RESUMEN

OBJECTIVE: Aim: To determine the effect of the developed complex treatment of patients with peritonitis on the dynamics of humoral factors of nonspecific reactivity in the course of the disease. PATIENTS AND METHODS: Materials and Methods: The study included 124 patients with toxic and terminal stages of peritonitis, who were divided into 3 groups. Group I (main) included 39 patients whose complex treatment included cytochrome C. Group II (main) included 41 patients whose complex treatment included cytochrome C and a solution containing levocarnitine and arginine hydrochloride. The comparison group comprised 44 patients who did not receive the specified drugs. The patients underwent determination of the levels of fibronectin, ceruloplasmin, and procalcitonin in the serum during the course of the disease. RESULTS: Results: In patients of the I and II main groups, the use of the proposed treatment contributed to the optimization of the production of acute phase proteins: a decrease in procalcitonin production during the study, optimization of ceruloplasmin and fibronectin production, especially in the II main group. In patients of the comparison group, decompensation in the production of humoral inflammatory factors was determined, associated with a significant increase in fibronectin production, a decrease in ceruloplasmin content, and an increase in procalcitonin throughout the entire period. CONCLUSION: Conclusions: The use of cytochrome C and a solution containing levocarnitine and arginine hydrochloride in the complex treatment of patients with disseminated peritonitis helps to optimize the production of acute phase proteins, which leads to a decrease in inflammation and the preservation of factors of nonspecific humoral activity at a subcompensated level.

Asunto(s)

Proteínas de Fase Aguda , Ceruloplasmina , Peritonitis , Polipéptido alfa Relacionado con Calcitonina , Humanos , Peritonitis/tratamiento farmacológico , Peritonitis/sangre , Femenino , Masculino , Persona de Mediana Edad , Ceruloplasmina/metabolismo , Proteínas de Fase Aguda/metabolismo , Polipéptido alfa Relacionado con Calcitonina/sangre , Fibronectinas/sangre , Citocromos c/sangre , Citocromos c/metabolismo , Periodo Posoperatorio , Arginina/sangre , Adulto , Anciano

RESUMEN

Neonatal iron deficiency anemia is prevalent among domestic pigs but does not occur in the offspring of wild boar. The main causes of this disorder in piglets of modern pig breeds are paucity of hepatic iron stores, high birth weight, and rapid growth. Replenishment of fetal iron stores is a direct result of iron transfer efficiency across the placenta. In this study, we attempted to investigate the molecular potential of iron transfer across the placenta as a possible cause of differences between wild boar and Polish Large White (PLW) offspring. Furthermore, by analyzing placentas from PLW gilts that had litters of different sizes, we aimed to elucidate the impact of the number of fetuses on placental ability to transport iron. Using RNA sequencing, we examined the expression of iron-related genes in the placentas from wild boar and PLW gilts. We did not reveal significant differences in the expression of major iron transporters among all analyzed placentas. However, in wild boar placentas, we found higher expression of copper-dependent ferroxidases such as ceruloplasmin, zyklopen, and hephaestin, which facilitate iron export to the fetal circulation. We also determined a close co-localization of ceruloplasmin and zyklopen with ferroportin, the only iron exporter.

Asunto(s)

Hierro , Tamaño de la Camada , Placenta , Sus scrofa , Animales , Femenino , Placenta/metabolismo , Hierro/metabolismo , Embarazo , Sus scrofa/metabolismo , Sus scrofa/genética , Porcinos , Ceruloplasmina/metabolismo , Ceruloplasmina/genética , Proteínas de Transporte de Catión/metabolismo , Proteínas de Transporte de Catión/genética , Transporte Biológico

RESUMEN

The lack of specific biological materials and biomarkers limits our knowledge of the mechanisms underlying intrauterine regulation of iron supply to the fetus. Determining the meconium content of proteins commonly used in the laboratory to assess the transport, storage, and distribution of iron in the body may elucidate their roles in fetal development. Ferritin, transferrin, haptoglobin, ceruloplasmin, lactoferrin, myeloperoxidase (MPO), neutrophil gelatinase-associated lipocalin (NGAL), and calprotectin were determined by ELISA in meconium samples obtained from 122 neonates. There were strong correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL (p < 0.05). Meconium concentrations of ferritin were several-fold higher than the concentrations of the other proteins, with the exception of calprotectin whose concentration was approximately three-fold higher than that of ferritin. Meconium ceruloplasmin concentration significantly correlated with the concentrations of MPO, NGAL, lactoferrin, and calprotectin. Correlations between the meconium concentrations of haptoglobin, transferrin, and NGAL may reflect their collaborative involvement in the storage and transport of iron in the intrauterine environment in line with their recognized biological properties. High meconium concentrations of ferritin may provide information about the demand for iron and its utilization by the fetus. The associations between ceruloplasmin and neutrophil proteins may indicate the involvement of ceruloplasmin in the regulation of neutrophil activity in the intrauterine environment.

Asunto(s)

Ceruloplasmina , Haptoglobinas , Hierro , Lipocalina 2 , Meconio , Humanos , Hierro/metabolismo , Meconio/metabolismo , Recién Nacido , Ceruloplasmina/metabolismo , Femenino , Haptoglobinas/metabolismo , Lipocalina 2/metabolismo , Transferrina/metabolismo , Transferrina/análisis , Ferritinas/metabolismo , Complejo de Antígeno L1 de Leucocito/metabolismo , Lactoferrina/metabolismo , Lactoferrina/análisis , Masculino , Peroxidasa/metabolismo , Biomarcadores/metabolismo , Adulto

RESUMEN

BACKGROUND AND AIMS: Few studies have focused on the outcomes of Wilson's disease (WD) diagnosed before age of 5 years. This study aimed to summarize the clinical features of early diagnosed WD and analyse treatment outcomes and the risk factors associated with treatment failure. METHODS: A total of 139 children confirmed with WD before 5 years were enrolled in this study. Only patients with follow-up over 1 year were analysed with Kaplan-Meier survival analysis. The composite outcomes included death, progression to liver failure or acute hepatitis, development of renal or neurological symptoms and persistent elevation of alanine aminotransferase (ALT). The treatment failure was defined as occurrence of at least one of above outcomes. RESULTS: Among 139 WD patients at diagnosis, two (1.4%) WD patients presented with symptomatic liver disease, whereas 137 (98.6%) were phenotypically asymptomatic, including 135 with elevated ALT and 2 with normal liver function. Median serum ceruloplasmin (Cp) was 3.1 mg/dL, and urinary copper excretion was 87.4 µg/24-h. There were 71 variants identified in the the copper-transporting ATPase beta gene, and 29 were loss of function (LOF). 51 patients with LOF variant were younger at diagnosis and had lower Cp than 88 patients without LOF. Among 93 patients with over 1 year of follow-up, 19 (20.4%) received zinc monotherapy, and 74 (79.6%) received a zinc/D-penicillamine combination therapy. 14 (15.1%) patients underwent treatment failure, and its occurrence was associated with poor compliance (p < .01). CONCLUSIONS: Cp is a reliable biomarker for early diagnosis, and zinc monotherapy is an effective treatment for WD during early childhood. Good treatment compliance is critical to achieve a favourable outcome.

Asunto(s)

Ceruloplasmina , ATPasas Transportadoras de Cobre , Degeneración Hepatolenticular , Penicilamina , Humanos , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/genética , Degeneración Hepatolenticular/tratamiento farmacológico , Degeneración Hepatolenticular/sangre , Degeneración Hepatolenticular/terapia , Femenino , Masculino , Preescolar , Ceruloplasmina/análisis , Ceruloplasmina/metabolismo , ATPasas Transportadoras de Cobre/genética , Penicilamina/uso terapéutico , Pronóstico , Alanina Transaminasa/sangre , Niño , Cobre/sangre , Factores de Riesgo , Insuficiencia del Tratamiento , Diagnóstico Precoz , Progresión de la Enfermedad , Estimación de Kaplan-Meier , Lactante , Quelantes/uso terapéutico

RESUMEN

BACKGROUND: It is widely known that sex differences have a significant impact on patients with major depressive disorder (MDD). This study aims to evaluate the sex-related connection between serum trace elements and changes in neurometabolism in the anterior cingulate cortex (ACC) of MDD patients. METHODS: 109 untreated MDD patients and 59 healthy controls underwent proton magnetic resonance spectroscopy (1H-MRS) under resting conditions. We measured metabolic ratios in the ACC from both sides. Additionally, venous blood samples were taken from all participants to detect calcium (Ca), phosphorus, magnesium (Mg), copper (Cu), ceruloplasmin (CER), zinc (Zn), and iron (Fe) levels. We performed association and interaction analyses to explore the connections between the disease and gender. RESULTS: In individuals with MDD, the Cu/Zn ratio increased, while the levels of Mg, CER, Zn and Fe decreased. Male MDD patients had lower Cu levels, while female patients had an increased Cu/Zn ratio. We observed significant gender differences in Cu, CER and the Cu/Zn ratio in MDD. Male patients showed a reduced N-acetyl aspartate (NAA)/phosphocreatine + creatine (PCr + Cr) ratio in the left ACC. The NAA/PCr + Cr ratio decreased in the right ACC in patients with MDD. In the left ACC of male MDD patients, the Cu/Zn ratio was inversely related to the NAA/PCr + Cr ratio, and Fe levels were negatively associated with the GPC + PC/PCr + Cr ratio. CONCLUSIONS: Our findings highlight gender-specific changes in Cu homeostasis among male MDD patients. The Cu/Zn ratio and Fe levels in male MDD patients were significantly linked to neurometabolic alterations in the ACC.

Asunto(s)

Ácido Aspártico , Trastorno Depresivo Mayor , Giro del Cíngulo , Hierro , Oligoelementos , Zinc , Humanos , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/metabolismo , Masculino , Femenino , Giro del Cíngulo/metabolismo , Giro del Cíngulo/diagnóstico por imagen , Adulto , Oligoelementos/sangre , Oligoelementos/metabolismo , Zinc/sangre , Zinc/metabolismo , Hierro/metabolismo , Hierro/sangre , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Ácido Aspártico/sangre , Persona de Mediana Edad , Factores Sexuales , Fosfocreatina/metabolismo , Fosfocreatina/sangre , Ceruloplasmina/metabolismo , Cobre/sangre , Cobre/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Magnesio/sangre , Magnesio/metabolismo , Fósforo/sangre , Creatina/metabolismo , Creatina/sangre , Calcio/sangre , Calcio/metabolismo , Estudios de Casos y Controles

RESUMEN

BACKGROUND: The essential trace element copper is relevant for many important physiological processes. Changes in copper homeostasis can result from disease and affect human health. A reliable assessment of copper status by suitable biomarkers may enable fast detection of subtle changes in copper metabolism. To this end, additional biomarkers besides serum copper and ceruloplasmin (CP) concentrations are required. OBJECTIVES: The aim of this study was to investigate the emerging copper biomarkers CP oxidase (CPO) activity, exchangeable copper (CuEXC) and labile copper in serum of healthy women and compare them with the conventional biomarkers total serum copper and CP. METHOD AND MAIN FINDINGS: This observational study determined CPO activity, the non CP-bound copper species CuEXC and labile copper, total serum copper and CP in sera of 110 healthy women. Samples were collected at four time points over a period of 24 weeks. The concentrations of total serum copper and CP were within the reference ranges. The comparison of all five biomarkers provided insight into their relationship, the intra- and inter-individual variability as well as the age dependence. The correlation and Principal Component Analyses (PCA) indicated that CP, CPO activity and total copper correlated well, followed by CuEXC, while the labile copper pool was unrelated to the other parameters. CONCLUSIONS: This study suggests that the non-CP-bound copper species represent copper pools that are differently regulated from total copper or CP-bound copper, making them interesting complementary biomarkers to enable a more complete assessment of body copper status with potential relevance for clinical application.

Asunto(s)

Biomarcadores , Cobre , Humanos , Cobre/sangre , Femenino , Biomarcadores/sangre , Adulto , Persona de Mediana Edad , Ceruloplasmina/metabolismo , Ceruloplasmina/análisis , Adulto Joven , Voluntarios Sanos , Anciano

RESUMEN

BACKGROUND: Systemic lupus erythematosus (SLE) and Wilson's disease (WD) are both systemic diseases that can affect multiple organs in the body. The coexistence of SLE and WD is rarely encountered in clinical practice, making it challenging to diagnose. CASE REPORT: We present the case of a 9-year-old girl who initially presented with proteinuria, haematuria, pancytopenia, hypocomplementemia, and positivity for multiple autoantibodies. She was diagnosed with SLE, and her blood biochemistry showed elevated liver enzymes at the time of diagnosis. Despite effective control of her symptoms, her liver enzymes remained elevated during regular follow-up. Laboratory tests revealed decreased serum copper and ceruloplasmin levels, along with elevated urinary copper. Liver biopsy revealed chronic active hepatitis, moderate inflammation, moderate-severe fibrosis, and a trend towards local cirrhosis. Genetic sequencing revealed compound heterozygous mutations in the ATP7B gene, confirming the diagnosis of SLE with WD. The girl received treatment with a high-zinc/low-copper diet, but her liver function did not improve. Upon recommendation following multidisciplinary consultation, she underwent liver transplantation. Unfortunately, she passed away on the fourth day after the surgery. CONCLUSIONS: SLE and WD are diseases that involve multiple systems and organs in the body, and SLE complicated with WD is rarely encountered in the clinic; therefore, it is easy to misdiagnose. Because penicillamine can induce lupus, it is not recommended. Liver transplantation is indicated for patients with liver disease who do not respond to medical treatment with WD. However, further research is needed to determine the optimal timing of liver transplantation for patients with SLE complicated with WD.

Asunto(s)

Degeneración Hepatolenticular , Lupus Eritematoso Sistémico , Niño , Femenino , Humanos , Ceruloplasmina/metabolismo , Ceruloplasmina/uso terapéutico , Cobre/orina , Degeneración Hepatolenticular/complicaciones , Degeneración Hepatolenticular/diagnóstico , Degeneración Hepatolenticular/tratamiento farmacológico , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/diagnóstico , Penicilamina/uso terapéutico

RESUMEN

This study aimed to assess how heat stress, specifically within the range of 35-38 °C, affects the populations of culturable intestinal lactobacilli, enterococci, and Escherichia coli, as well as the expression of Heat Shock Proteins (HSP70), in Lohmann Brown chickens. It also explored the influence of the chickens' blood transferrin and ceruloplasmin genotypes on these responses. Thirty chickens underwent eight hours of heat stress, maintained at an average temperature of 37 °C and a relative humidity of 75-80%, with continuous access to food and water. Behavioral monitoring was conducted throughout to prevent excessive heat-related mortality. The Lohmann Brown chickens from the Yerevan "Arax" poultry farm were initially classified based on their blood transferrin and ceruloplasmin genotypes to investigate potential correlations between intestinal bacterial composition and variations in these polymorphisms. A significant correlation was found between heat stress and the abundance of culturable enterococci within the intestinal microbiota, regardless of chicken TfAB, TfBC, CpAB, CpCC and TfAB, TfBC, CpAB, CpCD genotypes. Heat stress led to nearly double the HSP70 levels in chicken blood, along with a reduction in the culturable enterococci population by at least 10,000-fold in the intestinal microbiota. These findings are significant for targeted management strategies to mitigate heat stress in chicken populations.

Asunto(s)

Pollos , Microbioma Gastrointestinal , Animales , Pollos/microbiología , Respuesta al Choque Térmico , Escherichia coli/fisiología , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Enterococcus/fisiología , Enterococcus/genética , Ceruloplasmina/metabolismo , Ceruloplasmina/genética , Genotipo , Lactobacillus/genética , Transferrina/metabolismo , Transferrina/genética , Calor

RESUMEN

BACKGROUND: Essential tremor (ET), a prevalent movement disorder, has an elusive pathogenesis. A reduction in ceruloplasmin (Cp) levels can be found in some patients with ET. In addition, some studies have suggested an association between ET and neurodegeneration. As a ferroxidase, Cp is critical for iron metabolism, protecting against oxidative stress and neurodegeneration. Iron metabolism dysregulation, linked to ferroptosis, has implications in neurodegenerative diseases. Yet, research on Cp and ET remains limited. OBJECTIVES: This study aims to elucidate the relationship between ET and serum Cp levels. METHODS: We collected demographic and clinical data from 62 patients with ET satisfying the diagnostic criteria and compared these to data from 100 healthy controls. RESULTS: The median Cp levels in ET patients were 21.5 (18.8, 23.9) mg/dL, significantly lower than those in controls (23.1 [(20.7, 25.7) mg/dL; P = 0.006]). A reduction in Cp levels emerged as a risk factor for ET incidence (odds ratio (OR) = 0.873, 95% confidence interval (CI), 0.795, 0.959; P = 0.005). The area under the receiver operating characteristic (ROC) curve for serum Cp levels to predict the onset of ET was 0.629 (95% CI, 0.537-0.720; P = 0.006), and the optimal cut-off value for Cp levels was 19.5 mg/dL with a sensitivity of 91% and a specificity of 33.9%. CONCLUSION: Our analysis suggests that reduced Cp levels are associated with ET. We speculate that reduced Cp levels may be involved in the pathogenesis of ET, which requires further studies.

Asunto(s)

Ceruloplasmina , Temblor Esencial , Humanos , Ceruloplasmina/metabolismo , Temblor Esencial/sangre , Femenino , Masculino , Anciano , Persona de Mediana Edad , Curva ROC , Anciano de 80 o más Años , Biomarcadores/sangre

RESUMEN

BACKGROUND: Biliary tract cancers (BTCs) are usually diagnosed at an advanced stage, when the disease is incurable. Currently used tumor biomarkers have limited diagnostic value for BTCs, so there is an urgent need for sensitive and specific biomarkers for their earlier diagnosis. Deregulation of the homeostasis of trace elements is involved in the carcinogenesis of different cancers, including BTCs. The objective of the study is to determine/compare the total concentrations of copper (Cu), zinc (Zn) and iron (Fe) and the proportions of free Cu and Cu bound to ceruloplasmin (Cp) and the isotopic ratio of 65Cu/63Cu in serum samples from healthy volunteers and cancer patients using inductively coupled plasma-mass spectrometry-based methods (ICP-MS). PATIENTS AND METHODS: In this prospective, noninterventional, nonrandomized study 20 patients and 20 healthy volunteers will be enrolled to identify serum Cu, Zn and Fe levels, Cu isotopic fractionation as a predictive biomarker of response to systemic therapy of BTCs, which will be evaluated by computed tomography. Newly developed analytical methods based on ICP-MS will be applied to metal-based biomarker research in oncology. CONCLUSIONS: In the study the comparison of the total concentration of selected trace elements, the proportion of free Cu and Cu bound to Cp and the isotopic ratio of 65Cu/63Cu in serum samples from healthy volunteers and cancer patients will be conducted to provide the foundation for the development of a BTC cancer screening methodology and the data on their usability as a potential predictive biomarker for BTCs of response to systemic therapy.

Asunto(s)

Neoplasias del Sistema Biliar , Biomarcadores de Tumor , Cobre , Oligoelementos , Adulto , Femenino , Humanos , Masculino , Neoplasias del Sistema Biliar/sangre , Biomarcadores de Tumor/sangre , Estudios de Casos y Controles , Ceruloplasmina/metabolismo , Ceruloplasmina/análisis , Cobre/sangre , Hierro/sangre , Espectrometría de Masas/métodos , Estudios Prospectivos , Oligoelementos/sangre , Zinc/sangre , Ensayos Clínicos Controlados no Aleatorios como Asunto

RESUMEN

Chrysin is a natural flavonoid with powerful neuroprotective capacity. Cerebral ischemia/reperfusion injury (CIRI) is associated with oxidative stress and ferroptosis. Hypoxia-inducible factor 1α (HIF-1α) and ceruloplasmin (CP) are the critical targets for oxidation reactions and iron transport. But the regulatory mechanism between them is still unclear. Transient middle cerebral artery occlusion (tMCAO) model in rats and oxygen and glucose deprivation/re-oxygenation (OGD/R) model in PC12 cells were applied. Pathological tissue staining and biochemical kit were used to evaluate the effect of chrysin. The relationship between HIF-1α and CP was verified by transcriptomics, qRT-PCR and Western blot. In CIRI, HIF-1α/CP loop was discovered to be the regulatory pathway of ferroptosis. CIRI led to activation and nuclear translocation of HIF-1α, which promoted CP transcription and translation, and downstream ferroptosis. Inhibition of HIF-1α had opposite effect on CP and ferroptosis regulation. Overexpression of CP increased the expression of HIF-1α, nevertheless, inhibited the nuclear translocation of HIF-1α and alleviated CIRI. Silencing CP promoted HIF-1α elevation in nucleus and aggravated CIRI. Mechanistically, chrysin restrained HIF-1α nuclear translocation, thereby inhibiting CP transcription and translation, which in turn reduced downstream HIF-1α expression and mitigated ferroptosis in CIRI. Our results highlight chrysin restrains ferroptosis in CIRI through HIF-1α/CP loop.

Asunto(s)

Ceruloplasmina , Ferroptosis , Flavonoides , Subunidad alfa del Factor 1 Inducible por Hipoxia , Ratas Sprague-Dawley , Daño por Reperfusión , Flavonoides/farmacología , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Ferroptosis/efectos de los fármacos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Ratas , Células PC12 , Masculino , Ceruloplasmina/metabolismo , Ceruloplasmina/genética , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/patología , Fármacos Neuroprotectores/farmacología , Transducción de Señal/efectos de los fármacos

RESUMEN

The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.

Asunto(s)

Esclerosis Amiotrófica Lateral , Complejos de Coordinación , Enfermedades Neurodegenerativas , Tiosemicarbazonas , Humanos , Ratones , Animales , Cobre/metabolismo , Esclerosis Amiotrófica Lateral/metabolismo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Ratones Transgénicos , Médula Espinal/metabolismo , Ceruloplasmina/metabolismo , Modelos Animales de Enfermedad

RESUMEN

The family of flavodiiron proteins (FDPs) plays an important role in the scavenging and detoxification of both molecular oxygen and nitric oxide. Using electrons from a flavin mononucleotide cofactor molecular oxygen is reduced to water and nitric oxide is reduced to nitrous oxide and water. While the mechanism for NO reduction in FDPs has been studied extensively, there is very little information available about O2 reduction. Here we use hybrid density functional theory (DFT) to study the mechanism for O2 reduction in FDPs. An important finding is that a proton coupled reduction is needed after the O2 molecule has bound to the diferrous diiron active site and before the OO bond can be cleaved. This is in contrast to the mechanism for NO reduction, where both NN bond formation and NO bond cleavage occurs from the same starting structure without any further reduction, according to both experimental and computational results. This computational result for the O2 reduction mechanism should be possible to evaluate experimentally. Another difference between the two substrates is that the actual OO bond cleavage barrier is low, and not involved in rate-limiting the reduction process, while the barrier connected with bond cleavage/formation in the NO reduction process is of similar height as the rate-limiting steps. We suggest that these results may be part of the explanation for the generally higher activity for O2 reduction as compared to NO reduction in most FDPs. Comparisons are also made to the O2 reduction reaction in the family of heme­copper oxidases.

Asunto(s)

Hemo , Óxido Nítrico , Óxido Nítrico/metabolismo , Hemo/química , Oxidorreductasas/química , Ceruloplasmina/metabolismo , Oxígeno/química , Agua/metabolismo , Oxidación-Reducción

Asunto(s)

Ceruloplasmina , Mutación del Sistema de Lectura , Imagen por Resonancia Magnética , Enfermedades Neurodegenerativas , Humanos , Ceruloplasmina/deficiencia , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico , Enfermedades Neurodegenerativas/patología , Trastornos del Metabolismo del Hierro/genética , Trastornos del Metabolismo del Hierro/diagnóstico , Trastornos del Metabolismo del Hierro/diagnóstico por imagen , Trastornos del Metabolismo del Hierro/patología , Masculino , Femenino

RESUMEN

Solid tumors are characterized by hypoxic areas, which are prone for macrophage infiltration. Once infiltrated, macrophages polarize to tumor associated macrophages (TAM) to support tumor progression. Therefore, the crosstalk between TAMs and tumor cells is of current interest for the development of novel therapeutic strategies. These may comprise induction of an iron- and lipid peroxidation-dependent form of cell death, known as ferroptosis. To study the macrophage - tumor cell crosstalk we polarized primary human macrophages towards a TAM-like phenotype, co-cultured them with HT1080 fibrosarcoma cells, and analyzed the tumor cell response to ferroptosis induction. In TAMs the expression of ceruloplasmin mRNA increased, which was driven by hypoxia inducible factor 2 and signal transducer and activator of transcription 1. Subsequently, ceruloplasmin mRNA was transferred from TAMs to HT1080 cells via extracellular vesicles. In tumor cells, mRNA was translated into protein to protect HT1080 cells from RSL3-induced ferroptosis. Mechanistically this was based on reduced iron abundance and lipid peroxidation. Interestingly, in naïve macrophages also hypoxia induced ceruloplasmin under hypoxia and a co-culture of HT1080 cells with hypoxic macrophages recapitulated the protective effect observed in TAM co-cultures. In conclusion, TAMs provoke tumor cells to release iron and thereby protect them from lipid peroxidation/ferroptosis.

Asunto(s)

Ferroptosis , Fibrosarcoma , Humanos , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Macrófagos Asociados a Tumores/metabolismo , ARN Mensajero/genética , Hipoxia/metabolismo , Fibrosarcoma/genética , Hierro/metabolismo , Microambiente Tumoral

RESUMEN

Plasma-derived therapeutic proteins are produced through an industrial fractionation process where proteins are purified from individual intermediates, some of which remain unused and are discarded. Relatively few plasma-derived proteins are exploited clinically, with most of available plasma being directed towards the manufacture of immunoglobulin and albumin. Although the plasma proteome provides opportunities to develop novel protein replacement therapies, particularly for rare diseases, the high cost of plasma together with small patient populations impact negatively on the development of plasma-derived orphan drugs. Enabling therapeutics development from unused plasma fractionation intermediates would therefore constitute a substantial innovation. To this objective, we characterized the proteome of unused plasma fractionation intermediates and prioritized proteins for their potential as new candidate therapies for human disease. We selected ceruloplasmin, a plasma ferroxidase, as a potential therapy for aceruloplasminemia, an adult-onset ultra-rare neurological disease caused by iron accumulation as a result of ceruloplasmin mutations. Intraperitoneally administered ceruloplasmin, purified from an unused plasma fractionation intermediate, was able to prevent neurological, hepatic and hematological phenotypes in ceruloplasmin-deficient mice. These data demonstrate the feasibility of transforming industrial waste plasma fraction into a raw material for manufacturing of new candidate proteins for replacement therapies, optimizing plasma use and reducing waste generation.

Asunto(s)

Ceruloplasmina , Trastornos del Metabolismo del Hierro , Enfermedades Neurodegenerativas , Proteoma , Adulto , Humanos , Animales , Ratones , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Proteoma/metabolismo , Enfermedades Raras , Residuos Industriales

RESUMEN

Nonalcoholic steatohepatitis (NASH) is a condition that progresses from nonalcoholic fatty liver disease (NAFLD) and is characterized by hepatic fat accumulation, inflammation, and fibrosis. It has the potential to develop into cirrhosis and liver cancer, and currently no effective pharmacological treatment is available. In this study, we investigate the therapeutic potential of targeting ceruloplasmin (Cp), a copper-containing protein predominantly secreted by hepatocytes, for treating NASH. Our result show that hepatic Cp is remarkedly upregulated in individuals with NASH and the mouse NASH model. Hepatocyte-specific Cp ablation effectively attenuates the onset of dietary-induced NASH by decreasing lipid accumulation, curbing inflammation, mitigating fibrosis, and ameliorating liver damage. By employing transcriptomics and metabolomics approaches, we have discovered that hepatic deletion of Cp brings about remarkable restoration of bile acid (BA) metabolism during NASH. Hepatic deletion of Cp effectively remodels BA metabolism by upregulating Cyp7a1 and Cyp8b1, which subsequently leads to enhanced BA synthesis and notable alterations in BA profiles. In conclusion, our studies elucidate the crucial involvement of Cp in NASH, highlighting its significance as a promising therapeutic target for the treatment of this disease.

Asunto(s)

Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ceruloplasmina/metabolismo , Ceruloplasmina/farmacología , Ceruloplasmina/uso terapéutico , Hígado/metabolismo , Inflamación/patología , Fibrosis , Ácidos y Sales Biliares/metabolismo

RESUMEN

Ceruloplasmin (Cp) is a ferroxidase that plays a role in cellular iron homeostasis and is mainly expressed in the liver and secreted into the blood. Cp is also produced by adipose tissue, which releases it as an adipokine. Although a dysfunctional interaction of iron with the metabolism of lipids has been associated with several metabolic diseases, the role of Cp in adipose tissue metabolism and in the interplay between hepatocytes and adipocytes has been poorly investigated. We previously found that Cp-deficient (CpKO) mice become overweight and demonstrate adipose tissue accumulation together with liver steatosis during aging, suggestive of lipid dysmetabolism. In the present study, we investigated the lipid alterations which occur during aging in adipose tissue and liver of CpKO and wild-type mice both in vivo and ex vivo. During aging of CpKO mice, we observed adipose tissue accumulation and liver lipid deposition, both of which are associated with macrophage infiltration. Liver lipid deposition was characterized by accumulation of triglycerides, fatty acids and ω-3 fatty acids, as well as by a switch from unsaturated to saturated fatty acids, which is characteristic of lipid storage. Liver steatosis was preceded by iron deposition and macrophage infiltration, and this was observed to be already occurring in younger CpKO mice. The accumulation of ω-3 fatty acids, which can only be acquired through diet, was associated with body weight increase in CpKO mice despite food intake being equal to that of wild-type mice, thus underlining the alterations in lipid metabolism/catabolism in Cp-deficient animals.

Asunto(s)

Ácidos Grasos Omega-3 , Hígado Graso , Ratones , Animales , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Imagen por Resonancia Magnética , Triglicéridos , Hierro/metabolismo , Ácidos Grasos

RESUMEN

We describe a novel superoxide dismutase (SOD1) mutation-associated clinical phenotype of cerebellar ataxia and motor neuron disease with a variant in the ceruloplasmin (Cp) gene, which may have possibly contributed to a multi-factorial phenotype, supported by genetic and protein structure analyses.

Asunto(s)

Esclerosis Amiotrófica Lateral , Ataxia Cerebelosa , Enfermedad de la Neurona Motora , Humanos , Esclerosis Amiotrófica Lateral/genética , Ataxia Cerebelosa/genética , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Enfermedad de la Neurona Motora/genética , Mutación/genética , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismo

RESUMEN

Our previous study showed that not only bovine lactoferrin (LF), the protein of milk and neutrophils, but also the human species forms complexes with oleic acid (OA) that inhibit tumor growth. Repeated injections of human LF in complex with OA (LF/8OA) to hepatoma-carrying mice decelerated tumor growth and increased animals' longevity. However, whether the effect of the LF/8OA complex is directed exclusively against malignant cells was not studied. Hence, its effect on normal blood cells was assayed, along with its possible modulation of ceruloplasmin (CP), the preferred partner of LF among plasma proteins. The complex LF/8OA (6 µM) caused hemolysis, unlike LF alone or BSA/8OA (250 µM). The activation of neutrophils with exocytosis of myeloperoxidase (MPO), a potent oxidant, was induced by 1 µM LF/8OA, whereas BSA/8OA had a similar effect at a concentration increased by an order. The egress of heme-containing proteins, i.e., MPO and hemoglobin, from blood cells affected by LF/8OA was followed by a pronounced oxidative/halogenating stress. CP, which is the natural inhibitor of MPO, added at a concentration of 2 mol per 1 mol of LF/8OA abrogated its cytotoxic effect. It seems likely that CP can be used effectively in regulating the LF/8OA complex's antitumor activity.

Asunto(s)

Carcinoma Hepatocelular , Hemoproteínas , Ratones , Humanos , Animales , Ceruloplasmina/metabolismo , Ácido Oléico/farmacología , Lactoferrina/farmacología , Lactoferrina/metabolismo , Hemoproteínas/metabolismo , Hemo/metabolismo