CN116898889B - 菊苣乙酸乙酯萃取物在胃黏膜损伤类疾病预防和治疗药物中的应用 - Google Patents
菊苣乙酸乙酯萃取物在胃黏膜损伤类疾病预防和治疗药物中的应用 Download PDFInfo
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Abstract
本发明属于天然药物提取技术领域,具体公开了一种菊苣乙酸乙酯萃取物在胃黏膜损伤类疾病预防和治疗药物中的应用,本发明以菊苣乙酸乙酯萃取物为研究对象,综合运用药理学、生物学方法,显示其能够明显保护胃黏膜,预防乙醇对胃黏膜的损伤。菊苣乙酸乙酯萃取物,可以显著改善由乙醇诱导的GES‑1细胞凋亡现象,能够激活细胞Nrf2/HO‑1通路,激活细胞抗氧化作用,能够激活细胞自噬,并显著提高细胞自噬水平。预处理后能够显著地回升线粒体膜电位的下降,降低LDH的含量以及改善相关蛋白的表达。
Description
技术领域
本发明属于天然药物提取技术领域,具体公开了一种菊苣乙酸乙酯萃取物在胃黏膜损伤类疾病预防和治疗药物中的应用。
背景技术
胃黏膜是一个非常薄且脆弱的组织,位于胃壁的最内层。它具有动态平衡的自我修复机制,可以保护胃,也可以作为组织抵御外部病原体和有毒物质的天然防御。在正常的生理条件下,胃黏膜通过保持内黏膜屏障的完整性并控制粘液,碳酸氢盐以及生长因子等的分泌来保持其完整性。一旦外界给予胃的负担过重或刺激过强,动态平衡就会被打破,胃黏膜受损,很难再恢复如初,随之而来的就是一系列胃部不适的症状,常见的有上腹部不适或疼痛、恶心、呕吐、腹泻、食欲不振等各种胃病,严重时会造成胃部出血,甚至胃穿孔危及生命安全。
导致胃黏膜损伤类疾病的因素很多,如幽门螺杆菌感染、不良饮食和生活习惯、遗传等。其中,乙醇是最重要的诱发因素之一,其诱导的炎症反应和氧化应激与急性胃黏膜损伤的发病机制已经有报道。这类胃黏膜损伤疾病可能会出现严重的并发症,例如消化道出血、溃疡穿孔、幽门梗阻,甚至癌变,其最直观的表现是胃黏膜损伤。酒精性胃黏膜损伤疾病在临床上并不少见,因此,可以有效预防或者治疗酒精性胃黏膜损伤的药物具有广阔的临床应用前景。
目前市场上针对胃黏膜损伤治疗药物有制酸剂(碳酸氢钠等),胃黏膜保护剂(前列腺素及其衍生物、铝剂、铋剂、替普瑞酮、伊索拉定、瑞巴派特等),抗幽门螺旋菌药物等。但这些药物多有副作用,长期服用人体易出现耐受,疗效下降。
菊苣(Cichoriumintybus L.)在传统医学中具有清肝利胆,健胃消食,利尿消肿等多种功效。现代医学表明,菊苣具有保肝、抗癌降脂,抗氧化,抗动脉粥样硬化、提高免疫力等药理活性,临床中被广泛用于治疗各种肝胆疾病。截至目前,菊苣有助于调节肠道菌群的保健品数目最多,其次是有助于维持血糖和血脂健康水平保健食品。但目前有关菊苣对胃黏膜损伤类疾病的应用尚未有人报道,因此其作用机制还有待深入研究。
发明内容
本发明的目的是提供一种对胃黏膜损伤具有预防和治疗作用的菊苣乙酸乙酯萃取物及其制备方法和应用,菊苣乙酸乙酯萃取物对胃黏膜损伤具有显著的作用,几乎无毒副作用。菊苣乙酸乙酯萃取物可制备成胶囊剂、片剂、颗粒剂、散剂、口服液、丸剂中任一种剂型的药物。
胃黏膜损伤类疾病为胃炎、胃溃疡、胃癌。
本发明菊苣乙酸乙酯萃取物的提取方法步骤如下:
取菊苣茎叶100g装进三颈烧瓶中,加入1L 70%的乙醇-水溶液,加热回流3次,趁热抽滤,合并滤液,减压浓缩,剩余100mL的醇提液后停止旋蒸;取出5mL冷冻干燥作为菊苣醇提取物(CIET);取出分液漏斗,检查气密性后开始萃取;向分液漏斗中加入剩余醇提液和100mL的二氯甲烷,萃取三次收集下层溶液,将下层溶液旋干得到菊苣二氯甲烷萃取物(CIDCM);接着向上层溶液中加入100mL乙酸乙酯,萃取三次收集上层乙酸乙酯层,将上层溶液旋干得到菊苣乙酸乙酯萃取物(CIEA);保留下层水层,同样旋干得到菊苣水层萃取物。
加热回流3次的时间依次是2h、1.5h、1h。
本发明菊苣乙酸乙酯萃取物,可以显著改善由乙醇诱导的GES-1细胞凋亡现象。菊苣乙酸乙酯萃取物预处理后能够显著地回升线粒体膜电位的下降,降低LDH的含量以及改善相关蛋白的表达。
本发明菊苣乙酸乙酯萃取物,能够激活细胞Nrf2/HO-1通路,激活细胞抗氧化作用。
本发明菊苣乙酸乙酯萃取物,能够激活细胞自噬,并显著提高细胞自噬水平。
本发明与现有技术相比,其有益效果为:
(1)本发明以菊苣乙酸乙酯萃取物为研究对象,综合运用药理学、生物学方法,显示其能够明显保护胃黏膜,预防乙醇对胃黏膜的损伤,并对机制加以说明。
(2)本发明的中药萃取物毒副作用低。
附图说明:
图1为菊苣各提取物的活性筛选以及菊苣乙酸乙酯萃取物的细胞毒性和活性筛选。
图2为菊苣乙酸乙酯萃取物对EtOH诱导的GES-1中LDH含量的影响。
图3为菊苣乙酸乙酯萃取物对EtOH诱导的GES-1细胞线粒体膜电位的影响。
图4为菊苣乙酸乙酯萃取物对EtOH诱导的GES-1细胞在线粒体凋亡途径中关键蛋白表达。
图5为菊苣乙酸乙酯萃取物对EtOH诱导的GES-1细胞中Mapks家族相关蛋白的表达。
图6为菊苣乙酸乙酯萃取物对EtOH诱导的GES-1细胞中ROS释放水平的影响。
图7为菊苣乙酸乙酯萃取物对GES-1细胞中Nrf2因子核内外表达作用。
图8为菊苣乙酸乙酯萃取物对HO-1蛋白表达的影响。
图9为菊苣乙酸乙酯萃取物对GES-1细胞自噬的影响。
图10为菊苣乙酸乙酯萃取物对GES-1细胞自噬相关蛋白表达的影响。
图11为菊苣乙酸乙酯萃取物对酒精诱导的小鼠胃黏膜损伤保护作用。
具体实施方式
本发明通过以下实施例进一步详细说明本发明,但应注意本发明的范围并不受这些实施例的任何限制。
实施例1菊苣乙酸乙酯萃取物的制备
(1)取100g菊苣茎叶装进三颈烧瓶中,加入1L 70%乙醇水溶液,然后放入电热套中80℃加热回流冷凝,等微沸后将温度控制在60℃左右,2h后收集第一批滤液,趁热抽滤;
(2)保留药渣并继续向三颈烧瓶中加入1L 70%乙醇-水溶液,回流冷凝1.5h后收集第二批滤液,趁热抽滤;
(3)保留药渣并继续向三颈烧瓶中加入1L 70%乙醇-水溶液,回流冷凝1h后收集第三批滤液,弃去药渣,趁热抽滤,合并三批滤液;
(4)使用旋转蒸发仪减压浓缩,剩余100mL的醇提液后停止旋蒸,取出5mL冷冻干燥作为菊苣醇提取物(CIET);
(5)取出分液漏斗,检查气密性后开始萃取;向分液漏斗中加入剩余醇提液和100mL的二氯甲烷,萃取三次收集下层溶液,将下层溶液旋干得到菊苣二氯甲烷萃取物(CIDCM);接着向上层溶液中加入100mL乙酸乙酯,萃取三次收集上层乙酸乙酯层,将上层溶液旋干得到菊苣乙酸乙酯萃取物(CIEA);保留下层水层,同样旋干得到菊苣水层萃取物;
(6)将旋干后的提取物使用冷冻干燥机处理,最后从100g的菊苣药材提取得到二氯甲烷萃取物,乙酸乙酯萃取物,水层萃取物。
实施例2菊苣乙酸乙酯萃取物对酒精造成的胃黏膜损伤保护作用的评价
1.实验材料
1.1试剂:DMEM培养基(中乔新舟);胎牛血清FBS(Gibco);MDC(碧云天);罗丹明123(碧云天);LDH试剂盒(碧云天);ROS试剂盒(碧云天);乙醇(国药集团化学试剂有限公司)。
1.2材料:GES-1细胞(凯基生物公司),ICR小鼠(常州卡文斯实验动物有限公司)菊苣:新疆。
1.3器材:酶标仪(Devices公司);流式细胞仪(BD公司);高速冷冻离心机(艾本德公司)。
2.方法及结果
2.1菊苣各提取物的活性筛选以及菊苣乙酸乙酯萃取物的细胞毒性和活性筛选:分别用200-12.5μg/mL浓度的菊苣各提取物,以每孔为10μL预处理GES-1细胞,设置三个复孔,并在3h后加入6%EtOH共培养1.5h检测其活性。通过MTT检测,结果见图1-A。
图1-A结果表明菊苣乙酸乙酯层效果较好,发现经过CIEA预处理后其细胞活力恢复显著,并呈现明显的浓度依赖性。
2.2分别用不同浓度的CIEA单独处理GES-1细胞以检测CIEA对GES-1细胞是否存在细胞毒性,并筛选出安全的浓度范围。结果见图1-B。
图1-B结果表明,与对照组相比,CIEA的预处理组分,细胞存活率并没有降低,甚至有促增殖的作用。可以说明CIEA对GES-1细胞时不会产生细胞毒性,符合生物学要求,且筛选出CIEA在12.5-200μg/mL的浓度范围内进行后续实验。
2.3配置12.5-200μg/mL的CIEA,每孔10μL,处理GES-1细胞,3h后再向其中加入10μL使其终浓度为6%的EtOH,继续培养1.5h,MTT法来评估CIEA的药物活性。结果见图1-C。
图1-C结果表明,EtOH处理使细胞存活率明显被抑制,但是随着CIEA给药浓度的增加,细胞出现显著增殖。这充分说明CIEA有效减轻由EtOH诱导的的GES-1细胞活力下降现象。其中可以很明显的看到CIEA对EtOH引起的细胞活力下降的恢复作用有良好的剂量依赖性,为后续的实验筛选出了适宜的给药浓度。
2.4菊苣乙酸乙酯对EtOH诱导的GES-1中LDH含量的影响
GES-1在96孔板中培养24h,贴壁吸弃上清,PBS洗涤2次。用RPMI配制不同浓度的CIEA(15、30、60μg/mL),培养箱中培养3h后加入10μL终浓度为6%的Ethanol。每组设置4个平行复孔。然后将孔板置于CO2培养箱继续培养1.5h。在培养到指定时间前的1h,在阳性对照孔中加入10μL标准品,培养箱孵育1h。依说明书要求对样本进行处理,样品测定前,每孔加60μL的LDH工作液,避光孵育30min。酶标仪于490nm和600nm处测吸光度。结果见图2。
图2结果表明,EtOH组中LDH释放量与正常组相比是显著上升的,同时随着CIEA的预处理,这种现象得到改善,并表现出剂量依赖性,说明在CIEA的介入下,EtOH的细胞毒性有所降低,进一步说明CIEA可以降低EtOH对细胞膜的破坏,从而减少GES-1的细胞凋亡,起到了保护GES-1的作用。
2.5菊苣乙酸乙酯萃取物对EtOH诱导的GES-1细胞线粒体膜电位的影响
GES-1在6孔板中培养24h,贴壁吸弃,配制不同浓度的CIEA(15、30、60μg/mL),培养箱中培养3h后加入100μL终浓度为6%的EtOH。将接种完的孔板置于CO2培养箱继续培养1.5h。吸弃原有的上清液,用1×PBS洗涤3次,离心收集GES-1沉淀,PBS洗3次,Rhodamine123染色,室温避光染色30min,上机。结果如图3所示。
图3结果表明,经过不同浓度CIEA处理后,伴随着给药浓度的增加,清楚的看到线粒体膜电位有所回升,且上升趋势较为稳定。此图中GES-1细胞的线粒体膜电位逐渐变化,且呈现出与浓度增加正相关的趋势,那么显而易见CIEA一定程度上可以通过改变线粒体膜电位改善EtOH引起的GES-1细胞凋亡。
2.6菊苣乙酸乙酯对EtOH诱导的GES-1细胞在线粒体凋亡途径中关键蛋白表达
GES-1在6孔板中培养24h,贴壁吸弃,配制不同浓度的CIEA(15、30、60μg/mL),培养箱中培养3h后加入10μL终浓度为6%的EtOH。将接种完的孔板置于CO2培养箱继续培养1.5h。提取蛋白,进行后续Western Blot常规操作。结果如图4所示。
图4结果表明,作为促凋亡蛋白,EtOH单独处理的组分可以让Bax的表达明显增加,然而通过不同浓度CIEA的预处理,可以明显减少其表达。与之相反,Bcl-2作为抗凋亡蛋白,EtOH单独处理其表达最低,但随着给药浓度的增加,表达量递增,并且存在浓度依赖性。综上可以说明,CIEA可以通过线粒体凋亡途径中的Bcl-2家族对EtOH诱导的细胞凋亡有抵抗作用。当GES-1细胞受到EtOH的刺激时,下游导致细胞凋亡体生成的Cyto C、凋亡执行子caspase 3以及DNA损伤感应因子PARP 1与正常组相比表达明显上升,然而CIEA预处理可以很好的降低上述蛋白的表达,并且呈现浓度依赖性。也就是说,CIEA可以通过作用于细胞线粒体凋亡途径,很好的保护由EtOH诱导的细胞凋亡。
2.7菊苣乙酸乙酯萃取物对EtOH诱导的GES-1细胞中Mapks家族相关蛋白的表达
GES-1在6孔板中培养24h,贴壁吸弃,配制不同浓度的CIEA(15、30、60μg/mL),培养箱中培养3h后加入100μL终浓度为6%的EtOH。将接种完的孔板置于CO2培养箱继续培养1.5h。提取蛋白,进行后续Western Blot常规操作。结果如图5所示。
图5结果表明,EtOH处理不同时间后,P-ERK、p-JNK、p-p38蛋白在三个时间点的表达均呈现明显增加,但经CIEA处理后,其表达情况均有不同程度的减少。其中P-ERK在1h和2h均有减少,其中1h较为明显,p-JNK在1h减少的明显,p-p38在1h、4h均有减少。该结果说明MAPKs家族中的相关蛋白参与了CIEA对EtOH诱导的GES-1细胞凋亡的保护作用。
2.8菊苣乙酸乙酯萃取物对EtOH诱导的GES-1细胞中ROS释放水平的影响
GES-1在96孔板中培养24h,贴壁吸弃上清,PBS洗涤2次。用RPMI配制不同浓度的CIEA(15、30、60μg/mL),培养箱中培养3h后加入10μL终浓度为6%的Ethanol。在培养到指定时间前的1h,在阳性对照孔中加入10μL标准品,培养箱孵育1h。酶标仪于488nm和525nm处测吸光度。结果如图6所示。
图6结果表明,CIEA的处理可以使得GES-1细胞内的活性氧(ROS)增加,并且结果呈现浓度依赖性。这一数据说明CIEA能诱导GES-1细胞产生抗氧化作用。
2.9菊苣乙酸乙酯萃取物对GES-1细胞中Nrf2因子核内外表达作用
GES-1在6孔板中培养24h,贴壁吸弃,配制不同浓度的CIEA(15、30、60μg/mL),将接种完的孔板置于CO2培养箱继续培养6h。提取蛋白,进行后续Western Blot常规操作。结果如图7所示。
图7结果表明,对照组相比,CIEA(15μg/mL、30μg/mL、60μg/mL)预处理使Nrf2在细胞质定位中的表达下调,但在细胞核中上调。Keap 1与Nrf2解离后,短时间内增加,但是随后降解,因此表达为下调。由此实验数据显示,CIEA对EtOH诱导的GES-细胞凋亡的保护作用可能与Nrf-2和Keap-1的调节有关。
2.10菊苣乙酸乙酯萃取物对HO-1蛋白表达的影响
GES-1在6孔板中培养24h,贴壁吸弃,配制不同浓度的CIEA(15、30、60μg/mL),将接种完的孔板置于CO2培养箱继续培养24h。提取蛋白,进行后续Western Blot常规操作。结果如图8所示。
图8结果表明,CIEA处理过的GES-1细胞,HO-1的表达显著升高,说明CIEA可以通过诱导HO-1的高表达保护EtOH诱导的GES-1细胞凋亡。
2.11菊苣乙酸乙酯萃取物对GES-1细胞自噬的影响
GES-1在24孔板中培养24h,贴壁吸弃,配制不同浓度的CIEA(15、30、60μg/mL),将接种完的孔板置于CO2培养箱继续培养12h。制片,用荧光倒置显微镜观察细胞形态。结果如图9所示。
图9结果表明,空白对照组的荧光强度比较微弱,正常细胞都会有微量的自噬,随着CIEA给药浓度的增加,荧光强度呈现浓度依赖性增加,因此可以说明CIEA可以促进细胞自噬,从而起到保护GES-1细胞的作用。
2.12菊苣乙酸乙酯萃取物对GES-1细胞自噬相关蛋白表达的影响
GES-1在6孔板中培养24h,贴壁吸弃,配制不同浓度的CIEA(15、30、60μg/mL),培养箱中培养12h后提取蛋白,进行后续Western Blot常规操作。结果如图10所示。
图10结果表明,CIEA(15μg/mL、30μg/mL、60μg/mL)随着剂量的增加,Beclin1和LC3-II蛋白的表达均有显著的上调,由此数据可以认为,CIEA可以激发GES-1的自噬,来维持GES-1细胞的稳态。
2.13菊苣乙酸乙酯萃取物对酒精诱导的小鼠胃黏膜损伤保护作用
(1)将菊苣乙酸乙酯萃取物和奥美拉唑分别用CMC-Na溶解,下面以此溶液为例研究菊苣乙酸乙酯萃取物对酒精诱导的胃溃疡的预防及治疗效果。
(2)实验前将小鼠随机分为六组,每组6只:①空白对照组;②乙醇模型对照组;③CIEA低剂量组;④CIEA中剂量组;⑤CIEA高剂量组;⑥奥美拉唑阳性对照组。
(3)每日灌胃1次,空白对照组小鼠0.5% CMC-Na(10mL/kg/每天),乙醇模型对照组小鼠0.5% CMC-Na(10mL/kg/每天),CIEA组小鼠按100mg/kg、50mg/kg、25mg/kg的剂量对小鼠进行灌胃。
(4)各组灌胃7天后,全部动物严格禁食24h(不禁水),也不给予受试物,除空白对照组外,所有试验组动物按无水乙醇10mL/kg的剂量对小鼠进行灌胃,2h后处死动物。
(5)在造模结束后统一开始对小鼠进行眼球取血和胃组织取样,将小鼠腹部朝上置于冰盒上,并对小鼠进行腹部酒精消毒处理。沿小鼠肛门上方约1cm处剪开,再剖开腹部,于右侧找到连接食管和肠道的胃,沿胃大弯处剪开,再用生理盐水冲洗胃黏膜,擦拭后摊开胃黏膜称重,在解剖显微镜或肉眼下,用游标卡尺对出血点或出血带的长、宽进行测量,拍照留底。同时,根据CFDA指南中对胃黏膜损伤有辅助保护功能评价方法对小鼠的急性胃黏膜损伤进行评分。剖腹手术对胃进行解剖后,将胃(在较大曲率处)纵向切成两半(左和右)进行组织学观察,将胃的左半部分固定在装有10%甲醛溶液中(2mL离心管装满即可),以备后续实验。胃的右半部分先于液氮中定型后,置于2mL离心管中,于-80℃以备以后处理。结果图11所示。
图11结果表明,对照组的胃组织宏观无明显病变,胃黏膜的结构完整,单独处理EtOH的组分,有大面积的溃疡,红肿出血,但是奥美拉唑(Losec)和CIEA的预处理可以很好的改善这种情况。随着CIEA剂量的提高,溃疡指数方面的结果也相似。与对照组相比,EtOH的单独处理组分溃疡指数明显上升,而CIEA的预处理可以显著改善这一情况,并且呈现浓度依赖性。HE结果显示,胃组织由于酒精灌胃,出现了多处出血,伴随淋巴浸润,组织松散。预先CIEA干预后,胃组织的微观病理损伤得到明显改善。这些结果与先前在细胞层面的评估是一致的,由此可以进一步证实CIEA对EtOH诱导的胃黏膜损伤具有保护作用。
Claims (2)
1.一种菊苣乙酸乙酯萃取物的应用,其特征在于,所述菊苣乙酸乙酯萃取物用于制备乙醇诱导的胃黏膜损伤类疾病预防和治疗的药物;胃黏膜损伤类疾病为胃炎或胃溃疡;
所述菊苣乙酸乙酯萃取物的提取方法为:
取菊苣茎叶100g装进三颈烧瓶中,加入1L 70 %的乙醇-水溶液,加热回流3次,趁热抽滤,合并滤液,减压浓缩,剩余100 mL 的醇提液后停止旋蒸;取出5 mL冷冻干燥作为菊苣醇提取物;向分液漏斗中加入剩余醇提液和100mL二氯甲烷,萃取三次收集下层溶液,将下层溶液旋干得到菊苣二氯甲烷萃取物;接着向上层溶液中加入100mL乙酸乙酯,萃取三次收集上层乙酸乙酯层,将上层溶液旋干得到菊苣乙酸乙酯萃取物;保留下层水层,同样旋干得到菊苣水层萃取物;
加热回流3次的时间依次是2h、1.5h、1h。
2.如权利要求1所述的菊苣乙酸乙酯萃取物的应用,其特征在于,所述菊苣乙酸乙酯萃取物制备成胶囊剂、片剂、颗粒剂、散剂、口服液或丸剂中的任一种剂型的药物。
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