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1.
PLoS One ; 16(10): e0258433, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34644351

RESUMO

Abnormal calcium absorption and iron overload from iron hyperabsorption can contribute to osteoporosis as found in several diseases, including hemochromatosis and thalassemia. Previous studies in thalassemic mice showed the positive effects of the iron uptake suppressor, hepcidin, on calcium transport. However, whether this effect could be replicated in other conditions is not known. Therefore, this study aimed to investigate the effects of hepcidin on iron and calcium uptake ability under physiological, iron uptake stimulation and calcium uptake suppression. To investigate the potential mechanism, effects of hepcidin on the expression of iron and calcium transporter and transport-associated protein in Caco-2 cells were also determined. Our results showed that intestinal cell iron uptake was significantly increased by ascorbic acid together with ferric ammonium citrate (FAC), but this phenomenon was suppressed by hepcidin. Interestingly, hepcidin significantly increased calcium uptake under physiological condition but not under iron uptake stimulation. While hepcidin significantly suppressed the expression of iron transporter, it had no effect on calcium transporter expression. This indicated that hepcidin-induced intestinal cell calcium uptake did not occur through the stimulation of calcium transporter expression. On the other hand, 1,25(OH)2D3 effectively induced intestinal cell calcium uptake, but it did not affect intestinal cell iron uptake or iron transporter expression. The 1,25(OH)2D3-induced intestinal cell calcium uptake was abolished by 12 mM CaCl2; however, hepcidin could not rescue intestinal cell calcium uptake suppression by CaCl2. Taken together, our results showed that hepcidin could effectively and concurrently induce intestinal cell calcium uptake while reducing intestinal cell iron uptake under physiological and iron uptake stimulation conditions, suggesting its therapeutic potential for inactive calcium absorption, particularly in thalassemic patients or patients who did not adequately respond to 1,25(OH)2D3.


Assuntos
Cálcio/metabolismo , Hepcidinas/farmacologia , Transporte de Íons/efeitos dos fármacos , Ferro/metabolismo , Células CACO-2 , Calcitriol/farmacologia , Cloreto de Cálcio/farmacologia , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Humanos , Mucosa Intestinal/citologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Regulação para Cima/efeitos dos fármacos
2.
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
3.
J Coll Physicians Surg Pak ; 31(11): 1303-1307, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34689487

RESUMO

OBJECTIVE: To compare the prohepcidin and hepcidin levels in the afebrile neutropenic period and neutropenic fever in patients with hematological malignancy. STUDY DESIGN: Descriptive study. PLACE AND DURATION OF STUDY: Department of Hematology, Pamukkale University Hospital, Denizli, Turkey, between January 2018 and December 2019. METHODOLOGY: Neutropenic patients were compared with a healthy control group. Prohepcidin and hepcidin serum levels were to be measured in neutropenic and control groups. When fever occurred in neutropenic group, serum was taken again and the same values were compared, in addition to procalcitonin and CRP values. RESULTS: Prohepcidin and hepcidin levels were found to be significantly higher in the neutropenic group (n = 53) than the control group [n = 44, (med:166.65 ng/ml, IQR:147.66 - 187.38 ng/ml vs. med:47.49 ng/ml, IQR:15.61 - 82.51 ng/ml; p <0.001); (med:315 ng/ml, IQR:314.92 - 315 ng/ml vs. med:26.61 ng/ml, IQR:4.69 - 66.83 ng/ml; p <0.001)]. No significant difference was found in terms of these two analyses (167.29 ± 29.31 ng/ml vs. 167.15 ± 27.61 ng/ml; p = 0.979; 296.21 ± 37.19 ng/ml vs 299.16 ± 37.68 ng/ml; p= 0.629) in the neutropenic fever period compared to the afebrile neutropenic period. In neutropenic fever patients, procalcitonin and CRP (C-reactive protein) were found significantly higher than the afebnile neutropenic group (0.7 ± 1.2 ng/ml vs. 0.25 ± 0.76 ng/ml; p = 0.034; 10.27 ± 9.93 mg/dl vs 2.61 ± 2.78 mg/dl; p <0.001). CONCLUSION: Although there was no significant difference between afebnile neutropenia and neutropenic fever in patients in terms of hepcidin and prohepcidin levels, higher levels were found in both groups compared to the control group. Key Words: Hepcidin, Prohepcidin, Neutropenia, Febrile neutropenia.


Assuntos
Neutropenia Febril , Hepcidinas , Proteína C-Reativa , Humanos , Pró-Calcitonina , Precursores de Proteínas
4.
Nutrients ; 13(10)2021 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-34684502

RESUMO

Hepcidin is a regulator of iron metabolism. Diet affects the body's iron status, but how it influences hepcidin concentrations and the risk of gestational iron-deficiency anemia (IDA) remains unclear. We investigated relationships of food and nutrient intake with serum hepcidin levels in relation to the iron status at a population scale. A retrospective cross-sectional study was conducted based on data obtained from the Nationwide Nutrition and Health Survey in pregnant women, Taiwan (2017~2020). In total, 1430 pregnant women aged 20~45 years with a singleton pregnancy were included. Data from blood biochemistry, 24-h dietary recall, and a food frequency questionnaire were collected during a prenatal checkup. Adjusted multivariate linear and logistic regression analyses were employed to measure the beta coefficient (ß) and 95% confidence interval (CI) of serum hepcidin and the odds ratio (OR) of IDA. In IDA women, serum hepcidin levels were positively correlated with the intake frequency of Chinese dim sum and related foods (ß = 0.037 (95% CI = 0.015~0.058), p = 0.001) and dark leafy vegetables (ß = 0.013 (0.001~0.025), p = 0.040), but they were negatively correlated with noodles and related products (ß = -0.022 (-0.043~-0.001), p = 0.038). An adjusted multivariate logistic regression analysis showed that dietary protein [OR: 0.990 (0.981~1.000), p = 0.041], total fiber [OR: 0.975 (0.953~0.998), p = 0.031], and rice/rice porridge [OR: 1.007 (1.00~1.014), p = 0.041] predicted gestational IDA. Total carbohydrates [OR: 1.003 (1.000~1.006), p = 0.036], proteins [OR: 0.992 (0.985~0.999), p = 0.028], gourds/shoots/root vegetables [OR: 1.007 (0.092~1.010), p = 0.005], and to a lesser extent, savory and sweet glutinous rice products [OR: 0.069 (0.937~1.002), p = 0.067] and dark leafy vegetables [OR: 1.005 (0.999~1.011), p = 0.088] predicted IDA. The risk of IDA due to vegetable consumption decreased with an increasing vitamin C intake (p for trend = 0.024). Carbohydrates and vegetables may affect the gestational iron status through influencing hepcidin levels. Vitamin C may lower the risk of gestational IDA due to high vegetable consumption.


Assuntos
Anemia Ferropriva/epidemiologia , Dieta/estatística & dados numéricos , Hepcidinas/sangue , Complicações na Gravidez/epidemiologia , Adulto , Anemia Ferropriva/etiologia , Estudos Transversais , Dieta/efeitos adversos , Inquéritos sobre Dietas , Ingestão de Alimentos , Feminino , Humanos , Ferro/sangue , Modelos Lineares , Fenômenos Fisiológicos da Nutrição Materna , Pessoa de Meia-Idade , Estado Nutricional , Razão de Chances , Gravidez , Complicações na Gravidez/etiologia , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologia , Adulto Jovem
5.
Nutrients ; 13(10)2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34684558

RESUMO

Markers of iron metabolism are altered in new-onset diabetes, but their relationship with metabolic signals involved in the maintenance of energy balance is poorly understood. The primary aim was to explore the associations between markers of iron metabolism (hepcidin and ferritin) and markers of energy balance (leptin, ghrelin, and the leptin/ghrelin ratio) in both the fasted and postprandial states. These associations were also studied in the sub-groups stratified by diabetes status. This was a cross-sectional study of individuals without disorders of iron metabolism who were investigated after an overnight fast and, in addition, some of these individuals underwent a mixed meal test to determine postprandial responses of metabolic signals. The associations between hepcidin, ferritin, and leptin, ghrelin, leptin/ghrelin ratio were studied using several multiple linear regression models. A total of 76 individuals in the fasted state and 34 individuals in the postprandial state were included. In the overall cohort, hepcidin was significantly inversely associated with leptin (in the most adjusted model, the ß coefficient ± SE was -883.45 ± 400.94; p = 0.031) and the leptin/ghrelin ratio (in the most adjusted model, the ß coefficient ± SE was -148.26 ± 61.20; p = 0.018) in the fasted state. The same associations were not statistically significant in the postprandial state. In individuals with new-onset prediabetes or diabetes (but not in those with normoglycaemia or longstanding prediabetes or diabetes), hepcidin was significantly inversely associated with leptin (in the most adjusted model, the ß coefficient ± SE was -806.09 ± 395.44; p = 0.050) and the leptin/ghrelin ratio (in the most adjusted model, the ß coefficient ± SE was -129.40 ± 59.14; p = 0.037). Leptin appears to be a mediator in the link between iron metabolism and new-onset diabetes mellitus. These findings add to the growing understanding of mechanisms underlying the derangements of glucose metabolism.


Assuntos
Metabolismo Energético/fisiologia , Jejum/sangue , Ferritinas/sangue , Hepcidinas/sangue , Período Pós-Prandial/fisiologia , Estudos Transversais , Diabetes Mellitus/sangue , Feminino , Grelina/sangue , Humanos , Leptina/sangue , Modelos Lineares , Masculino , Refeições/fisiologia , Pessoa de Meia-Idade
6.
Nutrients ; 13(9)2021 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-34579127

RESUMO

We sought to investigate the effects of resistance training (RT) combined with erythropoietin (EPO) and iron sulfate on the hemoglobin, hepcidin, ferritin, iron status, and inflammatory profile in older individuals with end-stage renal disease (ESRD). ESRD patients (n: 157; age: 66.8 ± 3.6; body mass: 73 ± 15; body mass index: 27 ± 3), were assigned to control (CTL; n: 76) and exercise groups (RT; n: 81). The CTL group was divided according to the iron treatment received: without iron treatment (CTL-none; n = 19), treated only with iron sulfate or EPO (CTL-EPO or IRON; n = 19), and treated with both iron sulfate and EPO (CTL-EPO + IRON; n = 76). The RT group followed the same pattern: (RT-none; n = 20), (RT-EPO or IRON; n = 18), and (RT-EPO + IRON; n = 86). RT consisted of 24 weeks/3 days per week at moderate intensity of full-body resistance exercises prior to the hemodialysis section. The RT group, regardless of the iron treatment, improved iron metabolism in older individuals with ESRD. These results provide some clues on the effects of RT and its combination with EPO and iron sulfate in this population, highlighting RT as an important coadjutant in ESRD-iron deficiency.


Assuntos
Eritropoetina/uso terapêutico , Falência Renal Crônica/terapia , Treinamento de Força , Idoso , Ferritinas/sangue , Compostos Ferrosos/uso terapêutico , Hemoglobinas/análise , Hepcidinas/sangue , Humanos , Inflamação/terapia , Ferro/sangue , Pessoa de Meia-Idade
7.
Nutrients ; 13(9)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34578874

RESUMO

Hepcidin-25 is suggested as a surrogate iron status marker in athletes who show exercise-induced anemia; however, the implications of hepcidin concentration in this population remain poorly understood. This study aimed to investigate the relationship between hepcidin and body fat levels in rugby football players. We included 40 male university rugby football players (RUG) and 40 non-athlete controls. All participants underwent an anthropometric analysis and blood testing that included both hepcidin-25 and ferritin levels. The hepcidin-25 level was slightly (11.6%, p = 0.50) higher, and the ferritin level was significantly (35.9%, p < 0.05) lower, in the RUG group than in controls. The hepcidin-25 to-ferritin ratio was significantly higher (62.5%, p < 0.05) in the RUG group. While significant U-shaped correlations were observed between the body fat and ferritin levels in both groups, the correlations between the hepcidin levels and fat mass index were significantly higher in the RUG group (RUG: r = 0.79, controls: r = 0.45). Notably, the RUG with the lower fat mass index group had a higher hepcidin-25 level, lower ferritin level, and then significantly higher hepcidin-25/ferritin ratio. The hepcidin-25/ferritin ratio may serve as a biomarker for iron status in RUG, especially RUG with lower fat mass.


Assuntos
Tecido Adiposo/metabolismo , Atletas/estatística & dados numéricos , Ferritinas/sangue , Futebol Americano , Hepcidinas/sangue , Adulto , Biomarcadores/sangue , Humanos , Masculino , Universidades , Adulto Jovem
8.
Anal Chim Acta ; 1181: 338863, 2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34556214

RESUMO

Spiegelmers, mirror image L- RNA oligonucleotides, possesses high plasma stability and non-immunogenicity. Herein, a novel spiegelmer based impedimetric biosensor grafted with Au nanoparticles and molybdenum disulfide nanoflowers/graphene nanoribbons nanocomposite has been designed to detect hepcidin in spiked-in human serum sample. Firstly, molybdenum disulfide nanoflowers/graphene nanoribbons (MoS2NF-GNR) hybrid was drop-casted onto the FTO electrode followed by electro deposition of Au nanoparticles (AuNPs). Hepcidin specific thiolated spiegelmer was then immobilized on the MoS2NF-GNR@AuNPs for hepcidin detection. Electrochemical impedance spectroscopy was used to assess the performance of the sensing platform based on the variation of charge transfer resistance (ΔRct) relative to the Fe(CN)64-/3- electrochemical probe in the presence of hepcidin. The impedance signals were recorded at the frequency range of 10-1 to 105 Hz and potential was set as 0.18 V. Under optimized conditions, the limit of detection of spiegelmer based sensor for hepcidin was 0.173 pgmL-1 within a wide linear range of 0.005-10 ngmL-1. The biosensor possesses selectivity, acceptable reproducibility with RSD as 4.76% and stability for up to 20 days. The satisfactory recovery result (89.8-103.1 %) in human serum indicates that the sensor has applicability in clinical monitoring of hepcidin.


Assuntos
Ouro , Nanopartículas Metálicas , Dioxigenase FTO Dependente de alfa-Cetoglutarato , Técnicas Eletroquímicas , Hepcidinas , Humanos , Reprodutibilidade dos Testes
9.
Int J Mol Sci ; 22(18)2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34576090

RESUMO

Iron deficiency is the most common mammalian nutritional disorder. However, among mammalian species iron deficiency anemia (IDA), occurs regularly only in pigs. To cure IDA, piglets are routinely injected with high amounts of iron dextran (FeDex), which can lead to perturbations in iron homeostasis. Here, we evaluate the therapeutic efficacy of non-invasive supplementation with Sucrosomial iron (SI), a highly bioavailable iron supplement preventing IDA in humans and mice and various iron oxide nanoparticles (IONPs). Analysis of red blood cell indices and plasma iron parameters shows that not all iron preparations used in the study efficiently counteracted IDA comparable to FeDex-based supplementation. We found no signs of iron toxicity of any tested iron compounds, as evaluated based on the measurement of several toxicological markers that could indicate the occurrence of oxidative stress or inflammation. Neither SI nor IONPs increased hepcidin expression with alterations in ferroportin (FPN) protein level. Finally, the analysis of the piglet gut microbiota indicates the individual pattern of bacterial diversity across taxonomic levels, independent of the type of supplementation. In light of our results, SI but not IONPs used in the experiment emerges as a promising nutritional iron supplement, with a high potential to correct IDA in piglets.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Suplementos Nutricionais , Compostos Férricos/administração & dosagem , Compostos Férricos/uso terapêutico , Nanopartículas Magnéticas de Óxido de Ferro/administração & dosagem , Nanopartículas Magnéticas de Óxido de Ferro/química , Administração Oral , Anemia Ferropriva/sangue , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Duodeno/metabolismo , Compostos Férricos/farmacologia , Compostos Ferrosos/uso terapêutico , Hepcidinas/sangue , Hepcidinas/genética , Masculino , Microbiota , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Suínos
10.
Acta Derm Venereol ; 101(9): adv00558, 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34515804

RESUMO

Current understanding of the underlying pathophysiology of hidradenitis suppurativa (HS) links the disease with proinflammatory activation and autoimmune processes. This study investigated serum levels of interleukin (IL)-22, a cytokine critically involved in epithelial homeostasis, in the context of the broad clinical spectrum of patients with HS. The study also assessed the relationship between serum IL-22 and pro-inflammatory activation (as evidenced by serum level of IL-6) and serum hepcidin (central regulator of systemic iron homeostasis). Serum concentrations of IL-22 were assessed in 74 patients with HS and 15 healthy subjects. Compared with healthy controls, patients with HS demonstrated decreased levels of serum IL-22 (median; interquartile range (IQR): 12.4 pg/ml (9.8; 23.5) vs 34.8 pg/ml (24.8; 39.8), p < 0.001 vs controls). Disease severity (assessed both with Hurley staging and Hidradenitis Suppurativa Severity Index) did not differentiate IL-22 levels (p > 0.1 in both comparisons). Serum levels of IL-22 and IL-6 did not correlate with each other (R=-0.17, p = ns). In a subgroup of 24 patients with HS with pro-inflammatory activation, the mean level of IL-22 was similar to that of the remaining patients (median (IQR): 9.8 pg/ml (8.5; 15.0) vs 12.0 pg/ml (9.4; 16.3), p = ns). Patients with HS demonstrated a decreased level of hepcidin (mean: 31.3 ± 25.9 pg/ml), which correlated with the levels of IL-22 (R=0.36, p <0.05). Patients with HS demonstrated significantly decreased levels of serum IL-22, which was neither correlated with pro-inflammatory status nor associated with disease severity, but correlated modestly with serum hepcidin.


Assuntos
Hidradenite Supurativa , Citocinas , Hepcidinas , Hidradenite Supurativa/diagnóstico , Humanos , Interleucinas
12.
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
13.
Front Cell Infect Microbiol ; 11: 705087, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368018

RESUMO

Introduction: Hepcidin is the systemic master regulator of iron metabolism as it degrades the cellular iron exporter ferroportin. In bacterial infections, hepcidin is upregulated to limit circulating iron for pathogens, thereby increasing iron retention in macrophages. This mechanism withholds iron from extracellular bacteria but could be of disadvantage in infections with intracellular bacteria. We aimed to understand the role of hepcidin in infections with intra- or extracellular bacteria using different hepcidin inhibitors. Methods: For the experiments LDN-193189 and oversulfated heparins were used, which interact with the BMP6-SMAD pathway thereby inhibiting hepcidin expression. We infected male C57BL/6N mice with either the intracellular bacterium Salmonella Typhimurium or the extracellular bacterium Escherichia coli and treated these mice with the different hepcidin inhibitors. Results: Both inhibitors effectively reduced hepcidin levels in vitro under steady state conditions and upon stimulation with the inflammatory signals interleukin-6 or lipopolysaccharide. The inhibitors also reduced hepcidin levels and increased circulating iron concentration in uninfected mice. However, both compounds failed to decrease liver- and circulating hepcidin levels in infected mice and did not affect ferroportin expression in the spleen or impact on serum iron levels. Accordingly, both BMP-SMAD signaling inhibitors did not influence bacterial numbers in different organs in the course of E.coli or S.Tm sepsis. Conclusion: These data indicate that targeting the BMP receptor or the BMP-SMAD pathway is not sufficient to suppress hepcidin expression in the course of infection with both intra- or extracellular bacteria. This suggests that upon pharmacological inhibition of the central SMAD-BMP pathways during infection, other signaling cascades are compensatorily induced to ensure sufficient hepcidin formation and iron restriction to circulating microbes.


Assuntos
Proteína Morfogenética Óssea 6/metabolismo , Bactérias Gram-Negativas/patogenicidade , Hepcidinas , Sepse , Proteínas Smad/metabolismo , Animais , Ferro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Sepse/tratamento farmacológico
14.
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
15.
Nutrients ; 13(8)2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34444676

RESUMO

Iron deficiency with or without anemia, needing continuous iron supplementation, is very common in obese patients, particularly those requiring bariatric surgery. The aim of this study was to address the impact of weight loss on the rescue of iron balance in patients who underwent sleeve gastrectomy (SG), a procedure that preserves the duodenum, the main site of iron absorption. The cohort included 88 obese women; sampling of blood and duodenal biopsies of 35 patients were performed before and one year after SG. An analysis of the 35 patients consisted in evaluating iron homeostasis including hepcidin, markers of erythroid iron deficiency (soluble transferrin receptor (sTfR) and erythrocyte protoporphyrin (PPIX)), expression of duodenal iron transporters (DMT1 and ferroportin) and inflammatory markers. After surgery, sTfR and PPIX were decreased. Serum hepcidin levels were increased despite the significant reduction in inflammation. DMT1 abundance was negatively correlated with higher level of serum hepcidin. Ferroportin abundance was not modified. This study shed a new light in effective iron recovery pathways after SG involving suppression of inflammation, improvement of iron absorption, iron supply and efficiency of erythropoiesis, and finally beneficial control of iron homeostasis by hepcidin. Thus, recommendations for iron supplementation of patients after SG should take into account these new parameters of iron status assessment.


Assuntos
Gastrectomia/efeitos adversos , Hepcidinas/sangue , Ferro/deficiência , Adulto , Proteínas de Transporte de Cátions/análise , Estudos de Coortes , Suplementos Nutricionais , Duodeno/química , Duodeno/metabolismo , Eritrócitos/química , Feminino , Humanos , Absorção Intestinal/fisiologia , Ferro/administração & dosagem , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/complicações , Obesidade/cirurgia , Estudos Prospectivos , Protoporfirinas/sangue , Receptores da Transferrina/sangue , Fatores de Transcrição/análise
16.
Zhonghua Xue Ye Xue Za Zhi ; 42(5): 402-406, 2021 May 14.
Artigo em Chinês | MEDLINE | ID: mdl-34218583

RESUMO

Objective: To study the effect of iron deficiency level for oral iron absorption in iron deficient patients. Methods: 37 non-pregnant female patients who were diagnosed with iron deficiency and 13 healthy females who completed their physical examination at the outpatient department of the Anemia Center of the Institute of Hematology & Blood Diseases Hospital from July 2018 to June 2020 were included. Hepcidin and C2-C0 of oral iron absorption test were analyzed in different iron deficiency and serum ferritin level. Results: The median of Hepcidin in IDA, ID/IDE and healthy control group were 4.9 (2.17-32.86) , 26.98 (11.02-49.71) and 69.89 (42.23-138.96) µg/L (P<0.001) , respectively. Hepcidin level of IDA group was lower than that of ID/IDE group (adjusted P=0.005) and healthy control (adjusted P<0.001) . Hepcidin level of ID/IDE group had no significant difference compared with healthy control (adjusted P=0.22) . The mean of C2-C0 in IDA, ID/IDE and healthy control group were (35.30±21.68) , (37.90±14.06) and (23.57±10.14) µmol/L (P=0.130) , respectively. Multilinear regression analysis showed C0, SF, sTFR and HGB were independent factors for Hepcidin in iron deficient patients, with an equation of Hepcidin=-31.842-0.642*C0+2.239*SF+1.778*sTFR+0.365*HGB-0.274*RET-HB. We didn't find independent factor of C2-C0. Conclusion: The degree of iron deficiency had an effect on oral iron absorption. Patients of ID/IDE group absorbed iron more slowly than patients of IDA group. Iron deficient patients with normal gastrointestinal function absorbed more iron by oral administration when they were in a more serious iron deficient stage. Hepcidin was a better parameter to distinguish iron absorption level among different iron deficient patients than C2-C0 of oral iron absorption test.


Assuntos
Anemia Ferropriva , Anemia , Biomarcadores , Feminino , Hepcidinas , Humanos , Ferro
17.
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
18.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281283

RESUMO

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.


Assuntos
Eritropoese/efeitos dos fármacos , Eritropoese/fisiologia , Talassemia beta/tratamento farmacológico , Talassemia beta/fisiopatologia , Receptores de Activinas Tipo II/uso terapêutico , Desenvolvimento de Medicamentos , Fator de Transcrição GATA1/metabolismo , Hepcidinas/uso terapêutico , Humanos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Ferro/metabolismo , Modelos Biológicos , Mutação , Piperazinas/uso terapêutico , Quinolinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Crescimento Transformador beta/metabolismo , Globinas beta/genética , Talassemia beta/sangue
19.
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
20.
PLoS One ; 16(7): e0254851, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34283879

RESUMO

Erythroferrone (ERFE), the erythroid regulator of iron metabolism, inhibits hepcidin to increase iron availability for erythropoiesis. ERFE plays a pathological role during ineffective erythropoiesis as occurs in X-linked sideroblastic anemia (XLSA) and ß-thalassemia. Its measurement might serve as an indicator of severity for these diseases. However, for reliable quantification of ERFE analytical characterization is indispensable to determine the assay's limitations and define proper methodology. We developed a sandwich ELISA for human serum ERFE using polyclonal antibodies and report its extensive analytical validation. This new assay showed, for the first time, the differentiation of XLSA and ß-thalassemia major patients from healthy controls (p = 0.03) and from each other (p<0.01), showing the assay provides biological plausible results. Despite poor dilution linearity, parallelism and recovery in patient serum matrix, which indicated presence of a matrix effect and/or different immunoreactivity of the antibodies to the recombinant standard and the endogenous analyte, our assay correlated well with two other existing ERFE ELISAs (both R2 = 0.83). Nevertheless, employment of one optimal dilution of all serum samples is warranted to obtain reliable results. When adequately performed, the assay can be used to further unravel the human erythropoiesis-hepcidin-iron axis in various disorders and assess the added diagnostic value of ERFE.


Assuntos
Anemia Sideroblástica/diagnóstico , Hormônios Peptídicos/análise , Talassemia beta/diagnóstico , Adulto , Idoso , Anemia/sangue , Anemia/diagnóstico , Anemia Sideroblástica/sangue , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Eritropoese , Feminino , Hepcidinas/sangue , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/diagnóstico , Sobrecarga de Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Hormônios Peptídicos/sangue , Talassemia beta/sangue
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