RESUMEN
ABSTRACT: Iron plays a major role in the deterioration of ß-thalassemia. Indeed, the high levels of transferrin saturation and iron delivered to erythroid progenitors are associated with production of α-globin precipitates that negatively affect erythropoiesis. Matriptase-2/TMPRSS6, a membrane-bound serine protease expressed in hepatocytes, negatively modulates hepcidin production and thus is a key target to prevent iron overload in ß-thalassemia. To address safety concerns raised by the suppression of Tmprss6 by antisense oligonucleotides or small interfering RNA, we tested a fully human anti-matriptase-2 antibody, RLYB331, which blocks the protease activity of matriptase-2. When administered weekly to Hbbth3/+ mice, RLYB331 induced hepcidin expression, reduced iron loading, prevented the formation of toxic α-chain/heme aggregates, reduced ros oxygen species formation, and improved reticulocytosis and splenomegaly. To increase the effectiveness of RLYB331 in ß-thalassemia treatment even further, we administered RLYB331 in combination with RAP-536L, a ligand-trapping protein that contains the extracellular domain of activin receptor type IIB and alleviates anemia by promoting differentiation of late-stage erythroid precursors. RAP-536L alone did not prevent iron overload but significantly reduced apoptosis in the erythroid populations of the bone marrow, normalized red blood cell counts, and improved hemoglobin and hematocrit levels. Interestingly, the association of RLYB331 with RAP-536L entirely reversed the ß-thalassemia phenotype in Hbbth3/+ mice and simultaneously corrected iron overload, ineffective erythropoiesis, splenomegaly, and hematological parameters, suggesting that a multifunctional molecule consisting of the fusion of RLYB331 with luspatercept (human version of RAP-536L) would allow administration of a single medication addressing simultaneously the different pathophysiological aspects of ß-thalassemia.
Asunto(s)
Sobrecarga de Hierro , Proteínas de la Membrana , Serina Endopeptidasas , Talasemia beta , Ratones , Humanos , Animales , Hepcidinas , Talasemia beta/genética , Esplenomegalia , Sobrecarga de Hierro/tratamiento farmacológico , Hierro/metabolismoRESUMEN
Iron overload is one of the secondary osteoporosis etiologies. Cellular and molecular mechanisms involved in iron-related osteoporosis are not fully understood. AIM: The aim of the study was to investigate the respective roles of iron excess and hepcidin, the systemic iron regulator, in the development of iron-related osteoporosis. MATERIAL AND METHODS: We used mice models with genetic iron overload (GIO) related to hepcidin deficiency (Hfe-/- and Bmp6-/- ) and secondary iron overload (SIO) exhibiting a hepcidin increase secondary to iron excess. Iron concentration and transferrin saturation levels were evaluated in serum and hepatic, spleen, and bone iron concentrations were assessed by ICP-MS and Perl's staining. Gene expression was evaluated by quantitative RT-PCR. Bone micro-architecture was evaluated by micro-CT. The osteoblastic MC3T3 murine cells that are able to mineralize were exposed to iron and/or hepcidin. RESULTS: Despite an increase of bone iron concentration in all overloaded mice models, bone volume/total volume (BV/TV) and trabecular thickness (Tb.Th) only decreased significantly in GIO, at 12 months for Hfe-/- and from 6 months for Bmp6-/- . Alterations in bone microarchitecture in the Bmp6-/- model were positively correlated with hepcidin levels (BV/TV (ρ = +.481, p < .05) and Tb.Th (ρ = +.690, p < .05). Iron deposits were detected in the bone trabeculae of Hfe-/- and Bmp6-/- mice, while iron deposits were mainly visible in bone marrow macrophages in secondary iron overload. In cell cultures, ferric ammonium citrate exposure abolished the mineralization process for concentrations above 5 µM, with a parallel decrease in osteocalcin, collagen 1, and alkaline phosphatase mRNA levels. Hepcidin supplementation of cells had a rescue effect on the collagen 1 and alkaline phosphatase expression level decrease. CONCLUSION: Together, these data suggest that iron in excess alone is not sufficient to induce osteoporosis and that low hepcidin levels also contribute to the development of osteoporosis.
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Hemocromatosis , Sobrecarga de Hierro , Osteoporosis , Animales , Ratones , Hierro/metabolismo , Hepcidinas/genética , Hepcidinas/metabolismo , Hemocromatosis/genética , Fosfatasa Alcalina/metabolismo , Proteína de la Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Sobrecarga de Hierro/complicaciones , Sobrecarga de Hierro/genética , Sobrecarga de Hierro/metabolismo , Hígado/metabolismo , Osteoporosis/genética , Colágeno/metabolismo , Ratones NoqueadosRESUMEN
Carbon monoxide (CO) poisoning is one of the most common causes of poisoning death and its diagnosis requires an elevated carboxyhemoglobin (COHb) level. Noninvasive CO saturation by pulse oximetry (SpCO) has been available since 2005 and has the advantage of being portable and easy to use, but its accuracy in determining blood COHb level is controversial. To evaluate the accuracy of SpCO (index test) to estimate COHb (reference test). Systematic review and meta-analysis of diagnostic test accuracy (DTA) studies. Four electronic databases were searched (Medline, Embase, Cochrane Central Register of Controlled Trials, and OpenGrey) on 2 August 2022. All studies of all designs published since the 2000s evaluating the accuracy and reliability of SpCO measurement compared to blood COHb levels in human volunteers or ill patients, including children, were included. The primary outcome was to assess the diagnostic accuracy of SpCO for estimating COHb by blood sampling by modeling receiver operating characteristic (ROC) curves and calculating sensitivity and specificity (primary measures). The secondary measures were to calculate the limits of agreement (LOA) and the mean bias. This systematic review was conducted according to the Preferred Reporting Items for a Systematic Review and Meta-analysis-DTA 2018 guidelines and has been registered on International Prospective Register of Systematic Reviews (PROSPERO, CRD42020177940). The risk of bias was evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Twenty-one studies were eligible for the systematic review; 11 could be included for the quantitative analysis of the primary measures and 18 for the secondary measures. No publication bias was found. The area under the summary ROC curve was equal to 86%. The mean sensitivity and specificity were 0.77, 95% confidence interval (CI, 0.66-0.85) and 0.83, 95% CI (0.74-0.89), respectively (2089 subjects and 3381 observations). The mean bias was 0.75% and the LOA was -7.08% to 8.57%, 95% CI (-8.89 to 10.38) (2794 subjects and 4646 observations). Noninvasive measurement of COHb (SpCO) using current pulse CO oximeters do not seem to be highly accurate to estimate blood COHb (moderate sensitivity and specificity, large LOA). They should probably not be used to confirm (rule-in) or exclude (rule-out) CO poisoning with certainty.
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Intoxicación por Monóxido de Carbono , Carboxihemoglobina , Niño , Humanos , Carboxihemoglobina/análisis , Reproducibilidad de los Resultados , Oximetría , Intoxicación por Monóxido de Carbono/diagnóstico , Pruebas Diagnósticas de RutinaRESUMEN
Several human intestinal microbiota studies suggest that bacteriophages, viruses infecting bacteria, play a role in gut homeostasis. Currently, bacteriophages are considered a tool to precisely engineer the intestinal microbiota, but they have also attracted considerable attention as a possible solution to fight against bacterial pathogens resistant to antibiotics. These two applications necessitate bacteriophages to reach and kill their bacterial target within the gut environment. Unfortunately, exploitable clinical data in this field are scarce. Here, we review the administration of bacteriophages to target intestinal bacteria in mammalian experimental models. While bacteriophage amplification in the gut was often confirmed, we found that in most studies, it had no significant impact on the load of the targeted bacteria. In particular, we observed that the outcome of bacteriophage treatments is linked to the behavior of the target bacteria toward each animal model. Treatment efficacy ranges from poor in asymptomatic intestinal carriage to high in intestinal disease. This broad range of efficacy underlines the difficulties to reach a consensus on the impact of bacteriophages in the gut and calls for deeper investigations of key parameters that influence the success of such interventions before launching clinical trials.
Asunto(s)
Bacteriófagos , Microbioma Gastrointestinal , Terapia de Fagos , Animales , Antibacterianos , Bacterias , HumanosAsunto(s)
Estrés del Retículo Endoplásmico , Hepcidinas , Estrés del Retículo Endoplásmico/genética , Hepcidinas/genética , Hepcidinas/metabolismo , Humanos , Hierro/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , ARN Mensajero/genética , Proteínas de Unión al ARN , Serina Endopeptidasas/genéticaRESUMEN
BACKGROUND: Pulmonary embolism (PE) represents 2% to 5% of all causes of out-of-hospital cardiac arrest (OHCA) and is associated with extremely unfavorable prognosis. In PE-related OHCA, inconsistent data showed that thrombolysis during cardiopulmonary resuscitation may favor survival. METHODS: This was a retrospective, observational, multicenter study from July 2011 to March 2018. All adults with OHCA, treated by a mobile ICU and with a diagnosis of PE confirmed on hospital admission, were included. The primary end point was 30-day survival in a weighted population. RESULTS: Of the 14,253 patients admitted to hospitals, 328 had a final diagnosis of PE and 246 were included in the analysis. In the group that received thrombolysis during resuscitation (n = 58), 14 (24%) received alteplase, 43 (74%) received tenecteplase, and one (2%) received streptokinase. Thirty-day survival was higher in the thrombolysis group than in the control group (16% vs 6%; P = .005; adjusted log-rank test) but the good neurologic outcome was not significantly different (10% vs 5%; adjusted relative risk, 1.97; 95% CI, 0.70-5.56). Median duration of stay in the ICU was 1 (0-5) day for the thrombolysis group and 1 (0-3) day for the control group (P = .23). CONCLUSIONS: In patients with OHCA with confirmed PE and admitted with recuperation of spontaneous circulation in the hospital, there was significantly higher 30-day survival in those who received thrombolysis during cardiopulmonary resuscitation compared with patients who did not receive thrombolysis.
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Reanimación Cardiopulmonar , Paro Cardíaco Extrahospitalario/mortalidad , Paro Cardíaco Extrahospitalario/terapia , Terapia Trombolítica , Anciano , Terapia Combinada , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Paro Cardíaco Extrahospitalario/etiología , Embolia Pulmonar/complicaciones , Sistema de Registros , Estudios Retrospectivos , Análisis de Supervivencia , Tasa de SupervivenciaRESUMEN
Iron excess increases the hepatic expression of hepcidin, the systemic iron metabolism regulator that favors iron sequestration in the spleen. Genetic iron overload related to hepcidin insufficiency decreases the spleen iron concentration and increases hepatic iron concentration, whereas during secondary iron overload, the hepcidin expression increases together with spleen iron concentration in addition to hepatic iron concentrations increase. Links between iron metabolism and other metals being suggested, our aim was to investigate, during iron overload, the relationships between the hepatic hepcidin expression level and the hepatic and splenic concentrations of iron, manganese, copper, zinc, and molybdenum, determined using inductively coupled plasma mass spectrometry. Hepcidin-deficient mice, secondary iron overload mice models, and their respective controls were studied. Spleen molybdenum and manganese concentrations paralleled the modulation of both spleen iron concentrations, increasing in secondary iron overload and decreasing in hepcidin deficiency related iron overload, as well as hepatic hepcidin mRNA expression. Our data suggest that iron, manganese, and molybdenum metabolisms could share mechanisms controlling their distribution that are associated to hepcidin modulation. In diseases with abnormal hepcidin levels, including chronic inflammation, special attention should be paid to those metals that can participate with the phenotype.-Cavey, T., Latour, C., Island, M.-L., Leroyer, P., Guggenbuhl, P., Coppin, H., Roth, M.-P., Bendavid, C., Brissot, P., Ropert, M., Loréal, O. Spleen iron, molybdenum, and manganese concentrations are coregulated in hepcidin-deficient and secondary iron overload models in mice.
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Hepcidinas/genética , Sobrecarga de Hierro/metabolismo , Hierro/metabolismo , Manganeso/metabolismo , Molibdeno/metabolismo , Animales , Hepcidinas/deficiencia , Hepcidinas/metabolismo , Sobrecarga de Hierro/genética , Hígado/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Bazo/metabolismoRESUMEN
International guidelines promote screening by faecal tests in asymptomatic individuals at average risk of colorectal cancer (CRC), but uptake does not reach recommended levels in most countries. The aim of this study was to synthetize evidence on (a) interventions aiming to increase uptake of faecal tests for CRC screening, in asymptomatic individuals at average risk of CRC, (b) interventions that targeted general practitioner (GP) involvement and (c) interventions that targeted nonresponders or disadvantaged groups. A systematic review of randomized-controlled trials, searching PubMed, Embase and the Cochrane Library database, based on the Cochrane's Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols 2015 guidelines was performed. The risk of bias of included trials was assessed. From 24 included RCTs, the following interventions increase uptake of faecal tests: advance notification letter (OR 1.20-1.51), postal mailing (OR 1.31-7.70), telephone contacts with an advisor (OR 1.36-7.72). Three interventions showed positive effects of GP involvement such as a GP-signed invitation letter [odds ratio (OR)=1.26], GP communication training (OR=1.22) or mailing reminders to GPs (OR=14.8). Inconclusive results were found for studies comparing different types of faecal tests and those testing the effectiveness of providing various types of written information. Advance notification letters, postal mailing of the faecal tests, written reminders and telephone contacts with an advisor increase patient uptake of faecal tests. There was only limited evidence on the effect of GP involvement on screening test uptake and a lack of studies focusing on nonresponders or disadvantaged groups.
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Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/epidemiología , Detección Precoz del Cáncer/métodos , Sangre Oculta , Detección Precoz del Cáncer/tendencias , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodosRESUMEN
Lack of either bone morphogenetic protein 6 (BMP6) or the BMP coreceptor hemojuvelin (HJV) in mice leads to a similar phenotype with hepcidin insufficiency, hepatic iron loading, and extrahepatic iron accumulation in males. This is consistent with the current views that HJV is a coreceptor for BMP6 in hepatocytes. To determine whether BMP6 and HJV may also signal to hepcidin independently of each other, we intercrossed Hjv-/- and Bmp6-/- mice and compared the phenotype of animals of the F2 progeny. Loss of Bmp6 further repressed Smad signaling and hepcidin expression in the liver of Hjv-/- mice of both sexes, and led to iron accumulation in the pancreas and the heart of females. These data suggest that, in Hjv-/- females, Bmp6 can provide a signal adequate to maintain hepcidin to a level sufficient to avoid extrahepatic iron loading. We also examined the impact of Bmp6 and/or Hjv deletion on the regulation of hepcidin by inflammation. Our data show that lack of 1 or both molecules does not prevent induction of hepcidin by lipopolysaccharide (LPS). However, BMP/Smad signaling in unchallenged animals is determinant for the level of hepcidin reached after stimulation, which is consistent with a synergy between interleukin 6/STAT3 and BMP/SMAD signaling in regulating hepcidin during inflammation.
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Proteína Morfogenética Ósea 6/deficiencia , Eliminación de Gen , Hepcidinas/metabolismo , Lipopolisacáridos/farmacología , Proteínas de la Membrana/deficiencia , Animales , Proteína Morfogenética Ósea 6/metabolismo , Femenino , Proteínas Ligadas a GPI , Proteína de la Hemocromatosis , Masculino , Proteínas de la Membrana/metabolismo , Ratones Noqueados , Fenotipo , Transducción de Señal/efectos de los fármacosRESUMEN
Importance: Increasing participation in fecal screening tests is a major challenge in countries that have implemented colorectal cancer (CRC) screening programs. Objective: To determine whether providing general practitioners (GPs) a list of patients who are nonadherent to CRC screening enhances patient participation in fecal immunochemical testing (FIT). Design, Setting, and Participants: A 3-group, cluster-randomized study was conducted from July 14, 2015, to July 14, 2016, on the west coast of France, with GPs in 801 practices participating and involving adult patients (50-74 years) who were at average risk of CRC and not up-to-date with CRC screening. The final follow-up date was July 14, 2016. Interventions: General practitioners were randomly assigned to 1 of 3 groups: 496 received a list of patients who had not undergone CRC screening (patient-specific reminders group, 10â¯476 patients), 495 received a letter describing region-specific CRC screening adherence rates (generic reminders group, 10â¯606 patients), and 455 did not receive any reminders (usual care group, 10â¯147 patients). Main Outcomes and Measures: The primary end point was patient participation in CRC screening 1 year after the intervention. Results: Among 1482 randomized GPs (mean age, 53.4 years; 576 women [38.9%]), 1446 participated; of the 33â¯044 patients of these GPs (mean age, 59.7 years; 17â¯949 women [54.3%]), follow-up at 1 year was available for 31â¯229 (94.5%). At 1 year, 24.8% (95% CI, 23.4%-26.2%) of patients in the specific reminders group, 21.7% (95% CI, 20.5%-22.8%) in the generic reminders group, and 20.6% (95% CI, 19.3%-21.8%) in the usual care group participated in the FIT screening. The between-group differences were 3.1% (95% CI, 1.3%-5.0%) for the patient-specific reminders group vs the generic reminders group, 4.2% (95% CI, 2.3%-6.2%) for the patient-specific reminders group vs the usual care group, and 1.1% (95% CI, -0.6% to 2.8%) for generic reminders group vs the usual care group. Conclusions and Relevance: Providing French GPs caring for adults at average risk of CRC with a list of their patients who were not up-to-date with their CRC screening resulted in a small but significant increase in patient participation in FIT screening at 1 year compared with patients who received usual care. Providing GPs with generic reminders about regional rates of CRC screening did not increase screening rates compared with usual care. Trial Registration: clinicaltrials.gov Identifier: NCT02515344.
Asunto(s)
Neoplasias Colorrectales/diagnóstico , Detección Precoz del Cáncer/estadística & datos numéricos , Médicos Generales , Sangre Oculta , Cooperación del Paciente , Detección Precoz del Cáncer/métodos , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Clase SocialRESUMEN
Malaria, a major global health challenge worldwide, is accompanied by a severe anemia secondary to hemolysis and increased erythrophagocytosis. Iron is an essential functional component of erythrocyte hemoglobin and its availability is controlled by the liver-derived hormone hepcidin. We examined the regulation of hepcidin during malarial infection in mice using the rodent parasite Plasmodium berghei K173. Mice infected with Plasmodium berghei K173 develop a severe anemia and die after 18 to 22 days without cerebral malaria. During the early phase of blood-stage infection (days 1 to 5), a strong inflammatory signature was associated with an increased production of hepcidin. Between days 7 and 18, while infection progressed, red blood cell count, hemoglobin and hematocrit dramatically decreased. In the late phase of malarial infection, hepcidin production was reduced concomitantly to an increase in the messenger RNA expression of the hepcidin suppressor erythroferrone in the bone marrow and the spleen. Compared with wild-type mice, Erfe-/- mice failed to adequately suppress hepcidin expression after infection with Plasmodium berghei K173. Importantly, the sustained production of hepcidin allowed by erythroferrone ablation was associated with decreased parasitemia, providing further evidence that transient iron restriction could be beneficial in the treatment of malaria.
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Anemia/sangre , Anemia/etiología , Citocinas/metabolismo , Hepcidinas/sangre , Malaria/complicaciones , Proteínas Musculares/metabolismo , Anemia/diagnóstico , Animales , Biomarcadores , Citocinas/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Eritropoyesis , Regulación de la Expresión Génica , Malaria/parasitología , Masculino , Ratones , Ratones Noqueados , Proteínas Musculares/genética , Parasitemia , Plasmodium berghei , ARN Mensajero/genética , ARN Mensajero/metabolismo , Índice de Severidad de la EnfermedadAsunto(s)
Activinas/fisiología , Hepcidinas/biosíntesis , Inflamación/metabolismo , Proteínas Smad/fisiología , Activinas/deficiencia , Activinas/genética , Animales , Infecciones Bacterianas/metabolismo , Proteína Morfogenética Ósea 6/deficiencia , Proteína Morfogenética Ósea 6/fisiología , Endotoxemia/metabolismo , Infecciones por Escherichia coli/metabolismo , Regulación de la Expresión Génica , Hepcidinas/genética , Inflamación/inducido químicamente , Inflamación/etiología , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Procesamiento Proteico-Postraduccional , Pirazoles/farmacología , Pirimidinas/farmacología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Transducción de Señal , Trementina/toxicidad , Regulación hacia ArribaRESUMEN
Hepcidin, the main regulator of iron homeostasis, is repressed when erythropoiesis is acutely stimulated by erythropoietin (EPO) to favor iron supply to maturing erythroblasts. Erythroferrone (ERFE) has been identified as the erythroid regulator that inhibits hepcidin in stress erythropoiesis. A powerful hepcidin inhibitor is the serine protease matriptase-2, encoded by TMPRSS6, whose mutations cause iron refractory iron deficiency anemia. Because this condition has inappropriately elevated hepcidin in the presence of high EPO levels, a role is suggested for matriptase-2 in EPO-mediated hepcidin repression. To investigate the relationship between EPO/ERFE and matriptase-2, we show that EPO injection induces Erfe messenger RNA expression but does not suppress hepcidin in Tmprss6 knockout (KO) mice. Similarly, wild-type (WT) animals, in which the bone morphogenetic protein-mothers against decapentaplegic homolog (Bmp-Smad) pathway is upregulated by iron treatment, fail to suppress hepcidin in response to EPO. To further investigate whether the high level of Bmp-Smad signaling of Tmprss6 KO mice counteracts hepcidin suppression by EPO, we generated double KO Bmp6-Tmprss6 KO mice. Despite having Bmp-Smad signaling and hepcidin levels that are similar to WT mice under basal conditions, double KO mice do not suppress hepcidin in response to EPO. However, pharmacologic downstream inhibition of the Bmp-Smad pathway by dorsomorphin, which targets the BMP receptors, improves the hepcidin responsiveness to EPO in Tmprss6 KO mice. We concluded that the function of matriptase-2 is dominant over that of ERFE and is essential in facilitating hepcidin suppression by attenuating the BMP-SMAD signaling.
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Proteínas Morfogenéticas Óseas/metabolismo , Eritropoyetina/farmacología , Hepcidinas/metabolismo , Hígado/metabolismo , Proteínas de la Membrana/metabolismo , Serina Endopeptidasas/metabolismo , Transducción de Señal/fisiología , Proteínas Smad/metabolismo , Animales , Proteínas Morfogenéticas Óseas/genética , Hepcidinas/genética , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Serina Endopeptidasas/genética , Proteínas Smad/genéticaRESUMEN
UNLABELLED: Hereditary hemochromatosis, which is characterized by inappropriately low levels of hepcidin, increased dietary iron uptake, and systemic iron accumulation, has been associated with mutations in the HFE, transferrin receptor-2 (TfR2), and hemojuvelin (HJV) genes. However, it is still not clear whether these molecules intersect in vivo with bone morphogenetic protein 6 (BMP6)/mothers against decapentaplegic (SMAD) homolog signaling, the main pathway up-regulating hepcidin expression in response to elevated hepatic iron. To answer this question, we produced double knockout mice for Bmp6 and ß2-microglobulin (a surrogate for the loss of Hfe) and for Bmp6 and Tfr2, and we compared their phenotype (hepcidin expression, Bmp/Smad signaling, hepatic and extrahepatic tissue iron accumulation) with that of single Bmp6-deficient mice and that of mice deficient for Hjv, alone or in combination with Hfe or Tfr2. Whereas the phenotype of Hjv-deficient females was not affected by loss of Hfe or Tfr2, that of Bmp6-deficient females was considerably worsened, with decreased Smad5 phosphorylation, compared with single Bmp6-deficient mice, further repression of hepcidin gene expression, undetectable serum hepcidin, and massive iron accumulation not only in the liver but also in the pancreas, the heart, and the kidneys. CONCLUSION: These results show that (1) BMP6 does not require HJV to transduce signal to hepcidin in response to intracellular iron, even if the loss of HJV partly reduces this signal, (2) another BMP ligand can replace BMP6 and significantly induce hepcidin expression in response to extracellular iron, and (3) BMP6 alone is as efficient at inducing hepcidin as the other BMPs in association with the HJV/HFE/TfR2 complex; they provide an explanation for the compensatory effect of BMP6 treatment on the molecular defect underlying Hfe hemochromatosis in mice.
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Proteína Morfogenética Ósea 6/genética , Hemocromatosis/genética , Antígenos de Histocompatibilidad Clase I/genética , Proteínas de la Membrana/genética , Receptores de Transferrina/genética , Animales , Femenino , Proteínas Ligadas a GPI , Eliminación de Gen , Regulación de la Expresión Génica , Proteína de la Hemocromatosis , Hierro , Ratones , Ratones Endogámicos C57BL , FenotipoRESUMEN
Iron is essential for retinal function but contributes to oxidative stress-mediated degeneration. Iron retinal homeostasis is highly regulated and transferrin (Tf), a potent iron chelator, is endogenously secreted by retinal cells. In this study, therapeutic potential of a local Tf delivery was evaluated in animal models of retinal degeneration. After intravitreal injection, Tf spread rapidly within the retina and accumulated in photoreceptors and retinal pigment epithelium, before reaching the blood circulation. Tf injected in the vitreous prior and, to a lesser extent, after light-induced retinal degeneration, efficiently protected the retina histology and function. We found an association between Tf treatment and the modulation of iron homeostasis resulting in a decrease of iron content and oxidative stress marker. The immunomodulation function of Tf could be seen through a reduction in macrophage/microglial activation as well as modulated inflammation responses. In a mouse model of hemochromatosis, Tf had the capacity to clear abnormal iron accumulation from retinas. And in the slow P23H rat model of retinal degeneration, a sustained release of Tf in the vitreous via non-viral gene therapy efficently slowed-down the photoreceptors death and preserved their function. These results clearly demonstrate the synergistic neuroprotective roles of Tf against retinal degeneration and allow identify Tf as an innovative and not toxic therapy for retinal diseases associated with oxidative stress.
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Modelos Animales de Enfermedad , Inflamación/prevención & control , Hierro/toxicidad , Estrés Oxidativo/efectos de los fármacos , Degeneración Retiniana/prevención & control , Transferrina/farmacología , Animales , Células Cultivadas , Homeostasis/efectos de los fármacos , Técnicas para Inmunoenzimas , Inflamación/inducido químicamente , Masculino , Ratones , ARN Mensajero/genética , Ratas , Ratas Wistar , Reacción en Cadena en Tiempo Real de la Polimerasa , Degeneración Retiniana/inducido químicamente , Degeneración Retiniana/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
UNLABELLED: Gender-related disparities in the regulation of iron metabolism may contribute to the differences exhibited by men and women in the progression of chronic liver diseases associated with reduced hepcidin expression, e.g., chronic hepatitis C, alcoholic liver disease, or hereditary hemochromatosis. However, their mechanisms remain poorly understood. In this study we took advantage of the major differences in hepcidin expression and tissue iron loading observed between Bmp6-deficient male and female mice to investigate the mechanisms underlying this sexual dimorphism. We found that testosterone robustly represses hepcidin transcription by enhancing Egfr signaling in the liver and that selective epidermal growth factor receptor (Egfr) inhibition by gefitinib (Iressa) in males markedly increases hepcidin expression. In males, where the suppressive effects of testosterone and Bmp6-deficiency on hepcidin expression are combined, hepcidin is more strongly repressed than in females and iron accumulates massively not only in the liver but also in the pancreas, heart, and kidneys. CONCLUSION: Testosterone-induced repression of hepcidin expression becomes functionally important during homeostatic stress from disorders that result in iron loading and/or reduced capacity for hepcidin synthesis. These findings suggest that novel therapeutic strategies targeting the testosterone/EGF/EGFR axis may be useful for inducing hepcidin expression in patients with iron overload and/or chronic liver diseases.
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Receptores ErbB/metabolismo , Hepcidinas/metabolismo , Hierro/metabolismo , Hígado/metabolismo , Factores Sexuales , Transducción de Señal/fisiología , Testosterona/metabolismo , Animales , Proteína Morfogenética Ósea 6/deficiencia , Proteína Morfogenética Ósea 6/genética , Proteína Morfogenética Ósea 6/metabolismo , Proteínas de Transporte de Catión/metabolismo , Femenino , Homeostasis/fisiología , Riñón/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Miocardio/metabolismo , Páncreas/metabolismo , Proteínas Smad/metabolismoRESUMEN
Anemia is very common in patients suffering from infections or chronic inflammation and can add substantially to the morbidity of the underlying disease. It is mediated by excessive production of the iron-regulatory peptide hepcidin, but the signaling pathway responsible for hepcidin up-regulation in the inflammatory context is still not understood completely. In the present study, we show that activin B has an unexpected but crucial role in the induction of hepcidin by inflammation. There is a dramatic induction of Inhbb mRNA, encoding the activin ß(B)-subunit, in the livers of mice challenged with lipopolysaccharide, slightly preceding an increase in Smad1/5/8 phosphorylation and Hamp mRNA. Activin B also induces Smad1/5/8 phosphorylation in human hepatoma-derived cells and, synergistically with IL-6 and STAT-3 signaling, up-regulates hepcidin expression markedly, an observation confirmed in mouse primary hepatocytes. Pretreatment with a bone morphogenic protein type I receptor inhibitor showed that the effect of activin B on hepcidin expression is entirely attributable to its effect on bone morphogenetic protein signaling, most likely via activin receptor-like kinase 3. Activin B is therefore a novel and specific target for the treatment of anemia of inflammation.
Asunto(s)
Activinas/biosíntesis , Péptidos Catiónicos Antimicrobianos/genética , Inflamación/metabolismo , Proteínas Smad/metabolismo , Activinas/genética , Animales , Proteína Morfogenética Ósea 6/deficiencia , Proteína Morfogenética Ósea 6/genética , Proteína Morfogenética Ósea 6/metabolismo , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepcidinas , Humanos , Inflamación/etiología , Interleucina-6/deficiencia , Interleucina-6/genética , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: The bone morphogenetic protein BMP6 regulates hepcidin production by the liver. However, it is not yet known whether BMP6 derives from the liver itself or from other sources such as the small intestine, as has been recently suggested. This study was aimed at investigating the source of BMP6 further. DESIGN AND METHODS: We used three different strains of mice (C57BL/6, DBA/2, and 129/Sv) with iron overload induced either by an iron-enriched diet or by inactivation of the Hfe gene. We examined Bmp6 expression at both the mRNA (by quantitative PCR) and protein (by immunohistochemistry and Western blotting analyses) levels. RESULTS: We showed that iron overload induces Bmp6 mRNA expression in the liver but not in the duodenum of these mice. Bmp6 is also detected by immunohistochemistry in liver tissue sections of mice with iron overload induced either by an iron-enriched diet or by inactivation of the Hfe gene, but not in liver tissue sections from iron-loaded Bmp6-deficient mice. Bmp6 in the duodenum was below immunodetection threshold, thus confirming quantitative PCR data. Lack of specificity of available antibodies together with slight heterogeneity between 129 substrains may account for the differences with previously published data. CONCLUSIONS: Our data strongly support the importance of liver BMP6 for regulation of iron metabolism. Indeed, they demonstrate that intestinal Bmp6 expression is modulated by iron neither at the mRNA nor at the protein level.