New thiazolidinones reduce iron overload in mouse models of hereditary hemochromatosis and β-thalassemia
Open accessAbstract
Genetic iron-overload disorders, mainly hereditary hemochromatosis and untransfused β-thalassemia, affect a large population worldwide. The primary etiology of iron overload in these diseases is insufficient production of hepcidin by the liver, leading to excessive intestinal iron absorption and iron efflux from macrophages. Hepcidin agonists would therefore be expected to ameliorate iron overload in hereditary hemochromatosis and β-thalassemia. In the current study, we screened our synthetic library of 210 thiazolidinone compounds and identified three thiazolidinone compounds, 93, 156 and 165, which stimulated hepatic hepcidin production. In a hemochromatosis mouse model with hemochromatosis deficiency, the three compounds prevented the development of iron overload and elicited iron redistribution from the liver to the spleen. Moreover, these compounds also greatly ameliorated iron overload and mitigated ineffective erythropoiesis in β-thalassemic mice. Compounds 93, 156 and 165 acted by promoting SMAD1/5/8 signaling through differentially repressing ERK1/2 phosphorylation and decreasing transmembrane protease serine 6 activity. Additionally, compounds 93, 156 and 165 targeted erythroid regulators to strengthen hepcidin expression. Therefore, our hepcidin agonists induced hepcidin expression synergistically through a direct action on hepatocytes via SMAD1/5/8 signaling and an indirect action via eythroid cells. By increasing hepcidin production, thiazolidinone compounds may provide a useful alternative for the treatment of iron-overload disorders.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Some thiazolidinones have been shown to stimulate hepcidin activity in preclinical studies.
“Some thiazolidinones have been shown to stimulate hepcidin activity in preclinical studies.131”
From Iron metabolism and iron disorders revisited in the hepcidin era (2020) · cites this paper as [131]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Nemeth, E., Rivera, S., Gabayan, V., Keller, C., Taudorf, S., Pedersen, B. K., & Ganz, T. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420945 · Cited by 2,650 · see citing works
Self-citationIdentification of erythroferrone as an erythroid regulator of iron metabolism
Kautz, L., Jung, G., Valore, E. V., Rivella, S., Nemeth, E., & Ganz, T. (2014) · Nature Genetics · doi:10.1038/ng.2996 · Cited by 1,127 · see citing works
Self-citationBrissot, P., Pietrangelo, A., Adams, P. C., de Graaff, B., McLaren, C. E., & Loréal, O. (2018) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2018.16 · Cited by 430 · see citing works
Gao, J., Chen, J., Kramer, M., Tsukamoto, H., Zhang, A.-S., & Enns, C. A. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.01.010 · Cited by 326 · see citing works
Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis
Nicolas, G., Viatte, L., Lou, D.-Q., Bennoun, M., Beaumont, C., Kahn, A., Andrews, N. C., & Vaulont, S. (2003) · Nature Genetics · doi:10.1038/ng1150 · Cited by 311 · see citing works
Targeted disruption of the hepcidin 1 gene results in severe hemochromatosis
Lesbordes-Brion, J.-C., Viatte, L., Bennoun, M., Lou, D.-Q., Ramey, G., Houbron, C., Hamard, G., Kahn, A., & Vaulont, S. (2006) · Blood · doi:10.1182/blood-2006-02-003376 · Cited by 257 · see citing works
Preza, G. C., Ruchala, P., Pinon, R., Ramos, E., Qiao, B., Peralta, M. A., Sharma, S., Waring, A., Ganz, T., & Nemeth, E. (2011) · Journal of Clinical Investigation · doi:10.1172/jci57693 · Cited by 234 · see citing works
Self-citationHepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice
Gardenghi, S., Ramos, P., Marongiu, M. F., Melchiori, L., Breda, L., Guy, E., Muirhead, K., Rao, N., Roy, C. N., Andrews, N. C., et al. (2010) · Journal of Clinical Investigation · doi:10.1172/jci41717 · Cited by 220 · see citing works
Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis
Ramos, E., Ruchala, P., Goodnough, J. B., Kautz, L., Preza, G. C., Nemeth, E., & Ganz, T. (2012) · Blood · doi:10.1182/blood-2012-07-440743 · Cited by 213 · see citing works
Self-citationHou, Y., Zhang, S., Wang, L., Li, J., Qu, G., He, J., Rong, H., Ji, H., & Liu, S. (2012) · Gene · doi:10.1016/j.gene.2012.09.060 · Cited by 210 · see citing works
Corradini, E., Meynard, D., Wu, Q., Chen, S., Ventura, P., Pietrangelo, A., & Babitt, J. L. (2011) · Hepatology · doi:10.1002/hep.24359 · Cited by 194 · see citing works
Minihepcidin peptides as disease modifiers in mice affected by β-thalassemia and polycythemia vera
Casu, C., Oikonomidou, P. R., Chen, H., Nandi, V., Ginzburg, Y., Prasad, P., Fleming, R. E., Shah, Y. M., Valore, E. V., Nemeth, E., et al. (2016) · Blood · doi:10.1182/blood-2015-10-676742 · Cited by 148 · see citing works
Decreased hepcidin mRNA expression in thalassemic mice
Adamsky, K., Weizer, O., Amariglio, N., Breda, L., Harmelin, A., Rivella, S., Rachmilewitz, E., & Rechavi, G. (2004) · British Journal of Haematology · doi:10.1046/j.1365-2141.2003.04734.x · Cited by 108 · cited 1× · see citing works
“The common mechanism is lower level of hepcidin compared to that in Wt mice, giving rise to enhanced dietary iron uptake and iron egress out of macrophages and consequently iron deposition in various organs, especially the liver.(36,43) However in β-thalassemias, unlike in HH, ineffective erythropoiesis and hemolysis…”
BackgroundThe small molecule, genistein, increases hepcidin expression in human hepatocytes
Zhen, A. W., Nguyen, N. H., Gibert, Y., Motola, S., Buckett, P., Wessling-Resnick, M., Fraenkel, E., & Fraenkel, P. G. (2013) · Hepatology · doi:10.1002/hep.26490 · Cited by 74 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Iron metabolism and iron disorders revisited in the hepcidin era
Camaschella, C., Nai, A., & Silvestri, L. (2020) · Haematologica · doi:10.3324/haematol.2019.232124 · Cited by 734 · see citing works
- Authors
- Liu, J., Liu, W., Liu, Y., Miao, Y., Guo, Y., Song, H., Wang, F., Zhou, H., Ganz, T., Yan, B., & Liu, S.
- Affiliations
- Chinese Academy of Sciences (CN)
- Shandong University (CN)
- Zhejiang University (CN)
- Guangzhou University (CN)
- University of California, Los Angeles (US)
- Corresponding author
- Yan, Bing
- Liu, Sijin
- Venue
- Haematologica
- Published
- 2019-02-21
- Volume
- 104
- Issue
- 9
- Pages
- 1768-1781
- ISSN
- 0390-6078 (ISSN-L)
- 1592-8721
- PMC
- PMC6717595
- OpenAlex
- W2915137839
- Cited by
- 30
- References
- 14
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 4 · 2020: 7 · 2019: 2
- FWCI
- 3.53
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Haematologica (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- Funders
- National Natural Science Foundation of China (2014CB932000, 21425731, 91643204, 21637004, XDB14000000, 21621064, 91543204)
- Chinese Academy of Sciences (21621064, 21637004, XDB14000000, 21425731)
- National Key Research and Development Program of China (2016YFA0203103, 21621064, 2014CB932000)
- Topics
- Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
- Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
- Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
- Keywords
- thiazolidinones, iron overload, hereditary hemochromatosis, beta-thalassemia, Smad1/5/8 signaling, ERK1/2 phosphorylation, TMPRSS6, ineffective erythropoiesis, erythroid cells, hepatocytes, iron redistribution
- MeSH terms
- Animals, Chemistry, Pharmaceutical, Disease Models, Animal, Erythropoiesis, Hemochromatosis, Liver, Male, Phosphorylation, Drug Design, Signal Transduction, beta-Thalassemia, Iron Overload, Combinatorial Chemistry Techniques, Thiazolidinediones, Mice, Hepcidins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
