Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.

BACKGROUND: Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS: In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS: Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS: In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).

Activation of Intestinal HIF2α Ameliorates Iron-Refractory Anemia.

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.

Activated mesenchymal stem cells increase drug susceptibility of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa.

Methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa are major causes of hospital-acquired infections and sepsis. Due to increasing antibiotic resistance, new treatments are needed. Mesenchymal stem cells (MSCs) have antimicrobial effects, which can be enhanced by preconditioning with antibiotics. This study investigated using antibiotics to strengthen MSCs against MRSA and P. aeruginosa. MSCs were preconditioned with linezolid, vancomycin, meropenem, or cephalosporin. Optimal antibiotic concentrations were determined by assessing MSC survival. Antimicrobial effects were measured by minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and antimicrobial peptide (AMP) gene expression. Optimal antibiotic concentrations for preconditioning MSCs without reducing viability were 1 µg/mL for linezolid, meropenem, and cephalosporin and 2 µg/mL for vancomycin. In MIC assays, MSCs preconditioned with linezolid, vancomycin, meropenem, or cephalosporin inhibited MRSA or P. aeruginosa growth at lower concentrations than non-preconditioned MSCs (p ≤ 0.001). In MBC assays, preconditioned MSCs showed enhanced bacterial clearance compared to non-preconditioned MSCs, especially when linezolid and vancomycin were used against MRSA (p ≤ 0.05). Preconditioned MSCs showed increased expression of genes encoding the antimicrobial peptide genes hepcidin and LL-37 compared to non-preconditioned MSCs. The highest hepcidin expression was seen with linezolid and vancomycin preconditioning (p ≤ 0.001). The highest LL-37 expression was with linezolid preconditioning (p ≤ 0.001). MSCs' preconditioning with linezolid, vancomycin, meropenem, or cephalosporin at optimal concentrations enhances their antimicrobial effects against MRSA and P. aeruginosa without compromising viability. This suggests preconditioned MSCs could be an effective adjuvant treatment for antibiotic-resistant infections. The mechanism may involve upregulation of AMP genes.

Pre-emptive iron supplementation prevents myocardial iron deficiency and attenuates adverse remodelling after myocardial infarction.

AIMS: Heart failure (HF) after myocardial infarction (MI) is a major cause of morbidity and mortality. We sought to investigate the functional importance of cardiac iron status after MI and the potential of pre-emptive iron supplementation in preventing cardiac iron deficiency (ID) and attenuating left ventricular (LV) remodelling. METHODS AND RESULTS: MI was induced in C57BL/6J male mice by left anterior descending coronary artery ligation. Cardiac iron status in the non-infarcted LV myocardium was dynamically regulated after MI: non-haem iron and ferritin increased at 4 weeks but decreased at 24 weeks after MI. Cardiac ID at 24 weeks was associated with reduced expression of iron-dependent electron transport chain (ETC) Complex I compared with sham-operated mice. Hepcidin expression in the non-infarcted LV myocardium was elevated at 4 weeks and suppressed at 24 weeks. Hepcidin suppression at 24 weeks was accompanied by more abundant expression of membrane-localized ferroportin, the iron exporter, in the non-infarcted LV myocardium. Notably, similarly dysregulated iron homeostasis was observed in LV myocardium from failing human hearts, which displayed lower iron content, reduced hepcidin expression, and increased membrane-bound ferroportin. Injecting ferric carboxymaltose (15 µg/g body weight) intravenously at 12, 16, and 20 weeks after MI preserved cardiac iron content and attenuated LV remodelling and dysfunction at 24 weeks compared with saline-injected mice. CONCLUSION: We demonstrate, for the first time, that dynamic changes in cardiac iron status after MI are associated with local hepcidin suppression, leading to cardiac ID long term after MI. Pre-emptive iron supplementation maintained cardiac iron content and attenuated adverse remodelling after MI. Our results identify the spontaneous development of cardiac ID as a novel disease mechanism and therapeutic target in post-infarction LV remodelling and HF.

Effects of hypoxia-inducible factor-prolyl hydroxylase inhibitors vs. erythropoiesis-stimulating agents on iron metabolism in non-dialysis-dependent anemic patients with CKD: A network meta-analysis.

Objective: To compare the effects of five hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs), two erythropoiesis-stimulating agents (ESAs), and placebo on iron metabolism in renal anemia patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). Method: Five electronic databases were searched for studies. Randomized controlled clinical trials comparing HIF-PHIs, ESAs, and placebo in NDD-CKD patients were selected. The statistical program used for network meta-analysis was Stata/SE 15.1. The main outcomes were the change in hepcidin and hemoglobin (Hb) levels. The merits of intervention measures were predicted by the surface under the cumulative ranking curve method. Results: Of 1,589 original titles screened, data were extracted from 15 trials (3,228 participants). All HIF-PHIs and ESAs showed greater Hb level-raising ability than placebo. Among them, desidustat demonstrated the highest probability of increasing Hb (95.6%). Hepcidin [mean deviation (MD) = -43.42, 95%CI: -47.08 to -39.76], ferritin (MD= -48.56, 95%CI: -55.21 to -41.96), and transferrin saturation (MD = -4.73, 95%CI: -5.52 to -3.94) were decreased, while transferrin (MD = 0.09, 95%CI: 0.01 to 0.18) and total iron-binding capacity (MD = 6.34, 95%CI: 5.71 to 6.96) was increased in HIF-PHIs versus those in ESAs. In addition, this study observed heterogeneity in the ability of HIF-PHIs to decrease hepcidin. Compared with darbepoetin, only daprodustat (MD = -49.09, 95% CI: -98.13 to -0.05) could significantly reduce hepcidin levels. Meanwhile, daprodustat also showed the highest hepcidin-lowering efficacy (84.0%), while placebo was the lowest (8.2%). Conclusion: For NDD-CKD patients, HIF-PHIs could ameliorate functional iron deficiency by promoting iron transport and utilization, which may be achieved by decreasing hepcidin levels. Interestingly, HIF-PHIs had heterogeneous effects on iron metabolism. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=242777, Identifier CRD42021242777.

miR-761-hepcidin/Gpx4 pathway contribute to unexplained liver dysfunction in polycystic ovary syndrome by regulating liver iron overload and ferroptosis.

Aims: To investigate the underling mechanisms of liver dysfunction in patients with polycystic ovary syndrome (PCOS).Materials and methods: PCOS patients were enrolled according to the Amsterdam criteria while PCOS animal model was established by dihydrotestosterone (DHEA) sustained release tablet implantation on its neck. Further liver damage and iron overload were detected by HE and Prussian blue staining. The liver related enzymes, mRNA and protein levels of hepcidin and GPX4 were tested by ELISA, qRT-PCR and Western blot. RNA interference and miR-761 transfection were routinely performed while the regulation of miR-761 on hepcidin and GPX4 was confirmed by luciferase reporter gene analysis.Results: We found that a part of PCOS patients and animal model had unexplained liver damage, which is independent of nonalcoholic fatty liver disease (NAFLD) and accompanied by increased ferrum (Fe) deposition. Besides, the expression of hepcidin and GPX4 that is important effector proteins for ferroptosis was down regulated in liver, showing the importance of iron metabolism in this unexplained liver damage. Based on the miR-761-hepcidin/GPX4 axis, we systematically studied the effects of miR-761 on ferroptosis and Fe deposition, which further influence the phenotype and liver function of PCOS model. From both in vivo and in vitro levels, changes in PCOS disease phenotype and ferroptosis were observed through hierarchical antagonism or overexpression of miR-761, hepcidin and GPX4.Conclusions: our results provide a novel explanation for unexplained liver damage in PCOS and a potential therapeutic target.

Acute phase reactant proteins in Buerger's disease: Is it a systemic disease?

Aim: The aim of this study was evaluating acute phase reactant (APR) proteins including high sensitivity C-reactive protein (hsCRP), pentraxin 3 (PTX3), fibrinogen, complement C3, hepcidin, and albumin in patients suffering from Buerger's disease (BD) compared to controls.Methods: The APRs were evaluated in 92 cases of BD patients and 90 healthy age and sex matched controls of blood from Iran and Turkey. The diagnosis was done according to Shionoya's criteria. However, patients with age less than 40 were included, instead of those less than 50. The diagnosis was confirmed by angiography or CT angiography. The patients were categorized into active and quiescent phases of the disease according to clinical manifestation. Patients with rest pain, non-healing ulcer, and gangrene were categorized in the active phase of the disease and the patients with unchanged claudication for more than 6 months without trophic lesions or gangrene were categorized in the quiescent phase of the disease.Results: The serum level of PTX3, hsCRP, fibrinogen, C3, and hepcidin in BD was significantly higher than controls (p < 0.004). Also, albumin in the BD group was significantly lower than controls (p < 0.001). In patients that categorized in the active phase, fibrinogen, C3, and hsCRP were significantly higher and albumin was significantly lower compared to patients in the quiescent phase. No significant difference was found between the level of PTX3 and hepcidin in the patients in active and quiescent phases of the disease.Conclusion: The pattern of the level of APRs in BD seems more likely systemic inflammatory disorder than atherosclerosis obliterans. More clinical trials for evaluating the efficacy of anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids as a part of management of BD are required. Also, according to low level of albumin in TAO, a protein rich diet might be beneficial for BD patients in the active phase of their disease.

Advances in Risk Stratification and Treatment of Polycythemia Vera and Essential Thrombocythemia.

PURPOSE OF REVIEW: Estimating and modifying thrombotic risk is currently the mainstay of care for patients with polycythemia vera (PV) and essential thrombocythemia (ET). In recent years, however, increased attention has shifted towards quality of life and disease modification. In this review, we discuss recent advances in risk stratification, present updated results for ruxolitinib and interferon randomized clinical trials, discuss new approaches in antiplatelet and anticoagulant treatment, and summarize early phase trials of novel agents and emerging therapeutic concepts for the treatment of PV and ET. RECENT FINDINGS: International collaborations and novel technologies, i.e., next-generation sequencing and machine learning techniques, have demonstrated excellent abilities to improve thrombotic risk stratification in PV and ET. Updated results from ruxolitinib and interferon randomized clinical trials have confirmed excellent efficacy and safety of these agents, both as first- and second-line treatments. Early trials of novel agents (histone deacetylase inhibitors, telomerase inhibitors, lysine-specific demethylase-1 inhibitors, human double-minute 2 inhibitors, and hepcidin mimetics) have shown encouraging efficacy and safety in blood count control, reduction of splenomegaly, and alleviation of disease-related symptoms. Finally, accumulating evidence suggested that direct oral anticoagulants may be a valid therapeutic alternative to warfarin for prolonged thromboprophylaxis. International collaborations ("big data") with the help of new technologies represent an exciting new approach to analyze rare outcomes in rare diseases, especially for identifying novel prognostic biomarkers in PV and ET. Randomized clinical trials are also needed to fully elucidate whether novel agents may establish new standards of care.

Predictors of iron versus erythropoietin responsiveness in anemic hemodialysis patients.

Anemia protocols for hemodialysis patients usually titrate erythropoietin (ESA) according to hemoglobin and iron according to a threshold of ferritin, with variable response seen. A universally optimum threshold for ferritin may be incorrect, and another view is that ESA and iron are alternative anemia treatments, which should be selected based on the likely response to each. Hemodialysis patients developing moderate anemia were randomised to treatment with either an increase in ESA or a course of intravenous iron. Over 2423 patient-months in 197 patients, there were 133 anemia episodes with randomized treatment. Treatment failure was seen in 20/66 patients treated with ESA and 20/67 patients treated with iron (30.3 vs. 29.9%, p = 1.0). Successful ESA treatment was associated with lower C-reactive protein (13.5 vs. 28.6 mg/L, p = 0.038) and lower previous ESA dose (6621 vs. 9273 µg/week, p = 0.097). Successful iron treatment was associated with lower reticulocyte hemoglobin (33.8 vs. 35.5 pg, p = 0.047), lower hepcidin (91.4 vs. 131.0 µg/ml, p = 0.021), and higher C-reactive protein (29.5 vs. 12.6 mg/L, p = 0.085). A four-variable iron preference score was developed to indicate the more favorable treatment, which in a retrospective analysis reduced treatment failure to 17%. Increased ESA and iron are equally effective, though treatment failure occurs in almost 30%. Baseline variables including hepcidin can predict treatment response, and a four-variable score shows promise in allowing directed treatment with improved response rates.

Iron deficiency screening is a key issue in chronic inflammatory diseases: A call to action.

Iron deficiency is frequent in patients with chronic inflammatory conditions (e.g., chronic heart failure, chronic kidney disease, cancers, and bowel inflammatory diseases). Indeed, high concentrations of inflammatory cytokines increase hepcidin concentrations that lead to the sequestration of iron in cells of the reticuloendothelial system (functional iron deficiency). Iron parameters are often assessed only in the context of anemia, but iron deficiency, even without anemia, is present in about half of patients with inflammatory conditions. Iron deficiency worsens underlying chronic diseases and is an independent factor of morbidity and mortality. In daily practice, the most effective biomarkers of iron status are serum ferritin, which reflects iron storage, and transferrin saturation, which reflects the transport of iron. Serum ferritin is increased in an inflammatory context, and there is still no consensus on the threshold to be used in chronic inflammatory conditions. Nevertheless, recent recommendations of international guidelines agreed to define iron deficiency by serum ferritin <100 µg/L and/or transferrin saturation <20%. Iron parameters remain, however, insufficiently assessed in patients with chronic inflammatory conditions. Indeed, clinical symptoms of iron deficiency, such as fatigue, are not specific and often confused with those of the primary disease. Iron repletion, preferably by the intravenous route to bypass tissue sequestration, improves clinical signs and quality of life. Because of the negative impact of iron deficiency on chronic inflammatory diseases and the efficacy of intravenous iron repletion, screening of iron parameters should be part of the routine examination of all patients with chronic inflammatory diseases.

The Era of Antimicrobial Peptides: Use of Hepcidins to Prevent or Treat Bacterial Infections and Iron Disorders.

The current treatments applied in aquaculture to limit disease dissemination are mostly based on the use of antibiotics, either as prophylactic or therapeutic agents, with vaccines being available for a limited number of fish species and pathogens. Antimicrobial peptides are considered as promising novel substances to be used in aquaculture, due to their antimicrobial and immunomodulatory activities. Hepcidin, the major iron metabolism regulator, is found as a single gene in most mammals, but in certain fish species, including the European sea bass (Dicentrarchus labrax), two different hepcidin types are found, with specialized roles: the single type 1 hepcidin is involved in iron homeostasis trough the regulation of ferroportin, the only known iron exporter; and the various type 2 hepcidins present antimicrobial activity against a number of different pathogens. In this study, we tested the administration of sea bass derived hepcidins in models of infection and iron overload. Administration with hamp2 substantially reduced fish mortalities and bacterial loads, presenting itself as a viable alternative to the use of antibiotics. On the other hand, hamp1 seems to attenuate the effects of iron overload. Further studies are necessary to test the potential protective effects of hamp2 against other pathogens, as well as to understand how hamp2 stimulate the inflammatory responses, leading to an increased fish survival upon infection.

Ineffective Erythropoiesis in ß-Thalassaemia: Key Steps and Therapeutic Options by Drugs.

ß-thalassaemia is a rare genetic condition caused by mutations in the ß-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-ß superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in ß-thalassaemia from bench to bedside.

Oral ferroportin inhibitor vamifeport for improving iron homeostasis and erythropoiesis in ß-thalassemia: current evidence and future clinical development.

INTRODUCTION: In ß-thalassemia, imbalanced globin synthesis causes reduced red blood cell survival and ineffective erythropoiesis. Suppressed hepcidin levels increase ferroportin-mediated iron transport in enterocytes, causing increased iron absorption and potentially iron overload. Low hepcidin also stimulates ferroportin-mediated iron release from macrophages, increasing transferrin saturation (TSAT), potentially forming non-transferrin-bound iron, which can be toxic. Modulating the hepcidin-ferroportin axis is an attractive strategy to improve ineffective erythropoiesis and limit the potential tissue damage resulting from iron overload. There are no oral ß-thalassemia treatments that consistently ameliorate anemia and prevent iron overload. AREAS COVERED: The preclinical and clinical development of vamifeport (VIT-2763), a novel ferroportin inhibitor, was reviewed. PubMed, EMBASE and ClinicalTrials.gov were searched using the search term 'VIT-2763'. EXPERT OPINION: Vamifeport is the first oral ferroportin inhibitor in clinical development. In healthy volunteers, vamifeport had comparable safety to placebo, was well tolerated and rapidly decreased iron levels and reduced TSAT, consistent with observations in preclinical models. Data from ongoing/planned Phase II studies are critical to define its potential in ß-thalassemia and other conditions associated with iron overabsorption and/or ineffective erythropoiesis. If vamifeport potentially increases hemoglobin and reduces iron-related parameters, it could be a suitable treatment for non-transfusion-dependent and transfusion-dependent ß-thalassemia.

Antimicrobial peptides and other peptide-like therapeutics as promising candidates to combat SARS-CoV-2.

Introduction: There are currently no specific drugs and universal vaccines for Coronavirus disease 2019 (COVID-19), hence urgent effective measures are needed to discover and develop therapeutic agents. Applying peptide therapeutics and their related compounds is a promising strategy to achieve this goal. This review is written based on the literature search using several databases, previous studies, scientific reports, our current knowledge about the antimicrobial peptides (AMPs), and our personal analyses on the potential of the antiviral peptides for the treatment of COVID-19.Areas covered: In this review, we begin with a brief description of SARS-CoV2 followed by a comprehensive description of antiviral peptides (AVPs) including natural and synthetic AMPs or AVPs and peptidomimetics. Subsequently, the structural features, mechanisms of action, limitations, and therapeutic applications of these peptides are explained.Expert opinion: Regarding the lack and the limitations of drugs against COVID-19, AMPs, AVPs, and other peptide-like compounds such as peptidomimetics have captured the attention of researchers due to their potential antiviral activities. Some of these compounds comprise unique properties and have demonstrated the potential to fight SARS-CoV2, particularly melittin, lactoferrin, enfuvirtide, and rupintrivir that have the potential to enter animal and clinical trials for the treatment of COVID-19.

Hemocromatosis y rendimiento deportivo: una revisión sistemática / Hemochromatosis and sports performance: a systematic review / Hemocromatose e desempenho desportivo: uma revisão sistemática

INTRODUCCIÓN: La hemocromatosis hereditaria, al provocar hiperferritinemia, puede tener el potencial de aumentar la capacidad aeróbica y el rendimiento deportivo en atletas. Sin embargo, diversos estudios afirman que la sobrecarga de hierro podría afectar negativamente al rendimiento físico y la función muscular. OBJETIVO: Recopilar y analizar evidencias sobre la relación entre la hemocromatosis hereditaria y el rendimiento deportivo. MÉTODO: Se realizó una revisión sistemática, de acuerdo a los estándares PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), en las siguientes bases de datos: Scopus, Web of Science, PubMed y Dialnet. RESULTADOS: Tras aplicar los criterios de inclusión/exclusión, 13 artículos fueron incluidos y analizados. CONCLUSIONES: Existen variaciones en los genes que están relacionados con el estado de resistencia del atleta. Actualmente, el gen HFE no se sitúa entre los polimorfismos del ácido desoxirribonucleico que aumenten el rendimiento deportivo. Son mayoría las investigaciones en las que recalcan la necesidad de evaluar el estado de ingesta de hierro en el deportista

INTRODUCTION: Hereditary hemochromatosis, by causing hyperferritinemia, may have the potential to increase aerobic capacity and sports performance in athletes. However, various studies claim that iron overload could affect physical performance and muscle function negatively. OBJECTIVE: The aim of this review was to collect and analyze evidence on the relationship between hereditary hemochromatosis and sports performance. METHOD: A systematic review was carried out, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standards, in the following databases: Scopus, Web of Science, PubMed and Dialnet. RESULTS: After applying the inclusion / exclusion criteria, 13 articles were included and analyzed. CONCLUSIONS: There are variations in the genes which are related to the aerobic capacity of the athletes. Currently, the HFE gene is not among the deoxyribonucleic acid polymorphisms that increase sports performance. The vast majority of the studies analyzed emphasize the need to assess the state of iron intake in athletes

INTRODUÇÃO: A hiperferritinemia associada à hemocromatose hereditária, pode apresentar o potencial de aumentar a capacidade aeróbica e o desempenho desportivo em atletas. Contudo, vários estudos afirmam que a sobrecarga de ferro pode afetar negativamente o desempenho físico e a função muscular. OBJETIVO: Recolher e analisar evidências referentes à relação entre hemocromatose hereditária e desempenho desportivo. MÉTODO: Revisão sistemática de acordo com os padrões PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) através das seguintes bases de dados: Scopus, Web of Science, PubMed e Dialnet. RESULTADOS: Após a aplicação dos critérios de inclusão / exclusão, 13 artigos foram incluídos e analisados. CONCLUSÕES: Existem variações nos genes que estão relacionados com o estado de resistência do atleta. Atualmente, o gene HFE não está entre os polimorfismos de ácido desoxirribonucleico que aumentam o desempenho desportivo. A maioria dos estudos enfatiza a necessidade de avaliar o estado de ingestão de ferro em atletas

Intravenous iron in heart failure and chronic kidney disease.

Intravenous iron therapy is increasingly being used worldwide to treat anemia in chronic kidney disease and more recently iron deficiency in heart failure. Promising results were obtained in randomized clinical trials in the latter, showing symptomatic and functional capacity improvement with intravenous iron therapy. Meanwhile, confirmation of clinical benefit in hard-endpoints such as mortality and hospitalization is expected in large clinical trials that are already taking place. In chronic kidney disease, concern about iron overload is being substituted by claims of direct cardiovascular benefit of iron supplementation, as suggested by preliminary studies in heart failure. We discuss the pitfalls of present studies and gaps in knowledge, stressing the known differences between iron metabolism in heart and renal failure. Systemic and cellular iron handling and the role of hepcidin are reviewed, as well as the role of iron in atherosclerosis, especially in view of its relevance to patients undergoing dialysis. We summarize the evidence available concerning iron overload, availability and toxicity in CKD, that should be taken into account before embracing aggressive intravenous iron supplementation.

Immune Regulation, but Not Antibacterial Activity, Is a Crucial Function of Hepcidins in Resistance against Pathogenic Bacteria in Nile Tilapia (Oreochromis niloticus Linn.).

In this study, the functions of a recombinant propeptide (rProOn-Hep1) and the synthetic FITC-labelled mature peptides sMatOn-Hep1 and sMatOn-Hep2 were analyzed. Moreover, sMatOn-Hep1 and sMatOn-Hep2 were mildly detected in the lymphocytes of peripheral blood mononuclear cells (PBMCs) and strongly detected in head kidney macrophages. The in vitro binding and antibacterial activities of these peptides were slightly effective against several pathogenic bacteria. Immune regulation by sMatOn-Hep1 was also analyzed, and only sMatOn-Hep1 significantly enhanced the phagocytic index in vitro (p < 0.05). Interestingly, intraperitoneal injection of sMatOn-Hep1 (10 or 100 µg) significantly elevated the phagocytic activity, phagocytic index, and lysozyme activity and clearly decreased the iron ion levels in the livers of the treated fish (p < 0.05). Additionally, sMatOn-Hep1 enhanced the expression levels of CC and CXC chemokines, transferrin and both On-Hep genes in the liver, spleen and head kidney, for 1-96 h after injection, but did not properly protect the experimental fish from S. agalactiae infection after 7 days of treatment. However, the injection of S. agalactiae and On-Heps indicated that 100 µg of sMatOn-Hep1 was very effective, while 100 µg of rProOn-Hep1 and sMatOn-Hep2 demonstrated moderate protection. Therefore, On-Hep is a crucial iron-regulating molecule and a key immune regulator of disease resistance in Nile tilapia.

A hepcidin-based approach for iron therapy in hemodialysis patients: A pilot study.

INTRODUCTION: Hepcidin is a key factor that regulates iron homeostasis. In hemodialysis patients (HD), a high hepcidin level may decrease intestinal iron absorption and reduce the efficacy of Oral iron vs Intravenous iron therapy. Whether the hepcidin level in HD could guide oral iron therapy is unclear. METHODS: We report a monocentric study on nine "erythropoietin (EPO)-free" patients (without recombinant human EPO [rHU-EPO] for at least 6 months) and normal hepcidin level (<20 ng mL) during the study. After 15 days of washout, oral iron (ferrous sulfate 80 mg/day) was introduced. The primary end point was the hemoglobin response and iron store at 3 months. FINDINGS: Nine patients (8 men, 1 woman) with a median age of 62 years (range 42-79) were included. After 1 week of treatment, the median transferrin saturation index increased from 15% (range 6-61) to 34% (range 13-42), P = 0.62, reflecting intestinal absorption. The median ferritin level remained stable 80 µg/L (35-293) vs 82 µg/L (range 37-496) between M0 and M3, P = 0.43. During the 3-month study, median hemoglobin level increased from 11.5 d/dL (range10.4-13.7) to 12.8 g/dL (range 11.1-15.2), P = 0.01. No major side effects were observed. Quality of life assessed by the SF-36 criteria was similar during the 3-month study. DISCUSSION: Oral iron therapy is effective and safe in EPO-free patients with normal hepcidin levels. These findings suggest that serum hepcidin may be a marker for defining iron therapy strategies in HD patients. HD patients treated with rHU-EPO and with normal hepcidin levels could benefit from oral iron treatment.

Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis.

CONTEXT: Dapagliflozin and other SGLT2 inhibitors are known to increase hematocrit, possibly due to its diuretic effects and hemoconcentration. OBJECTIVE: Since type 2 diabetes is a proinflammatory state and since hepcidin, a known suppressor of erythropoiesis, is increased in proinflammatory states, we investigated the possibility that dapagliflozin suppresses hepcidin concentrations and thus increases erythropoiesis. DESIGN: Prospective, randomized, and placebo-controlled study. SETTING: Single endocrinology center. PATIENTS: Fifty-two obese type 2 diabetes patients. INTERVENTION: Patients were randomized (1:1) to either dapagliflozin (10 mg daily) or placebo for 12 weeks. Blood samples were collected before and after treatments and serum, plasma, and mononuclear cells (MNC) were prepared. MAIN OUTCOME MEASURE: Hepcidin and other hematopoietic factors. RESULTS: Following dapagliflozin treatment, there was a significant fall in HbA1c and a significant increase in hemoglobin concentration and hematocrit. Dapagliflozin treatment significantly reduced circulating hepcidin and ferritin concentrations while causing a significant increase in levels of the hepcidin inhibitor, erythroferrone, and a transient increase in erythropoietin. Additionally, dapagliflozin increased plasma transferrin levels and expression of transferrin receptors 1 and 2 in MNC, while there was no change in the expression of the iron cellular transporter, ferroportin. Dapagliflozin treatment also caused a decrease in hypoxia-induced factor-1α expression in MNC while it increased the expression of its inhibitor, prolyl hydroxylase-2. There were no significant changes in any of these indices in the placebo group. CONCLUSIONS: We conclude that dapagliflozin increases erythropoiesis and hematocrit through mechanisms that involve the suppression of hepcidin and the modulation of other iron regulatory proteins.

Hepcidin and its therapeutic potential in neurodegenerative disorders.

Abnormally high brain iron, resulting from the disrupted expression or function of proteins involved in iron metabolism in the brain, is an initial cause of neuronal death in neuroferritinopathy and aceruloplasminemia, and also plays a causative role in at least some of the other neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Friedreich's ataxia. As such, iron is believed to be a novel target for pharmacological intervention in these disorders. Reducing iron toward normal levels or hampering the increases in iron associated with age in the brain is a promising therapeutic strategy for all iron-related neurodegenerative disorders. Hepcidin is a crucial regulator of iron homeostasis in the brain. Recent studies have suggested that upregulating brain hepcidin levels can significantly reduce brain iron content through the regulation of iron transport protein expression in the blood-brain barrier and in neurons and astrocytes. In this review, we focus on the discussion of the therapeutic potential of hepcidin in iron-associated neurodegenerative diseases and also provide a systematic overview of recent research progress on how misregulated brain iron metabolism is involved in the development of multiple neurodegenerative disorders.