CN110025626B - 莫诺苷在制备治疗急性肠炎药物中的应用 - Google Patents
莫诺苷在制备治疗急性肠炎药物中的应用 Download PDFInfo
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Abstract
本发明公开了莫诺苷在制备治疗急性肠炎药物中的应用,属于医药技术领域,本发明通过体外及体内实验证实莫诺苷对细胞和小鼠没有明显毒副作用,能明显有效治疗DSS诱导的小鼠急性肠炎,并能显著干扰LPS诱导的结肠癌细胞急性炎症,抑制促炎因子的表达。莫诺苷具备治疗急性肠炎的作用,安全有效,优于传统的治疗药物,从而扩宽了其应用范围,也为治疗急性肠炎提供了新途径。
Description
技术领域
本发明涉及医药技术领域,涉及莫诺苷的新医药用途,特别是涉及莫诺苷在制备治疗急性肠炎药物中的应用。
背景技术
莫诺苷(morroniside)是中药山茱萸和接骨木才中含量最高的一种环烯醚萜苷化合物,分子式为C17H26O11,其结构式如下
近年陆续有研究结果显示,莫诺苷主要的药理活性包括:
1)神经保护作用:山茱萸烯醚萜苷能够增加内源性神经营养因子(NTFs)的产生,改善微环境,减轻钙离子(Ca2+)超载,抑制炎性因子,抑制神经元凋亡,对神经有保护与修复作用。
2)抗氧化应激的损伤:莫诺苷能通过降低细胞内活性氧(ROS)、一氧化氮(NO)的含量和抑制谷胱甘肽(GSH)降低的作用,增强大鼠皮层总抗氧化能力发挥神经保护作用;另外,显著抑制丙二醛(MDA)增加,降低细胞膜电位,抑制皮层脂质过氧化水平而抑制细胞凋亡,进而发挥神经保护作用。
3)抗炎:莫诺苷可提高胶质细胞源性神经营养因子(GDNF)及碱性成纤维细胞生长因子(BF-GF)的分泌,抑制白细胞介素-1β(IL-1β)及肿瘤坏死因子-α(TNF-α),从而抑制炎症反应介导的细胞损伤。
溃疡性结肠炎(Ulcerativecolitis,UC)是一种慢性非特异性结肠炎性疾病,临床呈现出慢性复发性、持续性及难治性的特点。UC肠道炎症的启动及恶化皆始于肠道粘膜屏障损伤,肠道内各种抗原易位,触发固有层免疫系统,诱导促炎因子分泌增多,抑制抗炎因子,最终导致级联放大的免疫炎症反应。促炎——抗炎因子失衡是导致肠道免疫调节紊乱及组织损伤的重要病理实质,亦是UC病情进展的核心环节。此外,遗传因素,环境刺激及饮食因素与免疫因素相互作用,导致UC病程迁延不愈,轻重不等。
目前对于UC的治疗,主要包括:1)传统治疗药物:氨基酸水杨酸类药物(5-ASA)、肾上腺糖皮质激素(GCS)和免疫抑制剂(环孢素A)等;2)生物治疗剂:英夫利昔(IFX);3)微生态制剂:益生菌、益生元和合生元;4)抗生素:青霉素类、妥布霉素、喹诺酮类和头孢类抗生素;5)其他治疗:中药治疗,手术治疗以及介入治疗等。这些治疗手段中,中药治疗中的汤剂,粉剂等治疗最为有效,且方便价廉。但目前对于UC慢性演变的有效控制手段,仍需进一步探索,希望寻找更具靶向性的新的中药制剂及中西药物联用策略。
发明内容
本发明的目的是提供莫诺苷在制备治疗急性肠炎药物中的应用。
为实现上述目的,本发明提供了如下方案:具体而言,本发明涉及莫诺苷(morroniside),分子式为C17H26O11,其结构式为
上述莫诺苷在制备治疗急性肠炎药物中的应用。莫诺苷可治疗硫酸葡聚糖钠盐(Dextran Sulfate Sodium Salt,DSS)诱导的小鼠急性结肠炎以及治疗脂多糖(Lipopolysaccharides,LPS)诱导的结肠癌细胞急性炎症。
以上目的通过如下实验加以验证:
1、动物实验:本发明以C57/BL6小鼠为研究对象,利用2%DSS构建急性结肠炎模型,总历时7天,在建模第3天开始用药物治疗。莫诺苷的使用剂量为90mg/kg和180mg/kg,以灌胃的方式给药,每天一次,连续治疗6天。另外,利用柳氮磺吡啶(Sulfasalazine,SASP)作为莫诺苷的阳性对照。于第10天结束实验,处死小鼠检测相关炎性指标。首先检测急性结肠炎的重要指标:体重、结肠长度、疾病活动指数(disease activity index,DAI),发现莫诺苷可减弱DSS对结肠的损伤,削弱其对小鼠体重、结肠长度的影响(参见图1-5)。进一步病理学检测发现,莫诺苷可减弱DSS导致的肠壁水肿程度,肠壁炎症浸润程度及粘膜上皮缺失程度,另外减弱杯状细胞的丢失程度(参见图6-9)。接着,本发明人检测莫诺苷治疗对局部结肠炎症性细胞因子的影响,发现莫诺苷可抑制促炎因子(IL-1β、IL-6和TNF-α)的表达水平(参见图10-12),且具体作用机制与NF-кB/STAT3信号通路相关(参见图13-16)。
2、体外细胞学实验:以结肠癌细胞HCT116和Caco-2为研究对象,利用莫诺苷预处理16小时,再加入LPS诱导急性炎症,2至3小时后收样,检测炎症因子的表达变化。另外,检测不同浓度莫诺苷对HCT116和Caco-2的细胞活性的影响。结果发现,莫诺苷可抑制LPS诱导的结肠癌细胞急性炎症,且对结肠癌细胞的增殖无明显影响(参见图17-20)。
本发明公开了以下技术效果:
(1)莫诺苷可有效治疗DSS诱导的小鼠急性肠炎,具体机制与NF-кB/STAT3信号通路相关。
(2)莫诺苷对结肠癌细胞无细胞毒性,且能干扰LPS诱导的结肠癌细胞急性炎症,抑制促炎因子的表达。
(3)莫诺苷具备治疗急性肠炎的作用,安全有效,优于传统的治疗药物,从而扩宽了其应用范围,也为治疗急性肠炎提供了新途径。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1:DSS诱导的小鼠急性肠炎的炎症的方案,及莫诺苷治疗急性肠炎期间小鼠体重的变化(分组:对照组(Control)、模型组(DSS)、莫诺苷低浓度组(DSS+Morroniside(90mg/kg))、莫诺苷高浓度组(DSS+Morroniside(180mg/kg))和SASP阳性对照组(DSS+SASP(100mg/kg)));
图2:造模及治疗结束最后一天(第九天),每组体重丢失情况的统计分析结果(n=9,*p<0.05,***p<0.001,****p<0.0001)。
图3:莫诺苷对小鼠急性肠炎的炎症的疾病活动指数的统计分析结果(n=9,**p<0.01,****p<0.0001)。
图4:DSS诱导的急性炎症对结肠长度的影响及莫诺苷治疗后结肠长度的变化的统计分析(n=9,*p<0.05,**p<0.01,***p<0.001)。
图5:DSS诱导的急性炎症对结肠长度的影响及莫诺苷治疗后结肠长度的变化的大体图。
图6:HE检测莫诺苷对结肠炎的治疗效果(对照组(Control)、模型组(DSS)、莫诺苷低浓度组(DSS+MOR(90mg/kg))、莫诺苷高浓度组(DSS+MOR(180mg/kg))和SASP阳性对照组(DSS+SASP(100mg/kg)))。
图7:根据HE结果,对莫诺苷缓解结肠炎的组织学评分统计结果(n=3,*p<0.05,**p<0.01,***p<0.001)。
图8:糖原染色(PAS)检测莫诺苷对结肠上皮的杯状细胞分泌多糖能力的影响(对照组(Control)、模型组(DSS)、莫诺苷低浓度组(DSS+MOR(90mg/kg))、莫诺苷高浓度组(DSS+MOR(180mg/kg))和SASP阳性对照组(DSS+SASP(100mg/kg)),箭头指示PAS阳性染色颗粒)。
图9:针对图8,PAS的阳性统计结果(n=3,*p<0.05,**p<0.01,***p<0.001)。
图10:检测莫诺苷治疗对小鼠肠炎炎症因子IL-1β的影响(对照组(ctrl,n=3);模型组(DSS,n=3);莫诺苷低浓度组(DSS+MOR L,n=3);莫诺苷高浓度组(DSS+MOR H,n=3);SASP阳性对照组(DSS+SASP,n=3))。
图11:检测莫诺苷治疗对小鼠肠炎炎症因子IL-6的影响。
图12:检测莫诺苷治疗对小鼠肠炎炎症因子TNF-α的影响。
图13:莫诺苷对炎症信号通路NF-кB/STAT3的关键蛋白p-p65和p-stat3的蛋白表达的调控。
图14:对关键的通路蛋白p-p65和p-stat3的蛋白表达水平的统计学分析(n=6,*p<0.05,***p<0.001)。
图15:免疫组织化学检测p-p65表达水平。
图16:免疫组织化学检测p-stat3表达水平。
图17:MTT检测不同浓度(0、5μm、10μm、20μm和50μm)的莫诺苷对结肠癌细胞HCT116的增殖活性的影响。
图18:MTT检测不同浓度(0、5μm、10μm、20μm和50μm)的莫诺苷对结肠癌细胞Caco-2的增殖活性的影响。
图19:在HCT116细胞中,RT-PCR检测莫诺苷对LPS诱导的急性肠炎的炎症因子(IL-1β、IL-6、TNF-α和IFN-γ)的表达调控。
图20:在Caco-2细胞中,RT-PCR检测莫诺苷对LPS诱导的急性肠炎的炎症因子(IL-1β、IL-6、TNF-α和IFN-γ)的表达调控。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
为使本发明的上述目的、特征和优点能够更加明显易懂,下面结合附图和具体实施方式对本发明作进一步详细的说明。
实施例1动物实验
1、主要实验材料:实验动物,C57/BL6小鼠(6-8周,雄性,体重18-20g),购自上海斯莱克实验动物有限公司,SPF级,饲养于厦门大学实验动物中心。DSS和SASP,购自上海翊圣生物科技有限公司。实验所需试剂及试剂盒购于Cell Signaling公司和南京建成生物工程研究所等。
2、实验方法:
(1)小鼠结肠炎模型建立50只小鼠随机分配为5组(n=10):对照组、DSS模型组、低剂量MOR组(MOR-L,90mg/kg/d)、高剂量MOR组(MOR-H,180mg/kg/d)和阳性对照组SASP组(100mg/kg/d)。方法简述如下,2%DSS通过饮水给药,连续七天,于第三天开始通过灌胃加药治疗,持续治疗6天,每天监测小鼠体重。第10天处死小鼠,且处死前一天检测DAI结果。
(2)结肠炎病情评估:处死小鼠后,解剖取出盲结肠,记录结肠长度变化及外观变化;取距离肛门4cm的肠道组织0.5cm,4%多聚甲醛固定,脱水包埋切片后,进行HE染色和PAS染色,观察结肠病理学变化和炎症浸润程度。
(3)结肠组织匀浆处理后qRT-PCR及WB检测取0.05g组织样本,加入RIPA裂解液300μl后匀浆机研磨,提取蛋白样本检测p-p65和p-stat3。取0.02g组织样本,加入Trizol RNA裂解液1ml,提取mRNA样本,检测炎症因子IL-1β、IL-6和TNF-α。
(4)免疫组织化学检测根据迈新生物公司的常规免疫组化实验方法结合相应抗体检测结肠组织与细胞内蛋白表达变化。
(5)用GraphPad Prism 5进行成组t检验。*p<0.05,表示具有显著统计学意;**p<0.01,***p<0.001,****p<0.0001,表示具有高度显著意义。
3、实验结果:
(1)莫诺苷对DSS诱导的小鼠急性肠炎的炎性指标的影响,包括:体重、DAI和结肠长度。如图1-2所示,DSS诱导的急性肠炎模型成功,而且莫诺苷可明显减轻急性肠炎导致的体重丢失,且低浓度组治疗效果优比高浓度组,与阳性对照组SASP的作用效果相当。另外,莫诺苷可减轻DSS诱导的急性肠炎的疾病活动指数,治疗作用依旧是低浓度组的作用较好(如图3所示)。同时,莫诺苷的治疗效果还体现在结肠长度的改变,如图4-5所示,莫诺苷治疗可抑制炎症导致的结肠缩短,与体重与DAI结果一致,低浓度组的疗效明显优于高浓度组(n=9,*p<0.05,**p<0.01,***p<0.001,****p<0.0001)。
(2)莫诺苷对结肠炎病理指标的影响:镜下可见,模型组的黏膜缺损,有轻度水肿,大量的炎性细胞浸润,且大肠腺体丢失,结肠上皮细胞排列紊乱(如图6所示)。根据黏膜结构的改变程度、炎症细胞浸润程度、上皮缺损程度和杯状细胞丢失程度进行评分,结果如图7所示,莫诺苷治疗的病理组织学活性评分低于模型组,且低浓度组低于高浓度组(n=3,*p<0.05,**p<0.01,***p<0.001)。而且进一步通过PAS染色发现(如图8所示),莫诺苷干预组的杯状细胞明显多于模型组,且分泌多糖的能力也明显高于模型组(如图9所示,n=3,*p<0.05,**p<0.01,***p<0.001)。
(3)莫诺苷对结肠组织的炎症因子的表达水平的影响。如图10-12所示,RT-PCR检测三个经典的促炎因子的表达,IL-1β、IL-6和TNF-α,结果证明莫诺苷治疗后可有效抑制上述炎症因子的表达。
(4)莫诺苷对炎症通路NF-кB/STAT3的关键蛋白p-p65和p-stat3的蛋白表达的调控。参见图13-14,WB检测结果证明,与模型组相比,莫诺苷干预后可抑制p-p65和p-stat3的表达(*p<0.05,***p<0.001)。另外,通过免疫组织化学检测p-p65和p-stat3的表达,结果和WB结果一致。
实施例2体外细胞实验
1、主要实验材料:结肠癌细胞株HCT116和Caco-2,购自上海细胞库,McCOY’s 5A培养基和RPMI-1640分别购于Sigma公司和赛默飞公司,其他试剂购自上海翊圣生物科技有限公司和美国MCE公司。
2、实验方法
(1)细胞活性检测:将两株结肠癌细胞,以0.5x104个/孔,种植于96孔板,待细胞铁壁后,开始加药处理,莫诺苷浓度梯度为0、5μm、10μm、20μm和50μm,24小时后,每孔加MTT溶液(5mg/ml用PBS配)20μl。继续孵育4小时,终止培养,小心吸弃孔内培养上清液,对于悬浮细胞需要离心后再吸弃孔内培养上清液。每孔加150μl DMSO,振荡10分钟,使结晶物充分融解。选择490nm波长,在酶联免疫监测仪上测定各孔光吸收值,记录结果。
(2)细胞总RNA提取及Real time PCR检测:将两株结肠癌细胞株,以5x105个/孔,接种于6孔板,待细胞贴壁后,更换无血清培养基,加Morroniside(50μm)预处理16小时,16小时后加入LPS(2μg/ml)处理2至3小时后,收样,利用翊圣RNA快速提取试剂盒,提取对照组,LPS组,加药组总RNA,反转后,Real time PCR检测炎症因子IL-1β、IL-6、TNF-α和IFN-γ。
3、实验结果:
(1)莫诺苷干预对结肠癌细胞增殖活性的调控。如图17-18所示,以结肠癌细胞HCT116和Caco-2为研究对象,以不浓度(0、5μm、10μm、20μm和50μm)的莫诺苷处理24小时后,MTT检测发现莫诺苷处理对细胞的增殖活性没有明显作用。
(2)莫诺苷干预对LPS诱导的急性肠炎模型的炎症因子表达的影响。如图19-20所示,在HCT116和Caco-2细胞中,提前16小时加入莫诺苷(50μm)预保护,在收样前两至三小时加LPS(2ug/ml)处理,最终检测炎症因子IL-1β、IL-6、TNF-α和IFN-γ表达。RT-PCR结果证明,LPS诱导后,上述炎症因子表达增高,同时加入莫诺苷处理后,可明显抑制炎症因子的表达。
以上所述的实施例仅是对本发明的优选方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案做出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (2)
1.莫诺苷在制备治疗急性肠炎药物中的应用。
2.根据权利要求1所述的莫诺苷在制备治疗急性肠炎药物中的应用,其特征在于,所述急性肠炎指硫酸葡聚糖钠盐诱导的急性肠炎。
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