{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:44:37Z","timestamp":1790775877841,"version":"4.1.0"},"reference-count":26,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2014,3,17]],"date-time":"2014-03-17T00:00:00Z","timestamp":1395014400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"published-print":{"date-parts":[[2014,4]]},"abstract":"<jats:p>Mild to moderate hyperhomocysteinemia has been implicated in neurodevelopmental disorders and neurodegenerative diseases in human studies. Although the molecular mechanisms underlying the effects of homocysteine (<jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>cy) neurotoxicity on the nervous system are not yet fully understood, inhibition of neural stem cell (<jats:styled-content style=\"fixed-case\">NSC<\/jats:styled-content>) proliferation and alterations in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation may be involved. The aim of the present study was to characterize the effects of <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>cy on <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation in <jats:styled-content style=\"fixed-case\">NSC<\/jats:styled-content>s, and to explore how <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>cy\u2010induced changes in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation patterns affect <jats:styled-content style=\"fixed-case\">NSC<\/jats:styled-content> proliferation. We found that <jats:sc>d<\/jats:sc>,<jats:sc>l<\/jats:sc>\u2010<jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>cy (30\u20131000\u00a0\u03bc<jats:sc>m<\/jats:sc>) but not <jats:sc>l<\/jats:sc>\u2010cysteine inhibited cell proliferation and reduced levels of global <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation in <jats:styled-content style=\"fixed-case\">NSC<\/jats:styled-content>s from neonatal rat hippocampus and increased cell injury. High levels of Hcy also induced an increase in <jats:italic>S<\/jats:italic>\u2010adenosylhomocysteine (<jats:styled-content style=\"fixed-case\">SAH<\/jats:styled-content>), a decrease in the ratio of <jats:italic>S\u2010<\/jats:italic>adenosylmethionine (<jats:styled-content style=\"fixed-case\">SAM<\/jats:styled-content>) to <jats:styled-content style=\"fixed-case\">SAH<\/jats:styled-content>, and a reduction in protein expression of the <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methyltransferases <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>1, <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3a and <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content>3b and their enzymatic activity. Moreover, the <jats:styled-content style=\"fixed-case\">DNMT<\/jats:styled-content> inhibitor zebularine reduced the global <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation level and inhibited <jats:styled-content style=\"fixed-case\">NSC<\/jats:styled-content> proliferation. Our results suggest that alterations in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation may be an important mechanism by which high levels of Hcy inhibit <jats:styled-content style=\"fixed-case\">NSC<\/jats:styled-content> viability <jats:italic>in\u00a0vitro<\/jats:italic>. Hcy\u2010induced <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> hypomethylation may be caused by a reduction in the DNMT activity which is regulated by the cellular concentrations of <jats:styled-content style=\"fixed-case\">SAM<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">SAH<\/jats:styled-content>, or their protein expression levels. Our results also suggest that <jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>cy may play a role in the pathogenesis of certain nervous system diseases via a molecular mechanism that involves negative regulation of <jats:styled-content style=\"fixed-case\">NSC<\/jats:styled-content> proliferation and alterations in <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> methylation.<\/jats:p>","DOI":"10.1111\/febs.12764","type":"journal-article","created":{"date-parts":[[2014,2,25]],"date-time":"2014-02-25T07:53:21Z","timestamp":1393314801000},"page":"2088-2096","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Homocysteine induces cytotoxicity and proliferation inhibition in neural stem cells via <scp>DNA<\/scp> methylation <i>in\u00a0vitro<\/i>"],"prefix":"10.1111","volume":"281","author":[{"given":"Ningning","family":"Lin","sequence":"first","affiliation":[{"name":"Department of 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