Participation of Hepcidins in the Inflammatory Response Triggered by λ-Carrageenin in Gilthead Seabream (Sparus aurata).

The role of hepcidins, antimicrobial peptides involved in iron metabolism, immunity, and inflammation, is studied. First, gilthead seabream (Sparus aurata L.) head-kidney leucocytes (HKLs) were incubated with λ-carrageenin to study the expression of hepcidin and iron metabolism-related genes. While the expression of most of the genes studied was upregulated, the expression of ferroportin gene (slc40a) was downregulated. In the second part of the study, seabream specimens were injected intramuscularly with λ-carrageenin or buffer (control). The expression of the same genes was evaluated in the head kidney, liver, and skin at different time points after injection. The expression of Hamp1m, ferritin b, and ferroportin genes (hamp1, fthb, and slc40a) was upregulated in the head kidney of fish from the λ-carrageenin-injected group, while the expression of Hamp2C and Hamp2E genes (hamp2.3 and hamp2.7) was downregulated. In the liver, the expression of hamp1, ferritin a (ftha), slc40a, Hamp2J, and Hamp2D (hamp2.5/6) genes was downregulated in the λ-carrageenin-injected group. In the skin, the expression of hamp1 and (Hamp2A Hamp2C) hamp2.1/3/4 genes was upregulated in the λ-carrageenin-injected group. A bioinformatic analysis was performed to predict the presence of transcription factor binding sites in the promoter region of hepcidins. The primary sequence of hepcidin was conserved among the different mature peptides, although changes in specific amino acid residues were identified. These changes affected the charge, hydrophobicity, and probability of hepcidins being antimicrobial peptides. This study sheds light on the poorly understood roles of hepcidins in fish. The results provide insight into the regulatory mechanisms of inflammation in fish and could contribute to the development of new strategies for treat inflammation in farm animals.

Hepcidin Status in Cord Blood: Observational Data from a Tertiary Institution in Belgium.

The hormone hepcidin plays an important role in intestinal iron absorption and cellular release. Cord blood hepcidin values reflect fetal hepcidin status, at least at the time of delivery, but are not available for the Belgian population. Therefore, we aimed (1) to provide the first data on cord blood hepcidin levels in a Belgian cohort and (2) to determine variables associated with cord blood hepcidin concentrations. A cross-sectional, observational study was performed at the University Hospital Leuven, Belgium. Cord blood samples were analyzed using a combination of weak cation exchange chromatography and time-of-flight mass spectrometry. Descriptive statistics, Spearman correlation tests, and Mann-Whitney U tests were performed. In total, 61 nonhemolyzed cord blood samples were analyzed. The median hepcidin level was 17.6 µg/L (IQR: 18.1; min-max: 3.9-54.7). A moderate correlation was observed between cord blood hepcidin and cord blood ferritin (r = 0.493) and hemoglobin (r = -0.342). Cord blood hepcidin was also associated with mode of delivery (p = 0.01), with higher hepcidin levels for vaginal deliveries. Nonetheless, larger studies are needed to provide more evidence on the actual clinical value and benefit of cord blood hepcidin measurements.

Serum Hepcidin, the Hepcidin/Ferritin Ratio and the Risk of Type 2 Diabetes: A Systematic Review and Meta-Analysis.

OBJECTIVES: To perform a meta-analysis on the relationship type 2 diabetes has with serum hepcidin and the hepcidin/ferritin ratio. METHODS: The following databases were searched using all relevant keywords: Web of Science, Medline, Scopus, Embase and Google Scholar. All studies that examined the relationship type 2 diabetes has with serum hepcidin or the hepcidin/ferritin ratio were included in this meta-analysis and systematic review provided, were published in English between 2011 and 2018. A random-effects model was used to pool the standardized mean difference (SMD). RESULTS: The SMD of serum hepcidin among patients with type 2 diabetes and healthy controls were compared across eight studies (n cases=878; n controls=2306). The pooled SMD of serum hepcidin did not differ significantly between study groups (SMD: 0.04; 95% confidence interval (CI): -0.29 to 0.35). In contrast, the serum hepcidin/ferritin ratio was examined across five studies (n cases=229; n controls=1426) and was found to be negatively associated with the risk of type 2 diabetes (SMD: -0.52; 95% confidence interval (CI): -0.85 to -0.19). There was no publication bias found for the associations serum hepcidin (Egger´s test: P =0.97) or the hepcidin/ferritin ratio (Egger´s test: P =0.75) had with type 2 diabetes. CONCLUSION: Although hepcidin has been proposed as a risk marker for type 2 diabetes, our metaanalysis found that the hepcidin/ferritin ratio was superior to hepcidin alone as a risk marker.

Association between interleukin-6 gene polymorphism and iron regulation in hemodialysis patients infected with HCV / Associação entre polimorfismo do gene da interleucina-6 e regulação do ferro em pacientes em hemodiálise infectados pelo HCV

ABSTRACT Backgrounds: Hepcidin is related to the pathogenesis of chronic renal failure anemia, which is considered a chronic inflammatory state as well as HCV infection. IL-6 stimulates the release of hepcidin from the liver, suppresses intestinal iron uptake, and releases iron from internal stores. Method: To detect the association between IL-6 gene polymorphism and anemia markers, 80 hemodialysis (HD) patients [40 negative HCV HD patients and 40 positive HCV HD patients] were studied by routine chemistry and complete blood count, in addition to the assessment of serum hepcidin, iron parameters [serum iron and serum ferritin], and hepatitis C markers. IL-6 polymorphism -174G/C was determined by MS-PCR, while IL-6 polymorphisms -597G/A and -572 G/C were detected by PCR-SSP. Results: Hepcidin was non-significantly elevated in HCV-positive compared with HCV-negative hemodialysis patients. A statistically significant difference was detected between the negative and positive HCV HD patients in frequencies of IL-6 -174 G/C and -597 G/A (P≤ 0.01 and P≤ 0.001, respectively). On the other hand, a non-significant difference was reported between negative and positive HCV HD patients in the frequencies of IL-6 -572 G/C. Conclusions: Our study indicated that IL-6 -174 G/C and -597 G/A polymorphisms may play a role in HCV susceptibility in HD patients. Additional prospective studies on a larger population are needed to confirm our findings.

RESUMO Introdução: A hepcidina está associada à patogênese da anemia por insuficiência renal crônica, considerada um estado inflamatório crônico e também infecção por HCV. A IL-6 estimula a liberação de hepcidina a partir do fígado, suprime a captação intestinal de ferro e libera ferro das reservas internas. Método: Para detectar a associação entre o polimorfismo do gene IL-6 e os marcadores de anemia, 80 pacientes em hemodiálise (HD) [40 pacientes em HD, negativos para HCV; e 40 em HD, positivos para HCV] foram avaliados por exames químicos de rotina e hemograma completo, além da avaliação da hepcidina sérica, parâmetros do ferro [ferro sérico e ferritina sérica] e marcadores de hepatite C. O polimorfismo da IL-6 -174G/C foi determinado por MS-PCR, enquanto os polimorfismos de IL-6 -597G/A e -572 G/C foram detectados por PCR-SSP. Resultados: A hepcidina não esteve significativamente elevada em pacientes com HCV em comparação com pacientes em hemodiálise negativos para HCV. Uma diferença estatisticamente significativa foi detectada entre os pacientes em HD HCV negativos comparados aos positivos nas frequências de IL-6 -174 G/C e -597 G/A (P≤ 0,01 e P≤ 0,001, respectivamente). Por outro lado, foi relatada uma diferença não significativa entre pacientes em HD HCV negativos e positivos nas frequências de IL-6 -572 G/C. Conclusões: Nosso estudo indicou que os polimorfismos de IL-6 -174 G/C e -597 G/A podem desempenhar um papel na suscetibilidade ao HCV em pacientes em HD. Ainda necessitamos de estudos prospectivos adicionais em uma população maior para confirmar nossos achados.

Urine hepcidin, netrin-1, neutrophil gelatinase-associated lipocalin and C-C motif chemokine ligand 2 levels in multicystic dysplastic kidney / Níveis de hepcidina, netrina-1, lipocalina associada a gelatinase neutrofílica e ligante de quimiocina C-C motif na urina do rim displásico multicístico

ABSTRACT Introduction: Glomerular hyperfiltration may lead to proteinuria and chronic kidney disease in unilateral multicystic dysplastic kidney (MCDK). We aimed to investigate the urine neutrophil-gelatinase-associated lipocalin (NGAL), netrin-1, hepcidin, and C-C motif chemokine ligand-2 (MCP-1/CCL-2) levels in patients with MCDK. Methods: Thirty-two patients and 25 controls were included. The urine hepcidin, netrin-1, NGAL, and MCP-1/CCL-2 levels were determined by ELISA. Results: The patients had higher serum creatinine (Cr) levels, urine albumin, and netrin-1/Cr ratio with lower GFR. There were positive correlations between urine protein/Cr, MCP-1/CCL-2/Cr, and netrin-1 with NGAL (r = 0.397, p = 0.031; r = 0.437, p = 0.041, r = 0.323, p = 0.042, respectively). Urine netrin-1/Cr was positively correlated with MCP-1/CCL-2/Cr (r = 0.356, p = 0.045). There were positive associations between the presence of proteinuria and netrin-1/Cr, MCP-1/CCL-2/Cr, and NGAL/Cr [Odds ratio (OR): 1.423, p = 0.037, OR: 1.553, p = 0.033, OR: 2.112, p = 0.027, respectively)]. ROC curve analysis showed that netrin-1/Cr, MCP-1/CCL-2/Cr, and NGAL/Cr had high predictive values for determining proteinuria p = 0.027, p = 0.041, p = 0.035, respectively). Urine hepcidin/Cr was negatively correlated with tubular phosphorus reabsorption and was positively correlated with urine NGAL/Cr (r = -0.418, p = 0.019; r = 0.682, p = 0.000; respectively). Conclusions: MCP-1/CCL-2 may play a role in the development of proteinuria in MCDK. Netrin-1 may be a protective factor against proteinuria-induced renal injury. Urine hepcidin/Cr may reflect proximal tubule damage in MCDK. Urine NGAL/Cr may be a predictor of tubule damage by proteinuria.

Resumo Introdução: A hiperfiltração glomerular pode causar proteinúria e doença renal crônica no rim displásico multicístico unilateral (RDM). Nosso objetivo foi investigar os níveis de lipocalina associada à gelatinase neutrofílica na urina (NGAL), netrina-1, hepcidina e quimiocina C-C com ligante-2 (MCP-1/CCL-2) em pacientes com RDM. Métodos: Trinta e dois pacientes e 25 controles foram incluídos. Os níveis urinários de hepcidina, netrin-1, NGAL e MCP-1/CCL-2 foram determinados por ELISA. Resultados: Os pacientes apresentaram níveis séricos mais elevados de creatinina (Cr), albumina na urina e relação netrina-1/Cr com menor TFG. Houve correlação positiva entre proteína na urina/Cr, MCP-1/CCL-2/Cr e netrina-1 com NGAL (r = 0,397, p = 0,031; r = 0,437, p = 0,041, r = 0,323, p = 0,042, respectivamente). A netrina-1/Cr na urina foi correlacionada positivamente com MCP-1/CCL-2/Cr (r = 0,356, p = 0,045). Houve associações positivas entre a presença de proteinúria e netrina-1/Cr, MCP-1/CCL-2/Cr e NGAL/Cr [Odds ratio (OR): 1,423, p = 0,037, OR: 1,553, p = 0,033, OR: 2,112, p = 0,027, respectivamente) ]. A análise da curva ROC mostrou que netrina-1/Cr, MCP-1/CCL-2/Cr e NGAL/Cr apresentaram altos valores preditivos para determinar a proteinúria p = 0,027, p = 0,041, p = 0,035, respectivamente). A hepcidina/Cr na urina foi correlacionada negativamente com a reabsorção tubular de fósforo e positivamente com a NGAL/Cr na urina (r = -0,418, p = 0,019; r = 0,682, p = 0,000; respectivamente). Conclusões: MCP-1/CCL-2 pode ter participação no desenvolvimento de proteinúria no RDM. A Netrina-1 pode ser um fator protetor contra lesão renal induzida por proteinúria. Hepcidina/Cr na urina pode refletir danos em túbulos proximais no RDM. O valor de NGAL/Cr urinário pode ser um preditor de danos nos túbulos por proteinúria.

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.

The effect of hepcidin on components of metabolic syndrome in chronic kidney disease: a cross-sectional study

SUMMARY BACKGROUND Hepcidin is an important regulator of iron homeostasis. OBJECTIVES This cross-sectional study was conducted to evaluate the association between hepcidin and components of metabolic syndrome in patients with chronic kidney disease (CKD). DESIGN AND SETTING 103 CKD patients and 59 healthy volunteers were included in the study from the University Hospital. METHODS Serum hepcidin levels were measured by enyzme-linked immunosorbent assay (ELISA) test. As for the study parameters, age, sex, body mass index, renal diseases, serum biochemistry, complete blood count, iron and total iron-binding capacity, ferritin, high-sensitive C-reactive protein (hsCRP), C- reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were evaluated. RESULTS The mean age of the patients was 58.63 ± 11.8 years. Hepcidin level was significantly associated with hypertension and higher uric acid levels (P < 0.05). There was a positive correlation between hepcidin and urea, uric acid, creatinine, ferritin, CRP, ESR, phosphorus, triglyceride, low-density lipoprotein (LDL), proteinuria and albuminuria in 24-hour urine collection. A negative correlation was found between hepcidin and estimated glomerular filtration rate (eGFR), hemoglobin, hematocrit, calcium, 25 OH vitamin D, pH, and bicarbonate levels. CONCLUSION Hepcidin, a well-known hormone regulator of iron metabolism, may play an important role in the pathogenesis of metabolic syndrome in patients with CKD, and further studies might delineate in-depth its potential as a promising early marker in these patients.

RESUMO FUNDAMENTO A hepcidina é um importante regulador da homeostase do ferro. OBJETIVOS Este estudo transversal foi realizado para avaliar a associação entre hepcidina e componentes da síndrome metabólica em pacientes com doença renal crônica (DRC). PROJETO E LOCAL Cento e três pacientes com DRC e 59 voluntários saudáveis foram incluídos no estudo no Hospital Universitário. MÉTODOS Os níveis séricos de hepcidina foram medidos pelo teste imunoenzimático (Elisa). Quanto aos parâmetros do estudo, idade, sexo, índice de massa corporal, doenças renais, bioquímica sérica, hemograma completo, capacidade de ligação total de ferro e ferro, ferritina, proteína C reativa altamente sensível (hsCRP), proteína C reativa (PCR) e taxa de sedimentação de eritrócitos (VHS) foram avaliados. RESULTADOS A idade média dos pacientes foi de 58,63±11,8 anos. Número de pacientes em cada estágio da DRC, do estágio I ao estágio V (não em terapia renal substitutiva). O nível de hepcidina foi significativamente associado à hipertensão e níveis mais altos de ácido úrico (P <0,05). Houve correlação positiva entre hepcidina e ureia, ácido úrico, creatinina, ferritina, PCR, VHS, fósforo, triglicerídeo, lipoproteína de baixa densidade (LDL), proteinúria e albuminúria na coleta de urina de 24 horas. Foi encontrada correlação negativa entre hepcidina e taxa de filtração glomerular estimada (TFGe), hemoglobina, hematócrito, cálcio, 25 OH de vitamina D, pH e níveis de bicarbonato. CONCLUSÃO A hepcidina é um hormônio bem conhecido que regula o metabolismo do ferro, mas também pode ser um importante contribuinte para os componentes da síndrome metabólica em pacientes com DRC.

Genetic Variability and Trajectories of DNA Methylation May Support a Role for HAMP in Patient Outcomes After Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND/OBJECTIVE: Preclinical evidence suggests that iron homeostasis is an important biological mechanism following aneurysmal subarachnoid hemorrhage (aSAH); however, this concept is underexplored in humans. This study examined the relationship between patient outcomes following aSAH and genetic variants and DNA methylation in the hepcidin gene (HAMP), a key regulator of iron homeostasis. METHODS: In this exploratory, longitudinal observational study, participants with verified aSAH were monitored for acute outcomes including cerebral vasospasm (CV) and delayed cerebral ischemia (DCI) and evaluated post-discharge at 3 and 12 months for long-term outcomes of death and functional status using the Modified Rankin Scale (mRS; poor = 3-6) and Glasgow Outcome Scale (GOS; poor = 1-3). Participants were genotyped for two genetic variants, and DNA methylation data were collected from serial cerebrospinal fluid over 14 days post-aSAH at eight methylation sites within HAMP. Participants were grouped based on their site-specific DNA methylation trajectory, with and without correcting for cell-type heterogeneity (CTH), and the associations between genetic variants and inferred DNA methylation trajectory groups and patient outcomes were tested. To correct for multiple testing, an empirical significance threshold was computed using permutation testing. RESULTS: Genotype data for rs10421768 and rs7251432 were available for 241 and 371 participants, respectively, and serial DNA methylation data were available for 260 participants. Acute outcome prevalence included CV in 45% and DCI in 37.1% of the overall sample. Long-term outcome prevalence at 3 and 12 months included poor GOS in 23% and 21%, poor mRS in 31.6% and 27.3%, and mortality in 15.1% and 18.2%, respectively, in the overall sample. Being homozygous for the rs7251432 variant allele was significantly associated with death at 3 months (p = 0.003) and was the only association identified that passed adjustment for multiple testing mentioned above. Suggestive associations (defined as trending toward significance, p value < 0.05, but not meeting empirical significance thresholds) were identified between the homozygous variant allele for rs7251432 and poor GOS and mRS at 3 months (both p = 0.04) and death at 12 months (p = 0.02). For methylation trajectory groups, no associations remained significant after correction for multiple testing. However, for methylation trajectory groups not adjusted for CTH, suggestive associations were identified between cg18149657 and poor GOS and mRS at 3 months (p = 0.003 and p = 0.04, respectively) and death at 3 months (p = 0.04), and between cg26283059 and DCI (p = 0.01). For methylation trajectory groups adjusted for CTH, suggestive associations were identified between cg02131995 and good mRS at 12 months (p = 0.02), and between cg26283059 and DCI (p = 0.01). CONCLUSIONS: This exploratory pilot study offers preliminary evidence that HAMP may play a role in patient outcomes after aSAH. Replication of this study and mechanistic investigation of the role of HAMP in patient outcomes after aSAH are needed.

Human Antimicrobial Peptides as Therapeutics for Viral Infections.

Successful in vivo infection following pathogen entry requires the evasion and subversion of multiple immunological barriers. Antimicrobial peptides (AMPs) are one of the first immune pathways upregulated during infection by multiple pathogens, in multiple organs in vivo. In humans, there are many classes of AMPs exhibiting broad antimicrobial activities, with defensins and the human cathelicidin LL-37 being the best studied examples. Whereas historically the efficacy and therapeutic potential of AMPs against bacterial infection has been the primary focus of research, recent studies have begun to elucidate the antiviral properties of AMPs as well as their role in regulation of inflammation and chemoattraction. AMPs as therapeutic tools seem especially promising against emerging infectious viral pathogens for which no approved vaccines or treatments are currently available, such as dengue virus (DENV) and Zika virus (ZIKV). In this review, we summarize recent studies elucidating the efficacy and diverse mechanisms of action of various classes of AMPs against multiple viral pathogens, as well as the potential use of human AMPs in novel antiviral therapeutic strategies.

High levels of serum IL-6 and serum hepcidin and low CD4 cell count were risk factors of anemia of chronic disease in HIV patients on the combination of antiretroviral therapy.

Purpose: This study aimed to determine whether high levels of serum IL-6 and serum hepcidin and CD4<350 cells/ul were risk factors for the anemia of chronic disease (ACD) in HIV-infected patients on the combination of antiretroviral (cARV) therapy with successful clinically and immunological responses. Patients and Methods: A matched case-control study was conducted in the VCT clinic of Sanglah General Hospital, Indonesia, between January 1 and September 1, 2016. The case group was HIV patients with ACD, while the control group was HIV patients without ACD. Purposive consecutive sampling was employed in HIV patients aged 15-65 years who have received cARV therapy for >6 months, had >95% adherence of cARV within 6 months, did not have any clinical failure, did not have any immunological failure and did not receive switch therapy within 6 months. Chi-square test and logistic regression analysis were performed. Results: A total of 42 cases and 42 controls were included in this study. Significant differences were found between case and control, which included serum IL-6, serum hepcidin, smoking, creatinine clearance, anemia at the initiation of cARV, CD4 at the initiation of cARV and actual CD4 (cell/µL). High levels of serum IL-6, high levels of serum hepcidin and CD4< 350 cells/µl were risk factors for ACD. After adjusted with anemia at cARV initiation and BMI, we found that high levels of serum IL-6 (adjusted OR: 17.682; 95% CI: 3.442-90.826), high levels of serum hepcidin (adjusted OR: 10.562; 95% CI: 2.531-44.076) and CD4 <350 cells/µl (adjusted OR: 4.181; 95% CI: 5.6-12.381) remain as risk factors for ACD. Conclusion: High levels of serum IL-6, high levels of serum hepcidin and CD4 count <350 cells/µL were risk factors for ACD in HIV patients with cARV therapy.

Increased Serum Hepcidin Levels in Children and Adolescents with Attention Deficit Hyperactivity Disorder.

OBJECTIVE: In this study, we aimed to evaluate the serum hepcidin levels in attention deficit hyperactivity disorder (ADHD) patients that were newly diagnosed with no history of psychotropic drugs. METHODS: A total of 70 ADHD patients and 69 healthy controls were enrolled in our study. During the diagnosis, the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version were applied. The sociodemographic data form, Turgay DSM-IV-Based Child and Adolescent Behavior Disorders Screening and Rating Scale, and Conners' Rating Scales-Revised: Long Form were used for the clinical evaluation. Serum hepcidin levels were measured and compared between the groups. RESULTS: No significant difference between the groups in terms of age (p=0.533) and gender (p=0.397) was determined. In addition, the groups did not differ significantly for the other sociodemographic variables recorded. Serum hepcidin levels were found to be significantly higher in the patients with ADHD than healthy controls (p=0.019). CONCLUSION: To the best of our knowledge, this study is the first to evaluate the total serum hepcidin levels in ADHD patients. Our study findings may suggest that high levels of hepcidin may cause iron dysregulation in ADHD patients. However, further studies are required to establish a definite conclusion.

Measurement of iron status in chronic kidney disease.

Anemia is a common complication of chronic kidney disease (CKD) in children, and dysregulation of iron homeostasis plays a central role in its pathogenesis. Optimizing iron status is a prerequisite for effective treatment of anemia. Insufficient iron can lead to inappropriate escalation of the erythropoiesis-stimulating agent (ESA) dose, which is associated with adverse outcomes. Excess iron supplementation also has negative sequelae including free radical tissue damage and increased risk of systemic infection. Notwithstanding the importance of optimizing bioavailable iron for erythropoiesis for children with advanced CKD, achieving this remains challenging for pediatric nephrologists due to the historical lack of practical and robust measures of iron status. In recent years, novel techniques have come to the fore to facilitate accurate and practical assessment of iron balance. These measures are the focus of this review, with emphasis on their relevance to the pediatric CKD population.

Hepcidin Deficiency Protects Against Atherosclerosis.

Objective- Inflammatory stimuli enhance the progression of atherosclerotic disease. Inflammation also increases the expression of hepcidin, a hormonal regulator of iron homeostasis, which decreases intestinal iron absorption, reduces serum iron levels and traps iron within macrophages. The role of macrophage iron in the development of atherosclerosis remains incompletely understood. The objective of this study was to investigate the effects of hepcidin deficiency and decreased macrophage iron on the development of atherosclerosis. Approach and Results- Hepcidin- and LDL (low-density lipoprotein) receptor-deficient ( Hamp-/-/ Ldlr-/-) mice and Hamp+/+/ Ldlr-/- control mice were fed a high-fat diet for 21 weeks. Compared with control mice, Hamp-/-/ Ldlr-/- mice had decreased aortic macrophage activity and atherosclerosis. Because hepcidin deficiency is associated with both increased serum iron and decreased macrophage iron, the possibility that increased serum iron was responsible for decreased atherosclerosis in Hamp-/-/ Ldlr-/- mice was considered. Hamp+/+/ Ldlr-/- mice were treated with iron dextran so as to produce a 2-fold increase in serum iron. Increased serum iron did not decrease atherosclerosis in Hamp+/+/ Ldlr-/- mice. Aortic macrophages from Hamp-/-/ Ldlr-/- mice had less labile free iron and exhibited a reduced proinflammatory (M1) phenotype compared with macrophages from Hamp+/+/ Ldlr-/- mice. THP1 human macrophages treated with an iron chelator were used to model hepcidin deficiency in vitro. Treatment with an iron chelator reduced LPS (lipopolysaccharide)-induced M1 phenotypic expression and decreased uptake of oxidized LDL. Conclusions- In summary, in a hyperlipidemic mouse model, hepcidin deficiency was associated with decreased macrophage iron, a reduced aortic macrophage inflammatory phenotype and protection from atherosclerosis. The results indicate that decreasing hepcidin activity, with the resulting decrease in macrophage iron, may prove to be a novel strategy for the treatment of atherosclerosis.

The effect of nonsurgical periodontal therapy on hepcidin and on inflammatory and iron marker levels

Abstract Serum hepcidin levels may increase in response to infection and inflammation. The present study investigated the effect of nonsurgical periodontal therapy (NSPT) on levels of serum hepcidin, inflammatory markers, and iron markers. An interventional study was conducted on 67 patients (age 30-65 years) without other diseases, except for chronic periodontitis (CP). Patients were allocated to either CP or control groups. The CP group received supragingival and subgingival scaling and root planing procedures, whereas the control group received supragingival scaling. Probing depth (PD), bleeding on probing, clinical attachment level (CAL), visible plaque index (VPI), serum hepcidin and interleukin-6 (IL-6) levels, high-sensitivity C-reactive protein (hs-CRP), hematological markers, and iron markers were measured at baseline and at 90 days after NSPT. The CP group had statistically significant lower mean values for mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) (p ≤ 0.05). The control group had statistically significant reductions in hemoglobin, hematocrit, MCV, and MCH (p ≤ 0.05). Serum hepcidin, IL-6, and erythrocyte sedimentation rate (ESR) levels were significantly decreased in both groups after NSPT. Periodontal markers were more markedly reduced in the CP group compared with the control group (p ≤ 0.05). These findings suggest that NSPT may reduce the serum levels of IL-6, hepcidin, and periodontal parameters.

Frequency and correlates of tardive dyskinesia in Indian patients with type I bipolar disorder.

BACKGROUND: Patients with Bipolar Disorder (BD) may have higher risk of Tardive Dyskinesia (TD). Theories for TD include inflammatory or oxidative stress and altered iron metabolism. The current frequency and clinical and biochemical correlates of TD in BD needs exploration. OBJECTIVES: To assess: (1) the frequency of TD in BD; (2) clinical correlates of TD in BD; (3) oxidative stress markers, inflammatory markers and hepcidin in TD in BD. MATERIALS & METHODS: In this cross-sectional study, 170 patients with BD were assessed for clinical characteristics using structured assessments. Inflammatory and oxidative markers like Interleukin-6 (IL-6), high sensitivity C-Reactive Protein (hsCRP), malondialdehyde (MDA), Total Antioxidant Status (TAS) and hepcidin were assessed by ELISA. RESULTS: Frequency of TD was 10.6% (95%C.I.=6.4%-16.2%). Compared to patients without TD, patients with TD were older (F=0.340;p=0.000), had more episodes of illness (U=962.5;p=0.044) higher rates of medical comorbidity (X2=6.924; p=0.009*), antipsychotic exposure (U=592.5;p=0.000), typical antipsychotic exposure (U=756.5;p=0.001) and cognitive deficits (F=1.129;p=0.001). The biomarkers levels did not differ between the groups. Hepcidin levels correlated with Abnormal involuntary Movements scale (AIMS) score (r=0.213;p=0.006). Patients treated with lithium were more likely to have TD, but also had greater exposure to antipsychotics than patients on valproate. CONCLUSION: About one-tenth of patients with BD-I have TD. The presence of TD is associated several clinical characteristics such as age, exposure to typical antipsychotics and chronicity of illness. Hepcidin was associated with greater severity of dyskinetic movements and needs further exploration.

Hepcidina y parámetros del hierro en donantes de sangre / Hepcidin and iron parameters on blood

Resumen Introducción: la hepcidina es la principal hormona peptídica reguladora de la absorción y distribución tisular del hierro. Estudios recientes han planteado la posibilidad de utilizarla como un biomarcador para evaluar el metabolismo del hierro y sus posibles alteraciones. Aunque, ante la esca­sa información sobre las propiedades diagnósticas de la hepcidina sérica, no han sido bien caracterizadas y no se cuenta con estudios suficientes en individuos sanos, e incluso en Colombia hasta el momento no se ha realizado ningún estudio referente al tema. Objetivo: estimar las concen­traciones de la hepcidina sérica, su rango de normalidad y su correlación con parámetros bioquímicos asociados al metabolismo del hierro en una población de donantes. Materiales y métodos: estudio descriptivo trans­versal que incluyó 85 donantes, a quienes se les realizó hemograma auto­matizado, se evaluó ferritina, transferrina y hierro total, mediante los mé­todos de electroquimioluminiscencia, inmunoturbidimetría y colorimetría. La determinación de hepcidina en suero se realizó por medio de una ELISA competitiva. Se utilizaron pruebas estadísticas, con un nivel de significan­cia de p< 0,05. Resultados: se observaron diferencias significativas en la concentración de hepcidina entre hombres y mujeres. La edad no fue un factor determinante de las concentraciones de hepcidina en los hombres Mediana (Me)=5,73 nM. Solo ferritina se correlacionó fuertemente con la hepcidina. El rango de normalidad de hepcidina encontrado en hombres estuvo entre 1,71 y 13,3 nM y entre 1,67 a 11,3 nM en mujeres. Conclusión: el nivel de hepcidina sérica es mayor en hombres y demuestra la fuerte asociación in vivo con los niveles de hepcidina sérica con el hierro de re­serva y circulante.

Abstract Introduction: The hepatic peptide hormone hepcidin is the principal regulator of iron absorption and tissue iron distribution. Recent studies have proposed hepcidin as a suitable biomarker to assess iron metabolism and its failures. Although the data were limited to information on the diagnostic properties of serum hepcidin, have not been well characterized and neither have enough studies in healthy individuals, and even in Colombia so far have not been any studies on the topic. Objective: quantify the concentrations of serum hepcidin, establish a normal range and determine the correlate with biochemical parameters associated with iron metabolism in a population of donors. Materials and methods: A cross-wise study was performed on total of 85 donors to whom an automatized blood panel was tested. Ferritin, iron and transferrin were measured through electrochimioluminiscence, inmmunoturbidimetry and colorimetry respectively. Seric hepcidin presence was evidenced by competitive ELISA. Data was statistically analized with a significance level of p< 0, 05. Results: Statistically significant differences were noticed in the hepcidin concentration when comparing women and men. Hepcidin concentrations in men were constant over age (median, 5.73nM). Only ferritin is strongly correlated with hepcidin. Normal values for women ranged between 1,67nM -11,3 nM while those for men did slightly higher 1,71 nM - 13,3 nM. Conclusions: Serum hepcidin levels are higher in men and demonstrates a strong in vivo correlation between seric hepcidin and iron either circulating or storage.

Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD.

BACKGROUND AND OBJECTIVES: Roxadustat (FG-4592), an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis, regulates iron metabolism, and reduces hepcidin, was evaluated in this phase 2b study for safety, efficacy, optimal dose, and dose frequency in patients with nondialysis CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The 145 patients with nondialysis CKD and hemoglobin ≤10.5 g/dl were randomized into one of six cohorts of approximately 24 patients each with varying roxadustat starting doses (tiered weight and fixed amounts) and frequencies (two and three times weekly) followed by hemoglobin maintenance with roxadustat one to three times weekly. Treatment duration was 16 or 24 weeks. Intravenous iron was prohibited. The primary end point was the proportion of patients achieving hemoglobin increase of ≥1.0 g/dl from baseline and hemoglobin of ≥11.0 g/dl by week 17 (16 weeks of treatment). Secondary analyses included mean hemoglobin change from baseline, iron utilization, and serum lipids. Safety was evaluated by frequency/severity of adverse events. RESULTS: Of the 145 patients enrolled, 143 were evaluable for efficacy. Overall, 92% of patients achieved hemoglobin response. Higher compared with lower starting doses led to earlier achievement of hemoglobin response. Roxadustat-induced hemoglobin increases were independent of baseline C-reactive protein levels and iron repletion status. Overall, over the first 16 treatment weeks, hepcidin levels decreased by 16.9% (P=0.004), reticulocyte hemoglobin content was maintained, and hemoglobin increased by a mean (±SD) of 1.83 (±0.09) g/dl (P<0.001). Overall mean total cholesterol level was reduced by a mean (±SD) of 26 (±30) mg/dl (P<0.001) after 8 weeks of therapy, independent of the use of statins or other lipid-lowering agents. No drug-related serious adverse events were reported. CONCLUSIONS: In patients with nondialysis CKD who were anemic, various starting dose regimens of roxadustat were well tolerated and achieved anemia correction with reduced serum hepcidin levels. After anemia correction, hemoglobin was maintained by roxadustat at various dose frequencies without intravenous iron supplementation.

Antimicrobial Peptides as Mediators of Innate Immunity in Teleosts.

Antimicrobial peptides (AMPs) have been identified throughout the metazoa suggesting their evolutionarily conserved nature and their presence in teleosts is no exception. AMPs are short (18-46 amino acids), usually cationic, amphipathic peptides. While AMPs are diverse in amino acid sequence, with no two AMPs being identical, they collectively appear to have conserved functions in the innate immunity of animals towards the pathogens they encounter in their environment. Fish AMPs are upregulated in response to pathogens and appear to have direct broad-spectrum antimicrobial activity towards both human and fish pathogens. However, an emerging role for AMPs as immunomodulatory molecules has become apparent-the ability of AMPs to activate the innate immune system sheds light onto the multifaceted capacity of these small peptides to combat pathogens through direct and indirect means. Herein, this review focuses on the role of teleost AMPs as modulators of the innate immune system and their regulation in response to pathogens or other exogenous molecules. The capacity to regulate AMP expression by exogenous factors may prove useful in modulating AMP expression in fish to prevent disease, particularly in aquaculture settings where crowded conditions and environmental stress pre-dispose these fish to infection.