Hepcidin Therapeutics

Κατσαρού, Αλεξάνδρα; Pantopoulos, Kostas

doi:10.3390/ph11040127

Cited by 76 publications

(79 citation statements)

References 184 publications

(205 reference statements)

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“…Most chronic liver diseases with iron overload outside the diagnosis of hereditary haemochromatosis have low serum hepcidin levels, and correction of the hepcidin deficiency by replacement or stimulation is an evolving management strategy . The objective is to restore iron homeostasis by decreasing duodenal absorption of iron and diminishing the release of ferric iron from intracellular storage sites.…”

Section: Resultsmentioning

confidence: 99%

“…The hepcidin molecule is difficult to synthesise because of its complex secondary structure, and management by replacement of the hepcidin molecule can be compromised by its rapid turnover . Small, biomimetic molecules that have hepcidin activity and the development of hepcidin agonists promise to improve management opportunities …”

Section: Resultsmentioning

confidence: 99%

“…In a hepcidin‐deficient murine model of severe haemochromatosis, minihepcidin has prevented hepatic iron deposition, reduced myocardial iron content, increased duodenal iron retention, and redistributed iron from the liver to the spleen . Proprietary preparations of synthetic human hepcidin are also being assessed in a similar fashion …”

Section: Resultsmentioning

confidence: 99%

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Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Czaja

2019

Aliment Pharmacol Ther

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Background: Disturbances in iron regulation have been described in diverse chronic liver diseases other than hereditary haemochromatosis, and iron toxicity may worsen liver injury and outcome. Aims:To describe manifestations and consequences of iron dysregulation in chronic liver diseases apart from hereditary haemochromatosis and to encourage investigations that clarify pathogenic mechanisms, define risk thresholds for iron toxicity, and direct management Methods: English abstracts were identified in PubMed by multiple search terms.Full length articles were selected for review, and secondary and tertiary bibliographies were developed.Results: Hyperferritinemia is present in 4%-65% of patients with non-alcoholic fatty liver disease, autoimmune hepatitis, chronic viral hepatitis, or alcoholic liver disease, and hepatic iron content is increased in 11%-52%. Heterozygosity for the C282Y mutation is present in 17%-48%, but this has not uniformly distinguished patients with adverse outcomes. An inappropriately low serum hepcidin level has characterised most chronic liver diseases with the exception of non-alcoholic fatty liver disease, and the finding has been associated mainly with suppression of transcriptional activity of the hepcidin gene. Iron overload has been associated with oxidative stress, advanced fibrosis and decreased survival, and promising therapies beyond phlebotomy and oral iron chelation have included hepcidin agonists. Conclusions:Iron dysregulation is common in chronic liver diseases other than hereditary haemochromatosis, and has been associated with liver toxicity and poor prognosis. Further evaluation of iron overload as a co-morbid factor should identify the key pathogenic disturbances, establish the risk threshold for iron toxicity, and promote molecular interventions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Czaja

2019

Aliment Pharmacol Ther

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“…Currently, there is considerable interest in strategies that target the HAMP/FPN axis for the treatment of diseases of iron overload (9). Our findings suggest that these strategies will additionally reduce iron reabsorption and increase renal iron content.…”

Section: Introductionmentioning

confidence: 67%

“…First, they suggest that strategies targeting the HAMP/FPN axis for the treatment of iron overload e.g. HAMP mimetics, FPN inhibitors, may reduce iron reabsorption and increase renal iron content (9). Second, they indicate that inhibition of iron reabsorption by HAMP may contribute to iron deficiency in the setting of chronic conditions, where HAMP is raised by inflammation, e.g.…”

Section: The Renal Hamp/fpn Axis Determines the Degree Of Renal And Hmentioning

confidence: 99%

The renal hepcidin/ferroportin axis controls iron reabsorption and determines renal and hepatic susceptibility to iron overload

Mohammad

Matakidou

Robbins

et al. 2020

Preprint

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ABSTRACTThe hepcidin/ferroportin axis controls systemic iron homeostasis by regulating iron acquisition from the duodenum and the reticuloendothelial system, respective sites of iron absorption and recycling. Ferroportin is also abundant in the kidney, where it has been implicated in iron reabsorption. However, it remains unknown whether hepcidin regulates ferroportin-mediated iron reabsorption and whether such regulation is important for systemic iron homeostasis. To address these questions, we generated a novel mouse model with an inducible renal-tubule specific knock-in of fpnC326Y, which encodes a hepcidin-resistant FPNC326Y. Under iron-replete conditions, female mice harbouring this allele had lower renal iron content and higher serum and liver iron levels than controls. Under conditions of excess iron availability, male and female mice harbouring this allele had greater liver iron overload, but lower renal iron overload relative to controls. In addition, hemochromatosis mice harbouring a ubiquitous knock-in of fpnC326Y did not develop renal iron overload otherwise seen in the setting of excess iron availability. These findings are the first formal demonstration that hepcidin regulates ferroportin-mediated iron reabsorption. They also show that loss of this regulation contributes to liver iron overload while protecting the kidney in the setting of hemochromatosis. Our findings have important implications. First, they indicate that targeting the hepcidin/ferroportin axis for treating iron overload disorders will inhibit iron reabsorption and increase renal iron content. Second, they suggest that inhibition of iron reabsorption by raised hepcidin in chronic inflammatory conditions contributes to iron deficiency and that parenteral iron supplementation in this setting may cause renal iron overload.

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Rifaximin protects SH‐SY5Y neuronal cells from iron overload‐induced cytotoxicity via inhibiting STAT3/NF‐κB signaling

Zhang

et al. 2022

Cell Biology International

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Acute or chronic liver disease‐caused liver failure is the cause of hepatic encephalopathy (HE), characterized by neuropsychiatric manifestations. Liver diseases potentially lead to peripheral iron metabolism dysfunction and surges of iron concentration in the brain, contributing to the pathophysiological process of degenerative disorders of the central nervous system. In this study, the mechanism of rifaximin treating HE was investigated. Ferric ammonium citrate (FAC)‐induced iron overload significantly reduced the proliferation and boosted the apoptosis in SH‐SY5Y cells through increasing reactive oxygen species (ROS) levels and inducing iron metabolism disorder. Rifaximin treatment could rectify the FAC‐induced iron overload and lipopolysaccharide (LPS)‐induced iron deposition, therefore, effectively protecting SH‐SY5Y cells from ROS‐induced cell injury and apoptosis. Signal transducer and activator of transcription 3 (STAT3)/nuclear factor‐kappa B (NF‐κB) signaling is involved in the protective function of rifaximin against LPS‐induced iron deposition. The therapeutic effect of rifaximin on HE associated with acute hepatic failure in mouse model was ascertained. In conclusion, Rifaximin could effectively protect SH‐SY5Y cells against injury caused by iron overload through the rectification of the iron metabolism disorder via the STAT3/NF‐κB signaling pathway.

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Hepcidin Therapeutics

Cited by 76 publications

References 184 publications

Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

Review article: iron disturbances in chronic liver diseases other than haemochromatosis – pathogenic, prognostic, and therapeutic implications

The renal hepcidin/ferroportin axis controls iron reabsorption and determines renal and hepatic susceptibility to iron overload

Rifaximin protects SH‐SY5Y neuronal cells from iron overload‐induced cytotoxicity via inhibiting STAT3/NF‐κB signaling

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