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

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 hepc...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214259/
https://www.ncbi.nlm.nih.gov/pubmed/28054602
http://dx.doi.org/10.1038/srep40097
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author 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
author_facet 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
author_sort Angmo, Stanzin
collection PubMed
description 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 (FeSO(4)) 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.
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spelling pubmed-52142592017-01-09 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 Sci Rep Article 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 (FeSO(4)) 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. Nature Publishing Group 2017-01-05 /pmc/articles/PMC5214259/ /pubmed/28054602 http://dx.doi.org/10.1038/srep40097 Text en Copyright © 2017, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
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
Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway
title Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway
title_full Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway
title_fullStr Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway
title_full_unstemmed Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway
title_short Identification of Guanosine 5′-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway
title_sort identification of guanosine 5′-diphosphate as potential iron mobilizer: preventing the hepcidin-ferroportin interaction and modulating the interleukin-6/stat-3 pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214259/
https://www.ncbi.nlm.nih.gov/pubmed/28054602
http://dx.doi.org/10.1038/srep40097
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