CN111166741B - Egcg在自身免疫疾病中的应用 - Google Patents
Egcg在自身免疫疾病中的应用 Download PDFInfo
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- CN111166741B CN111166741B CN201811338220.XA CN201811338220A CN111166741B CN 111166741 B CN111166741 B CN 111166741B CN 201811338220 A CN201811338220 A CN 201811338220A CN 111166741 B CN111166741 B CN 111166741B
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Abstract
本发明公开了EGCG在自身免疫疾病中的应用。本发明提供了EGCG或其药物组合物在制备抑制核酸引起的细胞或机体自身免疫反应产品中的应用。本发明还提供了EGCG或其药物组合物在制备抑制核酸介导的细胞或机体IFN‑β表达产品中的应用。本发明还提供了EGCG或其药物组合物在制备治疗核酸异常引起的自身免疫疾病产品中的应用。本发明的实验证明了EGCG可以用于制备治疗核酸引起的自身免疫疾病的产品。
Description
技术领域
本发明属于生物技术领域，尤其涉及一种EGCG在自身免疫疾病中的应用。
背景技术
核酸(DNA和RNA)感受器是机体识别侵染细胞的病毒核酸并激活免疫反应的关键蛋白质。正常状态下，机体自身的核酸处于受保护状态不会激活免疫反应，只有当外源病毒或者某些微生物感染机体时，其释放的核酸类物质会被机体识别并引发免疫因子的表达，进而启动免疫反应。
在一些特殊情况下，机体内核酸物质出现错误的剪切、修饰、亚细胞定位、结构变化、突变、异源杂交等异常状况导致核酸类物质累积，这些核酸会激活机体的免疫反应，进而引发自身免疫性疾病。其中一类典型的疾病称为AGS综合征(Aicardi–Goutièressyndrome)，其发病原因是由于控制核酸降解和定位的基因如TREX1、RNASEH2A、RNASEH2B、RNASEH2C、SAMHD1、ADAR1等发生突变导致核酸异常，进而引起强烈的自身免疫反应；还有一些免疫相关疾病也与核酸类物质的异常积累具有明显相关性，在临床上能够检测到大量抗核酸抗体的存在，如红斑狼疮(lupus erythematosus)、类风湿性关节炎(rheumatoidarthritis)、炎性肠病(inflammatory bowel disease)等；另外有文献报道黄斑变性(age-related macular degeneration)和神经退行性疾病(neurodegenerative diseases)也与核酸免疫反应通路的异常激活有关。
目前已知的能够识别核酸类物质并激活免疫反应的感受器包括DNA识别受体cGAS和RNA识别受体RIG-I、MDA5、LGP2等。其中cGAS在结合DNA后，能够催化ATP和GTP合成cGAMP，cGAMP作为第二信使分子与STING结合，进而激活干扰素通路，启动免疫反应；RIG-I、MDA5、DHX58在识别RNA后能够活化MAVS，进而激活干扰素通路。
发明内容
研究中发现G3BP1能够调控cGAS介导的干扰素通路的激活，另外有文献报道G3BP1能够控制RIG-I、MDA5、DHX58的定位，进而影响干扰素通路的激活。因此通过调控G3BP1的功能，就能够调节核酸引起的免疫反应。
为此本发明的一个目的是提供抑制G3BP1蛋白表达或活性的物质的用途。
本发明提供的抑制G3BP1蛋白表达或活性的物质在制备治疗核酸异常引起的疾病的产品中得到应用。
上述应用中，所述核酸异常引起的疾病包括核酸异常导致的AGS综合征、核酸异常导致的自身免疫疾病和核酸异常引起的免疫通路异常激活相关疾病。
上述应用中，所述核酸异常导致的自身免疫疾病包括红斑狼疮、类风湿性关节炎或炎性肠病；
所述核酸异常引起的免疫通路异常激活相关疾病包括老年性黄斑变性或神经退行性疾病。
本发明还提供了抑制G3BP1蛋白表达或活性的物质在制备抑制核酸引起的细胞或机体自身免疫反应产品中的应用。
本发明还提供了抑制G3BP1蛋白表达或活性的物质在制备抑制核酸介导的细胞或机体IFN-β表达产品中的应用。
上述应用中，所述抑制G3BP1蛋白表达或活性的物质为G3BP1蛋白抑制剂；
或所述抑制G3BP1蛋白表达或活性的物质为抑制G3BP1蛋白表达或活性的CRISPR系统，其中靶序列为ACCAAGATGAGGTCTTCGG。
上述应用中，所述G3BP1蛋白抑制剂为EGCG或其药物组合物或EGCG溶液。
上述应用中，所述EGCG的剂量(即浓度)为0.1mg/kg–1000mg/kg；其中kg为EGCG溶液中溶剂的质量(如水)，mg为EGCG溶液中EGCG质量；
或，所述EGCG的剂量为0.7mg/kg–14.36mg/kg。
上述抑制G3BP1蛋白表达或活性为抑制自身细胞或自身机体G3BP1蛋白表达或活性。
本发明另一个目的是提供一种产品。
本发明提供的产品，其活性成分为上述抑制G3BP1蛋白表达或活性的物质；
所述产品具有如下1)-3)中至少一种功能：
1)治疗核酸异常引起的疾病；
2)抑制核酸引起的细胞或机体自身免疫反应；
3)抑制核酸介导的细胞或机体IFN-β表达。
上述产品中，所述核酸异常引起的疾病包括核酸异常导致的AGS综合征、核酸异常导致的自身免疫疾病和核酸异常引起的免疫通路异常激活相关疾病。
和/或，所述核酸异常导致的自身免疫疾病具体包括红斑狼疮、类风湿性关节炎或炎性肠病；
所述核酸异常引起的免疫通路异常激活相关疾病具体包括老年性黄斑变性或神经退行性疾病。
在实施例中，EGCG是以EGCG溶液形式存在，其浓度为1-1000μM，具体为1-20μM(换算剂量为0.718mg/kg-14.36mg/kg)。
上述应用中，所述核酸为内源或外源，上述核酸为DNA、RNA或DNA和RNA的杂交链。
上述应用中，所述细胞为动物细胞或人细胞。
上述应用中，所述动物细胞为小鼠胚胎成纤维细胞。
上述应用中，所述药物组合物包括治疗有效量的EGCG或其药学上可接受的盐以及药物辅料。术语“有效量”可指为实现预期的效果所需的剂量和时段的有效的量。此有效量可能因某些因子而产生不同的变化，如疾病的种类或治疗时疾病的病症、被施用的特定标的器官的构造、病人个体大小、或疾病或症状的严重性。本领域具有通常知识者不需要过度实验即可凭经验决定特定化合物的有效量。所述“药物辅料”是指药物中常规采用的各种辅料，例如赋形剂、控释剂、稳定剂等，这属于本领域技术人员常规知识范围。
根据本发明的所述药物组合物可以是以下剂型：片剂例如但不限于普通片剂、速释片、缓释片、控释片、薄膜衣片、糖衣片、口含片、舌下片、生物粘附片等；胶囊剂例如但不限于硬胶囊、软胶囊等；注射剂例如但不限于无菌或者含抑菌剂的水性注射剂、油性注射剂、冷冻干粉针剂、注射用微球等；喷雾剂例如但不限于口腔喷雾剂、鼻腔喷雾剂、局部皮肤喷雾剂等；气雾剂例如但不限于肺吸入用气雾剂、局部皮肤气雾剂等；滴鼻剂例如但不限于滴鼻用溶液、滴鼻用凝胶等；粉雾剂例如但不限于空腔用粉雾剂、鼻腔用粉雾剂、局部皮肤用粉雾剂等；人体其他腔道如阴道、直肠、耳腔等用的栓剂、贴剂、凝胶剂。这些制剂的制备工艺是本领域技术人员根据已有的知识或者参考相关教科书或工具书或文献而可以制备的。
名词注释
MEF：小鼠胚胎成纤维细胞；
IFN-βmRNA：干扰素-β信使PNA；
lipo2000：转染试剂，来自Invitrogen；
TRIZOL：RNA提取试剂，来自Sigma-Aldrich；
TREX1：DNA 3′repair exonuclease 1；
RNASEH2A：Ribonuclease H2A；
RNASEH2B：Ribonuclease H2B；
RNASEH2C：Ribonuclease H2C；
SAMHD1：SAM domain and HD domain containing protein；
ADAR1：adenosine to inosine acting on RNA enzyme 1；
cGAS：cyclic GMP-AMP Synthase；
RIG-I：retinoic acid inducible gene I
DHX58：DEXH box polypeptide 58；
MAVS:mitochondrial antiviral signaling
STING:stimulator of IFN gene
G3BP1：GTPase-activating protein-(SH3domain)-binding protein 1
已知EGCG(Epigallocatechin Gallate)是G3BP1的抑制剂，实验结果发现EGCG能够明显抑制核酸引起的干扰素通路的激活。因此EGCG能用于核酸导致的AGS综合征及与核酸异常相关的疾病(如红斑狼疮、类风湿性关节炎、炎性肠病、老年性黄斑变性、神经退行性疾病等)的治疗。本发明的实验证明，EGCG可以用于制备治疗核酸引起的自身免疫疾病的产品。
附图说明
图1为EGCG抑制核酸引起的免疫反应。
图2为EGCG抑制核酸介导的IFN-βmRNA的表达量。
具体实施方式
下述实施例中所使用的实验方法如无特殊说明，均为常规方法。
下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。
下述实施例中所用EGCG分子式：
下述蛋白质G3BP1可为人源(序列1)。
实施例1、G3BP1缺失抑制核酸引起的免疫反应
1、MEF(WT：野生型，KO：G3BP1缺失。WT和KO细胞均来自同一细胞株：ATCC,SCRC-1008。KO细胞制备利用CRISPR系统(GeCKO，pXPR-001)完成，靶序列为ACCAAGATGAGGTCTTCGG)细胞种于12孔板，37℃培养12小时，得到受试细胞；
2、向上述1的细胞中通过lipo2000分别转染DNA(HT-DNA，D6898，Sigma-Aldrich)(1μg/ml，图1a)和RNA(poly(I:C)，tlrl-pic，InvivoGen)(1μg/ml，图1b)，刺激细胞3小时，得到转染DNA的细胞和转染RNA的细胞；
3、用TRIZOL提取转染后3小时的转染DNA细胞和转染RNA细胞的RNA，反转录，得到cDNA作为模板，RT-PCR检测IFN-βmRNA的表达量。
以不加核酸为实验对照(control)。
上述IFN-βmRNA检测所用的引物为
上游：TCCGAGCAGAGATCTTCAGGAA
下游：TGCAACCACCACTCATTCTGAG
内参基因为Hprt，内参引物为
上游：CAGTCCCAGCGTCGTGATTAG
下游：AAACACTTTTTCCAAATCCTCGG
结果如图1所示，与野生型(WT)相比，G3BP1的缺失能够明显抑制DNA(图2a)和RNA(图1b)介导的IFN-βmRNA的表达量。
实施例2、EGCG(EpigallocatechinGallate)抑制核酸引起的免疫反应
EGCG(Epigallocatechin Gallate)是G3BP1的抑制剂。
1、MEF细胞种于12孔板，37℃培养12小时，得到受试细胞；
2、向培养液中加入终浓度为0、10、20M的EGCG(Sigma-Aldrich，E4143)水溶液(换算为剂量分别为0、7.18mg/kg、14.36mg/kg；其中kg为水的质量，mg为EGCG质量)，培养1小时，得到待转染体系；
3、向上述2的待转染体系中通过lipo2000分别转染DNA(HT-DNA，D6898，Sigma-Aldrich)(1g/ml，图2a)和RNA(poly(I:C)，tlrl‐pic，InvivoGen)(1μg/ml，图2b)，刺激细胞3小时，得到转染DNA的细胞和转染RNA的细胞；
4、用TRIZOL提取转染后3小时的转染DNA细胞和转染RNA细胞的RNA，反转录，得到cDNA作为模板，RT-PCR检测IFN-βmRNA的表达量。
以不加核酸为对照(control)。
上述IFN-βmRNA检测所用的引物为
上游：TCCGAGCAGAGATCTTCAGGAA
下游：TGCAACCACCACTCATTCTGAG
内参基因为Hprt，内参引物为
上游：CAGTCCCAGCGTCGTGATTAG
下游：AAACACTTTTTCCAAATCCTCGG
结果如图2所示，与不加EGCG处理组(EGCG浓度为0组)相比，EGCG在10μM和20μM浓度下，能够明显抑制DNA(图2a)和RNA(图2b)介导的IFN-βmRNA的表达量。
上述结果表明EGCG能够明显抑制核酸引起的免疫反应。
因此EGCG能用于核酸引起的自身免疫疾病AGS综合征(Aicardi–Goutièressyndrome)的治疗，并由此引申至其它与核酸异常相关的疾病，如红斑狼疮(lupuserythematosus)、类风湿性关节炎(rheumatoid arthritis)、老年性黄斑变性(age-related macular degeneration)、神经退行性疾病(neurodegenerative diseases)、炎性肠病等)。
SEQUENCE LISTING
<110> 中国人民解放军军事科学院军事医学研究院
<120> EGCG在自身免疫疾病中的应用
<160> 1
<170> PatentIn version 3.5
<210> 1
<211> 466
<212> PRT
<213>人工序列
<400> 1
Met Val Met Glu Lys Pro Ser Pro Leu Leu Val Gly Arg Glu Phe Val
1 5 10 15
Arg Gln Tyr Tyr Thr Leu Leu Asn Gln Ala Pro Asp Met Leu His Arg
20 25 30
Phe Tyr Gly Lys Asn Ser Ser Tyr Val His Gly Gly Leu Asp Ser Asn
35 40 45
Gly Lys Pro Ala Asp Ala Val Tyr Gly Gln Lys Glu Ile His Arg Lys
50 55 60
Val Met Ser Gln Asn Phe Thr Asn Cys His Thr Lys Ile Arg His Val
65 70 75 80
Asp Ala His Ala Thr Leu Asn Asp Gly Val Val Val Gln Val Met Gly
85 90 95
Leu Leu Ser Asn Asn Asn Gln Ala Leu Arg Arg Phe Met Gln Thr Phe
100 105 110
Val Leu Ala Pro Glu Gly Ser Val Ala Asn Lys Phe Tyr Val His Asn
115 120 125
Asp Ile Phe Arg Tyr Gln Asp Glu Val Phe Gly Gly Phe Val Thr Glu
130 135 140
Pro Gln Glu Glu Ser Glu Glu Glu Val Glu Glu Pro Glu Glu Arg Gln
145 150 155 160
Gln Thr Pro Glu Val Val Pro Asp Asp Ser Gly Thr Phe Tyr Asp Gln
165 170 175
Ala Val Val Ser Asn Asp Met Glu Glu His Leu Glu Glu Pro Val Ala
180 185 190
Glu Pro Glu Pro Asp Pro Glu Pro Glu Pro Glu Gln Glu Pro Val Ser
195 200 205
Glu Ile Gln Glu Glu Lys Pro Glu Pro Val Leu Glu Glu Thr Ala Pro
210 215 220
Glu Asp Ala Gln Lys Ser Ser Ser Pro Ala Pro Ala Asp Ile Ala Gln
225 230 235 240
Thr Val Gln Glu Asp Leu Arg Thr Phe Ser Trp Ala Ser Val Thr Ser
245 250 255
Lys Asn Leu Pro Pro Ser Gly Ala Val Pro Val Thr Gly Ile Pro Pro
260 265 270
His Val Val Lys Val Pro Ala Ser Gln Pro Arg Pro Glu Ser Lys Pro
275 280 285
Glu Ser Gln Ile Pro Pro Gln Arg Pro Gln Arg Asp Gln Arg Val Arg
290 295 300
Glu Gln Arg Ile Asn Ile Pro Pro Gln Arg Gly Pro Arg Pro Ile Arg
305 310 315 320
Glu Ala Gly Glu Gln Gly Asp Ile Glu Pro Arg Arg Met Val Arg His
325 330 335
Pro Asp Ser His Gln Leu Phe Ile Gly Asn Leu Pro His Glu Val Asp
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Lys Ser Glu Leu Lys Asp Phe Phe Gln Ser Tyr Gly Asn Val Val Glu
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Leu Arg Ile Asn Ser Gly Gly Lys Leu Pro Asn Phe Gly Phe Val Val
370 375 380
Phe Asp Asp Ser Glu Pro Val Gln Lys Val Leu Ser Asn Arg Pro Ile
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Met Phe Arg Gly Glu Val Arg Leu Asn Val Glu Glu Lys Lys Thr Arg
405 410 415
Ala Ala Arg Glu Gly Asp Arg Arg Asp Asn Arg Leu Arg Gly Pro Gly
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Gly Pro Arg Gly Gly Leu Gly Gly Gly Met Arg Gly Pro Pro Arg Gly
435 440 445
Gly Met Val Gln Lys Pro Gly Phe Gly Val Gly Arg Gly Leu Ala Pro
450 455 460
Arg Gln
465
Claims (5)
1.抑制G3BP1蛋白表达或活性的物质在制备治疗核酸异常引起的疾病的产品中的应用，所述抑制G3BP1蛋白表达或活性的物质为抑制G3BP1蛋白表达或活性的CRISPR系统，其中靶序列为ACCAAGATGAGGTCTTCGG。
2.根据权利要求1所述的应用，其特征在于：所述核酸异常引起的疾病包括核酸异常导致的AGS综合征、核酸异常导致的自身免疫疾病和核酸异常引起的免疫通路异常激活相关疾病。
3.根据权利要求2所述的应用，其特征在于：
所述核酸异常导致的自身免疫疾病包括红斑狼疮、类风湿性关节炎或炎性肠病；
所述核酸异常引起的免疫通路异常激活相关疾病包括老年性黄斑变性或神经退行性疾病。
4.抑制G3BP1蛋白表达或活性的物质在制备抑制核酸引起的细胞或机体自身免疫反应产品中的应用，所述抑制G3BP1蛋白表达或活性的物质为抑制G3BP1蛋白表达或活性的CRISPR系统，其中靶序列为ACCAAGATGAGGTCTTCGG。
5.抑制G3BP1蛋白表达或活性的物质在制备抑制核酸介导的细胞或机体IFN-β表达产品中的应用，所述抑制G3BP1蛋白表达或活性的物质为抑制G3BP1蛋白表达或活性的CRISPR系统，其中靶序列为ACCAAGATGAGGTCTTCGG。
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| CN101804128A (zh) * | 2009-02-16 | 2010-08-18 | 烟台新时代健康产业有限公司 | 一种药物组合物、其制备方法及在制备治疗炎症性肠病的药物中的用途 |
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| 阎羽欣等.EGCG介导的免疫调节及其在自身免疫病模型中的应用.《现代免疫学》.2018,(第05期), * |
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