富硒长双歧杆菌的药效以及药代动力学研究

发布时间：2018-02-28 00:36

本文关键词： 硒长双歧杆菌富硒长双歧杆菌 CTX 肿瘤药代动力学　出处：《南京大学》2014年硕士论文　论文类型：学位论文

【摘要】：硒元素是人体必需的微量元素之一。机体硒水平与癌症发生率呈负相关,补硒能有效抑制肿瘤的发生。但是,以亚硒酸盐为主的无机硒有较大的毒性,且不易被吸收,不适合人和动物长期使用。双歧杆菌能够选择性的富集到肿瘤组织的无氧区,具有高度的靶向性,且双歧杆菌是人体内固有的有益菌,没有致病性,可以作为富集和转化硒的载体。本实验中,我们证实了硒能在长双歧杆菌中富集并评估了富硒长双歧杆菌对肿瘤生长以及荷瘤小鼠免疫功能的影响。利用高效液相色谱-电感耦合等离子质谱法分析,发现富硒长双歧杆菌中有机硒含量超过99%,有机硒的主要成分为硒代蛋氨酸(SeMet)。体内实验表明,三种剂量的Se-B.longum灌胃给药后,无论单独还是与环磷酰胺(CTX)联合使用,中剂量和高剂量的Se-B.longum均能显著性抑制肿瘤的生长,且与CTX联合使用后,肿瘤抑制效果显著提高并且能够显著性延长荷瘤小鼠的存活时间。此外,Se-B.longum与CTX联用后可以有效提高其免疫功能、提高NK细胞和T淋巴细胞的活性、增加IL-2以及TNF-α的水平并能增加白细胞数,从而降低CTX治疗产生的毒性。此外,本实验还分别考察了硒双歧杆菌的主要成分硒和长双歧杆菌在动物体内的药代动力学特征。不同剂量的硒双歧杆菌经Beagle犬灌胃后,原子荧光法分别测定给药后不同时间点血液中的硒含量、硒的组织分布及排泄。结果表明,在一定的剂量范围内,血液中的硒含量变化不明显,不能计算药代动力学参数；给药后2 h,硒主要分布的肝脏和肾脏；在动物的排泄物中未检测到硒元素。不同剂量的硒双歧杆菌经小鼠灌胃后,研究小鼠肠道菌群的变化及长双歧杆菌在肠道中的定植情况。结果表明,硒双歧杆菌可以调节肠道的菌群数量和结构；长双歧杆菌主要定植在小鼠的盲肠部位；给药后12h,双歧杆菌已大部分定植；给药后1d和7d,双歧杆菌的数量逐渐增加,且停药后3d双歧杆菌数量并没有减少。
[Abstract]:Selenium is one of the essential trace elements in human body. The level of selenium in body is negatively correlated with the incidence of cancer. Selenium supplementation can effectively inhibit the occurrence of tumor. However, inorganic selenium, which is mainly selenite, is toxic and is not easily absorbed. Bifidobacterium can be selectively enriched into the anaerobic region of tumor tissue and has a high targeting. Bifidobacterium is a beneficial bacterium inherent in the human body and has no pathogenicity. It can be used as a carrier for the enrichment and transformation of selenium. We confirmed that selenium can be enriched in Bifidobacterium longifera and evaluated the effect of Bifidobacterium selenium-enriched on tumor growth and immune function in tumor-bearing mice. The results were analyzed by high performance liquid chromatography-inductively coupled plasma mass spectrometry (HPLC-ICP-MS). It was found that the content of organic selenium in Bifidobacterium selenium-enriched was more than 990.The main component of organic selenium was selenomethionine SeMet.Invivo experiments showed that three doses of Se-B.longum were used either alone or in combination with cyclophosphamide (CTX). Both middle and high doses of Se-B.longum could significantly inhibit the growth of tumor, and combined with CTX could inhibit the growth of tumor. In addition, the combination of Se-B.longum and CTX could effectively improve the immune function and the activity of NK cells and T lymphocytes. Increase the levels of IL-2 and TNF- 伪 and increase the number of white blood cells, thereby reducing the toxicity of CTX therapy. The pharmacokinetic characteristics of selenium bifidobacterium and bifidobacterium longifera in animals were also investigated. Different doses of selenium bifidobacterium were fed by Beagle dogs. The content of selenium in blood, tissue distribution and excretion of selenium were determined by atomic fluorescence method at different time points after administration. The results showed that the changes of selenium content in blood were not obvious within a certain dose range, and the pharmacokinetic parameters could not be calculated. At 2 hours after administration, selenium was mainly distributed in liver and kidney, and selenium was not detected in animal excreta. The changes of intestinal flora in mice and the colonization of bifidobacterium longus in intestinal tract were studied. The results showed that Bifidobacterium selenoides could regulate the number and structure of intestinal flora, and that Bifidobacterium longifera was mainly located in the cecum of mice. Bifidobacterium was mostly colonized 12 hours after administration, and the number of bifidobacterium increased gradually at 1 and 7 days after administration, and the number of bifidobacterium did not decrease 3 days after drug withdrawal.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R965

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