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1.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281283

RESUMO

ß-thalassaemia is a rare genetic condition caused by mutations in the ß-globin gene that result in severe iron-loading anaemia, maintained by a detrimental state of ineffective erythropoiesis (IE). The role of multiple mechanisms involved in the pathophysiology of the disease has been recently unravelled. The unbalanced production of α-globin is a major source of oxidative stress and membrane damage in red blood cells (RBC). In addition, IE is tightly linked to iron metabolism dysregulation, and the relevance of new players of this pathway, i.e., hepcidin, erythroferrone, matriptase-2, among others, has emerged. Advances have been made in understanding the balance between proliferation and maturation of erythroid precursors and the role of specific factors in this process, such as members of the TGF-ß superfamily, and their downstream effectors, or the transcription factor GATA1. The increasing understanding of IE allowed for the development of a broad set of potential therapeutic options beyond the current standard of care. Many candidates of disease-modifying drugs are currently under clinical investigation, targeting the regulation of iron metabolism, the production of foetal haemoglobin, the maturation process, or the energetic balance and membrane stability of RBC. Overall, they provide tools and evidence for multiple and synergistic approaches that are effectively moving clinical research in ß-thalassaemia from bench to bedside.


Assuntos
Eritropoese/efeitos dos fármacos , Eritropoese/fisiologia , Talassemia beta/tratamento farmacológico , Talassemia beta/fisiopatologia , Receptores de Activinas Tipo II/uso terapêutico , Desenvolvimento de Medicamentos , Fator de Transcrição GATA1/metabolismo , Hepcidinas/uso terapêutico , Humanos , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Ferro/metabolismo , Modelos Biológicos , Mutação , Piperazinas/uso terapêutico , Quinolinas/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Crescimento Transformador beta/metabolismo , Globinas beta/genética , Talassemia beta/sangue
2.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202704

RESUMO

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 µM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 µM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.


Assuntos
Tamanho Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Criança , Pré-Escolar , Índices de Eritrócitos , Eritrócitos/metabolismo , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Everolimo/farmacologia , Citometria de Fluxo , Humanos , Ferro/metabolismo , Células K562 , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos
3.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199378

RESUMO

Iron-sulfur clusters are essential to almost every life form and utilized for their unique structural and redox-targeted activities within cells during many cellular pathways. Although there are three different Fe-S cluster assembly pathways in prokaryotes (the NIF, SUF and ISC pathways) and two in eukaryotes (CIA and ISC pathways), the iron-sulfur cluster (ISC) pathway serves as the central mechanism for providing 2Fe-2S clusters, directly and indirectly, throughout the entire cell in eukaryotes. Proteins central to the eukaryotic ISC cluster assembly complex include the cysteine desulfurase, a cysteine desulfurase accessory protein, the acyl carrier protein, the scaffold protein and frataxin (in humans, NFS1, ISD11, ACP, ISCU and FXN, respectively). Recent molecular details of this complex (labeled NIAUF from the first letter from each ISC protein outlined earlier), which exists as a dimeric pentamer, have provided real structural insight into how these partner proteins arrange themselves around the cysteine desulfurase, the core dimer of the (NIAUF)2 complex. In this review, we focus on both frataxin and the scaffold within the human, fly and yeast model systems to provide a better understanding of the biophysical characteristics of each protein alone and within the FXN/ISCU complex as it exists within the larger NIAUF construct. These details support a complex dynamic interaction between the FXN and ISCU proteins when both are part of the NIAUF complex and this provides additional insight into the coordinated mechanism of Fe-S cluster assembly.


Assuntos
Proteínas de Ligação ao Ferro/genética , Proteínas Ferro-Enxofre/genética , Ferro/metabolismo , Enxofre/metabolismo , Liases de Carbono-Enxofre/genética , Humanos , Proteínas de Ligação ao Ferro/metabolismo , Mitocôndrias/genética , Mitocôndrias/metabolismo , Complexos Multiproteicos/genética , Complexos Multiproteicos/ultraestrutura , Ligação Proteica/genética
4.
Int J Mol Sci ; 22(11)2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34199599

RESUMO

Orphan nuclear receptor estrogen-related receptor γ (ERRγ) is an important transcription factor modulating gene transcription involved in endocrine control of liver metabolism. Transferrin receptor 2 (TFR2), a carrier protein for transferrin, is involved in hepatic iron overload in alcoholic liver disease (ALD). However, TFR2 gene transcriptional regulation in hepatocytes remains largely unknown. In this study, we described a detailed molecular mechanism of hepatic TFR2 gene expression involving ERRγ in response to an endocannabinoid 2-arachidonoylglycerol (2-AG). Treatment with 2-AG and arachidonyl-2'-chloroethylamide, a selective cannabinoid receptor type 1 (CB1) receptor agonist, increased ERRγ and TFR2 expression in hepatocytes. Overexpression of ERRγ was sufficient to induce TFR2 expression in both human and mouse hepatocytes. In addition, ERRγ knockdown significantly decreased 2-AG or alcohol-mediated TFR2 gene expression in cultured hepatocytes and mouse livers. Finally, deletion and mutation analysis of the TFR2 gene promoter demonstrated that ERRγ directly modulated TFR2 gene transcription via binding to an ERR-response element. This was further confirmed by chromatin immunoprecipitation assay. Taken together, these results reveal a previously unrecognized role of ERRγ in the transcriptional regulation of TFR2 gene expression in response to alcohol.


Assuntos
Hepatopatias Alcoólicas/genética , Fígado/efeitos dos fármacos , Receptor CB1 de Canabinoide/genética , Receptores de Estrogênio/genética , Receptores da Transferrina/genética , Álcoois/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Endocanabinoides/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Glicerídeos/farmacologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/patologia , Camundongos , Regiões Promotoras Genéticas , Receptor CB1 de Canabinoide/agonistas , Deleção de Sequência/genética , Transferrina/genética , Transferrina/metabolismo
5.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203920

RESUMO

The negatively charged Asp325 residue has proved to be essential for iron export by human (HsFPN1) and primate Philippine tarsier (TsFpn) ferroportin, but its exact role during the iron transport cycle is still to be elucidated. It has been posited as being functionally equivalent to the metal ion-coordinating residue His261 in the C-lobe of the bacterial homolog BbFpn, but the two residues arise in different sequence motifs of the discontinuous TM7 transmembrane helix. Furthermore, BbFpn is not subject to extracellular regulation, contrary to its mammalian orthologues which are downregulated by hepcidin. To get further insight into the molecular mechanisms related to iron export in mammals in which Asp325 is involved, we investigated the behavior of the Asp325Ala, Asp325His, and Asp325Asn mutants in transiently transfected HEK293T cells, and performed a comparative structural analysis. Our biochemical studies clearly distinguished between the Asp325Ala and Asp325His mutants, which result in a dramatic decrease in plasma membrane expression of FPN1, and the Asp325Asn mutant, which alters iron egress without affecting protein localization. Analysis of the 3D structures of HsFPN1 and TsFpn in the outward-facing (OF) state indicated that Asp325 does not interact directly with metal ions but is involved in the modulation of Cys326 metal-binding capacity. Moreover, models of the architecture of mammalian proteins in the inward-facing (IF) state suggested that Asp325 may form an inter-lobe salt-bridge with Arg40 (TM1) when not interacting with Cys326. These findings allow to suggest that Asp325 may be important for fine-tuning iron recognition in the C-lobe, as well as for local structural changes during the IF-to-OF transition at the extracellular gate level. Inability to form a salt-bridge between TM1 and TM7b during iron translocation could lead to protein instability, as shown by the Asp325Ala and Asp325His mutants.


Assuntos
Ácido Aspártico/metabolismo , Proteínas de Transporte de Cátions/química , Proteínas de Transporte de Cátions/metabolismo , Sítios de Ligação , Transporte Biológico , Membrana Celular/metabolismo , Células HEK293 , Humanos , Ferro/metabolismo , Estrutura Secundária de Proteína , Relação Estrutura-Atividade
6.
Nanoscale ; 13(27): 11932-11942, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34195748

RESUMO

Cage forming proteins have numerous potential applications in biomedicine and biotechnology, where the iron storage ferritin is a widely used example. However, controlling ferritin cage assembly/disassembly remains challenging, typically requiring extreme conditions incompatible with many desirable cargoes, particularly for more fragile biopharmaceuticals. Recently, a ferritin from the hyperthermophile bacterium Thermotoga maritima (TmFtn) has been shown to have reversible assembly under mild conditions, offering greater potential biocompatibility in terms of cargo access and encapsulation. Like Archeoglobus fulgidus ferritin (AfFtn), TmFtn forms 24mer cages mediated by metal ions (Mg2+). We have solved the crystal structure of the wild type TmFtn and several mutants displaying different assembly/disassembly properties. These data combined with other biophysical studies allow us to suggest candidate interfacial amino acids crucial in controlling assembly. This work deepens our understanding of how these ferritin complexes assemble and is a useful step towards production of triggerable ferritins in which these properties can be finely designed and controlled.


Assuntos
Ferritinas , Ferro , Ferritinas/genética , Ferro/metabolismo , Thermotoga maritima
7.
Int J Mol Sci ; 22(12)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208600

RESUMO

Coumarins belong to a group of secondary metabolites well known for their high biological activities including antibacterial and antifungal properties. Recently, an important role of coumarins in plant resistance to pathogens and their release into the rhizosphere upon pathogen infection was discovered. It is also well documented that coumarins play a crucial role in the Arabidopsis thaliana growth under Fe-limited conditions. However, the mechanisms underlying interplay between plant resistance, accumulation of coumarins and Fe status, remain largely unknown. In this work, we investigated the effect of both mentioned factors on the disease severity using the model system of Arabidopsis/Dickeya spp. molecular interactions. We evaluated the disease symptoms in Arabidopsis plants, wild-type Col-0 and its mutants defective in coumarin accumulation, grown in hydroponic cultures with contrasting Fe regimes and in soil mixes. Under all tested conditions, Arabidopsis plants inoculated with Dickeya solani IFB0099 strain developed more severe disease symptoms compared to lines inoculated with Dickeya dadantii 3937. We also showed that the expression of genes encoding plant stress markers were strongly affected by D. solani IFB0099 infection. Interestingly, the response of plants to D. dadantii 3937 infection was genotype-dependent in Fe-deficient hydroponic solution.


Assuntos
Cumarínicos/metabolismo , Dickeya/fisiologia , Resistência à Doença , Ferro/metabolismo , Doenças das Plantas/microbiologia , Plantas/metabolismo , Plantas/microbiologia , Arabidopsis/metabolismo , Arabidopsis/microbiologia , Suscetibilidade a Doenças , Hidroponia , Folhas de Planta/microbiologia , Estresse Fisiológico
8.
Int J Mol Sci ; 22(12)2021 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204327

RESUMO

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


Assuntos
Proteínas de Transporte de Cátions/metabolismo , Hepcidinas/metabolismo , Homeostase , Ferro/metabolismo , Animais , Comunicação Autócrina , Transporte Biológico , Proteínas de Transporte de Cátions/química , Suscetibilidade a Doenças , Hepcidinas/química , Humanos , Ligantes , Redes e Vias Metabólicas , Comunicação Parácrina , Ligação Proteica , Transdução de Sinais , Distribuição Tecidual
9.
Nat Commun ; 12(1): 4403, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285238

RESUMO

Sulfur cycling is ubiquitous in sedimentary environments, where it mediates organic carbon remineralization, impacting both local and global redox budgets, and leaving an imprint in pyrite sulfur isotope ratios (δ34Spyr). It is unclear to what extent stratigraphic δ34Spyr variations reflect local aspects of the depositional environment or microbial activity versus global sulfur-cycle variations. Here, we couple carbon-nitrogen-sulfur concentrations and stable isotopes to identify clear influences on δ34Spyr of local environmental changes along the Peru margin. Stratigraphically coherent glacial-interglacial δ34Spyr fluctuations (>30‰) were mediated by Oxygen Minimum Zone intensification/expansion and local enhancement of organic matter deposition. The higher resulting microbial sulfate reduction rates led to more effective drawdown and 34S-enrichment of residual porewater sulfate and sulfide produced from it, some of which is preserved in pyrite. We identify organic carbon loading as a major influence on δ34Spyr, adding to the growing body of evidence highlighting the local controls on these records.


Assuntos
Bactérias Anaeróbias/metabolismo , Sedimentos Geológicos/microbiologia , Ferro/metabolismo , Oxigênio/metabolismo , Sulfetos/metabolismo , Enxofre/metabolismo , Carbono/metabolismo , Ciclo do Carbono , Geografia , Sedimentos Geológicos/análise , Sedimentos Geológicos/química , Ferro/química , Oxirredução , Peru , Sulfetos/química , Isótopos de Enxofre/análise
10.
Nutrients ; 13(7)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34209042

RESUMO

BACKGROUND AND AIMS: Altering dietary ferrous sulphate (FS) consumption exacerbates a murine model of colitis and alters the intestinal microbiome. We investigated the impact of oral ferric maltol (FM) and FS on mice with dextran sodium sulphate (DSS) induced colitis, and the microbiome of patients with iron deficiency. METHODS: Mice had acute colitis induced, with 2% DSS for 5 days, followed by water. During this period, groups of mice were fed standard chow (200 ppm iron, SC, n = 8), or SC with 200ppm FS supplementation (n = 16, FSS), or SC with 200 ppm FM supplementation (n = 16, FMS). Clinical, pathological and microbiome assessments were compared at days 1 and 10. Fecal bacterial gDNA was extracted and the microbiome assessed by sequencing. Statistical inferences were made using MacQIIME. Principal Coordinates Analysis were used to visualize beta-diversity cluster analysis. Ten patients with IDA were treated with FS, and six with inactive inflammatory bowel disease received FM, supplements for four weeks: pre- and mid-treatment fecal samples were collected: the microbiome was assessed (see above). RESULTS: In mice, after DSS treatment, there was a decrease in many genera in the SC and FSS groups: Lactobacillales increased in mice that received FMS. In humans, FS treatment led to an increase in five genera, but FM was not associated with any measurable change. The severity of DSS-induced colitis was greater with FSS than FMS. CONCLUSIONS: This study demonstrates differential and unique influences of ferric maltol and ferrous sulphate supplements on intestinal microbiota. These differences might contribute to the different side effects associated with these preparations.


Assuntos
Compostos Férricos/administração & dosagem , Compostos Férricos/farmacologia , Compostos Ferrosos/farmacologia , Pironas/administração & dosagem , Pironas/farmacologia , Administração Oral , Animais , Biodiversidade , Peso Corporal/efeitos dos fármacos , Colite/induzido quimicamente , Colite/microbiologia , Colite/patologia , Colo/efeitos dos fármacos , Colo/microbiologia , Colo/patologia , Sulfato de Dextrana , Fezes/microbiologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Ferro/metabolismo , Camundongos Endogâmicos C57BL , Filogenia
11.
Int J Mol Sci ; 22(10)2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34068996

RESUMO

Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (TET2), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies.


Assuntos
Eritropoese , Homeostase , Sobrecarga de Ferro/complicações , Ferro/metabolismo , Síndromes Mielodisplásicas/patologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Humanos , Síndromes Mielodisplásicas/etiologia , Síndromes Mielodisplásicas/metabolismo
12.
Int J Mol Sci ; 22(10)2021 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-34064887

RESUMO

Bacterial response to nitric oxide (NO) is of major importance for bacterial survival. NO stress is a main actor of the eukaryotic immune response and several pathogenic bacteria have developed means for detoxification and repair of the damages caused by NO. However, bacterial mechanisms of NO resistance by Gram-positive bacteria are poorly described. In the opportunistic foodborne pathogen Bacillus cereus, genome sequence analyses did not identify homologs to known NO reductases and transcriptional regulators, such as NsrR, which orchestrate the response to NO of other pathogenic or non-pathogenic bacteria. Using a transcriptomic approach, we investigated the adaptation of B. cereus to NO stress. A cluster of 6 genes was identified to be strongly up-regulated in the early phase of the response. This cluster contains an iron-sulfur cluster repair enzyme, a nitrite reductase and three enzymes involved in siroheme biosynthesis. The expression pattern and close genetic localization suggest a functional link between these genes, which may play a pivotal role in the resistance of B. cereus to NO stress during infection.


Assuntos
Bacillus cereus/metabolismo , Proteínas de Bactérias/metabolismo , Heme/análogos & derivados , Ferro/metabolismo , Óxido Nítrico/toxicidade , Nitrito Redutases/metabolismo , Estresse Oxidativo , Bacillus cereus/efeitos dos fármacos , Bacillus cereus/genética , Bacillus cereus/crescimento & desenvolvimento , Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Heme/biossíntese , Transcrição Genética
13.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064487

RESUMO

Liver injury in COVID-19 patients has progressively emerged, even in those without a history of liver disease, yet the mechanism of liver pathogenicity is still controversial. COVID-19 is frequently associated with increased serum ferritin levels, and hyperferritinemia was shown to correlate with illness severity. The liver is the major site for iron storage, and conditions of iron overload have been established to have a pathogenic role in development of liver diseases. We presented here six patients who developed severe COVID-19, with biochemical evidence of liver failure. Three cases were survived patients, who underwent liver biopsy; the other three were deceased patients, who were autopsied. None of the patients suffered underlying liver pathologies. Histopathological and ultrastructural analyses were performed. The most striking finding we demonstrated in all patients was iron accumulation into hepatocytes, associated with degenerative changes. Abundant ferritin particles were found enclosed in siderosomes, and large aggregates of hemosiderin were found, often in close contact with damaged mitochondria. Iron-caused oxidative stress may be responsible for mitochondria metabolic dysfunction. In agreement with this, association between mitochondria and lipid droplets was also found. Overall, our data suggest that hepatic iron overload could be the pathogenic trigger of liver injury associated to COVID-19.


Assuntos
COVID-19/diagnóstico , Sobrecarga de Ferro/etiologia , Falência Hepática/etiologia , Fígado/patologia , Índice de Gravidade de Doença , Adulto , Idoso , Antivirais , Biópsia , COVID-19/complicações , COVID-19/mortalidade , COVID-19/terapia , Feminino , Ferritinas/análise , Hepatócitos/citologia , Hepatócitos/patologia , Humanos , Ferro/análise , Ferro/metabolismo , Sobrecarga de Ferro/mortalidade , Sobrecarga de Ferro/patologia , Sobrecarga de Ferro/terapia , Fígado/citologia , Fígado/metabolismo , Falência Hepática/mortalidade , Falência Hepática/patologia , Falência Hepática/terapia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Mitocôndrias/patologia , Respiração com Pressão Positiva , SARS-CoV-2/isolamento & purificação
14.
Anticancer Res ; 41(6): 2795-2804, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083269

RESUMO

BACKGROUND/AIM: Neuroblastoma is the most common childhood extracranial solid malignancy. Although cancer cells need iron and lipids for active cell division, possible links between iron and lipid metabolism in neuroblastomas have not been studied. MATERIALS AND METHODS: We evaluated the levels and association between iron and cholesterol on in vitro neuroblastoma cancer models. RESULTS: We found that the levels of iron and cholesterol are diverse among neuroblastoma cell lines. There is a bi-directional association between iron and cholesterol in drug-resistant neuroblastoma SK-N-AS cells. In drug-resistant neuroblastoma cells, low concentration of an iron chelator did not have an impact on iron levels, but on cellular cholesterol levels. Furthermore, a cholesterol decreasing agent, simvastatin, influenced both iron and cholesterol levels in drug-resistant neuroblastoma cells. CONCLUSION: Cholesterol decreasing agents may be more effective than iron chelators for drug-resistant neuroblastoma treatment.


Assuntos
Colesterol/metabolismo , Ferro/metabolismo , Neuroblastoma/metabolismo , Anticolesterolemiantes/farmacologia , Linhagem Celular Tumoral , Humanos , Quelantes de Ferro/farmacologia , Neuroblastoma/patologia
15.
Int J Mol Sci ; 22(11)2021 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-34074047

RESUMO

In this review, we chart the major milestones in the research progress on the DyP-type peroxidase family over the past decade. Though mainly distributed among bacteria and fungi, this family actually exhibits more widespread diversity. Advanced tertiary structural analyses have revealed common and different features among members of this family. Notably, the catalytic cycle for the peroxidase activity of DyP-type peroxidases appears to be different from that of other ubiquitous heme peroxidases. DyP-type peroxidases have also been reported to possess activities in addition to peroxidase function, including hydrolase or oxidase activity. They also show various cellular distributions, functioning not only inside cells but also outside of cells. Some are also cargo proteins of encapsulin. Unique, noteworthy functions include a key role in life-cycle switching in Streptomyces and the operation of an iron transport system in Staphylococcus aureus, Bacillus subtilis and Escherichia coli. We also present several probable physiological roles of DyP-type peroxidases that reflect the widespread distribution and function of these enzymes. Lignin degradation is the most common function attributed to DyP-type peroxidases, but their activity is not high compared with that of standard lignin-degrading enzymes. From an environmental standpoint, degradation of natural antifungal anthraquinone compounds is a specific focus of DyP-type peroxidase research. Considered in its totality, the DyP-type peroxidase family offers a rich source of diverse and attractive materials for research scientists.


Assuntos
Antraquinonas/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas Fúngicas/metabolismo , Fungos/metabolismo , Lignina/metabolismo , Peroxidases/química , Peroxidases/metabolismo , Bacillus subtilis/enzimologia , Bacillus subtilis/metabolismo , Catálise , Escherichia coli/enzimologia , Escherichia coli/metabolismo , Fungos/crescimento & desenvolvimento , Ferro/metabolismo , Oxirredução , Filogenia , Staphylococcus aureus/enzimologia , Staphylococcus aureus/metabolismo , Streptomyces/enzimologia , Streptomyces/metabolismo
16.
Molecules ; 26(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068597

RESUMO

Research on nanomaterial exposure-related health risks is still quite limited; this includes standardizing methods for measuring metals in living organisms. Thus, this study validated an atomic absorption spectrophotometry method to determine fertility and bioaccumulated iron content in Drosophila melanogaster flies after feeding them magnetite nanoparticles (Fe3O4NPs) dosed in a culture medium (100, 250, 500, and 1000 mg kg-1). Some NPs were also coated with chitosan to compare iron assimilation. Considering both accuracy and precision, results showed the method was optimal for concentrations greater than 20 mg L-1. Recovery values were considered optimum within the 95-105% range. Regarding fertility, offspring for each coated and non-coated NPs concentration decreased in relation to the control group. Flies exposed to 100 mg L-1 of coated NPs presented the lowest fertility level and highest bioaccumulation factor. Despite an association between iron bioaccumulation and NPs concentration, the 500 mg L-1 dose of coated and non-coated NPs showed similar iron concentrations to those of the control group. Thus, Drosophila flies' fertility decreased after NPs exposure, while iron bioaccumulation was related to NPs concentration and coating. We determined this method can overcome sample limitations and biological matrix-associated heterogeneity, thus allowing for bioaccumulated iron detection regardless of exposure to coated or non-coated magnetite NPs, meaning this protocol could be applicable with any type of iron NPs.


Assuntos
Drosophila melanogaster/fisiologia , Comportamento Alimentar , Ferro/metabolismo , Nanopartículas de Magnetita/química , Animais , Bioacumulação , Quitosana/química , Fertilidade , Limite de Detecção , Nanopartículas de Magnetita/ultraestrutura , Eletricidade Estática , Difração de Raios X
17.
Nat Commun ; 12(1): 3447, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103494

RESUMO

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.


Assuntos
Sistema Cardiovascular/embriologia , Embrião de Mamíferos/patologia , Ferro/deficiência , Animais , Aorta Torácica/anormalidades , Biomarcadores/metabolismo , Diferenciação Celular , Vasos Coronários/embriologia , Vasos Coronários/patologia , Suplementos Nutricionais , Edema/patologia , Embrião de Mamíferos/anormalidades , Desenvolvimento Embrionário , Feminino , Perfilação da Expressão Gênica , Interação Gene-Ambiente , Proteínas de Fluorescência Verde/metabolismo , Ferro/metabolismo , Vasos Linfáticos/embriologia , Vasos Linfáticos/patologia , Camundongos Endogâmicos C57BL , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Penetrância , Fenótipo , Gravidez , Transdução de Sinais , Células-Tronco/patologia , Transgenes , Tretinoína/metabolismo
18.
Nutrients ; 13(5)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067622

RESUMO

The iron absorption process developsmainly in the proximal duodenum. This portion of the intestine is typically destroyed in celiac disease (CD), resulting in a reduction in absorption of iron and subsequent iron deficiency anemia (IDA). In fact, the most frequent extra-intestinal manifestation (EIM) of CD is IDA, with a prevalence between 12 and 82% (in relation with the various reports) in patients with new CD diagnosis. The primary treatment of CD is the gluten-free diet (GFD), which is associated with adequate management of IDA, if present. Iron replacement treatment historically has been based on oral products containing ferrous sulphate (FS). However, the absorption of FS is limited in patients with active CD and unpredictable in patients on a GFD. Furthermore, a poor tolerability of this kind of ferrous is particularly frequent in patients with CD or with other inflammatory bowel diseases. Normalization from anemic state typically occurs after at least 6 months of GFD, but the process can take up to 2 years for iron stores to replenish.


Assuntos
Anemia Ferropriva/dietoterapia , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Ferro/deficiência , Anemia Ferropriva/etiologia , Doença Celíaca/complicações , Doença Celíaca/fisiopatologia , Duodeno/fisiopatologia , Humanos , Absorção Intestinal/fisiologia , Ferro/metabolismo
19.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071287

RESUMO

Chorioamnionitis (CHORIO), placental insufficiency, and preterm birth are well-known antecedents of perinatal brain injury (PBI). Heme-oxygenase-1 (HO-1) is an important inducible enzyme in oxidative and inflammatory conditions. In the brain, HO-1 and the iron regulatory receptor, transferrin receptor-1 (TfR1), are known to be involved in iron homeostasis, oxidative stress, and cellular adaptive mechanisms. However, the role of HO pathway in the pathophysiology of PBI has not been previously studied. In this study, we set out to define the ontogeny of the HO pathway in the brain and determine if CHORIO changed its normal developmental regulation. We also aimed to determine the role of HO-1/TfR1 in CHORIO-induced neuroinflammation and peripheral inflammation in a clinically relevant rat model of PBI. We show that HO-1, HO-2, and TfR1 expression are developmentally regulated in the brain during the perinatal period. CHORIO elevates HO-1 and TfR1 mRNA expression in utero and in the early postnatal period and results in sustained increase in HO-1/TfR1 ratios in the brain. This is associated with neuroinflammatory and peripheral immune phenotype supported by a significant increase in brain mononuclear cells and peripheral blood double negative T cells suggesting a role of HO-1/TfR1 pathway dysregulation in CHORIO-induced neuroinflammation.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Corioamnionite/metabolismo , Heme Oxigenase-1/metabolismo , Homeostase , Animais , Lesões Encefálicas/metabolismo , Feminino , Heme Oxigenase (Desciclizante) , Heme Oxigenase-1/genética , Inflamação/metabolismo , Ferro/metabolismo , Estresse Oxidativo , Placenta/metabolismo , Gravidez , Nascimento Prematuro/metabolismo , RNA Mensageiro , Ratos , Receptores da Transferrina , Linfócitos T
20.
Ecotoxicol Environ Saf ; 220: 112392, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34102395

RESUMO

Understanding the molecular mechanisms of cadmium (Cd) tolerance and accumulation in plants is important to address Cd pollution. In the present study, we performed comparative transcriptome analysis to identify the Cd response processes in the roots of two turnip landraces, KTRG-B14 (high-Cd accumulation) and KTRG-B36 (low-Cd accumulation). Two common enhanced processes, glutathione metabolism and antioxidant system, were identified in both landraces. However, some differential antioxidant processes are likely employed by two landraces, namely, several genes encoding peptide methionine sulfoxide reductases and thioredoxins were up-regulated in B14, whereas flavonoid synthesis was potentially induced to fight against oxidative stress in B36. In addition to the commonly upregulated ZINC INDUCED FACILITATOR 1-like gene in two landraces, different metal transporter-encoding genes identified in B14 (DETOXIFICATION 1) and B36 (PLANT CADMIUM RESISTANCE 2-like, probable zinc transporter 10, and ABC transporter C family member 3) were responsible for Cd accumulation and distribution in cells. Several genes that encode extensins were specifically upregulated in B14, which may improve Cd accumulation in cell walls or regulate root development to absorb more Cd. Meanwhile, the induced high-affinity nitrate transporter 2.1-like gene was also likely to contribute to the higher Cd accumulation in B14. However, Cd also caused some toxic symptoms in both landraces. Cd stress might inhibit iron uptake in both landraces whereas many apoenzyme-encoding genes were influenced in B36, which may be attributed to the interaction between Cd and other metal ions. This study provides novel insights into the molecular mechanism of plant root response to Cd at an early stage. The transporters and key enzymes identified in this study are helpful for the molecular-assisted breeding of low- or high-Cd-accumulating plant resources.


Assuntos
Brassica napus/genética , Cádmio/metabolismo , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Proteínas de Plantas/genética , Raízes de Plantas/metabolismo , Poluentes do Solo/metabolismo , Antioxidantes/metabolismo , Biodegradação Ambiental , Brassica napus/metabolismo , Glutationa/metabolismo , Glicoproteínas/genética , Glicoproteínas/metabolismo , Ferro/metabolismo , Estresse Oxidativo , Proteínas de Plantas/metabolismo , Transcriptoma
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