In clinics, hepcidin levels are elevated in various anemia-related conditions, particularly in iron-refractory anemia and in high inflammatory states that suppress iron absorption, which remains an urgent unmet medical need. To identify effective treatment options for various types of iron-refractory anemia, the potential effect of hypoxia and pharmacologically-mimetic drug FG-4592 (Roxadustat) are evaluated, a hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) inhibitor, on mouse models of iron-refractory iron-deficiency anemia (IRIDA), anemia of inflammation and 5-fluorouracil-induced chemotherapy-related anemia. The potent protective effects of both hypoxia and FG-4592 on IRIDA as well as other 2 tested mouse cohorts are found. Mechanistically, it is demonstrated that hypoxia or FG-4592 could stabilize duodenal Hif2α, leading to the activation of Fpn transcription regardless of hepcidin levels, which in turn results in increased intestinal iron absorption and the amelioration of hepcidin-activated anemias. Moreover, duodenal Hif2α overexpression fully rescues phenotypes of Tmprss6 knockout mice, and Hif2α knockout in the gut significantly delays the recovery from 5-fluorouracil-induced anemia, which can not be rescued by FG-4592 treatment. Taken together, the findings of this study provide compelling evidence that targeting intestinal hypoxia-related pathways can serve as a potential therapeutic strategy for treating a broad spectrum of anemia, especially iron refractory anemia.
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http://dx.doi.org/10.1002/advs.202307022 | DOI Listing |
Turk J Pediatr
November 2024
Department of Pediatric Hematology, Faculty of Medicine, Hacettepe University, Ankara, Türkiye.
Background: Iron refractory iron deficiency anemia (IRIDA) is a rare autosomal recessive type of anemia characterized by unresponsiveness to oral iron therapy and partial response to parenteral iron therapy. In this article, we report the clinical presentation of four patients with IRIDA admitted to our clinic, including their laboratory values at admission and after oral and parenteral iron treatment, and the analysis of their mutation(s) in TMPRSS6 gene.
Case: Four patients from different families, aged between 3 and 14 years, two girls and two boys, two of whom were from consanguineous marriages, who were diagnosed with iron deficiency anemia in primary health care institutions and referred to our clinic because of inadequate response to oral iron treatment were included.
BMC Pediatr
November 2024
Department of Anatomy, Faculty of Medicine, University of Kelaniya, Colombo, Sri Lanka.
Background: The SLCO2A1 gene encodes a prostaglandin transporter and we report a novel mutation causing hypoproteinaemia and refractory anaemia due to chronic enteropathy.
Case Presentation: An 18-year-old boy of consanguineous parents was investigated for hypoproteinaemia and anaemia. He was short, pale and had generalised oedema.
FASEB Bioadv
August 2024
Department of Preemptive Medical Pharmacology for Mind and Body, Graduate School and School of Pharmaceutical Sciences Osaka University Suita Osaka Japan.
Chronic psychological stress has been reported to decrease circulating iron concentrations and impair hematopoiesis. However, the underlying mechanisms remain unclear. This study aimed to investigate the effects of psychological stress on biological iron metabolism by using the social defeat stress (SDS) model, a widely used model of depression.
View Article and Find Full Text PDFBr J Haematol
August 2024
Department of Pharmacology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Iron-refractory iron deficiency anaemia (IRIDA) is a rare autosomal recessive disorder, distinguished by hypochromic microcytic anaemia, low transferrin levels and inappropriately elevated hepcidin (HEPC) levels. It is caused by mutations in TMPRSS6 gene. Systematic screening of 500 pregnant women with iron deficiency anaemia having moderate to severe microcytosis with no other causes of anaemia were enrolled to rule out oral iron refractoriness.
View Article and Find Full Text PDFRinsho Ketsueki
July 2024
Department of Hematology, NHO Kyoto Medical Center.
The causes of iron deficiency anemia include blood loss, increased demand, insufficient dietary intake, and disorders affecting iron absorption. In certain circumstances, atrophic gastritis, either autoimmune or due to Helicobacter pylori infection, may contribute. On very rare occasions, iron-refractory iron deficiency anemia can develop as a consequence of TMPRSS6 mutations.
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