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      In vivo antimalarial activity of synthetic hepcidin against Plasmodium berghei in mice

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          Abstract

          The present study was designed to investigate the antimalarial activity of synthetic hepcidin and its effect on cytokine secretion in mice infected with Plasmodium berghei. The mice were infected with P. berghei intravenously and treated with hepcidin according to 4-day suppression test and Rane’s test. The serum levels of interleukins (IL-1 β, IL-2, IL-6, IL-10, IL-12p70, and IL-17A), tumor necrosis factor- α (TNF- α), and interferon- γ (IFN- γ) in the experimental mice were determined using a cytometric bead array (CBA) kit. The survival rate of the infected mice was also registered. Additionally, the serum iron, alanine transaminase (ALT), aspartate transaminase (AST), and total bilirubin (BIL) were detected to evaluate liver functions. Hepcidin exerted direct anti-malarial function in vivo and increased survival rate in a dose-dependent manner. In addition, the secretion of T helper cell type 1 (Th1), Th2, and Th17 cytokines, TNF- α, and IFN- γ were inhibited by hepcidin. In conclusion, our results demonstrated that synthetic hepcidin exerts in vivo antimalarial activity and possesses anti-inflammatory function, which provides a basis for future design of new derivatives with ideal anti-malarial activity.

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          Most cited references 14

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          LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.

          We report the isolation and characterization of a novel human peptide with antimicrobial activity, termed LEAP-1 (liver-expressed antimicrobial peptide). Using a mass spectrometric assay detecting cysteine-rich peptides, a 25-residue peptide containing four disulfide bonds was identified in human blood ultrafiltrate. LEAP-1 expression was predominantly detected in the liver, and, to a much lower extent, in the heart. In radial diffusion assays, Gram-positive Bacillus megaterium, Bacillus subtilis, Micrococcus luteus, Staphylococcus carnosus, and Gram-negative Neisseria cinerea as well as the yeast Saccharomyces cerevisiae dose-dependently exhibited sensitivity upon treatment with synthetic LEAP-1. The discovery of LEAP-1 extends the known families of mammalian peptides with antimicrobial activity by its novel disulfide motif and distinct expression pattern.
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            Interleukin-6 induces hepcidin expression through STAT3.

            Iron homeostasis is maintained through meticulous regulation of circulating hepcidin levels. Hepcidin levels that are inappropriately low or high result in iron overload or iron deficiency, respectively. Although hypoxia, erythroid demand, iron, and inflammation are all known to influence hepcidin expression, the mechanisms responsible are not well defined. In this report we show that the inflammatory cytokine interleukin-6 (IL-6) directly regulates hepcidin through induction and subsequent promoter binding of signal transducer and activator of transcription 3 (STAT3). STAT3 is necessary and sufficient for the IL-6 responsiveness of the hepcidin promoter. Our findings provide a mechanism by which hepcidin can be regulated by inflammation or, in the absence of inflammatory stimuli, by alternative mechanisms leading to STAT3 activation.
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              Host-mediated regulation of superinfection in malaria.

              In regions of high rates of malaria transmission, mosquitoes repeatedly transmit liver-tropic Plasmodium sporozoites to individuals who already have blood-stage parasitemia. This manifests itself in semi-immune children (who have been exposed since birth to Plasmodium infection and as such show low levels of peripheral parasitemia but can still be infected) older than 5 years of age by concurrent carriage of different parasite genotypes at low asymptomatic parasitemias. Superinfection presents an increased risk of hyperparasitemia and death in less immune individuals but counterintuitively is not frequently observed in the young. Here we show in a mouse model that ongoing blood-stage infections, above a minimum threshold, impair the growth of subsequently inoculated sporozoites such that they become growth arrested in liver hepatocytes and fail to develop into blood-stage parasites. Inhibition of the liver-stage infection is mediated by the host iron regulatory hormone hepcidin, whose synthesis we found to be stimulated by blood-stage parasites in a density-dependent manner. We mathematically modeled this phenomenon and show how density-dependent protection against liver-stage malaria can shape the epidemiological patterns of age-related risk and the complexity of malaria infections seen in young children. The interaction between these two Plasmodium stages and host iron metabolism has relevance for the global efforts to reduce malaria transmission and for evaluation of iron supplementation programs in malaria-endemic regions.
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                Author and article information

                Journal
                CJNM
                Chinese Journal of Natural Medicines
                Elsevier
                1875-5364
                20 March 2017
                : 15
                : 3
                : 161-167
                Affiliations
                1College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, China
                2Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
                3University of Chinese Academy of Sciences, Beijing 100009, China
                Author notes
                *Corresponding authors: LAI Ren, Tel/Fax: 86-25-84396849, E-mail: rlai72@ 123456njau.edu.cn ; YAN Xiu-Wen, yanxw@ 123456njau.edu.cn

                ΔCo-first author

                These authors have no conflict of interest to declare.

                Article
                S1875-5364(17)30032-8
                10.1016/S1875-5364(17)30032-8
                Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.
                Funding
                Funded by: China National Natural Science Foundation of Young Scientists
                Award ID: 31201717
                Funded by: Special Foundation for Young Scientists of Jiangsu Province
                Award ID: BK2012365
                Funded by: Jiangsu Province Science and Technology Support Project
                Award ID: BE2012748
                This work was supported by the grants from China National Natural Science Foundation of Young Scientists (No. 31201717), Special Foundation for Young Scientists of Jiangsu Province (No. BK2012365), Jiangsu Province Science and Technology Support Project (No. BE2012748).
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