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J. Liu et al.
strating that anemia was markedly ameliorated in β-tha- lassemia intermedia mice by our compounds through improving ineffective erythropoiesis. Collectively, these data support the potential of compounds 93, 165 and 156 as leads for treating complex iron overload disorders.
Our compounds have a distinct therapeutic profile from other hepcidin peptide mimics35 and chemical agonists.45 Hepcidin mimics, mini-hepcidin peptides, prevented iron overload in various mouse models, including Hamp1-/- mice,16 and also improved anemia and iron overload in β- thalassemic mice by improving ineffective erythropoiesis.17 Compared to these or full-length hepcidin, our compounds are much cheaper to synthesize and may be more readily modified for oral administration. Moreover, the develop- ment of hepcidin mimics is still in the experimental stage.16,17 Tmprss6 siRNA and Tmprss6 antisense oligonu- cleotides also diminished iron overload in Hfe-/- mice and improved ineffective erythropoiesis in β-thalassemic mice,46,47 but face challenges of cost of synthesis and lack of experience with the long-term administration of these classes of compounds. Only a few small molecular agonist candidates have been identified. Although genistein was found to stimulate hepcidin expression,48 it is a compound with a broad array of other activities. Our recent study demonstrated that two natural compounds, icariin and epimedin C, purified from Chinese medicinal plants, stim- ulated hepcidin expression.33 However, their purification and production on a large scale would be formidable.
As previously demonstrated, SMAD1/5/8 signaling fun- damentally determines baseline hepcidin expression under normal conditions.49,50 TMPRSS6 is crucially implicated in interactions with TFR2, HFE, hemojuvelin and BMP recep- tors in the suppression of hepcidin expression.51-54 Moreover, ERK1/2 phosphorylation was recently found to repress hepcidin expression by suppressing SMAD1/5/8 phosphorylation.28 In the current study, we discovered that hepcidin was upregulated at the transcriptional level through enhancement of SMAD1/5/8 phosphorylation as
observed reduced ERK phosphorylation in response to these hepcidin agonists. Thus, the reduction in TMPRSS6 and the diminished ERK1/2 phosphorylation presumably cooperated to increase hepcidin level, although their rela- tive contributions are not known thus far. However, no connection between P-ERK and TMPRSS6 was found in current literature. Nevertheless, more work should be done to elucidate the possible relationship between P-ERK and TMPRSS6 through SMAD1/5/8 signaling in fine-tuning hepcidin expression.
Erfe, Gdf15 and Twsg1 are stress erythropoiesis-respon- sive genes that suppress hepcidin expression, presumably to mobilize sufficient iron in support of erythropoiesis under various stresses associated with blood loss.32,55 In the present study, the expression of Erfe, Gdf15 and Twsg1 was significantly repressed in bone marrow cells from Wt and Hbbth3/+ mice responding to the administration of the inves- tigated compounds. These results suggest that our com- pounds also repressed Erfe, Gdf15 and Twsg1 to promote hepatic hepcidin expression. We conclude that our hep- cidin agonists induced hepcidin expression synergistically by a direct action on hepatocytes through SMAD1/5/8 sig- naling and by an indirect effect through erythroid cells.
To summarize, we here identified three promising hep- cidin agonists, compounds 93, 156 and 165. Although detailed pharmacological studies still need to be per- formed, the overall performance of these compounds to date warrants their further development for the treatment of HH, β-thalassemia and likely other iron disorders.
Acknowledgments
This work was supported by grants from the National Natural Science Foundation of China (grant numbers: 21425731, 21637004, 91543204, 91643204 and 21621064), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant number: XDB14000000), National Key Research and Development Program of China (grant number: 2016YFA0203103) and a grant under the national “973” pro- gram (grant number: 2014CB932000).
a result of the reduction of TMPRSS6,
and we also
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