CN113577047A - 调控ApoC3表达量的制剂在制备预防或治疗胰岛素抵抗型***药物中的应用 - Google Patents
调控ApoC3表达量的制剂在制备预防或治疗胰岛素抵抗型***药物中的应用 Download PDFInfo
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Abstract
本发明公开了调控ApoC3表达量的制剂在制备预防或治疗胰岛素抵抗型***药物中的应用。本发明通过发现，PCOS患者卵巢组织及颗粒细胞呈增殖状态，PCOS患者卵巢组织ApoC3高表达，PCOS模型大鼠卵巢组织ApoC3高表达，与PCOS卵巢局部胰岛素抵抗密切相关，进一步发现，利用胰岛素增敏剂可以下调卵巢中APOC3蛋白表达，改善模型大鼠卵巢组织的IR抵抗情况，因此可以将调控ApoC3表达量的制剂在制备预防或治疗胰岛素抵抗型***药物中的应用。
Description
技术领域：
本发明属于生物医药领域，具体涉及调控ApoC3表达量的制剂在制备预防或治疗胰岛素 抵抗型***药物中的应用。
背景技术：
一、胰岛素抵抗型的PCOS患者存在更为严重的糖脂代谢紊乱，尽早干预，对于改善PCOS患者生殖健康至关重要。
胰岛素抵抗(Insulin resistance,IR)和高胰岛素血症是***(Polycystic Ovary Syndrome，PCOS)患者主要病理基础，在PCOS的发生发展中起关键的作用，国内外研究发 现PCOS患者中50-70％存在IR及高胰岛素血症。PCOS患者胰岛素抵抗状态(PCOS-IR) 不仅影响其生育力，还与一系列的健康问题相关，包括月经稀发或闭经、异常子宫出血、自 然流产、妊娠高血压疾病、2型糖尿病、心血管疾病、子宫内膜癌等。2013年美国内分泌协 会颁布PCOS诊疗指南指出：***在PCOS患者中是突出存在的临床问题；PCOS-IR患者还 存在着诸多如妊娠糖尿病、先兆子痫等产科并发症，其罹患2型糖尿病、心血管疾病、子宫 内膜癌的风险比不伴IR的PCOS患者高2-6倍。2018年PCOS国际循证指南提出：PCOS属 于影响公共健康的疾病。我们前期研究亦发现：胰岛素抵抗型的PCOS患者存在更为严重的 糖脂代谢紊乱，尽早干预PCOS患者的胰岛素抵抗，对于提高妇女生殖健康有重要意义。
二、载脂蛋白C-Ⅲ可作为分子标记物，诊断PCOS患者的胰岛素抵抗状态。
ApoC3基因位于11号染色体A1/CIII/AIV基因簇内，全长3.1kb，编码ApoC3蛋白。ApoC3 蛋白是一个拥有79个氨基酸的糖蛋白，人体内主要在肝脏合成，少量在小肠合成，主要是调 节三酰甘油脂蛋白(TRLS)的分解与代谢。ApoC3作为脂蛋白脂酶(LPL)抑制剂，可通过 抑制脂肪酶、肝脂酶、胆固醇脂卵磷脂酰基转移酶的活性影响脂代谢。多位学者提出ApoC3 过多，不仅使脂蛋白与低密度脂蛋白受体结合受阻，而且使脂蛋白与TRLs及其残粒结合受 阻，抑制受体与极低密度脂蛋白(VLDL)、乳糜微粒(DM)有效结合，可以引起脂代谢紊乱， 可造成内脏脂肪堆积、肥胖、高甘油三酯血症、2型糖尿病等。
三、PCOS患者存在卵巢局部IR，与高表达的ApoC3密切相关，导致***功能障碍。
近20年来，越来越多的研究表明，胰岛素抵抗以及代偿性高胰岛素血症是PCOS的重 要特征改变之一，胰岛素代谢异常或胰岛素信号传导途径异常是PCOS发病机制的核心。PCOS-IR能够增加垂体对***释放激素的反应性，导致促***以及雄激素分泌 增加，破坏下丘脑-垂体-卵巢轴的正常功能，与高雄激素血症、生殖障碍和代谢综合征等密 切相关。多项研究表明在患有PCOS的女性中,胰岛素活性在经典靶器官(脂肪组织和骨骼肌 等)中缺失引起胰岛素抵抗。PCOS同时具有卵巢局部IR，如卵巢颗粒细胞IR，影响卵巢局 部葡萄糖代谢、胆固醇摄取、甾体激素生成以及细胞***增殖。有研究发现PCOS患者卵巢 颗粒细胞存在受体后胰岛素信号传导分子的改变，导致下游激酶活性的改变，减弱胰岛素信 号转导，促进卵巢局部胰岛素抵抗发生。可见，胰岛素活性缺陷的复杂机制也可表现在卵巢 局部，而这也是我们本次研究的主要内容。胰岛素在细胞内的信号传导途径包括调节葡萄糖 代谢的促代谢途径和引起细胞***增殖作用的促***途径等。卵巢局部IR时表现为细胞内胰 岛素的促代谢作用途径受损，而促***作用途径发生放大现象，使卵巢体积增加、卵泡发育 停滞、***障碍、及卵巢局部高雄激素状态，并导致生殖障碍。我们前期发现：PCOS患者 卵巢组织及颗粒细胞呈增殖状态。
发明内容：
本发明的目的是提供调控ApoC3表达量的制剂在制备预防或治疗胰岛素抵抗型多囊卵巢 综合征药物中的应用。
优选，所述的调控ApoC3表达量的制剂是降低ApoC3表达量的制剂。
进一步优选，所述的降低ApoC3表达量的制剂是胰岛素增敏剂。
优选，所述的胰岛素增敏剂可以为二甲双胍或小檗碱。
本发明通过发现，PCOS患者卵巢组织及颗粒细胞呈增殖状态，PCOS患者卵巢组织ApoC3高表达，PCOS模型大鼠卵巢组织ApoC3高表达，与PCOS卵巢局部胰岛素抵抗密 切相关，进一步发现，利用胰岛素增敏剂可以下调卵巢中APOC3蛋白表达，改善模型大鼠 卵巢组织的IR抵抗情况，因此可以将调控ApoC3表达量的制剂在制备预防或治疗胰岛素抵 抗型***药物中的应用。
附图说明：
图1是免疫组化法及Western blot检测PCNA表达，其中A是免疫组化检测PCNA表达，B 是Westernblot检测PCNA表达，C是Westernblot检测caspase 3的表达。
图2是PCOS-IR患者卵巢组织中ApoC3蛋白高表达(HE×40)，A.PCOS-IR卵巢颗粒细胞 ApoC3高表达，B.PCOS-NIR卵巢组织ApoC3低表达；
图3是PCOS模型组及对照组大鼠***上皮细胞(A.模型组，B.对照组)；
图4是模型组大鼠胰岛素、HOMA-IR高于对照组大鼠(p＜0.01)；
图5是用胰岛素增敏剂(高、中、低剂量小檗碱及二甲双胍)能改善模型大鼠卵巢组织的IR 抵抗情况，大鼠卵巢ApoC3表达随之下降的图。
具体实施方式：
以下实施例是对本发明的进一步阐述，而不是对本发明的限制。
实施例1：
材料与方法
1、临床样本的收集
由于PCOS的高度异质性，其诊断标准尚有分歧，本项目组采用2003年欧洲人类生殖和 胚胎与美国生殖医学会的(ESHRE/ASRM)鹿特丹专家会议推荐的诊断标准：
(1)、稀发***或无***；
(2)、高雄激素的临床表现和(或)高雄激素血症；
(3)、超声表现为多囊卵巢(一侧或双侧卵巢有12个以上直径为2～9mm的卵泡，和(或) 卵巢体积＞10ml)；
(4)、上述3条中符合2条，并排除其他高雄疾病如先天性肾上腺皮质增生、库兴综合征、 分泌雄激素的肿瘤。
由于PCOS的诊断需要排除其他相关高雄激素性疾病，故由专业研究人员按照鹿特丹专家 会议进行筛选PCOS患者。
病例纳入标准如下：
(1)、符合***的诊断标准；
(2)、年龄在18～45岁之间的女性；
(3)、本次治疗期间未曾使用过其他西药治疗；
(4)、知情同意，志愿受试，并可追踪观察者。
病例排除标准如下：
(1)、不符合***的诊断标准者；
(2)、年龄在18以下或45岁以上的女性，或为妊娠期、哺乳期妇女；
(3)、具有严重的心血管疾病、肝脏疾病、肾脏疾病、血液***疾病、肺脏疾病或影响其 生存的重大疾病，如肿瘤或艾滋病等；
(4)、有精神或法律上的残疾患者；
(5)、肾上腺、甲状腺、垂体等内分泌功能异常的患者；
(6)、怀疑或确有酒精、药物滥用病史的患者；
PCOS胰岛素抵抗组(实验组)入选30例，PCOS非胰岛素抵抗组(对照组)选择年龄、体重与PCOS胰岛素抵抗组患者匹配的患者，入选30例；两组患者均行腹腔镜下卵巢楔形切除 术，取楔形切除的卵巢组织进行研究。收集样本前，征得医院伦理委员会及患者同意，伦理 委员会审批号为：201401011，并与患者签署手术同意书。腹腔镜手术收集卵巢组织样本时， 其大小应达到整个卵巢组织的十分之一，在卵巢组织表面取一块类似金字塔样结构的组织， 该组织应包括有颗粒细胞、卵泡膜细胞、***、***等各种结构。手术将由广东省 妇幼保健院具有IV类腹腔镜执业资格的妇科内分泌主任医师进行，以确保临床样本收集的准 确性及代表性。
2、卵巢组织病理及免疫组化
A、组织切片制备
a组织块石蜡包埋
将活检取出的子宫内膜组织用4％甲醛溶液固定(配置方法：40％甲醛溶液和水按1:9比 例配制而成)。固定时间以12-24h为宜。将组织块放在固定的容器中用流水冲洗24h后依次 用一次70％酒精、80％酒精各脱水2小时，90％酒精脱水1h，95％酒精脱水40min，无水乙 醇Ⅰ脱水40min，无水乙醇Ⅱ脱水30min。并可将组织放于70％酒精中过夜。脱水后组织直接 浸入二甲苯透明剂中(二甲苯Ⅰ，二甲苯Ⅱ)，每次透明为10min。而后采用56℃-58℃石蜡将 组织浸入软蜡Ⅰ1h左右，再浸入软蜡Ⅱ40min；硬蜡Ⅰ40min，硬蜡Ⅱ1h。(一般浸蜡时间为3-4h) 软蜡熔点为45℃-50℃，硬蜡熔点为55℃-60℃。最后把蜡液注入包埋硬具中，迅速将组织块 平放入蜡液中，摆正并铺平，然后移至冷却台，使组织块同蜡液凝固在一起的过程。(硬蜡凝 固定型)
b石蜡切片
在切片前先切去标本周围过多的石蜡(此过程称为“修块”)，但也不能留得太少，否则易 造成组织破坏，连续切片时分片困难。一般切片厚度为5μm。贴片时先在干净的载玻片上涂 一层蛋白甘油，然后于60℃恒温箱中烘烤1-2h，直到玻片烘干；若组织剥脱可涂一层蛋清加 以固定。将贴好的片放置在干净的玻片盒中，4℃冰箱保存，备用。
B、免疫组化部分
a脱蜡和水化
脱蜡前，应将组织切片在室温中放置60min或60℃恒温箱中烘烤20min。然后把组织切 片置于二甲苯中浸泡10min，更换二甲苯后再浸泡10min；而后分别在无水乙醇中浸泡、95％ 乙醇中浸泡以及70％乙醇中各浸泡5min后，用PBS洗两次，每次各5min。接着用蒸馏水或 PBS配置新鲜的3％H2O2，室温封闭5～10min，PBS洗3次，每次2min。
b包埋
抗原修复，用于***固定的石蜡包埋组织切片。煮沸热修复，电炉或者水浴锅加热， 0.01M枸橼酸钠缓冲溶液(pH6.0)至95℃左右，放入组织切片加热10～15min，加热完毕用 自来水冷却至室温，方能将切片取出。用PBS洗5min后，滴加5％BSA封闭液，室温封闭15分钟。甩去多余液体，不洗。而后滴加一抗，4℃过夜(4℃过夜后在室温复温45min)。 第二天清晨用PBS洗3次每次2min。接着滴加聚合HRP标记抗兔子/小鼠IgG二抗，室温孵 育1h。然后用PBS洗3次每次2min。
c显色
用DAB显色试剂盒或者自配显色剂显色(镜下掌握显色程度)，观察至目的信号深背景 颜色浅时立即用蒸馏水终止。先用苏木素复染20s，蒸馏水洗2次每次2min。而后把切片依 次放入50％、70％、80％、90％、95％、100％乙醇中脱水，每次2min。接着将切片放入100％ 二甲苯10min透明。最后用中性树脂50ul封片，室温保存。
3、结果：
人组织样本caspase3及PCNA检测
(1)选取30例PCOS患者及非30例非PCOS卵巢组织进行研究，提取总蛋白，用Western blot检测caspase3的蛋白表达量，结果显示PCOS组中cleaved caspase3的表达量较正常组要 低，表明PCOS卵巢组织中细胞凋亡量要少于正常组。分别用免疫组化法及Westernblot检测 PCNA表达，免疫组化结果表明：PCOS患者中PCNA的表达较正常组增加(红棕色)，因为 PCNA与细胞增殖程度相关，PCNA的表达量增加表明PCOS中细胞增殖较正常组增多。 Western blot检测组织显示，PCOS组织中PCNA的表达量较正常组要高，结果与免疫组化的 结果一致。GAPDH为内参，两组caspase3及PCNA灰度进行统计，PCOS组明显高于对照， 具有统计学意义。误差线代表标准误，P<0.05。图1
(2)、前期预实验对PCOS患者卵巢组织进行免疫组化研究：发现PCOS-IR患者卵巢组织 中ApoC3蛋白高表达，见图2，其中A显示PCOS-IR患者卵巢组织中卵巢颗粒细胞的胞核、 胞浆中ApoC3均高表达，染色呈深棕黄色；B显示PCOS-NIR患者卵巢颗粒细胞的胞核、胞浆中ApoC3均低表达。免疫组化结果提示：ApoC3可能参与PCOS卵巢局部胰岛素抵抗。
实施例2：PCOS-IR大鼠模型的建立
一、材料与方法
1.实验动物
80只21日龄雌性SD大鼠，来源于广东省医学实验动物中心25℃恒温(50％湿度)，清洁级饲养。12小时光照(6：00～18：00)和12小时黑暗(18：00～6：00)周期交替 进行。自由摄取食物和水。
2.实验材料及仪器
DHEA、芝麻油、普通饲料(由广东省医学实验动物中心加工完成)、葡萄糖、0.9％生理 盐水、Elisa试剂盒、瑞-姬氏染色试剂盒、血糖仪(三诺)、血糖试纸、光学显微镜、离心机等。
3.方法
3.1大鼠动物模型造模方法选取21日龄SD雌性大鼠，参照随机数表法随机分成模型 组与空白对照组，对照组15只，模型组65只。分组后，模型组大鼠颈背部皮下注射溶于注射用芝麻油的脱氢表雄酮(Dehydroepiandrosterone,DHEA)溶液0.2ml(6mg/100g)，空白对照组大鼠颈背部皮下注射注射用芝麻油0.2ml，连续注射49天。每三天大鼠称重一次。
3.2造模成功评估方法
3.2.1大鼠***上皮细胞
经造模结束前10天，连续每天通过瑞-姬氏染色方法，观察大鼠***脱落细胞学变化， ***上皮细胞持续10天为角化状态，为诱导成功的PCOS大鼠。
具体实验方法为：用无菌棉签蘸少许生理盐水，***大鼠***轻轻捻动，取出棉签，将 带有***上皮细胞的黏液沿同一个方向涂抹在玻片上，自然干燥，每一只大鼠每日制作两张 玻片，用瑞-姬氏染色A试剂3-4滴均匀涂染30-60s，然后加B试剂6-10滴，再染色10min 后自来水冲洗，自然干燥后分别在40倍、100倍光学显微镜下观察***上皮细胞。
3.2.2大鼠空腹血糖及空腹胰岛素检测：将成功PCOS模型大鼠和空白组大鼠各随机选 取10只老鼠，当晚8时禁食，次晨8时取大鼠眶静脉血做空腹血糖(Fasting blood-glucose, FBG)和空腹胰岛素(Fasting insulin,FINS)检测。血糖水平通过葡萄糖氧化酶法(罗氏血糖仪) 检测，胰岛素(INS)采用酶联免疫(Enzyme linked immunosorbentassay,ELISA)方法检测。 按照2g/kg的剂量大鼠灌胃50％葡萄糖，在给葡萄糖后30，60，120min大鼠剪尾取一滴血 通过血糖仪监测大鼠血糖，绘制OGTT曲线，计算曲线下面积。以及在60,120min时眶静脉 取1ml血于含有抗凝剂的干燥管中，放置在冰上，待当日取材完毕后，离心15min(2500转/ 分)，仔细收集上清，用ELISA方法检测血清胰岛素。依据胰岛素抵抗指数(Homeostasis model assessment of insulin resistance,HOMA-IR)计算方法，HOMA-IR＝FBG(mmol/L)×FINS(m U/L)/22.5。
4、动物实验结果
PCOS-IR大鼠卵巢组织ApoC3蛋白高表达，使用胰岛素增敏剂能改善模型大鼠IR状态， 其卵巢组织ApoC3蛋白表达随之下降。
1、我们通过皮下注射脱氢表雄酮(溶解于芝麻油中)法，成功建立PCOS-IR大鼠模型。 结果显示模型组大鼠的***上皮细胞持续10天均为角化状态，无明显动情周期，而对照组 大鼠有动情周期。提示PCOS-IR大鼠模型建立成功，见图3。
2、模型组(PCOS-IR组)大鼠空腹胰岛素值、HOMA-IR指数明显高于对照组；模型组大鼠空腹胰岛素水平、服用葡萄糖后1h以及2h胰岛素均远高于对照组大鼠，p＜0.01，提示成功建立PCOS-IR大鼠模型，见图4。
3、Western Blot检测各组大鼠卵巢组织中APOC3蛋白的表达：
实验方法
60只PCOS-IR大鼠采用随机分组，每组12只分别为：模型组、小檗碱低剂量组、小檗碱中剂量组、小檗碱高剂量组、盐酸二甲双胍阳性对照组。
对照组采用胰岛素增敏剂盐酸二甲双胍(500mgbid)，根据动物公斤体重剂量折算系数 法换算出大鼠的等效剂量。治疗组大鼠分别以高剂量(162mg/kg)、中剂量(81mg/kg)、低剂 量(40.2mg/kg)的小檗碱进行灌胃干预，每天一次，每次2ml，二甲双胍组每日给予2ml盐 酸二甲双胍溶液(45mg/kg)灌胃。连续给药28天。
PCOS-IR大鼠卵巢组织中ApoC3蛋白高表达，且使用胰岛素增敏剂(高、中、低剂量小 檗碱及二甲双胍)能改善模型大鼠卵巢组织的IR抵抗情况，大鼠卵巢ApoC3表达随之下降， 见图5。
APOC3蛋白：结果显示，与正常组相比，模型组的APOC3蛋白表达量显著上调(P<0.01)， 高、低剂量组可下调APOC3蛋白表达(P<0.05，P<0.01)。中剂量下调APOC3蛋白表达，但 未显示出显著性差异(P>0.05)。(注：1.正常组；2.阳性药(二甲双胍)组；3.模型组；4.低剂量 小檗碱组；5.中剂量小檗碱组；6.高剂量小檗碱组)。
Claims (4)
1.调控ApoC3表达量的制剂在制备预防或治疗胰岛素抵抗型***药物中的应用。
2.根据权利要求1所述的应用，其特征在于，所述的调控ApoC3表达量的制剂是降低ApoC3表达量的制剂。
3.根据权利要求2所述的应用，其特征在于，所述的降低ApoC3表达量的制剂是胰岛素增敏剂。
4.根据权利要求3所述的应用，其特征在于，所述的胰岛素增敏剂可以为二甲双胍或小檗碱。
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