title: Downregulation of Insulin-Like Growth Factor-1 via Nitric Oxide Production in a Hypergalactosemic Model of Neonate Skin Fibroblast Cultures.
abstract: Galactosemia is a severe metabolic disorder known to cause hepatosplenomegaly, jaundice and cataracts in neonates, and many patients develop later complications such as mental retardation, disorders of motor function or speech, and hypergonadotrophic hypogonadism. The pathogenetic mechanisms of classical galactosemia are unclear; however, nitric oxide (NO) has been suggested to play a role.
  
  
  
  Insulin-like growth factor-1 (IGF-1) is important for the growth and development of children, and the aim of this study was to examine the association of NO production with IGF-1 gene expression under galactosemic conditions.
  
  
  
  Serum levels of IGF-1 and nitrite were measured in 15 galactosemia patients and 15 age- and gender-matched healthy controls. Fibroblast cultures established from postcircumcision foreskin of 3- to 8-day-old healthy neonates were treated for 72 h with 0-10 mM of galactose or 0-5 mM of galactose-1-phosphate (Gal-1-P) in the presence or absence of NO synthase inhibitor (L-NAME), and inducible NO synthase (iNOS) protein was measured using Western blot analysis. RT-PCR was performed to assess the IGF-1 gene expression.
  
  
  
  Galactosemia patients were observed to have significantly (p < 0.01) elevated serum nitrites and markedly decreased levels (p < 0.01) of serum IGF-1 as compared to healthy controls. The cotreatment of neonate skin fibroblast cultures with galactose and Gal-1-P significantly (p < 0.01) increased cellular levels of NO and iNOS protein expression, and decreased (p < 0.01) IGF-1 mRNA levels. Treatment with L-NAME, a NOS inhibitor, significantly (p < 0.05) alleviated a galactose/Gal-1-P-induced decrease in IGF-1 mRNA levels.
  
  
  
  These results suggest that NO mediates the downregulation of IGF-1 by Gal-1-P/galactose, thereby providing a new molecular mechanism and possible therapeutic insight for galactosemia-related complications.
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait.
authors.forename: Gursev S
authors.initials: GS
authors.lastname: Dhaunsi
authors.forename: Mazen
authors.initials: M
authors.lastname: Al-Essa
mesh_terms: D016022:Case-Control Studies; D002478:Cells, Cultured; D002675:Child, Preschool; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005347:Fibroblasts / Q000187:drug effects*; D005693:Galactosemias / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005695:Galactosephosphates; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007223:Infant; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D007730:Kuwait; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D005695:Galactosephosphates; D012333:RNA, Messenger; D009569:Nitric Oxide; D007334:Insulin-Like Growth Factor I; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester