CN1371385A - 免疫强化组合物 - Google Patents
免疫强化组合物 Download PDFInfo
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- CN1371385A CN1371385A CN00812124A CN00812124A CN1371385A CN 1371385 A CN1371385 A CN 1371385A CN 00812124 A CN00812124 A CN 00812124A CN 00812124 A CN00812124 A CN 00812124A CN 1371385 A CN1371385 A CN 1371385A
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- oligomeric lactulose
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Abstract
本发明提供了一种免疫强化组合物和促进产生干扰素-γ的组合物,两者皆包含低聚乳果糖作为活性成分。尤其本发明以食品形式提供了该组合物。口服或摄取所述组合物增强了消化道中的生物防御机构(免疫学功能),从而对消化道感染和类似疾病达到显著的治疗和预防作用。
Description
技术领域
本发明涉及免疫强化组合物以及促进产生干扰素γ的组合物。
背景技术
介于身体和外界间的皮肤和黏膜界面,尤其是消化道的肠膜和其他黏膜与许多外源体接触,包括病毒、细菌、寄生虫、疾病抗原和食物抗原。因此,皮肤和黏膜具有免疫***,将这些外源体拒之门外以保护身体。充当阻止外源体的一个免疫物质是免疫球蛋白A(IgA)。IgA在中和细菌或病毒毒性、控制细菌与组织的粘着以及抑制食物抗原引发的过敏方面都发挥了重要作用。IgA生产涉及淋巴集结的淋巴细胞和肠淋巴组织。
当消化道黏膜生物保护***的免疫功能低下时,外源微生物就会移居到消化道中并繁殖,从而引起消化道感染和细菌性痢疾等,还导致一些如发烧、呕吐、腹泻和腹痛症状。例如,免疫功能低下也可由过度劳累或压力造成的厌食引起。
年幼孩子、老年人和体弱多病的人特别容易受到外病原体的攻击,这是因为他们的免疫力差。因此,充当加速产生IgA并维持在高水平的物质将对这些个体和前面提及的消化道感染患者有益,尤其是当服用形式为饮料或其他食品时候。
然而,当今还没有有效的预防或治疗药物在内脏免疫功能低下和消化道感染的情况下能起到促进产生IgA的作用。细菌性痢疾疾病的治疗如今限制于针对脱水的流体输液和施用抗生素。
发明公开
因此,本发明的目的是提供一种新型消化道免疫强化组合物,用于预防和/或治疗这些消化道感染等,特别是这种组合物以饮料或其他食品形式存在。
为达到该目的,本发明人经过广泛研究,发现低聚乳果糖在人体中展示了理想的免疫强化作用,而且施用低聚乳果糖能治疗和预防消化道感染等,并在此新发现基础上完成了该发明。
本发明提供了一种免疫强化组合物,包括低聚乳果糖和载体。
本发明人还新发现施用这种组合物促进产生干扰素-γ(IFN-γ)。
因此,本发明提供了促进产生IFN-γ的组合物,包括低聚乳果糖和载体。
本发明的组合物必须含有低聚乳果糖(下文称为“LS”)作为活性成分。如本发明所用,术语“低聚乳果糖”表示众所周知的下列化学式的物质,具有化学名称O-β-D-吡喃半乳糖基-(1→4)-O-α-D-吡喃葡萄糖基-(1←2)-β-D-呋喃果糖苷。
LS能由多种方法生产。这些方法包括例如如日本审查专利公开S57-58905中所描述的方法,将衍生自气杆菌的果聚糖蔗糖酶应用到含有蔗糖和乳糖的溶液中;如日本未审查专利公开S64-85090中所描述的方法,将掷孢酵母属的真菌例如独特掷孢酵母(Sporobolomycessingularis)或其抽提物应用到含有蔗糖和乳糖的溶液中;或如日本未审查专利公开H2-35095所描述的方法,将拉恩杆菌属的真菌如Rahnella aquatilis,或其抽提物应用到含有蔗糖和乳糖的溶液中。
反应混合物主要包含由前述方法获得的LS或由此法制备的纯化的LS,可用在本发明的组合物中。
LS也已知是个至关重要的营养素(糖原),其对肠中双歧杆菌的选择性生长是必须的。
本发明组合物中的LS比例正常选自从约0.5到约70g/100g或优选从约5到约30g/100g的范围。
只要组合物能通过口腔施用或被摄取,对免疫强化组合物或促进产生IFN-γ的组合物的形式,本发明没有特别的限制。组合物能以多种形式提供,包括块、液体、糖浆或粉末。能采用的更具体的形式例子包括食品如液体或粉末甜味剂,饮料如软饮料、牛奶饮料和碳酸饮料,和点心如面包、饼干和糖果以及健康食品、药剂如散装(bulk)粉末、粉末、液体、悬浮液、片剂和发泡制品等。
这些形式中,饮料和发泡制品尤其合乎要求。
上述本发明组合物的形式能通过制定活性组份LS和适用于多种形式的食品载体或可药用载体的配方而产生。食品载体包括例如可食用性添加剂,如填充剂、甜味剂、其他碳水化合物、维生素、香料和色素。
更具体地,如果例如本发明的组合物是以食品形式,考虑到LS每日给与量(有效量)为约1到约30g,组合物从LS和合适的食品载体中制备以使得有效量能被容易地摄取。食品形式的一个典型例是饮料,其能制备成水溶液形式,含有0.5-70g/100ml或优选5-30g/100ml的活性成分。此种饮料的pH使用pH调节剂或缓冲液等能调节至约4.0到约6.5或优选地至约4.5到约6.0。
此种pH调节剂或缓冲液的典型例子包括弱酸如柠檬酸、酒石酸、苹果酸、乳酸、碳酸和其盐如柠檬酸钠、柠檬酸铵、酒石酸钠、苹果酸钠、乳酸钠、乳酸钙、碳酸钠和碳酸氢钠。碳酸氢钠也能用作pH调节剂或缓冲液。这些酸或其盐能单个使用或以两个或多个结合使用。其制订的配方量选自有益于上述产品饮料pH范围的范围,但一般不可以大于组合物重量的约2%或优选约0.05到约0.3%。
当组合物以此种饮料或其他食品形式存在时,各种碳水化合物、甜味剂和其他添加剂也能加入到本发明的组合物中,就象是将他们加入到普通饮料等中一样。碳水化合物的例子包括葡萄糖、果糖和其他单糖;麦芽糖、蔗糖和其他双糖;糊精、环糊精和其他多糖(LS除外);木糖醇、赤藓糖醇、山梨糖醇和其他糖醇;和糖酯等。甜味剂的例子包括天然甜味剂(新蛇菊苷A和其他蛇菊抽提物,sormatin和甘草皂苷等)和合成甜味剂(糖精和阿氏巴甜等)。这些碳水化合物和甜味剂制定的配方量一般不超过所得饮料重量的约15%或优选约13%。
当配制作为食品的本发明组合物时,一种、二种或多种例如下列添加剂,如必要,也可加入。该添加剂包括例如葡萄柚、苹果、橘子、柠檬、菠萝、香蕉、梨和其他水果果汁(浓缩果汁或果汁粉末等);维生素和维生素原(视黄醇棕榈酸酯、双苯酰硫胺、核黄素、盐酸吡哆醇、氰钴胺素、抗坏血酸钠、尼克酰胺、泛酸钙、叶酸、生物素、胆钙化甾醇、二酒石酸钙、生育酚、β-胡萝卜素以及水溶性和脂溶性维生素);香料(柠檬香料、橘子香料、葡萄柚香料和香草香精等);氨基酸、核酸和其盐(谷氨酸、谷氨酸钠、甘氨酸、丙氨酸、天冬氨酸、天冬酰胺钠和肌苷酸等);食用性纤维(聚葡萄糖、果胶、黄原胶、***胶和藻酸等);以及矿物质和微量元素(氯化钠、醋酸钠、硫酸镁、氯化钾、氯化镁、碳酸镁、氯化钙、磷酸氢二钾、磷酸二氢钠、甘油磷酸钙、柠檬酸铁钠、柠檬酸铁铵、柠檬酸铁、硫酸镁、硫酸铜、碘化钠、山梨酸钾、锌、镁、铜、碘和钴等)。
本发明组合物的制备采用混合前述成分的方法。对制备方法没有特别限制,如需要可将所有成分一步混合,或当同时使用油性和水性成分时,首先将油性成分溶解在适当的油性媒介上,然后在乳化剂帮助下用水性成分的水溶液乳化。此乳化方法可采用常规方法使用普通乳化分散设备进行,如在直接通道(pass-through)***或循环***中采用均质混合机或高压匀浆器等。各成分通常在室温下混合或乳化,但也可使用加热方法。然后将所得的本发明组份包装在一个适当的容器中,并采用常规方法灭菌如巴氏杀菌和无菌过滤等,从而生产出产品。
本发明的组合物还能加工成能溶解或分散在水中的发泡产品,如片剂、颗粒、粉末或胶囊等。这种发泡产品的制备以碳酸氢钠和/或碳酸钠作为发泡剂并使用中和剂。可能的中和剂包括例如柠檬酸、酒石酸、富马酸、抗坏血酸、乳酸和苹果酸等。发泡剂和中和剂在总成分中的比例优选选自发泡剂重量为8-60%和中和剂重量为10-70%。这些发泡产品的制备能根据常规方法如直接粉末压缩或干燥或潮湿颗粒压缩,可任选地加入合适量的碳酸钾。
对消化的或施用的本发明组合物剂量没有特别限制,剂量明智的确定是依据目的用途或使用者年龄、性别、体重或疾病的严重性以及其他因素。当本发明组合物为固体形状时,一般一次每剂量约1到约30g的活性成分被摄取,优选地经过30-200ml水中溶解。当本发明的组合物为饮料或其他液体形式时,每次服用约30到约200ml。本发明组合物每天摄取或施用量优选的为这样,其中包含约0.5到约70g或优选的约1到约30g或更优选的约3到约20g的活性成分被摄取或被施用。摄取或施用量通过一天多次吸取前述的固体或饮料形式能够获得。发明效果
在从口施用或摄取后,本发明的组合物能产生免疫强化或IFN-γ产生促进作用,增强消化道的生物防卫机构(免疫功能),因而有效预防和治疗了消化道感染等。
附图简述
附图1表示测试例2中对摄取了本发明组合物的被试者粒细胞部分的吞噬率(%)。
附图2表示测试例3中由给予了本发明组合物的实验大鼠淋巴集结淋巴细胞产生IFN-γ(pg/ml)的结果。
实施本发明的最佳方式
为进一步详细描述本发明,下列给出了制备本发明组合物的实施例,接着是本发明组合物及其有效成分LS的测试例。注意实施例中所用的“部分”和“%”全部基于重量。
实施例1-6
按照表1中所显示的配方将多种原料化合物混合并溶解在水中,从而提供本发明的组合物。香料和/维生素也能包括在实施例中的组合物中。每个制剂用水配至总体积1000ml。
表1
实施例7
实施例号 | 1 | 2 | 3 | 4 | 5 | 6 | |
阳离子(mEq/l) | Na+K+Ca2+Mg2+总阳离子 | 21510.527.5 | 15510.521.5 | 21510.527.5 | 15520.522.5 | 8410.513.5 | 27510.533.5 |
阴离子(mEq/l) | Cl-柠檬酸根离子(3-)乳酸根离子(-)酒石酸根离子(2-)苹果酸根离子(2-)总阴离子 | 16.51010027.5 | 10.51010021.5 | 16.5811127.5 | 10.51020022.5 | 6.5411113.5 | 17.51112233.5 |
新蛇菊苷A(mg/l) | 80 | 75 | 83 | 73 | 70 | 85 | |
糖类 果 糖(g/l)葡萄糖(g/l) | 202 | 181 | 172 | 163 | 152 | 221 | |
低聚乳果糖(g/l) | 100 | 50 | 10 | 60 | 30 | 200 |
将下列成分(总5g)混合并直接压缩成片剂,或将成分以粉末称重、混合和分开,或将成分以颗粒称重、混合、颗粒化、干燥和分开,以将本发明的组合物制成制剂形式。
LS55P 34%
(相当于LS 18.7%)
L-抗坏血酸 21%
L-酒石酸 20%
甜味剂 适量
碳酸氢钠 21%
氯化钠 适量
碳酸钾 0.5%
香料、色素 微量
总 100%
上述“LS55P”是含有55%LS的粉末。实施例8-10
本发明组合物的片剂、粉末或颗粒状制剂含有下列成分,如上述
实施例7制备。(实施例8配方)
LS55P 40%
(相当于LS 22%)
L-抗坏血酸 10%
L-酒石酸 23%
甜味剂 适量
碳酸氢钠 22%
柠檬酸钠 适量
碳酸钾 0.4%
香料、色素 微量
总 100%(总5g)(实施例9配方)
LS55P 40%
(相当于LS 22%)
L-抗坏血酸 11%
L-酒石酸 23%
甜味剂 适量
碳酸氢钠 22%
柠檬酸铵 0.8%
氰钴胺素 微量
柠檬酸钠 微量
碳酸钾 0.4%
香料、色素 微量
总 100%(总4.6g)(实施例10配方)
LS55P 40%
(相当于LS 22%)
L-酒石酸 29%
甜味剂 适量
碳酸氢钠 24%
柠檬酸铁铵 3.6%
氰钴胺素 微量
碳酸钾 0.5%
香料、色素 微量
总 100%(总4g)
实施例11-18
依据下列表2中所显示配方的本发明组合物的发泡片剂形式的制备如实施例7-10中的同样方式进行。
表2
实施例19-25
成分 | 实施例号 | |||||||
11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | |
LS55P(%)(相当于LS) | 40(22) | 30(16.5) | 40(22) | 60(33) | 50(27.5) | 35(19.3) | 45(24.8) | 35(19.3) |
L-抗坏血酸 | 11 | 16 | 10 | 8 | 10 | 10 | 10 | 13 |
L-酒石酸 | 23 | 23 | 23 | 13 | 19 | 20 | 20 | 25 |
甜味剂 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 |
碳酸氢钠 | 22 | 22 | 23 | 15 | 15 | 20 | 20 | 23 |
柠檬酸铁铵 | 0.8 | 0.8 | 1.0 | 0.8 | 0.8 | - | - | 0.7 |
柠檬酸亚铁钠 | - | - | - | - | - | 1.2 | - | - |
柠檬酸铁 | - | - | - | - | - | - | 0.8 | - |
柠檬酸钠 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 |
总重量(g) | 4.6 | 4.6 | 4.7 | 4.6 | 4.6 | 4.7 | 4.7 | 5.4 |
将下列表3中所显示的各成分(mg)混合并直接压缩以提供可咀嚼的片剂。
表3
成分 | 实施例号 | ||||||
19 | 20 | 21 | 22 | 23 | 24 | 25 | |
LS75P(mg)(相当于LSmg) | - | - | - | 700(525) | 3330(2498) | 600(450) | 350(263) |
LS55P(mg)(相当于LSmg) | 1800(990) | 3600(1980) | 4620(2541) | - | - | - | - |
糖酯(mg) | 40 | 80 | 841 | 20 | 80 | 15 | 7 |
聚葡萄糖(mg) | 150 | 400 | 300 | 100 | 300 | 60 | 60 |
蔗糖(mg) | 100 | 200 | 200 | 20 | 200 | 80 | 20 |
维生素C(mg) | 150 | 320 | 200 | 20 | 200 | - | - |
橘子汁粉末(mg) | 80 | 150 | - | - | 100 | 20 | 5 |
柠檬汁粉末(mg) | - | - | 84 | 40 | - | 10 | 5 |
酒石酸(mg) | - | - | - | - | 460 | 95 | 50 |
NaHCO3(mg) | - | - | - | - | 500 | 100 | 50 |
K2CO3(mg) | 30 | 40 | 40 | 40 | 30 | 8 | 8 |
香料和甜味剂 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 |
总重量(mg) | 2400 | 4950 | 5580 | 1000 | 5200 | 1000 | 5000 |
上述“LS75P”是含有75%LS的粉末。
实施例26-34
将下列表4中所显示的成分混合并用水配至100 ml以提供本发明组合物的健康饮料形式。
表4
成分(100ml中) | 实施例号 | ||||||||
26 | 27 | 28 | 29 | 30 | 31 | 32 | 33 | 34 | |
β-胡萝卜素(mg) | 3 | 5 | 10 | 15 | 1 | 2 | 30 | 5 | 3 |
聚葡萄糖(g) | 5 | 3 | 5 | 7 | 4 | 2 | 10 | 20 | 20 |
乳化剂(mg) | 6 | 10 | 20 | 30 | 5 | 6 | 20 | 15 | 8 |
油(mg) | 100 | 90 | 80 | 120 | 50 | 50 | 200 | 70 | 60 |
果糖(g) | - | 15 | 10 | - | 15 | 15 | 15 | 5 | 10 |
柠檬酸(mg) | 200 | 400 | 100 | 300 | 50 | 20 | - | - | - |
酒石酸(mg) | - | - | 50 | - | 50 | 10 | 100 | 200 | - |
乳酸(mg) | - | - | - | - | 50 | 10 | 100 | - | 200 |
抗坏血酸(mg) | 300 | 200 | 100 | 50 | 30 | 150 | 200 | 1000 | 50 |
生育酚(mg) | 10 | 5 | 10 | 20 | 20 | 0.5 | 20 | 10 | 5 |
LS55P(g)(相当于LSmg) | 2(1.1) | 5(2.75) | 10(5.5) | 3(1.65) | 8(4.4) | 7(3.85) | 5(2.75) | 12(6.6) | 10(5.5) |
香料和甜味剂 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 |
丙二醇脂肪酸酯用作乳化剂,红花油用作表面活性剂。
实施例35-45
将下列表5中所显示的成分混合并用水配至100ml以提供本发明组合物的饮料形式。
表中气体体积值表示二氧化碳含量,用1代表溶解的二氧化碳体积等于溶液体积,值越高则二氧化碳含量越高。
表5
测试实施例1
成分(100ml中) | 实施例号 | ||||||||||
35 | 36 | 37 | 38 | 39 | 40 | 41 | 42 | 43 | 44 | 45 | |
低聚乳果糖(g) | 3 | 12 | 9 | 1 | 8 | 2 | 4 | 10 | 15 | 7 | 13 |
异构化糖(g) | 8 | - | - | 7 | 7 | 8 | 5 | - | - | 9 | - |
纯化蔗糖(g) | - | 1 | 8 | 3 | 7 | 5 | 3 | - | - | - | - |
果糖(g) | 2 | 6 | - | 1 | - | - | 3 | - | - | - | 60 |
葡萄糖(g) | 2 | 2 | - | - | 2 | - | 3 | - | - | 2 | 4 |
柠檬酸(mg) | 3 | 2 | - | - | 8 | - | - | 2 | 5 | - | - |
酒石酸(mg) | - | 2 | - | 2 | - | - | - | - | - | 10 | - |
苹果酸(mg) | 4 | - | 8 | - | 5 | - | 4.5 | - | - | - | - |
乳酸(mg) | 8 | - | - | 2 | - | 20 | - | - | - | 10 | - |
柠檬酸钠(mg) | 20 | 30 | 10 | - | 80 | - | - | 100 | 55 | 70 | - |
酒石酸钠(mg) | 60 | - | - | 60 | 25 | 70 | - | - | - | 30 | 20 |
苹果酸钠(mg) | - | 80 | 150 | - | - | 100 | 45 | - | 10 | - | 50 |
乳酸钙(mg) | - | - | - | - | 15 | 10 | - | - | - | - | 5 |
氯化钠(mg) | - | - | 4 | - | 1 | 1.5 | - | - | 2 | - | - |
氯化钾(mg) | - | 3 | - | 2 | - | - | 5 | - | 1 | 1 | - |
氯化镁(mg) | 2 | - | 1 | - | - | - | - | - | 1 | - | - |
果汁(%) | 3 | - | 1 | 0.5 | 0.1 | - | - | - | - | 2 | 0.3 |
香料和甜味剂 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 | 适量 |
气体体积 | - | - | - | - | - | 3.0 | 2.0 | 2.5 | 2.3 | 3.3 | 1.5 |
pH | 5.0 | 6.3 | 5.8 | 4.9 | 5.8 | 5.3 | 5.5 | 5.6 | 6.4 | 5.6 | 5.9 |
如下操作,本实验采用安慰剂饮料作空白对照,依据双盲对比方法,测试了肠内菌群的作用和以饮料形式摄取本发明组合物的免疫功能。
1.被试者:28名成人男性
2.测试设计:采用安慰剂饮料作空白对照,双盲对比测试
3.组构成:
发明组:摄取本发明饮料组(n=14)
对照组:摄取安慰剂饮料组(n=14)
4.测试物质:
本发明饮料:
溶液制备是将5g的低聚乳果糖(LS)溶解在50ml水(1)中。
安慰剂饮料:
用蔗糖代替本发明饮料中的LS以相同方式制备。
5.剂量:每天一次(共50ml),临睡前服用,连续服用6周。
6.测定:肠内菌群和粪便中IgA浓度。
7.粪便采集方法:
摄取测试物质前和摄取6周后采集新鲜粪便。采集当日,将觉醒后***的粪便采集到可密封的聚乙烯袋中,并将口袋极其小心地密封使得口袋内无空气保留,最后存放在聚丙烯粪便收集器内的冰上。将采集的粪便称重并混合均匀,测定肠内菌群和IgA量。
8.肠内菌群的测定:
肠内菌群的研究依据光冈等的方法进行(光岡知足、腸内常在菌叢、臨床検查、23(4):320-334(1979)),作为制备培养基使用3种非选择性的培养基(BL琼脂、EG琼脂和胰胨(tryprycase)大豆血琼脂)和11种选择性的培养基(BS琼脂、NBGT琼脂、ES琼脂、修饰VS琼脂、新霉素纳格勒氏琼脂、修饰LBS琼脂、DHL琼脂、TATAC琼脂、PEES琼脂、土豆葡萄糖琼脂和GE琼脂)。这些培养基的组成记载在“腸内常在細菌叢、光岡知足、臨床検查、23(4):320-334(1979)”。
首先将1.0g左右的新鲜粪便精确称重并悬浮在9ml的厌氧稀释剂中(制备方法如前述参考中所描述),然后在二氧化碳气体下用稀释剂连续10倍稀释制备101-108的稀释液。将这样制得的106、107和108稀释液涂抹在BL和EG琼脂培养基上,将105、106和107的稀释液涂抹在胰胨大豆血琼脂培养基上,以及将101、103、105和107稀释液涂抹在其他选择性的培养基中,每个涂抹量为0.05ml。继而将BL、EG、BS、NBGT、ES、修饰VS、新霉素纳格勒氏和修饰LBS琼脂在替换二氧化碳气体后,使用钢丝绒方法放于厌氧瓶中,37℃厌氧培养48小时。胰胨大豆血琼脂和DHL琼脂以相似方式37℃培养24小时,而TATAC、PEES、土豆葡萄糖和GE琼脂则培养48小时。
培养后,每个培养基上的菌落计数,并依据菌落性质、革兰氏染色、孢子产生、需氧生长和显微镜下的形态学观察来鉴定菌落的水平。结果相对地表达为每1g粪便中细菌数的对数(log10CFU/g湿重粪便)。
9.粪便IgA浓度的测定:
(1)制备粪便IgA测定样品
将储存在-80℃的粪便样品冷干,并将2.0ml 0.1M的碳酸缓冲液(pH9.6)加入到0.2g的干燥粪便中震荡,然后1500转/分离心10分钟,并将上清液调至pH7.5用作IgA测定样品。
(2)粪便IgA测定样品中IgA浓度的测定
IgA浓度依据Tsuyuki等的方法采用ELISA测定(露木重雄、山崎省二、上村裕、木村昌伸、川島拓司、上田雄幹、マウス胆汁および小腸内容物中のIgA抗体および総IgAの酵素抗体法(ELISA)による測定、ビフイズス、2:9-13(1988))。
IgA抗体按下列方法测定。即:所用抗原是未标记的小鼠衍生的抗人IgA(25μg/ml,200μl),其被注入到孔中4℃过夜。用相同量的缓冲液代替抗原注入的孔作为对照。
次日,从孔中吸出溶液,将1%BSA溶液(0.1M碳酸缓冲液,200μl)作为隔离物加入,并于37℃反应60分钟。接着,将粪便IgA测定样品(40μl)加到抗原处理的孔和对照孔中,并于37℃反应45分钟。本反应后,加入过氧化物酶标记的小鼠衍生的抗人IgA(稀释1000倍,40μl),37℃反应45分钟。然后加入Sigma Fast ODP(Sigma Co.,200μl)生色反应15分钟,用3M HCl(50ml)终止反应,测定吸光度(490nm)。
样品中的IgA浓度以如下方式获得:从sIgA样品中(纯化的人分泌型IgA 5mg;Capple Co.)制作工作曲线,再将依据工作曲线所计算的样品IgA浓度转换成每1g干粪便的浓度。
10.统计学分析:
每组的平均值和标准偏差从摄取测试物质前和摄取6周后的值中计算得出。由重复的离散分析进行组间比较,有5%或更少的显著性水平。测试结果如在下列表6中显示。
表6
粪便IgA浓度(mg/g干重) | 肠内细菌数(log10CFU/g湿粪便) | 肠内细菌占有率(%) | |
本发明饮料摄取组n平均值±标准偏差(SD)摄取前摄取6周后 | 143.9±3.26.9±5.4 | 139.5±0.710.1±0.7 | 1319.6±15.232.1±15.2 |
安慰剂饮料摄取组n平均值±标准偏差(SD)摄取前摄取6周后 | 145.6±7.04.4±3.1 | 129.8±0.69.8±0.6 | 1223.5±12.618.8±9.2 |
从表6中所显示的结果中可明显得出下列结论:
1.在本发明饮料摄取组中,摄取本发明饮料导致了双歧杆菌数的增加(9.5±0.7→10.1±0.7log10CFU/g湿粪便,配对的T-检验;p=0.013)。相反,在安慰剂饮料摄取组中没有变化(9.8±0.6→9.8±0.6log10CFU/g湿粪便)。因此,组别间双歧杆菌数的变化存在显著的差异。
2.在本发明饮料摄取组中,摄取本发明饮料导致了双歧杆菌占有率的提高(19.6±15.2→32.1±15.2%,配对的T-检验;p=0.001)。相反,在安慰剂饮料摄取组中有降低的趋势(23.5±12.6→18.8±9.2%,配对的T-检验;p=0.110),因此,组别间依据双歧杆菌占有率的变化也存在显著的差异。
3.在本发明饮料摄取组中,粪便IgA浓度显著升高(3.9±3.2→6.9±5.4mg/g干重,配对的T-检验;p=0.014)。相反,在安慰剂饮料摄取组中没有变化(5.6±7.0→4.4±3.1mg/g干重),因此,组别间粪便IgA浓度的变化也存在显著的差异。
这表明粪便IgA浓度升高是摄取本发明测试饮料的结果。因此本发明饮料显然促进了消化道中IgA的产生。
本发明还证实盲肠IgA浓度在以相似方式摄取了LS的豚鼠中也显著地升高了。测试实施例2
本实验如下操作,测试了当本发明组合物(活性成分LS)被健康个体摄取后其对免疫指示物的作用。1.被试者
被试者是20只健康成人,在前个月内未服用任何抗生素。2.测试物质和摄取条件
被试者连续4周一天两次(上午10:00和下午3:00)摄取本发明饮料(5gLS溶解在50ml水中的溶液)。3.测试方法
被试者饮用测试物质,并在摄取第一天(第0周)和摄取后4周(第4周)采血。被试者在采血和收集粪便前一天下午9点后禁食。在测试期间,被试者要求避免过量饮食和摄取发酵食品。他们还要求在测试期间禁止服药。4.评价项目和方法
(1)血清转铁蛋白:比浊法分析
(2)粒细胞部分的吞噬作用:
将20μl的荧光珠(2μm荧光标记珠,Polyscience#18604,Lot No.425844)加入到1ml的葡萄糖培养基中(下列溶液A、下列溶液B和无菌水的混合物,体积比为1∶1∶8),并采用11000rpm离心30分钟洗涤。
葡萄糖培养基组成
溶液A:1.01M NaCl
0.31M CH3COONa
0.04M KCl
0.04M CaCl2
0.02M MgCl2
溶液B:0.07M葡萄糖
所得沉淀悬浮在1ml同样的葡萄糖培养基中,超声处理得到统一的珠液体。将100μl的这些荧光珠加入到100μl加入肝素的采自测试被试者的外周血中,37℃振荡温育0、5、10和30分钟。反应完成后,将2ml含溶血剂液体加入,完全溶解红血球,并置于冰上冷却后进行测定,所述溶血剂的液体由溶解在相等量缓冲液(Facs裂解缓冲液,Becton Dickinson Co.,Cat.No.349202)中的溶血剂组成。样品采用流式细胞仪(Coulter Epics XL-MCL System II)测定。将门(gate)对至粒细胞部分并安放检测荧光发射吞噬细胞作为最高峰,并分析此吞噬率。
(3)嗜酸性粒细胞:显微镜检5.统计学处理
所有数据表示为平均值±标准偏差,随机分组设计后,它们用Dunnett多重比较测试并评价显著性。显著性水平为5%或更小。6.结果(1)血清转铁蛋白
所获得的结果表示在表7中。
表7
摄取第一天(第0周) | 摄取4周后(第4周) | |
血清转铁蛋白(mg/dl) | 285±30 | 295±34※ |
平均值±标准偏差,n=20(第0周),n=17(第4周)
※:P<0.05,相对于第0周
表7结果显示血清转铁蛋白浓度与第0周比较,摄取4周后明显更高,其显著性水平小于5%。(2)粒细胞部分的吞噬作用
结果如图1显示(纵轴=粒细胞部分的吞噬率(%),横轴=测试期(周)),这表明平均值±标准偏差(30分钟反应值)对于粒细胞部分的吞噬率第0周为50.8±10.8%以及第4周为63.6±14.1%,从第0周到第4周有显著升高,其显著性小于1%。(3)血液嗜酸性粒细胞
结果在表8中显示。
同时进行的一般性血液测试(白细胞、嗜中性粒细胞、嗜碱性粒细胞、淋巴细胞和单核细胞)结果也在表8中显示出来。
表8
摄取第一天(第0周) | 摄取4周后(第4周) | |
白细胞(计数/μl) | 5443±1604 | 5536±2370 |
嗜中性粒细胞(%) | 59.9±11.0 | 59.9±6.7 |
嗜碱性粒细胞(%) | 1.0±0.7 | 1.0±0.5 |
嗜酸性粒细胞(%) | 4.7±3.9 | 3.2±2.0※ |
淋巴细胞(%) | 28.9±9.5 | 29.2±5.8 |
单核细胞(%) | 5.9±2.1 | 6.7±1.2 |
平均值±标准偏差,n=20(第0周),n=17(第4周)
※:P<0.05,相对于第0周
本表中的结果显示血液嗜酸性粒细胞第4周明显低于第0周,其显著性小于5%。7.讨论
上述结果显示摄取本发明组合物导致血清转铁蛋白和粒细胞吞噬作用的增加,这些对预防感染至关重要,因此显示了本发明组合物起到了增强了宿主对感染的预防功能。它们还暗示既然摄取本发明组合物导致血液嗜酸性粒细胞降低,因而本发明组合物具有抑制过敏反应的潜力。测试实施例3
本实验使用可遗传的糖尿病模型动物如下进行,以测试服用本发明组合物对肠道免疫的作用。1.测试动物
使用4周大的LETO大鼠和OLETF大鼠(各10只)。OLETF胚胎于1994年8月24日保藏在美国典型培养物保藏中心(ATCC),保藏号ATCC No.72016。LETO大鼠可购置并保存在大塚制药厂德岛实验动物管理室。2.动物饲养条件
大鼠交付后,检疫隔离一周。在此期间给它们喂食MF固体饲料(Oriental Yeast Co.)和自来水,可随意食用。它们关在不锈钢笼子里,一个笼子养一只大鼠,用明/暗循环,从7:00到19:00有光线。
在测试期间,低纤维(3%)、高脂肪(5%玉米油+10%牛脂肪)饲料的制备方法依据AIN76组成(美国营养研究所(1977)美国营养研究所特别委员会对营养研究标准的报告,J.Nutri.,107:1340-1348)作为对照饲料,并用LS代替对照饲料的蔗糖/玉米淀粉混合物部分以给予LS含量为5%的饲料作为本发明的饲料(饲料含有LS)。饲料组成如下列表9所显示。
表9
3.测试组别
成分(g/100g饲料) | 对照饲料 | 本发明饲料 |
酪蛋白 | 20.00 | 20.00 |
玉米淀粉/蔗糖(3∶10) | 57.20 | 52.20 |
玉米油 | 5.00 | 5.00 |
牛脂肪 | 10.00 | 10.00 |
纤维素 | 3.00 | 3.00 |
AIN76矿物混合物 | 3.50 | 3.50 |
AIN76维生素混合物 | 1.00 | 1.00 |
DL-甲硫氨酸 | 0.3 | 0.3 |
LS | - | 5.00 |
千卡 | 444 | 424 |
测试组(动物类型、饲料和动物数)如下:组别 动物 饲料 动物数1 LETO大鼠 对照饲料 102 LETO大鼠 本发明饲料 10 3 OLETF大鼠 对照饲料 104 OLETF大鼠 本发明饲料 104.测试进度
动物检疫隔离结束后,用对照饲料喂养2周。在隔离期结束时,LETO和OLETF大鼠分成前述组别,应使所有组都有相同的平均体重。组别分配后,引入测试饲料(在7周龄时),并自此将大鼠用测试饲料喂养22周。5.解剖
22周完成后(29周龄),在***麻醉下切开大鼠腹部,从腹部下腔静脉取血,因此大鼠由放血被处死。下腔静脉血以3000转/分离心15分钟,血清分离并在-80℃保存。处死后,每组中三只大鼠的小肠用于制备淋巴细胞。6.制备淋巴细胞
小肠淋巴集结淋巴细胞采用杆菌衍生的蛋白酶酶法制备(Boehringer-Mannheim Corp."Dispase II")。淋巴集结细胞的分离依据Fragaski等方法(Fragaski等,Journal of Immunological Methods 48,33-44(1989))。处死后,从十二指肠的上部到回肠的末端部的区域消毒取出。在无菌盐水仔细洗涤后,用注射器输送无菌盐水穿过肠子,洗去内容物。淋巴集结被切掉放到冰上的无菌纱布中。切离的淋巴集结放置到不完全的RPMI1640培养基上(含有10μg/ml庆大霉素的RPMI1640)。所有获得的淋巴集结37℃酶法处理40分钟,同时在含有1.5mg/ml中性蛋白酶的液体(酶液体)培养基(Joklik-修饰的MEM)中用搅拌子搅拌。收集开始分开的细胞,再加入相同的酶液体。本法重复3-4次。完全分离的细胞4℃以下350g离心10分钟,用PBS洗涤并悬浮在指定的培养基中,在红血球计数器上测定细胞数。
将每组三只大鼠的淋巴集结集中,并制得淋巴细胞。7.培养淋巴细胞
淋巴细胞被制备成在RPMI1640(含有2mM L-谷氨酰胺、50μM巯基乙醇、100U/ml青霉素、100μg/ml链霉素和10%FCS)中的细胞计数达到1×106个/ml。1ml/孔的淋巴细胞悬浮液在5.0μg/ml ConA(伴刀豆球蛋白A:衍生自Canavalia ensiformis,Sigma Co.)作细胞***促进剂的刺激下培养,在24孔板中用作细胞培养(FALCON3047)。
抗体生产测试由在5%CO2中37℃培养7天进行,细胞因子测试则在同样条件下培养3天。在脾淋巴细胞情况下每个样品一个孔,而在淋巴集结淋巴细胞情况下,每个样品三个孔。
培养完成后,板在1600转/分离心10分钟,收集上清液。收集的上清液储存冰冻在-20℃直到进行各种测定。8.细胞因子测定
淋巴细胞培养上清液中的IFN-γ由ELISA法采用商品化测定试剂盒测定。9.统计学处理
结果显示为平均值±标准偏差。对细胞因子浓度,组别对比由一元配置离散分析进行,接着Fisher保护的LSD多重比较。由于每组样品集中,在淋巴集结细胞的情况下不进行统计学处理。显著性水平小于5%。10.结果
从培养淋巴集结中产生IFN-γ的结果显示在图2中。
从这些结果中,与对照喂养组(组1和组3)比较,摄取带有本发明组合物饲料的组(组2和组4)中的LETO和OLETF大鼠显然表现出了更高的IFN-γ浓度。
Claims (17)
1.一种免疫强化组合物,包含低聚乳果糖和载体。
2.一种促进产生干扰素-γ的组合物,包含低聚乳果糖和载体。
3.权利要求1或2的组合物,其中每100g所述组合物中含有0.5-70g低聚乳果糖。
4.权利要求1或2的组合物,其中所述组合物以食品形式存在。
5.权利要求1或2的组合物,其中每天摄取1-30g低聚乳果糖。
6.一种用于预防和治疗消化道感染的药剂,包含低聚乳果糖和载体。
7.低聚乳果糖在制备免疫强化组合物中的应用。
8.低聚乳果糖在制备组合物中的应用,其中所述组合物促进产生干扰素-γ。
9.低聚乳果糖在制备药物组合物中的应用,其中所述药物组合物用于预防或治疗消化道感染。
10.患者免疫强化的方法,包括使患者服用或摄取有效量的低聚乳果糖。
11.权利要求10的方法,其中有效量的低聚乳果糖是1-30g/天。
12.促进患者产生干扰素-γ的方法,包括使患者服用或摄取有效量的低聚乳果糖。
13.权利要求12的方法,其中有效量的低聚乳果糖是1-30g/天。
14.在需要的患者中预防消化道感染的方法,包括使患者服用或摄取有效量的低聚乳果糖。
15.权利要求14的方法,其中有效量的低聚乳果糖是1-30g/天。
16.在需要的患者中治疗消化道感染的方法,包括使患者服用或摄取有效量的低聚乳果糖。
17.权利要求16的方法,其中有效量的低聚乳果糖是1-30g/天。
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CA2542332C (en) | 2003-10-16 | 2013-03-12 | Stephen John Ralph | Immunomodulating compositions and uses therefor |
US7087564B2 (en) * | 2004-03-05 | 2006-08-08 | Air Liquide America, L.P. | Acidic chemistry for post-CMP cleaning |
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JP5289952B2 (ja) * | 2006-07-19 | 2013-09-11 | 株式会社林原 | 免疫調節剤 |
US8017168B2 (en) | 2006-11-02 | 2011-09-13 | The Coca-Cola Company | High-potency sweetener composition with rubisco protein, rubiscolin, rubiscolin derivatives, ace inhibitory peptides, and combinations thereof, and compositions sweetened therewith |
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