CN111841501A - 一种治疗炎症性疾病的药物组合物及其应用 - Google Patents
一种治疗炎症性疾病的药物组合物及其应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及生物医药领域,具体涉及一种治疗炎症性疾病的药物组合物及其应用。
背景技术
炎症是临床中最常见的病症之一,是人体为了确保去除有害刺激并修复受损组织的一种防御反应。在一般情况下,炎症可以保护机体免受感染及伤害,是机体被外界有毒有害物质所刺激而产生的一种免疫应答反应。炎症反应的主要功能是发现外来致炎因子并作出相应的免疫应答以及对组织和细胞损伤的修复。从炎症最基本的病理过程来看,主要包括局部组织的变质、渗出和增生,当炎症反应到后期过度严重时,会由从局部反应变为全身反应,其主要表现为器官的变化、白细胞增多以及单核吞噬细胞系统细胞增生。
巨噬细胞在抗感染和抗肿瘤免疫等疾病中发挥关键的免疫激活和免疫效应作用。当病原体入侵或自身组织出现病理性改变时,组织内的巨噬细胞激活后既可以通过直接吞噬作用清除外来病原微生物,也能够释放多种炎症介质,如肿瘤坏死因子-α(TNF-α)、白介素-1β(IL-1β)、白介素-6(IL-6)、一氧化氮(NO)和前列腺素E2(PGE2)等,诱发炎症反应,从而达到清除病原体和控制疾病的目的。然而,在某些病原体的感染或机体出现病理性改变时,巨噬细胞功能失调可引起机体出现全身性急性炎症反应以及慢性炎症反应。因此,控制巨噬细胞的炎症作用是有效清除病原体、妥善控制炎症反应和减少组织损伤的关键环节。
据流行病学和临床资料显示,多数疾病的发生、发展过程中都伴随有炎症反应,炎症还能加速疾病的发展。此外,炎症反应还可引起一些自身免疫疾病或癌症,并且与许多慢性疾病如关节炎、骨质疏松、哮喘、阿尔察默病、心血管疾病、痴呆、癌症、肥胖及II型糖尿病等密切相关。因此,研究开发具有抗炎作用的药物对于临床应用意义重大。临床证实,中国传统中药中具有抗炎作用的药物众多,明确抗炎有效成分以及探索其抗炎作用机制已经成为学者们关注的热点。
现有技术中,针对炎症相关疾病的药物治疗方法存在着用药量大、毒副作用大以及价格昂贵的缺陷,因此,急需开发出抗炎效果好且用药量较低、毒副作用较小和价格相对便宜的抗炎药物。
发明内容
本发明旨在至少解决现有技术中存在的技术问题之一。为此,本发明提出一种药物组合物,能够有效治疗炎症性疾病。
本发明还提出上述药物组合物的应用。
根据本发明的第一方面实施例的药物组合物,包含水飞蓟宾和百里酚。
根据本发明实施例的药物组合物,至少具有如下有益效果:本发明的药物组合物将百里酚和水飞蓟宾联合使用,抗炎效果好,药效明显优于单独用药,且用药量低、毒副作用小、价格相对便宜;该药物组合物能够有效抑制LPS诱导所致的一氧化氮(NO)的释放,抑制细胞因子IL-1β,TNF-α的分泌以及活性氧ROS的产生。同时,其也可以抑制NF-κB信号通路及下游蛋白iNOS和COX-2的表达,并抑制了MAPK信号通路,使得其具有良好的抑制炎症的效果。
根据本发明的一些实施方式,所述水飞蓟宾包括化学式I所述的化合物、其药学上可接受的盐、其溶剂化物、其多晶型物和其互变异构体中的至少一种;
所述百里酚包括化学式II所述的化合物、其药学上可接受的盐、其溶剂化物、其多晶型物和其互变异构体中的至少一种;
根据本发明的一些实施方式,所述药物组合物还包括药学上可接受的辅料和/或溶剂。
根据本发明的一些实施方式,所述水飞蓟宾和百里酚的摩尔比为1:2~4。
优选地,所述水飞蓟宾和百里酚的摩尔比为1:2.5~3.5。
更优选地,所述水飞蓟宾和百里酚的摩尔比为1:3。
根据本发明的一些实施方式,所述水飞蓟宾的浓度为30~50μM。
优选地,所述水飞蓟宾的浓度为35~45μM。
更优选地,所述水飞蓟宾的浓度为40μM。
根据本发明的一些实施方式,所述百里酚的浓度为90~150μM。
优选地,所述百里酚的浓度为110~130μM。
更优选地,所述百里酚的浓度为120μM。
本发明的实施例表明,当药物组合物中水飞蓟宾浓度为40μM和百里酚浓度为120μM时,CI值最低,具有最强的抑制炎症效果。
进一步地,在本发明较佳的实施例中,所述药物组合物为非菌性抗炎药物。该化合物通过MTT实验得知其没有显著的细胞毒性,因此该化合物的抗炎作用不是通过细胞毒性而实现的,也表明可以在细胞水平证实该化合物的安全可靠性。
进一步地,在本发明较佳的实施例中,所述药物组合物为抑制NO释放或者抑制iNOS和/或COX-2表达或者抑制IL-6,TNF-α中至少一种细胞因子分泌或者抑制ROS产生的抑制剂类药物。具体的,其有显著抑制LPS诱导的巨噬细胞RAW264.7的NO过量释放的作用,另外,此类药物还能够有效抑制iNOS的表达,从而进一步的抑制NO的过量释放。其还可以抑制LPS诱导的巨噬细胞RAW264.7中COX-2的表达及PGE2过量释放,抑从而起到抗炎作用。
进一步地,在本发明较佳的实施例中,所述药物组合物为抑制NF-κB信号通路和MAPK信号通路的抗炎药物。
优选地,抑制NF-κB信号通路是通过抑制NF-κBp65的核移位进行抑制。
优选地,抑制MAPK信号通路是通过抑制p-ERK、p-JNK及p-p38进行抑制。
具体的,其能够显著的抑制NF-κBp65的核移位,从而能够抑制NF-κB炎症信号通路,进而下调iNOS和COX-2的表达及其他炎症细胞因子如IL-6水平,发挥抗炎作用。因此,该化合物可以用于制备抑制NF-κB信号通路达到治疗炎症效果的抗炎药物。
具体的,其能够显著的抑制p-ERK、p-JNK及p-p38,从而下调炎症细胞因子如IL-1β,TNF-α水平,发挥抗炎作用。因此,该化合物可以用于制备抑制MAPK信号通路达到治疗炎症效果的抗炎药物。
根据本发明的第二方面实施例的应用,上述药物组合物在制备治疗炎症性疾病药物中的应用;和/或
上述药物组合物在抑制巨噬细胞的炎症作用中的应用;和/或
上述药物组合物在制备以下(a)至(f)任一种抑制剂中的应用:
(a)iNOS和/或COX-2表达抑制剂;
(b)TNF-α及IL-1β中至少一种细胞因子分泌抑制剂;
(c)ROS产生抑制剂;
(d)NO释放抑制剂;
(e)NF-κB信号通路抑制剂;
(f)MAPK炎性信号通路抑制剂;和/或
上述药物组合物在制备以下(a)或(b)任一种抑制剂中的应用:
(a)NF-κBp65的核移位抑制剂;
(b)p-ERK、p-JNK及p-p38的表达抑制剂。
根据本发明的一些实施方式,所述炎症性疾病包括急性炎症和慢性炎症。
进一步地,所述急性炎症包括扭伤引起的局部炎症。
进一步地,所述炎症与痤疮、反酸/胃灼热、年龄相关性黄斑变性(AMD)、变态反应、变应性鼻炎、阿尔茨海默氏病、肌萎缩性侧索硬化症、贫血症、阑尾炎、动脉炎、关节炎、哮喘、动脉粥样硬化、自身免疫性疾病、龟头炎、睑缘炎、细支气管炎、支气管炎、大疱性类天疱疮、烧伤、滑囊炎、癌症、心脏停搏、心脏炎、腹腔病、蜂窝组织炎、宫颈炎、胆管炎、胆囊炎、绒毛膜羊膜炎、慢性阻塞性肺病(COPD)、肝硬化、结肠炎、充血性心力衰竭、结膜炎、环磷酰胺诱导的膀胱炎、囊性纤维化、膀胱炎、普通感冒、泪腺炎、痴呆、皮炎、皮肌炎、糖尿病、糖尿病性神经病、糖尿病性视网膜病变、糖尿病性肾病、糖尿病性溃疡、消化系统病、湿疹、肺气肿、脑炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维肌痛、纤维化、纤维织炎、胃炎、肠胃炎、龈炎、肾小球性肾炎、舌炎、心脏病、心瓣膜功能障碍、肝炎、化脓性汗腺炎、亨廷顿氏病、高脂血症性胰腺炎、高血压病、回肠炎、感染、炎性肠病、炎性心脏肥大、炎症性神经病变、胰岛素抗性、间质性膀胱炎、间质性肾炎、虹膜炎、缺血、缺血性心脏病、角膜炎、角膜结膜炎、喉炎、狼疮性肾炎、乳腺炎、乳突炎、脑膜炎、代谢综合征、偏头痛、多发性硬化、脊髓炎、心肌炎、肌炎、肾炎、非酒精性脂肪性肝炎、肥胖、脐炎、卵巢炎、睾丸炎、骨软骨炎、骨量减少、骨髓炎、骨质疏松、骨炎、耳炎、胰腺炎、帕金森氏病、腮腺炎、盆腔炎、寻常性大疱疮、心包炎、腹膜炎、咽炎、静脉炎、胸膜炎、肺炎、多囊性肾炎、直肠炎、前列腺炎、银屑病、牙髓炎、肾盂肾炎、门静脉炎、肾功能衰竭、再灌注损伤、视网膜炎、风湿热、鼻炎、输卵管炎、结节病、垂液腺炎、鼻窦炎、结肠痉挛、狭窄、口腔炎、中风、手术并发症、滑膜炎、腱炎、肌腱变性、腱鞘炎、血栓性静脉炎、扁桃体炎、创伤、创伤性脑损伤、移植排斥、膀胱三角炎、结核病、肿瘤、尿道炎、滑囊炎、葡萄膜炎、阴道炎、血管炎或外阴炎有关。
本发明的附加方面和优点将在下面的描述中部分给出,部分将从下面的描述中变得明显,或通过本发明的实践了解到。
附图说明
图1为本发明实施例1中的药物细胞毒性MTT实验结果数据图,其中,(a)为水飞蓟宾,(b)为百里酚,(c)为水飞蓟宾和百里酚联合;
图2为本发明实施例2中药物对LPS诱导的Griess实验结果数据图,其中,(a)为水飞蓟宾,(b)为百里酚,(c)为水飞蓟宾和百里酚联合;
图3为本发明实施例2中(a)isobologram图和(b)CI指数图;
图4为本发明实施例3中ELISA图,其中,(a)为TNF-α和(b)IL-6的ELISA图;
图5为本发明实施例4中水飞蓟宾和百里酚对LPS诱导的RAW264.7细胞ROS的影响;
图6为本发明实施例5中水飞蓟宾和百里酚对LPS诱导的RAW264.7细胞COX-2表达的影响图;
图7为本发明实施例5中水飞蓟宾和百里酚对LPS诱导的RAW264.7细胞NF-κB通路的影响图;
图8为本发明实施例5中水飞蓟宾和百里酚对LPS诱导的RAW264.7细胞MAPK通路的影响图。
具体实施方式
为详细说明本发明的技术内容、所实现目的及效果,以下结合实施方式并配合附图予以说明。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
实施例中使用的RAW264.7细胞为小鼠腹腔巨噬细胞细胞系,也是常用的炎症细胞模型之一。
水飞蓟宾(Silibinin)是2,3-二氢-3-(4-羟基-3-甲氧基苯基)-2-羟甲基-6-(3,5,7-三羟基-4-氧代苯并吡喃-2-基)苯并二氧六环,又称水飞蓟素、西利马林。水飞蓟宾是从菊利植物水飞蓟(Silybum marianum)果实中提取分离而得的一种黄酮类化合物。
百里酚(Thymol)是5-甲基-2-异丙基苯酚,又称百里香酚、麝香草酚、麝香草脑。常温下为无色晶体或无色结晶粉末,有百里草或麝香草的气味。微溶于水,能溶于冰醋酸和石蜡油,也溶于乙醇、氯仿、乙醚和橄榄油。天然存在于唇形科植物百里香草Thymusserpyllum L.、麝香草T.vulgaris L.、牛至草Origanum vulgare L.、香青兰Dracocephalum moldavicum L.、伞形科植物粗果芹Trachyspermum ammi(L.)Sprague种子中。
本实施例中使用的上述材料均为商业购得,其中,水飞蓟宾(上海源叶生物科技有限公司,货号B21185-20mg),百里酚(上海源叶生物科技有限公司,B21153-100mg)。
实施例1:细胞毒性实验
1、实验方法:
检测水飞蓟宾和百里酚对RAW264.7细胞的毒性,通过实验测定不同浓度的水飞蓟宾、百里酚以及两者联用对细胞的生长影响,具体实施方案如下:
用含有10%FBS的DMEM培养基将细胞从培养瓶中轻轻吹打下来,制成细胞悬浮液,以接种浓度5×104个/mL的浓度接种于96孔板(100μL/孔),置于5%CO2,37℃培养24小时。分别在不加入脂多糖(LPS)和加入LPS(1μg/mL)的情况下,分别用水飞蓟宾的浓度为10μM、20μM、30μM、40μM、50μM和百里酚的浓度为30μM、60μM、90μM、120μM、150μM,以及两者联合处理RAW264.7细胞,每个浓度设置5个复孔。5%CO2,37℃培养24小时后小心吸出培养液,每孔加入100μL无血清培养基配制的MTT溶液继续培养3h后,小心吸去孔内培养液。每孔加入100μLDMSO在培养箱静置十分钟用酶标仪测量490nm处各孔的吸光值。
2、实验结果:
实验结果如图1中(a)至(c)所示,水飞蓟宾和百里酚对细胞的生长没有太大影响,说明两者对细胞的毒性不大;同时,水飞蓟宾和百里酚联用对细胞的生长也没有太大影响,说明两者联用对细胞的毒性也较小;说明水飞蓟宾和百里酚两者单用或联用均具有较高的安全性,毒副作用小。
实施例2:Griess实验
1、实验方法:
Griess实验用于检测样品中的NO含量,通过给出相同浓度配比的水飞蓟宾和百里酚单独或者联合用药对产生NO含量的影响,具体实施方案如下:
用10%FBS的DMEM培养基将细胞从培养瓶中轻轻吹打下来,制成细胞悬浮液,加入含有的培养基中制成细胞悬浮液,以接种浓度5×105个/mL的浓度接种于96孔板(100μL/孔)的浓度接种于孔板孔,置于5%CO2,37℃培养。24小时后,弃去培养基,空白组和脂多糖组加入100μL基础培养基,实验组加入水飞蓟宾(10μM、20μM、30μM、40μM、50μM)和,二苯甲酞甲烷(30μM、60μM、90μM、120μM、150μM)以及它们1:3的组合物进行预处理,每个浓度设置个4复孔。1小时后,每孔加入1μL含LPS(1μg/mL)的DMEM基础培养基,然后置于5%CO2,37℃培养箱内培养。24h后,每孔取50μL上清液加入另一个96孔培养板中,再往每孔加入Griess试剂,轻轻摇动培养板混匀,置于室温暗室孵育15分钟后,用酶标光度计检测波长540nm处的吸光光度值,NO的浓度依据标准曲线进行计算。
2、实验结果:
脂多糖(lipopolysaccharide,LPS)刺激导致RAW264.7细胞中NO明显增加。如图2所示,其中,(a)为水飞蓟宾,(b)为百里酚,(c)为水飞蓟宾和百里酚联合的Griess实验结果数据图。如图2所示,水飞蓟宾和百里酚或两者联合均可以浓度依赖性抑制LPS诱导的NO,其中,水飞蓟宾和百里酚的组合比单独使用水飞蓟宾或百里酚对LPS诱导的一氧化氮具有更强的抑制作用。单独用水飞蓟宾(40μM)和百里酚(120μM)进行预处理,分别导致LPS诱导的NO降低23%和24%。而水飞蓟宾和百里酚的联合预处理可使NO水平降低70%。
进一步的,图3中(a)为等效应图(isobologram),(b)为一致性(ConsistencyIndex,CI)指数图,(a)isobologram图中,纵坐标“剂量A”为水飞蓟宾的剂量;横坐标“剂量B”为百里酚的剂量。从图3中(a)和(b)可以看出水飞蓟宾(40μM)和百里酚(120μM)具有联合协同CI值最低的点,所以以这两个浓度具有最强的抑制炎症效果。
实施例3:ELISA实验
本实验部分主要通过ELISA实验研究LPS诱导RAW264.7细胞后,对RAW264.7细胞中TNF-α和IL-6的表达水平的影响。
1、实验方法:
在24孔板(2×105细胞/孔)中铺板24小时后,将RAW264.7细胞用待测化合物预处理2小时,然后在无或有1μg/mLLPS的条件下刺激24小时。随后,收集细胞上清液,根据制造商的说明,通过ELISA试剂盒在Tecan酶标仪上于450nm处检测TNF-α和IL-6的水平。
2、实验结果:
图4为上述ELISA实验结果图,其中,(a)为TNF-α和(b)IL-6的ELISA图。如图4所示,单独用水飞蓟宾和百里酚治疗可以很好地抑制LPS诱导的TNF-α和IL-6。单独的水飞蓟宾对TNF-α抑制13%,对IL-6抑制72%。单独的百里酚对TNF-α产生10%的抑制,对IL-6产生26%的抑制。水飞蓟宾和百里酚联合治疗可强烈抑制TNF-α和IL-6,导致TNF-α抑制36%,IL-6抑制79%。该结果清楚地表明,该组合对IL-6和TNF-α具有比单独的水飞蓟宾和百里酚更大的抑制作用。
实施例4:ROS影响测试实验
1、实验方法:
本实验用2',7'-二氯荧光素-二乙酸酯(DCFH-DA)检测到ROS。RAW264.7(1×106细胞/培养皿)播种在35毫米培养皿中24小时。将细胞与化合物孵育2小时,然后再暴露于LPS(1μg/mL)24小时。用PBS缓冲液洗涤后,在黑暗条件下于37℃在培养基中用10μMDCFH-DA处理细胞30分钟。然后洗涤细胞,收获并通过荧光微板读取器以488nm的激发和525nm的发射进行检测。
2、实验结果:
如图5所示,与对照组相比,LPS诱导的RAW264.7细胞中ROS的荧光强度明显增强。但是,通过单独或联合使用水飞蓟宾和百里酚进行预处理可以明显降低这种强度。而且,水飞蓟宾联合百里酚对LPS诱导的ROS的抑制作用(83%)比水飞蓟宾(60%)和百里酚(54%)强。
实施例5:Westernblot实验
本实验部分主要通过Westernblot实验研究LPS诱导RAW264.7细胞后,对RAW264.7细胞COX-2表达、NF-κB通路和MAPK通路的影响。
1、实验方法:
RAW264.7细胞(5×106细胞/培养皿)在100mm皿中培养24小时。将细胞与水飞蓟宾和百里酚单独或组合孵育2小时,然后用LPS(1μg/mL)处理30分钟或24小时。用冰冷的PBS洗涤后,将细胞用100μL细胞裂解缓冲液在4℃裂解10分钟,以提取细胞蛋白。对于核蛋白提取,使用核提取试剂。将混合物以12,000rpm离心10分钟,然后测定蛋白质浓度。将蛋白质样品与上样缓冲液煮沸10分钟。通过SDS-PAGE(8%)分离样品,然后将其转移到0.45μm硝酸纤维素膜上。在室温下,用5%脱脂牛奶将膜封闭1小时。将一抗(COX-2,NF-κBp65,p-p38,p38,p-ERK,ERK,p-JNK,β-肌动蛋白和LaminB)在TBST中以1:1000稀释并在4℃下孵育C过夜。将膜洗涤3次,并与偶联有辣根过氧化物酶的二抗(1:5000)在室温下孵育1小时。通过增强的化学发光(ECL)检测试剂盒(Thermo,Rockford,IL,U.S.A.)可视化印迹。印迹的数字图像通过Odyseey红外成像系统(Li-CorBiotechnology)生成,并使用ImageJ软件(1.45s,NIH,美国)进行分析。
2、实验结果:
图6为水飞蓟宾和百里酚对LPS诱导的RAW264.7细胞COX-2表达的影响图,其中,图6上方为凝胶电泳图,分别显示了不同实验组中COX-2的表达情况,图6下方为COX-2表达水平矩形图,纵坐标表示COX-2的表达量(COX-2表达量与β-actin的比值)。如图6所示,与对照组相比,单独LPS处理有效地增加了COX-2的蛋白表达,表明LPS诱导的RAW264.7细胞中的炎症反应。单独应用水飞蓟宾,百里酚可引起COX-2表达适度下降(分别为25%和16%)。然而,水飞蓟宾和百里酚的联合治疗导致COX-2表达下降72%,这明显高于单独的水飞蓟宾和百里酚。
图7为水飞蓟宾和百里酚对LPS诱导的RAW264.7细胞NF-κB通路的影响图,其中,图7上方为凝胶电泳图,分别显示了不同实验组中p65的表达情况,图7下方为p65表达水平矩形图,纵坐标表示p65的表达量(p65表达量与Lamin B的比值)。如图7所示,在细胞核中,与对照组相比,LPS处理可明显诱导NF-κB(p65)向核内移位。单独或联合使用水飞蓟宾和百里酚进行的预处理可降低LPS诱导的NF-κB(p65)易位。水飞蓟宾和百里酚的联合预处理可抑制NF-κB(p65)45%,明显强于水飞蓟宾和百里酚的单独抑制作用(分别为26%和29%)。
图8为水飞蓟宾和百里酚对LPS诱导的RAW264.7细胞MAPK通路的影响图,其中,图8左侧为凝胶电泳图,分别显示了不同实验组中p-p38,p-JNK和p-ERK的表达情况,图8右侧分别为p-p38,p-JNK和p-ERK表达水平矩形图,纵坐标分别表示p-p38,p-JNK和p-ERK的表达量(p-p38/p38,p-JNK/β-actin和p-ERK/ERK的比值)。如图8所示,LPS处理诱导了p-p38,p-JNK和p-ERK的过度表达。水飞蓟宾和百里酚联合处理可显着降低p-p38,p-JNK和p-ERK的表达,而水飞蓟宾和百里酚可分别降低p-p38,p-JNK和p-ERK的表达。单独或联合应用水飞蓟宾和百里酚治疗的总p38和ERK的表达均未改变。
综合以上所有结果表明水飞蓟宾和百里酚合用可通过抑制NF-κB和下调MAPK信号通路抑制炎症介质(NO,IL-6,TNF-α和COX-2)和ROS的产生。
在本发明中,我们评估了水飞蓟宾联合百里酚在脂多糖(LPS)诱导的RAW264.7细胞中的协同抗炎作用。结果表明,水飞蓟宾联合百里酚对LPS诱导的RAW264抑制一氧化氮(NO),肿瘤坏死因子-α(TNF-α)和白介素-6(IL-6)的作用均强于单一使用任一化合物。该组合还强烈抑制了活性氧(ROS)和环氧合酶2(COX-2)。机理研究表明,水飞蓟宾与百里酚的协同抗炎作用与抑制核因子-κB(NF-κB)和下调丝裂原激活的蛋白激酶(MAPK)信号通路中的磷酸化有关。这些发现表明水飞蓟宾可以与百里酚协同作用,以增强其抗炎活性。同时,从上述实验结果可知,当药物组合物中水飞蓟宾浓度为40μM和百里酚浓度为120μM时,CI值最低,具有最强的抑制炎症效果。
综上所述,本发明提供的药物组合物中,百里酚和水飞蓟宾联合使用,具有抗炎效果好,药效明显优于单独用药,且用药量低、毒副作用小、价格相对便宜等优点。本发明提供的药物组合物能够有效抑制LPS诱导所致的一氧化氮(NO)的释放,抑制细胞因子IL-1β和TNF-α的分泌以及活性氧ROS的产生。同时,其也可以抑制NF-κB信号通路及下游蛋白iNOS和COX-2的表达,并抑制了MAPK信号通路,使得其具有良好的抑制炎症的效果。
以上所述仅为本发明的实施例,并非因此限制本发明的专利范围,凡是利用本发明说明书及附图内容所作的等同变换,或直接或间接运用在相关的技术领域,均同理包括在本发明的专利保护范围内。
Claims (10)
1.一种药物组合物,其特征在于,包含水飞蓟宾和百里酚。
3.根据权利要求1所述的药物组合物,其特征在于,还包括药学上可接受的辅料和/或溶剂。
4.根据权利要求1所述的药物组合物,其特征在于,所述水飞蓟宾和百里酚的摩尔比为1:2~4;优选地,所述水飞蓟宾和百里酚的摩尔比为1:2.5~3.5;更优选地,所述水飞蓟宾和百里酚的摩尔比为1:3。
5.根据权利要求1所述的药物组合物,其特征在于,所述水飞蓟宾的浓度为30~50μM;优选地,所述水飞蓟宾的浓度为35~45μM;更优选地,所述水飞蓟宾的浓度为40μM。
6.根据权利要求1所述的药物组合物,其特征在于,所述百里酚的浓度为90~150μM;优选地,所述百里酚的浓度为110~130μM;更优选地,所述百里酚的浓度为120μM。
7.权利要求1至6任一项所述的药物组合物在制备治疗炎症性疾病药物中的应用。
8.权利要求1至6任一项所述的药物组合物在制备巨噬细胞炎症作用抑制剂中的应用。
9.权利要求1至6任一项所述的药物组合物在制备以下(a)至(f)任一种抑制剂中的应用:
(a)iNOS和/或COX-2表达抑制剂;
(b)TNF-α及IL-1β中至少一种细胞因子分泌抑制剂;
(c)ROS产生抑制剂;
(d)NO释放抑制剂;
(e)NF-κB信号通路抑制剂;
(f)MAPK炎性信号通路抑制剂。
10.权利要求1至6任一项所述的药物组合物在制备以下(a)或(b)任一种抑制剂中的应用:
(a)NF-κBp65的核移位抑制剂;
(b)p-ERK、p-JNK及p-p38的表达抑制剂。
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