title: Identification of Guanosine 5'-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway.
abstract: Hepcidin, a peptide hormone, is a key regulator in mammalian iron homeostasis. Increased level of hepcidin due to inflammatory conditions stimulates the ferroportin (FPN) transporter internalization, impairing the iron absorption; clinically manifested as anemia of inflammation (AI). Inhibiting hepcidin-mediated FPN degradation is proposed as an important strategy to combat AI. A systematic approach involving in silico, in vitro, ex vivo and in vivo studies is employed to identify hepcidin-binding agents. The virtual screening of 68,752 natural compounds via molecular docking resulted into identification of guanosine 5'-diphosphate (GDP) as a promising hepcidin-binding agent. The molecular dynamics simulations helped to identify the important hepcidin residues involved in stabilization of hepcidin-GDP complex. The results gave a preliminary indication that GDP may possibly inhibit the hepcidin-FPN interactions. The in vitro studies revealed that GDP caused FPN stabilization (FPN-GFP cell lines) and increased the FPN-mediated cellular iron efflux (HepG2 and Caco-2 cells). Interestingly, the co-administration of GDP and ferrous sulphate (FeSO4) ameliorated the turpentine-induced AI in mice (indicated by increased haemoglobin level, serum iron, FPN expression and decreased ferritin level). These results suggest that GDP a promising natural small-molecule inhibitor that targets Hepcidin-FPN complex may be incorporated with iron supplement regimens to ameliorate AI.
authors.affiliation: National Agri-food Biotechnology Institute (NABI), S.A.S. Nagar, Punjab, India.
authors.forename: Stanzin
authors.initials: S
authors.lastname: Angmo
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab, India.
authors.forename: Neha
authors.initials: N
authors.lastname: Tripathi
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab, India.
authors.forename: Sheenu
authors.initials: S
authors.lastname: Abbat
authors.affiliation: National Agri-food Biotechnology Institute (NABI), S.A.S. Nagar, Punjab, India.
authors.forename: Shailesh
authors.initials: S
authors.lastname: Sharma
authors.affiliation: National Agri-food Biotechnology Institute (NABI), S.A.S. Nagar, Punjab, India.
authors.forename: Shelley Sardul
authors.initials: SS
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Panjab University, Chandigarh, India.
authors.forename: Avishek
authors.initials: A
authors.lastname: Halder
authors.affiliation: National Agri-food Biotechnology Institute (NABI), S.A.S. Nagar, Punjab, India.
authors.forename: Kamalendra
authors.initials: K
authors.lastname: Yadav
authors.affiliation: Department of Microbiology, Panjab University, Chandigarh, Punjab, India.
authors.forename: Geeta
authors.initials: G
authors.lastname: Shukla
authors.affiliation: Department of Biochemistry, Panjab University, Chandigarh, India.
authors.forename: Rajat
authors.initials: R
authors.lastname: Sandhir
authors.affiliation: National Agri-food Biotechnology Institute (NABI), S.A.S. Nagar, Punjab, India.
authors.forename: Vikas
authors.initials: V
authors.lastname: Rishi
authors.affiliation: National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Punjab, India.
authors.forename: Prasad V
authors.initials: PV
authors.lastname: Bharatam
authors.affiliation: National Institutes of Health (NIH), 9000 Rockville Pike, Bethesda, Maryland, USA.
authors.forename: Hariom
authors.initials: H
authors.lastname: Yadav
authors.affiliation: National Agri-food Biotechnology Institute (NABI), S.A.S. Nagar, Punjab, India.
authors.forename: Nitin Kumar
authors.initials: NK
authors.lastname: Singhal
mesh_terms: D018798:Anemia, Iron-Deficiency / Q000188:drug therapy; D000818:Animals; D018938:Caco-2 Cells; D027682:Cation Transport Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D006153:Guanosine Diphosphate / Q000378:metabolism*; D056945:Hep G2 Cells; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014131:Trace Elements / Q000378:metabolism*; D016896:Treatment Outcome; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D064451:Hepcidins; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014131:Trace Elements; D000098742:Ferroportin; D006153:Guanosine Diphosphate; D007501:Iron