Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 704
Filtrar
1.
Sci Rep ; 11(1): 19618, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34608227

RESUMO

The pathophysiology and the factors determining disease severity in COVID-19 are not yet clear, with current data indicating a possible role of altered iron metabolism. Previous studies of iron parameters in COVID-19 are cross-sectional and have not studied catalytic iron, the biologically most active form of iron. The study was done to determine the role of catalytic iron in the adverse outcomes in COVID-19. We enrolled adult patients hospitalized with a clinical diagnosis of COVID-19 and measured serum iron, transferrin saturation, ferritin, hepcidin and serum catalytic iron daily. Primary outcome was a composite of in-hospital mortality, need for mechanical ventilation, and kidney replacement therapy. Associations between longitudinal iron parameter measurements and time-to-event outcomes were examined using a joint model. We enrolled 120 patients (70 males) with median age 50 years. The primary composite outcome was observed in 25 (20.8%) patients-mechanical ventilation was needed in 21 (17.5%) patients and in-hospital mortality occurred in 21 (17.5%) patients. Baseline levels of ferritin and hepcidin were significantly associated with the primary composite outcome. The joint model analysis showed that ferritin levels were significantly associated with primary composite outcome [HR (95% CI) = 2.63 (1.62, 4.24) after adjusting for age and gender]. Both ferritin and serum catalytic iron levels were positively associated with in-hospital mortality [HR (95% CI) = 3.22 (2.05, 5.07) and 1.73 (1.21, 2.47), respectively], after adjusting for age and gender. The study shows an association of ferritin and catalytic iron with adverse outcomes in COVID-19. This suggests new pathophysiologic pathways in this disease, also raising the possibility of considering iron chelation therapy.


Assuntos
COVID-19/patologia , Ferro/sangue , Adulto , Idoso , COVID-19/mortalidade , COVID-19/virologia , Estudos Transversais , Feminino , Ferritinas/sangue , Ferritinas/metabolismo , Hepcidinas/sangue , Hepcidinas/metabolismo , Mortalidade Hospitalar , Humanos , Ferro/química , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Respiração Artificial , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Transferrina/química , Transferrina/metabolismo
2.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360974

RESUMO

Erythropoietin (EPO) downregulates hepcidin expression to increase the availability of iron; the downregulation of hepcidin is mediated by erythroferrone (ERFE) secreted by erythroblasts. Erythroblasts also express transferrin receptor 2 (TFR2); however, the possible role of TFR2 in hepcidin downregulation is unclear. The purpose of the study was to correlate liver expression of hepcidin with the expression of ERFE and TFR2 in murine bone marrow and spleen at 4, 16, 24, 48, 72 and 96 h following administration of a single dose of EPO. Splenic Fam132b expression increased 4 h after EPO injection; liver hepcidin mRNA was decreased at 16 h. In the spleen, expression of TFR2 and transferrin receptor (TFR1) proteins increased by an order of magnitude at 48 and 72 h after EPO treatment. The EPO-induced increase in splenic TFR2 and TFR1 was associated with an increase in the number of Tfr2- and Tfr1-expressing erythroblasts. Plasma exosomes prepared from EPO-treated mice displayed increased amount of TFR1 protein; however, no exosomal TFR2 was detected. Overall, the results confirm the importance of ERFE in stress erythropoiesis, support the role of TFR2 in erythroid cell development, and highlight possible differences in the removal of TFR2 and TFR1 from erythroid cell membranes.


Assuntos
Eritropoetina/farmacologia , Receptores da Transferrina/genética , Animais , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Eritroblastos/efeitos dos fármacos , Eritroblastos/metabolismo , Exossomos/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Receptores da Transferrina/metabolismo , Baço/metabolismo
3.
Int J Mol Sci ; 22(16)2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34445419

RESUMO

Dysregulation of brain iron metabolism is one of the pathological features of aging and Alzheimer's disease (AD), a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. While physical inactivity is one of the risk factors for AD and regular exercise improves cognitive function and reduces pathology associated with AD, the underlying mechanisms remain unclear. The purpose of the study is to explore the effect of regular physical exercise on modulation of iron homeostasis in the brain and periphery of the 5xFAD mouse model of AD. By using inductively coupled plasma mass spectrometry and a variety of biochemical techniques, we measured total iron content and level of proteins essential in iron homeostasis in the brain and skeletal muscles of sedentary and exercised mice. Long-term voluntary running induced redistribution of iron resulted in altered iron metabolism and trafficking in the brain and increased iron content in skeletal muscle. Exercise reduced levels of cortical hepcidin, a key regulator of iron homeostasis, coupled with interleukin-6 (IL-6) decrease in cortex and plasma. We propose that regular exercise induces a reduction of hepcidin in the brain, possibly via the IL-6/STAT3/JAK1 pathway. These findings indicate that regular exercise modulates iron homeostasis in both wild-type and AD mice.


Assuntos
Doença de Alzheimer/reabilitação , Encéfalo/metabolismo , Ferro/metabolismo , Músculo Esquelético/metabolismo , Doença de Alzheimer/metabolismo , Animais , Modelos Animais de Doenças , Exercício Físico , Regulação da Expressão Gênica , Hepcidinas/metabolismo , Homeostase , Humanos , Interleucina-6/metabolismo , Masculino , Espectrometria de Massas , Camundongos , Camundongos Transgênicos , Comportamento Sedentário
4.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204327

RESUMO

Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Hepcidinas/metabolismo , Homeostase , Ferro/metabolismo , Animais , Comunicação Autócrina , Transporte Biológico , Proteínas de Transporte de Cátions/química , Suscetibilidade a Doenças , Hepcidinas/química , Humanos , Ligantes , Redes e Vias Metabólicas , Comunicação Parácrina , Ligação Proteica , Transdução de Sinais , Distribuição Tecidual
5.
Am J Hematol ; 96(10): 1275-1286, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34310730

RESUMO

Hematopoietic cell transplantation (HCT) brings important alterations in erythropoiesis and iron metabolism. Hepcidin, which regulates iron metabolism, increases in iron overload or inflammation and decreases with iron deficiency or activated erythropoiesis. Erythroferrone (ERFE) is the erythroid regulator of hepcidin. We investigated erythropoiesis and iron metabolism after allogeneic HCT in 70 patients randomized between erythropoietin (EPO) treatment or no EPO, by serially measuring hepcidin, ERFE, CRP (inflammation), soluble transferrin receptor (sTfR, erythropoiesis), serum iron and transferrin saturation (Tsat; iron for erythropoiesis) and ferritin (iron stores). We identified biological and clinical factors associated with serum hepcidin and ERFE levels. Serum ERFE correlated overall with sTfR and reticulocytes and inversely with hepcidin. Erythroferrone paralleled sTfR levels, dropping during conditioning and recovering with engraftment. Inversely, hepcidin peaked after conditioning and decreased during engraftment. Erythroferrone and hepcidin were not significantly different with or without EPO. Multivariate analyses showed that the major determinant of ERFE was erythropoiesis (sTfR, reticulocytes or serum Epo). Pretransplant hepcidin was associated with previous RBC transfusions and ferritin. After transplantation, the major determinants of hepcidin were iron status (ferritin at all time points and Tsat at day 56) and erythropoiesis (sTfR or reticulocytes or ERFE), while the impact of inflammation was less clear and clinical parameters had no detectable influence. Hepcidin remained significantly higher in patients with high compared to low pretransplant ferritin. After allogeneic HCT with or without EPO therapy, significant alterations of hepcidin occur between pretransplant and day 180, in correlation with iron status and inversely with erythroid ERFE.


Assuntos
Eritropoese , Transplante de Células-Tronco Hematopoéticas , Hepcidinas/metabolismo , Ferro/metabolismo , Hormônios Peptídicos/metabolismo , Adulto , Idoso , Eritropoese/efeitos dos fármacos , Eritropoetina/uso terapêutico , Feminino , Hepcidinas/sangue , Humanos , Ferro/sangue , Masculino , Pessoa de Meia-Idade , Hormônios Peptídicos/sangue , Transplante Homólogo
6.
Am J Clin Nutr ; 114(4): 1408-1417, 2021 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-34258619

RESUMO

BACKGROUND: Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES: The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS: We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS: The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS: Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.


Assuntos
Adenocarcinoma/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Hepcidinas/metabolismo , Ferro/metabolismo , Neoplasias Pancreáticas/metabolismo , Idoso , Estudos de Casos e Controles , Feminino , Genótipo , Hepcidinas/genética , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
7.
J Alzheimers Dis ; 82(4): 1487-1497, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34180415

RESUMO

BACKGROUND: Accumulation of iron is a consistent feature of Alzheimer's disease (AD) brains. The underlying cause, however, remains debatable. OBJECTIVE: To explore whether local hepcidin synthesized by brain cells contributes to iron accumulation in AD brains. METHODS: Brain tissue from the cingulate cortex of 33 cases of AD pre-assigned to Braak stage I-VI, 6 cases of non-dementia, and 15 cases of non-AD dementia were analyzed for transcriptional upregulation of hepcidin by RT-qPCR and RT-PCR. Change in the expression of ferritin, ferroportin (Fpn), microglial activation marker Iba1, IL-6, and TGFß2 was determined by western blotting. Total tissue iron was determined by colorimetry. RESULTS: Significant transcriptional upregulation of hepcidin was observed in Braak stage III-VI relative to Braak stage I and II, non-AD dementia, and non-dementia samples. Ferritin was increased in Braak stage V, and a significant increase in tissue iron was evident in Braak stage III-VI. The expression of Iba1 and IL-6 was also increased in Braak stage III-VI relative to Braak stage I and II and non-AD dementia samples. Amyloid-ß plaques were absent in most Braak stage I and II samples, and present in Braak stage III-VI samples with few exceptions. CONCLUSION: These observations suggest that upregulation of brain hepcidin is mediated by IL-6, a known transcriptional activator of hepcidin. The consequent downregulation of Fpn on neuronal and other cells results in accumulation of iron in AD brains. The increase in hepcidin is disease-specific, and increases with disease progression, implicating AD-specific pathology in the accumulation of iron.


Assuntos
Doença de Alzheimer/patologia , Anti-Infecciosos/metabolismo , Ferritinas/metabolismo , Hepcidinas/metabolismo , Regulação para Cima , Idoso , Autopsia , Encéfalo/patologia , Feminino , Humanos , Interleucina-6/metabolismo , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
PLoS One ; 16(6): e0253475, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34161397

RESUMO

Hepcidin is a peptide hormone that targets the iron exporter ferroportin, thereby limiting iron entry into the bloodstream. It is generated in hepatocytes mainly in response to increased body iron stores or inflammatory cues. Iron stimulates expression of bone morphogenetic protein 6 (BMP6) from liver sinusoidal endothelial cells, which in turn binds to BMP receptors on hepatocytes and induces the SMAD signaling cascade for transcriptional activation of the hepcidin-encoding HAMP mRNA. SMAD signaling is also essential for inflammatory HAMP mRNA induction by the IL-6/STAT3 pathway. Herein, we utilized human Huh7 hepatoma cells and primary murine hepatocytes to assess the effects of iron perturbations on signaling to hepcidin. Iron chelation appeared to slightly impair signaling to hepcidin. Subsequent iron supplementation not only failed to reverse these effects, but drastically reduced basal HAMP mRNA and inhibited HAMP mRNA induction by BMP6 and/or IL-6. Thus, treatment of cells with excess iron inhibited basal and BMP6-mediated SMAD5 phosphorylation and induction of HAMP, ID1 and SMAD7 mRNAs in a dose-dependent manner. Iron also inhibited IL-6-mediated STAT3 phosphorylation and induction of HAMP and SOCS3 mRNAs. These responses were accompanied by induction of GCLC and HMOX1 mRNAs, known markers of oxidative stress. We conclude that hepatocellular iron overload suppresses hepcidin by inhibiting the SMAD and STAT3 signaling pathways downstream of their respective ligands.


Assuntos
Desferroxamina/farmacologia , Hepatócitos/metabolismo , Hepcidinas/metabolismo , Sobrecarga de Ferro/metabolismo , Sideróforos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Proteína Morfogenética Óssea 6/farmacologia , Linhagem Celular Tumoral , Hepatócitos/efeitos dos fármacos , Humanos , Interleucina-6/farmacologia , Camundongos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Proteínas Smad/metabolismo
9.
Nutrients ; 13(5)2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-34063414

RESUMO

Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is elevated. High Fpn1-mediated iron export depletes intracellular iron, causing a paradoxical increase in Dmt1-mediated iron import. Increased activity of both transporters causes excessive iron absorption, thus initiating body iron loading. Logically then, silencing of intestinal Dmt1 or Fpn1 could be an effective therapeutic intervention in HH. It was previously established that Dmt1 knock down prevented iron-loading in weanling Hamp (encoding hepcidin) KO mice (modeling type 2B HH). Here, we tested the hypothesis that Dmt1 silencing combined with dietary iron restriction (which may be recommended for HH patients) will mitigate iron loading once already established. Accordingly, adult Hamp KO mice were switched to a low-iron (LFe) diet and (non-toxic) folic acid-coupled, ginger nanoparticle-derived lipid vectors (FA-GDLVs) were used to deliver negative-control (NC) or Dmt1 siRNA by oral, intragastric gavage daily for 21 days. The LFe diet reduced body iron burden, and experimental interventions potentiated iron losses. For example, Dmt1 siRNA treatment suppressed duodenal Dmt1 mRNA expression (by ~50%) and reduced serum and liver non-heme iron levels (by ~60% and >85%, respectively). Interestingly, some iron-related parameters were repressed similarly by FA-GDLVs carrying either siRNA, including 59Fe (as FeCl3) absorption (~20% lower), pancreatic non-heme iron (reduced by ~65%), and serum ferritin (decreased 40-50%). Ginger may thus contain bioactive lipids that also influence iron homeostasis. In conclusion, the combinatorial approach of FA-GDLV and Dmt1 siRNA treatment, with dietary iron restriction, mitigated pre-existing iron overload in a murine model of HH.


Assuntos
Administração Oral , Gengibre/química , Hepcidinas/genética , Hepcidinas/metabolismo , Sobrecarga de Ferro/metabolismo , Ferro na Dieta/metabolismo , Nanopartículas/química , Fatores de Transcrição/metabolismo , Animais , Duodeno/metabolismo , Enterócitos/metabolismo , Ácido Fólico , Expressão Gênica , Hemocromatose/genética , Homeostase , Ferro/metabolismo , Sobrecarga de Ferro/genética , Lipídeos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição/genética
10.
Nat Metab ; 3(7): 969-982, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34155415

RESUMO

Colorectal cancer (CRC) requires massive iron stores, but the complete mechanisms by which CRC modulates local iron handling are poorly understood. Here, we demonstrate that hepcidin is activated ectopically in CRC. Mice deficient in hepcidin specifically in the colon tumour epithelium, compared with wild-type littermates, exhibit significantly diminished tumour number, burden and size in a sporadic model of CRC, whereas accumulation of intracellular iron by deletion of the iron exporter ferroportin exacerbates these tumour parameters. Metabolomic analysis of three-dimensional patient-derived CRC tumour enteroids indicates a prioritization of iron in CRC for the production of nucleotides, which is recapitulated in our hepcidin/ferroportin mouse CRC models. Mechanistically, our data suggest that iron chelation decreases mitochondrial function, thereby altering nucleotide synthesis, whereas exogenous supplementation of nucleosides or aspartate partially rescues tumour growth in patient-derived enteroids and CRC cell lines in the presence of an iron chelator. Collectively, these data suggest that ectopic hepcidin in the tumour epithelium establishes an axis to sequester iron in order to maintain the nucleotide pool and sustain proliferation in colorectal tumours.


Assuntos
Neoplasias Colorretais/metabolismo , Hepcidinas/metabolismo , Ferro/metabolismo , Mitocôndrias/metabolismo , Nucleotídeos/metabolismo , Animais , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Humanos , Camundongos
11.
PLoS One ; 16(6): e0252998, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34143808

RESUMO

Mucosal damage, barrier breach, inflammation, and iron-deficiency anemia (IDA) typify ulcerative colitis (UC) in humans. The anemia in UC appears to mainly relate to systemic inflammation. The pathogenesis of this 'anemia of inflammation' (AI) involves cytokine-mediated transactivation of hepatic Hamp (encoding the iron-regulatory hormone, hepcidin). In AI, high hepcidin represses iron absorption (and iron release from stores), thus lowering serum iron, and restricting iron for erythropoiesis (causing anemia). In less-severe disease states, inflammation may be limited to the intestine, but whether this perturbs iron homeostasis is uncertain. We hypothesized that localized gut inflammation will increase overall iron demand (to support the immune response and tissue repair), and that hepatic Hamp expression will decrease in response, thus derepressing (i.e., enhancing) iron absorption. Accordingly, we developed a rat model of mild, acute colitis, and studied iron absorption and homeostasis. Rats exposed (orally) to DSS (4%) for 7 days had intestinal (but not systemic) inflammation, and biomarker analyses demonstrated that iron utilization was elevated. Iron absorption was enhanced (by 2-3-fold) in DSS-treated, WT rats of both sexes, but unexpectedly, hepatic Hamp expression was not suppressed. Therefore, to gain a better understanding of regulation of iron absorption during acute colitis, Hamp KO rats were used for further experimentation. The severity of DSS-colitis was similar in Hamp KOs as in WT controls. In the KOs, increased iron requirements associated with the physiological response to colitis were satisfied by mobilizing hepatic storage iron, rather than by increasing absorption of enteral iron (as occurred in WT rats). In conclusion then, in both sexes and genotypes of rats, iron absorption was appropriately modulated to match physiological demand for dietary iron during acute intestinal inflammation, but regulatory mechanisms may not involve hepcidin.


Assuntos
Colite/fisiopatologia , Sulfato de Dextrana/efeitos adversos , Hepcidinas/genética , Ferro/metabolismo , Animais , Colite/induzido quimicamente , Colite/genética , Colite/metabolismo , Modelos Animais de Doenças , Feminino , Técnicas de Inativação de Genes , Hepcidinas/metabolismo , Absorção Intestinal , Fígado/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Índice de Gravidade de Doença
12.
Sci Rep ; 11(1): 13386, 2021 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-34183746

RESUMO

Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin (FPN1). However, the functions of FPN1 in hepatocyte secretion and macrophage polarization remain unknown. CD68 immunohistochemical staining and double immunofluorescence staining for F4/80 and Ki67 in transgenic mouse livers showed that the number of macrophages in FPN1-/+ and FPN1-/- mouse livers was significantly increased compared to that in WT (FPN+/+) mice. FPN1 downregulation in hepatic cells increased the levels of the M2 markers CD206, TGF- ß, VEGF, MMP-9, Laminin, Collagen, IL-4 and IL-10. Furthermore, the expression of CD16/32 and iNOS, as M1 markers, exhibited the opposite trend. Meanwhile, α-SMA immunohistochemistry and Sirius red staining showed that the trend of liver fibrosis in FPN1-/- mice was more significant than that in control mice. Similarly, in vitro FPN1 knockdown in L02-Sh/L02-SCR liver cell lines yielded similar results. Taken together, we demonstrated that downregulated FPN1 expression in hepatocytes can promote the proliferation and polarization of macrophages, leading to hepatic fibrosis. Above all, the FPN1 axis might provide a potential target for hepatic fibrosis.


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Hepatócitos/metabolismo , Cirrose Hepática/metabolismo , Macrófagos/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação para Baixo/fisiologia , Hepcidinas/metabolismo , Humanos , Ferro/metabolismo , Fígado/metabolismo , Ativação de Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fenótipo , Células THP-1
13.
Mol Cell Biochem ; 476(9): 3365-3381, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33942218

RESUMO

Iron is an essential trace element involved in oxidation-reduction reactions, oxygen transport and storage, and energy metabolism. Iron in excess can be toxic for cells, since iron produces reactive oxygen species and is important for survival of pathogenic microbes. There is a fine-tuning in the regulation of serum iron levels, determined by intestinal absorption, macrophage iron recycling, and mobilization of hepatocyte stores versus iron utilization, primarily by erythroid cells in the bone marrow. Hepcidin is the major regulatory hormone of systemic iron homeostasis and is upregulated during inflammation. Hepcidin metabolism is altered in chronic kidney disease. Ferroportin is an iron export protein and mediates iron release into the circulation from duodenal enterocytes, splenic reticuloendothelial macrophages, and hepatocytes. Systemic iron homeostasis is controlled by the hepcidin-ferroportin axis at the sites of iron entry into the circulation. Hepcidin binds to ferroportin, induces its internalization and intracellular degradation, and thus inhibits iron absorption from enterocytes, and iron release from macrophages and hepatocytes. Recent data suggest that hepcidin, by slowing or preventing the mobilization of iron from macrophages, may promote atherosclerosis and may be associated with increased cardiovascular disease risk. This article reviews the current data regarding the molecular and cellular pathways of systemic and autocrine hepcidin production and seeks the answer to the question whether changes in hepcidin translate into clinical outcomes of all-cause and cardiovascular mortality, and cardiovascular and renal end-points.


Assuntos
Biomarcadores/metabolismo , Doenças Cardiovasculares/diagnóstico , Hepcidinas/metabolismo , Homeostase , Ferro/metabolismo , Nefropatias/diagnóstico , Animais , Doenças Cardiovasculares/metabolismo , Humanos , Nefropatias/metabolismo
14.
Expert Opin Ther Pat ; 31(7): 585-595, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33975503

RESUMO

INTRODUCTION: Iron is a crucial element necessary for blood formation in the body and its normal growth. However, irregular metabolism of iron due to absence of an elimination mechanism may deposit excess iron in the organs (iron overload) leading to metabolic disorders. Interactions between the iron regulatory peptide hormone, hepcidin and the iron exporter ferroportin plays major role in regulating the iron metabolism. Mutations in the ferroportin encoding genes, and dysregulation of hepsidin production often results in iron overload resulting in conditions like hemochromatosis, ß-thalassemia, and sickle cell anemia. Until today, there is no efficacious treatment available for managing iron overload targeting ferroportin inhibition via oral administration. AREAS COVERED: Novel salts of substituted benzoimidazole compounds useful for the prophylaxis and/or treatment of iron overload are claimed. These compounds act as hepcidin mimetic and inhibit the ferroportin thereby preventing iron overload. The claimed actives are useful in the treatment of disease conditions such as neurodegenerative and cardiac diseases triggered by iron overload. Preclinical studies of these salts on mouse model are also discussed. EXPERT OPINION: Prevention and/or treatment of iron overload is critical. The claimed compounds are the first oral drug candidate to treat iron overload and reach the pre-clinical development stage.


Assuntos
Benzimidazóis/farmacologia , Proteínas de Transporte de Cátions/antagonistas & inibidores , Sobrecarga de Ferro/tratamento farmacológico , Administração Oral , Animais , Benzimidazóis/química , Proteínas de Transporte de Cátions/metabolismo , Modelos Animais de Doenças , Desenvolvimento de Medicamentos , Hepcidinas/metabolismo , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/fisiopatologia , Camundongos , Patentes como Assunto , Sais
15.
Int J Lab Hematol ; 43(5): 1159-1167, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33835732

RESUMO

INTRODUCTION: The aim of our study was to examine the relationship of hepcidin-25 with red blood cell and reticulocyte indices and to evaluate the diagnostic properties of hepcidin-25 in the assessment of positive iron balance in end-stage renal disease (ESRD) patients. METHODS: Eighty anemic ESRD patients (hemoglobin < 110 g/L) were classified as having iron deficiency (ID, N = 20), iron sufficiency (IS, N = 29), and positive iron balance (PB, N = 31) using the conventional biomarkers for iron status evaluation. Hepcidin-25 was determined by a chemiluminescent direct ELISA. RESULTS: Hepcidin-25 was significantly negatively correlated with the proportion of hypochromic erythrocytes (%HYPO) (P = .034) and immature reticulocyte fraction (P = .010) in ID and with the absolute reticulocyte concentration in ID (P = .048) and PB (P = .040). In multivariate models, hepcidin-25 was independently negatively associated with the mean reticulocyte hemoglobin content (CHr; ß = -0.493, P = .004) and red blood cell size factor (RSf) (ß = -0.334, P = .036) only in the PB group. The best hepcidin-25 value to exclude PB was 66.13 µg/L, showing a sensitivity of 61.3%, a specificity of 75.5%, and an AUC of 0.808. CONCLUSION: Our results suggest that hepcidin-25 levels are independently negatively associated with the iron demand for the most recent erythropoiesis only in PB. Hepcidin-25 performed acceptable in discriminating anemic ESRD patients with positive iron balance and may prove to be a useful additional tool in the evaluation of iron status.


Assuntos
Hepcidinas/sangue , Ferro/sangue , Falência Renal Crônica/sangue , Adulto , Idoso , Estudos Transversais , Índices de Eritrócitos , Eritrócitos/metabolismo , Eritrócitos/patologia , Feminino , Hepcidinas/metabolismo , Humanos , Ferro/metabolismo , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Reticulócitos/metabolismo , Reticulócitos/patologia
16.
Int J Mol Sci ; 22(6)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804198

RESUMO

Body iron levels are regulated by hepcidin, a liver-derived peptide that exerts its function by controlling the presence of ferroportin (FPN), the sole cellular iron exporter, on the cell surface. Hepcidin binding leads to FPN internalization and degradation, thereby inhibiting iron release, in particular from iron-absorbing duodenal cells and macrophages involved in iron recycling. Disruption in this regulatory mechanism results in a variety of disorders associated with iron-deficiency or overload. In recent years, increasing evidence has emerged to indicate that, in addition to its role in systemic iron metabolism, FPN may play an important function in local iron control, such that its dysregulation may lead to tissue damage despite unaltered systemic iron homeostasis. In this review, we focus on recent discoveries to discuss the role of FPN-mediated iron export in the microenvironment under both physiological and pathological conditions.


Assuntos
Proteínas de Transporte de Cátions/genética , Microambiente Celular/genética , Hepcidinas/genética , Ferro/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Hepcidinas/metabolismo , Homeostase/genética , Humanos , Fígado/metabolismo , Macrófagos/metabolismo , Ligação Proteica
17.
BMC Vet Res ; 17(1): 155, 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33849522

RESUMO

BACKGROUND: Vertebrate hosts limit the availability of iron to microbial pathogens in order to nutritionally starve the invaders. The impact of iron deficiency induced by the iron chelator deferoxamine mesylate (DFO) was investigated in Atlantic salmon SHK-1 cells infected with the facultative intracellular bacterium Piscirickettsia salmonis. RESULTS: Effects of the DFO treatment and P. salmonis on SHK-1 cells were gaged by assessing cytopathic effects, bacterial load and activity, and gene expression profiles of eight immune biomarkers at 4- and 7-days post infection (dpi) in the control group, groups receiving single treatments (DFO or P. salmonis) and their combination. The chelator appears to be well-tolerated by host cells, while it had a negative impact on the number of bacterial cells and associated cytotoxicity. DFO alone had minor effects on gene expression of SHK-1 cells, including an early activation of IL-1ß at 4 dpi. In contrast to few moderate changes induced by single treatments (either infection or chelator), most genes had highest upregulation in the infected groups receiving DFO. The mildest induction of hepcidin-1 (antimicrobial peptide precursor and regulator of iron homeostasis) was observed in cells exposed to DFO alone, followed by P. salmonis infected cells while the addition of DFO to infected cells further increased the mRNA abundance of this gene. Transcripts encoding TNF-α (immune signaling) and iNOS (immune effector) showed sustained increase at both time points in this group while cathelicidin-1 (immune effector) and IL-8 (immune signaling) were upregulated at 7 dpi. The stimulation of protective gene responses seen in infected cultures supplemented with DFO coincided with the reduction of bacterial load and activity (judged by the expression of P. salmonis 16S rRNA), and damage to cultured host cells. CONCLUSION: The absence of immune gene activation under normal iron conditions suggests modulation of host responses by P. salmonis. The negative effect of iron deficiency on bacteria likely allowed host cells to respond in a more protective manner to the infection, further decreasing its progression. Presented findings encourage in vivo exploration of iron chelators as a promising strategy against piscirickettsiosis.


Assuntos
Doenças dos Peixes/microbiologia , Ferro/deficiência , Piscirickettsia/efeitos dos fármacos , Infecções por Piscirickettsiaceae/veterinária , Animais , Carga Bacteriana , Linhagem Celular , Quelantes/farmacologia , Desferroxamina/farmacologia , Regulação da Expressão Gênica , Hepcidinas/genética , Hepcidinas/metabolismo , Piscirickettsia/patogenicidade , Infecções por Piscirickettsiaceae/microbiologia , RNA Mensageiro/metabolismo , Salmo salar
18.
Aging (Albany NY) ; 13(8): 11296-11314, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33820875

RESUMO

As a necessary trace element, iron is involved in many physiological processes. Clinical and basic studies have found that disturbances in iron metabolism, especially iron overload, might lead to bone loss and even be involved in postmenopausal osteoporosis. Hepcidin is a key regulator of iron homeostasis. However, the exact role of hepcidin in bone metabolism and the underlying mechanism remain unknown. In this study, we found that in postmenopausal osteoporosis cohort, the concentration of hepcidin in the serum was significantly reduced and positively correlated with bone mineral density. Ovariectomized (OVX) mice were then used to construct an osteoporosis model. Hepcidin overexpression in these mice significantly improved bone mass and rescued the phenotype of bone loss. Additionally, overexpression of hepcidin in OVX mice greatly reduced the number and differentiation of osteoclasts in vivo and in vitro. This study found that overexpression of hepcidin significantly inhibited ROS production, mitochondrial biogenesis, and PGC-1ß expression. These data showed that hepcidin protected osteoporosis by reducing iron levels in bone tissue, and in conjunction with PGC-1ß, reduced ROS production and the number of mitochondria, thus inhibiting osteoclast differentiation and bone absorption. Hepcidin could provide new targets for the clinical treatment of postmenopausal osteoporosis.


Assuntos
Hepcidinas/metabolismo , Proteínas Nucleares/metabolismo , Osteoporose Pós-Menopausa/patologia , Proteínas de Ligação a RNA/metabolismo , Fatores de Transcrição/metabolismo , Idoso , Animais , Densidade Óssea/genética , Diferenciação Celular/genética , Células Cultivadas , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Hepcidinas/sangue , Hepcidinas/genética , Humanos , Ferro/metabolismo , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Biogênese de Organelas , Osteoclastos/citologia , Osteoclastos/patologia , Osteoporose Pós-Menopausa/sangue , Osteoporose Pós-Menopausa/diagnóstico , Pós-Menopausa/sangue , Pós-Menopausa/metabolismo , Cultura Primária de Células , Espécies Reativas de Oxigênio/metabolismo
19.
Am J Pathol ; 191(7): 1165-1179, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33891874

RESUMO

The liver plays a pivotal role in the regulation of iron metabolism through its ability to sense and respond to iron stores by release of the hormone hepcidin. Under physiologic conditions, regulation of hepcidin expression in response to iron status maintains iron homeostasis. In response to tissue injury, hepcidin expression can be modulated by other factors, such as inflammation and oxidative stress. The resulting dysregulation of hepcidin is proposed to account for alterations in iron homeostasis that are sometimes observed in patients with liver disease. This review describes the effects of experimental forms of liver injury on iron metabolism and hepcidin expression. In general, models of acute liver injury demonstrate increases in hepcidin mRNA and hypoferremia, consistent with hepcidin's role as an acute-phase reactant. Conversely, diverse models of chronic liver injury are associated with decreased hepcidin mRNA but with variable effects on iron status. Elucidating the reasons for the disparate impact of different chronic injuries on iron metabolism is an important research priority, as is a deeper understanding of the interplay among various stimuli, both positive and negative, on hepcidin regulation. Future studies should provide a clearer picture of how dysregulation of hepcidin expression and altered iron homeostasis impact the progression of liver diseases and whether they are a cause or consequence of these pathologies.


Assuntos
Hepcidinas/metabolismo , Ferro/metabolismo , Hepatopatias/metabolismo , Animais , Modelos Animais de Doenças
20.
Front Immunol ; 12: 612144, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33868231

RESUMO

Lung cancer has the highest death rate among cancers globally. Hepcidin is a fascinating regulator of iron metabolism; however, the prognostic value of hepcidin and its correlation with immune cell infiltration in lung cancer remain unclear. Here, we comprehensively clarified the prognostic value and potential function of hepcidin in lung cancer. Hepcidin expression was significantly increased in lung cancer. High hepcidin expression was associated with sex, age, metastasis, and pathological stage and significantly predicted an unfavorable prognosis in lung cancer patients. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) results suggested that hepcidin is involved in the immune response. Furthermore, hepcidin expression was positively correlated with the infiltration levels of immune cells and the expression of diverse immune cell marker sets. Importantly, hepcidin may affect prognosis partially by regulating immune infiltration in lung cancer patients. Hepcidin may serve as a candidate prognostic biomarker for determining prognosis associated with immune infiltration in lung cancer.


Assuntos
Regulação Neoplásica da Expressão Gênica , Hepcidinas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Biologia Computacional/métodos , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Ontologia Genética , Hepcidinas/metabolismo , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Terapia de Alvo Molecular , Infiltração de Neutrófilos/genética , Infiltração de Neutrófilos/imunologia , Prognóstico , Transdução de Sinais , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia , Regulação para Cima
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...