CN112107608B - 大花红景天提取物在制备溃疡性结肠炎药物中的应用 - Google Patents
大花红景天提取物在制备溃疡性结肠炎药物中的应用 Download PDFInfo
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Abstract
本发明公开了一种大花红景天提取物在制备溃疡性结肠炎药物中的应用；本发明中通过将大花红景天提取物应用到治疗溃疡性结肠炎的药物中，能够降低溃疡性结肠炎患者血清中IL‑1β、IL‑6以及LPS的含量，并能够防止结肠缩短以及缓解结肠损伤，进而达到治疗溃疡性结肠炎的目的，治疗效果显著，显效快且无毒副作用。
Description
技术领域
本发明涉及治疗溃疡性结肠炎药物技术领域，具体涉及一种大花红景天提取物在制备溃疡性结肠炎药物中的应用。
背景技术
溃疡性结肠炎是一种病因尚不十分清楚的结肠和直肠慢性非特异性炎症性疾病，病变局限于大肠黏膜及黏膜下层。病变多位于乙状结肠和直肠，也可延伸至降结肠，甚至整个结肠。病程漫长，常反复发作，在全球范围内得病率逐步提升。
目前应用于治疗溃疡性结肠炎的药物主要是5-氨基水杨酸类、糖皮质激素类和免疫抑制剂类等药物；然而，这几种药物除治疗作用外都具有不同程度的副作用，对于溃疡性结肠炎的治疗尚未达到预期。
发明内容
本发明的目的在于提供一种大花红景天提取物在制备溃疡性结肠炎药物中的应用，该大花红景天提取物能够降低血清中IL-1β、IL-6以及LPS的含量，并能够防止结肠缩短以及缓解结肠损伤，进而达到治疗溃疡性结肠炎的目的，治疗效果显著，显效快且无毒副作用。
为了实现本发明的上述目的，特采用以下技术方案：
本发明第一方面提供一种大花红景天提取物在制备溃疡性结肠炎药物中的应用。
大花红景天(学名：Rhodiola crenulata(HK.f.et.Thoms)H.Ohba)产于西藏、云南西北部、四川西部。大花红景天提取物中含有多种对机体有益成分，主要类型有香豆素类、黄酮类、多酚类、生物碱类、多糖类等，本发明中通过将大花红景天提取物应用到治疗溃疡性结肠炎的药物中，能够降低溃疡性结肠炎患者血清中IL-1β、IL-6以及LPS的含量，并能够防止结肠缩短以及缓解结肠损伤，进而达到治疗溃疡性结肠炎的目的，治疗效果显著，显效快且无毒副作用。
优选地，所述大花红景天提取物由如下方法制得：
将大花红景天置于水中进行水煮，再对水煮后的溶液进行旋蒸、冷冻干燥，制得所述大花红景天提取物。
优选地，所述水煮次数为1～3次。
优选地，每次所述水煮中料液比为1∶8～1∶12；水煮时间为0.8～1.2h。
优选地，所述旋蒸温度为45～55℃。
本发明通过上述大花红景天提取物的制备方法，能够有效提取大花红景天中的有效成分，使得制备得到的大花红景天提取物对溃疡性结肠炎具有优异的治疗效果。
优选地，所述大花红景天提取物中红景天苷百分含量不低于1.5％，络塞维百分含量不低于0.03％。通过对大花红景天提取物中红景天苷以及络塞维含量的限定，能够更好的提高大花红景天提取物对溃疡性结肠炎的治疗效果。
本发明第二方面提供一种用于治疗溃疡性结肠炎的药物，所述药物包括治疗有效量的所述大花红景天提取物和药学上可接受的辅料。
优选地，所述辅料含量为2～80％。
优选地，所述辅料选自糖粉、微晶纤维素、淀粉、糊精、灭菌单蒸水和生理盐水中的任意一种或多种。
优选地，所述药物剂型为丸剂、颗粒剂、胶囊剂、片剂、散剂、膏剂、口服液剂、注射剂和糖浆剂。
与现有技术相比，本发明的有益效果至少包括：
本发明中通过将大花红景天提取物应用到治疗溃疡性结肠炎的药物中，能够降低溃疡性结肠炎患者血清中IL-1β、IL-6以及LPS的含量，并能够防止结肠缩短以及缓解结肠损伤，进而达到治疗溃疡性结肠炎的目的，治疗效果显著，显效快且无毒副作用。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍。在所有附图中，类似的元件或部分一般由类似的附图标记标识。附图中，各元件或部分并不一定按照实际的比例绘制。
图1为本发明实验例中各组小鼠代表性结肠长度以及统计结果；
图2为本发明实验例中各组结肠病理切片HE染色及评分结果；
图3为本发明实验例中各组小鼠血清中IL-1β炎症因子的检测结果；
图4为本发明实验例中各组小鼠血清中IL-6炎症因子的检测结果；
图5为本发明实验例中各组小鼠血清中LPS的检测结果；
图6为本发明实验例中各组小鼠结肠病理切片TUNEL染色及分析结果；
图7为本发明实验例中各组小鼠结肠病理切片ZO-1的IHC染色及分析结果；
图8为本发明实验例中各组小鼠结肠病理切片Occludin的IHC染色及分析结果。
具体实施方式
下面将结合实施例对本发明技术方案的实施例进行详细的描述。以下实施例仅用于更加清楚地说明本发明的技术方案，因此只作为示例，而不能以此来限制本发明的保护范围。
需要注意的是，除非另有说明，本申请使用的技术术语或者科学术语应当为本发明所属领域技术人员所理解的通常意义。
以下各实施例采用的原料以及设备如下：
硫酸葡聚糖钠盐(Dextran sulfate，DSS；分子量，36-50kDa)：购买于International Laboratory。
5-氨基水杨酸：购于上海阿拉丁生化科技股份有限公司。
小鼠血清IL-1β以及IL-6酶联免疫试剂盒：购买于美国R&D System公司。
LPS酶联免疫试剂盒：购买于中国CUSABIO公司。
大花红景天：干燥药材，由西藏药业提供。
实施例1
本实施例为大花红景天提取物的制备方法，该制备方法包括如下步骤：
取400g大花红景天药材，按料液比1:10经水煮提取两次，每次提取时间为1小时，两次提取物合并后于50℃旋蒸后冷冻干燥，制得大花红景天提取物。
利用岛津LC-MS-8045超高效液相串联三重四极杆质谱对实施例1中制备得到的红景天提取物中主要化合物进行定量分析；
液相条件如下：色谱柱选择了Shim-pack XR-ODSII(Shimadzu；2.0ID×100mm，2.2μm)。流动相设置为A相：去离子水(含0.1％formic acid)；B相：乙腈，采用线性梯度洗脱程序。流动相梯度洗脱程序设置如下：0-1min，5％B，1-5min 5-100％B，5-7min 100％B，7.01min 5％B，7.01-10.00min 5％B。流速为0.30mL/min。进样量为10μL。柱温控制为35℃。
ESI质谱条件如下：Spary流量(氮气)为3L/min，Heat Gas流量(F)为10L/min，DryGas流量(G)为10L/min，Interface Temp(I)是300℃，DL Temp(D)为260℃，加热块温度(H)则设置在400℃。
在负离子模式下，化合物离子对条件如下：红景天苷，m/z 299-119；Q1 Pre偏差，14V；Q3 Pre，12V；CE，14V；驻留时间100ms。络赛维，m/z 427-293；Q1 Pre偏差，20V；Q3 Pre，10V；CE，12V；驻留时间100ms。
结果：
红景天苷标曲：y＝10-5x-0.4382，0.24-20μg/mL，LOQ 0.08μg/mL；
络赛维标曲：y＝3*10-6x，0.08-2.22μg/mL，LOQ 0.08μg/mL。
红景天苷，1.81％(g/g)；络赛维，0.034％(g/g)。
实施例2
本实施例为一种用于治疗溃疡性结肠炎的药物，药物包括实施例1中制得的大花红景天提取物和灭菌单蒸水药学上可接受的辅料。
辅料为灭菌单蒸水；辅料含量为80％。
实验例
本实验例为实施例1制得的大花红景天提取物对溃疡性结肠炎的研究
实验动物：
SPF级C57BL/6J雄鼠60只，18-20g，购买于斯贝福生物技术有限公司[SCXK(京)2019-0010]，饲养于西南医科大学动物实验中心。
实验分组及方法：
所有小鼠在实验前进行一周的环境适应，SPF环境下饲养，每12小时进行黑夜/白昼更替，自由饮水。于实验前1天将小鼠随机分为正常组、模型组、5-氨基水杨酸组(5-ASA，100mg/kg)、红景天低剂量组(125mg/kg)、红景天中剂量组(250mg/kg)、红景天高剂量组(500mg/kg)；每组10只。
除正常组小鼠外，其余各组小鼠于实验第1天开始以3.5％的DSS溶液替代饮用水，进行急性肠炎造模，于第六天更换为灭菌单蒸水，正常小鼠一直饮用灭菌单蒸水。此外，实验第1天起，正常组和模型组每天1次灌胃给予正常灭菌单蒸水；5-氨基水杨酸组每天1次灌胃给予5-氨基水杨酸溶液(100mg/kg；溶于灭菌单蒸水)；红景天低、中、高剂量组分别每天1次灌胃给予红景天提取物(125、250、500mg/kg；溶于灭菌单蒸水)。每只小鼠每次灌胃0.1mL液体。于第16天，麻醉后处死小鼠，取血，分离血清；取结直肠，进行后续实验。
HE染色：
将结肠经冰PBS缓冲液清洗，通过福尔马林固定，石蜡包埋。石蜡切片脱蜡后，进行苏木精和伊红染色。在光学显微镜下观察小鼠结肠病理组织改变。
病理切片评分标准：上皮细胞评分：0，无损伤；1，少于50％面积杯状细胞损失；2，大于50％面积杯状细胞损失；3，隐窝部分损失；4，隐窝大面积缺失。炎性浸润评分：0，正常；1，浸润隐窝基底；2，浸润至黏膜肌层；3，广泛浸润黏膜肌层，黏膜增厚；4，浸润达黏膜下层。粘膜损伤评分：0，正常；1，部分粘膜损伤；2，大面积粘膜损伤；3，粘膜完全脱落。
组织学评分＝上皮细胞评分+炎性浸润情况评分+粘膜损伤评分。
血清IL-1β以及IL-6炎症因子检测：
小鼠全血收集在离心管中，0-4℃静置1-2h进行凝固分层。3000rpm离心5min，取上清转至新离心管中；再次12000rpm，4℃离心10min，再次取上清，液氮速冻15min后-80℃冰箱保存。
血清IL-1β以及IL-6炎症因子水平采用ELISA试剂盒进行检测，严格按厂家说明进行操作。
血清LPS检测：
血清LPS含量采用ELISA试剂盒进行检测，严格按厂家说明进行操作。
统计学分析：
采用Graphpad Prism 8.0进行分析；均采用one-way ANOVA，Tukey法进行后续多组比较分析；P<0.05具有统计学差异。
实验结果：
大花红景天提取物对结肠长度的影响结果：
对各组结肠长度进行测量，其中，各组代表性结肠长度以及统计结果如图1所示；图1中A为各组代表性结肠长度，B为各组结肠长度统计结果；***代表P<0.001，与正常组比较；##代表P<0.01，###代表P<0.001，与模型组比较；
由图1可知：
模型组小鼠结肠明显变短，5-氨基水杨酸组结肠稍有变长，但无统计学差异。而大花红景天提取物低、中、高剂量组的结肠较模型组均有显著变长，有统计学差异(p<0.05)，其中大花红景天提取物高剂量组小鼠结肠长度与正常组相近；可见，本申请大花红景天提取物优于5-氨基水杨酸的治疗效果。
各组结肠病理切片HE染色结果：
各组结肠病理切片HE染色结果如图2所示；图2中，A为各组结肠HE染色结果图；B为各组结肠病理评分结果；***代表P<0.001，与正常组比较；#代表P<0.05，与模型组比较。
由图2可知：模型组出现明显的黏膜变薄，腺体隐窝变短，可见细胞核增大拉长，多位于上皮细胞基底部或中部，伴随杯状细胞减少，炎性细胞浸润增加，证明肠炎造模成功；此外，大花红景天提取物低剂量组较模型组症状稍轻，但也出现隐窝消失，杯状细胞丢失，炎症浸润的现象；5-氨基水杨酸及中、高剂量的大花红景天提取物对DSS所致结肠损伤有不同程度的显著保护作用，与模型组比较，结肠病理改变获得明显缓解，其中高剂量红景天提取物对DSS所致肠道损伤的保护作用有统计学意义(p<0.05)。
各组小鼠血清中炎症因子检测结果：
各组小鼠血清中IL-1β以及IL-6炎症因子的检测结果如图3、4所示；图3、4中，***代表P<0.001，与正常组比较；#代表P<0.05，##代表P<0.01，###代表P<0.001，与模型组比较；
由图3、4可知：
模型组小鼠血清IL-1β以及IL-6水平均显著升高；而5-氨基水杨酸及不同剂量的大花红景天提取物显著的降低了DSS所致血清IL-1β以及IL-6水平的增高，可见，大花红景天提取物具有抗炎作用，能够有效治疗DSS。
各组小鼠血清中LPS的检测结果：
各组小鼠血清中LPS的检测结果如图5所示；图5中，***代表P<0.001，与正常组比较；#代表P<0.05，与模型组比较。
由图5可知：
模型组小鼠血清中的LPS水平显著增高，证明肠道通透性改变；而5-氨基水杨酸及中高剂量的大花红景天提取物可显著减少血清LPS的水平(p<0.05)，可见，大花红景天提取物能够具有肠道保护作用。
TUNEL染色检测细胞凋亡情况
石蜡切片脱蜡至水后，滴加20μg/mL不含DNase的蛋白酶K(碧云天，ST533)孵育30min，PBS洗涤后根据TUNEL细胞凋亡检测试剂盒(碧云天，C1098)操作；封片后显微镜镜检。
镜检结果如图6所示，图6中，A为各组结肠TUNEL染色结果图；B为各组结肠细胞凋亡分析；Ctrl为正常组，DSS为模型组，RCE-L为红景天低剂量组，RCE-M为红景天中剂量组，RCE-H为红景天高剂量组；***代表P<0.001，与正常组比较；###代表P<0.001，与模型组比较；
由图6可知，与正常组相比，DSS组结肠组织中出现显著增多的TUNEL阳性的凋亡细胞，而低、中、高剂量的红景天提取物有剂量依赖性的减少肠道凋亡细胞，差异均有统计学意义。
IHC染色
石蜡切片脱蜡至水后，于柠檬酸抗原修复缓冲液(PH6.0；Servicebio，G1202)中进行抗原修复；切片在3％过氧化氢溶液(双氧水：纯水＝1:9)中避光孵育25min，阻断内源性过氧化物酶。进而采用3％BSA室温封闭30min，一抗(ZO-1，Servicebio，GB11195；occludin，Servicebio，GB111401)4℃孵育过夜，洗涤后与相应二抗(HRP标记，Servicebio，GB23303)室温孵育50min，再次洗涤后，进行DAB显色液(Servicebio，G1211)显色以及Harris苏木素(Servicebio，G1004)复染细胞核；封片后显微镜镜检。
镜检结果如图7、图8所示，图7中，A为各组结肠ZO-1的IHC染色结果图；B为各组结肠ZO-1蛋白表达分析；Ctrl为正常组，DSS为模型组，RCE-L为红景天低剂量组，RCE-M为红景天中剂量组，RCE-H为红景天高剂量组；*代表P<0.05，与正常组比较；#代表P<0.05，与模型组比较；蓝色为细胞核；棕黄色提示为ZO-1阳性表达；
图8中，A为各组结肠Occludin的IHC染色结果图；B为各组结肠Occludin蛋白表达分析；Ctrl为正常组，DSS为模型组，RCE-L为红景天低剂量组，RCE-M为红景天中剂量组，RCE-H为红景天高剂量组；*代表P<0.05，与正常组比较；#代表P<0.05，与模型组比较；蓝色为细胞核；棕黄色提示为Occludin阳性表达；
由图7可知，DSS破坏肠道粘膜，粘连蛋白ZO-1表达明显减少，而红景天提取物组ZO-1表达明显增高，提示红景天提取物具有肠道保护作用。
由图8可知，DSS破坏肠道粘膜，粘连蛋白Occludin表达明显减少，而红景天提取物组Occludin表达明显增高，提示红景天提取物具有肠道保护作用。
以上仅是申请人大量研究中的部分实验结果，但已经可以说明：
本发明中大花红景天提取物能够降低溃疡性结肠炎患者血清中IL-1β、IL-6以及LPS的含量，并能够防止结肠缩短以及缓解结肠损伤，进而达到治疗溃疡性结肠炎的目的，治疗效果显著。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围，其均应涵盖在本发明的权利要求和说明书的范围当中。
Claims (5)
1.大花红景天提取物在制备治疗溃疡性结肠炎药物中的应用；
所述大花红景天提取物由如下方法制得：
取400g大花红景天药材，按料液比1:10经水煮提取两次，每次提取时间为1小时，两次提取物合并后于50℃旋蒸后冷冻干燥，制得所述大花红景天提取物；
所述大花红景天提取物中红景天苷百分含量为1.81％，络塞维百分含量为0.034％。
2.一种用于治疗溃疡性结肠炎的药物，其特征在于，包括治疗有效量的权利要求1中所述大花红景天提取物和药学上可接受的辅料。
3.根据权利要求2所述的药物，其特征在于，所述辅料含量为2～80％。
4.根据权利要求2或3所述的药物，其特征在于，所述辅料选自糖粉、微晶纤维素、淀粉、糊精、灭菌单蒸水和生理盐水中的任意一种或多种。
5.根据权利要求2所述的药物，其特征在于，所述药物剂型为丸剂、颗粒剂、胶囊剂、片剂、散剂、膏剂、口服液剂和糖浆剂。
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