CN114588251A - 靶向补体抑制剂在制备改善肝脏衰老药物中的应用 - Google Patents

靶向补体抑制剂在制备改善肝脏衰老药物中的应用 Download PDF

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CN114588251A
CN114588251A CN202210125653.7A CN202210125653A CN114588251A CN 114588251 A CN114588251 A CN 114588251A CN 202210125653 A CN202210125653 A CN 202210125653A CN 114588251 A CN114588251 A CN 114588251A
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何松青
周毅
袁观斗
曾永联
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First Affiliated Hospital of Guangxi Medical University
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Abstract

本发明公开了靶向补体抑制剂在制备改善肝脏衰老药物中的应用。靶向补体抑制剂CR2‑Crry在制备改善肝脏衰老药物中的应用，所述的CR2‑Crry的氨基酸序列如SEQ ID NO.1所示。靶向补体抑制剂CR2‑Crry可改善D‑半乳糖诱导肝脏衰老模型的衰老指标。小鼠每天皮下注射D‑半乳糖800mg/kg,共持续8周，建立小鼠衰老模型。实验组小鼠在皮下注射D‑半乳糖1周后，开始每天腹腔注射CR2‑crry蛋白0.08mg。8周后取肝脏组织及血清，通过衰老指标检测肝脏的衰老改变。

Description

靶向补体抑制剂在制备改善肝脏衰老药物中的应用
技术领域
本发明属于生物医药领域，具体涉及靶向补体抑制剂在制备改善肝脏衰老药物中的应用。
背景技术
衰老是一个不可避免的过程，它会导致所有生物体的功能衰退。肝细胞衰老(senescence)是指肝细胞生理功能的衰减，包括增殖能力下降、细胞周期停滞、衰老相关基因表达增加，伴有形态学衰老改变。肝细胞衰老显著的特征细胞周期依赖性激酶抑制剂(cyclin dependent kinase inhibitor，CDKI)p16、p21的表达增加；肝细胞衰老的机制目前并不十分明确，以往的研究表明，其损伤机制为炎症反应和氧化应激。减轻肝脏炎症反应和氧化应激损伤可能为延缓或逆转肝细胞衰老提供一种新的方法。从而为治疗衰老相关的肝脏疾病提供有效的治疗策略。
发明内容
本发明的目的是针对现有技术的不足，提供靶向补体抑制剂在制备改善D-半乳糖诱导肝脏衰老药物中的应用。
本发明利用补体受体2(Complement receptor 2,CR2)融合C3活化抑制因子Crry，通过CR2靶向性结合到补体活化部位，利用Crry特异性抑制C3活化，进而抑制补体系统活化。通过建立D-半乳糖诱导小鼠肝脏衰老模型，比较CR2-Crry治疗组与对照组的肝脏衰老水平变化，结果证明CR2-Crry可显著改善肝脏衰老，减轻肝脏炎症反应和氧化应激损伤。本发明还通过C3基因敲除小鼠进一步验证了抑制补体系统对D-半乳糖诱导肝脏衰老的改善作用。
因此，本发明的第一个目的是提供靶向补体抑制剂CR2-Crry在制备改善肝脏衰老药物中的应用，所述的CR2-Crry的氨基酸序列如SEQ ID NO.1所示。
优选，所述的肝脏衰老是D-半乳糖诱导的肝脏衰老。
优选，所述的改善肝脏衰老药物为在D-半乳糖诱导肝脏衰老时减轻肝细胞衰老的药物。
优选，所述的改善肝脏衰老药物为在D-半乳糖诱导肝脏衰老时减轻肝脏损伤的药物。
优选，所述的改善肝脏衰老药物为在D-半乳糖诱导肝脏衰老时减少肝脏炎症反应的药物。
优选，所述的改善肝脏衰老药物为在D-半乳糖诱导肝脏衰老时减少氧化应激反应的药物。
本发明的第二个目的是提供一种改善肝脏衰老的药物，其含有有效量的靶向补体抑制剂CR2-Crry作为活性成分，所述的靶向补体抑制剂CR2-Crry的氨基酸序列如SEQ IDNO.1所示。
本发明具有以下有益效果：
1.靶向补体抑制剂CR2-Crry具有靶向性强、高效、安全、不影响宿主全身免疫功能的优点。
2.靶向补体抑制剂CR2-Crry可改善D-半乳糖诱导肝脏衰老模型的衰老指标。小鼠每天皮下注射D-半乳糖800mg/kg,共持续8周，建立小鼠衰老模型。实验组小鼠在皮下注射D-半乳糖1周后，开始每天腹腔注射CR2-crry蛋白0.08mg。8周后取肝脏组织及血清，通过衰老指标检测肝脏的衰老改变。
3.靶向补体抑制剂CR2-Crry可改善D-半乳糖诱导的肝功能和病理学损伤。
4.靶向补体抑制剂CR2-Crry可改减轻D-半乳糖诱导肝脏衰老时肝脏炎症反应。
5.靶向补体抑制剂CR2-Crry可减轻D-半乳糖诱导肝脏衰老时肝脏氧化应激反应。
附图说明
图1是补体抑制剂CR2-Crry对补体系统活化的影响。A:Elisa检测小鼠血清C3a水平。B:小鼠肝组织内C3d免疫组化检测。**表示P＜0.01，***表示P＜0.001。
图2是补体抑制剂CR2-Crry对肝脏损伤的影响。A、B：生化检测小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)水平。C：肝组织HE染色。*表示P＜0.05，**表示P＜0.01，***表示P＜0.001。
图3是补体抑制剂CR2-Crry对肝脏衰老指标的影响。A：SA-β-gal表达水平。B、C：肝脏组织P16和P21 mRNA的相对表达水平。D：肝脏组织P16和P21蛋白表达水平。*表示P＜0.05，***表示P＜0.001。
图4是补体抑制剂CR2-Crry对小鼠肝脏促炎因子的影响。A:IL-1β的相对表达水平。B：IL-6的相对表达水平。C：TNF-α的相对表达水平。*表示P＜0.05，**表示P＜0.01，***表示P＜0.001。
图5是补体抑制剂CR2-Crry对氧化应激指标的影响。A：超氧化物歧化酶(SOD)。B:过氧化氢酶(CAT)水平。C：丙二醛(MDA)水平。*表示P＜0.05，**表示P＜0.01，***表示P＜0.001。
图6是C3 KO对补体系统活化、肝脏损伤、衰老指标、促炎因子和氧化应激指标的影响。A:Elisa检测小鼠血清C3a水平。B:小鼠肝组织内C3d免疫组化检测。C、D：生化检测小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)水平。E：肝组织HE染色。F：SA-β-gal表达水平。G、H：肝脏组织P16和P21 mRNA的相对表达水平。I：肝脏组织P16和P21蛋白表达水平。J:IL-1β的相对表达水平。K：IL-6的相对表达水平。L：TNF-α的相对表达水平。M：超氧化物歧化酶(SOD)。N:过氧化氢酶(CAT)水平。O：丙二醛(MDA)水平。*表示P＜0.05，**表示P＜0.01，***表示P＜0.001。
具体实施方式：
以下实施例是对本发明的进一步说明，而不是对本发明的限制。以下实例中未具体注明的实验方法，均可按照常规方法进行，或按照所用产品生产厂商的使用说明；所使用的材料、试剂等，如无特殊说明，均可通过商业途径得到。
以下实施例中所用的野生型小鼠为C57BL/6野生型小鼠。
靶向补体抑制剂CR2-Crry的制备：是将补体受体2(Complement receptor 2，CR2)连接膜结合性调节因子(Crry)而制备得到的，具体制备参见：Atkinson C,Song H,Lu B,etal.Targeted complement inhibition by C3d recognition ameliorates tissueinjury without apparent increase in susceptibility to infection.J ClinInvest.2005；115(9):2444-2453文中Methods中CR2-Crry fusion protein的制备。制备的用于实施例中的靶向补体抑制剂CR2-Crry的氨基酸序列如SEQ ID NO.1所示，含585个氨基酸。
补体C3基因敲除小鼠(C3 KO小鼠)为B6；129S4-C3tm1Crr/J品系，购自TheJackson Laboratories(Bar Harbor,Maine,USA)。
实施例1
1、实验相关整体模型的建立
雄性小鼠6-8周龄，体重18-20g，健康清洁级。温度25±2℃；湿度50％～60％；光循环按照14h光照/10h黑暗设置。小鼠分笼饲养，自由进食，饮用清洁水。
C57BL/6野生小鼠模型组(D-gal)，于颈背部皮下每日注射800mg/kg的D–半乳糖，持续注射8周。
C57BL/6野生小鼠对照组(Control)，于颈部皮下每日皮下注射同剂量生理盐水，持续注射8周，无其他处理。
补体抑制剂CR2-Crry处理组(D-gal+CR2-Crry)，使用C57BL/6野生型小鼠，于颈背部皮下每日注射800mg/kg的D–半乳糖，在皮下注射D-半乳糖1周后，开始每日腹腔注射一次CR2-crry蛋白0.08mg，其余操作同野生小鼠模型组。
补体C3基因敲除小鼠模型组小鼠(C3 KO+D-gal)B6；129S4-C3tm1Crr/J品系，于颈背部皮下每日注射800mg/kg的D–半乳糖，持续注射8周。
每组设置6只小鼠。
所有小鼠模型均在8周后通过下腔静脉取静脉血及移除肝脏组织。部分肝脏组织经10％福尔马林固定24h后石蜡包埋用于组织学检测。部分肝脏组织放入OCT包埋剂至完全覆盖组织，置入液氮中至完全凝固，用于后续的冰冻切片和SA-β-gal染色。其余肝脏组织放置-80℃冰箱保存用于RNA提取。静脉血4℃下静置6h后离心取血清以备检测肝功能等相关指标。模型出现以下情况则提示造模失败：衰老指标未见明显升高(包括SA-β-gal染色、P16和P21表达水平)。
2.抑制补体活化对D-半乳糖诱导肝脏衰老的作用
通过对C57BL/6野生型及C3基因敲除小鼠进行D-半乳糖诱导肝脏衰老模型，并对C57BL/6野生型实验组进行CR2-Crry干预，研究抑制补体活化对肝脏衰老的影响。
2.1CR2-Crry可显著抑制D-半乳糖诱导的补体系统活化
通过Elisa检测发现D-半乳糖诱导衰老模型组小鼠血清C3a水平显著升高(图1A)，免疫组化检测发现D-半乳糖诱导衰老模型组小鼠肝组织内有大量C3d沉积(图1B)，提示补体系统的过度活化。CR2-Crry可显著抑制D-半乳糖诱导的肝组织内C3d与血清C3a水平(图1A-B)。这说明在衰老肝脏中补体过度活化，而CR2-Crry可显著抑制补体系统在肝组织内的活化。
2.2抑制补体系统活化可减轻肝脏损伤
通过生化检测发现D-半乳糖模型组小鼠血清ALT及AST显著升高(图2A&B)，同时HE染色可见其肝细胞表现为广泛的水肿、空泡和细胞质疏松，肝细胞排列紊乱，多发性和广泛性肝门静脉炎症和肝细胞坏死(图2C)。而CR2-Crry可显著降低ALT和AST及肝细胞损伤(图2A-C)。
2.3抑制补体系统活化可显著改善肝脏衰老
冰冻切片染色发现D-半乳糖诱导小鼠肝脏SA-β-gal表达水平显著升高(图3A)。RT-qPCR检测发现D-半乳糖诱导小鼠肝脏组织P16和P21的mRNA相对表达水平表达增加，其中以18S rRNA为内部参照(图3B&C)。Western blot检测发现D-半乳糖诱导小鼠肝脏组织P16和P21的蛋白表达水平表达增加(图3D)。而CR2-Crry可显著降低肝脏SA-β-gal表达水平和肝脏组织P16和P21表达水平(图3A-D)，其差异具有显著性。
qRT-PCR检测引物序列：
18S rRNA:forward,5’-GTAACCCGTTGAACCCCATT-3’；reverse,5’-CCATCCAATCGGTAGTAGCG-3’。
P16:forward,5’-CCAACGCCCCGAACTCTTTC-3’；reverse,5’-GTAGTGGGGTCCTCGCAGTT-3’。
P21:forward,5’-TCTGGTGTCTGAGCGGCCTG-3’；reverse,5’-CGAGGTCCCACGCCTATGGA-3’。
2.4抑制补体系统活化可减轻D-半乳糖诱导的肝脏炎症反应
通过qRT-qPCR检测小鼠肝组织内促炎因子表达，以18S rRNA为内部参照，D-半乳糖模型组TNF-α、IL-6和IL-1β的相对表达量显著升高，CR2-Crry可显著降低小鼠肝内TNF-α、IL-6、IL-1β的相对表达水平(图4A-C)。
RT-PCR检测引物序列：
18S rRNA:forward,5’-GTAACCCGTTGAACCCCATT-3’；reverse,5’-CCATCCAATCGGTAGTAGCG-3’。
TNF-α:forward,5’-GAGGACAGCAAGGGACTAGC-3’；reverse,5’-AGGGAGGCCATTTGGGAACT-3’。
IL-6:forward,5’-CTCTGCAAGAGACTTCCATCCAGT-3’；reverse,5’-ACTCCAGGTAGCTATGGTACTCCA-3’。
IL-1β:forward,5’-ACTACAGGCTCCGAGATGAACA-3’；reverse,5’-TTGCTTGGGATCCACACTCTCC-3’。
2.5抑制补体系统活化可减轻D-半乳糖诱导的肝脏氧化应激反应
与D-半乳糖模型组相比，D-gal+CR2-Crry处理组小鼠的抗氧化物，包括过氧化氢酶(CAT)和超氧化物歧化酶(SOD)升高(图5A和B)。相反，在D-gal+CR2-Crry组中观察到脂质过氧化产物丙二醛(MDA)水平显著降低(图5C)。
2.6补体C3缺乏可减轻D-半乳糖诱导的肝脏损伤与衰退
与D-半乳糖模型组相比，C3 KO+D-gal处理组小鼠的血清C3a水平和肝脏组织C3d表达显著降低(图6A和B)；同时，C3 KO可显著降低ALT、AST、肝脏病理组织学改变、SA-β-gal、P16、P21、TNF-α、IL-6、IL-1β和MDA的表达水平(图6C-L和O)。相反，在C3 KO+D-gal组中观察到CAT和SOD水平显著升高(图6M和N)。
综上所述，我们的研究表明补体抑制可能是一种新型且有前景的延缓衰老的方法，有望为治疗肝脏衰老相关的疾病提供有效的保护策略。
序列表
<110> 广西医科大学第一附属医院
<120> 靶向补体抑制剂在制备改善肝脏衰老药物中的应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 585
<212> PRT
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1 5 10 15
Tyr Ser Leu Pro Ile Val Pro Gly Thr Val Leu Arg Tyr Thr Cys Ser
20 25 30
Pro Ser Tyr Arg Leu Ile Gly Glu Lys Ala Ile Phe Cys Ile Ser Glu
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Asn Gln Val His Ala Thr Trp Asp Lys Ala Pro Pro Ile Cys Glu Ser
50 55 60
Val Asn Lys Thr Ile Ser Cys Ser Asp Pro Ile Val Pro Gly Gly Phe
65 70 75 80
Met Asn Lys Gly Ser Lys Ala Pro Phe Arg His Gly Asp Ser Val Thr
85 90 95
Phe Thr Cys Lys Ala Asn Phe Thr Met Lys Gly Ser Lys Thr Val Trp
100 105 110
Cys Gln Ala Asn Glu Met Trp Gly Pro Thr Ala Leu Pro Val Cys Glu
115 120 125
Ser Asp Phe Pro Leu Glu Cys Pro Ser Leu Pro Thr Ile His Asn Gly
130 135 140
His His Thr Gly Gln His Val Asp Gln Phe Val Ala Gly Leu Ser Val
145 150 155 160
Thr Tyr Ser Cys Glu Pro Gly Tyr Leu Leu Thr Gly Lys Lys Thr Ile
165 170 175
Lys Cys Leu Ser Ser Gly Asp Trp Asp Gly Val Ile Pro Thr Cys Lys
180 185 190
Glu Ala Gln Cys Glu His Pro Gly Lys Phe Pro Asn Gly Gln Val Lys
195 200 205
Glu Pro Leu Ser Leu Gln Val Gly Thr Thr Val Tyr Phe Ser Cys Asn
210 215 220
Glu Gly Tyr Gln Leu Gln Gly Gln Pro Ser Ser Gln Cys Val Ile Val
225 230 235 240
Glu Gln Lys Ala Ile Trp Thr Lys Lys Pro Val Cys Lys Glu Ile Leu
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Cys Pro Ala Pro Ser Gln
260 265 270
Leu Pro Ser Ala Lys Pro Ile Asn Leu Thr Asp Glu Ser Met Phe Pro
275 280 285
Ile Gly Thr Tyr Leu Leu Tyr Glu Cys Leu Pro Gly Tyr Ile Lys Arg
290 295 300
Gln Phe Ser Ile Thr Cys Lys Gln Asp Ser Thr Trp Thr Ser Ala Glu
305 310 315 320
Asp Lys Cys Ile Arg Lys Gln Cys Lys Thr Pro Ser Asp Pro Glu Asn
325 330 335
Gly Leu Val His Val His Thr Gly Ile Gln Phe Gly Ser Arg Ile Asn
340 345 350
Tyr Thr Cys Asn Gln Gly Tyr Arg Leu Ile Gly Ser Ser Ser Ala Val
355 360 365
Cys Val Ile Thr Asp Gln Ser Val Asp Trp Asp Thr Glu Ala Pro Ile
370 375 380
Cys Glu Trp Ile Pro Cys Glu Ile Pro Pro Gly Ile Pro Asn Gly Asp
385 390 395 400
Phe Phe Ser Ser Thr Arg Glu Asp Phe His Tyr Gly Met Val Val Thr
405 410 415
Tyr Arg Cys Asn Thr Asp Ala Arg Gly Lys Ala Leu Phe Asn Leu Val
420 425 430
Gly Glu Pro Ser Leu Tyr Cys Thr Ser Asn Asp Gly Glu Ile Gly Val
435 440 445
Trp Ser Gly Pro Pro Pro Gln Cys Ile Glu Leu Asn Lys Cys Thr Pro
450 455 460
Pro Pro Tyr Val Glu Asn Ala Val Met Leu Ser Glu Asn Arg Ser Leu
465 470 475 480
Phe Ser Leu Arg Asp Ile Val Glu Phe Arg Cys His Pro Gly Phe Ile
485 490 495
Met Lys Gly Ala Ser Ser Val His Cys Gln Ser Leu Asn Lys Trp Glu
500 505 510
Pro Glu Leu Pro Ser Cys Phe Lys Gly Val Ile Cys Arg Leu Pro Gln
515 520 525
Glu Met Ser Gly Phe Gln Lys Gly Leu Gly Met Lys Lys Glu Tyr Tyr
530 535 540
Tyr Gly Glu Asn Val Thr Leu Glu Cys Glu Asp Gly Tyr Thr Leu Glu
545 550 555 560
Gly Ser Ser Gln Ser Gln Cys Gln Ser Asp Gly Ser Trp Asn Pro Leu
565 570 575
Leu Ala Lys Cys Val Ser Arg Ser Ile
580 585

Claims (7)

1.靶向补体抑制剂CR2-Crry在制备改善肝脏衰老药物中的应用，所述的CR2-Crry的氨基酸序列如SEQ ID NO.1所示。
2.根据权利要求1所述的应用，其特征在于，所述的肝脏衰老是D-半乳糖诱导的肝脏衰老。
3.根据权利要求1所述的应用，其特征在于，所述的改善肝脏衰老药物为在D-半乳糖诱导肝脏衰老时减轻肝细胞衰老的药物。
4.根据权利要求1所述的应用，其特征在于，所述的改善肝脏衰老药物为在D-半乳糖诱导肝脏衰老时减轻肝脏损伤的药物。
5.根据权利要求1所述的应用，其特征在于，所述的改善肝脏衰老药物为在D-半乳糖诱导肝脏衰老时减少肝脏炎症反应的药物。
6.根据权利要求1所述的应用，其特征在于，所述的改善肝脏衰老药物为在D-半乳糖诱导肝脏衰老时减少氧化应激反应的药物。
7.一种改善肝脏衰老的药物，其特征在于，含有有效量的靶向补体抑制剂CR2-Crry作为活性成分，所述的靶向补体抑制剂CR2-Crry的氨基酸序列如SEQ ID NO.1所示。
CN202210125653.7A 2022-02-10 2022-02-10 靶向补体抑制剂在制备改善肝脏衰老药物中的应用 Pending CN114588251A (zh)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120171206A1 (en) * 2009-07-02 2012-07-05 Stephen Tomlinson Methods of stimulating liver regeneration
CN109078168A (zh) * 2018-07-26 2018-12-25 广西医科大学第附属医院 靶向补体抑制剂在制备改善脑死亡供肝药物中的应用
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CN109078168A (zh) * 2018-07-26 2018-12-25 广西医科大学第附属医院 靶向补体抑制剂在制备改善脑死亡供肝药物中的应用
CN109248177A (zh) * 2018-08-23 2019-01-22 许瑞安 鳄鱼甲有效组分的制备及其抗氧化、抗肝纤维化的应用
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