Regulator Of Iron Homeostasis Research Articles (Page 6)

A Phase 1b Study of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Myelofibrosis and Anemia

TMPRSS6 Inhibition Rapidly Reverses Liver Iron Overload and Prevents an Increase of Splenic Pro-Inflammatory Macrophages in a Mouse Model of Beta-Thalassemia

Osteoblast-Derived Erythroferrone Regulates Stress Erythropoiesis

Phase 1 Healthy Volunteer Study of DISC-3405, a Recombinant Humanized Antibody Targeting TMPRSS6

Initial Results from a Phase 1/2 Study Evaluating Divesiran, a Novel Galnac Conjugated siRNA, in Patients with Polycythemia Vera (SANRECO)

Pharmacological Inhibition of TMPRSS6 Decreases Hemoglobin Concentration and Red Blood Cell (RBC) Hemolysis in a Mouse Model of Sickle Cell Disease

Preterm infants are most at risk of iron deficiency. However, our knowledge of the regulation of iron homeostasis in preterm infants is poor. The main goal of our research was to develop and validate an animal model of human prematurity to assess iron status in preterm infants. We performed a cesarean section on sows on the 109th day of pregnancy, which corresponds to the last trimester of human pregnancy. Preterm piglets showed decreased body weight, red blood cell indices, plasma iron level and transferrin saturation. Interestingly, higher hepatic and splenic non-heme iron content and plasma and hepatic ferritin levels were found in premature piglets compared with term ones. In addition, premature piglets showed higher mRNA levels of iron-regulatory hormone hepcidin in the liver than term animals, which have not been reflected in higher plasma hepcidin-25 levels. We also showed changes in hepcidin regulators, including hepatic bone morphogenetic protein 6, plasma erythroferrone and growth differentiation factor 15 in preterm piglets. Consequently, no difference was observed in iron-exporter ferroportin levels in the spleen and liver. Overall, it seems that premature piglets show a pattern of iron metabolism characteristic of functional iron deficiency and iron accumulation in the tissue.

gp130 functions as a shared signal-transducing subunit not only for interleukin (IL)-6 but also for eight other human cytokine receptor complexes. The IL-6 signaling pathway mediated through gp130 encompasses classical, trans, or cluster signaling, intricately regulated by a diverse array of modulators affecting IL-6, its receptor, and gp130. Currently, only a limited number of small molecule antagonists and agonists for gp130 are known. This review aims to comprehensively examine the current knowledge of these modulators and provide insights into their pharmacological properties, particularly in the context of cancer and other diseases. Notably, the prominent gp130 modulators SC144, bazedoxifene, and raloxifene are discussed in detail, with a specific focus on the discovery of SC144's iron-chelating properties. This adds a new dimension to the understanding of its pharmacological effects and therapeutic potential in conditions where iron homeostasis is significant. Our bioinformatic analysis of gp130 and genes related to iron homeostasis reveals insightful correlations, implicating the role of iron in the gp130 signaling pathway. Overall, this review contributes to the evolving understanding of gp130 modulation and its potential therapeutic applications in various disease contexts. SIGNIFICANCE STATEMENT: This perspective provides a timely and comprehensive analysis of advancements in gp130 signaling research, emphasizing the therapeutic implications of the currently available modulators. Bioinformatic analysis demonstrates potential interplay between gp130 and genes that regulate iron homeostasis, suggesting new therapeutic avenues. By combining original research findings with a broader discussion of gp130's therapeutic potential, this perspective significantly contributes to the field.

The treatment of infected bone defects (IBDs) needs simultaneous elimination of infection and acceleration of bone regeneration. One mechanism that hinders the regeneration of IBDs is the iron competition between pathogens and host cells, leading to an iron deficient microenvironment that impairs the innate immune responses. In this work, an in situ modification strategy is proposed for printing iron-active multifunctional scaffolds with iron homeostasis regulation ability for treating IBDs. As a proof-of-concept, ultralong hydroxyapatite (HA) nanowires are modified through in situ growth of a layer of iron gallate (FeGA) followed by incorporation in the poly(lactic-co-glycolic acid) (PLGA) matrix to print biomimetic PLGA based composite scaffolds containing FeGA modified HA nanowires (FeGA-HA@PLGA). The photothermal effect of FeGA endows the scaffolds with excellent antibacterial activity. The released iron ions from the FeGA-HA@PLGA help restore the iron homeostasis microenvironment, thereby promoting anti-inflammatory, angiogenesis and osteogenic differentiation. The transcriptomic analysis shows that FeGA-HA@PLGA scaffolds exert anti-inflammatory and pro-osteogenic differentiation by activating NF-κB, MAPK and PI3K-AKT signaling pathways. Animal experiments confirm the excellent bone repair performance of FeGA-HA@PLGA scaffolds for IBDs, suggesting the promising prospect of iron homeostasis regulation therapy in future clinical applications.

bmp10 maintains cardiac function by regulating iron homeostasis

Injury systemically disrupts the homeostatic balance and can cause organ failure. LF mediates both iron-dependent and iron-independent mechanisms, and the role of LF in regulating iron homeostasis is vital in terms of metabolism. In this study, we evaluated the organ-level effect and gene expression change of bLf in the cutaneous repair process. An excisional full-thickness skin defect (FTSD) wound model was created in male Sprague Dawley rats (180-250 g) (n = 48) fed a high-fat diet (HFD) and the PHGPx, SLC7A11 and SLC40A1 genes and iron metabolism were evaluated. The animals were randomly divided into 6 groups: 1- Control, 2- bLf (200 mg/kg/day, oral), 3- FTSD (12 mm in diameter, dorsal), 4- HFD + bLf, 5- HFD + FTSD, 6- HFD + FTSD + bLf. Histologically, iron accumulation was demonstrated by Prussian blue staining in the liver, kidney, and intestinal tissues. Gene expression analysis was performed with qPCR. Histologically, iron accumulation was demonstrated by Prussian blue staining in the liver, kidney, and intestinal tissues. Prussian blue reactions were detected in the kidney. PHPGx and SLC7A11 genes in kidney and liver tissue were statistically significant (P < 0.05) except for the SLC40A1 gene (P > 0.05). Expression changes of the three genes were not statistically significant in analyses of rat intestinal tissue (P = 0.057). In the organ-level ferroptotic damage mechanism triggered by wound formation. BLf controls the expression of three genes and manages iron deposition in these three tissues. In addition, it suppressed the increase in iron that would drive the cell to ferroptosis and anemia caused by inflammation, thereby eliminating iron deposition in the tissues.

We previously reported that high mobility group box 1 (HMGB1), a danger-associated molecular pattern (DAMP), increases intracellular iron levels in the postischemic brain by upregulating hepcidin, a key regulator of iron homeostasis, triggering ferroptosis. Since hepatocytes are the primary cells that produce hepcidin and control systemic iron levels, we investigated whether cerebral ischemia induces hepcidin upregulation in hepatocytes. Following middle cerebral artery occlusion (MCAO) in a rodent model, significant liver injury was observed. This injury was evidenced by significantly elevated Eckhoff’s scores and increased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Additionally, total iron levels were significantly elevated in the liver, with intracellular iron accumulation detected in hepatocytes. Hepcidin expression in the liver, which is primarily localized in hepatocytes, increased significantly starting at 3 h after MCAO and continued to increase rapidly, reaching a peak at 24 h. Interestingly, HMGB1 levels in the liver were also significantly elevated after MCAO, with the disulfide form of HMGB1 being the major subtype. In vitro experiments using AML12 hepatocytes showed that recombinant disulfide HMGB1 significantly upregulated hepcidin expression in a Toll-like receptor 4 (TLR4)- and RAGE-dependent manner. Furthermore, treatment with a ROS scavenger and a peptide HMGB1 antagonist revealed that both ROS generation and HMGB1 induction contributed to hepatocyte activation and liver damage following MCAO–reperfusion. In conclusion, this study revealed that cerebral ischemia triggers hepatocyte activation and liver injury. HMGB1 potently induces hepcidin not only in the brain but also in the liver, thereby influencing systemic iron homeostasis following ischemic stroke.

Ferritin is an iron storage protein essential for iron homeostasis regulation and an indicator of iron stores. It is an acute phase reactant and is elevated in inflammation and chronic infection. Periodontitis is a chronic inflammatory disease with periodontopathogens possessing haemolytic activity which leads to increased local iron concentration and iron disorder. Inflammation and excess systemic iron are mediating risk factors of type 2 diabetes mellitus. To evaluate and compare the salivary ferritin levels in subjects with chronic periodontitis with and without type 2 diabetes mellitus. Unstimulated saliva sample was collected by standardized spitting technique from 45 individuals, aged between 30 and 65 years divided into three groups. Group I-Healthy individuals, Group II-Subjects with chronic periodontitis with type 2 diabetes mellitus, Group III-Subjects with chronic periodontitis without type 2 diabetes mellitus. The salivary ferritin levels are analysed using latex-enhanced turbidimetric assay in an autoanalyzer. The salivary ferritin level was elevated in chronic periodontitis with type 2 diabetes mellitus (Group II) and in chronic periodontitis without type 2 diabetes mellitus (Group III).

The role of the iron-sulfur [Fe-S] cluster transcriptional regulator IscR in maintaining [Fe-S] homeostasis in bacteria is still poorly characterized in many groups. Caulobacter crescentus and other Alphaproteobacteria have a single operon encoding [Fe-S] cluster biosynthesis enzymes. We showed that the expression of this operon increases in iron starvation, but not in oxidative stress, and is controlled mainly by IscR. Transcriptome analysis comparing an iscR null mutant strain with the wild-type (wt) strain identified 94 differentially expressed genes (DEGs), with 47 upregulated and 47 downregulated genes in the ΔiscR mutant. We determined the IscR binding sites in conditions of sufficient or scarce iron by Chromatin Immunoprecipitation followed by DNA sequencing (ChIP-seq), identifying two distinct putative DNA binding motifs. The estimated IscR regulon comprises 302 genes, and direct binding to several regulatory regions was shown by Electrophoresis Mobility Shift Assay (EMSA). The results showed that the IscR and Fur regulons partially overlap and that IscR represses the expression of the respiration regulator FixK, fine-tuning gene regulation in response to iron and redox balance.

Iron, an essential micronutrient, is involved in several physiological activities, including oxygen transport, cellular respiration, and DNA synthesis. Its homeostasis is strictly controlled to avoid overload and deficiency. Ferrous iron is taken up by intestinal enterocytes through the apical membrane with the help of divalent metal transporter 1 (DMT1). Iron can then be discharged into the bloodstream by ferroportin 1 (FPN1) or stored intracellularly in ferritin. Hepcidin, a hormone produced in the liver, binds to FPN1 and causes its internalization and degradation, a key factor in controlling systemic iron levels. Thus, hepcidin limits the absorption and release of iron by decreasing the iron outflow from enterocytes and macrophages. Iron-responsive element/iron regulatory protein (IRE/IRP) system and hypoxia-inducible factor 2 (HIF-2) are important cellular regulators of iron homeostasis. The IRE/IRP system post-transcriptionally regulates the expression of iron-related proteins in response to iron availability. At the same time, HIF-2 promotes the expression of iron transporters and metabolic enzymes under hypoxic conditions. Iron-related disorders can result from disruptions in these regulatory mechanisms; for instance, mutations in the genes encoding hepcidin, FPN1, or hereditary hemochromatosis protein (HFE) can cause iron overload disorders like hemochromatosis, while iron deficiency anemia is caused by impaired iron absorption due to genetic defects or nutritional deficiencies. A deeper understanding of these intricate mechanisms is crucial for developing effective strategies to prevent and treat iron-related disorders.

Bone morphogenetic protein 2 (BMP2) and BMP6 are key regulators of systemic iron homeostasis. All BMPs are generated as inactive precursor proteins that dimerize and are cleaved to generate the bioactive ligand and inactive prodomain fragments, but nothing is known about how BMP2 or BMP6 homodimeric or heterodimeric precursor proteins are proteolytically activated. Here, we conducted in vitro cleavage assays, which revealed that BMP2 is sequentially cleaved by furin at two sites, initially at a site upstream of the mature ligand, and then at a site adjacent to the ligand domain, while BMP6 is cleaved at a single furin motif. Cleavage of both sites of BMP2 is required to generate fully active BMP2 homodimers when expressed in Xenopus embryos or liver endothelial cells, and fully active BMP2/6 heterodimers in Xenopus. We analyzed BMP activity in Xenopus embryos expressing chimeric proteins consisting of the BMP2 prodomain and BMP6 ligand domain, or vice versa. We show that the prodomain of BMP2 is necessary and sufficient to generate active BMP6 homodimers and BMP2/6 heterodimers, whereas the BMP6 prodomain cannot generate active BMP2 homodimers or BMP2/6 heterodimers. We examined BMP2 and BMP6 homodimeric and heterodimeric ligands generated from native and chimeric precursor proteins expressed in Xenopus embryos. Whereas native BMP6 is not cleaved when expressed alone, it is cleaved to generate BMP2/6 heterodimers when co-expressed with BMP2. Furthermore, BMP2-6 chimeras are cleaved to generate BMP6 homodimers. Our findings reveal an important role for the BMP2 prodomain in dimerization and proteolytic activation of BMP6.

Obesity is a chronic disease with a complex etiology, characterized by a persistent inflammatory state induced by various pro-inflammatory cytokines, including interleukin-6. This condition leads to increased production of hepcidin, a protein hormone responsible for regulating iron homeostasis. Hepcidin's primary function is to inhibit iron absorption by enterocytes, the cells lining the small intestine. Symptoms of iron deficiency, which is crucial for oxygen transport, energy production, and immune system support, can be varied and often nonspecific, such as general weakness, pallor, or concentration difficulties, potentially prolonging the diagnostic process. This article aims to analyze the relationship between obesity and iron deficiency in the metabolic context. Obesity, being one of the most prevalent health issues of the modern world, is associated with numerous complications, including disturbances in iron metabolism. Iron deficiency in obese individuals can lead to anemia, reduced physical performance, and cognitive impairments. Traditional treatment methods for this micronutrient deficiency involve supplementation. However, supplementation shows reduced efficacy in overweight and obese individuals, likely due to elevated hepcidin levels. A more effective approach should include interventions targeting not only the supplementation of the missing micronutrient but also weight reduction.

Refining the Rab7-V1G1 axis to mitigate iron deposition: Protective effects of quercetin in alcoholic liver disease

Trace elemental iron is an essential nutrient that participates in diverse metabolic processes. Dysregulation of cellular iron homeostasis, both iron deficiency and iron overload, is detrimental and tightly associated with diseases pathogenesis. IRPs-IREs system locates at the center for iron homeostasis regulation. Additionally, ferritinophagy, the autophagy-dependent ferritin catabolism for iron recycle, is emerging as a novel mechanism for iron homeostasis regulation. It is still unclear whether IRPs-IREs system and ferritinophagy are synergistic or redundant in determining iron homeostasis. Here we report that IRP2, but not IRP1, is indispensable for ferritinophagy in response to iron depletion. Mechanistically, IRP2 ablation results in compromised AMPK activation and defective ATG9A endosomal trafficking, leading to the decreased engulfment of NCOA4-ferritin complex by endosomes and the subsequent dysregulated endosomal microferritinophagy. Moreover, this defective endosomal microferritinophagy exacerbates DNA damage and reduces colony formation in IRP2 depleted cells. Collectively, this study expands the physiological function of IRP2 in endosomal microferritinophagy and highlights a potential crosstalk between IRPs-IREs and ferritinophagy in manipulating iron homeostasis.

INTRODUCTION: Polycystic ovarian syndrome (PCOS) is the utmost prevailing, complex endocrinopathy of reproductive-aged women and one of the fundamental reasons for female infertility. It has been acclaimed as a metabolic syndrome variant in women and comprises a crucial segment of the female population at risk of cardiovascular diseases and type 2 diabetes mellitus. Vitamin D deficiency is connected with deleterious metabolic outcomes in PCOS and may be responsible for exacerbating PCOS symptoms. This hormonal deficiency is linked with insulin resistance (IR), adiposity, impaired glucose and lipid metabolism, and systemic pro-inflammatory milieu in PCOS women. Ferritin, a regulator of iron homeostasis, is linked with IR and obesity. There is an absolute interrelation of even slightly raised body iron stores with aggravated risk of IR, diabetes, cardiovascular events, and metabolic syndrome in PCOS. AIMS: This study was designed to assess and compare Vitamin D and ferritin status in PCOS and control group women. We also aimed to analyze the association of Vitamin D and body iron stores with IR and adiposity in PCOS women. MATERIAL AND METHODS: Women with a diagnosis of PCOS, between 18 and 40 years of age, were recruited and compared with healthy controls. Baseline information was obtained from all the participants, and biochemical parameters such as Vitamin D and ferritin were analyzed. RESULTS: This study demonstrated that women with PCOS have significantly decreased Vitamin D levels compared to controls. A compromised Vitamin D status in PCOS women is associated with higher IR, body mass index (BMI), waist/hip ratio, and lipid accumulation product (LAP). PCOS women showed increased serum ferritin concentration that correlated with IR and BMI. CONCLUSION: An inadequate Vitamin D and raised ferritin status in PCOS women are associated with IR and adiposity. These biochemical markers might be the hallmark of metabolic aberrations in PCOS and their assessment would be worthwhile for evaluating cardiovascular and diabetes risks in these women. Furthermore, the correlation of the LAP index with the IR index suggests that obesity has a strong impact on IR.