Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
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Advances in Clinical and Experimental Medicine

2020, vol. 29, nr 4, April, p. 499–504

doi: 10.17219/acem/111807

Publication type: original article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Receptor-mediated attenuation of insulin-like growth factor-1 activity by galactose-1-phosphate in neonate skin fibroblast cultures: Galactosemia pathogenesis

Mazen Al-Essa1,A,B,C,D,E,F, Gursev Dhaunsi1,A,B,C,D,E,F

1 Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait

Abstract

Background. The pathogenesis of classical galactosemia, a rare metabolic disorder associated with developmental complications in neonates and children due to inherited deficiency of galactose-1-phosphate (Gal-1-P) uridylyltransferase (GALT), is known to be mediated by elevated Gal-1-P levels and involves a cascade of cytokines, reactive oxygen species (ROS) and growth factors.
Objectives. To examine ex vivo the effect of Gal-1-P on the mitogenic activity of different growth factors, particularly insulin-like growth factor-1 (IGF-1), known to regulate growth and development from the fetal stage to adulthood.
Material and Methods. Fibroblasts derived from the foreskin of 3–8-day-old healthy neonates were cultured for 1–14 days with 0–20 mM galactose or 0–10 mM Gal-1-P and then stimulated with 5% fetal bovine serum (FBS) or 50 ng/mL of platelet-derived growth factor (PDGF) or fibroblast growth factor (FGF) or IGF-1 for 24 h. DNA synthesis was measured and protein expression of PDGFR, FGFR and IGF-1R was assessed with western blotting.
Results. Supra-physiological concentrations of galactose significantly decreased FBSand IGF-1-induced BrdU incorporation. The presence of Gal-1-P (5–10 mM) in culture medium for 7–14 days significantly (p < 0.01) decreased IGF-1-, PDGFand FBS-stimulated DNA synthesis. While treatment with Gal-1-P selectively and significantly (p < 0.01) reduced the protein expression of IGF-1 receptor, galactose treatment did not have any marked effect on examined growth factor receptors.
Conclusion. This study demonstrates that Gal-1-P impairs IGF-1 activity through IGF-1-receptor impairment, thereby providing a new insight into the molecular mechanisms of galactosemia pathogenesis.

Key words

neonates, growth factors, DNA synthesis, IGF-1 receptor, galactosemia

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