CN103142868A - 一种抑制蛋白酪氨酸磷酸酶-1b的药物 - Google Patents
一种抑制蛋白酪氨酸磷酸酶-1b的药物 Download PDFInfo
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Abstract
本发明公开了一种抑制蛋白酪氨酸磷酸酶-1B(PTP-1B)的药物，其特征在于：所述的这种药物的组成及各味药占所述的药物的总重量的百分比范围为，杜仲(25.5％-30.6％)，天麻(27.6％-33.5％)，薄荷(28.2％-37.3％)，檀香(18.7％-25.3％)。所述的这种药物的制备方法采用常用的制备方法，将其粉碎，混合，制成散剂或者其它任何一种药剂学上的剂型。实验表明，这种抑制PTP-1B的药物能有效的降低糖尿病大鼠血浆PTP-1B地含量并抑制其活性，能有效地降低糖尿病大鼠的血糖水平。
Description
技术领域
本发明涉及一种一种抑制蛋白酪氨酸磷酸酶-1B的药物的药物
背景技术
糖尿病(diabetes)是多种致病因子作用于机体导致胰岛功能减退、胰岛素抵抗等而引发的糖、蛋白质、脂肪、水和电解质等一系列代谢紊乱综合征，临床上以高血糖为主要特点。我国目前糖尿病的总体患病率已达9.7％。同期糖尿病前期的患病率高达15.5％。根据调查结果所做出的推算显示我国总糖尿病患病人数达9千2百万以上，糖尿病前期人数达1亿4千8百万以上。近年来很多研究显示：蛋白酪氨酸磷酸酶1B(Protein Tyrosine Phosphatase-1B，PTP-1B)可能在胰岛素抵抗中发挥了重要的作用。它是胰岛素信号转导中一个十分关键的分子。通过去磷酸化信号分子，从而终止胰岛素信号转导。PTP-1B缺失小鼠，其表型及寿命都正常，同时胰岛素和瘦素的敏感性明显增加，能够抵抗饮食诱导的肥胖的发生。许多研究也进一步证实PTP-1B可以负性调节胰岛素和瘦素的信号转导。PTP-1B是蛋白质的酪氨酸磷酸化的重要参与因子。而蛋白质的酪氨酸磷酸化是翻译后修饰的主要方式之一，此反应受作用相反的一对酶调节，即蛋白酪氨酸激酶(protein tyrosine kinase，PTK)使酪氨酸磷酸化和蛋白酪氨酸磷酸酶使其脱磷酸。其中蛋白酪氨酸磷酸酶-1B(PTP-1B)由于分子量小，易于获得，倍受研究者的关注。近十年来研究发现，PTP与2型糖尿病的胰岛素信号传导、高血脂、肥胖密切相关。研究发现，人类共有112种PTPs。PTPs超家族分为酪氨酸特异性、双特异性和低分子量磷酸酶三大类。酪氨酸特异性磷酸酶和低分子量磷酸酶主要作用于含磷酸化酪氨酸的蛋白质，双特异性磷酸酶作用于含磷酸化丝氨酸或含磷酸化苏氨酸的蛋白质。PTPs家族还可以分为8个亚族：①酪氨酸特异性PTPs。②双特异性PTPs。③细胞分裂周期蛋白25(cdc25)亚族。④第10号染色体缺失的磷酸酶和张力蛋白同源基因(PTEN)亚族。⑤myotubularins。⑥再生肝磷酸酶(PRL)亚族。⑦低分子量PTPs。⑧新发现的cdc14亚族。与胰岛素信号调节紧密相关的是酪氨酸特异性PTPs，它又可以分为受体型和非受体型两类。受体型酶位于细胞膜上，可以把细胞外基质信号向胞内传导；非受体型酶主要位于胞内，结构上包括一个单独的催化区和包含肉瘤同源区段2在内的氨基端或羧基端延伸区，延伸区可能具有靶向调控功能。PTP-1B是胞内PTPs的代表，是第一个被鉴定并纯化的哺乳动物PTP，由435个氨基酸残基组成，分子量约50kD。人类的PTP-1B基因全长约74kb，共10个外显子，位于20q13.1-13.2。PTP-1B广泛表达于肌肉、心、肝、肾、脑等各种组织中，其C端有一富含脯氨酸残基的片段，PTP-1B通过该片段与内质网相连，此片段可水解断裂，从而释放出有 活性的PTP-1B。
PTP-1B生理功能有：①与胰岛素受体及其底物作用，可以减弱胰岛素信号传导。胰岛素的信号传导也能反馈地影响PTP-1B的活性。②使瘦素相关的Janus激酶去磷酸化，阻止瘦素信号传导1～13.2。与多种生长因子及底物相互作用，调控细胞的生长、分化。此外，PTP-1B还与催乳素信号传导、整合素信号传导和血小板凝集等关系密切。
PTP-1B的生理调节：PTP-1B的活性和基因表达在体内受多种因素调节。生长因子、蛋白激酶Galpha(i2)、蛋白激酶B、Cu2+等均可不同程度地降低PTP-1B的活性。蛋白激酶Galpha(i2)还可在胰岛素敏感组织内抑制PTP-1B的表达。研究发现运动可以降低胰岛素抵抗大鼠肝脏组织中PTP-1B的表达。另外，PTP-1B也受其自身底物的调节。
PTP-1B与2型糖尿病：PTP-1B与胰岛素信号传导：胰岛素信号传导首先需要胰岛素与胰岛素受体结合。胰岛素受体是由α2β2亚单位组成的四聚体，α亚单位与胰岛素结合后β亚单位的酪氨酸及胰岛素受体底物发生磷酸化而被激活。磷脂酰肌醇3激酶(phosphatidylinositol3-kianse，PI3K)等下游蛋白也被活化，葡萄糖转运蛋白4由细胞内转至细胞膜，最终葡萄糖进入细胞。在上述过程中的磷酸化反应可以被PTP-1B等因子逆转，从而阻止胰岛素信号的传导。因此，PTP-1B是胰岛素信号传导的一个重要负性调节物质。如果PTP-1B结构或活性改变，将改变其对胰岛素信号传导的抑制作用。外周组织胰岛素抵抗和胰岛β细胞功能受损是2型糖尿病发病机制的两个基本条件，而胰岛素信号传导被抑制是胰岛素抵抗的重要环节。PTP-1B升高表达可引起胰岛素抵抗，从而引发2型糖尿病。资料表明，PTP-1B的表达水平在糖尿病或发生胰岛素抵抗时明显升高。有关使转基因鼠表达人PTP-1B的研究发现，与对照组相比，实验组鼠肌肉中胰岛素刺激引起的胰岛素受体酪氨酸磷酸化水平降低35％，PI3K活性降低40％～60％，葡萄糖转运所需的蛋白激酶c活性也减弱；表达PTP-1B的小鼠全身葡萄糖清除和肌肉的葡萄糖摄取减少了40％～50％。有研究表明体重指数正常的初诊2型糖尿病较正常对照者存在明显的胰岛素抵抗，而PTP-1B在前者内脏脂肪组织中的表达较后者显著增高，几乎是后者的4倍。可见内脏脂肪组织PTP-1B的表达升高在胰岛素抵抗中也有重要作用。另有研究报道采用PTP-1B反义寡核苷酸处理糖尿病模型小鼠(ob/ob小鼠)，抑制其PTP-1B表达，发现在肝、脂肪和骨骼肌内PTP-1B的表达下调时，ob/ob小鼠血糖恢复正常，与糖代谢有关的各个指标也都趋于正常。以上结果说明，PTP-1B在拮抗胰岛素信号传导中具有重要作用。
糖尿病患者体内PTP(尤其是PTP-1B)含量及活性的异常可能存在多方面的原因，但基因变异被认为是主要因素。PTP-1B的基因变异与糖尿病有密切关系。有报道，在对653个样 本的研究中，先用限速酶AVAI对样本的一种单核苷酸多肽链消化后，再利用外显子PCR放大技术对其编码发现，带有PTP981T/981C基因型的人群患患2型糖尿病的概率大大增加。
本专利所申请的药物是以纯天然植物杜仲，天麻，薄荷，檀香混合加工提炼而成的一种抑制蛋白酪氨酸磷酸酶-1B药物，对由PTP-1B异常(胰岛素抵抗)引起的糖尿病有特殊的疗效。其中，所述的杜仲占所述的药物的总重量的百分比在25.5％-30.6％；所述的天麻占所述的药物的总重量的百分比在27.6％-33.5％之间，所述的薄荷占所述的药物的总重量的百分比在28.2％-37.3％之间，所述的檀香占所述的药物的总重量的百分比在18.7％-25.3％之间。
发明内容
1本发明所要解决的技术问题在于提供一种抑制蛋白酪氨酸磷酸酶-1B的药物，含4味中药。
2本发明所要解决的技术问题还在于：提供抑制蛋白酪氨酸磷酸酶-1B的药物。
3该药物能有效治疗糖尿病而无任何副作用。
附图说明
附图1显示了本专利所申请的对蛋白酪氨酸磷酸酶-1B有抑制作用的药物有降低糖尿病大鼠血浆蛋白酪氨酸磷酸酶-1B含量的作用，图中a为正常组，b组，c组，d组，e组，f组，和g组为糖尿病空白对照组和不同用药组。
a.正常空白对照
b.糖尿病空白对照
c.糖尿病用本专利所申请的对蛋白酪氨酸磷酸酶-1B有抑制作用的药物
d.糖尿病单用杜仲
e.糖尿病单用天麻
f.糖尿病单用薄荷
g.糖尿病单用檀香
附图2显示了本专利所申请的对蛋白酪氨酸磷酸酶-1B有抑制作用的药物对糖尿病大鼠血浆蛋白酪氨酸磷酸酶-1B的活性有抑制作用，图中a为正常组，b组，c组，d组，e组，f组，和g组为糖尿病空白对照组和不同用药组。
a.正常空白对照
b.糖尿病空白对照
c.糖尿病用本专利所申请的对蛋白酪氨酸磷酸酶-1B有抑制作用的药物
d.糖尿病单用杜仲
e.糖尿病单用天麻
f.糖尿病单用薄荷
g.糖尿病单用檀香
附图3显示了本专利所申请的对蛋白酪氨酸磷酸酶-1B有抑制作用的药物有降低对糖尿病大鼠血糖的作用，图中图中a为正常组，b组，c组，d组，e组，f组，和g组为糖尿病空白对照组和不同用药组。
a.正常空白对照
b.糖尿病空白对照
c.糖尿病用本专利所申请的对蛋白酪氨酸磷酸酶-1B有抑制作用的药物
d.糖尿病单用杜仲
e.糖尿病单用天麻
f.糖尿病单用薄荷
g.糖尿病单用檀香。
Claims (1)
1.一种抑制蛋白酪氨酸磷酸酶-1B(PTP-1B)的药物，其特征在于：所述的这种药物由杜仲，天麻，薄荷，檀香组成，其中，所述的杜仲占所述的药物的总重量的百分比在25.5％-30.6％；所述的天麻占所述的药物的总重量的百分比在27.6％-33.5％之间，所述的薄荷占所述的药物的总重量的百分比在28.2％-37.3％之间，所述的檀香占所述的药物的总重量的百分比在18.7％-25.3％之间。
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| CN101658641A (zh) * | 2009-09-25 | 2010-03-03 | 江西本草天工科技有限责任公司 | 含天麻杜仲叶苦丁茶的保健制剂及其制备方法 |
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| CN101658641A (zh) * | 2009-09-25 | 2010-03-03 | 江西本草天工科技有限责任公司 | 含天麻杜仲叶苦丁茶的保健制剂及其制备方法 |
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