Nutri-epigenetics ameliorates blood-brain barrier damage and neurodegeneration in hyperhomocysteinemia: role of folic acid.
Nutri-epigenetics ameliorates blood-brain barrier damage and neurodegeneration in hyperhomocysteinemia: role of folic acid.
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DOI：
10.1007/s12031-013-0122-5
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发表时间：
2014-02
期刊：
影响因子：
--
通讯作者：
Tyagi N
中科院分区：
文献类型：
--
作者：
Kalani A;Kamat PK;Givvimani S;Brown K;Metreveli N;Tyagi SC;Tyagi N
营养的表观遗传机制（营养表观遗传学）对理解人类健康很重要。营养补充剂，例如叶酸，一碳代谢中的辅因子，调节表观遗传改变，并可能在维持神经元完整性方面发挥重要作用。叶酸还可以改善高同型半胱氨酸血症，这是同型半胱氨酸水平升高的结果。高同型半胱氨酸血症诱导的氧化应激可能在表观遗传学上介导脑血管重塑并导致神经退行性变;然而，这种改变背后的机制仍不清楚。因此，本研究旨在观察叶酸对高同型半胱氨酸血症诱导的表观遗传和分子改变导致神经毒性级联反应的保护作用。为了验证这一假设，我们采用了8周龄雄性野生型（WT）胱硫醚-β-合酶杂合子敲除蛋氨酸喂养（CBS+/−+Met）、WT和CBS+/−+Met小鼠，补充叶酸（FA）[WT+FA和CBS+/−+ Met+FA，分别为0.0057 μg g−1天−1剂量饮用水/4周]。CBS+/−+Met小鼠脑中的高同型半胱氨酸血症伴随着亚甲基四氢叶酸还原酶的减少和S-腺苷高半胱氨酸水解酶表达的增加、氧化应激症状、DNA甲基转移酶的上调、基质金属蛋白酶的升高、金属蛋白酶的组织抑制剂的下降、紧密连接蛋白的表达减少、血脑屏障的通透性增加、神经变性、和突触毒性。向CBS+/−+Met小鼠脑补充叶酸导致同型半胱氨酸水平降低，并挽救了致病性和表观遗传学改变，显示出其对同型半胱氨酸诱导的神经毒性的保护作用。
Epigenetic mechanisms underlying nutrition (nutrition epigenetics) are important in understanding human health. Nutritional supplements, for example folic acid, a cofactor in one-carbon metabolism, regulate epigenetic alterations and may play an important role in the maintenance of neuronal integrity. Folic acid also ameliorates hyperhomocysteinemia, which is a consequence of elevated levels of homocysteine. Hyperhomocysteinemia induces oxidative stress that may epigenetically mediate cerebrovascular remodeling and leads to neurodegeneration; however, the mechanisms behind such alterations remain unclear. Therefore, the present study was designed to observe the protective effects of folic acid against hyperhomocysteinemia-induced epigenetic and molecular alterations leading to neurotoxic cascades. To test this hypothesis, we employed 8-weeks-old male wild-type (WT) cystathionine-beta-synthase heterozygote knockout methionine-fed (CBS+/−+Met), WT, and CBS+/−+Met mice supplemented with folic acid (FA) [WT+FA and CBS+/−+ Met+FA, respectively, 0.0057-μg g−1 day−1 dose in drinking water/4 weeks]. Hyperhomocysteinemia in CBS+/−+Met mouse brain was accompanied by a decrease in methylenetet-rahydrofolate reductase and an increase in S-adenosylho-mocysteine hydrolase expression, symptoms of oxidative stress, upregulation of DNA methyltransferases, rise in matrix metalloproteinases, a drop in the tissue inhibitors of metallo-proteinases, decreased expression of tight junction proteins, increased permeability of the blood–brain barrier, neuro-degeneration, and synaptotoxicity. Supplementation of folic acid to CBS+/−+Met mouse brain led to a decrease in the homocysteine level and rescued pathogenic and epigenetic alterations, showing its protective efficacy against homocysteine-induced neurotoxicity.
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影响因子：
15.1
作者：
Cui J;Chen S;Zhang C;Meng F;Wu W;Hu R;Hadass O;Lehmidi T;Blair GJ;Lee M;Chang M;Mobashery S;Sun GY;Gu Z
通讯作者：
Gu Z
影响因子：
2.9
作者：
Pogribny, Igor P.;Karpf, Adam R.;Tryndyak, Volodymyr P.
通讯作者：
Tryndyak, Volodymyr P.
影响因子：
7.3
作者：
Colado, MI;OShea, E;Green, AR
通讯作者：
Green, AR
影响因子：
5.7
作者：
McNeil, Chris J.;Beattie, John H.;Gordon, M-J;Pirie, Lynn P.;Duthie, Susan J.
通讯作者：
Duthie, Susan J.
影响因子：
4.8
作者：
Thaler, Roman;Agsten, Marlies;Varga, Franz
通讯作者：
Varga, Franz