CN114984100A - 乌梅水提物在制备防治溃疡性结肠炎产品中的用途 - Google Patents
乌梅水提物在制备防治溃疡性结肠炎产品中的用途 Download PDFInfo
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Abstract
本发明公开了乌梅水提物在制备防治溃疡性结肠炎产品中的用途,属于医药技术领域,本发明乌梅水提物能够有效治疗和缓解溃疡性结肠炎的症状:包括结肠缩短、DAI评分等情况;能够抑制TNF‑α和IL‑17炎症因子的释放,缓解炎症症状和减轻肠道症状;保护肠黏膜屏障和修复结肠损伤,能够进一步调节肠道菌群组成、促进菌群恢复,特别地上调优势菌Blautia,下调有害菌Proteobacteria、Verrucomicrobiota和Desulfobacterota。因此,乌梅水提物能够用于抑制炎性因子的释放、调控菌群失调修复肠黏膜屏障损伤从而制备治疗或者预防溃疡性结肠炎的有效药物。
Description
技术领域
本发明涉及医药技术领域,具体涉及乌梅水提物在制备防治溃疡性结肠炎产品中的用途。
背景技术
溃疡性结肠炎(UC)是一种慢性炎症性肠病,主要症状有腹泻、腹痛、发烧以及直肠出血等,该病具有病程长、反复发作的特点,其发病率在世界范围内呈上升趋势。UC的病理生理学是多因素的,主要涉及遗传易感性、上皮屏障缺陷、免疫反应失调和环境因素。现代大量研究表明,溃疡性结肠炎可能是肠道炎症、上皮屏障功能障碍和肠道菌群失调的结果。肠道菌群的紊乱会损伤肠黏膜细胞,影响肠黏膜的菌群屏障功能。肠黏膜屏障作为肠道内环境与外界接触的第一道防线,如果遭到破坏,肠道中的致病微生物和其产生的毒素会通过肠黏膜屏障入侵人体,导致细菌移位,进入肝肠循环,加剧肠黏膜屏障损伤,从而导致肠道炎症反应的发生。
目前对于溃疡性结肠炎缺乏有效治疗方法,被WHO列为难治性疾病之一。虽然糖皮质激素、水杨酸制剂及免疫抑制剂的应用能够缓解症状,但是长期服用会产生一定的依赖性,严重影响患者的生活质量。因此,对于寻找安全、无毒副作用的药物和方法治疗溃疡性结肠炎迫在眉睫。随着溃疡性结肠炎基础研究的进展,治疗的着眼点聚焦在针对发病机制的重要环节。近年来,中医药在缓解肠道炎症、修复肠黏膜、调节肠道菌群等方面展现出独特的优势,加之其安全性高,价格低廉,逐渐成为抗结肠炎药物及新型免疫抑制剂、益生菌发酵中药制剂开发的研究热点。乌梅为蔷薇科梅Prunus mume Sieb.et Zucc.的干燥近成熟果实,具有悠久的药食同源历史,广泛融入日常饮食和保健,现代药理研究证实乌梅具有抑菌、镇咳、抗肿瘤及抗氧化等多种药理作用。然而,关于乌梅在溃疡性结肠炎疾病的防治优势并未得到充分利用,也没有关于乌梅在抗结肠炎中调控肠道菌群的报道以及在调控肠道菌群产品中的应用。针对上述技术问题,本发明提供乌梅水提物在制备防治溃疡性结肠炎产品中的用途。
发明内容
本发明提供了乌梅水提物在制备防治溃疡性结肠炎产品中的用途,有效治疗和缓解溃疡性结肠炎的症状:包括结肠缩短、DAI评分情况;能够抑制炎症因子TNF-α和IL-17的释放,缓解炎症症状和减轻肠道症状;能够保护肠黏膜屏障和修复结肠损伤;能够进一步调节肠道菌群组成、促进菌群恢复,特别地上调优势菌Blautia,下调有害菌属Proteobacteria、Verrucomicrobiota和Desulfobacterota。
本发明提供了乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述乌梅水提物在制备调控动物肠道菌群的药物中的用途。
优选的,所述乌梅水提物上调大鼠肠道Blautia菌群丰度以及下调Proteobacteria、Verrucomicrobiota和Desulfobacterota菌群丰度。
优选的,所述乌梅水提物在制备抑制炎症因子释放的药物中的用途。
优选的,所述炎症因子包括TNF-α、IL-17。
优选的,所述乌梅水提物在制备恢复肠粘膜损伤药物中的用途。
优选的,所述乌梅水提物在制备调控大鼠结肠组织中ZO-1、Occludin和Claudin-1蛋白表达升高以及Claudin-2蛋白表达降低的药物中的用途。
优选的,所述乌梅水提物的制备方法为:按照1:10的体积比向乌梅生药材加水,浸泡30min,煎煮30min后过滤,得到滤渣,按照1:8的体积比向滤渣中加水,煎煮2次后的滤液浓缩至生药比为3.642g/ml,真空冷冻干燥成粉末即得。
优选的,所述真空冷冻干燥的工艺参数为:于-60℃~-40℃预冷处理35~50min,设置真空度为200~800Pa,于~40℃真空冷冻干燥36~40h。
优选的,将所述乌梅水提物和医药载体或食品载体制备成片剂、丸剂、颗粒剂、胶囊剂或口服液剂。
与现有技术相比,本发明的有益效果在于:
本发明乌梅水提物能够有效治疗和缓解溃疡性结肠炎的症状:包括结肠缩短、DAI评分等情况;能够抑制TNF-α和IL-17炎症因子的释放,缓解炎症症状和减轻肠道症状;保护肠黏膜屏障和修复结肠损伤,能够进一步调节肠道菌群组成、促进菌群恢复,特别地上调优势菌Blautia,下调有害菌Proteobacteria、Verrucomicrobiota和Desulfobacterota。因此,乌梅水提物能够用于抑制炎性因子的释放、调控菌群失调修复肠黏膜屏障损伤从而制备治疗或者预防溃疡性结肠炎的有效药物。
附图说明
图1本发明实施例5中为各组大鼠溃疡性结肠炎的常规观察(a)大鼠结肠到盲肠的长度,(b)大鼠结肠长度柱形图(c)各组大鼠DAI评分;
图2为本发明实施例5中大鼠肠道组织HE染色分析图;
图3为本发明实施例5中大鼠结肠组织炎症因子浓度图,其中,(a)为大鼠结肠组织TNF-α含量;(b)为大鼠结肠组织IL-17含量;
图4为本发明实施例5中乌梅水提物对大鼠结肠组织中蛋白ZO-1、Occludin、Claudin-1和Claudin-2表达量;
图5为本发明实施例5中高剂量乌梅水提物对DSS诱导的大鼠肠道菌群α多样性分析示意图;
图6为本发明实施例5中高剂量乌梅水提物对DSS诱导的大鼠肠道菌群PCoA(2D)分析示意图;
图7为本发明实施例5中高剂量乌梅水提物对DSS诱导的大鼠肠道菌群结构门水平上的影响示意图;
图8为本发明实施例5中门水平微生物群落组间差异分析;
图9为本发明实施例5中高剂量乌梅水提物对DSS诱导的大鼠肠道菌群结构属水平上的影响示意图;
图10为本发明实施例5中高剂量乌梅水提物对Blautia菌属的影响。
具体实施方式
为了使本领域技术人员更好地理解本发明的技术方案能予以实施,下面结合具体实施例和附图对本发明作进一步说明,但所举实施例不作为对本发明的限定。下述试验方法和检测方法,如没有特殊说明,均为常规方法;所述试剂和原料,如没有特殊说明,均为市售。
实施例1
乌梅水提物的制备方法:按照1:10的体积比向乌梅生药材加水浸泡30min,煎煮30min后过滤,按照1:8的体积比向滤渣中加水,重复煎煮2次后,得到滤液,滤液浓缩至生药比为3.642g/ml,真空冷冻干燥成粉末即得。
所述真空冷冻干燥的工艺参数为:于-60℃预冷处理35min,设置真空度为200Pa,于~60℃真空冷冻干燥36h。
实施例2
与实施例1相比,真空冷冻干燥工艺不同。
所述真空冷冻干燥的工艺参数为:于-40℃预冷处理50min,设置真空度为800Pa,于~40℃真空冷冻干燥40h。
实施例3
与实施例1相比,真空冷冻干燥工艺不同。
所述真空冷冻干燥的工艺参数为:于-50℃预冷处理42min,设置真空度为500Pa,于~40℃真空冷冻干燥38h。
实施例4
与实施例1相比,真空冷冻干燥工艺不同。
所述真空冷冻干燥的工艺参数为:于-55℃预冷处理48min,设置真空度为700Pa,于~40℃真空冷冻干燥37h。
实施例5
乌梅水提物对大鼠结肠组织的作用研究如下:
1.动物分组及给药方案
SPF级大鼠,雄性,220±20g,购于郑州市惠济区华兴实验动物养殖场,大鼠适应性饲养5天后,将大鼠随机分为6组,每组8只,分别为对照组(Control)、模型组(DSS)、阳性药组(DSS+美沙拉嗪,Mes,0.5mg/ml)、低剂量乌梅水提物组(DSS+乌梅水提物,FML,0.63g/kg)、中剂量乌梅水提物组(DSS+乌梅水提物,FMM,1.26g/kg)、高剂量乌梅水提物组(DSS+乌梅水提物,FMH,2.52g/kg),实施例1~4制备的乌梅水提物的理化性质近似,本研究均采用实施例3制得的乌梅水提物。采用DSS诱导法建立溃疡性结肠炎模型:除对照组外,大鼠自由饮用3%DSS溶液,连续七天。自造模第二天起,给药组各组连续给药,每日一次,连续七天,对照组和模型组灌胃给予对照组和模型组等体积的蒸馏水。
2.实验方法及数据处理
2.1疾病活动指数DAI(disease activity index)
每日给药后观察大鼠毛色、粪便、活动等情况,称重并记录,评估大鼠疾病活动指数DAI(disease activity index),DAI=(体质量下降分数+大便性状分数+便血分值)/3。按照DAI评分标准进行评分,其中,粪便性状分数的评分标准为:正常为0分,介于正常与松散状之间为1分,松散状为2分,介于松散状与稀便之间为3分,稀便为4分;隐血程度分数的评分标准为:无便血为0分,介于无便血和隐血间为1分,隐血阳性为2分,介于隐血与肉眼便血间为3分,肉眼便血为4分;体质量下降分数的评分标准为:<1%为0分,1%~5%为1分,5%~11%为2分,11%~15%为3分,>15%为4分。
2.2结肠长度
于实验第9天,采用颈椎脱臼法处死各组大鼠,分离整段结肠组织,用标尺测量结肠至盲肠末端的完整结肠组织长度,进行统计学分析。
2.3结肠病理组织学观察
取各组大鼠病变结肠组织常规石蜡包埋,切片,HE染色用于组织学检查。
2.4结肠组织炎症因子检测
取出大鼠结肠组织重量按重量(mg):体积(ul)=1:9的比例加入9倍体积的匀浆介质(0.9%的生理盐水),冰水浴条件下,机械匀浆,制备成10%的匀浆液,3000r/min,离心10min,取上清液,按照试剂盒说明书步骤测定TNF-α、1L-17含量。
2.5结肠蛋白检测
将大鼠的结肠组织剪成细小的碎片,按每20mg组织加入250μl裂解液的比例加入裂解液(裂解液中加入蛋白酶和磷酸酶抑制剂),匀浆器匀浆直至完全裂解。裂解后的样品4℃,12000r,离心15分钟,取上清,用BCA法测定上清液的蛋白质浓度。加入蛋白上样缓冲液,充分混匀后沸水水浴10min后离心取上清上样。用10%SDS-聚丙烯酰胺凝胶分离,当染料到达胶底部时切断电源,停止电泳,于25V恒流和0.45μm孔径NC膜条件下进行半干式转膜30min,室温封闭于5%脱脂奶粉60min,稀释一抗,室温孵育2h,用TNBS洗涤3次,每次5min。随后根据用量,按照1:5000稀释HRP标记的二抗,与膜37℃孵育1h。用TBST洗涤3次,每次5min。膜的正面加入ECL后暗室避光5min,曝光,显影定影。采用凝胶图像处理系统分析目标带的表达量。
2.6粪便样品采集及处理
于实验第九天处死大鼠,剖开腹腔,取出肛门至盲肠末端的完整结肠组织并置于冰盘上,沿肠系膜纵向剖开结肠组织,取出结肠内粪便颗粒(2~3粒)收集于冻存管中,立即放于液氮内保存,待提取粪便中细菌的DNA。
2.7粪便中细菌16srDNA的提取及测序
使用DNA提取试剂盒提取粪便中的总DNA,利用1%琼脂糖凝胶电泳检测DNA提取质量,使用NanoDrop2000测定DNA浓度和纯度。对16S rRNA基因V3-V4可变区进行PCR扩增,利用Illumina公司的Miseq PE300/NovaSeq PE250平台进行测序(上海美吉生物医药科技有限公司)。
2.8数据处理
数据分析采用SPSS22.0统计学分析,正态分布的连续变量进行多样本均数比较采用单因素方差分析;非正态分布的连续变量进行多样本均数比较采用非参数检验。检验水准α=0.05,p<0.05为具有统计学意义。
3.结果与讨论
3.1乌梅水提物对DSS诱导的溃疡性结肠炎大鼠的一般体征影响
在造模开始后,模型组和各个给药组均出现轻度腹泻症状,运动迟缓,大便湿软,体重减轻,摄食减少。实验初始,大鼠的体重相似,均没有腹泻。结肠长度(图1(a-b))和DAI评分(图1(c))作为初步评估指标。实验期间,对照组大鼠的体重稳步增加而没有腹泻;相反,饮用DSS溶液的各组大鼠结肠长度明显缩短,摄食量减少,体重不断下降。从第3天开始,在DSS大鼠中观察到严重腹泻。乌梅可以剂量依赖性地增加大鼠结肠长度。并且经乌梅给药后,大鼠疾病活动指数评分在第6天就开始下降。
3.2乌梅水提物对DSS诱导的溃疡性结肠炎大鼠的组织病理学影响
结肠的形态变化,如图2所示。从HE染色可以看出,对照组无组织学异常性改变,DSS组大鼠结肠上皮组织溃疡伴发炎性细胞浸润,整个肠壁变薄,隐窝的连续性结构已破坏,固有层腺体大量萎缩,绒毛长度缩短等。乌梅治疗后可逆转以上症状,减轻黏膜层炎性细胞浸润,乌梅可剂量依赖性有效地损伤黏膜的恢复。
3.3乌梅水提物对DSS肠道损伤大鼠结肠组织的炎症因子的影响
检测各组大鼠结肠组织中TNF-α和IL-17含量,结果如图3所示。模型组大鼠结肠组织中炎性细胞因子TNF-α和IL-17的浓度高于对照组(P<0.01)。然而,乌梅中、高剂量给药后可以呈剂量依赖性的有效降低结肠组织中TNF-α的含量(P<0.01),其中低剂量乌梅对TNF-α有逆转作用,但不具有统计学差异。此外,乌梅高剂量给药组能够有效降低IL-17的含量(P<0.01),而中、低剂量乌梅对该细胞因子的改善并不明显。
3.4乌梅水提物对肠黏膜屏障紧密连接蛋白的影响
检测各组大鼠结肠组织中蛋白ZO-1、Occludin、Claudin-1和Claudin-2表达量,结果如图4所示。与正常组相比,模型组大鼠结肠ZO-1、Occludin、Claudin-1蛋白表达水平明显降低,Claudin-2蛋白表达水平明显升高(p<0.01),致使肠黏膜通透性增加,从而造成肠黏膜屏障功能的损伤。而乌梅不同剂量给药组均能一定程度的逆转以上改变,从而改善肠黏膜功能。其中,乌梅高剂量组、中剂量组大鼠结肠中的ZO-1、Occludin蛋白表达量均明显升高(p<0.01),以乌梅高剂量组差异最为显著。除此之外,乌梅高剂量给药组能够显著上调Claudin-1蛋白表达(p<0.01),乌梅低剂量和中剂量组给药组的Claudin-1蛋白表达有所升高,但是结果并无统计学差异。对于Claudin-2蛋白,只有乌梅高剂量给药组能够有效下调Claudin-2蛋白表达,差异具有统计学意义(p<0.01),而乌梅低剂量和中剂量组治疗效果并无显著差异。
3.5结肠肠道菌群物种多样性分析
通过对样品的多样性分析(α分析)可以反映微生物群落的物种丰度和多样性,我们采用两个指标进行评价,Chao1反映样本中物种丰富度,而不考虑每个物种的占比情况(均匀度);Simpson反映物种的丰富度和均匀度,结果如图5所示。结果表明高剂量乌梅水提物干预后并没有显著改善肠道菌群内微生物群落的物种丰度和多样性。β多样性是度量不同样本间菌群组成的相似度大小的指标,通过PCA(Principal ComponentAnalysis)对数据进行分析,采用多元统计方法确定各个组份间大鼠肠道菌落组成的相似性。结合PCA(图6)的分析结果直观表明各组样本组内聚类,组间离散。模型组和正常组相对处于不同区域,表明其之间肠道菌群结构及多样性存在差异。而给予高剂量乌梅水提物后,可一定程度调控并改善紊乱的肠道菌群。
3.6结肠肠道菌群物种丰度变化及组间差异分析
基于OTU的绝对丰度及注释信息,对每组中样本在门水平和属水平上的序列数目占总序列数的比例进行统计分析,确定各组在门和属水平上的物种组成差异。
图7显示了不同组大鼠肠道菌群在门水平的结构图。在对照组中,菌群谱反映正常大鼠肠道菌群的构成,其中Firmicutes(75.05%)、Bacteroidetes(19.95%)、Actinobacteria(3.42%)及Proteobacteria(1.34%)为4大主要的细菌门类,在模型组中,菌谱反映了疾病情况下大鼠肠道菌群的构成,其中Firmicutes(66.88%)、Bacteroidetes(21.16%)、Verrucomicrobiota(6.15%)、Proteobacteria(2.47%)为四大主要的细菌门类。相较对照组而言,Bacteroidetes、Verrucomicrobiota和Proteobacteria比例有所上升,而Firmicutes比例则有所下降。在高剂量乌梅给药组中,Firmicutes(76.89%)、Bacteroidetes(20.47%)和Proteobacteria(0.77%)为主要的细菌门类,Bacteroidetes和Firmicutes两类菌的占比与空白对照组相似。其中Proteobacteria、Verrucomicrobiota及Desulfobacterota在各组中变化显著(P<0.05),与空白对照组相比,在模型组中以上3种菌群相对丰度有所增加,给予高剂量乌梅水提物后,其相对丰度有所减少(如图8所示)。以上表明,乌梅水提物可以下调有害菌门Proteobacteria、Verrucomicrobiota及Desulfobacterota起到治疗溃疡性结肠炎的效果。
图9显示了不同组大鼠肠道菌群在属水平的结构图。在对照组中,相对丰度较高的菌属有norank-f-Muribaculaceae(16.28%),Lactobacillus(13.98%),Romboutsia(11.39%),Blautia(5.9%),Allobaculum(5.3%)。与正常组相比,模型组大鼠Blautia丰度显著下调(P<0.05),经乌梅给药后Blautia丰度显著增加(P<0.05)(图10)。以上表明,有益菌属Blautia与乌梅水提物治疗溃疡性结肠炎疾病显著相关。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (9)
1.乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述乌梅水提物在制备调控动物肠道菌群的药物中的用途。
2.根据权利要求1所述的乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述乌梅水提物上调大鼠肠道Blautia菌群丰度以及下调Proteobacteria、Verrucomicrobiota和Desulfobacterota菌群丰度。
3.根据权利要求1所述的乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述乌梅水提物在制备抑制炎症因子释放药物中的用途。
4.根据权利要求3所述的乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述炎症因子包括TNF-α、IL-17。
5.根据权利要求1所述的乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述乌梅水提物在制备恢复肠粘膜损伤药物中的用途。
6.根据权利要求1所述的乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述乌梅水提物在制备调控大鼠结肠组织中ZO-1、Occludin和Claudin-1蛋白表达升高以及Claudin-2蛋白表达降低的药物中的用途。
7.根据权利要求1所述的乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述乌梅水提物的制备方法为:按照1:10的体积比向乌梅生药材加水,浸泡30min,煎煮30min后过滤,得到滤渣,按照1:8的体积比向滤渣中加水,煎煮2次后的滤液浓缩至生药比为3.642g/ml,真空冷冻干燥成粉末即得。
8.根据权利要求7所述的乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,所述真空冷冻干燥工艺参数为:于-60℃~-40℃预冷处理35~50min,设置真空度为200~800Pa,于~40℃真空冷冻干燥36~40h。
9.根据权利要求1所述的乌梅水提物在制备防治溃疡性结肠炎产品中的用途,其特征在于,将所述乌梅水提物和医药载体或食品载体制备成片剂、丸剂、颗粒剂、胶囊剂或口服液剂。
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