CN110123850B - 沙棘果浆在预防多囊卵巢综合征药物中的应用 - Google Patents
沙棘果浆在预防多囊卵巢综合征药物中的应用 Download PDFInfo
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Abstract
本申请公开了沙棘果浆的新用途,即沙棘果浆在制备用于预防多囊卵巢综合征的药物中的应用和沙棘果浆在制备用于预防多囊卵巢综合征的保健食品中的应用。本申请发现沙棘果浆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,证实沙棘果浆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。本申请对于直接利用沙棘果浆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
本申请涉及沙棘果浆用途技术领域,特别涉及沙棘果浆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。
发明内容
本申请公开沙棘果浆的新用途,即沙棘果浆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,提供沙棘果浆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,提供沙棘果浆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。
本申请首次证实沙棘果浆对女性生殖领域高发疾病多囊卵巢综合征具有有效预防作用。并通过严谨的科学实验,证实沙棘果浆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。本申请对于直接利用沙棘果浆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为各组小鼠体重增长比柱状图;
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-Sham组(模型组),3-沙棘果浆组。
具体实施方式
本申请提供沙棘果浆在制备用于预防多囊卵巢综合征的药物中的应用;
本申请提供沙棘果浆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。
本申请发现沙棘果浆对多囊卵巢综合征具有非常有效的预防作用。沙棘果浆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。
为了证实沙棘果浆具有上述新功能,做了如下实验。
1.技术方案:
(1)沙棘果浆制备:
采集新鲜成熟沙棘果,洗净晾干,用双层纱布包裹,通过物理挤压法获得果浆。
(2)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,通过灌胃给予沙棘果浆,检测沙棘果浆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、沙棘果浆保护组。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;沙棘果浆保护组,提前一周灌胃给予5ml/kg(0.2ml)沙棘果浆,再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5ml/kg(0.2ml)沙棘果浆,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。
(3)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。具体判断标准: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。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;动情后期可见多种细胞类型,白细胞,无核的上皮细胞及梭形上皮细胞;动情间期可见大量白细胞,极少量或不可见其他细胞。
4.实验结果
4.1沙棘果浆可以保护卵巢内卵泡正常成熟功能,显著预防PCOS小鼠卵巢多囊样病变,改善卵巢形态。
卵泡发育障碍及无排卵是PCOS患者生殖功能障碍的核心特征,PCOS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。病检结果显示卵巢呈多囊样改变,黄体数目显著减少,白膜增厚,白膜下见许多不同程度的卵泡及闭锁卵泡。卵巢白膜明显胶原化,呈板层状包绕卵巢,最终形成空泡样改变,导致排卵异常。本申请发现沙棘果浆可以显著预防PCOS小鼠卵巢多囊样病变,改善卵巢形态。
(1)大体观察: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: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;模型组小鼠的卵巢闭锁卵泡增多并且呈囊状扩张,卵泡膜细胞增生,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,卵泡膜细胞层较厚;沙棘果浆保护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沙棘果浆可以显著预防PCOS小鼠的动情周期紊乱,保护小鼠生育能力。
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,将动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)。在动情周期中卵巢、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,意味着卵巢具有周期性排卵功能。在PCOS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。本申请发现沙棘果浆可有效预防PCOS小鼠动情周期的紊乱。
如图3所示在本实验中,检测到正常对照组呈现规律动情周期,模型组动情周期紊乱,甚至出现持续间期,不再出现动情期,提示无排卵。给予沙棘果浆保护组,实验全程未出现动情周期紊乱,始终保持与正常组相似的规律动情周期及正常动情期,证明给予沙棘果浆保护后,动情周期没有被损伤。
由此证明:沙棘果浆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。
4.3沙棘果浆可以保护机体正常体重维持功能,有效预防多囊卵巢综合征小鼠的肥胖状态发生。
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。本申请发现沙棘果浆可以显著预防多囊卵巢综合征小鼠的肥胖,保护小鼠维持正常体重的功能。
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,而给予沙棘果浆预防性保护的小鼠,在给与高脂饲料喂养及来曲唑增加体内雄激素后,体重维持正常,没有出现体重增加。
4.4沙棘果浆可以预防PCOS小鼠的高血糖状态,减轻胰岛素抵抗,保护小鼠机体维持正常葡萄糖代谢功能
胰岛素抵抗是多囊卵巢综合征最主要的表现之一,本申请发现沙棘果浆有很好的预防胰岛素抵抗、降低血糖的作用。
如图6及图7所示,模型组(Model)小鼠相较于正常对照组(Control)小鼠,血糖有明显恶化,严重的葡萄糖耐量受损,而沙棘果浆保护组的血糖基本正常。
本实验证明沙棘果浆对高脂喂养及来曲唑造成的体内高雄激素水平所造成的糖耐量受损具有明显的预防性保护作用。
4.5沙棘果浆可增加卵巢组织中AMH含量,维持卵巢的储备功能。
多囊卵巢综合征对患者最大的影响是失去生育能力。AMH属于是一种表达纯化的二聚体糖蛋白,在人体中主要位于19号染色体中,该糖蛋白与抑制素、激活素相同属于转化生长因子β超家族。AMH在卵巢不同反应人群中表达不同,AMH与卵巢反应、临床妊娠率、胚胎的种植率等呈正相关,AMH可能在卵泡的发育和功能上起到一定的作用,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。因此血清AMH是预测临床妊娠率的独立因素。本申请发现沙棘果浆可以使患PCOS小鼠卵巢组织中的AMH含量增高。
如图8所示,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。如图所示,较正常对照组相比,沙棘果浆保护组小鼠卵巢中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AMH的表达较正常组有所减少。这表明沙棘果浆可以增加卵巢组织中AMH的含量,进而在有高糖高脂高雄激素损害因素存在时,可以保护卵巢的储备功能。
由以上实验结果可知,
(1)沙棘果浆可以有效保护小鼠卵巢卵子成熟功能,显著预防PCOS小鼠卵巢多囊样病变
(2)沙棘果浆可以显著预防PCOS小鼠的动情周期紊乱,保护小鼠生育功能
(3)沙棘果浆可以预防PCOS小鼠的肥胖状态,保护小鼠维持正常体重的功能
(4)沙棘果浆可以预防PCOS小鼠的高血糖状态,减轻胰岛素抵抗,保护小鼠机体维持正常葡萄糖代谢功能
(5)沙棘果浆可维持小鼠AMH水平,保护PCOS小鼠卵巢的储备功能
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 (2)
1.沙棘果浆作为单一活性成分用于制备预防多囊卵巢综合征的药物中的应用。
2.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。
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