CN111529691A - 甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用 - Google Patents
甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用 Download PDFInfo
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- male hypogonadism
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Abstract
本发明提供了甲状旁腺激素(1‑34)在制备治疗男性性腺功能减退症的药物中的应用，属于性功能药物技术领域。PTH1‑34提高生物体血清和睾丸中睾酮含量的作用同时促进雄性生物体的睾丸间质干细胞分化的作用。因此PTH1‑34作为活性成分在制备治疗男性性腺功能减退症药物中的应用。本发明还提供了包括甲状旁腺激素(1‑34)和甲状旁腺激素相关肽的组合物及其在制备治疗男性性腺功能减退症、诱导睾丸间质干细胞分化或提高睾丸和血清中睾酮含量的药物中的应用。
Description
技术领域
本发明属于性功能药物技术领域，具体涉及甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用。
背景技术
“提高生殖健康水平，改善出生人口素质”是我国中长期科学和技术发展规划纲要的主题，也是我国人口健康战略的核心内容之一。我国是发展中国家的人口大国，研究国民的生殖健康是我们从事生殖生物学与生殖医学研究者所面临的巨大机遇和挑战。
男性性腺功能减退症是由于雄性激素缺乏、减少或其作用不能发挥所导致的性功能减退性疾病。睾丸间质细胞分泌的睾酮是雄性体内雄激素的最主要来源。人体血清中的睾酮是间质细胞受脑垂体分泌的促黄体生成激素(Luteinizing hormone,LH)刺激而产生的，并受一系列负反馈机制调节。临床研究表明，男性下丘脑-垂体轴功能随着年龄增长而逐渐下降，从而导致LH脉冲释放的幅度减弱，最终影响睾丸间质细胞合成和分泌雄性激素。此外，睾丸间质细胞在分化发育过程中分为四个显著不同的阶段：间质干细胞(StemLeydig cell)、祖间质细胞(Progenitor Leydig cell)、幼间质细胞(Immature Leydigcell)和成年间质细胞(Adult Leydig cell)。而这些发育过程中由于增殖分化异常、数量减少及激素合成分泌功能减退也会导致体内雄激素缺乏。
目前，临床上治疗性腺功能减退症主要通过睾酮补充疗法，然而，该疗法除了需要定期注射睾酮以外，还存在显著的安全性问题。首先，长期定量补充睾酮会使患者易生痤疮并患红细胞增多症；其次，容易造成血清睾酮浓度的大幅度波动，进而引起患者情绪和迟发性性腺功能低下综合征症状的明显起伏；再次，患者容易出现水、钠潴留及阴茎异常勃起、排尿困难等不良反应，甚至肝肾功能受损及引发前列腺癌等疾病。
甲状旁腺激素(parathyroid hormone，PTH)是甲状旁腺主细胞分泌的碱性单链多肽类激素。它的主要功能是调节脊椎动物体内钙和磷的代谢，促使血钙水平升高，血磷水平下降。PTH促使血浆钙离子浓度升高，其作用的主要靶器官是骨和肾脏。它动员骨钙入血，促进肾小管对钙离子的重吸收和磷酸盐的排泄，使血钙浓度增加和血磷浓度下降。此外，PTH还间接促进肠道对钙离子的吸收。PTH1-34与84个氨基酸的人PTH的N端氨基酸34个(生物活性区)序列完全相同。PTH1-34与甲状旁腺激素1受体(Parathyroid hormone 1 receptor，PTH1R)结合后，通过激活细胞内腺苷酸环化酶-环磷酸腺苷-蛋白激酶A(PKA)途径与磷酯酶C(PLC)-胞浆钙离子-蛋白激酶C(PKC)两条信号转导通路发挥生物学作用，临床上常用于治疗骨质疏松症。
发明内容
有鉴于此，本发明的目的在于提供一种甲状旁腺激素(1-34)的新用途，即甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用。
本发明提供了甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用。
本发明提供了甲状旁腺激素(1-34)在制备诱导睾丸间质干细胞分化的药物中的应用。
本发明提供了甲状旁腺激素(1-34)在制备提高睾丸和血清中睾酮含量的药物中的应用
优选的，所述的甲状旁腺激素(1-34)源自人、小鼠或大鼠。
优选的，所述的甲状旁腺激素(1-34)的氨基酸序列如SEQ ID No1所示。
优选的，所述的甲状旁腺激素(1-34)的剂量不低于10ng/睾丸/天。
本发明还提供了一种用于男性性腺功能减退症的组合物，包括甲状旁腺激素(1-34)和甲状旁腺激素相关肽；
所述甲状旁腺激素(1-34)和甲状旁腺激素相关肽质量比为1:1。
所述甲状旁腺激素相关肽的氨基酸序列如SEQ ID No.2所示。
本发明提供了所述组合物在制备治疗男性性腺功能减退症、诱导睾丸间质干细胞分化或提高睾丸和血清中睾酮含量的药物中的应用。
本发明提供了所述组合物在改善男性性腺功能减退症、诱导睾丸间质干细胞分化或提高睾丸和血清中睾酮含量的食品中的应用。
本发明提供的甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用。本发明提供的甲状旁腺激素激动剂甲状旁腺激素(1-34)，用以诱导睾丸间质干细胞的分化，增加睾丸和血清中睾酮含量，最终改善或者治愈男性性腺功能减退症。实验结果证明，采用qPCR检测睾酮合成通路上相关基因的表达情况，表明PTH1-34处理后，能有效上调睾丸间质细胞中Lhcgr、Cyp11a1、Cyp17a1、Hsd3b1、Hsd17b3和Insl3的mRNA水平特定基因的表达，睾酮含量检测结果表明PTH1-34促进睾丸间质干细胞分化后睾酮产量增加。同时血清睾酮检测结果表明，PTH1-34增加血清睾酮含量。PTH1-34上调间质干细胞的再生时特定基因Star、Cyp11a1、Hsd3b1和Hsd17b3的mRNA水平，且有统计学意义。
本发明提供了所述组合物在制备治疗男性性腺功能减退症、诱导睾丸间质干细胞分化或提高睾丸和血清中睾酮含量的药物中的应用。
附图说明
图1为实施例1中PTH1-34刺激睾丸间质干细胞分化后睾酮含量情况；其中，数据用平均数±标准误表示，样本量为6；“*”表示P<0.05；“***”表示P<0.001；
图2为实施例1中PTH1-34刺激睾丸间质干细胞分化后上调睾丸间质细胞特定基因的表达情况；其中，数据用平均数±标准误表示，样本量为6；“*”表示P<0.05；“**”表示P<0.01，“***”表示P<0.001；
图3为实施例2中PTH1-34刺激间质干细胞的再生时血清睾酮含量结果；其中，数据用平均数±标准误表示，样本量为6；“*”表示P<0.05；
图4为实施例2中PTH1-34刺激间质干细胞的再生时mRNA变化情况，其中，数据用平均数±标准误表示，样本量为6；“*”表示P<0.05；“**”表示P<0.01，“***”表示P<0.001，与对照组相比，PTH1-34上调Star、Cyp11a1、Hsd3b1和Hsd17b3的mRNA水平，且有统计学意义。
具体实施方式
本发明提供了甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用。
在本发明中，所述的甲状旁腺激素(1-34)可以通过从自然界生物体中分离、多肽化学合成；所述的甲状旁腺激素(1-34)也可以通过体外重组表达获得，例如经原核微生物(如：大肠杆菌)基因工程菌表达后纯化、真核微生物(如：啤酒酵母、毕赤酵母和乳酸克鲁韦酵母等)基因工程菌表达后纯化或由动物细胞(如：中国仓鼠CHO、仓鼠BHK、鼠骨髓瘤细胞小鼠成纤维细胞、猴CV1细胞和人淋巴细胞等)等进行表达并纯化。所述的甲状旁腺激素(1-34)优选源自人、小鼠或大鼠。所述的甲状旁腺激素(1-34)的氨基酸序列优选如SEQ ID No1所示(Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn Ser MetGlu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His Asn Phe)。本发明对所述重组PTH1-34的制备方法没有特殊限制，采用本领域所熟知的重组蛋白的制备方法即可。所述甲状旁腺激素(1-34)还包括通过化学或生物的手段以共价键或离子键等连接形式进行修饰，例如，为了多肽的稳定性、安全性和长效性的目的而进行聚乙二醇化。
本发明提供了甲状旁腺激素(1-34)在制备诱导睾丸间质干细胞分化的药物中的应用。
在本发明中，所述甲状旁腺激素(1-34)与上述应用中甲状旁腺激素(1-34)完全一致，在此不做赘述。
在本发明中，每天睾丸内注射PTH1-34(0、1和10ng/睾丸)到EDS后第28天，然后取睾丸，经RNA提取和qPCR扩增，PTH1-34刺激间质干细胞再生时上调Star、Cyp11a1、Hsd3b1和Hsd17b3的mRNA水平，且有统计学意义(10ng/睾丸/天用量)。
本发明提供了甲状旁腺激素(1-34)在制备提高睾丸和血清中睾酮含量的药物中的应用。
在本发明中，所述甲状旁腺激素(1-34)与上述应用中甲状旁腺激素(1-34)完全一致，在此不做赘述。
在本发明中，所述的甲状旁腺激素(1-34)的剂量优选不低于10ng/睾丸/天。采用1pg/ml、10pg/ml和100pg/ml PTH1-34的浓度处理曲细精管，结果表明，与对照组和1pg/ml浓度处理组相比，大于10pg/ml浓度的PTH1-34能显著提高睾酮浓度，且100pg/ml浓度的PTH1-34的能极显著提高睾酮浓度。与对照组相比，100pg/ml浓度的PTH1-34上调Lhcgr、Cyp11a1、Cyp17a1、Hsd3b1、Hsd17b3和Insl3的mRNA水平，且有统计学意义。每天睾丸内注射PTH1-34(0、1和10ng/睾丸)到EDS后第28天，测定血清睾酮水平，与对照相比，PTH1-34(10ng/睾丸/天)可显著提高血清睾酮水平。
本发明还提供了一种用于男性性腺功能减退症的组合物，包括甲状旁腺激素(1-34)和甲状旁腺激素相关肽质量比为1:1。
在本发明中，所述甲状旁腺激素(1-34)和甲状旁腺激素相关肽质量比为1:1。甲状旁腺激素相关肽的氨基酸序列如SEQ ID No.2(Ala Val Ser Glu His Gln Leu Leu HisAsp Lys Gly Lys Ser Ile Gln Asp Leu Arg Arg Arg Phe Phe Leu His His Leu IleAla Glu Ile His Thr Ala Glu Ile Arg Ala Thr Ser Glu Val Ser Pro Asn Ser LysPro Ser Pro Asn Thr Lys Asn His Pro Val Arg Phe Gly Ser Asp Asp Glu Gly ArgTyr Leu Thr Gln Glu Thr Asn Lys Val Glu Thr Tyr Lys Glu Gln Pro Leu Lys ThrPro)。所述甲状旁腺激素(1-34)和甲状旁腺激素相关肽的来源没有特殊限制，采用本领域所熟知的原料来源即可。
本发明提供了所述组合物在制备治疗男性性腺功能减退症、诱导睾丸间质干细胞分化或提高睾丸和血清中睾酮含量的药物中的应用。
在本发明中，所称的“药物”是指可以用于预防或治疗某种疾病的单一化合物、多种化合物形成的组合物、中药材及其提取物，或指以单一化合物为主要活性成分的组合物或制剂(formulation)，还指由多种化合物为活性成分的组合物或制剂。“药物”应理解为不仅指根据一国之法律规定，通过其设立的行政机构审批并准予生产的产品，还指在为了获得通过审批和准予生产的过程中，所形成的含单一化合物为活性成分的各类物质形态。“形成”应理解为通过化学合成、生物转化或购买等途径获得。
所述药物中除含有PTH1-34的组合物外，还包括各种与所含化合物或组合物相适应的药物辅料，以制成有利于给药的剂型，如：但不仅限于水溶液注射剂、粉针剂、丸剂、散剂、片剂、贴剂、栓剂、乳剂、霜剂、凝胶剂、颗粒剂、胶囊剂、气雾剂、喷雾剂、粉雾剂、缓释剂和控释剂等。这些药用辅料既可以是各种制剂中常规使用的，如：但不仅限于等渗剂、缓冲液、矫味剂、赋形剂、填充剂、粘合剂、崩解剂和润滑剂等；也可以是为了与所述物质相适应而选择使用的，如：乳化剂、增溶剂、抑菌剂、止痛剂和抗氧剂等，这类辅料能有效提高组合物所含化合物的稳定性和溶解性或改变化合物的释放速率和吸收速率等，从而改善各种化合物在生物体内的代谢，进而增强组合物的给药效果。此外，还可以为实现特定的给药目的或方式，如：缓释给药、控释给药和脉冲给药等，而使用的辅料，如：但不仅限于明胶、白蛋白、壳聚糖、聚醚和聚酯类高分子材料，如：但不仅限于，聚乙二醇、聚氨酯、聚碳酸酯及其共聚物等。所称的“有利于给药”的主要表现有：但不仅限于提高治疗效果、提高生物利用度、降低毒副作用和提高患者顺应性等。
在水溶液注射剂中，辅料一般包括等渗剂和缓冲液，以及必要的乳化剂(如：Tweeen-80、Pluronic和Poloxamer等)、增溶剂和抑菌剂等。此外，还包括含有药学上可接受的其它药用辅料，如：抗氧剂、pH调节剂和止痛剂等。用于制取口服液体制剂的辅料一般包括溶剂，以及必要的矫味剂、抑菌剂、乳化剂和着色剂等。用于制取片剂的辅料一般包括填充剂(如：淀粉、糖粉、糊精、乳糖、可压性淀粉、微晶纤维素、硫酸钙、磷酸氢钙和甘露醇等)、粘合剂(如：乙醇、淀粉浆、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、明胶溶液、蔗糖溶液和聚乙烯吡咯烷酮的水溶液或醇溶液等)、崩解剂(如：干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮和交联羧甲基纤维素钠)和润滑剂(如：硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇4,000、聚乙二醇6,000和月桂醇硫酸镁等)等。用于制取乳剂的辅料一般为水、油(如：脂肪酸)、乳化剂，以及必要的防腐剂和矫味剂等。用于制取颗粒剂的辅料与片剂类似，但造粒过程不同。根据需要，将制得的颗粒剂与助流剂混合后装入胶囊即得胶囊剂。
本发明所称的“生物体”、“动物”或“患者”是指人、野生动物和家畜(Livestock)。野生动物为自然状态下未经人工驯化的动物。家畜是为了提供食物来源而人工饲养的动物，如：但不仅限于狗、猫、鼠、大鼠、仓鼠、猪、兔、奶牛、水牛、公牛、绵羊、山羊、鹅和鸡等。给予治疗的“患者”或“生物体”优先选择哺乳动物，尤其是人。
本发明提供了所述组合物在改善男性性腺功能减退症、诱导睾丸间质干细胞分化或提高睾丸和血清中睾酮含量的食品中的应用。
本发明所称的“食品”是指包括本发明提供的各种化合物、组合物或提取物制成可食用的单一化合物或组合物。该种单一化合物或组合物的生产和制造应当符合相关食品安全标准，但是这些食品安全标准不得限定本发明。
下面结合实施例对本发明提供的甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用进行详细的说明，但是不能把它们理解为对本发明保护范围的限定。
实施例1
PTH1-34对大鼠睾丸间质干细胞的促分化作用
雄性Sprague-Dawley大鼠(90日龄)，实验前7天腹腔注射乙二胺四乙酸(EDS，剂量为75毫克/公斤体重)，二氧化碳处死后，将睾丸取出，置于冰冷的磷酸缓冲液中，剪除被膜，血管与曲细精管剥离，将曲细精管分离成单根，将曲细精管均分至12孔板中，于诱导分化培养基(sigma公司的DMEM/12培养基，加上5毫摩尔/升的氯化锂和5纳克/毫升的LH)在37℃，5％二氧化碳的条件下培养2周。在第二周，具体分组，加入不同浓度的PTH1-34处理曲细精管，具体分组为对照组、1、10和100pg/ml PTH1-34。每3.5天更换一次培养基，收集培养基，用化学发光免疫法(将IMMULITE2000全自动化学发光免疫分析仪开机预热至少2小时，将冻存的培养基在室温解冻后振荡离心；在睾酮测定专用的分杯管中各加入至少300ul标准血清或样本，按顺序置入托盘中；在化学发光免疫分析仪中加入西门子公司的总睾酮测定试剂盒，上机测定睾酮。)分析培养基中睾酮含量，同时收集曲细精管提取RNA，逆转录试剂盒(货号：11753500，购自Invitrogen公司)反转录1微克RNA，42℃逆转录30分钟后，85℃处理5分钟终止反应，40S核糖体蛋白S16基因(40S核糖体蛋白S16基因(RPS16，其引物序列由华大基因合成)作为内参，qPCR检测睾酮合成通路上Star、Scarb1、Nr5a1、Lhcgr、Cyp11a1、Cyp17a1、Hsd3b1、Hsd17b3和Insl3相关基因的表达情况。
qPCR操作步骤如下：
15ul的反应体系，冰上操作，实验前准备工：离心机打开预冷，拿出cDNA样本、标准品(标准曲线)、引物、SYBR、Rnase free water，尽量至于碎冰上自然冻融，溶解后将cDNA样本、标准品(标准曲线)、引物轻微振荡混匀(漩涡器)，然后低速离心。
1.反应体系见如下表1。
上述的试剂合起来为13ul，按所需要的样本数量来配(比实际孔数多配一些)；
2.将上述配好的混合液混匀，在96孔板中每个加13μl；
3.再在每个孔中加入2ul的样本(稀释好的cDNA)及标准品；
4.将96孔板贴好膜，短时间低速离心；
5.将96孔板放入Q-PCR仪(Bio-Rad，美国)中，按照如下扩增程序扩增：
95℃2min；96℃，5s，60℃10s，Plate road，39个循环；65℃，5s；95℃，0.5℃/s。
引物序列见下如表2。
表2 qPCR检测用引物信息
图1为PTH1-34刺激睾丸间质干细胞分化后睾酮含量情况；图中，数据用平均数±标准误表示，样本量为6；“*”表示P<0.05；“***”表示P<0.001，与对照组相比，PTH1-34增加培养基睾酮产量有统计学意义。曲细精管在诱导分化培养基中培养1周后，加入不同浓度的PTH1-34(0pg/ml、1pg/ml、10pg/ml和100pg/ml)，在第二周结束时收集培养基测量睾酮水平，10pg/ml和100pg/ml PTH1-34显著增高培养基睾酮水平。
图2为PTH1-34刺激睾丸间质干细胞分化后上调睾丸间质细胞特定基因的表达情况，其中：数据用平均数±标准误表示，样本量为6；“*”表示P<0.05；“**”表示P<0.01，“***”表示P<0.001。在诱导分化培养基中加入PTH1-34，其工作浓度分为0pg/ml、1pg/ml、10pg/ml和100pg/ml。0pg/ml组作为对照组，内参为核糖体蛋白S16基因(Rps16，其引物序列由深圳华大基因研究院合成)；由图2可知，与对照组相比，PTH1-34上调Lhcgr、Cyp11a1、Cyp17a1、Hsd3b1、Hsd17b3和Insl3的特定基因mRNA的水平，且有统计学意义。
实施例2
PTH1-34对EDS处理的睾酮低下症的治疗作用
雄性Sprague-Dawley大鼠(90日龄)18只。腹腔注射75mg/kg EDS理杀死睾丸间质细胞，分3组(每组6只)：1)空白(生理盐水)；2)PTH1-34(1ng/睾丸/天)；3)PTH1-34(10ng/睾丸/天)；从EDS第7天后每天睾丸内注射到EDS第28天。处理动物，取血和睾丸，用实施例1公开的方法进行化学发光免疫法分析血清中睾酮含量，从睾丸间质细胞中提取RNA进行qPCR，检测Star、Cyp11a1、Hsd3b1和Hsd17b3的mRNA水平，内参为Rps16(具体参见实施例1)。
图3为PTH1-34刺激间质干细胞的再生时血清睾酮；其中，数据用平均数±标准误表示，样本量为6；“*”表示P<0.05，与对照组相比，PTH1-34增加血清睾酮产量有统计学意义；给予大鼠腹腔注射75mg/kg EDS处理7天后，每天睾丸内注射PTH1-34(0、1和10ng/睾丸)到EDS后第28天，然后取血测定血清睾酮水平；与对照相比，PTH1-34(10ng/睾丸/天)可显著提高血清睾酮水平。
图4为PTH1-34刺激间质干细胞的再生时mRNA变化情况，其中，数据用平均数±标准误表示，样本量为6；“*”表示P<0.05；“**”表示P<0.01，“***”表示P<0.001。给予大鼠腹腔注射75mg/kg EDS处理7天后，每天睾丸内注射PTH1-34(0、1和10ng/睾丸)到EDS后第28天，然后取睾丸，用于提取RNA进行qPCR检测睾丸间质细胞标记物的mRNA表达量；0pg/ml组作为对照组，与对照组相比，PTH1-34上调Star、Cyp11a1、Hsd3b1和Hsd17b3的mRNA水平，且有统计学意义。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
序列表
<110> 温州医科大学附属第二医院、温州医科大学附属育英儿童医院
<120> 甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用
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Claims (10)
1.甲状旁腺激素(1-34)在制备治疗男性性腺功能减退症的药物中的应用。
2.甲状旁腺激素(1-34)在制备诱导睾丸间质干细胞分化的药物中的应用。
3.甲状旁腺激素(1-34)在制备提高睾丸和血清中睾酮含量的药物中的应用。
4.根据权利要求1～3任意一项所述应用，其特征在于，所述甲状旁腺激素(1-34)源自人、小鼠或大鼠。
5.根据权利要求1～3任意一项所述应用，其特征在于，所述甲状旁腺激素(1-34)的氨基酸序列如SEQ ID No 1所示。
6.根据权利要求1或2所述应用，其特征在于，所述甲状旁腺激素(1-34)的剂量不低于10ng/睾丸/天。
7.根据权利要求1或3所述应用，其特征在于，所述甲状旁腺激素(1-34)的浓度不低于100pg/ml。
8.一种用于男性性腺功能减退症的组合物，其特征在于，包括甲状旁腺激素(1-34)、促黄体生成激素和神经生长因子；
所述甲状旁腺激素(1-34)和甲状旁腺激素相关肽质量比为1:1；
所述甲状旁腺激素相关肽的氨基酸序列如SEQ ID No.2所示。
9.权利要求7或8所述组合物在制备治疗男性性腺功能减退症、诱导睾丸间质干细胞分化或提高睾丸和血清中睾酮含量的药物中的应用。
10.权利要求7或8所述组合物在改善男性性腺功能减退症、诱导睾丸间质干细胞分化或提高睾丸和血清中睾酮含量的食品中的应用。
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