄糖,0.011g/L苯酚红·钠,0.35g/L碳酸钠,PH7.0)将上述小鼠的淋巴细胞从其脾中轻柔地分离。剩余的RBC用NH4Cl处理除去,并将分离出来的淋巴细胞悬浮在完全培养基中。
根据文献公开的方法制备腹膜巨噬细胞(Gallily,R.,and M.Feldman.,Immunology12,p197-,1967)。
腹腔注射可溶性葡聚糖低聚物后用汉克斯平衡盐溶液收集巨噬细胞,然后将细胞悬浮在完全培养基中。
在培养皿中,以浓度2×105细胞/ml再悬浮2×105细胞/ml的巨噬细胞,并在培养基中、在测量NO(氧化氮)生成之前、在刀豆素A(ConA,5?g/ml)和LPS(1?g/ml)的刺激下培养20小时。
因为NO在空气中很容易被氧化为稳定的亚硝酸盐,所以亚硝酸盐的量可通过油脂反应测得。
将0.1ml包含30%乙酸中的1%磺胺和60%乙酸中的0.1%N-(1-萘基)乙二胺-二-氯化氢的混合物加到0.1ml培养基中,在室温下培养20分钟。通过ELISA读取仪检测到550nm处的吸收。
作为NO生成的测得结果,与用作阴性对照的PBS-处理组相比,注射了源自野生型酵母菌KCTC7911和源自酵母菌变异菌株IS2的可溶性葡聚糖低聚物的实验组表现了NO生成的更多增加。而且,确认了源自酵母菌变异菌株IS2的可溶性葡聚糖低聚物比源自KCTC7911菌株的可溶性葡聚糖低聚物具有更高的NO生成能力(见图1)。
图1显示了腹腔注射后,可溶性葡聚糖低聚物对小鼠淋巴细胞NO生成的影响。
实验实施例2.可溶性葡聚糖低聚物对IL-2生成的影响
使用灭菌筛从用实施例3制备的可溶性葡聚糖低聚物处理的小鼠脾中分离淋巴细胞。同时,用NH4Cl处理除去红细胞,并将分离的淋巴细胞悬浮在完全培养基中。
将收集的细胞调整到2×105细胞/ml并等分到96孔培养板上。脾细胞用ConA,(5?g/ml)处理并在37℃下、在5%CO2培养箱中培养48小时。培养结束后,通过酶免试剂盒(ELISA kit)(Endogen Co.)测定由Con-A刺激产生的IL-2释放量。
将抗-IL-2抗体(Becton Dikinson Co.)加到96孔培养板上吸附24小时,洗去未吸附的抗体。接着,将0.1ml的样品加到其上并培养1小时。然后,每一个孔用含10%吐温-20的PBS清洗并向其上加入检测Ab。再次清洗之后,处理细菌蛋白-HRP并在室温下培养1个小时。向其中加入TMB底物(Becton Dikinson Co.)并加入终止液以终止反应。测定450nm处的吸收。
在给药源自KCTC7911的可溶性葡聚糖低聚物的地方,IL-2生成没有变化,甚至当细胞受Con-A刺激时。
然而,在给药源自酵母菌变异IS2的可溶性葡聚糖低聚物和细胞受Con-A刺激的地方,显示了来自腹膜巨噬细胞IL-2的生成增加(见图2)。
图2显示了腹腔注射后,可溶性葡聚糖低聚物对小鼠脾细胞IL-2生成的影响
实验实施例3.可溶性葡聚糖低聚物对癌细胞增殖的抑制效果
对癌细胞系生长的抑制效果由MTT(3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑溴化物)细胞增殖分析测定。
作为本实验的细胞系,本实验用到6种类型的细胞系,即LyD9细胞系,该细胞系为小鼠骨髓IL-3依赖的造血干细胞系;Raw264.7细胞系,该细胞系为小鼠巨噬细胞系;EL4细胞系,该细胞系为小鼠T淋巴细胞系;Jurkat细胞系,该细胞系为人T淋巴细胞系;HeLa细胞系,该细胞系为人子宫颈癌细胞系和KAT03细胞系,该细胞系为人胃癌细胞系。
细胞用指定浓度的样品处理并培养44小时,向其中加入MTT溶液以鉴定细胞活力。
将癌细胞的浓度调整到2×105细胞/ml并转移到96孔板的每一个孔中。在早期的培养中,可溶性葡聚糖低聚物以浓度范围0.5-5mg/ml内的各种浓度加到培养基中,进一步在5%CO2培养箱中、在37℃下培养48小时。
用MTT分析测得细胞活力。
将MTT(Sigma Co.,USA)试剂加到每一个孔中,并进一步培养4个小时。向其中加入100ml 0.04N的异丙醇盐酸,该混合物在室温下培养20分钟,通过ELISA读取仪检测到550nm处的最终吸收。
如图3到8所示的,本发明的可溶性葡聚糖低聚物显示了强大的对癌细胞增殖抑制活性。特别地,源自酵母菌变异IS2的可溶性葡聚糖低聚物比源自KCTC7911的可溶性葡聚糖低聚物显示了更强大的活性,具体来说,在相同浓度下,与源自KCTC7911的可溶性葡聚糖低聚物相比,源自酵母菌变异IS2的可溶性葡聚糖低聚物显示的效力是前者的2-6.6倍。可以肯定的是,在大多数癌细胞系中,可溶性葡聚糖低聚物的有效浓度范围为2.5-5.0mg。
实验实施例4.毒性测试
方法
用实施例3的低聚物在ICR小鼠(平均体重25±5g)和斯普拉-道来氏大鼠(235±10g,Jung-Ang Lab Animal Inc.)上进行急性毒性实验。对包括10只小鼠或大鼠的4组分别口服给药测试样品4mg/kg、40mg/kg、400mg/kg、4,000mg/kg或溶剂(0.2ml,i.p.),观察两周。
结果
在任一组中或对任一种性别都没有对死亡率、临床表现、体重变化和总调查结果的治疗相关影响。这些结果说明本发明的提取物是有效和安全的。
下面将描述配制方法和赋形剂,但本发明并不限于这些。具有代表性的实施例如下所述。
粉末的制备
实施例3的干粉末...............................50mg
乳糖..........................................100mg
滑石..........................................10mg
通过混合上述成份及填充密封包装进行粉末制备。
片剂的制备
实施例3的干粉末...............................50mg
玉米淀粉......................................100mg
乳糖..........................................100mg
硬脂酸镁......................................2mg
通过混合上述成份及压片进行片剂的制备。
胶囊的制备
实施例3的干粉末...............................50mg
玉米淀粉......................................100mg
乳糖..........................................100mg
硬脂酸镁......................................2mg
通过混合上述成份及采用常规明胶制备方法填充明胶胶囊来制备片剂。
注射剂的制备
实施例3的干粉末...............................50mg
注射用蒸馏水..................................最优量
PH控制剂......................................最优量
通过溶解活性成份,控制PH到7.5,然后将所有成份填充到2ml安瓿瓶(ample)中,并用常规制备注射剂的方法灭菌进行注射剂的制备。
液体的制备
实施例3的干粉末...............................0.1-80g
糖........................................5-10g
柠檬酸....................................0.05-0.3%
焦糖......................................0.005-0.02%
维生素C...................................0.1-1%
蒸馏水....................................79-94%
CO2气.....................................0.5-0.82%
通过溶解活性成份,填充所有成份及采用常规液体制备方法灭菌进行液体的制备。
保健品的制备
实施例3的干粉末...........................1000mg
维生素混合物..............................最优量
?维生素A乙酸酯...........................70mg
?维生素E.................................1.0mg
?维生素B1................................0.13mg
?维生素B2................................0.15mg
?维生素B6................................0.5mg
?维生素B12...............................0.2mg
?维生素C.................................10mg
?生物素..................................10mg
?烟酰胺..................................1.7mg
?叶酸....................................50mg
?泛酸钙..................................0.5mg
矿物混合物................................最优量
?硫酸亚铁................................1.75mg
?氧化锌..................................0.82mg
?碳酸镁..................................25.3mg
?磷酸单钾................................15mg
磷酸二钙..................................55mg
柠檬酸钾..................................90mg
碳酸钙....................................100mg
氯化镁................................24.8mg
上面提到的维生素和矿物混合物可以在很多方面进行变化。但是不能认为这些变化背离了本发明的思想和范围。
健康饮料的制备
实施例3的干粉末.......................1000mg
柠檬酸................................1000mg
低聚糖................................100g
杏浓缩物..............................2g
牛磺酸................................1g
蒸馏水................................900ml
通过溶解活性成份,混合,在85℃搅拌1小时,过滤,将所有成份填充到1000ml安瓿瓶中及采用常规健康饮料的制备方法灭菌进行健康饮料的制备。
上述就是对本发明的描述,显而易见地,可以在很多方面对它们进行变化,但是不能认为这些变化背离了本发明的思想和范围。而且,是要将那些对于本领域技术人员来说显而易见的变化包括在下述权利要求的范围之内的。
工业实用性
如本发明详细说明中描述的,本发明涉及M.W.范围为1,000到10,000的可溶性葡聚糖低聚物,该低聚物通过用商业可得的β-葡聚糖水解酶处理由分离酵母变异IS2细胞壁得到的不溶性β-葡聚糖来制备。该可溶性葡聚糖低聚物在促进免疫活性和抑制癌细胞生长方面显示强大效力,可用作治疗或保健食品来治疗和预防免疫缺陷和癌症疾病。
Claims (8)
1.源自酵母菌变异菌株(KCTC 0959BP)细胞壁的通过用水解酶处理不溶性β-葡聚糖得到的可溶性葡聚糖低聚物,其具有免疫促进活性和癌细胞增殖抑制活性。
2.制备可溶性葡聚糖低聚物的方法,该方法包括以下步骤:(a)在培养基中培养酵母菌(酿酒酵母)变异IS2(KCTC 0959BP)以用于接种;(b)将上述酵母菌培养溶液接种到培养基中,分批进料培养并离心得到酵母菌;(c)向其中加入NaOH以从酵母菌细胞壁中提取β-葡聚糖;(d)将提取的β-葡聚糖与水解酶反应,然后经过滤得到可溶性葡聚糖低聚物;和(e)最后冷冻干燥以得到分子量小于50,000的可溶性葡聚糖低聚物。
3.一种药物组合物,该药物组合物包括根据权利要求2所述的制备方法得到的源自酵母菌变异菌株(KCTC 0959BP)细胞壁的可溶性葡聚糖低聚物,该组合物作为活性成份用来治疗或预防免疫缺陷疾病。
4.一种药物组合物,该药物组合物包括根据权利要求2制备方法得到的源自酵母菌变异菌株(KCTC 0959BP)细胞壁的可溶性葡聚糖低聚物,该组合物作为活性成份用来治疗或预防癌症疾病。
5.根据权利要求4的药物组合物,其中,所述癌症选自肺癌、砷细胞肺癌、结肠癌、骨癌、胰腺癌、皮肤癌、脑或颈癌、皮肤或内眼黑素瘤、子宫癌、卵巢癌、直肠癌、胃癌、肛周癌、结肠癌、乳腺癌、子宫内膜癌、子宫颈癌、阴道癌、外阴癌、何杰金淋巴瘤、食道癌、肠癌、内分泌腺癌、甲状腺癌、甲状旁腺癌、肾上腺癌、平滑组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞瘤、膀胱癌、肾癌、输尿管癌、肾细胞癌、肾骨盆癌、CNS肿瘤、原发性CNS淋巴瘤、脊髓瘤、脑干神经胶质瘤或垂体腺瘤。
6.包括源于酵母菌变异菌株IS2(KCTC 0959BP)的可溶性葡聚糖低聚物的药物组合物在制备用于治疗或预防人体或哺乳动物的免疫缺陷和癌症疾病的治疗性药物方面的用途。
7.包含如权利要求1所述的源自酵母菌变异菌株IS2(KCTC 0959BP)的可溶性葡聚糖低聚物和饮食学可接受的添加剂的保健食品,所述保健食品用于治疗或预防免疫缺陷和癌症疾病。
8.根据权利要求7的保健食品,其中,所述保健食品可以以粉末、颗粒、片剂、咀嚼片、胶囊或饮料形式提供。
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CN101463373B (zh) * | 2009-01-04 | 2011-08-10 | 广东省食品工业研究所 | 一种高纯度酵母免疫活性β-1,3-葡聚糖的制备方法 |
CN111321183A (zh) * | 2018-12-14 | 2020-06-23 | 大汉酵素生物科技股份有限公司 | 具抗癌抗病毒抗发炎、促进成骨细胞增生促进肠道干细胞增生的多糖发酵组合物及制备方法 |
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KR100734898B1 (ko) | 2005-10-28 | 2007-07-03 | 주식회사 글루칸 | 베타-글루칸을 유효성분으로 포함하는 신장질환 치료용 약학적 조성물 |
KR100797152B1 (ko) * | 2006-11-24 | 2008-01-23 | 고려대학교 산학협력단 | β-글루칸을 다량 함유하는 개량된 사카로마이세스세레비지애 JUL3 균주의 대량 생산 방법 |
LT6145B (lt) | 2014-04-14 | 2015-04-27 | Uab "Biocentras" | TERAPINĖ ß-GLIUKANŲ KOMPOZICIJA, MODULIUOJANTI ŽMOGAUS IMUNINĘ SISTEMĄ IR INICIJUOJANTI VĖŽINIŲ LĄSTELIŲ ARDYMĄ |
WO2021006684A1 (ko) * | 2019-07-10 | 2021-01-14 | 한국식품연구원 | 피부암 억제 활성이 우수한 효모 초음파 추출물의 제조방법 및 상기 방법으로 제조된 효모 초음파 추출물을 함유한 피부암 억제용 조성물 |
WO2021256470A1 (en) * | 2020-06-16 | 2021-12-23 | Sophy Inc. | Beta-glucan for immuno-enhancement and/or immuno-balancing, and for adjuvant use |
CN115501246B (zh) * | 2022-10-31 | 2023-08-08 | 湖南天根乐微君科技有限公司 | 一种能有效修复、淡化、祛除疤痕的组合物及其制备方法与应用 |
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US5622939A (en) * | 1992-08-21 | 1997-04-22 | Alpha-Beta Technology, Inc. | Glucan preparation |
JPH0833496A (ja) * | 1994-07-25 | 1996-02-06 | K I Kasei Kk | オリゴ糖の製造法 |
KR0156986B1 (ko) * | 1995-02-20 | 1998-10-15 | 이신영 | 영지 버섯의 액체 배양에 의한 다당류의 생산 방법 |
US6143883A (en) * | 1998-12-31 | 2000-11-07 | Marlyn Nutraceuticals, Inc. | Water-soluble low molecular weight beta-glucans for modulating immunological responses in mammalian system |
JP2001035470A (ja) * | 1999-07-26 | 2001-02-09 | Nippon Muki Co Ltd | 蓄電池用セパレータ |
KR100390546B1 (ko) * | 2001-02-19 | 2003-07-07 | 주식회사 엔바이오테크놀러지 | 면역활성 촉진기능이 향상된 사카로마이세스 세레비지애균주 및 그 제조방법 |
WO2003039568A1 (fr) * | 2001-11-06 | 2003-05-15 | Orient Cancer Therary Co.,Ltd. | Compositions anticancereuses |
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Cited By (2)
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CN101463373B (zh) * | 2009-01-04 | 2011-08-10 | 广东省食品工业研究所 | 一种高纯度酵母免疫活性β-1,3-葡聚糖的制备方法 |
CN111321183A (zh) * | 2018-12-14 | 2020-06-23 | 大汉酵素生物科技股份有限公司 | 具抗癌抗病毒抗发炎、促进成骨细胞增生促进肠道干细胞增生的多糖发酵组合物及制备方法 |
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