CN116966188A - 丁香素在制备治疗和/或预防炎症性肠病药物中的应用 - Google Patents
丁香素在制备治疗和/或预防炎症性肠病药物中的应用 Download PDFInfo
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- CN116966188A CN116966188A CN202310863409.5A CN202310863409A CN116966188A CN 116966188 A CN116966188 A CN 116966188A CN 202310863409 A CN202310863409 A CN 202310863409A CN 116966188 A CN116966188 A CN 116966188A
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Abstract
本发明提供了丁香素在制备治疗和/或预防炎症性肠病药物中的应用。本发明采用DSS诱导的C57BL/6J小鼠结肠炎模型,发现脱硫弧菌鞭毛蛋白(DVF)促进肠道炎症发生,而丁香素处理改善DVF诱导的小鼠体重下降及疾病活动指数等炎症相关参数,进一步探究其抗炎作用的具体机制,结果表明丁香素能够作为DVF与NLR家族凋亡抑制蛋白(NAIP)互作界面抑制剂,从而靶向抑制巨噬细胞NAIP/NLRC4炎症小体的持续激活及细胞焦亡,减少炎症因子的释放。综上所述,该中药单体丁香素可为今后治疗炎症性肠病及其相关疾病提供新途径。
Description
技术领域
本发明属于丁香素新用途领域,尤其是涉及中药单体丁香素在制备治疗和/或预防炎症性肠病药物中的应用。
背景技术
炎症性肠病(inflammatory bowel disease,IBD)是一种慢性复发性肠道炎症性疾病,包括溃疡性结肠炎(Ulcerative Colitis,UC)和克罗恩病(Crohn’s Disease,CD)。近年来我国IBD发病率激增,发病年龄较轻,多是反复发作,防治较为困难,严重影响患者生活质量。IBD的病因和发病机制仍未明确,目前认为其发生主要与遗传因素、环境因素、免疫因素和肠道菌群等多因素的相互作用有关。目前尚无任何病原体被一致认定是IBD病因,但IBD患者存在显著肠道菌群失调,促炎菌(大肠埃希菌、肠球菌属及脱硫弧菌等)增多。这些菌群的改变可通过直接侵入或通过其代谢物破坏肠屏障、打破调节性T细胞和其它免疫细胞的平衡以及增加促炎/减少抑炎因子的释放等途径促进IBD的发生发展。在维持肠道稳态中,巨噬细胞是通过先天免疫受体[如Toll样受体(TLRs)和Nod样受体(NLRs)]感知微生物相关分子模式(MAMPs)的主要参与者之一。NLR家族中含半胱氨酸的天冬氨酸蛋白酶激活和招募结构域蛋白4(NLRC4)和NLR家族凋亡抑制蛋白(NAIP)能组装成炎症小体。肠道巨噬细胞可耐受肠道共生菌群,而有害菌可激活肠道巨噬细胞的NLRC4炎症小体,进一步导致细胞焦亡和炎症因子释放,促进IBD的发生。脱硫弧菌属(Desulfovibrio)是人体肠道中的优势硫酸盐还原菌之一,革兰阴性,专性厌氧,不产芽孢。已有研究表明,活动期UC患者中脱硫弧菌高度富集。脱硫弧菌鞭毛蛋白(DVF)不仅与细菌的运动相关,还参与细菌与宿主的粘附和定植,然而其与宿主肠道细胞如何发生作用目前罕有报道。我们前期发现,DVF与巨噬细胞NAIP互作激活NLRC4炎症小体,促进肠道炎症的发生,因此靶向DVF/NAIP互作界面对于防治IBD具有重要临床意义。传统的中医中药具有毒副作用小的优点,展示出良好的应用前景。因此,迫切需要从中医药中识别有效物质,探究其与机体的相互作用及作用机制,对于IBD的防治具有十分重要的意义。
丁香素是从丁香等多种植物中提取的一种多酚,别名丁香鞣质,易溶于水,有利于在临床和科研中应用。桃金娘科植物丁香的花蕾和其果实在我国已用于治疗慢性消化不良、胃肠充气、高血压、痛经、皮肤霉菌病等。已知丁香素具有抑制病毒DNA合成、抑制NO和PGE2生成以及抑制钙离子激活的透明质酸酶活性等药理作用。此外,亦有研究表明丁香素在抗氧化、抗炎、抗菌、抗病毒、改善认知症状等方面发挥一定作用,但丁香素在IBD治疗中的应用仍有待进一步探索。
发明内容
有鉴于此,本发明旨在克服现有技术中的缺陷,提出了丁香素在制备治疗和/或预防炎症性肠病药物中的应用。
为达到上述目的,本发明的技术方案是这样实现的:
本发明的第一方面,提出了丁香素或其药学上可接受的盐、水合物、溶剂化物、对映异构体、立体异构体或互变异构体在制备治疗和/或预防炎症性肠病药物中的应用。
在本发明的一些实施例中,所述炎症性肠病为炎症性肠病及其相关疾病。
在本发明的一些实施例中,所述炎症性肠病包括DVF/NAIP互作激活肠道巨噬细胞的NLRC4炎症小体引起的炎症性肠病。
本发明的第二方面,提供了一种治疗和/或预防炎症性肠病的药物,所述药物的活性成分包括丁香素或其药学上可接受的盐、水合物、溶剂化物、对映异构体、立体异构体或互变异构体和一种或一种以上药学上可接受的辅料。
在本发明的一些实施例中,所述辅料选自载体、稀释剂、粘合剂、润滑剂或湿润剂。
在本发明的一些实施例中,所述药物的剂型为注射液、片剂、粉剂、颗粒剂、丸剂、胶囊、口服液、膏剂、霜剂或喷剂。
在本发明的一些实施例中,所述药物的给药方式为口服、胃肠内给药、皮下注射、喷射、物理或化学介导方法给药或与其他物质混合或包裹后给药。
在本发明的一些实施例中,所述炎症性肠病为炎症性肠病及其相关疾病。
在本发明的一些实施例中,所述炎症性肠病包括DVF/NAIP互作激活肠道巨噬细胞的NLRC4炎症小体引起的炎症性肠病。
本发明的第三方面,提供了丁香素或其药学上可接受的盐、水合物、溶剂化物、对映异构体、立体异构体或互变异构体在制备DVF/NAIP互作界面抑制剂中的应用。
相对于现有技术,本发明具有以下优势:
本发明采用DSS诱导的C57BL/6J小鼠结肠炎模型,表明丁香素处理改善DVF诱导的小鼠体重下降、疾病活动指数和脾重等炎症相关参数,组织学染色也发现小鼠肠道炎症受到抑制,病理学评分下降。进一步探究丁香素发挥抗炎作用的具体机制,结果显示丁香素能够作为DVF/NAIP互作界面抑制剂,抑制DVF与NAIP结合,从而抑制巨噬细胞NAIP/NLRC4炎性小体复合物的持续激活及细胞焦亡,减少炎症因子的释放。综上所述,该中药单体丁香素可为今后治疗IBD及其相关疾病的治疗药物提供新途径。
附图说明
图1为丁香素对结肠炎小鼠体重的影响;
图2为丁香素对结肠炎小鼠疾病活动指数的影响;
图3为丁香素对结肠炎小鼠脾重的影响;
图4为丁香素对结肠炎小鼠结肠长度影响;
图5为丁香素对结肠炎小鼠的结肠上皮组织病理影响图;
图6为丁香素对结肠炎小鼠的组织病理学评分图;
图7为GSDMD、IL-18以及IL-1β在小鼠肠道中的表达情况;
图8为结肠炎小鼠肠道炎症因子IL-1β的mRNA的相对表达量;
图9为巨噬细胞中GSDMD、IL-18以及IL-1β的表达情况。
具体实施方式
除有定义外,以下实施例中所用的技术术语具有与本发明所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂,如无特殊说明,均为常规生化试剂;所述实验方法,如无特殊说明,均为常规方法。
本发明所述的“丁香素”是一种多酚成分,分子式为:C41H30O26,分子量:938.66,结构式为:
本发明中所述的“药学上可接受的盐”指由药学上可接受的无毒性的酸或碱制备而来的盐,其中的酸或碱包括无机酸或碱或有机酸或碱。所述的无机酸包括但不限于盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸。所述的无机碱选自钙、镁、锂、钠、锌、铝或钾。所述的有机酸包括但不限于甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。所述的有机碱包括但不限于二乙醇胺、三乙胺、乙胺丁醇、胆碱、普鲁卡因、赖氨酸等。
本发明中所述的“溶剂化物”是指丁香素或其药学上可接受的盐与至少一种溶剂分子通过非共价分子间作用力结合而形成的物质。常见的溶剂化物包括(但不限于)水合物、乙醇合物、丙酮合物等。
本发明所述的丁香素可以以立体异构体的形式存在,并因此涵盖所有可能的立体异构体形式,包括但不限于顺反异构体、互变异构体、对映异构体、非对映异构体等,本发明所述丁香素也可以以前述的立体异构体的任何组合或任何混合物,例如内消旋体、外消旋体、阻转异构体的等量混合物等形式存在。例如单一对映异构体,单一非对映异构体或以上的混合物,或单一阻转异构体或其混合物。
本发明所述的“治疗”指在疾病已开始发展后减缓、中断、阻止、控制、停止、减轻、或逆转一种体征、症状、失调、病症、或疾病的进展或严重性,但不一定涉及所有疾病相关体征、症状、病症、或失调的完全消除。
本发明所述的“预防”是指通过施用本发明所述的产品来抑制症状或者延缓特定症状紧张的所有行为。
下面结合实施例来详细说明本发明。
材料来源:
C57BL/6J小鼠购自:北京华阜康生物科技股份有限公司;
丁香素(Eugeniin)购自:成都普思生物科技股份有限公司;
3%葡聚糖硫酸钠(DSS)购自:MP公司;
脱硫弧菌鞭毛蛋白(DVF)购自:苏州泓迅生物科技股份有限公司
实施例1丁香素对溃疡性结肠炎小鼠疾病症状的影响
将体重18-20g左右的健康8周龄雌性C57BL/6J小鼠32只,随机分为4组,每组8只,即PBS组,DVF组,Eugeniin组,DVF+Eugeniin组,待小鼠适应SPF级环境1周后进行给药。将丁香素(Eugeniin)溶于磷酸盐缓冲液(PBS)中,按照小鼠的体重,以40mg/kg的剂量灌胃;鞭毛蛋白以2μg/天灌胃。所有小鼠均采用3%葡聚糖硫酸钠(DSS)7天进行结肠炎造模。DSS溶液每两天更换一次。实验动物分组及给药方法见表1。
表1动物实验设计
在开始给药造模后,每天对小鼠进行称重并计算体重变化率,注意观察小鼠的一般情况。此外,每天对小鼠大便性状及潜血情况进行评估。利用小鼠的体重下降百分比、粪便性状和潜血情况进行评分,三者之和为结肠炎小鼠的疾病活动指数评分(DiseaseActivity Index,DAI score)。具体评分细则见表2。
表2疾病活动指数评分表
各组小鼠的体重变化见图1,与DVF组相比,丁香素可改善DSS和DVF诱导的小鼠结肠炎模型的体重下降(*P<0.05);各组小鼠的疾病活动指数见图2,与DVF组相比,丁香素可减轻DSS和DVF诱导的小鼠结肠炎模型的疾病活动指数(*P<0.05);各组小鼠的脾重见图3,可见,与DVF组相比,丁香素可使小鼠的脾重降低(**P<0.01)。
在给药后第10天,给予小鼠吸入二氧化碳安乐死。开腹留取各组小鼠的脾脏并称重,留取结直肠并测量其长度。用冰PBS缓冲液冲净肠内容物后将结肠沿纵向铺平于载玻片上,一半组织剪碎后置于无RNA酶冻存管中,快速放入-80℃冰箱保存,用于后续westernblot和Realtime-PCR实验。剩余一半组织置于10%甲醛中固定,经脱水透明、浸蜡包埋、切片展片和脱蜡染色后制备成病理切片。通过病理切片观察实验小鼠结肠组织的形态学变化,并分别从炎症情况、黏膜损伤、隐窝损伤、病理学损伤范围等四个指标进行评分,四个指标之和即为组织病理学评分。具体评分细则见表3。
表3组织病理学评分标准
各组小鼠的结肠长度见图4,与DVF组相比,给予丁香素后结肠炎小鼠的结肠缩短程度得到缓解(*P<0.05)。
各组小鼠的结肠病理切片结果见图5,组织病理学评分见图6。PBS组、Eugeniin组、DVF组小鼠的结肠上皮结构破坏,隐窝消失,结肠组织中炎性细胞(中性粒细胞、淋巴细胞等)大量浸润;黏膜下层明显水肿,结缔组织排列疏松并伴有淋巴细胞浸润,组织病理学评分未见明显差异。DVF+Eugeniin组小鼠的结肠组织可见轻度的隐窝消失及上皮结构破坏,伴有少量的炎性细胞浸润,黏膜下层炎症累及较少,肌层结构基本正常,组织病理学评分较DVF组下降(*P<0.05)。该实验结果表明丁香素能够有效预防和改善DVF和DSS诱导的溃疡性结肠炎小鼠的组织病理学损伤。
小鼠结肠组织中细胞焦亡通路的蛋白表达水平见图7。与PBS组小鼠相比,DVF组肠道GSDMD、IL-1β和IL-18的水平明显增加,而DVF+Eugeniin抑制了DVF诱导的GSDMD、IL-1β和IL-18增加。该实验结果表明丁香素能够有效抑制DVF诱导的巨噬细胞焦亡和炎症的发生。
各组实验小鼠结肠组织的炎症因子IL-1β表达水平见图8。与PBS组相比,DVF组小鼠结肠组织中炎症因子IL-1β(*P<0.05)的mRNA表达水平增加。而与DVF组相比,实验组小鼠结肠组织中炎症因子IL-1β(**P<0.01)的mRNA表达水平显著降低。体外DVF处理巨噬细胞后焦亡相关蛋白的表达见图9,该实验结果表明丁香素能够有效抑制DVF和DSS诱导的溃疡性结肠炎小鼠的炎症因子转录水平。
本发明经过实验证实,丁香素显示出抗溃疡性结肠炎的活性。丁香素可改善DVF和DSS诱导的小鼠结肠炎模型的体重下降,减轻疾病活动指数,降低小鼠脾重,改善结肠炎模型实验小鼠的结肠炎症状,并能够有效抑制DVF/NAIP互作,抑制巨噬细胞NAIP/NLRC4炎性小体复合物的持续激活,降低小鼠肠上皮细胞炎症因子的表达,能够用于制备抗溃疡性结肠炎药物。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.丁香素或其药学上可接受的盐、水合物、溶剂化物、对映异构体、立体异构体或互变异构体在制备治疗和/或预防炎症性肠病药物中的应用。
2.根据权利要求1所述的应用,其特征在于:所述炎症性肠病为炎症性肠病及其相关疾病。
3.根据权利要求1所述的应用,其特征在于:所述炎症性肠病包括DVF/NAIP互作激活肠道巨噬细胞的NLRC4炎症小体引起的炎症性肠病。
4.一种治疗和/或预防炎症性肠病的药物,其特征在于:所述药物的活性成分包括丁香素或其药学上可接受的盐、水合物、溶剂化物、对映异构体、立体异构体或互变异构体和一种或一种以上药学上可接受的辅料。
5.根据权利要求1所述的药物,其特征在于:所述辅料选自载体、稀释剂、粘合剂、润滑剂或湿润剂。
6.根据权利要求1所述的药物,其特征在于:所述药物的剂型为注射液、片剂、粉剂、颗粒剂、丸剂、胶囊、口服液、膏剂、霜剂或喷剂。
7.根据权利要求1所述的药物,其特征在于:所述药物的给药方式为口服、胃肠内给药、皮下注射、喷射、物理或化学介导方法给药或与其他物质混合或包裹后给药。
8.根据权利要求1所述的药物,其特征在于:所述炎症性肠病为炎症性肠病及其相关疾病。
9.根据权利要求1所述的药物,其特征在于:所述炎症性肠病包括DVF/NAIP互作激活肠道巨噬细胞的NLRC4炎症小体引起的炎症性肠病。
10.丁香素或其药学上可接受的盐、水合物、溶剂化物、对映异构体、立体异构体或互变异构体在制备DVF/NAIP互作界面抑制剂中的应用。
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