CN114480625A - Mapk信号通路抑制在慢性骨髓炎改善、诊断和治疗中的应用 - Google Patents
Mapk信号通路抑制在慢性骨髓炎改善、诊断和治疗中的应用 Download PDFInfo
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Abstract
本发明公开了一种MAPK信号通路抑制在慢性骨髓炎改善、诊断和治疗中的应用。本发明发现基于转录组学分析显示慢性骨髓炎的发病和MAPK信号通路相关,IKBκB、MAP3K7、NFATC1、NFκB2有可能成为新的临床诊断和疾病治疗的靶点。本发明提供了一种改善慢性骨髓炎的方法,使患者在早期就得以治疗,进而提高治愈率和生活质量。本发明提供一种治疗手段和药物组合物,实现慢性骨髓炎的精准治疗。本发明还提供一种筛选预防或治疗慢性骨髓炎待筛选物质的方法,对慢性骨髓炎的诊断、预后和预测具有重要作用。
Description
技术领域
本发明涉及生物医药技术领域,特别涉及MAPK信号通路抑制在慢性骨髓炎改善、诊断和治疗中的应用。
背景技术
伴随社会工业化的进程,创伤性骨髓炎的发病率逐年升高,业已成为慢性骨髓炎的代名词,其病程长,迁延难愈,是骨科的难点和热点问题。其致病菌多样,非手术难以有效控制感染,术后也存在着骨愈合困难,骨不连高发,感染易复发等特点。虽然根据病史、查体、细菌培养及影像学检查可以对大多数慢性骨髓炎作出诊断,但值得注意的是,有约30%的患者细菌培养呈阴性,即使作为诊断“金标准”的病理检查,也可能因切片取材问题而出现“假阴性”或其他具有感染性质的结果。因此,深入研究慢性骨髓炎的发病机制,寻找可行新的诊断方法和精准的诊断指标是目前临床亟待解决的问题,有助于提高诊断的精确度并为治疗新靶点的发现提供依据。
转录组(Transcriptome)包括mRNA、非编码RNA等,是细胞或组织中的所有转录产物的集和,也是目前研究细胞及整体转录水平的最有效的手段[5]。转录组学(Transcriptomics)是指在组织、动物或人体层面研究基因转录、表达和作用规律。基于转录组学的特点和作用,目前己在疾病机理、临床诊断和药物研发领域广泛应用。RNA测序(RNA-Sequencing,RNA-Seq)技术是目前转录组学研究的一种有效的技术手段。
发明内容
为了弥补现有技术的不足,本发明的目的之一,提供一种改善慢性骨髓炎的方法,使患者在早期就得以治疗,进而提高治愈率和生活质量。
本发明的目的之二,提供一种治疗手段和药物组合物,实现慢性骨髓炎的治疗。
本发明的目的之三,提供一种筛选预防或治疗慢性骨髓炎待筛选物质的方法。
为了实现上述目的,本发明采用如下技术方案:
本发明提供了MAPK信号通路抑制在慢性骨髓炎改善中的应用。
进一步地,所述MAPK信号通路抑制是抑制IκBKβ表达、MAP3K7表达、NFATC1表达和/或NFκB2表达。
本发明提供了诊断慢性骨髓炎的产品,所述产品包括检测样本中MAPK信号通路表达水平的试剂。
所述产品包括芯片、制剂或试剂盒。其中,所述芯片包括固相载体以及固定在固相载体的寡核苷酸探针,所述寡核苷酸探针包括用于检测MAPK信号通路转录水平的针对MAPK信号通路的寡核苷酸探针;所述试剂盒包括用于检测MAPK信号通路转录水平的引物或芯片。
固相载体可采用基因芯片领域的各种常用材料,例如但不限于尼龙膜,经活性基团(如醛基、氨基等)修饰的玻片或硅片、未修饰的玻片、塑料片等。
本发明中基因检测试剂盒或基因芯片可用于检测包括IκBKβ、MAP3K7、NFATC1和/或NFκB2在内的多个基因(例如,与慢性骨髓炎相关的多个基因)的表达水平,将慢性骨髓炎的多个标志物同时进行检测,可大大提高慢性骨髓炎诊断的准确率。
本发明提供了MAPK信号通路抑制在制备治疗慢性骨髓炎的药物组合物中的应用。
进一步地,所述的药物组合物包括MAPK信号通路的抑制剂,和/或与所述抑制剂配伍的其他药类以及药学上可接受的载体和/或辅料,所述抑制剂能够抑制MAPK信号通路或涉及MAPK信号通路上游或下游途径的物质的表达。
在本发明中,术语“探针”指能与另一分子的特定序列或亚序列或其它部分结合的分子。除非另有指出,术语“探针”通常指能通过互补碱基配对与另一多核苷酸(往往称为“靶多核苷酸”)结合的多核苷酸探针。根据杂交条件的严谨性,探针能和与该探针缺乏完全序列互补性的靶多核苷酸结合。探针可作直接或间接的标记,其范围包括引物。杂交方式,包括,但不限于:溶液相、固相、混合相或原位杂交测定法。
在本发明中,药学上可接受的载体包括(但并不限于):稀释剂、赋形剂如乳糖、氯化钠、葡萄糖、尿素、淀粉、水等、填充剂如淀粉、蔗糖等;粘合剂如单糖浆、葡萄糖溶液、淀粉溶液、纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂如甘油;崩解剂如干淀粉、海藻酸钠、海带多糖粉末、琼脂粉末、碳酸钙和碳酸氢钠;吸收促进剂季铵化合物、十二烷基硫酸钠等;表面活性剂如聚氧化乙烯山梨聚糖脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘油酯、十六烷醇等;致湿剂如甘油、淀粉等;吸附载体如淀粉、乳糖、斑脱土、硅胶、高岭土和皂粘土等;润滑剂如滑石粉、硬脂酸钙和镁、聚乙二醇、硼酸粉末等。
在本发明中,药物组合物可以使用不同的添加剂进行制备,例如缓冲剂、稳定剂、抑菌剂、等渗剂、螯合剂、pH控制剂及表面活性剂。
本发明所述的药物组合物可口服给药、非胃肠道给药、通过吸入喷雾给药、局部给药、直肠给药、鼻给药、颊给药、***给药或通过植入的贮药装置给药。优选口服给药或注射给药。本发明的药物组合物可含有任何常用的无毒可药用载体、辅料或赋形剂。在某些情况下,药用酸、碱或缓冲剂可用来调节制剂的pH以提高所配制的化合物或其给药剂型的稳定性。本发明所用术语非胃肠道包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、鞠内、损伤部位内、和颅内注射或输注技术。只要能达到目标组织,本发明所述药物组合物可以通过任何途径给予受体。
本发明药物组合物可以以任何口服剂型的形式口服给药,包括但不限于胶囊、片剂、乳剂和水悬浮液、分散剂和溶液。对于口服片剂,常用载体包括乳糖和玉米淀粉。一般还加入润滑剂例如硬脂酸镁。为了以胶囊形式口服给药,适用的稀释剂包括乳糖和无水玉米淀粉。当口服施用水悬浮液和/或乳液时,可将活性组分悬浮或溶解在油相中,并与乳化剂和/或悬浮剂合并。如果需要的话,可加入一些甜味剂和/或矫味剂和/或着色剂。适当时,可将用于口服给药的剂量单位制剂包微囊。例如,通过在聚合物、蜡等中将颗粒物质包衣或包埋,也可制备所述制剂已延长或维持释放。本发明的药物组合物可以用于降低内源性的MAPK信号通路过表达,通过降低MAPK信号通路的表达,从而治疗因MAPK信号通路表上调导致的慢性骨髓炎。
在本发明中,可将抑制MAPK信号通路表达的化合物作为裸RNA与递送试剂一起作为核酸(如重组质粒或病毒载体)给受试者施用,所述核酸包含抑制MAPK信号通路表达的序列。递送试剂可以是亲脂试剂、聚阳离子、脂质体等。
本发明的药物还可与其他治疗慢性骨髓炎的药物联用,其他治疗性化合物可以与主要的活性成分同时给药,甚至在同一组合物中同时给药。还可以以单独的组合物或与主要的活性成分不同的剂量形式单独给予其它治疗性化合物。主要成分的部分剂量可以与其它治疗性化合物同时给药,而其它剂量可以单独给药。在治疗过程中,可以根据症状的严重程度、复发的频率和治疗方案的生理应答,调整本发明药物组合物的剂量。
本发明药物组合物可以局部给药的药物组合物,可以配制成软膏、乳膏剂、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。
本发明的药物组合物可以按药剂学上有效的量进行给药,本发明的用语“药剂学上有效的量”指的是以可适用于医学治疗或预防的合理的受惠/危险比率足以治疗或预防疾病的量,可根据包括疾病的严重程度、药物的活性、患者的年龄、体重、健康、性别、患者对药物的敏感度、所使用的本发明组合物的给药时间、给药途径及排出比率、治疗时间、与所使用的本发明的组合物配合或同时使用的药物的要素及其它医学领域中公知的要素来决定有效用量水平。本发明的药物组合物可作为单独的治疗剂进行给药,或是与其它治疗剂并用地进行给药,可以与以往的治疗剂依次地或同时地进行给药。此外,可单次或多次地进行给药。重要的是,需要对上述要素均加以考虑,并且以无副作用的最少的量可取得最大效果的量进行给药。
术语“治疗”是指不以治愈为目的,而是减缓(减少)靶定的病理状况或病症或防止复发。如果接受治疗有效量的治疗剂之后,患者成功地被“治疗”,患者显示出可观测到的和/或可度量的一种或多种特定疾病的迹象和症状的减少或消失。例如,使在一定程度上减少和/或减轻与特定慢性骨髓炎相关联的一种或多种症状的时间增加;减少的发病率和死亡率,以及改善生活质量。疾病的迹象或症状的减轻能够为患者感知。如果患者感受到疾病稳定,患者也被视为得到治疗。
在本发明中,术语“样本”包括(但不限于)细胞、组织、脏器、体液(血液、淋巴液等)、消化液、咳痰、肺胞支气管清洗液、尿、粪便等。优选的,所述样本为组织、血液。
本发明还提供了MAPK信号通路在筛选预防或治疗慢性骨髓炎的待筛选物质中的应用。
进一步,所述的筛选预防或治疗慢性骨髓炎的待筛选物质的步骤包括:
待筛选物质处理表达或含有MAPK信号通路基因的体系;和
检测所述体系中MAPK信号通路基因的表达;
其中,若所述待筛选物质可降低MAPK信号通路基因的表达或活性(优选显著降低,如低20%以上,较佳的低50%以上,更佳的低80%以上),则表明该待筛选物质是预防或治疗慢性骨髓炎的待筛选物质。
进一步,上面所述的体系包括(但不限于):细胞体系、亚细胞体系、溶液体系、组织体系、器官体系或动物体系。
与现有技术相比,本发明提供了一种改善慢性骨髓炎的方法,使患者在早期就得以治疗,进而提高治愈率和生活质量。本发明提供一种治疗手段和药物组合物,实现慢性骨髓炎的精准治疗。本发明还提供一种筛选预防或治疗慢性骨髓炎待筛选物质的方法,对慢性骨髓炎的诊断、预后和预测具有重要作用。本发明预测分析的基因可能在慢性骨髓炎以及感染性骨不连的致病机制中起了重要作用,有可能成为新的防治骨不连的靶点,同时也为临床诊断和治疗提供了可靠的实验依据。
附图说明
图1是慢性骨髓炎病灶的X光检查结果示意图;
图2是慢性骨髓炎病灶组织骨病理示意图;
图3是Control(正常骨)组和Necrosis(病灶骨)样本PCA分析结果示意图;
图4是Control(正常骨)组和Necrosis(病灶骨)样本的相关性分析示意图;
图5是Top100差异基因聚类热图;
图6是全部差异基因KEGG pathway富集;
图7是GO生物学过程示意图;
图8是共有基因GO功能网络图;
图9是基于靶点筛选的创伤性骨不连机制图
具体实施方式
下面结合附图和实施例对本发明作进一步详细的说明。以下实施例仅用于说明本发明而不用于限制本发明的范围。
实施例:采集和分析慢性骨髓炎患者骨组织的转录组信息,为探究慢性骨髓炎发病的分子机制,明确MAPK信号通路在慢性骨髓炎发病过程中的作用。
1、材料与方法
1.1研究对象与分组
1.1.1病例纳入标准及排除标准
选取创伤导致慢性骨髓炎病例,患者年龄18-65岁,无主要脏器及周围血管病变,无糖尿病及其他免疫***疾病。病例排除标准为:年龄小于18岁或者大于65岁,合并有其他脏器疾病或全身情况差而不能耐受手术;患者不配合治疗及随访;糖尿病或其他免疫***疾病患者。
1.1.2病理组织学检查
Necrosis组及Control组样本,置10%***液中固定24h以上,再冲洗后置EDTA符合脱钙液脱钙7天,脱钙完成后进行脱水、石蜡包埋,置切片机上进行切片(厚度5μm)。切片在二甲苯中脱蜡2次;使用梯度浓度乙醇中脱水,最后蒸馏水清洗;苏木精染液及0.5%的伊红染液染色;二甲苯透明;中性树胶封片,光学显微镜下观察组织切片。
1.2慢性骨髓炎患者骨组织转录组学研究
1.2.1骨组织样本RNA提取、测序
清创术中收集患者病灶骨样本,去除软组织,并在行自体骨植骨时取自体髂骨颗粒(纯松质骨),用无菌生理盐水冲洗,立即保存于液氮中备用。RNA提取前,样本采用液氮碾磨,用Trizol提取总样品的RNA,并分离和纯化。采用NanoDrop ND-1000对总RNA的量与纯度进行质控。再通过Bioanalyzer 2100对RNA的完整性进行检测,浓度>50ng/μL,RIN值>7.0,OD260/280>1.8,total RNA>1μg满足下游实验。
使用oligo(dT)磁珠通过两轮的纯化对其中的带有PolyA(多聚腺苷酸)的mRNA进行特异性捕获。将捕获到的mRNA在高温条件下利进行片段化,将片段化的RNA通过逆转录酶的作用下合成cDNA。然后使用E.coli DNA polymerase I,与RNase H,将这些DNA与RNA的复合双链转化成DNA双链,并在二链中掺入dUTP Solution,补齐双链DNA的末端,两端分别加上A碱基,与带有T碱基的接头连接,oligo(dT)磁珠进行筛选和纯化。二链采用UDG酶消化,预变性,形成片段大小为300bp±50bp的文库。参照Illumina NovaseqTM4000标准操作对上述文库进行高通量双端测序。
1.2.2差异基因筛选
Illumina HiSeq Xten高通量测序平台基于边合成边测序技术对cDNA文库进行测序,最终获得原始数据Raw Data,过滤数据获得clean Reads,使用Trinity法对cleanReads进行denovo组装。借助于TopHat2对测序产生的clean Reads与参照基因组进行对比,得到有关的位置信息,以及测序样本中的特征信息。使用FPKM作为计算转录本或基因表达水平的指标。参照Fold Change≧2且FDR<0.01的标准筛选本研究差异基因。
1.2.3GO富集和KEGG富集分析
通过Ensemble(www.Ensemble.org)和NCBI数据库(www.ncbi.nlm.nih.gov)对测序所得到的有SNP位点相关基因进行筛选,并注释到基因本体论(gene ontology,GO)数据库(www.geneontology.org)和京都基因与基因组百科全书(Kyoto Encyclopedia ofGenes and Genormes,KEGG)数据库(www.Kegg.jp)上进行比对分析。使用R 3.6.3软件,进行GO富集分析以及KEGG富集。
2.研究结果
2.1慢性骨髓炎患者影像及病理学检查
对慢性骨髓炎病灶进行影像学及病理检查,并进行分析,X光检查结果如图1所示,病灶组织骨病理如图2所示,其中图2从左往右顺序分别表示了死骨组织,淋巴细胞浸润和纤维骨组织伴退变。影像学结果表明,病灶部位出现软组织水肿、骨质破坏或增生、骨膜反应、骨缺损、死骨等。病理组织学检查结果表明,病灶组织出现死骨,局部有淋巴细胞浸润,有些伴有纤维骨组织退变。以上均是慢性骨髓炎常见的典型特征。
2.2 RNA检测及质控结果
采用Nanodrop、Aglient 2100方法检测样品的RNA纯度、浓度和完整性,Bioanalyzer 2100对RNA的完整性进行检测。选取浓度>50ng/μL,RIN值>7.0,OD260/280>1.8,total RNA>1μg作为后续测序实验的样本。Control(正常骨)组和Necrosis(病灶骨)组4个生物学重复得到的过滤后clean reads(×106)以及clean reads占比结果表明,cleanreads占比均大于90%。各样本碱基质量值大于等于30占比均在98%以上,提示测序质量较好。质控合格、样本RNA检测结果及测序质量结果见表1。
表1质控合格样本RNA检测结果及测序质量结果
2.3各组生物学重复样本的基因表达量及相关性分析
两组样本的基因表达量的Pearson相关系数见图3和图4。相关系数越高,代表基因表达水平越相似。PCA分析结果显示,Control组的4个生物学重复样本Control_1、Control_2、Control_3、Control_4的检测结果一致性较好(Control表示正常骨),而Necrosis组中生物学重复样品Necrosis_1与Necrosis_2、Necrosis_3Necrosis_4存在明显偏离(Necrosis表示病灶骨)。因此,为了减少误差,后续分析将Necrosis_1样本数据剔除。
2.4差异表达基因(DEGs)的筛选及聚类分析
Control组和Necrosis组之间检测到DEGs 5548个,其中Necrosis组上调DEGs2701个,下调DEGs 2847个。对其中Top 100的差异基因进行聚类分析DEGs(p value<0.01,qvalue<0.05,fold change>2)进行聚类分析,获得聚类热图(图5,Top100差异基因聚类热图,色块的颜色越红,表达量越高;颜色越蓝,表达量越低。),更直观看到组间DEGs表达量的变化以及组内样品表达一致性。
2.5 KEGG Pathway富集分析以及GO生物学过程富集分析
对全部差异基因进行KEGG通路富集分析(pathway)和GO生物学过程(biologicalprocess)富集分析,如图6所示。KEGG通路富集主要在PI3K-AKT signaling pathway、Hipposignaling pathway、Rheumatoid arthritis、TGF-beta signaling pathway、TNFsignaling pathway、Vascular smooth muscle contraction、NF-kappa B signalingpathway、Wnt signaling pathway等通路。GO生物学过程(biological process)富集分析主要在skeletal system development、angiogenesis collagen fibril organization、blood vessel development、collagen binding等生物学过程(如图7所示)。
2.7 MAPK信号通路靶点筛选
慢性骨髓炎细菌感染促进RANKL介导的破骨细胞生成主要是通过MAPK信号通路中ERK、JNK、P38通路等,上调转录因子NFATc1和c-FOS表达,进而促进骨吸收实现。因此,本发明对Control组和Necrosis组的DEGs中检测到的富集到MAPK信号通路的基因进行筛选,并与Control组和Necrosis组的DEGs中Osteoclast differentiation信号通路相关的基因取交集(差异基因与信号通路富集见表3),发现共有基因有:IκBKβ(IKKβ,inhibitorofnuclear factor kappa B kinase subunit beta)、MAP3K7(mitogen-activated proteinkinase kinase kinase 7)、NFATC1(nuclear factor of activated T cells 1)、NFκB2(nuclear factor kappa B subunit 2)。
表3
将上述共有基因与其GO功能中与骨形成相关的生物学过程(biologicalprocess)绘制网络图,见图8。结果显示IκBKβ与NF-kappaB signaling、I-kappaBphosphorylation、IkappaB kinase activity、response to virus、kinase activity等GO功能相关;MAP3K7与activation of MAPKK activity、activation of MAPK activity,magnesium ion binding、stimulatory C-type lectin receptor signaling pathway、positive regulation of T cell cytokine production、MAP kinase kinase kinaseactivity、transforming growth factor beta receptor signaling pathway、Wntsignaling pathway、calcium modulating pathway、NF-kappaB signaling、I-kappaBphosphorylation、JNK cascade、IkappaB kinase complex、positive regulation ofinterleukin-2production、positive regulation of JUN kinase activity等GO功能相关;NFATC1与Wnt signaling pathway、calcineurin-NFAT signaling cascade、Fc-epsilon receptor signaling pathway、mitogen-activated protein kinase p38binding、negative regulation of vascular smooth muscle cell differentiation等GO功能相关;NFκB2与response to lipopolysaccharide、NF-kappaB2 complex、NF-kappaBsignaling、positive regulation of NF-kappaB transcription factor activity等GO功能相关。
骨修复重建是基于破骨细胞的骨吸收与成骨细胞的骨形成的耦联机制。慢性骨髓炎在骨感染过程中,正常的骨重建过程被炎症改变,导致骨代谢紊乱。细菌内毒素可刺激分泌多种促炎症因子,如肿瘤坏死因子(tumor necrosis factor,TNF-α)、白细胞介素(interleukin,IL)6等,与成骨细胞表面的TNFR1结合,抑制成骨细胞分化,从而减少骨形成。如图9所示,在破骨细胞方面,SPA上调NF-κB受体激活蛋白配体(RANKL),使其与破骨细胞上的受体RANK结合,激活下游的MAPK等信号通路,MAPK信号通路激活是通过执行保守的三级酶促级联反应:磷酸化的MAP3K激活MAPKK(磷酸化),最终激活MAPK(磷酸化)。破骨细胞内与RANKL相关的信号转导通路主要有:NF-κB通路、MAPK通路、PI3K/Akt通路和CN/NFAT通路等。RANKL与RANK结合后,激活P38MAPK,活化的P38通过下游底物MAPK激活蛋白激酶-2,进而调控下游转录因子c-fos、NFATc1表达,促进破骨细胞分化。NF-κB通路被认为在破骨细胞激活发挥最重要的作用,NF-κB的抑制剂IκBK(静止细胞中在胞浆内与NF-κB结合,阻止其进入细胞核发挥作用)降解,使NF-κB不能转入细胞核中与其相应耙基因的启动子结合,从而不能通过启动或调控基因转录来调节破骨细胞的分化功能。上述过程中NFATc1和c-fos是其成熟过程中两个关键转录因子,可诱导破骨细胞特异基因TRAP、cathepsin K的表达,促进骨吸收。本发明通过转录组学实验,筛选到与破骨细胞增殖分化以及MAPK信号通路相关的靶点IκBKβ、MAP3K7、NFATC1、NFκB2,支持了炎症诱导的破骨细胞增殖分化在创伤性骨髓炎骨不连的致病机制的作用,上述基因可能成为创伤性骨不连的诊断和治疗的潜在靶点,其在骨不连的调控作用值得进一步深入研究。
本发明研究证实了MAPK信号通路抑制可改善慢性骨髓炎,因此抑制IκBKβ表达、MAP3K7表达、NFATC1表达和/或NFκB2表达可应用慢性骨髓炎的改善。
此外,本发明还提供一种诊断慢性骨髓炎的产品,所述产品包括检测样本中MAPK信号通路表达水平的试剂,所述产品包括芯片、制剂或试剂盒。
本发明的一实施方式还提供一种MAPK信号通路抑制在制备治疗慢性骨髓炎的药物组合物中的应用;所述的药物组合物包括MAPK信号通路的抑制剂,和/或与所述抑制剂配伍的其他药类以及药学上可接受的载体和/或辅料,所述抑制剂能够抑制MAPK信号通路或涉及MAPK信号通路上游或下游途径的物质的表达。
在本发明中,药物组合物可以使用不同的添加剂进行制备,例如缓冲剂、稳定剂、抑菌剂、等渗剂、螯合剂、pH控制剂及表面活性剂。
本发明所述的药物组合物可口服给药、非胃肠道给药、通过吸入喷雾给药、局部给药、直肠给药、鼻给药、颊给药、***给药或通过植入的贮药装置给药。优选口服给药或注射给药。本发明的药物组合物可含有任何常用的无毒可药用载体、辅料或赋形剂。在某些情况下,药用酸、碱或缓冲剂可用来调节制剂的pH以提高所配制的化合物或其给药剂型的稳定性。本发明所用术语非胃肠道包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、鞠内、损伤部位内、和颅内注射或输注技术。只要能达到目标组织,本发明所述药物组合物可以通过任何途径给予受体。
本发明药物组合物可以以任何口服剂型的形式口服给药,包括但不限于胶囊、片剂、乳剂和水悬浮液、分散剂和溶液。对于口服片剂,常用载体包括乳糖和玉米淀粉。一般还加入润滑剂例如硬脂酸镁。为了以胶囊形式口服给药,适用的稀释剂包括乳糖和无水玉米淀粉。当口服施用水悬浮液和/或乳液时,可将活性组分悬浮或溶解在油相中,并与乳化剂和/或悬浮剂合并。如果需要的话,可加入一些甜味剂和/或矫味剂和/或着色剂。适当时,可将用于口服给药的剂量单位制剂包微囊。例如,通过在聚合物、蜡等中将颗粒物质包衣或包埋,也可制备所述制剂已延长或维持释放。本发明的药物组合物可以用于降低内源性的MAPK信号通路过表达,通过降低MAPK信号通路的表达,从而治疗因MAPK信号通路表上调导致的慢性骨髓炎。
在本发明中,可将抑制MAPK信号通路表达的化合物作为裸RNA与递送试剂一起作为核酸(如重组质粒或病毒载体)给受试者施用,所述核酸包含抑制MAPK信号通路表达的序列。递送试剂可以是亲脂试剂、聚阳离子、脂质体等。
本发明的药物还可与其他治疗慢性骨髓炎的药物联用,其他治疗性化合物可以与主要的活性成分同时给药,甚至在同一组合物中同时给药。还可以以单独的组合物或与主要的活性成分不同的剂量形式单独给予其它治疗性化合物。主要成分的部分剂量可以与其它治疗性化合物同时给药,而其它剂量可以单独给药。在治疗过程中,可以根据症状的严重程度、复发的频率和治疗方案的生理应答,调整本发明药物组合物的剂量。
本发明药物组合物可以局部给药的药物组合物,可以配制成软膏、乳膏剂、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。
本发明的药物组合物可以按药剂学上有效的量进行给药,本发明的用语“药剂学上有效的量”指的是以可适用于医学治疗或预防的合理的受惠/危险比率足以治疗或预防疾病的量,可根据包括疾病的严重程度、药物的活性、患者的年龄、体重、健康、性别、患者对药物的敏感度、所使用的本发明组合物的给药时间、给药途径及排出比率、治疗时间、与所使用的本发明的组合物配合或同时使用的药物的要素及其它医学领域中公知的要素来决定有效用量水平。本发明的药物组合物可作为单独的治疗剂进行给药,或是与其它治疗剂并用地进行给药,可以与以往的治疗剂依次地或同时地进行给药。此外,可单次或多次地进行给药。重要的是,需要对上述要素均加以考虑,并且以无副作用的最少的量可取得最大效果的量进行给药。
术语“治疗”是指不以治愈为目的,而是减缓(减少)靶定的病理状况或病症或防止复发。如果接受治疗有效量的治疗剂之后,患者成功地被“治疗”,患者显示出可观测到的和/或可度量的一种或多种特定疾病的迹象和症状的减少或消失。例如,使在一定程度上减少和/或减轻与特定慢性骨髓炎相关联的一种或多种症状的时间增加;减少的发病率和死亡率,以及改善生活质量。疾病的迹象或症状的减轻能够为患者感知。如果患者感受到疾病稳定,患者也被视为得到治疗。
在本发明中,术语“样本”包括(但不限于)细胞、组织、脏器、体液(血液、淋巴液等)、消化液、咳痰、肺胞支气管清洗液、尿、粪便等。优选的,所述样本为组织、血液。
本发明一实施方式还提供MAPK信号通路在筛选预防或治疗慢性骨髓炎的待筛选物质中的应用。
进一步,所述的筛选预防或治疗慢性骨髓炎的待筛选物质的步骤包括:
待筛选物质处理表达或含有MAPK信号通路基因的体系;和
检测所述体系中MAPK信号通路基因的表达;
其中,若所述待筛选物质可降低MAPK信号通路基因的表达或活性(优选显著降低,如低20%以上,较佳的低50%以上,更佳的低80%以上),则表明该待筛选物质是预防或治疗慢性骨髓炎的待筛选物质。
进一步,上面所述的体系包括(但不限于):细胞体系、亚细胞体系、溶液体系、组织体系、器官体系或动物体系。
上述实施例的说明只是用于理解本发明的方法及其核心思想。应当指出,对于本领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也将落入本发明权利要求的保护范围内。
Claims (7)
1.MAPK信号通路抑制在慢性骨髓炎改善中的应用。
2.根据权利要求1所述的应用,其特征在于:所述MAPK信号通路抑制是抑制IκBKβ表达、MAP3K7表达、NFATC1表达和/或NFκB2表达。
3.一种诊断慢性骨髓炎的产品,其特征在于:所述产品包括检测样本中MAPK信号通路表达水平的试剂。
4.根据权利要求3所述的产品,其特征在于:所述产品包括芯片、制剂或试剂盒。
5.MAPK信号通路抑制在制备治疗慢性骨髓炎的药物组合物中的应用。
6.根据权利要求5所述的应用,其特征在于:所述的药物组合物包括MAPK信号通路的抑制剂。
7.MAPK信号通路抑制在筛选预防或治疗慢性骨髓炎的待筛选物质中的应用。
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