CN110075139A - 沙棘籽油在预防多囊卵巢综合征药物中的应用 - Google Patents
沙棘籽油在预防多囊卵巢综合征药物中的应用 Download PDFInfo
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Abstract
本申请公开了沙棘籽油的新用途,即沙棘籽油在制备用于预防多囊卵巢综合征的药物中的应用和沙棘籽油在制备用于预防多囊卵巢综合征的保健食品中的应用。本申请发现沙棘籽油对多囊卵巢综合征具有良好的预防作用,并通过严谨的科学实验,证实沙棘籽油不仅可以预防小鼠多囊卵巢综合征的发生,阻止卵巢的多囊样病变,预防动情周期紊乱,还可以有效保护小鼠体内血糖稳定、维持体重稳定等。该发明对于直接利用沙棘籽油预防多囊卵巢综合征的发生提供了证据和基础。
Description
技术领域
本申请涉及沙棘籽油用途技术领域,特别涉及沙棘籽油在预防多囊卵巢综合征药物中的应用。
背景技术
多囊卵巢综合征(polycystic ovary syndrome,PCOS)是一种以胰岛素抵抗、雄激素增高和卵巢多囊为主要临床特征的内分泌疾病。PCOS所表现的高雄激素血症和卵巢功能障碍,常伴有糖脂代谢紊乱如高胰岛素血症和血脂异常,最终导致肥胖、2型糖尿病和心血管疾病的发生,PCOS患者患糖尿病的风险是健康人群的4倍。肥胖的PCOS患者则表现出更为严重的胰岛素抵抗、腹部脂肪沉积和高雄激素血症,超过60%的PCOS患者超重或肥胖,约70%存在胰岛素抵抗。
PCOS是育龄女性最常见的生殖内分泌紊乱性疾病之一,在我国的发病率为12.5%~15%,可导致女性不孕,严重危害女性健康。PCOS的病因尚不明确,主要包括遗传因素、不健康的生活方式和内分泌代谢紊乱。其核心病理机制是胰岛素抵抗和高雄激素血症。主要临床表现为胰岛素抵抗、高雄激素血症、高脂血症、肥胖和慢性炎症等,并伴随异常月经、卵巢多囊样病变。目前对于多囊卵巢综合征的治疗主要包括外科手术治疗和药物治疗。手术有卵巢打孔术,但因为其疗效差、并发症多,目前已很少采用;药物治疗作用有限,只能起到对症治疗的作用。
所以,多囊卵巢综合征的预防具有重要意义。近年来,改变饮食、改善生活方式以及保健品的应用已成为预防多囊卵巢综合征发生的重要方式,但由于多囊卵巢综合征的病因不明,临床表现多样,并发症多,目前尚无有效预防多囊卵巢综合征的药物。
中药沙棘(Seabuckthorn)在我国具有悠久的药用历史,《四部医典》记载了沙棘可用于止咳、平喘、活血化瘀等作用。沙棘的活性成份有400多种,主要包括:维生素类、黄酮类化合物、三萜、甾体类化合物、油和脂肪酸、氨基酸和蛋白质、酚类及有机酸类、挥发油类、微量元素、磷脂类、5-羟色胺、糖类等物质。沙棘籽油由沙棘籽经过超临界萃取或亚临界低温萃取得到的棕黄色到棕红色透明油状液体,内含黄酮、有机酸、生物碱、甾醇类、三萜烯类、SOD及各种维生素(VC、VE等)和微量元素(锌、铬、锰、硒、镁、钙)等140多种生物活性成分。沙棘籽油已被证实可有效预防癌症、心血管系统疾病、呼吸系统疾病、胃肠疾病等,具有维持人体健康的作用。但是,迄今为止,尚未见关于沙棘籽油对女性生殖领域高发疾病多囊卵巢综合征具有预防作用的报道。
发明内容
本申请公开沙棘籽油的新用途,即沙棘籽油在预防多囊卵巢综合征药物中的应用,解决目前尚无有效预防多囊卵巢综合征的药物的问题。
根据本申请的实施例,提供沙棘籽油在制备用于预防多囊卵巢综合征的药物中的应用;
根据本申请的实施例,提供沙棘籽油在制备用于预防多囊卵巢综合征的保健食品中的应用。
进一步地,所述药物的剂型包括软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
进一步地,所述保健食品的剂型包括软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
本申请首次发现沙棘籽油对多囊卵巢综合征具有良好的预防作用,并通过严谨的科学实验,证实沙棘籽油不仅可以预防小鼠多囊卵巢综合征的发生,阻止卵巢的多囊样病变,预防动情周期紊乱,还可以有效保护小鼠体内血糖稳定、维持体重稳定等。该发明对于直接利用沙棘籽油预防多囊卵巢综合征的发生提供了证据和基础。
附图说明
为了更清楚地说明本申请实施例或现有技术中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本申请的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为本申请的技术路线图;
图2为各组小鼠卵巢组织石蜡切片H&E染色结果;
图3为各组小鼠阴道分泌物观察结果;
图4为各组小鼠体重变化折线图;
图5为各组小鼠体重增加比柱状图;
图6为各组小鼠糖耐量实验结果;
图7为各组小鼠糖耐量实验曲线下面积结果;
图8为各组小鼠AMH表达结果。
其中,1-正常对照组,2-模型组(Sham组),3-沙棘籽油组。
具体实施方式
本申请提供沙棘籽油在制备用于预防多囊卵巢综合征的药物中的应用;
本申请提供沙棘籽油在制备用于预防多囊卵巢综合征的保健食品中的应用。
进一步地,所述药物的剂型包括软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
进一步地,所述保健食品的剂型包括软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
本申请发现沙棘籽油对多囊卵巢综合征具有非常有效的预防作用。沙棘籽油可以有效抵抗高雄激素水平及高糖高脂肪饮食诱导的多囊卵巢综合征的发生,不仅可以预防胰岛素抵抗,还有效预防多囊卵巢综合征时体重增加、动情周期紊乱、卵子发育及排卵异常等。
为了证实沙棘籽油具有上述新功能,做了如下实验。
1.技术方案:
(1)动物模型建立:
来曲唑是芳香化酶抑制剂,可以抑制卵巢雄激素向雌激素的转化,从而造成高雄激素血症。高脂喂养可以造成胰岛素抵抗。对ICR小鼠给予高脂喂养加灌胃给来曲唑,200ug/只/天,给予21天可以造成胰岛素抵抗及高雄激素血症的多囊卵巢综合征模型,动情周期紊乱,出现持续间期,血糖升高(此为业界公认的多囊卵巢综合征标准造模手段)。
本实验在小鼠多囊卵巢综合征动物模型建立过程中给予干预,通过灌胃给予沙棘籽油,检测沙棘籽油对卵巢的保护作用以及对多囊卵巢综合征致病因素的抵抗作用。
具体实施:将4周龄ICR小鼠分为正常对照组、模型组(sham组)、沙棘籽油预防组(Oil组)。正常对照组给予正常饮食饲养,并且每日灌胃给予等量生理盐水;模型组给予高脂饲料喂养,并且每日灌胃给来曲唑,200ug/只/天,诱发多囊卵巢综合征发生;沙棘籽油预防组,提前一周灌胃给予2.5ml/kg(0.1ml)沙棘籽油,在给予高脂饲料喂养及每日灌胃给来曲唑,200ug/只/天,并且继续每日灌胃给予2.5ml/kg(0.1ml)沙棘籽油,对抗多囊卵巢综合征诱发因素。
实验持续21天,期间进行动物状态监测,第22天取材,进行进一步实验。
(2)实验结果监测及数据收集
a.每2日检测并记录各组小鼠体重、摄食及动情周期变化。
b.每7日检测禁食后血糖,并在给药处理后第21天给予葡萄糖耐量OGTT实验。
c.给药处理后第22天,取材。通过石蜡包埋剂切片染色技术,观察卵巢形态学改变。通过免疫组化技术检测AMH改变。
2.技术路线图
技术路线图如图1所示。
3.主要技术
1)建立小鼠PCOS动物模型
来曲唑是芳香化酶抑制剂,可以抑制卵巢雄激素向雌激素的转化,从而造成高雄激素血症。高脂喂养可以造成胰岛素抵抗。高脂喂养加灌胃给来曲唑,200ug/只/天,给予21天可以造成胰岛素抵抗及高雄激素血症的PCOS模型。
2)口服糖耐量实验(OGTT)
小鼠禁食16-18h,灌胃葡萄糖3g/kg体重,测定记录0min,15min,30min,60min,90min,120min时间点血糖。
3)阴道脱落细胞冲洗图片法检测动情周期
用滴管吸取适量生理盐水,每隔2天,在同一时间点冲洗、吸取阴道分泌物于载玻片上,迅速于显微镜下观察细胞形态,判断动情周期。
4.实验结果
4.1沙棘籽油可以显著预防多囊卵巢综合征小鼠卵巢多囊样病变,对小鼠卵巢起保护作用。
卵泡发育障碍及无排卵是多囊卵巢综合征患者生殖功能障碍的核心特征,多囊卵巢综合征患者卵泡发育障碍基本表现是卵泡募集数量过多,卵泡选择及优势化受阻,卵泡发育停滞,导致无排卵。可见卵巢表面平滑、白膜增厚,白膜下见许多不同程度的卵泡及闭锁卵泡,偶见白体。卵巢白膜明显胶原化,形成胶原纤维素宽带,此种胶原纤维较正常粗,呈板层状包绕卵巢,最终形成空泡样改变,导致排卵异常。
本申请发现沙棘籽油可以显著预防多囊卵巢综合征小鼠卵巢多囊样病变,改善卵巢形态,对小鼠卵巢起保护作用。
(1)大体肉眼观察:正常对照组小鼠的卵巢形态正常,色泽红润;模型组小鼠的卵巢偏大,表面苍白,卵巢表面可见单个或较多的囊性扩张卵泡。
(2)组织形态学:卵巢组织石蜡切片H&E染色结果如图2所示。正常对照组小鼠的卵巢在HE染色下可见多个不同发育阶段的卵泡及黄体,颗粒细胞形态完整且排列整齐,多为8~9层;模型组小鼠的卵巢内卵泡闭锁增多并且呈囊状扩张,看似成熟期的卵泡内未见卵细胞,可见颗粒细胞层数变薄,排列松散,部分脱落,黄体形成较少,卵泡膜细胞增生;沙棘籽油组小鼠卵巢内均可见黄体和多个发育不同阶段的卵泡,接近成熟期的卵泡可见卵细胞及放射冠,颗粒细胞排列较紧密,层数增多,卵泡膜细胞层较薄,形态接近正常对照组。
4.2沙棘籽油可以显著预防多囊卵巢综合征小鼠的动情周期紊乱,对小鼠生殖能力起保护作用。
在多囊卵巢综合征患者中,月经失调是最典型的临床表现之一,表现为月经稀发、月经量少甚至闭经。表现在小鼠上,则为动情周期紊乱,即持续的间期。动情周期是指雌性哺乳动物从上一次发情开始至下一次发情开始,或指上一次排卵至下一次排卵之间的时间间隔。通常根据动物的精神状态、雌性动物对雄性动物产生的性欲表现、卵巢内卵泡的生长发育、排卵和黄体形成的情况及雌性生殖道(子宫、阴道等)的生理变化等几个主要方面,将发情周期划分为动情前期(前情期)、动情期、动情后期(后情期)及间情期(间期)。在发情周期中卵巢、子宫与阴道等主要附属性器官也处于不断变化。拥有规律的动情周期是哺乳动物性成熟的标志,意味着卵巢开始出现周期性排卵。
本申请发现沙棘籽油可有效预防多囊卵巢综合征小鼠动情周期的紊乱,对小鼠生殖能力起保护作用。
如图3所示,显微镜下观察小鼠阴道分泌物可见:正常对照组(动情前期)可见成群或单独出现的梭形上皮细胞,白细胞较少。Sham模型组(动情间期)可见大量白细胞,无其他细胞类型。沙棘籽油组(动情期)见大量鳞状上皮细胞,形状大而不规则,无核,白细胞消失;
根据每2天检测动情周期的持续观察发现:正常组动情周期均基本正常,表现为规律的4~5d动情周期的变化。模型组(sham)小鼠从实验第9天始出现动情周期紊乱、延长,阴道涂片示持续处于动情间期,无排卵,直至最后全部小鼠均呈持续性间期;沙棘籽油保护组小鼠则自始至终未出现动情周期紊乱的现象,始终保持与正常组类似的动情周期状态。
由此证明:沙棘籽油对高脂饮食及高雄激素水平诱导的多囊卵巢综合征模型小鼠动情周期的紊乱有很好的预防和保护作用,对小鼠生殖能力起保护作用。
4.3沙棘籽油可以预防多囊卵巢综合征小鼠的肥胖状态,对小鼠正常体重维持起保护作用。
在多囊卵巢综合征患者中约50%-70%伴有超重或肥胖,临床研究表明,多囊卵巢综合征合并肥胖的患者,胰岛素抵抗、高性激素血症等症状更严重,因此减轻体重是缓解多囊卵巢综合征症状的一个有效途径。
本申请发现沙棘籽油可以显著预防多囊卵巢综合征小鼠的肥胖,对小鼠正常体重维持起保护作用。
如图4和图5所示,模型组小鼠相对于正常对照组小鼠,体重明显增加,而给予沙棘籽油保护的小鼠,在给与高脂饲料喂养及来曲唑增加体内雄激素后,体重上升远低于模型组。
4.4沙棘籽油可以预防多囊卵巢综合征小鼠的高血糖状态,减轻胰岛素抵抗,对小鼠胰岛功能及机体葡萄糖代谢起保护作用。
胰岛素抵抗是多囊卵巢综合征最主要的表现之一,本申请发现沙棘籽油可以预防多囊卵巢综合征小鼠的高血糖状态,减轻胰岛素抵抗,沙棘籽油对高脂饮食及高雄激素血症造成的机体糖耐量受损具有显著的预防作用。
如图6和图7所示,在实验进行第21天,对小鼠进口服葡萄糖耐量实验(OGTT)。将小鼠过夜禁食16小时,灌胃给予葡萄糖3g/kg体重,测定记录0min,15min,30min,60min,90min,120min时间点血糖。发现模型组小鼠相较于正常对照组小鼠,血糖有明显恶化,出现严重的葡萄糖耐量受损,而沙棘籽油组的血糖基本正常。
由此证明:沙棘籽油能明显改善高脂喂养及来曲唑所造成的机体糖耐量受损状态。
4.5沙棘籽油可增加卵巢的储备功能,增加卵巢组织中AMH含量,对卵巢功能储备起保护作用。
研究表明,年龄增长导致生育能力下降的根本原因与卵巢里可募集的卵泡数减少及卵子质量下降有关,因而生育潜能下降又称之为卵巢储备功能下降。抗苗勒管激素(Anti-Mullerian hormone,AMH)是目前倍受关注的女性生殖生理调节因子之一。AMH由卵巢早期生长卵泡分泌,参与卵泡的生长发育,随自然年龄变化的特点同卵巢储备能力的变化,与卵巢功能密切相关,能准确反映生育年龄女性机体内分泌状态,AMH由窦前卵泡和小窦卵泡的颗粒细胞分泌,抑制卵泡的生长,防止卵泡过快过早的消耗,保存卵巢的储备,近年的临床研究发现月经周期第3天血清中AMH水平随着年龄的增加而进行性的下降,在绝经期后无法检测到。因此AMH是用于评估卵巢储备功能最有效直接的因子之一。
本申请发现沙棘籽油可明显提高多囊卵巢综合征小鼠卵巢中AMH的表达,对卵巢功能储备起保护作用。
AMH蛋白主要表达于卵巢组织切片颗粒细胞的胞浆、胞膜和胞核,呈棕黄色。如图8所示,较正常对照组相比,沙棘籽油保护组(沙棘籽油组)小鼠卵巢中AMH的表达明显增加,主要分布于颗粒细胞所在的区域;模型组的表达较正常组有所减少。这表明沙棘籽油可以增加卵巢组织中AMH的含量,进而增加卵巢的储备功能。
由以上实验结果可知,
(1)沙棘籽油可以显著预防多囊卵巢综合征小鼠卵巢多囊样病变,对小鼠卵巢起保护作用。
(2)沙棘籽油可以显著预防多囊卵巢综合征小鼠的动情周期紊乱,对小鼠生殖能力起保护作用。
(3)沙棘籽油可以有效预防多囊卵巢综合征小鼠的肥胖状态,对小鼠正常体重维持起保护作用。
(4)沙棘籽油可以有效预防多囊卵巢综合征小鼠的高血糖状态,减轻胰岛素抵抗,对小鼠胰岛功能及机体葡萄糖代谢起保护作用。
(5)沙棘籽油可显著增加多囊卵巢综合征小鼠卵巢的储备功能,对卵巢功能储备起保护作用。
本领域技术人员在考虑说明书及实践这里公开的申请后,将容易想到本申请的其它实施方案。本申请旨在涵盖本申请的任何变型、用途或者适应性变化,这些变型、用途或者适应性变化遵循本申请的一般性原理并包括本申请未公开的本技术领域中的公知常识或惯用技术手段。说明书和实施例仅被视为示例性的,本申请的真正范围和精神由下面的权利要求指出。
应当理解的是,本申请并不局限于上面已经描述的内容,并且可以在不脱离其范围进行各种修改和改变。本申请的范围仅由所附的权利要求来限制。
Claims (4)
1.沙棘籽油在制备用于预防多囊卵巢综合征的药物中的应用。
2.沙棘籽油在制备用于预防多囊卵巢综合征的保健食品中的应用。
3.根据权利要求1所述应用,其特征在于,所述药物的剂型包括软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
4.根据权利要求2所述应用,其特征在于,所述保健食品的剂型包括软胶囊、滴丸、乳剂、片剂、洗剂、搽剂、软膏剂或栓剂。
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CN111544459A (zh) * | 2020-06-10 | 2020-08-18 | 宁夏医科大学 | 一种植物果油在制备治疗由放化疗引起的卵巢损伤的药物和保健食品中的应用 |
US11911426B2 (en) | 2020-06-10 | 2024-02-27 | Ningxia Medical University | Use of a plant in preparation of medicines and health products for preventing and treating ovarian injury |
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