CN113134002B - 克来夫定的应用 - Google Patents
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- CN113134002B CN113134002B CN202110453902.0A CN202110453902A CN113134002B CN 113134002 B CN113134002 B CN 113134002B CN 202110453902 A CN202110453902 A CN 202110453902A CN 113134002 B CN113134002 B CN 113134002B
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
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Abstract
本发明提供了克来夫定的应用,包括用于下调与肿瘤发生或发展正相关的基因的表达水平,上调与肿瘤发生或发展负相关的基因的表达水平,上调与增强或重启免疫系统反应正相关的基因的表达水平,下调与增强或重启免疫系统反应负相关的基因的表达水平,上调与组织修复正相关的基因的表达水平,上调与病毒抑制正相关的基因的表达水平,下调与由于氧化应急及脂肪代谢而导致的组织纤维化正相关的基因的表达水平,或上调与由于氧化应急及脂肪代谢而导致的组织纤维化负相关的基因的表达水平,等。
Description
技术领域
本发明属于医药和细胞学技术领域,具体而言,本发明涉及涉及克来夫定的应用等。
背景技术
克来夫定(Clevudine)是合成的L-构型含氟核苷类似物,用于治疗乙型肝炎病毒(HBV)感染,也能与常用抗癌药物联用,对多种癌症的治疗有着协同增效的效果。核苷类似物药物通过抑制乙肝病毒的逆转录酶(RT)活性,来控制病毒复制,从而实现抗病毒治疗。因此理论上,这类药物因只能控制病毒复制而不能将病毒清除,通常需很长时间的使用,甚至终身服用,不但给病人帶來长期经济负担及精神压力,而且即使长期用药,仍有存留HBV的一些基因产物,如HBVSAg、 HBVx等,诱发肝癌(与近80%肝癌病例有关)。
尽管没有现有技术启示,本发明人仍旧认为,弄清楚克来夫定对人体各基因的表达水平的影响具有重要意义,能够为克来夫定能否长期用药以及可能的副作用、不良反应或疗效等提供依据。
然而,本发明人曾经研究了大量与HBV发展相关的基因及其编码蛋白质,尤其是宿主因子,然而,并没有发现其与克来夫定用药的相关性。即使这样,本发明人仍旧没有放弃,并时刻留心,终于凭借长期的深入研究,令人意外地,发现克来夫定用药能下调与肿瘤发生、发展正相关的基因的表达水平,上调与肿瘤发生、发展负相关的基因的表达水平,上调与增强或重启免疫系统反应正相关的基因的表达水平,下调与增强或重启免疫系统反应负相关的基因的表达水平,上调与组织修复正相关的基因的表达水平,上调与病毒抑制正相关的基因的表达水平,以及下调与由于氧化应急及脂肪代谢而导致的组织纤维化正相关的基因的表达水平。
尽管许多基因的用途是已经被明确证明,例如,提髙钟样受体(TLR2,TLR4,TLR6)基因表达, 或/和提高TLR4的配体(adapter) TICAM基因表达,会剌激固有免疫系统(innate immunity) 及适应性免疫系统(adaptive immune system);拮抗抑制细胞凋亡因子PD-1、BIRCs等的表达,会促进肿瘤细胞凋亡或坏死;NEAT1参与调节免疫系统钟样受体活性;SEL1L3 (sel-1 suppressor of lin-12-like 3)参与乙肝病毒颗粒及病毒蛋白的降解;阿片样生长因子受体(OGFRL1)修复坏死部位,促使被破坏的组识复常,等等,然而,克来夫定用药与之表达的相关性并没有任何公开和启示。
发明内容
本发明要解决的技术问题在于提供克来夫定的新的应用等,包括克来夫定在制备用于药物或试剂中的应用,将克来夫定与细胞一起孵育而进行的方法,检测克来夫定对基因表达的影响的方法等。
具体而言,在第一方面,本发明提供了克来夫定在制备用于选自如下之一的药物或试剂中的应用:
(1)下调与肿瘤发生、发展正相关的基因的表达水平,或上调与肿瘤发生、发展负相关的基因的表达水平,
(2)上调与增强或重启免疫系统反应正相关的基因的表达水平,或下调与增强或重启免疫系统反应负相关的基因的表达水平,
(3)上调与组织修复正相关的基因的表达水平,
(4)上调与病毒抑制正相关的基因的表达水平,或
(5)下调与由于氧化应急及脂肪代谢而导致的组织纤维化正相关的基因的表达水平,或上调与由于氧化应急及脂肪代谢而导致的组织纤维化负相关的基因的表达水平。
在本文中,术语“药物”、“试剂”、“相关(性)”和“影响”等具有本领域技术人员所熟知的词典含义。例如,试剂可以是进行体外试验所用的物质,相关可以包括正相关和负相关,影响可以包括上调(即增加、增强或促进等)和下调(即减少、降低或抑制等)。
在本文中,“选自如下之一”表明是所示选项之间是“或”的关系。例如,本发明第一方面的应用可以优选是克来夫定在制备用于上调与病毒抑制正相关的基因的表达水平的药物或试剂中的应用。
在第二方面,本发明提供了选自如下之一的方法,其包括将克来夫定与细胞一起孵育的步骤:
(1)下调与肿瘤发生、发展正相关的基因的表达水平,或上调与肿瘤发生、发展负相关的基因的表达水平,
(2)上调与增强或重启免疫系统反应正相关的基因的表达水平,或下调与增强或重启免疫系统反应负相关的基因的表达水平,
(3)上调与组织修复正相关的基因的表达水平,
(4)上调与病毒抑制正相关的基因的表达水平,或
(5)下调与由于氧化应急及脂肪代谢而导致的组织纤维化正相关的基因的表达水平,或上调与由于氧化应急及脂肪代谢而导致的组织纤维化负相关的基因的表达水平。
优选本发明第二方面的方法是体外方法,如可以是体外细胞水平的方法,不涉及体内治疗。例如,本发明第二方面的方法可以优选是体外上调与组织修复正相关的基因的表达水平的方法。在本发明的具体实施方式中,细胞是HepG2或HepG2.2.15。
优选在本发明中,与肿瘤发生、发展正相关的基因或与肿瘤发生、发展负相关的基因是BIRC2,BIRC3,RASSFs,IL6ST,RRM2B,PD-1,RAD51AP1,SCFD1,ARHGAP11A,TRIM23,CDHR2,TFPI,DNAJB4,或MBNL2基因。
优选在本发明中,与增强或重启免疫系统反应正相关的基因或与增强或重启免疫系统反应负相关的基因是TLR4,TICAM2,TRAM1, TLR2,TLR6,NEAT1,STAT4,ATF2,MAPK6,SGMS2,C21ORF91, IL-10, EOMES,GBP3,或GBP5基因。
优选在本发明中,上调与组织修复正相关的基因是OGFRL1基因。
优选在本发明中,上调与病毒抑制正相关的基因是SEL1L3基因。
也优选在本发明中,与由于氧化应急及脂肪代谢而导致的组织纤维化正相关的基因或与由于氧化应急及脂肪代谢而导致的组织纤维化负相关的基因是PDK4, NOX1,TXNIP,或BGN基因。
本发明中,相应的基因均公开于公共数据库中,例如可以从NCBI网站(https://www.ncbi.nlm.nih.gov)获取。
在第三方面,本发明提供了一种体外检测克来夫定对与肿瘤发生、发展相关的基因的表达影响的方法,其包括:
(1)在含有或不含有克来夫定的培养基中培养细胞;
(2)收获步骤(1)培养的细胞并裂解;
(3)从步骤(2)获得的裂解物中抽提RNA;
(4)使用illumina系统进行建库并测序;和
(5)对步骤(4)获得的序列中的肿瘤相关基因进行RNAseq分析。
优选在本发明第三方面的方法中,细胞是HepG2或HepG2.2.15。
优选在本发明第三方面的方法中,基因是BIRC2,BIRC3,RASSFs,IL6ST,RRM2B,PD-1,RAD51AP1,SCFD1,ARHGAP11A,TRIM23,CDHR2,TFPI,DNAJB4,或MBNL2基因。
在本发明中,分析包括比较含有和不含有克来夫定的培养基中培养细胞中相关基因的表达水平。
在第四方面,本发明提供了一种体外检测克来夫定对与增强或重启免疫系统反应相关的基因的表达影响的方法,其包括:
(1)在含有或不含有克来夫定的培养基中培养细胞;
(2)收获步骤(1)培养的细胞并裂解;
(3)从步骤(2)获得的裂解物中抽提RNA;
(4)使用illumina系统进行建库并测序;和
(5)对步骤(4)获得的序列中的免疫相关基因进行RNAseq分析。
选在本发明第四方面的方法中,细胞是HepG2或HepG2.2.15。
优选在本发明第四方面的方法中,基因是TLR4,TICAM2,TRAM1, TLR2,TLR6,NEAT1,STAT4,ATF2,MAPK6,SGMS2,C21ORF91, IL-10, EOMES,GBP3,或GBP5基因。
在第五方面,本发明提供了一种体外检测克来夫定对与组织修复相关的基因的表达影响的方法,其包括:
(1)在含有或不含有克来夫定的培养基中培养细胞;
(2)收获步骤(1)培养的细胞并裂解;
(3)从步骤(2)获得的裂解物中抽提RNA;
(4)使用illumina系统进行建库并测序;和
(5)对步骤(4)获得的序列中的免疫相关基因进行RNAseq分析。
优选在本发明第五方面的方法中,细胞是HepG2或HepG2.2.15。
优选在本发明第五方面的方法中,基因是OGFRL1基因。
在第六方面,本发明提供了一种体外检测克来夫定对与病毒抑制相关的基因的表达影响的方法,其包括:
(1)在含有或不含有克来夫定的培养基中培养细胞;
(2)收获步骤(1)培养的细胞并裂解;
(3)从步骤(2)获得的裂解物中抽提RNA;
(4)使用illumina系统进行建库并测序;和
(5)对步骤(4)获得的序列中的免疫相关基因进行RNAseq分析。
优选在本发明第六方面的方法中,细胞是HepG2或HepG2.2.15。
优选在本发明第六方面的方法中,基因是SEL1L3基因。
在第七方面,本发明提供了一种体外检测克来夫定对与由于氧化应急及脂肪代谢而导致的组织纤维化相关的基因的表达影响的方法,其包括:
(1)在含有或不含有克来夫定的培养基中培养细胞;
(2)收获步骤(1)培养的细胞并裂解;
(3)从步骤(2)获得的裂解物中抽提RNA;
(4)使用illumina系统进行建库并测序;和
(5)对步骤(4)获得的序列中的免疫相关基因进行RNAseq分析。
优选在本发明第七方面的方法中,细胞是HepG2或HepG2.2.15。
优选在本发明第七方面的方法中,基因是PDK4, NOX1, TXNIP,或BGN基因。
本发明的有益效果在于:提供了新的克来夫定的应用,通过克来夫定,能下调与肿瘤发生、发展正相关的基因的表达水平,上调与肿瘤发生、发展负相关的基因的表达水平,上调与增强或重启免疫系统反应正相关的基因的表达水平,下调与增强或重启免疫系统反应负相关的基因的表达水平,上调与组织修复正相关的基因的表达水平,上调与病毒抑制正相关的基因的表达水平,下调与由于氧化应急及脂肪代谢而导致的组织纤维化正相关的基因的表达水平,和上调与由于氧化应急及脂肪代谢而导致的组织纤维化负相关的基因的表达水平;也提供了新的方法,能检测出克来夫定对与肿瘤发生或发展相关、与增强或重启免疫系统反应相关、与组织修复相关、与病毒抑制相关、和与由于氧化应急及脂肪代谢而导致的组织纤维化相关的基因的表达影响。
为了便于理解,以下将通过具体的实施例对本发明进行详细地描述。需要特别指出的是,这些描述仅仅是示例性的描述,并不构成对本发明范围的限制。依据本说明书的论述,本发明的许多变化、改变对所属领域技术人员来说都是显而易见的。
另外,本发明引用了公开文献,这些文献是为了更清楚地描述本发明,它们的全文内容均纳入本文进行参考,就好像它们的全文已经在本文中重复叙述过一样。
附图说明
图1是RNAseq分析的流程图。
具体实施方式
以下通过实施例进一步说明本发明的内容。如未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段和市售的常用仪器、试剂,可参见《分子克隆实验指南(第3版)》(科学出版社)、《微生物学实验(第4版)》(高等教育出版社)以及相应仪器和试剂的厂商说明书等参考。
实施例1. 实验方法
一、HepG2以及HepG2.2.15与克来夫定共孵育实验
实验药物:克来夫定(代号:化合物B或TP-0239)
细胞株: HepG2及其衍生细胞株HepG2.2.15。
细胞培养条件:HepG2:DMEM+10%FBS;HepG2.2.15:DMEM+10%FBS+ 400μg/ml G418。
实验步骤:
1. 体外培养细胞株HepG2和HepG2.2.15,细胞生长至对数生长期后,收集细胞,1000rpm离心5min,弃上清,适量培养基悬浮,调整细胞浓度至1.75×105个/2ml。将细胞悬液接种到6孔细胞培养板中,每孔2ml,每个细胞点9个孔。放置细胞培养箱(37℃,5%CO2)
2. 次日,用DMSO配制以下浓度的化合物B母液:10mM,100mM。按照1:1000加入培养基(空白对照组加入等体积的DMSO)。用含有化合物B/DMSO的培养基换液培养,每种细胞和不同浓度药物对应的培养样本重复3个,此日记作Day0。
3. 每24h,用含有化合物B/DMSO的培养基换液,细胞长至70-80%即传代,连续给药培养4周。
4.Day 28,收集细胞,用PBS 清洗两次,用1ml Trizol裂解,-80℃保存,次日进行RNAseq实验。
二、RNAseq实验
利用生物素标记的核糖体探针捕获总RNA中的核糖体rRNA,并利用探针上的磁珠去除捕获倒的核糖体序列。对剩余的RNA片段进行片段化处理,并逆转录合成cDNA第一链和第二链,逆转录产物的末端进行末端修复,然后在3’末端加A碱基。随后,将该片段与llumina通用的接头相连接。连接产物经过纯化,去除连接不完整的产物及空的接头自连产物后,运用与接头序列互补的通用引物对之进行PCR扩增。PCR扩增产物经过纯化去除引物二聚体、琼脂糖凝胶电泳质检以及浓度测定后,按照llumina的标准流程进行二代测序。
具体而言,实验步骤如下:
(一)、抽提RNA
1、 在细胞中加入1ml Trizol试剂。
2、 加入200μL氯仿,混匀。室温下静置试管5min。
3、 4°C 下12000 x g离心15min。
4、 转移等量上清液到新的无核酸酶的微型离心管中。
5、 各离心管中加入RLT缓冲液,混匀。
6、 各离心管中均加入乙醇,混匀,然后快速旋转。
7、 将样品加入到柱子(RNeasy MinElute spin column, QIAGEN)中(柱子放在一个2ml的收集管中),轻轻盖上盖子,≥8000 x g(或≥1000 rpm)离心15秒, 弃掉过滤到收集管中的液体。
8、在柱子中加入500ul缓冲液RPE,轻轻盖上盖子,离心,弃掉过滤到收集管中的液体。
9、在柱子中再次加入500ul缓冲液RPE,轻轻盖上盖子,离心,弃掉过滤到收集管中的液体。
10、将柱子放入新的1.5 mL收集管中。在柱子中直接加入30ul 去RNA酶水,轻轻盖上盖子,≥8000 x g(或≥10000 rpm)离心1min,洗脱RNA。
(二)、使用illumina系统进行建库并测序,其流程参考illumina官方protocol。
(三)、RNAseq分析参照附图1进行,其中基因表达定量分析方法如下:
RSEM(V1.2.29)( Li B, Dewey C N. RSEM: accurate transcriptquantification from RNA-Seq data with or without a reference genome[J]. BMCbioinformatics, 2011, 12(1): 323.)可以从RNA-seq 数据中精确定量基因或转录本的表达量。在该项目的分析中,我们以BAM为输入文件,设定RSEM的参数--estimate-rspd估算测序序列的起始位置的分布(read start position distribution,RSPD),其他为默认参数,分别评估了每个样本中所有基因或转录本的表达量。 然后用R语言的edgeR(v3.8.5)包对所得到的基因或转录本的表达量进行TMM(trimmed mean of M values)( Robinson MD, Oshlack A. A scaling normalization method for differential expressionanalysis of RNA-seq data[J]. Genome Biology, 2010,11(3):1-9.)和CPM(count permillion)标准化。TMM主要是对不同样本的测序深度标准化,估算每个样本的表达水平因子。CPM主要是对样本间的表达量进行标准化。 在下游的分析中,我们主要是应用TMM和CPM标准化的表达量做比较分析。我们还分别用Gene Ontology(gene2go.20141211)、GenRef(gene_info.20141211)和GENCODE(v19)数据库对所检测到的基因进行注释。这些基因的表达量可用于后续的主成分(PCA)和聚类分析。
TMM标准化公式:Ygk表示在第k个样本比对到基因g的reads数目。Nk表示比对到第k个样本所有基因的总reads数目。分母为对照样本中基因的表达量和总的reads数目。Ag为基因表达的绝对值。TMM认为大部分基因不存在差异表达,所以公式分别去掉M值和A值两端的30%和5%,再估算样本的表达水平因子。
基因表达即基因从DNA到RNA转录和蛋白翻译的过程,转录本的丰度体现基因的表达水平,转录本丰度越高,则基因表达水平越高。在RNA-seq分析中,通过计算比对到基因组特定区域的序列(clean reads)来衡量基因或转录本的表达水平。实施例2-7即使用的标准化后的基因表达数值。
实施例2.TP-0239对肿瘤相关基因的表达的影响
使用TP-0239对肿瘤相关基因(如,BIRC2,BIRC3,RASSFs,IL6ST,RRM2B,PD-1,RAD51AP1,SCFD1,ARHGAP11A,TRIM23,CDHR2,TFPI,DNAJB4,MBNL2)的基因表达情况如下表2.1和2.2所示。结果表明,TP-0239能下调大量与肿瘤发生、发展正相关的基因表达水平,而且能上调大量与肿瘤发生、发展负相关的基因表达水平。
表2.1 TP-0239对HepG2细胞的肿瘤相关基因的表达的影响
表2.2 TP-0239对HepG2.2.15细胞的肿瘤相关基因的表达的影响
实施例3. TP-0239对免疫相关基因的表达的影响
使用TP-0239对靶向免疫或炎症信号通路检查点基因(如,TLR4,TICAM2,TRAM1,TLR2,TLR6,NEAT1,STAT4)及干扰素(INFs) 相关通路基因(如ATF2,MAPK6,SGMS2,C21ORF91, IL-10, EOMES,GBP3,GBP5)等的基因表达情况如下表3.1所示。结果表明,TP-0239能上调大量与增强或重启免疫系统反应正相关的基因表达水平,而且能下调大量与增强或重启免疫系统反应负相关的基因表达水平。
表3.1 TP-0239对HepG2.2.15细胞的免疫相关基因的表达的影响
实施例4.TP-0239对组织修复相关基因的表达的影响
使用TP-0239对组织修复相关基因(如OGFRL1)的基因表达情况如下表4.1所示。结果表明,TP-0239能上调与组织修复正相关的基因表达水平。
表4.1 TP-0239对HepG2.2.15细胞损伤的修复相关基因的表达的影响
实施例5. TP-0239对寄主细胞病毒抑制相关基因的表达的影响
使用TP-0239对寄主病毒抑制相关基因(如SEL1L3)的基因表达情况如下表5.1所示。结果表明,TP-0239能上调与病毒抑制正相关的基因表达水平。
表5.1 TP-0239对HepG2.2.15细胞的寄主病毒限制相关基因的表达的影响
实施例6. TP-0239对组织纤维化相关基因的表达的影响
使用TP-0239对由于氧化应急及脂肪代谢而导致的组织纤维化相关基因(如PDK4,NOX1, TXNIP,BGN)的基因表达情况如下表6.1所示。结果表明,TP-0239能下调与由于氧化应急及脂肪代谢而导致的组织纤维化正相关的基因表达水平,而且能上调与由于氧化应急及脂肪代谢而导致的组织纤维化负相关的基因表达水平。
表6.1 TP-0239对HepG2.2.15细胞的组织纤维化相关基因的表达的影响
Claims (1)
1.下调BIRC2基因的表达水平的体外方法,其包括将克来夫定与HepG2或HepG2.2.15细胞一起孵育的步骤。
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