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1.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445558

RESUMO

Cell-based therapy is a highly promising treatment paradigm in ischemic disease due to its ability to repair tissue when implanted into a damaged site. These therapeutic effects involve a strong paracrine component resulting from the high levels of bioactive molecules secreted in response to the local microenvironment. Therefore, the secreted therapeutic can be modulated by preconditioning the cells during in vitro culturing. Herein, we investigated the potential use of magnetic resonance imaging (MRI) probes, the "iron-quercetin complex" or IronQ, for preconditioning peripheral blood mononuclear cells (PBMCs) to expand proangiogenic cells and enhance their secreted therapeutic factors. PBMCs obtained from healthy donor blood were cultured in the presence of the iron-quercetin complex. Differentiated preconditioning PBMCs were characterized by immunostaining. An enzyme-linked immunosorbent assay was carried out to describe the secreted cytokines. In vitro migration and tubular formation using human umbilical vein endothelial cells (HUVECs) were completed to investigate the proangiogenic efficacy. IronQ significantly increased mononuclear progenitor cell proliferation and differentiation into spindle-shape-like cells, expressing both hematopoietic and stromal cell markers. The expansion increased the number of colony-forming units (CFU-Hill). The conditioned medium obtained from IronQ-treated PBMCs contained high levels of interleukin 8 (IL-8), IL-10, urokinase-type-plasminogen-activator (uPA), matrix metalloproteinases-9 (MMP-9), and tumor necrosis factor-alpha (TNF-α), as well as augmented migration and capillary network formation of HUVECs and fibroblast cells, in vitro. Our study demonstrated that the IronQ-preconditioning PBMC protocol could enhance the angiogenic and reparative potential of non-mobilized PBMCs. This protocol might be used as an adjunctive strategy to improve the efficacy of cell therapy when using PBMCs for ischemic diseases and chronic wounds. However, in vivo assessment is required for further validation.


Assuntos
Movimento Celular , Fibroblastos/fisiologia , Ferro/farmacologia , Leucócitos Mononucleares/fisiologia , Neovascularização Fisiológica , Quercetina/farmacologia , Cicatrização , Adulto , Antioxidantes/farmacologia , Meios de Cultivo Condicionados/farmacologia , Fibroblastos/citologia , Humanos , Leucócitos Mononucleares/citologia , Oligoelementos/farmacologia , Adulto Jovem
2.
Chem Commun (Camb) ; 57(67): 8352-8355, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34337637

RESUMO

By repurposing DNICs designed for other medicinal purposes, the possibility of protease inhibition was investigated in silico using AutoDock 4.2.6 (AD4) and in vitro via a FRET protease assay. AD4 was validated as a predictive computational tool for coordinatively unsaturated DNIC binding using the only known crystal structure of a protein-bound DNIC, PDB- (calculation RMSD = 1.77). From the in silico data the dimeric DNICs TGTA-RRE, [(µ-S-TGTA)Fe(NO)2]2 (TGTA = 1-thio-ß-d-glucose tetraacetate) and TG-RRE, [(µ-S-TG)Fe(NO)2]2 (TG = 1-thio-ß-d-glucose) were identified as promising leads for inhibition via coordinative inhibition at Cys-145 of the SARS-CoV-2 Main Protease (SC2Mpro). In vitro studies indicate inhibition of protease activity upon DNIC treatment, with an IC50 of 38 ± 2 µM for TGTA-RRE and 33 ± 2 µM for TG-RRE. This study presents a simple computational method for predicting DNIC-protein interactions; the in vitro study is consistent with in silico leads.


Assuntos
Inibidores Enzimáticos/farmacologia , Ferro/farmacologia , Óxidos de Nitrogênio/farmacologia , Peptídeo Hidrolases/metabolismo , SARS-CoV-2/efeitos dos fármacos , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/química , Humanos , Ferro/química , Modelos Moleculares , Estrutura Molecular , Óxidos de Nitrogênio/química , SARS-CoV-2/enzimologia
3.
J Hazard Mater ; 419: 126508, 2021 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-34323729

RESUMO

Anaerobic wastewater treatment is a promising technology for refractory pollutant treatment. The nano zero-valent iron (nZVI) assisted anaerobic system could enhance contaminant removal. In this work, we added nZVI into an anaerobic system to investigate the effects on system performances and metabolic mechanism for chloramphenicol (CAP) wastewater treatment. As nZVI concentrations increased from 0 to 1 g/L, the CAP removal efficiency was appreciably improved from 46.5% to 99.2%, while the CH4 production enhanced more than 20 times. The enhanced CAP removal resulted from the enrichments of dechlorination-related bacteria (Hyphomicrobium) and other functional bacteria (e.g., Zoogloea, Syntrophorhabdus) associated with refractory contaminants degradation. The improved CH4 production was ascribed to the increases in fermentative-related bacteria (Smithella and Acetobacteroides), homoacetogen (Treponema), and methanogens. The increased abundances of anaerobic functional genes further verified the mechanism of CH4 production. Furthermore, the abundances of potential hosts of antibiotic resistance genes (ARGs) were reduced under high nZVI concentration (1 g/L), contributing to ARGs attenuation. This study provides a comprehensive analysis of the mechanism in metabolic performance enhancement and ARGs attenuation during nZVI-assisted anaerobic CAP wastewater treatment.


Assuntos
Cloranfenicol , Purificação da Água , Anaerobiose , Antibacterianos/farmacologia , Resistência Microbiana a Medicamentos , Ferro/farmacologia
4.
Biomolecules ; 11(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34200319

RESUMO

The aim of the study was to investigate the influence of a pulsed electric field (PEF) on the level of iron ion accumulation in Saccharomyces cerevisiae cells and to select PEF conditions optimal for the highest uptake of this element. Iron ions were accumulated most efficiently when their source was iron (III) nitrate. When the following conditions of PEF treatment were used: voltage 1500 V, pulse width 10 µs, treatment time 20 min, and a number of pulses 1200, accumulation of iron ions in the cells from a 20 h-culture reached a maximum value of 48.01 mg/g dry mass. Application of the optimal PEF conditions thus increased iron accumulation in cells by 157% as compared to the sample enriched with iron without PEF. The second derivative of the FTIR spectra of iron-loaded and -unloaded yeast cells allowed us to determine the functional groups which may be involved in metal ion binding. The exposure of cells to PEF treatment only slightly influenced the biomass and cell viability. However, iron-enriched yeast (both with or without PEF) showed lower fermentative activity than a control sample. Thus obtained yeast biomass containing a high amount of incorporated iron may serve as an alternative to pharmacological supplementation in the state of iron deficiency.


Assuntos
Eletroforese em Gel de Campo Pulsado/métodos , Ferro/metabolismo , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/metabolismo , Transporte Biológico/fisiologia , Biomassa , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Relação Dose-Resposta a Droga , Ferro/farmacologia , Imagem Óptica/métodos
5.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209797

RESUMO

Macrophages play critical roles in both innate and adaptive immunity and are known for their high plasticity in response to various external signals. Macrophages are involved in regulating systematic iron homeostasis and they sequester iron by phagocytotic activity, which triggers M1 macrophage polarization and typically exerts antitumor effects. We previously developed a novel cryo-thermal therapy that can induce the mass release of tumor antigens and damage-associated molecular patterns (DAMPs), promoting M1 macrophage polarization. However, that study did not examine whether iron released after cryo-thermal therapy induced M1 macrophage polarization; this question still needed to be addressed. We hypothesized that cryo-thermal therapy would cause the release of a large quantity of iron to augment M1 macrophage polarization due to the disruption of tumor cells and blood vessels, which would further enhance antitumor immunity. In this study, we investigated iron released in primary tumors, the level of iron in splenic macrophages after cryo-thermal therapy and the effect of iron on macrophage polarization and CD4+ T cell differentiation in metastatic 4T1 murine mammary carcinoma. We found that a large amount of iron was released after cryo-thermal therapy and could be taken up by splenic macrophages, which further promoted M1 macrophage polarization by inhibiting ERK phosphorylation. Moreover, iron promoted DC maturation, which was possibly mediated by iron-induced M1 macrophages. In addition, iron-induced M1 macrophages and mature DCs promoted the differentiation of CD4+ T cells into the CD4 cytolytic T lymphocytes (CTL) subset and inhibited differentiation into Th2 and Th17 cells. This study explains the role of iron in cryo-thermal therapy-induced antitumor immunity from a new perspective.


Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Crioterapia/efeitos adversos , Ferro/metabolismo , Ferro/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Linfócitos T Citotóxicos/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Polaridade Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Quelantes de Ferro/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Ativação de Macrófagos/fisiologia , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Células RAW 264.7 , Linfócitos T Citotóxicos/fisiologia
6.
Exp Hematol ; 99: 12-20.e3, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34077792

RESUMO

Red blood cell production, or erythropoiesis, is a proliferative process that requires tight regulation. Erythropoietin (Epo) is a glycoprotein cytokine that plays a major role in erythropoiesis by triggering erythroid progenitors/precursors of varying sensitivity. The concentration of Epo in bone marrow is hypothesized to be suboptimal, and the survival of erythroid cells has been suggested to depend on Epo sensitivity. However, the key factors that control Epo sensitivity remain unknown. Two types of transferrin receptors (TfRs), TfR1 and TfR2, are known to play a role in iron uptake in erythroid cells. Here, we hypothesized that TfRs may additionally modulate Epo sensitivity during erythropoiesis by modulating Epo receptor (EpoR) signaling. Using an Epo-sensitive UT-7 (UT7/Epo) erythroid cell and human erythroid progenitor cell models, we report that iron-loaded transferrin, that is, holo-transferrin (holo-Tf), synergizes with suboptimal Epo levels to improve erythroid cell survival, proliferation, and differentiation. This is accomplished via the major signaling pathways of erythropoiesis, which include signal transducer and activator of transcription 5 (STAT5), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and phosphoinositide-3-kinase (PI3K)/AKT. Furthermore, we found that this cooperation is improved by, but does not require, the internalization of TfR1. Interestingly, we observed that loss of TfR2 stabilizes EpoR levels and abolishes the beneficial effects of holo-Tf. Overall, these data reveal novel signaling properties of TfRs, which involve the regulation of erythropoiesis through EpoR signaling.


Assuntos
Antígenos CD/metabolismo , Proliferação de Células/efeitos dos fármacos , Eritroblastos/metabolismo , Eritropoetina/farmacologia , Ferro/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Receptores da Transferrina/metabolismo , Transferrina/farmacologia , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Eritropoetina/metabolismo , Humanos , Ferro/metabolismo , Transferrina/metabolismo
7.
Theranostics ; 11(14): 7072-7091, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093872

RESUMO

Simultaneous targeting of both the tumor microenvironment and cancer cells by a single nanomedicine has not been reported to date. Here, we report the dual properties of zero-valent-iron nanoparticle (ZVI-NP) to induce cancer-specific cytotoxicity and anti-cancer immunity. Methods: Cancer-specific cytotoxicity induced by ZVI-NP was determined by MTT assay. Mitochondria functional assay, immunofluorescence staining, Western blot, RT-qPCR, and ChIP-qPCR assays were used to dissect the mechanism underlying ZVI-NP-induced ferroptotic cancer cell death. The therapeutic potential of ZVI-NP was evaluated in immunocompetent mice and humanized mice. Immune cell profiles of allografts and ex vivo cultured immune cells were examined by flow cytometry analysis, RT-qPCR assay, and immunofluorescence. Results: ZVI-NP caused mitochondria dysfunction, intracellular oxidative stress, and lipid peroxidation, leading to ferroptotic death of lung cancer cells. Degradation of NRF2 by GSK3/ß-TrCP through AMPK/mTOR activation was enhanced in such cancer-specific ferroptosis. In addition, ZVI-NP attenuated self-renewal ability of cancer and downregulated angiogenesis-related genes. Importantly, ZVI-NP augmented anti-tumor immunity by shifting pro-tumor M2 macrophages to anti-tumor M1, decreasing the population of regulatory T cells, downregulating PD-1 and CTLA4 in CD8+ T cells to potentiate their cytolytic activity against cancer cells, while attenuating PD-L1 expression in cancer cells in vitro and in tumor-bearing immunocompetent mice. In particular, ZVI-NPs preferentially accumulated in tumor and lung tissues, leading to prominent suppression of tumor growth and metastasis. Conclusions: This dual-functional nanomedicine established an effective strategy to synergistically induce ferroptotic cancer cell death and reprogram the immunosuppressive microenvironment, which highlights the potential of ZVI-NP as an advanced integrated anti-cancer strategy.


Assuntos
Ferroptose/efeitos dos fármacos , Ferro/farmacologia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Macrófagos/efeitos dos fármacos , Nanopartículas Metálicas/química , Fator 2 Relacionado a NF-E2/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Aloenxertos , Animais , Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Imunoprecipitação da Cromatina , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Ferro/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Nanopartículas Metálicas/administração & dosagem , Nanopartículas Metálicas/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Camundongos SCID , Microscopia Eletrônica de Transmissão , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Mitocôndrias/ultraestrutura , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Proteínas Quinases , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral/imunologia
8.
Nutrients ; 13(6)2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34072630

RESUMO

There is limited evidence regarding the potential risk of untargeted iron supplementation, especially among individuals who are iron-replete or have genetic hemoglobinopathies. Excess iron exposure can increase the production of reactive oxygen species, which can lead to cellular damage. We evaluated the effect of daily oral supplementation on relative leukocyte telomere length (rLTL) and blood mitochondrial DNA (mtDNA) content in non-pregnant Cambodian women (18-45 years) who received 60 mg of elemental iron as ferrous sulfate (n = 190) or a placebo (n = 186) for 12 weeks. Buffy coat rLTL and mtDNA content were quantified by monochrome multiplex quantitative polymerase chain reaction. Generalized linear mixed-effects models were used to predict the absolute and percent change in rLTL and mtDNA content after 12 weeks. Iron supplementation was not associated with an absolute or percent change in rLTL after 12 weeks compared with placebo (ß-coefficient: -0.04 [95% CI: -0.16, 0.08]; p = 0.50 and ß-coefficient: -0.96 [95% CI: -2.69, 0.77]; p = 0.28, respectively). However, iron supplementation was associated with a smaller absolute and percent increase in mtDNA content after 12 weeks compared with placebo (ß-coefficient: -11 [95% CI: -20, -2]; p = 0.02 and ß-coefficient: -11 [95% CI: -20, -1]; p= 0.02, respectively). Thus, daily oral iron supplementation for 12 weeks was associated with altered mitochondrial homeostasis in our study sample. More research is needed to understand the risk of iron exposure and the biological consequences of altered mitochondrial homeostasis in order to inform the safety of the current global supplementation policy.


Assuntos
DNA Mitocondrial , Suplementos Nutricionais , Ferro , Leucócitos/efeitos dos fármacos , Telômero/efeitos dos fármacos , Adulto , Antioxidantes/administração & dosagem , Antioxidantes/farmacologia , Camboja , DNA Mitocondrial/sangue , DNA Mitocondrial/efeitos dos fármacos , Feminino , Humanos , Ferro/administração & dosagem , Ferro/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Adulto Jovem
9.
Nutrients ; 13(5)2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33946398

RESUMO

Anemia remains a condition with high prevalence in populations worldwide, and the prevalence of anemia among children under five years old in Brazil is approximately 40%, being higher in communities marked by social inequities. Diverse government programs during recent decades targeted iron-deficiency anemia, considering its impacts throughout the lifetime. The objective of this study was to investigate the effects of two government iron supplementation programs on health outcomes related to iron-deficiency anemia among children up to 4 years old in Brazilian municipalities. A longitudinal panel encompassing data from 5570 municipalities from 1998 to 2019 was investigated using a difference-in-differences framework with multiple interventions and distinct times of adhesion, and fixed-effects models were estimated to control for invariant municipal characteristics throughout the period in order to ensure comparability. The results indicate significant effects of the federal programs in reducing hospitalizations and lengths of stay due to iron-deficiency anemia, especially in non-poor municipalities. There was complementarity in the effects of the programs; however, neither of the programs influenced mortality rates. Thus, it is important to consider possible improvements in the operationalization of the programs, in order to achieve better results in the reduction of severe iron-deficiency anemia among children up to 4 years old.


Assuntos
Anemia Ferropriva/epidemiologia , Anemia Ferropriva/prevenção & controle , Ferro/farmacologia , Brasil/epidemiologia , Fenômenos Fisiológicos da Nutrição Infantil , Pré-Escolar , Suplementos Nutricionais , Programas Governamentais , Humanos , Lactente , Ferro/administração & dosagem , Estudos Longitudinais
10.
Biochemistry (Mosc) ; 86(5): 533-539, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33993863

RESUMO

Binding of dinitrosyl iron complex (DNIC) to albumin was studied using time-resolved fluorescence (TRF) and electron spin resonance (ESR) spectroscopy. It was found that the fluorescence lifetime of bovine serum albumin (BSA) and human serum albumin (HSA) decreases with binding and depends on DNIC concentration. The observed biexponential pattern of the BSA tryptophan (Trp) fluorescence decay is explained by the presence of two tryptophan residues in the protein molecule. We believe that DNIC forms stable complexes with the cysteine (Cys34) residue in the domain I of albumin. It was shown that the lifetime of albumin tryptophan fluorescence decreased during co-incubation of BSA with DNICs and glutathione. Effects of DNIC on the binding of specific spin-labeled fatty acids with albumin in human blood plasma were studied in vitro. The presence of DNIC in blood plasma does not change conformation of albumin domains II and III. We suggest that the most possible interaction between DNICs and albumin is the formation of a complex; and nitrosylation of the cysteine residue in the albumin domain I occurs without the changes in albumin conformation.


Assuntos
Ferro/farmacologia , Óxidos de Nitrogênio/farmacologia , Soroalbumina Bovina/efeitos dos fármacos , Albumina Sérica/efeitos dos fármacos , Albumina Sérica/metabolismo , Adulto , Idoso , Animais , Bovinos , Espectroscopia de Ressonância de Spin Eletrônica , Glutationa/química , Humanos , Ferro/química , Masculino , Pessoa de Meia-Idade , Óxidos de Nitrogênio/química , Conformação Proteica , Albumina Sérica/química , Soroalbumina Bovina/química , Soroalbumina Bovina/metabolismo , Espectrometria de Fluorescência
11.
J Bacteriol ; 203(13): e0002721, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-33875547

RESUMO

Ehrlichia chaffeensis causes human monocytic ehrlichiosis by replicating within phagosomes of monocytes/macrophages. A function disruption mutation within the pathogen's ECH_0660 gene, which encodes a phage head-to-tail connector protein, resulted in the rapid clearance of the pathogen in vivo, while aiding in induction of sufficient immunity in a host to protect against wild-type infection challenge. In this study, we describe the characterization of a cluster of seven genes spanning from ECH_0659 to ECH_0665, which contained four genes encoding bacterial phage proteins, including the ECH_0660 gene. Assessment of the promoter region upstream of the first gene of the seven genes (ECH_0659) in Escherichia coli demonstrated transcriptional enhancement under zinc and iron starvation conditions. Furthermore, transcription of the seven genes was significantly higher under zinc and iron starvation conditions for E. chaffeensis carrying a mutation in the ECH_0660 gene compared to the wild-type pathogen. In contrast, for the ECH_0665 gene mutant with the function disruption, transcription from the genes was mostly similar to that of the wild type or was moderately downregulated. Recently, we reported that this mutation caused a minimal impact on the pathogen's in vivo growth, as it persisted similarly to the wild type. The current study is the first to describe how zinc and iron contribute to E. chaffeensis biology. Specifically, we demonstrated that the functional disruption in the gene encoding the phage head-to-tail connector protein in E. chaffeensis results in the enhanced transcription of seven genes, including those encoding phage proteins, under zinc and iron limitation. IMPORTANCE Ehrlichia chaffeensis, a tick-transmitted bacterium, causes human monocytic ehrlichiosis by replicating within phagosomes of monocytes/macrophages. A function disruption mutation within the pathogen's gene encoding a phage head-to-tail connector protein resulted in the rapid clearance of the pathogen in vivo, while aiding in induction of sufficient immunity in a host to protect against wild-type infection challenge. In the current study, we investigated if the functional disruption in the phage head-to-tail connector protein gene caused transcriptional changes resulting from metal ion limitations. This is the first study describing how zinc and iron may contribute to E. chaffeensis replication.


Assuntos
Proteínas de Bactérias/genética , Ehrlichia chaffeensis/genética , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Genes Bacterianos/genética , Ferro/farmacologia , Mutação , Zinco/farmacologia , Animais , Bacteriófagos/genética , Ehrlichiose/microbiologia , Escherichia coli/genética , Humanos , Imunidade , Monócitos/microbiologia , Carrapatos/microbiologia , Transcrição Genética
12.
Food Chem ; 356: 129697, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-33838606

RESUMO

The purpose of this umbrella review was to evaluate the quality of evidence, validity and biases of the associations between red and processed meat consumption and multiple cancer outcomes according to existing systematic reviews and meta-analyses. The umbrella review identified 72 meta-analyses with 20 unique outcomes for red meat and 19 unique outcomes for processed meat. Red meat consumption was associated with increased risk of overall cancer mortality, non-Hodgkin lymphoma (NHL), bladder, breast, colorectal, endometrial, esophageal, gastric, lung and nasopharyngeal cancer. Processed meat consumption might increase the risk of overall cancer mortality, NHL, bladder, breast, colorectal, esophageal, gastric, nasopharyngeal, oral cavity and oropharynx and prostate cancer. Dose-response analyses revealed that 100 g/d increment of red meat and 50 g/d increment of processed meat consumption were associated with 11%-51% and 8%-72% higher risk of multiple cancer outcomes, respectively, and seemed to be not correlated with any benefit.


Assuntos
Produtos da Carne/efeitos adversos , Neoplasias/etiologia , Carne Vermelha/efeitos adversos , Dano ao DNA/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Ferro/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Fatores de Risco
13.
Nutrients ; 13(5)2021 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-33921980

RESUMO

Iron-fortified formulas and iron drops (both usually ferrous sulfate, FS) prevent early life iron deficiency, but may delay growth and adversely affect neurodevelopment by providing excess iron. We used a rat pup model to investigate iron status, growth, and development outcomes following daily iron supplementation (10 mg iron/kg body weight, representative of iron-fortified formula levels) with FS or an alternative, bioavailable form of iron, ferrous bis-glycinate chelate (FC). On postnatal day (PD) 2, sex-matched rat litters (n = 3 litters, 10 pups each) were randomly assigned to receive FS, FC, or vehicle control until PD 14. On PD 15, we evaluated systemic iron regulation and CNS mineral interactions and we interrogated iron loading outcomes in the hippocampus, in search of mechanisms by which iron may influence neurodevelopment. Body iron stores were elevated substantially in iron-supplemented pups. All pups gained weight normally, but brain size on PD 15 was dependent on iron source. This may have been associated with reduced hippocampal oxidative stress but was not associated with CNS mineral interactions, iron regulation, or myelination, as these were unchanged with iron supplementation. Additional studies are warranted to investigate iron form effects on neurodevelopment so that iron recommendations can be optimized for all infants.


Assuntos
Sistema Nervoso Central/crescimento & desenvolvimento , Suplementos Nutricionais , Compostos Ferrosos/farmacologia , Glicina/farmacologia , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Ferro/farmacologia , Animais , Animais Recém-Nascidos , Sistema Nervoso Central/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase/efeitos dos fármacos , Ferro/sangue , Bainha de Mielina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Oligoelementos/análise , Ganho de Peso/efeitos dos fármacos
14.
Nutrients ; 13(4)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810451

RESUMO

A major problem of oral iron supplementation efficacy in children is its tolerability and compliance. We aimed to determine the safety and efficacy of a novel food supplement >Your< Iron Syrup in the replenishment of iron stores and improvement of hematological parameters in iron-deficient children aged nine months to six years. We randomized 94 healthy children with iron deficiency in a ratio of 3:1 to either receive >Your< Iron Syrup or placebo. A 12-week supplementation with >Your< Iron Syrup resulted in a significant increase in ferritin and hemoglobin levels as compared to placebo (p = 0.04 and p = 0.02). Adverse events were reported with similar frequencies across both study arms. >Your< Iron Syrup represents an effective, well-tolerated, and safe option for the management of nutritional iron deficiency in children.


Assuntos
Anemia Ferropriva/tratamento farmacológico , Suplementos Nutricionais , Composição de Medicamentos , Hemoglobinas/metabolismo , Ferro/química , Ferro/farmacologia , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Ferro/administração & dosagem , Masculino
15.
Theranostics ; 11(11): 5418-5429, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859755

RESUMO

Background: Ferroptosis is a form of iron-dependent programmed cell death that differs from apoptosis with regards to both mechanism and cell morphology. Therefore, ferroptotic-based cancer therapy has shown significant potential to overcome the weaknesses of conventional therapeutics mediated by apoptosis pathways. Effective ferroptosis can be induced by the intracellular Fenton reaction that is dependent on the adequate supply of iron ions and H2O2 in cells. However, these are often insufficient due to intrinsic cellular regulation. Methods: In this study, we designed a cisplatin prodrug-loaded manganese-deposited iron oxide nanoplatform (Pt-FMO) to trigger intracellular cascade reactions that lead to generation of reactive oxygen species (ROS) to enhance ferroptotic effect. The Pt-FMO causes the tumor microenvironment responsive to release manganese, iron ions and Pt-drugs. As manganese is an element that is able to catalyze the Fenton reaction more effectively than iron, coupled with the Pt-drugs that can promote generation of H2O2 in cells, the Pt-FMO is expected to significantly strengthen catalysis of the Fenton reaction, which favors the ferroptotic effect. Moreover, the Pt-drugs will eventually function as cisplatin. Thus, Pt-FMO is an ideal candidate for tumor ferroptotic combined with apoptotic treatment. Results: In vivo results demonstrated that, at a dosage of only 8.89% Pt content, Pt-FMO is able to achieve a similar treatment effect as cisplatin. Hence, Pt-FMO exhibited significantly lower systemic toxicity compared to cisplatin. Additionally, Pt-FMO exhibits effective T2 -weighted MRI enhancement for tumor imaging. Conclusion: The Pt-FMO nanoplatform is designed to introduce mutual beneficial cascade reactions for promoting ferroptosis and apoptosis in combination with tumor MRI. The Pt-FMO system, which causes ferroptosis combined with apoptosis, can efficiently induce tumor cell death.


Assuntos
Apoptose/efeitos dos fármacos , Cisplatino/farmacologia , Compostos Férricos/farmacologia , Ferroptose/efeitos dos fármacos , Ferro/farmacologia , Compostos de Manganês/farmacologia , Manganês/farmacologia , Óxidos/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Células HeLa , Humanos , Peróxido de Hidrogênio/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pró-Fármacos/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Microambiente Tumoral/efeitos dos fármacos
16.
Curr Opin Chem Biol ; 61: 170-178, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33714882

RESUMO

Chemical tools capable of detecting ferrous iron with oxidation-state specificity have only recently become available. Coincident with this development in chemical biology has been increased study and appreciation for the importance of ferrous iron during infection and more generally in host-pathogen interaction. Some of the recent findings are surprising and challenge long-standing assumptions about bacterial iron homeostasis and the innate immune response to infection. Here, we review these recent developments and their implications for antibacterial therapy.


Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Ferro/farmacologia , Humanos
17.
Int J Nanomedicine ; 16: 2071-2085, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33727814

RESUMO

Background: Radiation therapy remains an important treatment modality in cancer therapy, however, resistance is a major problem for treatment failure. Elevated expression of glutathione is known to associate with radiation resistance. We used glutathione overexpressing small cell lung cancer cell lines, SR3A-13 and SR3A-14, established by transfection with γ-glutamylcysteine synthetase (γ-GCS) cDNA, as a model for investigating strategies of overcoming radiation resistance. These radiation-resistant cells exhibit upregulated human copper transporter 1 (hCtr1), which also transports cisplatin. This study was initiated to investigate the effect and the underlying mechanism of iron-platinum nanoparticles (FePt NPs) on radiation sensitization in cancer cells. Materials and Methods: Uptakes of FePt NPs in these cells were studied by plasma optical emission spectrometry and transmission electron microscopy. Effects of the combination of FePt NPs and ionizing radiation were investigated by colony formation assay and animal experiment. Intracellular reactive oxygen species (ROS) were assessed by using fluorescent probes and imaged by a fluorescence-activated-cell-sorting caliber flow cytometer. Oxygen consumption rate (OCR) in mitochondria after FePt NP and IR treatment was investigated by a Seahorse XF24 cell energy metabolism analyzer. Results: These hCtr1-overexpressing cells exhibited elevated resistance to IR and the resistance could be overcome by FePt NPs via enhanced uptake of FePt NPs. Overexpression of hCtr1 was responsible for the increased uptake/transport of FePt NPs as demonstrated by using hCtr1-transfected parental SR3A (SR3A-hCtr1-WT) cells. Increased ROS and drastic mitochondrial damages with substantial reduction of oxygen consumption rate were observed in FePt NPs and IR-treated cells, indicating that structural and functional insults of mitochondria are the lethal mechanism of FePt NPs. Furthermore, FePt NPs also increased the efficacy of radiotherapy in mice bearing SR3A-hCtr1-WT-xenograft tumors. Conclusion: These results suggest that FePt NPs can potentially be a novel strategy to improve radiotherapeutic efficacy in hCtr1-overexpressing cancer cells via enhanced uptake and mitochondria targeting.


Assuntos
Ligas/farmacologia , Transportador de Cobre 1/metabolismo , Ferro/farmacologia , Nanopartículas Metálicas/química , Mitocôndrias/metabolismo , Neoplasias/metabolismo , Platina/farmacologia , Tolerância a Radiação , Aerobiose , Animais , Linhagem Celular Tumoral , Respiração Celular/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Nanopartículas Metálicas/ultraestrutura , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Modelos Biológicos , Tolerância a Radiação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Resultado do Tratamento , Raios X
18.
J Nutr ; 151(5): 1073-1083, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33693820

RESUMO

BACKGROUND: Maternal iron deficiency (ID) is associated with poor pregnancy and fetal outcomes. The effect is thought to be mediated by the placenta but there is no comprehensive assessment of placental responses to maternal ID. Additionally, whether the influence of maternal ID on the placenta differs by fetal sex is unknown. OBJECTIVES: To identify gene and protein signatures of ID mouse placentas at mid-gestation. A secondary objective was to profile the expression of iron genes in mouse placentas across gestation. METHODS: We used a real-time PCR-based array to determine the mRNA expression of all known iron genes in mouse placentas at embryonic day (E) 12.5, E14.5, E16.5, and E19.5 (n = 3 placentas/time point). To determine the effect of maternal ID, we performed RNA sequencing and proteomics in male and female placentas from ID and iron-adequate mice at E12.5 (n = 8 dams/diet). RESULTS: In female placentas, 6 genes, including transferrin receptor (Tfrc) and solute carrier family 11 member 2, were significantly changed by maternal ID. An additional 154 genes were altered in male ID placentas. A proteomic analysis quantified 7662 proteins in the placenta. Proteins translated from iron-responsive element (IRE)-containing mRNA were altered in abundance; ferritin and ferroportin 1 decreased, while TFRC increased in ID placentas. Less than 4% of the significantly altered genes in ID placentas occurred both at the transcriptional and translational levels. CONCLUSIONS: Our data demonstrate that the impact of maternal ID on placental gene expression in mice is limited in scope and magnitude at mid-gestation. We provide strong evidence for IRE-based transcriptional and translational coordination of iron gene expression in the mouse placenta. Finally, we discover sexually dimorphic effects of maternal ID on placental gene expression, with more genes and pathways altered in male compared with female mouse placentas.


Assuntos
Anemia Ferropriva/metabolismo , Placenta/metabolismo , Complicações na Gravidez/metabolismo , Proteoma/metabolismo , Transcriptoma/fisiologia , Animais , Feminino , Regulação da Expressão Gênica , Ferro/metabolismo , Ferro/farmacologia , Camundongos , Ferroproteínas não Heme/genética , Ferroproteínas não Heme/metabolismo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
19.
Nat Commun ; 12(1): 1211, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619262

RESUMO

Primary production in the Southern Ocean (SO) is limited by iron availability. Hydrothermal vents have been identified as a potentially important source of iron to SO surface waters. Here we identify a recurring phytoplankton bloom in the high-nutrient, low-chlorophyll waters of the Antarctic Circumpolar Current in the Pacific sector of the SO, that we argue is fed by iron of hydrothermal origin. In January 2014 the bloom covered an area of ~266,000 km2 with depth-integrated chlorophyll a > 300 mg m-2, primary production rates >1 g C m-2 d-1, and a mean CO2 flux of -0.38 g C m-2 d-1. The elevated iron supporting this bloom is likely of hydrothermal origin based on the recurrent position of the bloom relative to two active hydrothermal vent fields along the Australian Antarctic Ridge and the association of the elevated iron with a distinct water mass characteristic of a nonbuoyant hydrothermal vent plume.


Assuntos
Eutrofização/fisiologia , Fontes Hidrotermais/química , Ferro/farmacologia , Oceanos e Mares , Fitoplâncton/crescimento & desenvolvimento , Regiões Antárticas , Biomassa , Carbono/análise , Clorofila/análise , Eutrofização/efeitos dos fármacos , Cinética , Nitrogênio/análise , Fósforo/análise , Fitoplâncton/efeitos dos fármacos , Água/química
20.
Food Chem ; 349: 129144, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33540218

RESUMO

Ferritin is an iron-containing protein and functions in the maintenance of iron balance in organisms. Currently the interaction among ferritin, ion iron, and food bioactive compounds is still unclear. In this study, the mechanism underlying the interaction of ferritin, ion iron, and chlorogenic acid was investigated, as well as the effect of chlorogenic acid on the physicochemical properties of ferritin. The results showed that chlorogenic acid could interact with Fe(III) to form chlorogenic acid-Fe(III) complexes, which then bonded with ferritin via hydrogen bonds in the ferritin-chlorogenic acid-Fe(III) complexes. The chlorogenic acid showed a high efficiency in Fe(II) chelation and hydroxyl radical (•OH) capture, and could promote iron oxidation and iron release induced by ferritin. Chlorogenic acid could also effectively reduce the polymerization extent of ferritin induced by Fe(III) and Fe(II). This study elucidates the interactions of multiple components in foodstuffs by using a protein-metal-polyphenol model.


Assuntos
Ácido Clorogênico/metabolismo , Ácido Clorogênico/farmacologia , Ferritinas/química , Ferritinas/metabolismo , Ferro/metabolismo , Ferro/farmacologia , Multimerização Proteica/efeitos dos fármacos , Oxirredução , Ligação Proteica , Estrutura Quaternária de Proteína
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