CN114588171A - 褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜o-糖链结构异常疾病产品中的应用 - Google Patents
褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜o-糖链结构异常疾病产品中的应用 Download PDFInfo
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Abstract
本发明属于海洋药物开发技术领域,本发明提供了褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜O‑糖链结构异常疾病产品中的应用。本发明采用饮水添加DSS造模的肠炎肠黏膜损伤小鼠模型,证明了褐藻胶低聚糖能显著改善肠炎肠黏膜损伤小鼠的肠黏膜杯状细胞减少,也证明了褐藻胶低聚糖能显著改善肠炎肠黏膜损伤小鼠肠黏膜O‑糖链组成比例失调、短链O‑糖链含量升高和长链O‑糖链含量降低。本发明产品的原料来源于海洋褐藻多糖,具有资源丰富、制备工艺简单、产品稳定性好,易于产业化,安全性高等诸多优点,在防治肠炎所致肠黏膜O‑糖链结构异常相关疾病的新药和特医食品的开发领域具有广阔的开发应用前景。
Description
技术领域
本发明涉及海洋药物开发技术领域,尤其涉及褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜O-糖链结构异常疾病产品中的应用。
背景技术
肠道屏障是一种物理屏障,主要由上皮细胞、免疫细胞、分泌细胞以及其分泌的黏液层组成。结肠黏液层主要由杯状细胞分泌的富含O-糖链的糖蛋白组成。在正常生理条件下,肠道黏膜可以选择性地吸收水分和营养物质并有效防止病原体、毒素和过敏原从腔内扩散到其他组织、器官和血液中。然而,当肠道发生炎症,肠道黏膜受损时,微生物和内毒素可跨越肠黏膜屏障,导致肠源性感染,甚至发展为全身炎症反应,导致器官衰竭、炎症性肠病,脓毒症、急性胰腺炎等(Huo et al,Journal of Agricultural and Food Chemistry,2020,70:711-735)疾病。肠黏膜损伤的一个重要标志就是肠道黏液层破坏,黏液相关糖蛋白表达异常,肠道菌群紊乱,肠黏膜表面的O-糖链数量/结构等受损或表达异常。因此,保护肠粘膜O-糖链正常的结构具有重要应用价值。
前期研究表明(Shang et al,Carbohydrate Polymers,2018,179:173-185),虽然海洋多糖的口服生物利用度低,但低聚糖和寡糖经口服到达消化道后端,可以和肠道菌群发生互作,进入肠道病灶部位并发挥功能。在此过程中,一方面褐藻多糖和寡糖可以被肠道菌群发酵产生有益短链脂肪酸,修复肠道受损黏膜(Li et al,Microbiome,2019,7(1):98);另一方面,某些海洋多糖如岩藻聚糖硫酸酯和浒苔多糖,也可以被肠道菌群降解利用,作为益生元调节紊乱的肠道菌群(公开号CN108440681A),促进有益菌的生长和定殖。前期研究还发现,红藻多糖具有抗肠炎保护肠黏膜作用(Pan et al,Carbohydrate Polymers,2022,278:118921)。此外,褐藻酸盐具有抗真菌(公开号为CN112426430A)、预防和治疗高血脂(公开号为CN105395563A)、防治肝损伤(公开号为CN103977021A)、防治帕金森(公开号为CN103948611A)等多种活性。褐藻酸盐具有低毒性,被广泛应用于食品、制药、化妆品行业。褐藻胶低聚糖由海藻酸盐制备而来,目前尚无褐藻胶低聚糖在保护肠黏膜O-糖链中应用的相关报道。
发明内容
为克服现有技术中存在的上述缺陷,本发明提供了褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜O-糖链结构异常疾病产品中的应用。
为了实现上述发明目的,本发明提供以下技术方案:
本发明提供了褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜O-糖链结构异常疾病产品中的应用。
优选的,所述褐藻胶低聚糖是以海藻酸盐为原料,经化学降解法、物理降解法和/或酶法降解法制得。
优选的,所述褐藻胶低聚糖包括低聚甘露糖醛酸或低聚古罗糖醛酸。
优选的,所述褐藻胶低聚糖的平均分子量为0.3~15kDa。
优选的,所述炎症所致肠黏膜O-糖链结构异常疾病包括器官衰竭、炎症性肠病、脓毒症和急性胰腺炎。
优选的,所述产品包括药物、保健品和特医食品。
与现有技术相比,本发明的有益效果如下:
1、本发明采用饮水添加DSS造模的肠炎肠黏膜损伤小鼠模型,证明了所述褐藻胶低聚糖能显著改善肠炎肠黏膜损伤小鼠的肠黏膜杯状细胞减少。
2、本发明采用饮水添加DSS造模的肠炎肠黏膜损伤小鼠模型,证明了所述褐藻胶低聚糖能显著改善肠炎肠黏膜损伤小鼠肠黏膜O-糖链组成比例失调、短链O-糖链含量升高和长链O-糖链含量降低。
3、本发明产品的原料来源于海洋褐藻多糖,具有资源丰富、制备工艺简单、产品稳定性好,易于产业化,安全性高等诸多优点,在防治肠炎所致肠黏膜O-糖链结构异常相关疾病的新药和特医食品的开发领域具有广阔的开发应用前景。
附图说明
图1为低聚古罗糖醛酸分子量分布图;
图2为低聚古罗糖醛酸的1H-NMR图谱;
图3为低聚甘露糖醛酸分子量分布图;
图4为低聚甘露糖醛酸的1H-NMR图谱;
图5为小鼠结肠组织病理学切片染色图(注:H&E表示苏木精-伊红染色;AB表示阿利新蓝染色;NC表示正常未造模Control组小鼠;MD表示DSS造模Model组小鼠;LMG表示低聚古罗糖醛酸治疗组小鼠;LMM表示低聚甘露糖醛酸治疗组小鼠);
图6为小鼠结肠三类O-糖链相对含量分布图(注:NC表示正常未造模Control组小鼠;MD表示DSS造模Model组小鼠;LMG表示低聚古罗糖醛酸治疗组小鼠;LMM表示低聚甘露糖醛酸治疗组小鼠;SA表示唾液酸化;NSA表示非唾液酸化;F表示岩藻糖化;NF表示非岩藻糖化;S表示硫酸化;NS表示非硫酸化;#P<0.05表示与Control组小鼠相比;##P<0.01表示与Control组小鼠相比;*P<0.05表示与Model组小鼠相比;**P<0.01表示与Model组小鼠相比);
图7为小鼠结肠O-糖链相对含量分布图(注:NC表示正常未造模Control组小鼠;MD表示DSS造模Model组小鼠;LMG表示低聚古罗糖醛酸治疗组小鼠;LMM表示低聚甘露糖醛酸治疗组小鼠;#P<0.05表示与Control组小鼠相比;##P<0.01表示与Control组小鼠相比;*P<0.05表示与Model组小鼠相比;**P<0.01表示与Model组小鼠相比);
图8为G1-G3的O-糖链结构示意图;
图9为G4-G6的O-糖链结构示意图;
图10为G7-G9的O-糖链结构示意图;
图11为G10-G12的O-糖链结构示意图;
图12为G13-G15的O-糖链结构示意图;
图13为G16-G18的O-糖链结构示意图;
图14为G19-G21的O-糖链结构示意图;
图15为G22-G24的O-糖链结构示意图;
图16为G25-G27的O-糖链结构示意图;
图17为G28-G30的O-糖链结构示意图;
图18为G31-G33的O-糖链结构示意图;
图19为G34-G36的O-糖链结构示意图。
具体实施方式
本发明提供了褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜O-糖链结构异常疾病产品中的应用。
在本发明中,所述褐藻胶低聚糖优选以海藻酸盐为原料,进一步优选以海藻酸钠为原料,经化学降解法、物理降解法和/或酶法降解法制得。
在本发明中,所述褐藻胶低聚糖优选包括低聚甘露糖醛酸或低聚古罗糖醛酸。
在本发明中,所述褐藻胶低聚糖的平均分子量优选为0.3~15kDa,进一步优选为10kDa。
在本发明中,所述炎症所致肠黏膜O-糖链结构异常疾病优选包括器官衰竭、炎症性肠病、脓毒症和急性胰腺炎。
在本发明中,所述产品优选包括药物、保健品和特医食品。
下面结合实验例对本发明提供的技术方案进行详细的说明,但是不能把它们理解为对本发明保护范围的限定。
实验例1
(1)低聚古罗糖醛酸和低聚甘露糖醛酸的制备:
将海藻酸钠配成10wt%水溶液,采用1wt%稀盐酸加热到85℃后搅拌降解4.5小时,冷却后用10wt%的碳酸钠水溶液中和,再用5wt%稀盐酸调节pH到3.65,离心上清液A用于低聚甘露糖醛酸(LMM)的制备,沉淀B用于低聚古罗糖醛酸(LMG)的制备。其中含低聚甘露糖醛酸的上清液A部分用5wt%稀盐酸调节pH到1,离心后收集沉淀,用2mol/L NaOH溶解调节pH到7,加入3倍体积95wt%乙醇后收集沉淀,经无水乙醇脱水后干燥,得到LMM。含低聚古罗糖醛酸的沉淀B部分用2mol/L NaOH溶解调节pH到8.5,加入3倍体积95wt%乙醇后收集沉淀,经无水乙醇脱水后干燥,得到LMG。
采用十八角度激光散射仪对制备的LMM和LMG进行分子量分析,结果如图1和图3所示,其中LMG重均分子量为8.6kD,LMM重均分子量为4.41kD。采用1H-NMR图谱对其进行古罗糖醛酸(G)和甘露糖醛酸(M)含量分析,结果如图2和图4所示,其中LMG的G含量为91.86%,LMM的M含量为72.7%。
(2)研究LMM和LMG对黏膜损伤小鼠结肠完整度及杯状细胞数量的影响:
C57/6J小鼠(雄性,6周龄)在SPF级动物房通风的笼子里饲养,所有小鼠被饲养在温度可控(23℃)的环境下,每天12小时光照,自由饮水和进食。经过2周适应期后,18只小鼠随机平均分为3组:正常未造模Control组(NC,n=6);DSS造模Model模型组(MD,n=6);低聚古罗糖醛酸治疗组(LMG,n=6);低聚甘露糖醛酸治疗组(LMM,n=6);在第一个造模周期中,LMM组、LMG组和MD组小鼠在饮用水中添加1wt%DSS,NC组给与正常饮水,连续7天,随后三组小鼠均给予常规饮用水7天。在第二个周期中,即从第14天到第21天,LMM组、LMG组和MD组小鼠在饮用水中添加2.5wt%DSS,NC组小鼠仍给与正常饮水,第22到24天,三组小鼠均给予常规饮用水3天。在第14~24天,LMM组、LMG组小鼠分别灌胃给予100mg/kg的LMM和LMG溶液,每天1次,NC组和MD组小鼠给予等量的生理盐水。
第25天处死所有小鼠,解剖小鼠,取部分结肠组织做病理学切片分析,其余部分-80℃冻存。结果如图5所示。由图5可知,H&E染色(苏木精-伊红染色法)结果表明,NC组小鼠结肠绒毛排布整齐,未见明显炎症细胞浸润和肠黏膜损伤情况,MD组小鼠结肠绒毛明显破坏且有炎症细胞浸润现象结肠黏膜损伤严重,LMM、LMG组小鼠结肠绒毛排列整齐,未见明显炎症细胞浸润和结肠黏膜损伤情况;AB染色(阿利新蓝染色)结果表明,NC组、LMM组、LMG组小鼠结肠杯状细胞排列规整、丰富,黏膜完整;MD组小鼠结肠杯状细胞严重缺损,黏膜破坏严重。
(3)研究LMM和LMG对黏膜损伤小鼠结肠三类O-糖链相对含量分布的影响:
取上述步骤(2)中冻存的小鼠结肠进行O-糖链分析,具体实验步骤如下:首先采用高通量组织均质器对结肠组织进行脱脂和均质。胰蛋白酶对组织中的蛋白进行酶解消化,酶解反应结束后,离心取上清,加入三倍乙醇对其中含O-糖链部分的糖肽进行醇沉,后使用3kDa超滤管对其进行分离得到粗粘蛋白型糖肽。采用还原剂保护的β-消除法制备糖醇形式的O-糖链,用LMGC-LC-ESI-MS/MS对其进行分析,利用DeconTools(http://omics.pnl.gov/)去卷积化软件和GlycReSoft 2.0(http://code.google.com/p/glycresoft/downloads/list)对O-糖链进行初步自动处理。然后使用CarbBank数据库中可用的结构对鉴定的O-糖链进行结构验证。使用Xcalibur对基于各O-糖链的峰面积对其进行相对定量分析,采用SNFG命名法用Glyworkbench 2绘制O-糖链的结构。
共鉴定得到了36种O-糖链,将其命名为G1-G36,各组样品O-糖链含量的相对丰度如表1所示。其中,G1-G3的O-糖链结构示意图如图8所示,G4-G6的O-糖链结构示意图如图9所示,G7-G9的O-糖链结构示意图如图10所示,G10-G12的O-糖链结构示意图如图11所示,G13-G15的O-糖链结构示意图如图12所示,G16-G18的O-糖链结构示意图如图13所示,G19-G21的O-糖链结构示意图如图14所示,G22-G24的O-糖链结构示意图如图15所示,G25-G27的O-糖链结构示意图如图16所示,G28-G30的O-糖链结构示意图如图17所示,G31-G33的O-糖链结构示意图如图18所示,G34-G36的O-糖链结构示意图如图19所示。
表1各组样品O-糖链含量相对丰度(Mean±SD)
对小鼠结肠O-糖链进行唾液酸化、非唾液酸化、岩藻糖化、非岩藻糖化、硫酸化和非硫酸化分类分析,结果如图6所示。由图6可知,相较于NC组小鼠,结肠黏膜损伤MD组小鼠结肠O-糖链中唾液酸化O-糖链丰度显著降低,岩藻糖化和硫酸化O-糖链丰度显著增高,与之相反的MD组小鼠结肠O-糖链中非唾液酸化O-糖链丰度显著上升,非岩藻糖化和非硫酸化O-糖链丰度显著降低。给与LMM和LMG后可显著改善黏膜损伤引起的小鼠肠道O-糖链相对丰度的失调。LMM和LMG均能显著降低小鼠黏膜损伤引起的岩藻糖化和硫酸化O-糖链丰度的增高,同时对唾液酸化降低的情况也有相应的升高唾液酸化O-糖链相对丰度的趋势。
(4)研究LMM和LMG对黏膜损伤小鼠结肠O-糖链链长的影响:
对上述步骤(3)中鉴定得到的36种O-糖链进行相对含量定量分析,共发现10种O-糖链在相对含量丰度上存在显著性差异(图7)。其中链长较短的G5、G6、G10、G12、G16糖链在黏膜损伤模型组中丰度显著增高,而链长较长的G29、G31、G33糖链在黏膜损伤模型组中丰度显著降低,这一结果表明黏膜损伤显著降低了黏膜表面O-糖链的链长,而LMM和LMG能显著逆转黏膜损伤对黏膜表面O-糖链的链长缩短的影响。在链长较长的G29、G31、G33糖链中,LMM和LMG均能不同程度提高这三种长链O-糖链的丰度,在链长较短的G5、G6、G10、G12、G16糖链中,LMM和LMG均能不同程度降低这五种短链O-糖链的丰度。
综上所示,以上实验结果表明,本发明的低聚甘露糖醛酸(LMM)和低聚古罗糖醛酸(LMG)能显著改善黏膜损伤小鼠结肠黏膜的损伤程度。改善由于黏膜损伤引起的小鼠结肠黏膜O-糖链唾液酸化降低,岩藻糖化和硫酸化丰度显著增高的情况,同时保护由于黏膜损伤引起的小鼠结肠O-糖链链长的缩短。
所述的褐藻胶低聚糖在保护肠黏膜O-糖链中的应用,褐藻低聚糖可用于防治肠黏膜受损的保健品、补充膳食纤维、益生元制品、营养补充剂,或者与益生菌、及抗肠炎的药物联用,或以褐藻胶低聚糖及其衍生物为母核制备的衍生物用于防治肠黏膜受损的药物、功能食品或生物制品中。本发明产品的原料来源于海洋褐藻多糖,具有资源丰富、制备工艺简单、产品稳定性好,易于产业化,安全性高等诸多有点,在肠黏膜受损的新药和特医食品的开发领域具有广阔的开发应用前景。
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,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.褐藻胶低聚糖在制备预防和/或治疗炎症所致肠黏膜O-糖链结构异常疾病产品中的应用。
2.根据权利要求1所述的应用,其特征在于,所述褐藻胶低聚糖是以海藻酸盐为原料,经化学降解法、物理降解法和/或酶法降解法制得。
3.根据权利要求1或2所述的应用,其特征在于,所述褐藻胶低聚糖包括低聚甘露糖醛酸或低聚古罗糖醛酸。
4.根据权利要求3所述的应用,其特征在于,所述褐藻胶低聚糖的平均分子量为0.3~15kDa。
5.根据权利要求1所述的应用,其特征在于,所述炎症所致肠黏膜O-糖链结构异常疾病包括器官衰竭、炎症性肠病、脓毒症和急性胰腺炎。
6.根据权利要求1所述的应用,其特征在于,所述产品包括药物、保健品和特医食品。
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