CN114432330A - 胡黄连苷ii在制备预防和治疗炎症性肠病药物中的用途 - Google Patents
胡黄连苷ii在制备预防和治疗炎症性肠病药物中的用途 Download PDFInfo
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Abstract
本发明提供了一种胡黄连苷II作为预防和治疗炎症性肠病的药物。还提供了一种胡黄连苷II，其能够改善炎症性肠病中体重减轻、腹泻、血便的症状。能够抑制NF‑κB通路。能够降低促炎因子TNF‑α，IL‑1β、TLR4、COX2的表达。通过实验研究发现，在动物实验中，Pic能有效缓解DSS诱导的急性IBD所导致的小鼠体重减轻、腹泻、隐血血便等症状并减轻结肠隐窝破坏程度和结肠组织炎性浸润程度。
Description
技术领域
本发明公开了胡黄连苷II在制备预防和治疗炎症性肠病药物中的用途，属于医药技术领域。
背景技术
炎症性肠病（Inflammatory bowel disease，IBD）包括克罗恩病（Crohn'sdisease，CD）和溃疡性结肠炎（Ulcerative colitis，UC），是一种受多种因素影响的慢性、持续性肠道炎症反应，其临床症状主要表现为腹泻、腹痛和黏液脓血便等。流行病学研究显示，我国IBD患者数量呈快速上升趋势，CD发病高峰为18-45岁，男女比例为1.5:1，UC患病率约为11.6/10万人，26-49岁为疾病高发年龄段，患者男女比例为1:1-1.3:1。70%-80%的CD患者出现肠梗阻、腹腔脓肿、肠穿孔、肠瘘、大出血等并发症，因而可能需要接受一次甚至多次手术治疗，这给患者带来了极大的痛苦。约30%的UC患者需要全结直肠切除，这具有很高的致残率，因此IBD也被称为“绿色癌症”，严重危害人类健康。
IBD的发病机制尚未完全明确，目前认为主要与环境、生活习惯、遗传易感性、机体免疫等因素密切相关。临床上多采用药物对IBD患者进行治疗，病情严重或有严重并发症者采用外科手术治疗。IBD的传统治疗药物包括氨基水杨酸制剂、皮质类固醇、免疫抑制剂和生物制剂等，这些药物虽能在一定程度上起到缓解急性发作、减少复发及并发症的作用，但长期使用存在一定局限性和副作用。如氨基水杨酸制剂会导致恶心、呕吐、可逆性男性不育、再生障碍性贫血；皮质类固醇会导致激素依赖；免疫抑制剂可致骨髓抑制、肝毒性、胰腺炎等；生物制剂在应用过程中则可能引起感染、恶性肿瘤等发生风险升高；而手术治疗存在一定风险，且术后并发症发生率也较高。因此，结合发病机制，靶向关键通路，研发高效低毒的药物，对于治疗IBD具有重要意义。
胡黄连苷II（Picroside II，Pic）是一种环烯醚萜苷类化合物，主要存在于传统中药胡黄连中。Pic具有抗炎、抗癌、抗氧化等作用。核因子κB（NF-κB）是一种特异性转录因子，参与炎症反应，调节多种促炎因子，包括白细胞介素-6（IL-6）、白细胞介素-1（IL-1）、TNF-α等，因此可以通过抑制NF-κB的激活从而治疗炎症。Pic通过激活核因子E2相关因子2（Nrf2）通路和抑制NF-κB与丝裂原活化蛋白激酶（PicPK）信号通路对软骨起保护作用，对治疗骨关节炎，子宫内膜炎有一定的效果。Pic作为天然产物的提取物，具有来源广、毒性低、成本低等特点。但如今却未见Pic对炎症性肠病有治疗效果的报道。
发明内容
本发明的目的是提供一种胡黄连苷II作为预防和治疗炎症性肠病的药物。
本发明提供了一种胡黄连苷II，其能够改善炎症性肠病中体重减轻、腹泻、血便的症状。
本发明提供了一种胡黄连苷II，其能够抑制NF-κB 通路。
本发明提供了一种胡黄连苷II，其能够降低促炎因子TNF-α，IL-1β、TLR4、COX2的表达。
通过实验研究发现，在动物实验中，Pic能有效缓解DSS诱导的急性IBD所导致的小鼠体重减轻、腹泻、隐血血便等症状并减轻结肠隐窝破坏程度和结肠组织炎性浸润程度。
通过实验研究发现，在动物实验中，Pic能有效抑制IBD所导致的小鼠结肠长度变短。
通过实验研究发现，在动物实验中，Pic能有效改善IBD所致的小鼠结肠病变。
通过实验研究发现，在动物实验中，Pic可以通过NF-κB信号通路有效缓解实验组的严重程度。
通过实验研究发现，在动物实验中Pic可以降低结肠中促炎因子IL-1β、TNF-α、COX2、TLR4的水平，抑制p65磷酸化。
本发明的发明人通过发现Pic明显改善DSS诱导的IBD小鼠的体重减轻、腹泻、血便等症状，抑制结肠缩短，减轻结肠组织的炎性浸润程度，还可通过抑制NF-κB 通路，降低促炎因子TNF-α，IL-1β、TLR4、COX2的表达。故证实Pic具有治疗IBD的作用。且Pic为传统中药胡黄连的天然产物，成本低，药效好，具有广阔的应用前景。
附图说明
图1为Pic治疗DSS诱导的IBD小鼠后，小鼠的体重变化；
图2为Pic治疗DSS诱导的IBD小鼠后，小鼠的腹泻、血便临床评分；
图3为图2的小鼠照片图；
图4为Pic治疗DSS诱导的IBD小鼠后，小鼠的结肠长度变化的照片图；
图5位Pic治疗DSS诱导的IBD小鼠后，小鼠的结肠长度变化的柱状图；
图6为Pic治疗DSS诱导的IBD小鼠后，小鼠的结肠病理变化；
图7为Pic治疗DSS诱导的IBD小鼠后，小鼠的结肠病理评分变化；
图8为Pic治疗DSS诱导的IBD小鼠后，小鼠结肠组织内促炎因子p65水平变化；
图9为Pic治疗DSS诱导的IBD小鼠后，小鼠结肠组织内促炎因子p-p65水平变化；
图10为Pic治疗DSS诱导的IBD小鼠后，小鼠结肠组织内促炎因子TLR4水平变化；
图11为Pic治疗DSS诱导的IBD小鼠后，小鼠结肠组织内促炎因子COX2水平变化；
图12为Pic治疗DSS诱导的IBD小鼠后，小鼠结肠组织内促炎因子IL-1β水平变化。
具体实施方式
下面结合附图对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案，而不能以此来限制本发明的保护范围。
1.小鼠预处理及模型建立
40只雄性C57BL/6小鼠随机分为正常对照组(Control组)、模型组（Vehicle组）、Pic 20mg/kg组、Pic 40mg/kg组，每组10只。实验期共22d。前13d，Pic 20mg/kg组、Pic40mg/kg组每天分别给予Pic 20mg/kg、40mg/kg灌胃一次；Control组与Vehicle组给予蒸馏水即可。第三周，除Control组外，均在原有基础上给予3%DSS（重量体积比，即每100mL蒸馏水中溶解3g的DSS）供自由饮用9d诱导急性IBD。每天记录小鼠体重、饮水量、粪便性状、血便情况。
2.样本搜集与预处理
2.1 肠组织的搜集及组织学检测
颈椎脱臼法处死小鼠后，将其盲肠末端至肛门的整个结肠和直肠段取出，测量长度及观察各组小鼠结肠的变化，经磷酸盐缓冲溶液 (DPBS)洗涤后，取相同部位1cm结肠在4%的多聚甲醛中固定后，将肠组织经乙醇脱水、二甲苯透明、石蜡包埋、切片后于光学显微镜下观察肠组织形态并拍照。
2.2 HE染色观察组织病理学变化
对小鼠肠组织病理切片损伤进行评分，每个切片随机选取15个高倍视野(400倍)计分，取平均值。
2.3 免疫荧光检测
对小鼠肠组织切片进行免疫荧光检测TLR-4、p-65、p-p65、COX-2、IL-1β等指标。
1. 统计学方法
采用GraphPad Prism 8.0.2统计软件进行分析，实验数据均以(x±s表示，运用单因素方差分析进行多样本间的均数比较，以P＜0.05为差异具有统计学意义。
实施例一
实验目的：通过记录小鼠体重变化、腹泻及血便情况来说明Pic对IBD的治疗作用。
实验设计：利用DSS进行模型制备后，通过每日记录各组小体重变化、腹泻及血便情况来说明Pic对IBD的治疗作用。结果如图1、图2、图3所示。
结果分析：当给予Pic处理后，实验组（Pic 20mg/kg组和Pic 40mg/kg）组的小鼠体重减轻情况、腹泻及血便情况显著缓解。
结果说明：Pic能有效治疗IBD所导致的小鼠体重减轻、腹泻及血便。
实施例二
实验目的：通过记录小鼠结肠长度变化来说明Pic对IBD的治疗作用。
实验设计：在处死后，通过记录各组小鼠结肠长度来说明Pic对IBD的治疗作用。结果如图4、图5所示。
结果分析：当给予Pic处理后，实验组（Pic 20mg/kg组和Pic 40mg/kg组）的小鼠结肠长度显著恢复。
结果说明：Pic能有效抑制IBD所导致的小鼠结肠长度变短。
实施例三
实验目的：通过HE染色法来说明Pic对组织损伤的改善作用。
实验设计：在处死后，通过获取各组小鼠相同部位的结肠组织进行HE染色来说明Pic对组织损伤的改善作用。结果如图8-12所示。
结果分析：当给予Pic处理后，实验组（Pic 20mg/kg组和Pic 40mg/kg组）的结肠组织损伤程度显著改善。
结果说明：Pic能有效改善IBD所致的小鼠结肠病变。
实施例四
实验目的：通过免疫荧光来说明Pic对小鼠IBD严重程度的影响及其作用通路。
实验设计：在处死后，通过免疫荧光检测各组小鼠相同部位结肠组织中转录因子p65、p-p65与促炎因子TLR4、COX2、IL-1β的表达变化。结果如图6所示。
结果分析：当给予Pic处理后，实验组（Pic 20mg/kg组和Pic 40mg/kg组）p65、p-p65、TLR4、COX2、IL-1β的表达水平均显著降低。
结果说明：Pic可以通过NF-κB信号通路有效缓解实验组（Pic 20mg/kg组和Pic40mg/kg组）IBD的严重程度。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变形，这些改进和变形也应视为本发明的保护范围。
Claims (4)
1.胡黄连苷II在制备预防和治疗炎症性肠病药物中的用途。
2.如权利要求1所述的用途，所述用途包括胡黄连苷II能够改善炎症性肠病中体重减轻、腹泻、血便的症状。
3.如权利要求1所述的用途，所述用途包括胡黄连苷II能够抑制NF-κB 通路。
4.如权利要求1所述的用途，所述用途包括胡黄连苷II能够降低促炎因子TNF-α，IL-1β、TLR4、COX2的表达。
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| CN108653272A (zh) * | 2017-03-31 | 2018-10-16 | 中国科学院上海药物研究所 | 青蒿素衍生物治疗炎症性肠病的医学用途 |
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| CN104822386A (zh) * | 2012-12-31 | 2015-08-05 | 永进药品株式会社 | 从东北婆婆纳中分离的含有大量活性成分的纯化提取物、其制备以及包含该提取物作为活性成分用于预防或治疗炎症、过敏和哮喘的组合物 |
| CN108653272A (zh) * | 2017-03-31 | 2018-10-16 | 中国科学院上海药物研究所 | 青蒿素衍生物治疗炎症性肠病的医学用途 |
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