{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T03:42:48Z","timestamp":1777434168898,"version":"3.51.4"},"reference-count":74,"publisher":"SAGE Publications","issue":"14","license":[{"start":{"date-parts":[[2015,11,1]],"date-time":"2015-11-01T00:00:00Z","timestamp":1446336000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antioxidants &amp; Redox Signaling"],"published-print":{"date-parts":[[2015,11]]},"abstract":"<jats:p>\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Aims:<\/jats:italic>\n                    <\/jats:bold>\n                    Glutathione (GSH) is the main antioxidant against cell damage. Several pathological states course with reduced nucleophilic tone and perturbation of redox homeostasis due to changes in the 2GSH\/GSSG ratio. Here, we investigated the regulation of the rate-limiting GSH biosynthetic heterodimeric enzyme \u03b3-glutamyl-cysteine ligase (GCL) by microRNAs (miRNAs).\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Results:<\/jats:italic>\n                    <\/jats:bold>\n                    \u201c\n                    <jats:italic toggle=\"yes\">In silico<\/jats:italic>\n                    \u201d analysis of the 3\u2032- untranslated regions (UTRs) of both catalytic (GCLc) and regulatory (GCLm) subunits of GCL enabled an identification of miR-433 as a strong candidate for the targeting of GCL. Transitory overexpression of miR-433 in human umbilical vein endothelial cells (HUVEC) showed a downregulation of both GCLc and GCLm in a nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-independent manner. Increases in pro-oxidant stimuli such as exposure to hydrogen peroxide or GSH depletion in endothelial and hepatic cells caused an expected increase in GCLc and GCLm protein expression and abrogation of miR-433 levels, thus supporting a cross-regulation of these pathways. Treatment of HUVEC with miR-433 resulted in reduced antioxidant and redox potentials, increased S-glutathionylation, and reduced endothelial nitric oxide synthase activation.\n                    <jats:italic toggle=\"yes\">In vivo<\/jats:italic>\n                    models of renal and hepatic fibrosis were associated with transforming growth factor \u03b21 (TGF-\u03b21)-related reduction of GCLc and GCLm levels that were miR-433 dependent.\n                    <jats:bold>\n                      <jats:italic toggle=\"yes\">Innovation and Conclusion:<\/jats:italic>\n                    <\/jats:bold>\n                    We describe for the first time an miRNA, miR-433, capable of directly targeting GCL and promoting functional consequences in endothelial physiology and fibrotic processes by decreasing GSH levels.\n                    <jats:italic toggle=\"yes\">Antioxid. Redox Signal.<\/jats:italic>\n                    23, 1092\u20131105.\n                  <\/jats:p>","DOI":"10.1089\/ars.2014.6025","type":"journal-article","created":{"date-parts":[[2014,10,29]],"date-time":"2014-10-29T15:11:59Z","timestamp":1414595519000},"page":"1092-1105","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":44,"title":["Targeting of Gamma-Glutamyl-Cysteine Ligase by miR-433 Reduces Glutathione Biosynthesis and Promotes TGF-\u03b2-Dependent Fibrogenesis"],"prefix":"10.1177","volume":"23","author":[{"given":"Cristina","family":"Espinosa-Diez","sequence":"first","affiliation":[{"name":"\u201d Consejo Superior de Investigaciones Cient\u00edficas\u2013Universidad Aut\u00f3noma de Madrid","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Fierro-Fern\u00e1ndez","sequence":"additional","affiliation":[{"name":"\u201d Consejo Superior de Investigaciones 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