Identification of Guanosine 5'-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway.
Identification of Guanosine 5'-diphosphate as Potential Iron Mobilizer: Preventing the Hepcidin-Ferroportin Interaction and Modulating the Interleukin-6/Stat-3 Pathway.
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DOI：
10.1038/srep40097
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发表时间：
2017-01-05
影响因子：
4.6
通讯作者：
Singhal NK
中科院分区：
文献类型：
--
作者：
Angmo S;Tripathi N;Abbat S;Sharma S;Singh SS;Halder A;Yadav K;Shukla G;Sandhir R;Rishi V;Bharatam PV;Yadav H;Singhal NK
海普西丁是一种多肽激素，是哺乳动物铁稳态的关键调节因子。炎症引起的海普西丁水平升高刺激铁转运蛋白(FPN)转运体内化，损害铁的吸收；临床表现为炎症性贫血(AI)。抑制海普西丁介导的FPN降解被认为是对抗AI的重要策略。采用一种系统的方法，包括硅胶、体外、体外和体内研究，以确定庚西丁结合剂。通过分子对接对68,752种天然化合物进行虚拟筛选，结果表明鸟苷5‘-二磷酸(GDP)是一种很有前途的海普西丁结合剂。分子动力学模拟有助于确定参与稳定海普西丁-GDP复合体的重要的海普西丁残基。这一结果初步表明GDP可能抑制了海普西丁-FPN的相互作用。体外研究表明，GDP可使FPN稳定(FPN-GFP细胞系)，并增加FPN介导的细胞铁外流(HepG2和Caco-2细胞)。有趣的是，GDP和硫酸亚铁(FeSO4)联合给药改善了松节油诱导的小鼠的AI(表现为增加了血红蛋白水平、血清铁、FPN表达和降低了铁蛋白水平)。这些结果表明，GDP是一种很有前途的天然小分子抑制剂，靶向于海普西丁-FPN复合体，可以与补铁方案联合使用来改善AI。
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.
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影响因子：
20.3
作者：
Poli, Maura;Girelli, Domenico;Arosio, Paolo
通讯作者：
Arosio, Paolo
影响因子：
6.3
作者：
Sakamori, Ryotaro;Takehara, Tetsuo;Hayashi, Norio
通讯作者：
Hayashi, Norio
影响因子：
15.9
作者：
Babitt, Jodie L.;Huang, Franklin W.;Lin, Herbert Y.
通讯作者：
Lin, Herbert Y.
影响因子：
2.6
作者：
Coccia, MA;Cooke, K;Molineux, G
通讯作者：
Molineux, G
影响因子：
15.9
作者：
Nicolas, G;Chauvet, C;Vaulont, S
通讯作者：
Vaulont, S