Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.613
Filtrar
1.
Redox Biol ; 46: 102118, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34474395

RESUMO

Ceruloplasmin (Cp) is a ferroxidase enzyme that is essential for cell iron efflux and has been postulated to have a neuroprotective role. During the myelination process, oligodendrocytes (OLs) and Schwann cells (SCs) express high levels of Cp, but the role of this enzyme in glial cell development and function is completely unknown. To define the function of Cp in the myelination of the central and peripheral nervous systems, we have conditionally knocked-out Cp specifically in OLs and SCs during early postnatal development as well as in aged mice. Cp ablation in early OLs (postnatal day 2, P2) significantly affects the differentiation of these cells and the synthesis of myelin through the first four postnatal weeks. The total number of mature myelinating OLs was reduced, and the density of apoptotic OLs was increased. These changes were accompanied with reductions in the percentage of myelinated axons and increases in the g-ratio of myelinated fibers. Cp ablation in young myelinating OLs (P30 or P60) did not affect myelin synthesis and/or OL numbers, however, Cp loss in aged OLs (8 months) induced cell iron overload, apoptotic cell death, brain oxidative stress, neurodegeneration and myelin disruption. Furthermore, Cp deletion in SCs affected postnatal SC development and myelination and produced motor coordination deficits as well as oxidative stress in young and aged peripheral nerves. Together, our data indicate that Cp ferroxidase activity is essential for OLs and SCs maturation during early postnatal development and iron homeostasis in matured myelinating cells. Additionally, our results suggest that Cp expression in myelinating glial cells is crucial to prevent oxidative stress and neurodegeneration in the central and peripheral nervous systems.


Assuntos
Ceruloplasmina , Bainha de Mielina , Animais , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Camundongos , Bainha de Mielina/metabolismo , Oligodendroglia , Estresse Oxidativo/genética , Células de Schwann
2.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576235

RESUMO

This study examined ceruloplasmin levels in patients with HFrEF, depending on cardiopulmonary exercise testing (CPET) parameters; a correlation was found between ceruloplasmin (CER) and iron and hepatic status, inflammatory and redox biomarkers. A group of 552 patients was divided according to Weber's classification: there were 72 (13%) patients in class A (peak VO2 > 20 mL/kg/min), 116 (21%) patients in class B (peak VO2 16-20 mL/kg/min), 276 (50%) patients in class C (peak VO2 10-15.9 mL/kg/min) and 88 (16%) patients in class D (peak VO2 < 10 mL/kg/min). A higher concentration of CER was found in patients with peak VO2 < 16 mL/kg/min and VE/CO2 slope > 45 compared to patients with VE/CO2 slope < 45 (escectively CER 30.6 mg/dL and 27.5 mg/dL). A significantly positive correlation was found between ceruloplasmin and NYHA class, RV diameter, NT-proBNP, uric acid, total protein, fibrinogen and hepatic enzymes. CER was positively correlated with both total oxidant status (TOS), total antioxidant capacity (TAC) and malondialdehyde. A model constructed to predict CER concentration indicated that TOS, malondialdehyde and alkaline phosphatase were independent predictive variables (R2 0.14, p < 0.001). CER as a continuous variable was an independent predictor of pVO2 ≤ 12 mL/kg/min after adjustment for sex, age and BMI. These results provide the basis of a new classification to encourage the determination of CER as a useful biomarker in HFrEF.


Assuntos
Biomarcadores/sangue , Ceruloplasmina/biossíntese , Insuficiência Cardíaca/sangue , Inflamação , Oxidantes , Volume Sistólico , Adulto , Antioxidantes/farmacologia , Índice de Massa Corporal , Ceruloplasmina/metabolismo , Teste de Esforço , Feminino , Insuficiência Cardíaca/diagnóstico , Humanos , Fígado/enzimologia , Masculino , Malondialdeído , Pessoa de Meia-Idade , Oxirredução , Estresse Oxidativo , Consumo de Oxigênio , Análise de Regressão , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Biomolecules ; 11(8)2021 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-34439909

RESUMO

WD is caused by ATP7B variants disrupting copper efflux resulting in excessive copper accumulation mainly in liver and brain. The diagnosis of WD is challenged by its variable clinical course, onset, morbidity, and ATP7B variant type. Currently it is diagnosed by a combination of clinical symptoms/signs, aberrant copper metabolism parameters (e.g., low ceruloplasmin serum levels and high urinary and hepatic copper concentrations), and genetic evidence of ATP7B mutations when available. As early diagnosis and treatment are key to favorable outcomes, it is critical to identify subjects before the onset of overtly detrimental clinical manifestations. To this end, we sought to improve WD diagnosis using artificial neural network algorithms (part of artificial intelligence) by integrating available clinical and molecular parameters. Surprisingly, WD diagnosis was based on plasma levels of glutamate, asparagine, taurine, and Fischer's ratio. As these amino acids are linked to the urea-Krebs' cycles, our study not only underscores the central role of hepatic mitochondria in WD pathology but also that most WD patients have underlying hepatic dysfunction. Our study provides novel evidence that artificial intelligence utilized for integrated analysis for WD may result in earlier diagnosis and mechanistically relevant treatments for patients with WD.


Assuntos
Inteligência Artificial , Degeneração Hepatolenticular/diagnóstico , Degeneração Hepatolenticular/genética , Adulto , Algoritmos , Encéfalo/embriologia , Ceruloplasmina/metabolismo , Cobre/metabolismo , ATPases Transportadoras de Cobre/biossíntese , DNA Mitocondrial/metabolismo , Diagnóstico por Computador , Feminino , Lógica Fuzzy , Ácido Glutâmico/metabolismo , Degeneração Hepatolenticular/fisiopatologia , Humanos , Fígado/metabolismo , Masculino , Informática Médica/métodos , Pessoa de Meia-Idade , Mutação , Redes Neurais de Computação , Fenótipo , Análise de Componente Principal
4.
Chemistry ; 27(59): 14690-14701, 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34343376

RESUMO

Ferritins are nanocage proteins that store iron ions in their central cavity as hydrated ferric oxide biominerals. In mammals, further the L (light) and H (heavy) chains constituting cytoplasmic maxi-ferritins, an additional type of ferritin has been identified, the mitochondrial ferritin (MTF). Human MTF (hMTF) is a functional homopolymeric H-like ferritin performing the ferroxidase activity in its ferroxidase site (FS), in which Fe(II) is oxidized to Fe(III) in the presence of dioxygen. To better investigate its ferroxidase properties, here we performed time-lapse X-ray crystallography analysis of hMTF, providing structural evidence of how iron ions interact with hMTF and of their binding to the FS. Transient iron binding sites, populating the pathway along the cage from the iron entry channel to the catalytic center, were also identified. Furthermore, our kinetic data at variable iron loads indicate that the catalytic iron oxidation reaction occurs via a diferric peroxo intermediate followed by the formation of ferric-oxo species, with significant differences with respect to human H-type ferritin.


Assuntos
Ceruloplasmina , Compostos Férricos , Animais , Apoferritinas/metabolismo , Sítios de Ligação , Ceruloplasmina/metabolismo , Ferritinas/metabolismo , Humanos , Ferro/metabolismo , Oxirredução
5.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445367

RESUMO

Rheumatoid arthritis (RA) is a chronic multisystem disease, therapy of which remains a challenge for basic research. The present work examined the effect of unconjugated bilirubin (UCB) administration in adjuvant-induced arthritis (AIA)-an experimental model, in which oxidative stress (OS), inflammation and inadequate immune response are often similar to RA. Male Lewis rats were randomized into groups: CO-control, AIA-untreated adjuvant-induced arthritis, AIA-BIL-adjuvant-induced arthritis administrated UCB, CO-BIL-control with administrated UCB. UCB was administered intraperitoneally 200 mg/kg of body weight daily from 14th day of the experiment, when clinical signs of the disease are fully manifested, to 28th day, the end of the experiment. AIA was induced by a single intradermal immunization at the base of the tail with suspension of Mycobacterium butyricum in incomplete Freund's adjuvant. Clinical, hematologic, biochemical and histologic examinations were performed. UCB administration to animals with AIA lead to a significant decrease in hind paws volume, plasma levels of C-reactive protein (CRP) and ceruloplasmin, drop of leukocytes, lymphocytes, erythrocytes, hemoglobin and an increase in platelet count. UCB administration caused significantly lowered oxidative damage to DNA in arthritic animals, whereas in healthy controls it induced considerable oxidative damage to DNA. UCB administration also induced atrophy of the spleen and thymus in AIA and CO animals comparing to untreated animals. Histological signs of joint damage assessed by neutrophils infiltration and deposition of fibrin were significantly reduced by UCB administration. The effects of exogenously administered UCB to the animals with adjuvant-induced arthritis might be identified as therapeutic, in contrast to the effects of UCB administration in healthy animals rather classified as toxic.


Assuntos
Anti-Inflamatórios/administração & dosagem , Artrite Experimental/tratamento farmacológico , Bilirrubina/administração & dosagem , Adjuvante de Freund/efeitos adversos , Lipídeos/efeitos adversos , Mycobacterium/imunologia , Animais , Anti-Inflamatórios/farmacologia , Artrite Experimental/induzido quimicamente , Artrite Experimental/metabolismo , Bilirrubina/farmacologia , Proteína C-Reativa , Ceruloplasmina/metabolismo , Injeções Intraperitoneais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fragmentos de Peptídeos/sangue , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Resultado do Tratamento
6.
Int J Mol Sci ; 22(15)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34360993

RESUMO

The ferroxidase ceruloplasmin (CP) plays a crucial role in iron homeostasis in vertebrates together with the iron exporter ferroportin. Mutations in the CP gene give rise to aceruloplasminemia, a rare neurodegenerative disease for which no cure is available. Many aspects of the (patho)physiology of CP are still unclear and would benefit from the availability of recombinant protein for structural and functional studies. Furthermore, recombinant CP could be evaluated for enzyme replacement therapy for the treatment of aceruloplasminemia. We report the production and preliminary characterization of high-quality recombinant human CP in glycoengineered Pichia pastoris SuperMan5. A modified yeast strain lacking the endogenous ferroxidase has been generated and employed as host for heterologous expression of the secreted isoform of human CP. Highly pure biologically active protein has been obtained by an improved two-step purification procedure. Glycan analysis indicates that predominant glycoforms HexNAc2Hex8 and HexNAc2Hex11 are found at Asn119, Asn378, and Asn743, three of the canonical four N-glycosylation sites of human CP. The availability of high-quality recombinant human CP represents a significant advancement in the field of CP biology. However, productivity needs to be increased and further careful glycoengineering of the SM5 strain is mandatory in order to evaluate the possible therapeutic use of the recombinant protein for enzyme replacement therapy of aceruloplasminemia patients.


Assuntos
Ceruloplasmina/genética , Microbiologia Industrial/métodos , Engenharia de Proteínas/métodos , Saccharomycetales/genética , Ceruloplasmina/metabolismo , Humanos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomycetales/metabolismo
7.
Life Sci ; 281: 119770, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34197883

RESUMO

Metal ion homeostasis is an essential physiological mechanism necessary for achieving an adequate balance of these ions' concentrations in the different cellular compartments. This fact is of great importance because both an excess and a deficiency of cellular metal ion levels are usually equally harmful due to the exacerbated increase in oxidative stress that may occur in both cases. Metal ion homeostasis ensures an equilibrium among multiple functions associated with the body's antioxidative defense network controlled by metallic micronutrients such as zinc and copper, some of the central regulators of redox processes. These micronutrients significantly modulate the activity of some isoforms of superoxide dismutase (SOD) and other enzymes such as metallothioneins (MTs) and ceruloplasmin (CP), which are directly or indirectly involved in the regulation of redox homeostasis. Although it is well known that both melatonin (MEL) and vitamin D have important roles as natural antioxidants, often some of these effects are related to their actions on antioxidative processes dependent on metal ions. Thus, in addition to their classical antioxidative properties usually associated with mitochondrial effects, it is known that MEL and vitamin D modulate the expression and activity of Cu/Zn-dependent SOD isoforms, MTs and CP; function as copper chelators and regulate genomic and non-genomic mechanisms related to the zinc transport. This review summarizes the main findings related to the crucial participation of zinc and copper in physiological antioxidative status and their relationship with the non-classical antioxidant effects of MEL and vitamin D, suggesting a potential synergism among these four micronutrients.


Assuntos
Antioxidantes/farmacologia , Cobre/metabolismo , Homeostase , Melatonina/farmacologia , Vitamina D/farmacologia , Zinco/metabolismo , Ceruloplasmina/metabolismo , Humanos , Metalotioneína/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos
8.
Anticancer Res ; 41(8): 3815-3823, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281841

RESUMO

BACKGROUND/AIM: A previous report showed that immune complex-ceruloplasmin (CP) in urine is associated with carcinogenesis and malignant behavior in bladder cancer (BC). We investigated the pathological significance and prognostic roles of urine and tissue levels of CP protein in BC patients. MATERIALS AND METHODS: Urine CP levels were measured using an enzyme-linked immunosorbent assay in 97 patients. CP expression in BC tissues was evaluated by immunohistochemical analysis in 176 patient samples. RESULTS: Urine CP levels were positively associated with tumor grade and pT stage in non-muscle invasive BC (NMIBC). CP expression in BC tissues was positively associated with tumor growth and progression. Multivariate analysis demonstrated that high urine CP levels was an independent predictor of recurrence in the urinary tract in NMIBC (hazard ratio=2.87, p=0.016). CONCLUSION: CP-related markers, especially urine CP levels, are useful biomarkers of malignant potential and prognosis in NMIBC.


Assuntos
Biomarcadores Tumorais/metabolismo , Ceruloplasmina/metabolismo , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Idoso , Biomarcadores Tumorais/urina , Ceruloplasmina/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias da Bexiga Urinária/metabolismo
9.
J Magn Reson Imaging ; 54(4): 1098-1106, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33949744

RESUMO

BACKGROUND: Excessive iron accumulation is one of the main pathogeneses of Parkinson's disease (PD). Ceruloplasmin plays an important role in keeping the iron homoeostasis. PURPOSE: To explore the association between serum ceruloplasmin depletion and subcortical iron distribution in PD. STUDY TYPE: Prospective. POPULATION: One hundred and twenty-one normal controls, 34 PD patients with low serum ceruloplasmin (PD-LC), and 28 patients with normal serum ceruloplasmin (PD-NC). SEQUENCE: Enhanced susceptibility-weighted angiography (ESWAN) on a 3 T scanner. ASSESSMENT: Quantitative susceptibility mapping was employed to quantify the regional iron content by using a semi-automatic method. Serum ceruloplasmin concentration was measured from peripheral blood sample. Clinical assessments were conducted by a neurologist. STATISTICAL TESTS: General linear model was used to compare the intergroup difference of region iron distribution among groups, and the statistics was adjusted by Bonferroni method (P < 0.01). Partial correlation analysis was used to detect the association between regional iron distribution and serum ceruloplasmin concentration (P < 0.05). RESULTS: Compared with normal controls, significant iron accumulation in substantia nigra, putamen, and red nucleus was observed in PD-LC, while the only region showing significant iron accumulation was SN in PD-NC. Between PD-NC and PD-LC, the iron accumulation in putamen remained significantly different, which had a negative correlation with serum ceruloplasmin in whole PD patients (r = -0.338, P = 0.008). DATA CONCLUSION: Nigral iron accumulation characterizes PD patients without significant association with serum ceruloplasmin. Differentially, when PD patients appear with reduced serum ceruloplasmin, more widespread iron accumulation would be expected with additionally involving putamen and red nucleus. All these findings provide insightful evidence for the abnormal iron metabolism behind the ceruloplasmin depletion in PD. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: 2.


Assuntos
Ceruloplasmina , Doença de Parkinson , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ceruloplasmina/metabolismo , Humanos , Ferro/metabolismo , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Doença de Parkinson/diagnóstico por imagem , Estudos Prospectivos , Substância Negra
10.
J Cell Biol ; 220(8)2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-34047770

RESUMO

The lysosome (or vacuole in fungi and plants) is an essential organelle for nutrient sensing and cellular homeostasis. In response to environmental stresses such as starvation, the yeast vacuole can adjust its membrane composition by selectively internalizing membrane proteins into the lumen for degradation. Regarding the selective internalization mechanism, two competing models have been proposed. One model suggests that the ESCRT machinery is responsible for the sorting. In contrast, the ESCRT-independent intralumenal fragment (ILF) pathway proposes that the fragment generated by homotypic vacuole fusion is responsible for the sorting. Here, we applied a microfluidics-based imaging method to capture the complete degradation process in vivo. Combining live-cell imaging with a synchronized ubiquitination system, we demonstrated that ILF cargoes are not degraded through intralumenal fragments. Instead, ESCRTs function on the vacuole membrane to sort them into the lumen for degradation. We further discussed challenges in reconstituting vacuole membrane protein degradation.


Assuntos
Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Membranas Intracelulares/metabolismo , Lisossomos/metabolismo , Proteínas de Membrana/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Vacúolos/metabolismo , Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Complexos Endossomais de Distribuição Requeridos para Transporte/genética , Ferritinas/genética , Ferritinas/metabolismo , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Lisossomos/genética , Proteínas de Membrana/genética , Técnicas Analíticas Microfluídicas , Microscopia de Fluorescência , Proteólise , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Fatores de Tempo , Imagem com Lapso de Tempo , Ubiquitinação , Vacúolos/genética
12.
BMC Gastroenterol ; 21(1): 229, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-34020599

RESUMO

BACKGROUND: Wilson's disease (WD) is a rare autosomal recessive disease associated with defective biliary excretion of copper. The simultaneous occurrence of WD and systemic lupus erythematosus (SLE) has seldom been reported. Therefore, this study aimed to report the co-occurrence of SLE and WD with hepatic involvement in a patient so as to improve the understanding of the coexistence of these two conditions. CASE PRESENTATION: A 35-year-old woman with SLE was found to have liver fibrosis during a routinely abdominal ultrasound examination. Her laboratory evaluation showed low serum ceruloplasmin and high 24 h urine copper levels. The slit-lamp examination revealed the presence of Kayseri-Fleischer ring in her cornea. Liver biopsy demonstrated the enlargement of the portal area with hyperplasia of the fibrous tissue, infiltration of lymphoid plasma cells, swelling of hepatocytes, and steatosis, demonstrating liver fibrosis. Ensuing genetic testing confirmed the diagnosis of WD. CONCLUSIONS: Clinicians should bear in mind that unexplained liver fibrosis in patients with SLE may be related to WD, so as to avoid a missed or delayed diagnosis.


Assuntos
Degeneração Hepatolenticular , Lúpus Eritematoso Sistêmico , Adulto , Ceruloplasmina/metabolismo , Cobre/metabolismo , Feminino , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/genética , Humanos , Lúpus Eritematoso Sistêmico/complicações
13.
Sci Rep ; 11(1): 7674, 2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33828154

RESUMO

Pathogenic genetic variants in the ATP7B gene cause Wilson disease, a recessive disorder of copper metabolism showing a significant variability in clinical phenotype. Promoter mutations have been rarely reported, and controversial data exist on the site of transcription initiation (the core promoter). We quantitatively investigated transcription initiation and found it to be located in immediate proximity of the translational start. The effects human single-nucleotide alterations of conserved bases in the core promoter on transcriptional activity were moderate, explaining why clearly pathogenic mutations within the core promoter have not been reported. Furthermore, the core promoter contains two frequent polymorphisms (rs148013251 and rs2277448) that could contribute to phenotypical variability in Wilson disease patients with incompletely inactivating mutations. However, neither polymorphism significantly modulated ATP7B expression in vitro, nor were copper household parameters in healthy probands affected. In summary, the investigations allowed to determine the biologically relevant site of ATP7B transcription initiation and demonstrated that genetic variations in this site, although being the focus of transcriptional activity, do not contribute significantly to Wilson disease pathogenesis.


Assuntos
ATPases Transportadoras de Cobre/genética , Cobre/sangue , Degeneração Hepatolenticular/genética , Regiões Promotoras Genéticas/genética , Sítio de Iniciação de Transcrição , Ceruloplasmina/metabolismo , Voluntários Saudáveis , Células Hep G2 , Humanos , Polimorfismo Genético
14.
Int J Mol Sci ; 22(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33923052

RESUMO

Proper functioning of all organs, including the brain, requires iron. It is present in different forms in biological fluids, and alterations in its distribution can induce oxidative stress and neurodegeneration. However, the clinical parameters normally used for monitoring iron concentration in biological fluids (i.e., serum and cerebrospinal fluid) can hardly detect the quantity of circulating iron, while indirect measurements, e.g., magnetic resonance imaging, require further validation. This review summarizes the mechanisms involved in brain iron metabolism, homeostasis, and iron imbalance caused by alterations detectable by standard and non-standard indicators of iron status. These indicators for iron transport, storage, and metabolism can help to understand which biomarkers can better detect iron imbalances responsible for neurodegenerative diseases.


Assuntos
Doença de Alzheimer/diagnóstico , Biomarcadores/sangue , Encéfalo/metabolismo , Ferroptose/fisiologia , Ferro/metabolismo , Doença de Alzheimer/metabolismo , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Ceruloplasmina/deficiência , Ceruloplasmina/metabolismo , Ferritinas/sangue , Ferritinas/líquido cefalorraquidiano , Ferritinas/metabolismo , Humanos , Ferro/sangue , Ferro/líquido cefalorraquidiano , Distúrbios do Metabolismo do Ferro/metabolismo , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas/metabolismo , Estresse Oxidativo/fisiologia , Transferrina/líquido cefalorraquidiano , Transferrina/metabolismo
15.
Metallomics ; 13(5)2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-33881539

RESUMO

Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.


Assuntos
COVID-19/metabolismo , Ferritinas/química , Ferritinas/metabolismo , SARS-CoV-2 , Biomarcadores/química , Biomarcadores/metabolismo , Biotecnologia , Ceruloplasmina/metabolismo , Sistemas de Liberação de Medicamentos , Ferritinas/genética , Ferroptose/fisiologia , Glicosilação , Homeostase , Humanos , Inflamação/metabolismo , Ferro/metabolismo , Nanotecnologia , Neoplasias/diagnóstico , Neoplasias/metabolismo , Prognóstico , Distribuição Tecidual
16.
Inorg Chem ; 60(10): 7207-7216, 2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-33852289

RESUMO

Here, we present a 1.9 Å resolution crystal structure of Mycoplasma Penetrans ferritin, which reveals that its ferroxidase center is located on the inner surface of ferritin but not buried within the four-helix of each subunit. Such a ferroxidase center exhibits a lower iron oxidation activity as compared to the reported ferritin. More importantly, we found that Fe2+ enters into the center via the rarely reported B-channels rather than the normal 3- or 4-fold channels. All these findings may provide the structural bases to explore the new iron oxidation mechanism adopted by this special ferritin, which is beneficial for understanding the relationship between the structure and function of ferritin.


Assuntos
Ceruloplasmina/metabolismo , Ferritinas/metabolismo , Compostos Ferrosos/metabolismo , Mycoplasma/química , Ceruloplasmina/química , Ferritinas/química , Compostos Ferrosos/química , Simulação de Dinâmica Molecular , Mycoplasma/metabolismo , Oxirredução
17.
Arch Toxicol ; 95(4): 1251-1266, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33779765

RESUMO

CONTEXT: The addition of silver (Ag) to food items, and its migration from food packaging and appliances results in a dietary exposure in humans, estimated to 70-90 µg Ag/day. In view of the well-known bactericidal activity of Ag ions, concerns arise about a possible impact of dietary Ag on the gut microbiota (GM), which is a master determinant of human health and diseases. Repeated oral administration of Ag acetate (AgAc) can also cause systemic toxicity in rats with reported NOAELs of 4 mg AgAc/b.w./d for impaired fertility and 0.4 mg AgAc/b.w./d for developmental toxicity. OBJECTIVE: The objective of this study was to investigate whether oral exposure to AgAc can induce GM alterations at doses causing reproductive toxicity in rats. METHODS: Male and female Wistar rats were exposed during 10 weeks to AgAc incorporated into food (0, 0.4, 4 or 40 mg/kg b.w./d), and we analyzed the composition of the GM (α- and ß-diversity). We documented bacterial function by measuring short-chain fatty acid (SCFA) production in cecal content. Ferroxidase activity, a biomarker of systemic Ag toxicity, was measured in serum. RESULTS AND CONCLUSIONS: From 4 mg/kg b.w./d onwards, we recorded systemic toxicity, as indicated by the reduction of serum ferroxidase activity, as well as serum Cu and Se concentrations. This systemic toxic response to AgAc might contribute to explain reprotoxic manifestations. We observed a dose-dependent modification of the GM composition in male rats exposed to AgAc. No impact of AgAc exposure on the production of bacterial SCFA was recorded. The limited GM changes recorded in this study do not appear related to a reprotoxicity outcome.


Assuntos
Acetatos/toxicidade , Microbioma Gastrointestinal/efeitos dos fármacos , Reprodução/efeitos dos fármacos , Compostos de Prata/toxicidade , Acetatos/administração & dosagem , Administração Oral , Animais , Ceruloplasmina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Masculino , Nível de Efeito Adverso não Observado , Ratos , Ratos Wistar , Compostos de Prata/administração & dosagem
18.
Angew Chem Int Ed Engl ; 60(15): 8376-8379, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33460502

RESUMO

The iron redox cycle in ferritins is not completely understood. Bacterioferritins are distinct from other ferritins in that they contain haem groups. It is acknowledged that the two iron motifs in bacterioferritins, the di-nuclear ferroxidase centre and the haem B group, play key roles in two opposing processes, iron sequestration and iron mobilisation, respectively, and the two redox processes are independent. Herein, we show that in Escherichia coli bacterioferritin, there is an electron transfer pathway from the haem to the ferroxidase centre suggesting a new role(s) haem might play in bacterioferritins.


Assuntos
Proteínas de Bactérias/metabolismo , Ceruloplasmina/metabolismo , Grupo dos Citocromos b/metabolismo , Ferritinas/metabolismo , Heme/metabolismo , Proteínas de Bactérias/química , Ceruloplasmina/química , Grupo dos Citocromos b/química , Transporte de Elétrons , Escherichia coli/química , Escherichia coli/metabolismo , Ferritinas/química , Heme/química
19.
Angew Chem Int Ed Engl ; 60(15): 8361-8369, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33482043

RESUMO

Both O2 and H2 O2 can oxidize iron at the ferroxidase center (FC) of Escherichia coli bacterioferritin (EcBfr) but mechanistic details of the two reactions need clarification. UV/Vis, EPR, and Mössbauer spectroscopies have been used to follow the reactions when apo-EcBfr, pre-loaded anaerobically with Fe2+ , was exposed to O2 or H2 O2 . We show that O2 binds di-Fe2+ FC reversibly, two Fe2+ ions are oxidized in concert and a H2 O2 molecule is formed and released to the solution. This peroxide molecule further oxidizes another di-Fe2+ FC, at a rate circa 1000 faster than O2 , ensuring an overall 1:4 stoichiometry of iron oxidation by O2 . Initially formed Fe3+ can further react with H2 O2 (producing protein bound radicals) but relaxes within seconds to an H2 O2 -unreactive di-Fe3+ form. The data obtained suggest that the primary role of EcBfr in vivo may be to detoxify H2 O2 rather than sequester iron.


Assuntos
Proteínas de Bactérias/metabolismo , Ceruloplasmina/metabolismo , Grupo dos Citocromos b/metabolismo , Escherichia coli/química , Ferritinas/metabolismo , Peróxido de Hidrogênio/metabolismo , Ferro/metabolismo , Oxigênio/metabolismo , Proteínas de Bactérias/química , Ceruloplasmina/química , Grupo dos Citocromos b/química , Escherichia coli/metabolismo , Ferritinas/química , Peróxido de Hidrogênio/química , Ferro/química , Modelos Moleculares , Oxirredução , Oxigênio/química
20.
Int J Mol Sci ; 22(2)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33440850

RESUMO

Neurodegenerative disorders can induce modifications of several proteins; one of which is ceruloplasmin (Cp), a ferroxidase enzyme found modified in the cerebrospinal fluid (CSF) of neurodegenerative diseases patients. Cp modifications are caused by the oxidation induced by the pathological environment and are usually associated with activity loss. Together with oxidation, deamidation of Cp was found in the CSF from Alzheimer's and Parkinson's disease patients. Protein deamidation is a process characterized by asparagine residues conversion in either aspartate or isoaspartate, depending on protein sequence/structure and cellular environment. Cp deamidation occurs at two Asparagine-Glycine-Arginine (NGR)-motifs which, once deamidated to isoAspartate-Glycine-Arginine (isoDGR), bind integrins, a family of receptors mediating cell adhesion. Therefore, on the one hand, Cp modifications lead to loss of enzymatic activity, while on the other hand, these alterations confer gain of function to Cp. In fact, deamidated Cp binds to integrins and triggers intracellular signaling on choroid plexus epithelial cells, changing cell functioning. Working in concert with the oxidative environment, Cp deamidation could reach different target cells in the brain, altering their physiology and causing detrimental effects, which might contribute to the pathological mechanism.


Assuntos
Ceruloplasmina/genética , Ceruloplasmina/metabolismo , Suscetibilidade a Doenças , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Neurônios/metabolismo , Motivos de Aminoácidos , Aminoácidos/metabolismo , Animais , Encéfalo/metabolismo , Ceruloplasmina/química , Mutação com Ganho de Função , Predisposição Genética para Doença , Humanos , Integrinas/metabolismo , Mutação com Perda de Função , Oligopeptídeos/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...