CN113855674A - 氯喹的应用 - Google Patents
氯喹的应用 Download PDFInfo
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- CN113855674A CN113855674A CN202111303923.0A CN202111303923A CN113855674A CN 113855674 A CN113855674 A CN 113855674A CN 202111303923 A CN202111303923 A CN 202111303923A CN 113855674 A CN113855674 A CN 113855674A
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- chloroquine
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Abstract
本发明公开了氯喹的应用。本发明提供的氯喹在制备具有如下任一功能产品中的应用:A1、治疗动物组织器官的炎症;A2、治疗动物组织器官的纤维化;A3、保护动物组织器官;A4、降低动物组织器官的损伤;A5、抑制组织器官中CXCR对肾脏保护或改善肾单位功能;A6、促进肾脏组织中有机阴离子转运蛋白。本发明氯喹能改善动物身体机能。本发明低剂量的氯喹处理改善小鼠身体机能,具对肝脏和肾脏有保护作用,对心脏无毒副作用。
Description
技术领域
本发明涉及氯喹的应用,具体涉及氯喹在改善动物身体机能中的应用,属于生物医药领域。
背景技术
近年来,人口老龄化是世界尤其是中国面临的日益严峻的社会问题,高龄常常是诸多慢性疾病的主要危险因素之一,如老年痴呆、骨关节炎、心血管疾病、癌症等。老年人口与疾病发生率的增加将对各国的养老保障系统以及医疗体系造成巨大地冲击,严重影响人们的日常生活,给社会和家庭带来沉重负担,影响社会持续性发展。虽然衰老是不可避免的,但它是可调控的。因此延缓衰老,即提高老年个体的健康寿命,预防衰老相关疾病将是应对老龄化挑战的最佳解决策略。如何延缓衰老,实现“健康衰老”,是保证社会长治久安、经济持续性发展的必要条件。因此,延缓衰老及衰老相关疾病已成为全球科研领域亟需解决和突破的热点及难点。当前衰老研究已成为生命领域的一大热点,诸多延缓衰老的手段也应运而生,比如小分子药物干预、生活方式干预(运动、饮食限制)、基因疗法等。其中,延缓衰老的小分子药物具有较好的应用潜力,在诸多模式生物中的探索研究中发现多种小分子可以对酵母、线虫、果蝇及小鼠健康状况有所延缓,其中靶向于营养素信号通路、氧化应激、内源性代谢物补充等的居多,如雷帕霉素、维生素C、槲皮素、烟酰胺等。但是大部分化合物的安全性与有效性仍有待深入的、多方面的评估,特别是临床试验的评价。据知,目前仅有少数的药物被批准进行临床试验,包括二甲双胍、烟酰胺,不过试验结果并未达到人们的预期:提高受试者的生存期。因此,鉴定发现有效的延缓衰老的药物是至关重要的,并且这将对缓解人口老龄化危机有着非常积极的推动作用。
氯喹(Chloroquine,CQ)是一种氨基喹啉类药物,且通过了FAD批准可用于抗击疟疾的药物,也可以作为常用的溶酶体抑制剂(Philip wing lok ho.,et al.Age-dependentaccumulation of oligomeric SNCA/α-synuclein from impaired degradation inmutant LRRK2 knockin mouse model of Parkinson disease:role for therapeuticactivation of chaperone-mediated autophagy(CMA).2020.16(2):347-370.)。氯喹具有易吸收、合成简单、疗效高、使用简单、价格普遍实惠等优点,一直被用于对抗疟疾等一系列疾病,包括炎症性疾病、传染病,甚至多种类型的癌症。有研究表明氯喹及其同系物在缓解疾病的同时,也显示出了一定的生物毒性(Joe,P.,et al.Chloroquine and nanoparticledrug delivery:A promising combination.Pharmacology Therapeutics.2018.191,43-49.)。因其自身呈弱碱性,氯喹进入生物体内后会影响酸性囊泡,增加溶酶体和反式高尔基网络(TGN)囊泡的pH值,破坏包括酸性水解酶在内的几种酶,并抑制新合成蛋白质的翻译。
氯喹的研究主要集中在肿瘤治疗和抗病毒方面(Rodrigo,C.,et al.Clinicalevidence for repurposing chloroquine and hydroxychloroquine as antiviralagents:a systematic review.Clin Microbiol Infect.2020.26(8):979-987.),在CQ治疗肝癌小鼠肿瘤的增殖的研究中发现,氯喹可能通过抑制肿瘤细胞的自噬活性来抑制肿瘤细胞的增殖。在大鼠的研究中发现,氯喹通过抑制与自噬有关的线粒体的功能进而抑制自噬(Ericsson,J.,et al.Studies on induced cellular autophagy:II.Characterization of the membranes bordering autophagosomes in parenchymalliver cells.Experimental Cell Research.1969.56(23):393-405.),而氯喹的抗病毒作用很有可能也与其抑制自噬有关。另外,研究者发现CQ可延长蠕虫和基因突变早衰小鼠的寿命(Qiao,M.,et al.Boosting ATM activity alleviates aging and extendslifespan in a mouse model of progeria.Elife.2018.7:e34836.)。此外,另一项研究发现,CQ降低了人内皮细胞中衰老相关(β)-半乳糖苷酶的活性(Boisen,L.,etal.Evaluation of endothelial cell culture as a model system of vascularageing.Experimental Gerontology.2010.45(10):779-787.)。这些研究表明,CQ在一定程度上可以起到延缓衰老的作用。此外,有研究表明每天给予高剂量(250mg)的氯喹会增加心律失常和心脏毒性的风险(Wozniacka,A.,Cygankiewicz,I.,Chudzik,M.,Sysa-Jedrzejowska,A.,and Wranicz,J.K.(2006).The cardiac safety of chloroquinephosphate treatment in patients with systemic lupus erythematosus:theinfluence on arrhythmia,heart rate variability and repolarizationparameters.Lupus 15,521-525.),且长期服用会对肠道和肝脏产生副作用。氯喹的长期相对低剂量(0.1mg/Kg)单一用药是否可改善小鼠身体机能尚未有报道,改善机能的分子机制也未知。
发明内容
本发明的目的是提供氯喹的应用,具体目的是提供氯喹在改善动物身体机能中的应用。
本发明氯喹能改善动物身体机能。
本发明提供的氯喹在制备具有如下任一功能产品中的应用:
A1、治疗动物组织器官的炎症;
A2、治疗动物组织器官的纤维化;
A3、保护动物组织器官;
A4、降低动物组织器官的损伤;
A5、抑制组织器官中CXCR对肾脏保护或改善肾单位功能;
A6、促进肾脏组织中有机阴离子转运蛋白。
上述的应用中,所述组织为血管和/或小肠;
所述器官为心脏、肝脏、肾脏和肺脏中的至少一种。
上述的应用中,所述A2中器官为肺脏、肾脏和肝脏中的至少一种;
所述A3中器官为肝脏。
上述的应用中,所述动物为C1)或C2):
C1)哺乳动物;
C2)人或大鼠。
上述的应用中,所述产品为药品或保健品。
本发明还提供了一种药品或保健品,其活性成分为所述氯喹。
上述的药品或保健品的辅料为水。
上述的药品或保健品中,所述氯喹的浓度具体为0.2~5μM。
本发明所述药品或保健品在使用时,所述氯喹的给药剂量为1μM。
本发明所述药品或保健品在使用时,所述氯喹的给药剂量为0.1mg/kg体重。
本发明所述药品或保健品在使用时,所述氯喹的给药时间为5个月。
本发明进一步提供了一种培育身体机能改善的动物的方法,包含以下步骤:
以每千克体重给予0.1mg的氯喹处理,处理5个月,培育出身体机能改善和/或衰老延缓的动物。
上述的方法中,所述身体机能改善具有如下B1)-B3)任一表现:
B1)动物代谢能耗、呼吸熵、耗氧量和二氧化碳排出量稳定;
B2)血液和组织器官中炎症因子的降低;
B3)组织器官的纤维化程度降低;
上述的方法中,所述动物为C1)或C2):
C1)哺乳动物;
C2)人或大鼠。
本发明具有以下优点:
1、为了研究低剂量的氯喹处理改善小鼠身体机能,用氯喹或单独的载体对照治疗健康的24个月大的Sprague Dawley(SD)雄性大鼠,每周两次经水给药,持续5个月。发现低剂量氯喹的长期给药延长了大鼠6.16%的中位寿命和13.12%的最大寿命,降低血液中TNFα、循环白细胞(WBC)、中性粒细胞(NEU)、中丙氨酸转氨酶(ALT)和总胆红素(TBiL)的数量或浓度,能有效减轻肾脏、肺和肝脏组织的纤维化,肾小球体积减小,肺脏和肝脏衰老程度减轻,降低肝脏中CD68阳性巨噬细胞的数量,能够保持体重和血糖,稳定大鼠的代谢功能、器官总净重、器官指数,维持组织的完整性。低剂量的氯喹具对肝脏和肾脏有保护作用,对心脏无毒副作用。
2、为了研究低剂量氯喹处理改善小鼠身体机能的机制,进行了RNA测序分析,肾脏、肝脏和小肠对氯喹治疗效果更佳明显。相比之下,与炎症反应、白细胞迁移、细胞杀伤和细胞死亡的正调控相关的基因在衰老过程中增加,并在施用氯喹后至少在四种组织中下调。此外,基因集富集分析(GSEA)显示,氯喹治疗减弱了老年大鼠肾脏、肝脏、心脏和主动脉组织中的炎症反应和IFN-γ反应。
综上,本发明经实验证明了低剂量的氯喹通过降低动物组织器官的验证、减缓动物组织器官的纤维化,并保护动物组织器官,抑制组织器官中CXCR对肾脏保护或改善肾单位功能,促进肾脏组织中有机阴离子转运蛋白,以改善身体机能;并进一步强调在临床试验中使用低剂量氯喹时监测心脏功能的必要性,即低剂量不损伤心脏功能,是未来临床应用的潜在治疗选择。
附图说明
图1中A为生存曲线百分比的量化;B为TNF-α、IL-6、MCP-1、IL-7、IL-7β的ELISA结果;C为白细胞(WBC)和中性粒细胞(NEU)的数量和比例;DD为肝脏组织的CD68的免疫染色代表性图片;E为肝脏组织的CD68的免疫染色的统计结果;F为血常规检测结果;G为肾脏、肝脏、心脏和主动脉组织的炎症应答的GSEA结果;H为肾脏、肝脏、心脏和主动脉组织的干扰素TNF-γ的GSEA结果;I为肝脏和肾脏组织的TNF-α信号通路中NF-κB的GSEA结果;J为肝脏组织的IL-6信号通路以及与JAK-STAT3信号通路相关的GSEA结果。
图2中A为肾脏、小肠、肝脏、心脏和肺脏组织的masson染色代表性图片,B为肾脏、小肠、肝脏、心脏和肺脏组织的masson染色的统计结果;C为CQ治疗后肝、肾和肺纤维化相关的挽救DEGs热图;D为肝脏组织的TGF-β信号通路的GSEA结果。
图3中A为肾脏、小肠、肝脏、心脏、肺脏和主动脉的HE染色和统计结果;B为GSEA基因集富集分析(Gene set enrichment analysis,GSEA)图显示CQ治疗后肾、肝、肺的SASP降低;C为显示6个组织经CQ处理后SASP相关救援DEGs的热图。
图4中A为心脏超声代表性图片;B为左心室射血分数(EF)、左心室缩短分数(SF)和二尖瓣流入早期与晚期充盈峰值速度比(E/A)的统计分析结果;图中Y-Ctrl表示溶剂处理后的年轻鼠,O-Ctrl表示溶剂处理后的年老鼠,O-CQ表示氯喹处理后的年老鼠;C为肾脏和心脏的DEG热图;D为心脏中的一系列心脏病相关的促衰老DEG的网络图;E为心脏副作用基因的QPCR结果。
图5中A条形图显示了六种组织中挽救DEG、未能挽救DEG和促衰老DEG的百分比,A中从上至下的标记依次表示挽救DEG、挽救DEG失败、促衰老DEG;B为玫瑰图显示了六种组织中老化DEG、CQ DEG、挽救DEG、未能挽救DEG和促衰老DEG的数量;C为基于肾脏功能富集分析的在救援DEG中富集的代表性GO术语和通路;D为肾脏中CQ治疗后Slc24a3、Slc17a2、Slc31a1和Slc36a4的变化热图;E为基因集富集分析(GSEA)图,显示CQ治疗后趋化因子受体结合肾脏趋化因子减少;F为显示了在肾脏CQ治疗后与干扰素刺激反应元件(ISRE)和CXCR趋化因子相关的救援DEG的热图;G为网络图显示与肾脏疾病相关的救援DEG;H为肾脏组织的QPCR结果。
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。
以下实施例中的定量试验,均设置三次重复实验,结果取平均值。
下述实施例中的小鼠及给药方法如下:
所有动物实验均按照中国科学院动物管理和使用委员会批准的方案进行。健康SD雄性大鼠在23-24℃的SPF级环境中,在12小时明暗交替光照,自由获得正常的食物,自由饮水。每周更换一次笼子垫料。
本发明中氯喹购自Sigma公司,货号C6628;氯喹溶解于3ml水中(最低饮水量),每周两次经水给药;对照给予正常饮水。
所有其他试剂均从Sigma购买。
试验所有数据采用SPSS12.0(SPSS Inc.,USA)统计软件的独立样本t检验处理统计。
实施例1、氯喹延长大鼠寿命
将26只24月龄的年老SD大鼠随机分为2组,O-Ctrl组和O-CQ组,分别为16只和10只,O-CQ组给予氯喹(其水溶液的浓度1μM)处理,使氯喹的给药剂量为0.1mg/kg体重;O-Ctrl组给予等量的水处理,每周两次经水给药(给药的方式是饮用),至给药后5个月时进行大鼠寿命的统计。其结果如图1中A所示延长大鼠6.16%的中位寿命和13.12%的最大寿命。以上结果表明:低剂量(具体为0.1mg/kg)长时程的氯喹可以延长大鼠的寿命。
实施例2、低剂量氯喹降低机体炎症
将26只24月龄的年老SD大鼠随机分为2组,O-Ctrl组和O-CQ组,分别为16只和10只,O-CQ组给予氯喹(其水溶液的浓度1μM)处理,使氯喹的给药剂量为0.1mg/kg体重;O-Ctrl组给予等量的水处理,每周两次经水给药,给药5个月后,以5只2个月大的年轻鼠(Y-Ctrl组)为对照,进行组织取材。取全血进行血常规的检测,分离血浆进行炎症因子的检测,并分离心、肝、肾、血管、肠道和肺脏组织进行组织RNA的提取,进行RNA-seq检测。具体方法如下:
常规血液分析:
使用血液学分析仪(深圳迈瑞BC-5180CRP)测试用CQ或赋形剂处理的大鼠的新鲜全血中的血液生化。实验按照制造商的说明进行。
酶联免疫吸附试验(ELISA):
通过酶联免疫吸附测定(ELISA,生物科学)测试用CQ或载体治疗的大鼠血浆中的炎症细胞因子水平。IL-6(Thermo,88-50625),TNFα(Thermo,88-7340),MCP-1(Thermo,BMS631),IL-1β(Thermo,88-6010),IL-7(Thermo,ERA33RB)按照制造商的说明。使用酶标仪(Thermo,MK3)对结果进行量化。
RT-qPCR:
来自不同组织的总RNA 通过TRIzol(Gibco,15596018)提取,并使用GoScript逆转录系统(Promega,A5001)转化为cDNA。RT-qPCR是在CFX384实时系统(Bio-Rad)上使用SYBRqPCR混合物(TOYOBO,QPS-201)进行的。Actb用作内部对照以标准化靶基因的表达。
RNA测序:
将同组每只大鼠等量提取的RNA混合,分成3个技术重复进行RNA-seq测序。虽然这种混合程序可能涵盖小鼠之间的异质性,但这种方法有助于确定不同处理组之间的关键转录组的变化。转录组文库构建使用NEBNext UltraTM定向RNA文库制备试剂盒(NEB,美国)进行。生成的文库由Novogene生物信息学技术在Illumina平台上测序。
RNA-seq数据处理:
使用Trim Galore软件(0.4.5版)(https://github.com/FelixKrueger/TrimGalore)修剪原始数据,以去除低质量读取和使用适配器读取。然后使用HISAT2(版本2.2.1)将清洗后的读数映射到CSC大鼠参考基因组(rn6)。每个注释基因的表达水平由HTSeq(版本0.12.4)计算。差异表达基因(DEG)使用DESeq2包(版本1.30.0)计算,Benjamin-Hochberg调整P值<0.05和|log2(倍数变化)|>0.5。使用Metascape(http://metascape.org)进行GO术语和通路富集分析。使用具有默认参数的GSEA(版本4.1.0)进行基因集富集分析。特定疾病相关基因来自DisGeNET(https://www.disgenet.org)和MalaCards(https://www.malacards.org)。所有测序数据均保存在基因组序列档案(GSA)(https://bigd.big.ac.cn/gsa/)中,登录号为CRA004738。
结果如下:如图1中B和C所示,氯喹治疗的大鼠也倾向于降低老年大鼠的血清TNF-α水平和循环白细胞(WBC)和中性粒细胞(NEU)的数量。如图1中D和E所示,氯喹治疗后肝脏组织CD68阳性巨噬细胞的数量显著降低。如图1中F所示,CQ有提高动物血液中LYM百分含量的趋势。此外,还通过心、肝、肺、肾、主动脉和小肠组织进行了RNA-seq检测,进行了GSEA的分析;如图1中G所示,对多组织进行炎性反应的基因富集,结果表明低剂量的CQ给药后会显著下调肾脏、肝脏、心脏和主动脉组织的炎症。如图1中H所示,低剂量的CQ会在肾脏、肝脏、心脏和主动脉中显著下调干扰素IFN-γ的反应。如图1中I所示,低剂量的CQ会显著降低肝脏和肾脏组织中的TNF-α信号通路中的NF-κB。如图1中J所示,低剂量的CQ给药后会显著下调IL-6相关的炎症信号。以上结果表明,低剂量(0.1mg/kg)的CQ有降低动物机体慢性炎症的作用,特别是在肾脏、肝脏、心脏和主动脉上作用明显。
实施例3、低剂量氯喹减缓机体纤维化的发生
将26只24月龄的年老SD大鼠随机分为2组,O-Ctrl组和O-CQ组,分别为16只和10只,O-CQ组给予氯喹(其水溶液的浓度1μM)处理,使氯喹的给药剂量为0.1mg/kg体重;O-Ctrl组给予等量的水处理,每周两次经水给药,给药5个月后,以5只2个月大的年轻鼠(Y-Ctrl组)为对照,进行心、肝、肺、肾、主动脉、肠道组织的灌流取材,进行Masson纤维化的染色。同时提取心、肝、肾、血管、肠道和肺脏组织的RNA,进行RNA-seq检测。具体方法如下:
Masson染色方法:
使用Masson三色染色液试剂盒(Solarbio,G1340)以O-CQ组的年老鼠、O-Ctrl组的年老鼠和Y-Ctrl组的年轻大鼠的心脏、肝脏、肾脏、肺脏、血管和小肠组织为供试组织进行染色,具体步骤如下:
1)对组织进行石蜡包埋并切片;
2)切片常规脱蜡至水;
3)用配好的Weigert铁苏木素染色液染色5-10分钟;
4)酸性乙醇分化液分化5-15秒,水洗;
5)1%的氨水蓝化液返蓝15秒,水洗;
6)蒸馏水洗1分钟;
7)丽春红品红染色液染色5-10分钟;
8)在上述操作中按蒸馏水:弱酸溶液=2:1比例配置弱酸工作液,用弱酸工作液洗1分钟;弱酸溶液具体为乙酸溶液,浓度为体积百分含量0.2%的乙酸溶液;
9)用配置好的磷钼酸溶液洗1-2分钟;
10)弱酸工作液洗1分钟;
11)直接放入苯胺蓝染色液中染色1-2分钟;
12)体积百分含量95%乙醇快速脱水;
13)无水乙醇脱水3次,每次5-10秒;
14)二甲苯透明3次,每次1-2分钟;
15)封片,观察成像。
RT-qPCR:
来自不同组织的总RNA通过TRIzol(Gibco,15596018,)提取,并使用GoScript逆转录系统(Promega,A5001)转化为cDNA。RT-qPCR是在CFX384实时系统(Bio-Rad)上使用SYBRqPCR混合物(TOYOBO,QPS-201)进行的。Actb用作内部对照以标准化靶基因的表达。
RNA测序:
将同组每只大鼠等量提取的RNA混合,分成3个技术重复进行RNA-seq测序。虽然这种混合程序可能涵盖小鼠之间的异质性,但这种方法有助于确定不同处理组之间的关键转录组的变化。转录组文库构建使用NEBNext UltraTM定向RNA文库制备试剂盒(NEB,美国)进行。生成的文库由Novogene生物信息学技术在Illumina平台上测序。
RNA-seq数据处理:
使用Trim Galore软件(0.4.5版)(https://github.com/FelixKrueger/TrimGalore)修剪原始数据,以去除低质量读取和使用适配器读取。然后使用HISAT2(版本2.2.1)将清洗后的读数映射到UCSC大鼠参考基因组(rn6)。每个注释基因的表达水平由HTSeq(版本0.12.4)计算。差异表达基因(DEG)使用DESeq2包(版本1.30.0)计算,Benjamin-Hochberg调整P值<0.05和|log2(倍数变化)|>0.5。使用Metascape(http://metascape.org)进行GO术语和通路富集分析。使用具有默认参数的GSEA(版本4.1.0)进行基因集富集分析。特定疾病相关基因来自DisGeNET(https://www.disgenet.org)和MalaCards(https://www.malacards.org)。所有测序数据均保存在基因组序列档案(GSA)(https://bigd.big.ac.cn/gsa/)中,登录号为CRA004738。
结果如下:如图2中A和B所示,氯喹治疗减轻了老年肾脏、肺和肝脏的纤维化。对心脏和小肠的纤维化也有降低的趋向。如图2中C所示,低剂量的CQ给药后会显著下调在肾纤维化、肝纤维化和肺纤维化中上调的DEGs。如图2中D所示,低剂量的CQ会在肝脏组织的转化生长因子TGF-β信号通路中显著下调。
实施例4、低剂量氯喹保护组织器官
将26只24月龄的年老SD大鼠随机分为2组,O-Ctrl组和O-CQ组,分别为16只和10只,O-CQ组给予氯喹(其水溶液的浓度1μM)处理,使氯喹的给药剂量为0.1mg/kg体重;O-Ctrl组给予等量的水处理,每周两次经水给药,给药5个月后,以5只2个月大的年轻鼠(Y-Ctrl组)为对照,进行心、肝、肺、肾、主动脉、肠道组织的灌流取材,并进行HE染色。同时提取心、肝、肾、血管、肠道和肺脏组织的RNA,进行RNA-seq检测。具体方法如下:
HE染色方法:
1)对组织进行石蜡包埋并切片;
2)切片常规脱蜡至水;
3)用苏木精染色液染色5分钟;
4)流水稍洗去苏木精染色液1-3秒;
5)体积百分含量1%盐酸乙醇1-3秒;
6)水洗10-30秒;
7)蒸馏水洗1-2秒;
8)0.5%伊红染色1-3分钟;
9)蒸馏水洗1-2秒;
10)体积百分含量80%的乙醇洗1-2秒;
11)体积百分含量95%的乙醇洗3-5秒;
12)无水乙醇浸泡5-10分钟;
13)石炭酸二甲苯浸泡5-10分钟;
14)二甲苯透明3次,每次2分钟;
15)中性树胶封固,观察成像。
RT-qPCR:
来自不同组织的总RNA通过TRIzol(Gibco,15596018)提取,并使用GoScript逆转录系统(Promega,A5001)转化为cDNA。RT-qPCR是在CFX384实时系统(Bio-Rad)上使用SYBRqPCR混合物(TOYOBO,QPS-201)进行的。Actb用作内部对照以标准化靶基因的表达。
RNA测序:
将同组每只大鼠等量提取的RNA混合,分成3个技术重复进行RNA-seq测序。虽然这种混合程序可能涵盖小鼠之间的异质性,但这种方法有助于确定不同处理组之间的关键转录组的变化。转录组文库构建使用NEBNext UltraTM定向RNA文库制备试剂盒(NEB,美国)进行。生成的文库由Novogene生物信息学技术在Illumina平台上测序。
RNA-seq数据处理:
使用Trim Galore软件(0.4.5版)(https://github.com/FelixKrueger/TrimGalore)修剪原始数据,以去除低质量读取和使用适配器读取。然后使用HISAT2(版本2.2.1)将清洗后的读数映射到UCSC大鼠参考基因组(rn6)。每个注释基因的表达水平由HTSeq(版本0.12.4)计算。差异表达基因(DEG)使用DESeq2包(版本1.30.0)计算,Benjamin-Hochberg调整P值<0.05和|log2(倍数变化)|>0.5。使用Metascape(http://metascape.org)进行GO术语和通路富集分析。使用具有默认参数的GSEA(版本4.1.0)进行基因集富集分析。特定疾病相关基因来自DisGeNET(https://www.disgenet.org)和MalaCards(https://www.malacards.org)。所有测序数据均保存在基因组序列档案(GSA)(https://bigd.big.ac.cn/gsa/)中,登录号为CRA004738。
结果如下:如图3中A所示,低剂量的CQ能够降低老年大鼠的肾小球和心肌纤维的直径,缩短小肠绒毛长度,主动脉壁厚度,降低肝脏和肺脏的损伤评分。如图3中B所示,显示6个组织经CQ处理后的衰老相关的分泌表型(senescence-associated secretoryphenotype,SASP)相关的救援DEGs的热图。低剂量的CQ能够显著下调衰老过程中上调的Cxcl2、Wnt2等基因。如图3所示,GSEA基因集富集分析(Gene set enrichment analysis,GSEA)图显示CQ治疗后肾、肝、肺的SASP降低。以上结果表明:低剂量的氯喹有降低衰老带来的蛋白质分泌,保护组织器官年轻化的作用。
实施例5、低剂量氯喹不损伤大鼠心脏功能
将26只24月龄的年老SD大鼠随机分为2组,O-Ctrl组和O-CQ组,分别为16只和10只,O-CQ组给予氯喹处理,使氯喹的给药剂量为0.1mg/kg体重;O-Ctrl组给予等体积的水处理,每周两次经水给药,至给药后5个月时,以5只2个月大的年轻鼠(Y-Ctrl组)为对照,进行心脏超声检测。同时取心脏组织,提取RNA,进行RNA-seq的检测。
结果:如图4中A和B所示,老年大鼠的心脏功能在很大程度上不受氯喹治疗的影响。表明氯喹不会引起心脏副作用。如图4中C所示,由CQ处理改变的促衰老基因的生物学意义。在心脏中检测到超过一半的促衰老DEG(1678/2934),其中大部分(1594/1678)被上调。如图4中D所示,与心脏疾病相关的促衰老DEGs的网络图,通过对促衰老DEGs与心脏病相关基因的综合分析,发现CQ治疗诱导的基因网络与肥厚型心肌病、心律失常和心力衰竭有关。例如,Caps2在难治性缺血性终末期心力衰竭患者中也增加,在老年心脏中通过CQ治疗进一步增强(图4中E)。此外,Myh7是一种与心肌病相关的基因,在老年心脏中被上调,并被CQ进一步增强(图4中E)。这些数据表明,尽管心脏功能看似正常,但低剂量CQ治疗可能会在转录水平上引起促衰老副作用。
综上,低剂量氯喹在组织水平上不损伤大鼠心脏功能,但可能会在转录水平上引起促衰老副作用。
实施例6、转录组分析氯喹对老年肾脏的保护作用
将26只24月龄的年老大鼠随机分为2组,O-Ctrl组和O-CQ组,分别为16只和10只,O-CQ组给予氯喹处理,使氯喹的给药剂量为0.1mg/kg体重;O-Ctrl组给予等体积的水处理,每周两次经水给药,至给药后5个月时,以5只2个月大的年轻鼠(Y-Ctrl组)为对照,进行肾脏的高通量RNA测序。
结果如下:如图5中A和B所示,肾脏在CQ治疗后显示出大多数救援基因的上调。这解释了CQ治疗显着对老年肾脏的保护作用。如图5中C所示,表明低剂量CQ可改善肾功能,包括营养物质的代谢处理和废物的去除。此外,老年肾脏中的CQ抑制了一些生物学过程,例如对病毒的反应、对生物刺激的反应调节和免疫效应过程。一致地,如图5中D所示,由CQ上调的救援DEG包含一系列肾脏特异性有机阴离子转运蛋白,如Slc17a2、Slc24a3、Slc31a1和Slc36a4,它们在调节体内阴离子平衡中起着至关重要的作用(Nigam等人,2015)。此外,如图5中E和F所示,CQ处理减弱了CXCR相关的趋化基因,包括Cxcl1、Cxcl2、Cxcl6和Cxcl9以及含有干扰素刺激反应元件(ISRE)的基因,例如Mx2、Mx1、Oas1a、Oas2和Cgas。如图5中G所示,对转录图谱与肾脏疾病相关的基因进行了综合比较分析,发现CQ相关的救援DEGs与一系列肾脏疾病的发病相关,如肾纤维化、肾炎和慢性肾功能衰竭。此外,如图5中H所示,证实了Mx2的上调,Mx2是一种介导先天免疫的IFN刺激基因,通过RT-qPCR在老年肾脏中被CQ治疗抑制。因此,上述数据表明,低剂量CQ治疗对老年肾脏具有有益作用,可能会减少先天免疫途径并改善离子转运功能。与上述证明的CQ对肾脏的有益作用一致。
以上表明,氯喹能够改善肾单位功能。低剂量(具体为1μM)的氯喹有可能减少肾脏中先天免疫途径并改善离子转运功能,从而对保护肾脏。
以上对本发明进行了详述。对于本领域技术人员来说,在不脱离本发明的宗旨和范围,以及无需进行不必要的实验情况下,可在等同参数、浓度和条件下,在较宽范围内实施本发明。虽然本发明给出了特殊的实施例,应该理解为,可以对本发明作进一步的改进。总之,按本发明的原理,本申请欲包括任何变更、用途或对本发明的改进,包括脱离了本申请中已公开范围,而用本领域已知的常规技术进行的改变。按以下附带的权利要求的范围,可以进行一些基本特征的应用。
Claims (10)
1.氯喹在制备具有如下任一功能产品中的应用:
A1、治疗动物组织器官的炎症;
A2、治疗动物组织器官的纤维化;
A3、保护动物组织器官;
A4、降低动物组织器官的损伤;
A5、抑制组织器官中CXCR对肾脏保护或改善肾单位功能;
A6、促进肾脏组织中有机阴离子转运蛋白。
2.根据权利要求1所述的应用,其特征在于:所述组织为血管和/或小肠;
所述器官为心脏、肝脏、肾脏和肺脏中的至少一种。
3.根据权利要求2所述的应用,其特征在于:所述A2中器官为肺脏、肾脏和肝脏中的至少一种;
所述A3中器官为肝脏。
4.根据权利要求1-3中任一项所述的应用,其特征在于:所述动物为C1)或C2):
C1)哺乳动物;
C2)人或大鼠。
5.根据权利要求1-4中任一项所述的应用,其特征在于:所述产品为药品或保健品。
6.一种药品或保健品,其特征在于:其活性成分为所述氯喹。
7.根据权利要求6所述的药品或保健品,其特征在于:所述药品或保健品的辅料为水。
8.根据权利要求6或7所述的药品或保健品,其特征在于:所述药品或保健品中所述氯喹的浓度为0.2~5μM。
9.一种培育身体机能改善的动物的方法,其特征在于,包含以下步骤:
以每千克体重给予0.1mg的氯喹处理,处理5个月,培育出身体机能改善的动物。
10.根据权利要求9所述的方法,其特征在于:其中,所述身体机能改善具有如下B1)-B3)任一表现:
B1)动物代谢能耗、呼吸熵、耗氧量和二氧化碳排出量稳定;
B2)血液和组织器官中炎症因子的降低;
B3)组织器官的纤维化程度降低;
和/或,
所述动物为C1)或C2):
C1)哺乳动物;
C2)人或大鼠。
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