{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T02:54:46Z","timestamp":1761101686567},"reference-count":33,"publisher":"American Society of Hematology","issue":"10","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,5,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Induction of fetal hemoglobin (Hb F) is an important therapeutic tool in ameliorating complications of sickle cell disease. Nitric oxide has been implicated in the mechanism of Hb F synthesis induced by hydroxyurea (HU). This study examined whether zileuton (ZL), a structural analog of hydroxyurea, possessed Hb F\u2013inducing properties and the potential role nitric oxide plays. ZL caused a dose-dependent increase in \u03b3-globin expression in K562 cells. This effect was confirmed by a dose-dependent increase in Hb F synthesis in erythroid progenitors from individuals with sickle cell anemia and normal hemoglobin genotypes. l-arginine had no effect on Hb F production; however, it dose-dependently inhibited ZL's ability to induce Hb F. The nitric oxide synthase inhibitor NG-monomethyl\u2013l-arginine (l-NMMA) inhibited l-arginine's effect and restored ZL-mediated increase in Hb F synthesis. In addition, 8-PCPT\u2013cGMP (8-(4-chlorophenylthio)guanosine 3\u2032,5\u2032-cyclic monophosphate) inhibited ZL-mediated induction of Hb F synthesis. When comparing l-NMMA effects alone on ZL and HU, a partial reversal of increased Hb F synthesis was seen only with HU. Neither l-arginine alone nor l-arginine in combination with l-NMMA effected hydroxyurea-mediated induction of Hb F synthesis. This study demonstrates that ZL induces Hb F through a mechanism that involves l-arginine\/nitric oxide\/cGMP in a manner distinctly different from HU.<\/jats:p>","DOI":"10.1182\/blood-2003-08-2969","type":"journal-article","created":{"date-parts":[[2004,2,9]],"date-time":"2004-02-09T20:23:35Z","timestamp":1076358215000},"page":"3945-3950","update-policy":"http:\/\/dx.doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":36,"title":["Zileuton induces hemoglobin F synthesis in erythroid progenitors: role of the l-arginine\u2013nitric oxide signaling pathway"],"prefix":"10.1182","volume":"103","author":[{"suffix":"Jr","given":"Johnson","family":"Haynes","sequence":"first","affiliation":[{"name":"From the Departments of Medicine, Pediatrics, Cell Biology, and Neuroscience, University of South Alabama Comprehensive Sickle Cell Center, Mobile, AL; and the Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B. Surendra","family":"Baliga","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine, Pediatrics, Cell Biology, and Neuroscience, University of South Alabama Comprehensive Sickle Cell Center, Mobile, AL; and the Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boniface","family":"Obiako","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine, Pediatrics, Cell Biology, and Neuroscience, University of South Alabama Comprehensive Sickle Cell Center, Mobile, AL; and the Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Solomon","family":"Ofori-Acquah","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine, Pediatrics, Cell Biology, and Neuroscience, University of South Alabama Comprehensive Sickle Cell Center, Mobile, AL; and the Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Betty","family":"Pace","sequence":"additional","affiliation":[{"name":"From the Departments of Medicine, Pediatrics, Cell Biology, and Neuroscience, University of South Alabama Comprehensive Sickle Cell Center, Mobile, AL; and the Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"key":"2020021219532498400_REF1","unstructured":"Carter GW, Young PR, Albert DH, et al. 5-Lipoxygenase inhibitory activity of zileuton. 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