CN114159582A - 改性nTiO2在缓解消化道脂质代紊乱中的应用 - Google Patents
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Abstract
本发明提了一种Choline修饰MetSe掺杂nTiO2的制备方法，以及该改性改性nTiO2结合肠羧酸酯酶2的分子位点Ces2hp.G148A能显著降低游离脂肪酸的生成，并维持肠道中甘油三酯和酯化胆固醇的浓度，从而保障其肠道脂质代谢的稳态。
Description
技术领域
本发明涉及生物医学技术领域，尤其涉及改性nTiO2结合肠羧酸酯酶2的分子位点在缓解消化道脂质代谢紊乱方面的应用。
背景技术
肠道是外界环境接触人体的窗口，研究发现，儿童容易受到环境危害的影响，从而患上腹泻、食物中毒等由环境因素引起的肠道疾病。据报道，2015年有 526,000多名5岁以下儿童死于腹泻疾病，这是第二大死亡原因。
CES2是编码羧酸酯酶大家族的成员。该家族成员负责各种异生素(例如可卡因和海洛因)以及具有酯、硫酯或酰胺键的内源性底物的水解或酯交换反应。它们可能参与脂肪酰基和胆固醇酯的代谢，并可能在血脑屏障系统中起作用。该基因编码的蛋白质是主要的肠道酶，在肠道药物清除中起作用。
随着纳米技术的快速发展，纳米技术在社会生活各方面取得了巨大的应用，特别在生物医学和药物学领域，纳米材料的应用更是全面和深入的。纳米二氧化钛(nTiO2)是一种广泛使用和大量生产的纳米材料，它的光催化性能、杀菌作用和氧化还原活性促进了其在医药领域的广泛使用。然而，nTiO2可以自发产生电子- 空穴对，从而产生超氧阴离子(O2-)和羟基自由基(·OH)，从而引发氧化还原反应。因此，研究肠道对nTiO2毒性的抵御机制，将为进一步开发无毒的nTiO2提供新的科学依据。
发明内容
本发明的目的是开发一种无毒的nTiO2其结合肠羧酸酯酶2的分子位点可以缓解消化道脂质代谢紊乱。
为实现发明目的，本发明采取如下的技术方案：
改性nTiO2在缓解消化道脂质代紊乱中的应用，其特征在于，改性nTiO2结合肠羧酸酯酶2的分子位点Ces2hp.G148A。
进一步地，所述改性nTiO2为Choline修饰MetSe掺杂nTiO2。
本发明的另一目的在于所述改性nTiO2的制备方法，采取如下的技术方案：
改性nTiO2的制备方法，包括如下步骤：
1)MetSe-nTiO2纳米颗粒的制备
取蛋氨酸硒粉末，加入无水乙醇，超声震荡得分散体系A；再取乙酸乙酯，边搅拌边逐滴加入到分散系A中，搅拌，得到分散体系B；取醋酸和无水乙醇混合液，边搅拌边逐滴加入分散系B中，继续搅拌；离心分离沉淀物，分别用蒸馏水和无水乙醇清洗，室温下风干；用马弗炉焙烧，碾磨后，过滤、杀菌制得样品；
2)胆碱表面修饰
将碳酸氢钾溶入去离子水中，取碳酸氢钾溶液并使用氢氧化钾和盐酸调溶液 pH值；将胆碱加入所制得的碳酸溶液中，搅拌；将MetSe-TiO2纳米颗粒样品加入去离子水中进行超声分散；将所配制的MetSe-TiO2纳米颗粒悬液在超声的环境下逐滴加入到胆碱Choline溶液中，将混合溶液避光处理，在室温下持续搅拌；最后将制得的Choline-MetSe-TiO2纳米颗粒使用饱和碳酸氢钠溶液和去离子水清洗。
具体地，所述的改性nTiO2的制备方法，包括如下步骤：
1)MetSe-nTiO2纳米颗粒的制备
采用有机试剂沉积法，称取0.14g蛋氨酸硒粉末，加入50mL无水乙醇，超声震荡2h得分散体系A；再量取2.0mL乙酸乙酯，边搅拌边逐滴加入到A分散系中，用磁力搅拌仪搅拌30分钟，得到分散体系B；将体积比1:9的醋酸和无水乙醇混合液10mL，边搅拌边逐滴加入分散系B中，继续搅拌2h；离心分离沉淀物，分别用蒸馏水和无水乙醇清洗两遍，室温下风干；用马弗炉500℃焙烧6h，碾磨后，过滤、杀菌制得样品。
2)胆碱表面修饰
将1g碳酸氢钾溶入100mL的去离子水中，量取40mL碳酸氢钾溶液并使用氢氧化钾和盐酸将溶液pH值调为5.8；将2g胆碱加入所制得的碳酸溶液中，置于磁力搅拌器上搅拌；将MetSe-TiO2纳米颗粒样品加入5mL去离子水中进行超声分散。将所配制的MetSe-TiO2纳米颗粒悬液在超声的环境下逐滴加入到胆碱choline溶液中，将混合溶液避光处理，在室温下持续搅拌36h；最后将制得的 Choline-MetSe-TiO2纳米颗粒使用饱和碳酸氢钠溶液和去离子水各清洗2遍。
本发明的Choline-MetSe-nTiO2对小鼠肠道具有保护作用，与普通nTiO2相比，还能显著降低游离脂肪酸的生成，并维持肠道中甘油三酯和酯化胆固醇的浓度，从而保障其肠道脂质代谢的稳态。
附图说明
图1.A-D：口服普通nTiO2和光激发后的nTiO2后，小鼠消化道微生物菌落的组成变化；E：口服普通nTiO2和光激发后的nTiO2后，小鼠消化道微生物细菌的功能变化。
图2.A：口服普通nTiO2和光激发后的nTiO2后，小鼠小肠上皮发生差异表达的功能基因数量变化；B-C：口服普通nTiO2和光激发后的nTiO2对小鼠小肠上皮脂质代谢和稳态维持相关功能富集的影响。
图3.A：不同处理组条件下，小肠微生物的组成和消化道组织功能基因的表达量进行整合分析；B：响应nTiO2和光激发后nTiO2关键基因的筛选。
图4.A-B-D：口服普通nTiO2和光激发后的nTiO2后，小鼠小肠上皮脂质代谢产物的变化情况。
图5.A：运用molecular docking方法，解析Ces2响应nTiO2的作用方式和结合位点；B：通过体外细胞点突变的方式，确定Ces2响应nTiO2的作用方式和结合位点；图5C：进一步分析发现Ces2与其配体(己酸胆固醇酯)的氢键距离变远；图5D：催化三联体突变后，Ces2催化脂质代谢的效率降低，nTiO2可有效提升该条件下Ces2的催化效率，当进一步用紫外光激活nTiO2后，催化效率的提升更显著。
具体实施例
下面结合实施例对本发明做进一步说明。
实施例1
nTiO2改性方法可综合归纳为有机-无机试剂综合法，具体如下：
1)MetSe-nTiO2纳米颗粒的制备
采用有机试剂沉积法。称取0.14g蛋氨酸硒粉末，加入50mL无水乙醇，超声震荡2h得分散体系A。再量取2.0mL乙酸乙酯，边搅拌边逐滴加入到A分散系中，用磁力搅拌仪搅拌30分钟，得到分散体系B。将体积比1:9的醋酸和无水乙醇混合液10mL，边搅拌边逐滴加入分散系B中，继续搅拌2h。离心分离沉淀物，分别用蒸馏水和无水乙醇清洗两遍，室温下风干。用马弗炉500℃焙烧6h，碾磨后，过滤、杀菌制得样品。
2)胆碱(Choline)表面修饰
将1g碳酸氢钾溶入100mL的去离子水中，量取40mL碳酸氢钾溶液并使用氢氧化钾和盐酸将溶液pH值调为5.8。将2g胆碱加入所制得的碳酸溶液中，置于磁力搅拌器上搅拌。将MetSe-TiO2纳米颗粒样品加入5mL去离子水中进行超声分散。将所配制的MetSe-TiO2纳米颗粒悬液在超声的环境下逐滴加入到choline溶液中，将混合溶液避光处理，在室温下持续搅拌36h。最后将制得的Choline-MetSe-TiO2纳米颗粒使用饱和碳酸氢钠溶液和去离子水各清洗2遍。
验证试验：
获得的MetSe-nTiO2，以ICR小鼠为模型进行油酸修饰纳米二氧化钛的灌胃试验。每组10个小鼠，通过食道灌注生理盐水(对照组)、试验一组(常规的 nTiO2)和试验二组(Choline-MetSe-nTiO2)，nTiO2剂量设定为0.2mmol/公斤代谢体重，每天灌注一次，试验期为14天，试验期结束后评估其是否会导致动物肠道脂质代谢紊乱，测定指标主要包括两部分：1)肠道Ces2基因和肠道完整性相关基因(PTEN、IGFBP5、PCNA和OCLN)的表达量；2)肠道脂质代谢相关参数(甘油三酯、游离脂肪酸、总胆固醇和酯化胆固醇)，评估 Choline-MetSe-nTiO2的使用对肠道脂质代谢的扰动，具体结果见表1和表2，图 1至图5。
表1添加不同形式的TiO2对小鼠肠道功能基因表达量的影响(以b-actin为内参)
表2添加不同形式的TiO2对小鼠肠道中脂质代谢的影响(以b-actin为内参)
结果发现，与普通nTiO2相比，给小鼠灌注Choline-MetSe-nTiO2的脂代谢(Ces2)和紧密连接相关基因(PTEN、IGFBP5、PCNA和OCLN)的表达量显著变化，并与对照组保持一致(见表1)，提示Choline-MetSe-nTiO2对小鼠肠道完成性具有保护作用。同时，与普通nTiO2相比，给小鼠灌注Choline-MetSe-nTiO2可显著降低游离脂肪酸的生成，并维持肠道中甘油三酯和酯化胆固醇的浓度(见表2)，从而保障其肠道脂质代谢的稳态。
从如图1中可以看到通过口腔灌注nTiO2，小肠中的微生物菌群发生紊乱，发生改变的微生物菌落，主要功能均与脂代谢相关，提示nTiO2可使微生物脂质代谢发生紊乱，采用的方法为肠道微生物16srDNA测序。
从图2中可以看到：nTiO2灌注可显著调节小肠中功能基因表达的变化，表达量发生变化基因的功能也主要集中于脂类代谢，采用方法为肠道组织RNA-seq 测序。
从图3中可以看到：CES2功能基因在TiO2诱导的肠道脂质代谢紊乱中起主导作用，采用生物信息学分析，将肠道组织RNA-seq测序结果和肠道内容物 16srDNA测序结果进行整合。
图4中发明人进一步对nTiO2及用光激发后的nTiO2(UVnTiO2)对肠道组织脂质代谢和肠道微生物菌群进行研究，发现其脂代谢发生进一步紊乱，提示nTiO2主要通过肠道脂代谢紊乱导致肠道受损。同时，对CES2基因进行药物激活，发现药物激活后脂质代谢紊乱的情况发生好转，提示了CES2在预防肠道脂质代谢紊乱中发挥重要作用，小鼠试验设计与上所述相同，测定指标为肠道组织中的脂质代谢产物。
图5中通过运用molecular docking的方法进行了研究，发现CES2蛋白中的位点Ces2hp.G148A，在Ces2抵御nTiO2的入侵并缓解肠道脂肪酸代谢紊乱过程中起关键作用。Ces2hp.G148A的特征是：Ces2h基因的特征是在HGGX基序和邻近的催化三联体(Ser，Glu和His，图5A)中形成的氧阴离子空穴通过两步反应促进催化(图5B)，其催化过程所需要能量来自·OH或O2-。己酸胆固醇酯是上述催化过程的配体，其催化位点是Ces2hp.G148A(图5C)。
Claims (4)
1.改性nTiO2在缓解消化道脂质代紊乱中的应用，其特征在于，改性nTiO2结合肠羧酸酯酶2的分子位点Ces2hp.G148A。
2.根据权利要求1所述的改性nTiO2在缓解消化道脂质代紊乱中的应用，其特征在于，改性nTiO2为Choline修饰MetSe掺杂nTiO2。
3.改性nTiO2的制备方法，其特征在于包括如下步骤：
1)MetSe-nTiO2纳米颗粒的制备
取蛋氨酸硒粉末，加入无水乙醇，超声震荡得分散体系A；再取乙酸乙酯，边搅拌边逐滴加入到分散系A中，搅拌，得到分散体系B；取醋酸和无水乙醇混合液，边搅拌边逐滴加入分散系B中，继续搅拌；离心分离沉淀物，分别用蒸馏水和无水乙醇清洗，室温下风干；用马弗炉焙烧，碾磨后，过滤、杀菌制得样品；
2)胆碱表面修饰
将碳酸氢钾溶入去离子水中，取碳酸氢钾溶液并使用氢氧化钾和盐酸调溶液pH值；将胆碱加入所制得的碳酸溶液中，搅拌；将MetSe-TiO2纳米颗粒样品加入去离子水中进行超声分散；将所配制的MetSe-TiO2纳米颗粒悬液在超声的环境下逐滴加入到胆碱Choline溶液中，将混合溶液避光处理，在室温下持续搅拌；最后将制得的Choline-MetSe-TiO2纳米颗粒使用饱和碳酸氢钠溶液和去离子水清洗。
4.根据权利要求3所述的改性nTiO2的制备方法，其特征在于包括如下步骤：
1)MetSe-nTiO2纳米颗粒的制备
采用有机试剂沉积法，称取0.14g蛋氨酸硒粉末，加入50mL无水乙醇，超声震荡2h得分散体系A；再量取2.0mL乙酸乙酯，边搅拌边逐滴加入到A分散系中，用磁力搅拌仪搅拌30分钟，得到分散体系B；将体积比1:9的醋酸和无水乙醇混合液10mL，边搅拌边逐滴加入分散系B中，继续搅拌2h；离心分离沉淀物，分别用蒸馏水和无水乙醇清洗两遍，室温下风干；用马弗炉500℃焙烧6h，碾磨后，过滤、杀菌制得样品。
2)胆碱表面修饰
将1g碳酸氢钾溶入100mL的去离子水中，量取40mL碳酸氢钾溶液并使用氢氧化钾和盐酸将溶液pH值调为5.8；将2g胆碱加入所制得的碳酸溶液中，置于磁力搅拌器上搅拌；将MetSe-TiO2纳米颗粒样品加入5mL去离子水中进行超声分散。将所配制的MetSe-TiO2纳米颗粒悬液在超声的环境下逐滴加入到胆碱choline溶液中，将混合溶液避光处理，在室温下持续搅拌36h；最后将制得的Choline-MetSe-TiO2纳米颗粒使用饱和碳酸氢钠溶液和去离子水各清洗2遍。
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