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Hepcidin is a peptide hormone that targets the iron exporter ferroportin, thereby limiting iron entry into the bloodstream. It is generated in hepatocytes mainly in response to increased body iron stores or inflammatory cues. Iron stimulates expression of bone morphogenetic protein 6 (BMP6) from liver sinusoidal endothelial cells, which in turn binds to BMP receptors on hepatocytes and induces the SMAD signaling cascade for transcriptional activation of the hepcidin-encoding HAMP mRNA. SMAD signaling is also essential for inflammatory HAMP mRNA induction by the IL-6/STAT3 pathway. Herein, we utilized human Huh7 hepatoma cells and primary murine hepatocytes to assess the effects of iron perturbations on signaling to hepcidin. Iron chelation appeared to slightly impair signaling to hepcidin. Subsequent iron supplementation not only failed to reverse these effects, but drastically reduced basal HAMP mRNA and inhibited HAMP mRNA induction by BMP6 and/or IL-6. Thus, treatment of cells with excess iron inhibited basal and BMP6-mediated SMAD5 phosphorylation and induction of HAMP , ID1 and SMAD7 mRNAs in a dose-dependent manner. Iron also inhibited IL-6-mediated STAT3 phosphorylation and induction of HAMP and SOCS3 mRNAs. These responses were accompanied by induction of GCLC and HMOX1 mRNAs, known markers of oxidative stress. We conclude that hepatocellular iron overload suppresses hepcidin by inhibiting the SMAD and STAT3 signaling pathways downstream of their respective ligands.

Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art.

The liver is an organ that is particularly exposed to reactive oxygen species (ROS), which not only arise during metabolic functions but also during the biotransformation of xenobiotics. The disruption of redox balance causes oxidative stress, which affects liver function, modulates inflammatory pathways and contributes to disease. Thus, oxidative stress is implicated in acute liver injury and in the pathogenesis of prevalent infectious or metabolic chronic liver diseases such as viral hepatitis B or C, alcoholic fatty liver disease, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Moreover, oxidative stress plays a crucial role in liver disease progression to liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Herein, we provide an overview on the effects of oxidative stress on liver pathophysiology and the mechanisms by which oxidative stress promotes liver disease.

Iron overload is associated with various pathological changes which contribute to heart failure. Here, we examined mechanisms via which iron alters cardiomyocyte insulin sensitivity. Treatment of primary adult and neonatal cardiomyocytes as well as H9c2 cells with iron decreased insulin sensitivity determined via Western blotting or immunofluorescent detection of Akt and p70S6K phosphorylation and glucose uptake. Using CellROX deep red or DCF-DA probes we also observed that iron increased generation of reactive oxygen species (ROS), and that pretreatment with the superoxide dismutase mimetic MnTBAP reduced ROS production and attenuated iron-induced insulin resistance. SKQ1 and allopurinol but not apocynin reduced iron-induced ROS suggesting mitochondria and xanthine oxidase contribute to cellular ROS in response to iron. Western blotting for LC3-I, LC3-II and P62 levels as well as immunofluorescent co-detection of autophagosomes with Cyto-ID and lysosomal cathepsin activity indicated that iron attenuated autophagic flux without altering total expression of Atg7 or beclin-1 and phosphorylation of mTORC1 and ULK1. This conclusion was reinforced via protein accumulation detected using Click-iT HPG labelling after iron treatment. The adiponectin receptor agonist AdipoRon increased autophagic flux and improved insulin sensitivity both alone and in the presence of iron. We created an autophagy-deficient cell model by overexpressing a dominant-negative Atg5 mutant in H9c2 cells and this confirmed that reduced autophagy flux correlated with less insulin sensitivity. In conclusion, our study showed that iron promoted a cascade of ROS production, reduced autophagy and insulin resistance in cardiomyocytes.

The iron regulatory hormone hepcidin limits iron fluxes to the bloodstream by promoting degradation of the iron exporter ferroportin in target cells. Hepcidin insufficiency causes hyperabsorption of dietary iron, hyperferremia and tissue iron overload, which are hallmarks of hereditary hemochromatosis. Similar responses are also observed in iron-loading anemias due to ineffective erythropoiesis (such as thalassemias, dyserythropoietic anemias and myelodysplastic syndromes) and in chronic liver diseases. On the other hand, excessive hepcidin expression inhibits dietary iron absorption and leads to hypoferremia and iron retention within tissue macrophages. This reduces iron availability for erythroblasts and contributes to the development of anemias with iron-restricted erythropoiesis (such as anemia of chronic disease and iron-refractory iron-deficiency anemia). Pharmacological targeting of the hepcidin/ferroportin axis may offer considerable therapeutic benefits by correcting iron traffic. This review summarizes the principles underlying the development of hepcidin-based therapies for the treatment of iron-related disorders, and discusses the emerging strategies for manipulating hepcidin pathways.

The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in lipopolysaccharide (LPS)-treated wild type mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv -/- mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wild type animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv -/- mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen to stimulate f erroportin mRNA translation. Prolonged LPS treatment eliminated ferroportin mRNA and permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is a critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient when combined with iron depletion.

Background and purpose Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. Its role in cancer metastasis remains unclear. In this study, we aimed to investigate the potential involvement of ferroptosis in gastric cancer (GC) metastasis. Methods GC cells (AGS, MKN45, HGC27) were used to explore the role of ferroptosis in single and clustered cells with extracellular matrix (ECM) detachment in vitro. We overexpressed glutathione peroxidase 4 (GPX4) to inhibit ferroptosis and assessed the changes in cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Then tumor tissues from 54 GC patients with and without lymphatic metastasis were collected for immunohistochemical staining to investigate the expression of ferroptosis and EMT markers. Finally, Kaplan–Meier survival curves were used to investigate the relationship between overall survival and expression of GPX4 in 178 GC patients. Results Detached single cells had lower viability than adherent cells, but cell clustering improved their survival under matrix-detached conditions. Detached single cells exhibited an induction of iron-dependent reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, lipid peroxidation, upregulation of ACSL4, TFRC and HO-1, increased iron levels, and changes in mitochondrial morphology. Opposite effects were observed in detached clustered cells, including the upregulation of the ferroptosis suppressors GPX4 and SLC7A11. Overexpression of GPX4 inhibited ferroptosis and promoted GC cell proliferation, migration, invasion, and EMT. Immunohistochemical analysis of tumor tissues from GC patients indicated that lymphatic metastasis was associated with higher potential for ferroptosis inhibition and EMT induction. Finally, Kaplan–Meier survival curves demonstrated a significant decrease in overall survival among GC patients with high GPX4 expression. Conclusions Our study provides the first evidence that inhibition of ferroptosis is a crucial mechanism promoting GC metastasis. GPX4 may be a valuable prognostic factor for GC patients. These findings suggest that targeting ferroptosis inhibition may be a promising strategy for GC patients with metastatic potential. Trial registration The ethical approval code of this study in Institutional Review Board of Peking Union Medical College Hospital is No: K1447.

The survival, growth, and virulence of Leishmania spp., a group of protozoan parasites, depends on the proper access and regulation of iron. Macrophages, Leishmania’s host cell, may divert iron traffic by reducing uptake or by increasing the efflux of iron via the exporter ferroportin. This parasite has adapted by inhibiting the synthesis and inducing the degradation of ferroportin. To study the role of iron in leishmaniasis, we employed Hjv−/− mice, a model of hemochromatosis. The disruption of hemojuvelin (Hjv) abrogates the expression of the iron hormone hepcidin. This allows unrestricted iron entry into the plasma from ferroportin-expressing intestinal epithelial cells and tissue macrophages, resulting in systemic iron overload. Mice were injected with Leishmania major in hind footpads or intraperitoneally. Compared with wild-type controls, Hjv−/− mice displayed transient delayed growth of L. major in hind footpads, with a significant difference in parasite burden 4 weeks post-infection. Following acute intraperitoneal exposure to L. major, Hjv−/− peritoneal cells manifested increased expression of inflammatory cytokines and chemokines (Il1b, Tnfa, Cxcl2, and Ccl2). In response to infection with L. infantum, the causative agent of visceral leishmaniasis, Hjv−/− and control mice developed similar liver and splenic parasite burden despite vastly different tissue iron content and ferroportin expression. Thus, genetic iron overload due to hemojuvelin deficiency appears to mitigate the early development of only cutaneous leishmaniasis.

The objective of this study was to develop chitosan (CS) nanoparticles (NPs) loaded with deferoxamine mesylate (DFO) for slow release of this iron-chelating drug. Drug nanoencapsulation was performed via ionic gelation of chitosan using sodium tripolyphosphate (TPP) as cross-linker. Nanoparticles with a size ranging between 150 and 400 nm were prepared for neat CS/TPP with a 2/1 molar ratio while their yield was directly dependent on the applied stirring rate during the preparation process. DFO at different content (20, 45 and 75 wt %) was encapsulated into these nanoparticles. We found that drug loading correlates with increasing DFO content while the entrapment efficiency has an opposite behavior due to the high solubility of DFO. Hydrogen-bonding between amino and hydroxyl groups of DFO with reactive groups of CS were detected using FT-IR spectroscopy while X-ray diffraction revealed that DFO was entrapped in amorphous form in the CS nanoparticles. DFO release is directly dependent on the content of loaded drug, while model analysis revealed that the release mechanism of DFO for the CS/TPP nanoparticles is by diffusion. Treatment of murine RAW 264.7 macrophages with nanoencapsulated DFO promoted an increased expression of transferrin receptor 1 (TfR1) mRNA, a typical homeostatic response to iron deficiency. These data provide preliminary evidence for release of pharmacologically active DFO from the chitosan nanoparticles.

Hepcidin is an iron regulatory peptide hormone that is secreted from hepatocytes and inhibits iron efflux from tissues to plasma. Under inflammatory conditions, hepcidin is transcriptionally induced by IL-6/STAT3 signaling and promotes hypoferremia, an innate immune response to infection. If this pathway remains unresolved, chronic overexpression of hepcidin contributes to the anemia of inflammation, a common medical condition. Previous work showed that carbon monoxide (CO) releasing drugs (CORMs) can attenuate inflammatory induction of hepcidin. Because CO is physiologically generated during heme degradation by heme oxygenase 1 (HO-1), an IL-6-inducible enzyme with anti-inflammatory properties, we hypothesized that hepatocellular HO-1 may operate as a physiological feedback regulator of hepcidin that resolves inflammatory signaling. To address this, we generated and analyzed hepatocyte-specific HO-1 knockout (Hmox1Alb-Cre) mice. We show that these animals mount appropriate hepcidin-mediated hypoferremic response to LPS-induced inflammation, with kinetics similar to those of control Hmox1fl/fl mice. Likewise, primary hepatocytes from Hmox1Alb-Cre and Hmox1fl/fl mice exhibit similar degree and kinetics of hepcidin induction following IL-6 treatment. We conclude that hepatocellular HO-1 has no physiological function on hepcidin regulation by the inflammatory pathway.