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Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research 2.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 11965

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Guest Editor
Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Pécs, H-7624 Pécs, Hungary
Interests: CX3CL1-CX3CR1 axis; inflammation; signal transduction; macrophages; microglia; neurodegenerative diseases; iron-related disorders; reproduction
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Special Issue Information

Dear Colleagues,

Iron is essential in many biological processes in the human body; therefore, iron metabolism is strictly controlled to maintain systemic iron balance. The major regulator of iron homeostasis is the peptide hormone hepcidin, which regulates iron release from the cells via its receptor ferroportin. The balance between labile iron pool and iron storage using ferritin is crucial to maintain proper cellular mechanisms by preventing iron-mediated oxidative damage. In recent years, iron-related disorders, iron-overload diseases, and iron-deficient diseases have been under deep examination to develop new and efficient therapies. The disturbances of iron metabolism are also implicated in neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, as well as in metabolic disorders such as diabetes or thyroid diseases. Identification of new regulatory mechanisms of hepcidin or iron-related genes may reveal new therapeutic targets.

The aim of this Special Issue is to obtain novel findings in the field of regulation of iron metabolism and related disorders at cellular or physiological levels.

Dr. Edina Pandur
Guest Editor

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Keywords

  • iron
  • hepcidin
  • ferroportin
  • ferritin
  • regulation
  • anemia
  • therapies
  • cell signaling
  • inflammation
  • disorders

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Published Papers (6 papers)

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Research

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10 pages, 2890 KiB  
Article
Elevated Hepcidin Expression in Human Carotid Atheroma: Sex-Specific Differences and Associations with Plaque Vulnerability
by Xi-Ming Yuan, Nargis Sultana, Moumita Ghosh-Laskar and Wei Li
Int. J. Mol. Sci. 2024, 25(3), 1706; https://doi.org/10.3390/ijms25031706 - 30 Jan 2024
Viewed by 965
Abstract
Hepcidin is upregulated by increased body iron stores and inflammatory cytokines. It is associated with cardiovascular events, arterial stiffness, and increased iron accumulation in human atheroma with hemorrhage. However, it is unknown whether the expression of hepcidin in human carotid plaques is related [...] Read more.
Hepcidin is upregulated by increased body iron stores and inflammatory cytokines. It is associated with cardiovascular events, arterial stiffness, and increased iron accumulation in human atheroma with hemorrhage. However, it is unknown whether the expression of hepcidin in human carotid plaques is related to plaque severity and whether hepcidin expression differs between men and women. Carotid samples from 58 patients (38 males and 20 females) were immunostained with hepcidin, macrophages, ferritin, and transferrin receptor. Immunocytochemistry of hepcidin was performed on THP-1 macrophages exposed to iron or 7betahydroxycholesterol. Hepcidin expression significantly increases with the progression of human atherosclerotic plaques. Plaques of male patients have significantly higher levels of hepcidin. Expressions of hepcidin are significantly correlated with the accumulation of CD68-positive macrophages and transferrin receptor 1 (TfR1) and apoptosis. In vitro, hepcidin is significantly increased in macrophages exposed to iron and moderately increased following 7-oxysterol treatment. In the cultured cells, suppression of hepcidin protected against macrophage cell death, lysosomal membrane permeabilization, and oxidative stress. Hepcidin may play a crucial role in the development and progression of atherosclerosis. The differential expression of hepcidin in male and female patients and its significant correlations with plaque severity, highlight the potential of hepcidin as a biomarker for risk stratification and therapeutic targeting in atherosclerosis. Full article
(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research 2.0)
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16 pages, 3208 KiB  
Article
Oral Iron Absorption of Ferric Citrate Hydrate and Hepcidin-25 in Hemodialysis Patients: A Prospective, Multicenter, Observational Riona-Oral Iron Absorption Trial
by Naohisa Tomosugi, Yoshitaka Koshino, Chie Ogawa, Kunimi Maeda, Noriaki Shimada, Kimio Tomita, Shoichiro Daimon, Tsutomu Shikano, Kazuyuki Ryu, Toru Takatani, Kazuya Sakamoto, Satonori Ueyama, Daisuke Nagasaku, Masato Nakamura, Shibun Ra, Masataka Nishimura, Chieko Takagi, Yoji Ishii, Noritoshi Kudo, Shinsuke Takechi, Takashi Ishizu, Takamoto Yanagawa, Masamichi Fukuda, Yutaka Nitta, Takayuki Yamaoka, Taku Saito, Suzuko Imayoshi, Momoyo Omata, Joji Oshima, Akira Onozaki, Hiroaki Ichihashi, Yasuhisa Matsushima, Hisahito Takae, Ryoichi Nakazawa, Koichi Ikeda, Masato Tsuboi, Keiko Konishi, Shouzaburo Kato, Maki Ooura, Masaki Koyama, Tsukasa Naganuma, Makoto Ogi, Shigeyuki Katayama, Toshiaki Okumura, Shigemi Kameda and Sayuri Shiraiadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2023, 24(18), 13779; https://doi.org/10.3390/ijms241813779 - 7 Sep 2023
Viewed by 1304
Abstract
Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at [...] Read more.
Oral ferric citrate hydrate (FCH) is effective for iron deficiencies in hemodialysis patients; however, how iron balance in the body affects iron absorption in the intestinal tract remains unclear. This prospective observational study (Riona-Oral Iron Absorption Trial, R-OIAT, UMIN 000031406) was conducted at 42 hemodialysis centers in Japan, wherein 268 hemodialysis patients without inflammation were enrolled and treated with a fixed amount of FCH for 6 months. We assessed the predictive value of hepcidin-25 for iron absorption and iron shift between ferritin (FTN) and red blood cells (RBCs) following FCH therapy. Serum iron changes at 2 h (ΔFe2h) after FCH ingestion were evaluated as iron absorption. The primary outcome was the quantitative delineation of iron variables with respect to ΔFe2h, and the secondary outcome was the description of the predictors of the body’s iron balance. Generalized estimating equations (GEEs) were used to identify the determinants of iron absorption during each phase of FCH treatment. ΔFe2h increased when hepcidin-25 and TSAT decreased (−0.459, −0.643 to −0.276, p = 0.000; −0.648, −1.099 to −0.197, p = 0.005, respectively) in GEEs. FTN increased when RBCs decreased (−1.392, −1.749 to −1.035, p = 0.000) and hepcidin-25 increased (0.297, 0.239 to 0.355, p = 0.000). Limiting erythropoiesis to maintain hemoglobin levels induces RBC reduction in hemodialysis patients, resulting in increased hepcidin-25 and FTN levels. Hepcidin-25 production may prompt an iron shift from RBC iron to FTN iron, inhibiting iron absorption even with continued FCH intake. Full article
(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research 2.0)
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Review

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20 pages, 2157 KiB  
Review
Sigma Receptors: Novel Regulators of Iron/Heme Homeostasis and Ferroptosis
by Nhi T. Nguyen, Valeria Jaramillo-Martinez, Marilyn Mathew, Varshini V. Suresh, Sathish Sivaprakasam, Yangzom D. Bhutia and Vadivel Ganapathy
Int. J. Mol. Sci. 2023, 24(19), 14672; https://doi.org/10.3390/ijms241914672 - 28 Sep 2023
Cited by 2 | Viewed by 1787
Abstract
Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their [...] Read more.
Sigma receptors are non-opiate/non-phencyclidine receptors that bind progesterone and/or heme and also several unrelated xenobiotics/chemicals. They reside in the plasma membrane and in the membranes of the endoplasmic reticulum, mitochondria, and nucleus. Until recently, the biology/pharmacology of these proteins focused primarily on their role in neuronal functions in the brain/retina. However, there have been recent developments in the field with the discovery of unexpected roles for these proteins in iron/heme homeostasis. Sigma receptor 1 (S1R) regulates the oxidative stress-related transcription factor NRF2 and protects against ferroptosis, an iron-induced cell death process. Sigma receptor 2 (S2R), which is structurally unrelated to S1R, complexes with progesterone receptor membrane components PGRMC1 and PGRMC2. S2R, PGRMC1, and PGRMC2, either independently or as protein–protein complexes, elicit a multitude of effects with a profound influence on iron/heme homeostasis. This includes the regulation of the secretion of the iron-regulatory hormone hepcidin, the modulation of the activity of mitochondrial ferrochelatase, which catalyzes iron incorporation into protoporphyrin IX to form heme, chaperoning heme to specific hemoproteins thereby influencing their biological activity and stability, and protection against ferroptosis. Consequently, S1R, S2R, PGRMC1, and PGRMC2 potentiate disease progression in hemochromatosis and cancer. These new discoveries usher this intriguing group of non-traditional progesterone receptors into an unchartered territory in biology and medicine. Full article
(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research 2.0)
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13 pages, 2232 KiB  
Review
Using Mendelian Randomization to Study the Role of Iron in Health and Disease
by Tara Zeitoun and Ahmed El-Sohemy
Int. J. Mol. Sci. 2023, 24(17), 13458; https://doi.org/10.3390/ijms241713458 - 30 Aug 2023
Cited by 2 | Viewed by 3306
Abstract
Iron has been shown to play a dual role in health and disease, with either a protective or harmful effect. Some of the contradictory findings from observational studies may be due to reverse causation, residual confounding, or small sample size. One approach that [...] Read more.
Iron has been shown to play a dual role in health and disease, with either a protective or harmful effect. Some of the contradictory findings from observational studies may be due to reverse causation, residual confounding, or small sample size. One approach that may overcome these limitations without the high cost of randomized control trials is the use of Mendelian randomization to examine the long-term role of iron in a variety of health outcomes. As there is emerging evidence employing Mendelian randomization as a method of assessing the role of micronutrients in health and disease, this narrative review will highlight recent Mendelian randomization findings examining the role of iron in cardiometabolic disorders, inflammation, neurological disorders, different cancers, and a number of other health-related outcomes. Full article
(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research 2.0)
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30 pages, 2097 KiB  
Review
The Regulation of Ferroptosis by Noncoding RNAs
by Xiangnan Zheng and Cen Zhang
Int. J. Mol. Sci. 2023, 24(17), 13336; https://doi.org/10.3390/ijms241713336 - 28 Aug 2023
Cited by 3 | Viewed by 2264
Abstract
As a novel form of regulated cell death, ferroptosis is characterized by intracellular iron and lipid peroxide accumulation, which is different from other regulated cell death forms morphologically, biochemically, and immunologically. Ferroptosis is regulated by iron metabolism, lipid metabolism, and antioxidant defense systems [...] Read more.
As a novel form of regulated cell death, ferroptosis is characterized by intracellular iron and lipid peroxide accumulation, which is different from other regulated cell death forms morphologically, biochemically, and immunologically. Ferroptosis is regulated by iron metabolism, lipid metabolism, and antioxidant defense systems as well as various transcription factors and related signal pathways. Emerging evidence has highlighted that ferroptosis is associated with many physiological and pathological processes, including cancer, neurodegeneration diseases, cardiovascular diseases, and ischemia/reperfusion injury. Noncoding RNAs are a group of functional RNA molecules that are not translated into proteins, which can regulate gene expression in various manners. An increasing number of studies have shown that noncoding RNAs, especially miRNAs, lncRNAs, and circRNAs, can interfere with the progression of ferroptosis by modulating ferroptosis-related genes or proteins directly or indirectly. In this review, we summarize the basic mechanisms and regulations of ferroptosis and focus on the recent studies on the mechanism for different types of ncRNAs to regulate ferroptosis in different physiological and pathological conditions, which will deepen our understanding of ferroptosis regulation by noncoding RNAs and provide new insights into employing noncoding RNAs in ferroptosis-associated therapeutic strategies. Full article
(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research 2.0)
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13 pages, 1821 KiB  
Review
The Ferritin, Hepcidin and Cytokines Link in the Diagnoses of Iron Deficiency Anaemia during Pregnancy: A Review
by Yvonne Chibanda, Matthew Brookes, David Churchill and Hafid Al-Hassi
Int. J. Mol. Sci. 2023, 24(17), 13323; https://doi.org/10.3390/ijms241713323 - 28 Aug 2023
Cited by 1 | Viewed by 1815
Abstract
Following a diagnosis of iron deficiency anaemia in pregnancy, iron supplements are prescribed using UK guidelines; however, despite this, the condition remains highly prevalent, affecting up to 30% of pregnant women in the UK. According to the World Health Organisation, it globally accounts [...] Read more.
Following a diagnosis of iron deficiency anaemia in pregnancy, iron supplements are prescribed using UK guidelines; however, despite this, the condition remains highly prevalent, affecting up to 30% of pregnant women in the UK. According to the World Health Organisation, it globally accounts for 45% in the most vulnerable groups of pregnant women and infants (<5 years old). Recently, the efficacy of iron replacement therapy and the effectiveness of current standard testing of iron parameters have been reviewed in order to evaluate whether a more accurate diagnosis can be made using alternative and/or supplementary markers. Furthermore, many questions remain about the mechanisms involved in iron metabolism during pregnancy. The most recent studies have shed more light on serum hepcidin and raised questions on the significance of pregnancy related inflammatory markers including cytokines in iron deficiency anaemia. However, research into this is still scarce, and this review aims to contribute to further understanding and elucidating these areas. Full article
(This article belongs to the Special Issue Recent Advance on Iron Metabolism, Ferritin and Hepcidin Research 2.0)
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