Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway

Angmo, Stanzin ; Tripathi, Neha ; Abbat, Sheenu ; Sharma, Shailesh ; Singh, Shelley Sardul ; Halder, Avishek ; Yadav, Kamalendra ; Shukla, Geeta ; Sandhir, Rajat ; Rishi, Vikas ; Bharatam, Prasad V. ; Yadav, Hariom ; Singhal, Nitin Kumar (2017) Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway Scientific Reports, 7 (1). ISSN 2045-2322

Full text not available from this repository.

Official URL: http://doi.org/10.1038/srep40097

Related URL: http://dx.doi.org/10.1038/srep40097

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.

Item Type:Article
Source:Copyright of this article belongs to PMC.
ID Code:116354
Deposited On:12 Apr 2021 09:26
Last Modified:12 Apr 2021 09:26

Repository Staff Only: item control page