CN106798826B - 麦冬寡糖在制备促进棕色脂肪生成药物中的应用 - Google Patents
麦冬寡糖在制备促进棕色脂肪生成药物中的应用 Download PDFInfo
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Abstract
本发明涉及麦冬寡糖的新用途。本发明公开了麦冬寡糖在制备促进棕色脂肪生成、促进白色脂肪组织分解及产热功能药物中的应用。并进一步公开麦冬寡糖在制备防治肥胖、增强机体抗寒能力药物或食品中的应用。经试验证明,麦冬寡糖在上述应用中,疗效确切安全无毒性。以上用途的公开属首次公开,为制备安全减肥、抗寒药物或保健食品提供了新的途径。
Description
技术邻域
本发明涉及麦冬寡糖的新用途。
背景技术
麦冬为百合科植物麦冬Ophiopogon japonicas(L.f)Ker-Gawl.的干燥块根,味甘、微苦,性微寒,有养阴生津、润肺清心之功,主要用于肺燥干咳、阴虚痨嗽、喉痹咽痛、津伤口渴、内热消渴、心烦失眠和肠燥便秘等。麦冬中含有的化学成分类型主要有皂苷、黄酮、氨基酸和糖类。有研究表明麦冬对四氧嘧啶、链脲佐菌素诱导的高血糖动物和自发性糖尿病小鼠具有显著的降血糖作用。
肥胖是指人体脂肪组织过度蓄积导致机体正常生理功能不同程度损害的一种病理状态。肥胖严重影响人类的身心健康,是许多2型糖尿病等代谢性疾病、心脑血管疾病、呼吸系统疾病以及恶性肿瘤等慢性非传染性疾病的危险因素,被世界卫生组织认定为影响健康的主要危险因素之一。随着全球经济飞速发展以及生活方式的变化,世界肥胖问题日益严重。全球目前有超过15亿的超重和肥胖人口,预计到2030年超重人群将增加到21.6亿,肥胖人群将增加到11.2亿。因此,肥胖相关并发症的发病率及病死率将不断增加,肥胖的防治日趋严峻,如何安全有效地治疗肥胖成为迫切需要解决的问题。
目前,肥胖的治疗主要包括改变生活方式、手术治疗和药物治疗3种方法:(1)改变生活方式,包括饮食疗法和参加有氧运动,但生活方式的干预往往让人难以坚持,大多只能取得短暂的成功;(2)手术治疗,主要包括Bariatric手术、去脂整形术和胃内水球疗法,虽然手术是目前最有效的治疗方法,但其存在很大的风险;(3)目前可选的减肥药物非常有限,如化学药物利莫那班(rimonabant)和西布曲明(sibutramine)已退出欧洲联盟的市场。因此,目前可用于减肥的有效措施非常少,迫切需要有新的减肥方法出现。
哺乳动物体内主要存在2种类型的脂肪组织,即白色脂肪组织(white adiposetissue,WAT)和棕色脂肪组织(brown adipose tissue,BAT)。其中,白色脂肪组织占正常健康成人体质量的10%,主要功能是储存脂肪以作为人体能源库和皮下隔热垫;棕色脂肪负责分解引发肥胖的白色脂肪,将白色脂肪转化成二氧化碳、水和热量,它可以加快人体新陈代谢,促进白色脂肪消耗,防止肥胖的发生。棕色脂肪组织产生热量主要依赖于解偶联蛋白1(UCP1)的活化,UCP1是特异性存在于棕色脂肪细胞中的一种线粒体蛋白,能将线粒体氧化磷酸化脱偶联后,代谢脂肪酸,产生能量,这对机体维持体温非常重要。有关啮齿类动物的实验研究发现,诱导白色脂肪组织向棕色脂肪组织转化可以减轻该动物体质量、提高该动物机体的血糖稳态。另有研究表明,在超重和肥胖人群中棕色脂肪组织的数量明显减少,棕色脂肪组织的数量与BMI、脂肪含量呈反比,棕色脂肪组织确实存在于成人体内并发挥作用,并且肥胖的发生也与棕色脂肪组织数量的减少有着密切联系。棕色脂肪组织的存在及生理功能提示了一种控制肥胖症的新策略。通过调控棕色脂肪的分化通路,使棕色脂肪增加或促使白色脂肪向棕色脂肪转化可能成为治疗肥胖的有效方法,已成为肥胖研究的热点。
发明内容
本发明首次公开了麦冬寡糖在促进棕色脂肪生成,提高棕色脂肪组织UCP1蛋白表达,以增强棕色脂肪组织分解白色脂肪组织和产热功能方面的作用。并进一步公开麦冬寡糖在抑制体重异常增长、防治肥胖、增强机体抗寒能力方面的作用。在小鼠急性毒性试验中没有表现出毒性反应,疗效确切安全。为制备安全减肥、抗寒药物或保健食品提供了新的原料途径。
具体为:
1、麦冬寡糖在制备促进棕色脂肪生成药物中的应用。
2、麦冬寡糖在制备促进白色脂肪组织分解及产热功能药物中的应用。
3、麦冬寡糖在制备防治肥胖药物、保健品或食品中的应用。
4、麦冬寡糖在制备增强机体抗寒能力药物、保健品或食品中的应用。
麦冬寡糖来源优选中药材麦冬的寡糖提取物,优选分子量范围为500~2500之间。
具体实施方式
下面结合实施例对本发明做进一步的说明。
各实施例中所涉及的固体混合物中之固体,液体中之液体,以及液体中之固体的百分比分别是以wt/wt、vol/vol、wt/vol计算,除非另有说明。
实施例1:麦冬寡糖的制备
取麦冬药材适量,剪碎,加10倍量95%乙醇,回流2小时,过滤,弃滤液,挥干乙醇,加10倍量蒸馏水,水浴提取2次,滤过,合并滤液,减压浓缩至密度为1.2g/ml,加乙醇至醇浓度为80%,静置12小时,沉淀,分别以无水乙醇、无水乙醚、丙酮洗涤,55℃烘干,即得麦冬粗提取物。取麦冬粗提取物,溶于适量蒸馏水中,以3000r/min的转速离心,除去沉淀,用Sephadex G-75层析柱上样,以蒸馏水洗脱,流速为0.5ml/min,以自动部分收集器收集,合并洗脱峰,冷冻干燥,得到纯化后的麦冬寡糖。采用硫酸-蒽酮法测定总寡糖含量,得到寡糖含量为97.64%的麦冬寡糖样品。将Sephadex G-75柱层析所得麦冬寡糖样品溶于去超纯水,配成2μg/ml溶液,分别取0.5μl样品溶液与5mg/ml的基质2,5-二羟基苯甲酸(DHB)互溶挥干溶液,采用MALDI-TOF-MASS进样检测麦冬寡糖的分子量范围。经MALDI-TOF-MASS进样检测,该麦冬寡糖样品的分子量范围在500~2500之间。
实施例2:麦冬寡糖对肥胖模型小鼠的体重、棕色脂肪生成及其UCP1蛋白表达的影响
1、实验动物:
4-5周龄C57BL/6J雄性小鼠,SPF级,平均体质量(15.5±0.7)g,由广东省医学实验动物中心提供,动物合格证号:SCXK(粤)2013-0002。
2、实验方法:
2.1动物模型建立及分组
将60只小鼠随机分为正常对照组(n=10)和肥胖造模组(n=50),正常对照组以普通饲料喂养,肥胖造模组喂饲高脂饲料(含基础饲料79%、猪油10%、蛋黄粉10%、胆固醇1%)。喂饲10周后,选择体质量高于正常对照组小鼠平均体质量20%的个体为肥胖模型动物。本实验成功诱导肥胖模型小鼠38只(成功率为76%),将肥胖模型小鼠按照随机数字表法分为肥胖模型对照组(10只)、麦冬寡糖低剂量组(9只)、麦冬寡糖中剂量组(10只)、麦冬寡糖高剂量组(9只)。除正常对照组喂饲普通饲料外,其他各组继续喂养高脂饲料,同时,麦冬寡糖低剂量组、麦冬寡糖中剂量组、麦冬寡糖高剂量组分别按0.1ml/10g灌胃给予浓度为1.5mg/ml、3.0mg/ml、6.0mg/ml的麦冬寡糖混悬液,正常对照组和肥胖模型对照组灌胃给予等体积蒸馏水,1次/天,连续6周。
2.2指标监测
最后一次给药后,动物禁食不禁水过夜,于第2天清晨进行空腹体质量称量并记录,随后将动物麻醉,断头处死,迅速取肩胛间区棕色脂肪组织,除去附着的肌肉及白色脂肪组织,称重并记录。随后,将取出的棕色脂肪组织于10%福尔马林溶液中固定,按免疫组化染色试剂盒说明书采用ABC法进行免疫组织化学染色。将染色的切片于200倍显微镜下观察,每张切片随机摄取10个视野,用Image-Pro Plus 6.0软件分析UCP1阳性表达的光密度值(IOD)。
3、实验结果:
由表1可见,与正常对照组比较,肥胖模型对照组小鼠的体质量显著增加(P<0.01),棕色脂肪重量/体重显著降低(P<0.01),UCP1蛋白表达明显减少(P<0.05)。提示该高脂饲料喂养所致的肥胖模型小鼠的体质量异常增长、棕色脂肪组织生成减少、棕色脂肪组织的分解和产热功能减弱。与肥胖模型组比较,麦冬寡糖中、高剂量组小鼠的体质量显著降低(P<0.05或0.01),棕色脂肪重量显著增加(P<0.01),棕色脂肪重量/体重显著提高(P<0.01),UCP1蛋白表达明显增加(P<0.05)。提示麦冬寡糖可以促进肥胖模型小鼠棕色脂肪的生成,提高棕色脂肪组织UCP1蛋白的表达以增强肥胖模型小鼠棕色脂肪组织分解白色脂肪组织和产热功能,明显抑制肥胖模型小鼠的体重异常增长。
注:与正常对照组比较:##P<0.01;与模型对照组比较:*P<0.05**P<0.01
实施例3:SD大鼠经口给予麦冬寡糖急性毒性试验
1、实验动物:
SPF级SD大鼠24只,雌雄各半,体重130~150g,由广东省医学实验动物中心提供,动物合格证号:SCXK(粤)2013-0002。
2、实验方法:
试验设给药组及空白对照组,每组12只动物,雌雄各半。麦冬寡糖给药组给药剂量为36g/kg,按可通过灌胃针的最大浓度1.8g/ml、给药容积20ml/kg灌胃给药。对照组灌胃给予等体积灭菌注射用水。
每日观察并记录大鼠的外观、精神状态、呼吸、皮肤被毛、粪尿、眼、耳、鼻、口腔、生殖器等一般情况及其它中毒表现和死亡情况。每两天测定大鼠体重一次,每周测定大鼠摄食量一次,连续观察14天。
3、实验结果:
(1)一般状况及死亡情况观察
给药后直至第14天,各动物精神及行为活动状况良好、皮肤被毛清洁、大小便正常,亦未见其他毒性反应症状。观察结束后大体解剖未见脏器明显异常。
(2)体重
雌、雄大鼠在各时间点体重与灭菌注射用水对照组雌、雄大鼠体重相比,差异无统计学意义(P>0.05),提示麦冬寡糖经口灌胃给药对大鼠体重无明显影响。详见表2。
上表中,“对照组”是指“空白对照组”,“给药组”是指“麦冬寡糖给药组”。
(3)摄食量
麦冬寡糖经口灌胃给药对雌、雄鼠平均摄食量无明显影响。详见表3。
表3麦冬寡糖单次经口灌胃给药对SD大鼠平均摄食量的影响
4、结论:
综上所述,在本实验室条件下,SD大鼠按36g/kg的剂量以最大浓度1.8g/ml、最大体积20ml/kg单次经口灌胃给予麦冬寡糖,14天观察期内,大鼠未出现死亡,精神及行为活动状况良好、皮肤被毛清洁、大小便正常,体重增长正常,摄食量未见异常。观察结束后大体解剖未见脏器异常。表明麦冬寡糖对雌雄大鼠经口LD50均>36g·kg-1,按急性毒性剂量分级标准属实际无毒级物质。
Claims (4)
1.麦冬寡糖在制备促进棕色脂肪生成药物中的应用,其中所述的麦冬寡糖的分子量范围为500到2500之间。
2.麦冬寡糖在制备促进白色脂肪组织分解及产热功能药物中的应用,其中所述的麦冬寡糖的分子量范围为500到2500之间。
3.麦冬寡糖在制备增强机体抗寒能力保健品或食品中的应用,其中所述的麦冬寡糖的分子量范围为500到2500之间。
4.如权利要求1或2或3所述的应用,其特征在于,麦冬寡糖来源于中药材麦冬的寡糖提取物。
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