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1.
Eur J Epidemiol ; 35(8): 763-773, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32816244

RESUMO

Iron metabolism and anemia may play an important role in multiple organ dysfunction syndrome in Coronavirus disease 2019 (COVID-19). We conducted a systematic review and meta-analysis to evaluate biomarkers of anemia and iron metabolism (hemoglobin, ferritin, transferrin, soluble transferrin receptor, hepcidin, haptoglobin, unsaturated iron-binding capacity, erythropoietin, free erythrocyte protoporphyrine, and erythrocyte indices) in patients diagnosed with COVID-19, and explored their prognostic value. Six bibliographic databases were searched up to August 3rd 2020. We included 189 unique studies, with data from 57,563 COVID-19 patients. Pooled mean hemoglobin and ferritin levels in COVID-19 patients across all ages were 129.7 g/L (95% Confidence Interval (CI), 128.51; 130.88) and 777.33 ng/mL (95% CI, 701.33; 852.77), respectively. Hemoglobin levels were lower with older age, higher percentage of subjects with diabetes, hypertension and overall comorbidities, and admitted to intensive care. Ferritin level increased with older age, increasing proportion of hypertensive study participants, and increasing proportion of mortality. Compared to moderate cases, severe COVID-19 cases had lower hemoglobin [weighted mean difference (WMD), - 4.08 g/L (95% CI - 5.12; - 3.05)] and red blood cell count [WMD, - 0.16 × 1012 /L (95% CI - 0.31; - 0.014)], and higher ferritin [WMD, - 473.25 ng/mL (95% CI 382.52; 563.98)] and red cell distribution width [WMD, 1.82% (95% CI 0.10; 3.55)]. A significant difference in mean ferritin levels of 606.37 ng/mL (95% CI 461.86; 750.88) was found between survivors and non-survivors, but not in hemoglobin levels. Future studies should explore the impact of iron metabolism and anemia in the pathophysiology, prognosis, and treatment of COVID-19.


Assuntos
Anemia/diagnóstico , Infecções por Coronavirus , Coronavirus/metabolismo , Ferro/metabolismo , Pandemias , Pneumonia Viral , Betacoronavirus , Biomarcadores/análise , Biomarcadores/sangue , Técnicas de Laboratório Clínico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/epidemiologia , Eritropoetina , Ferritinas/sangue , Hemoglobinas/análise , Hemoglobinas/metabolismo , Hepcidinas/sangue , Hepcidinas/metabolismo , Humanos , Ferro/sangue , Pneumonia Viral/epidemiologia , Receptores da Transferrina/sangue , Transferrina/análise , Transferrina/metabolismo
2.
J Chromatogr A ; 1625: 461298, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32709341

RESUMO

This study has examined the batch binding behaviour of different thermo-responsive co-polymer grafted chromatographic materials under different temperature and protein loading conditions. The effect of molecular composition of poly(N-isopropylacrylamide) (PNIPAAm)-based co-polymers on the phase transition properties has been documented. Sixteen co-polymers of different compositions were synthesized by free radical polymerization methods. Most underwent relatively sharp phase transitions upon application of increasing temperature. However, the value of the lower critical solution temperature (LCST) varied due to differences in co-polymer compositions. In general, it was found that the LCST increased for co-polymers containing more hydrophilic moieties, but decreased for co-polymers with more hydrophobic moieties. Moreover, the LCST increased, together with increased width of the transition temperature, when highly branched monomeric moieties (i.e. N­tert­octyl groups) were present. When bulky side chains (octadecyl or triphenylmethyl groups) were located in the polymer structures the LCST transition was absent. Based on these findings, 6 thermo-responsive co-polymers of different compositions were individually immobilised onto cross-linked Sepharose 6 Fast Flow by a "grafting-from" method. Bovine holo-lactoferrin and bovine holo-transferrin at different concentrations in the range 1-100 mg/mL were then employed as target proteins to evaluate the adsorption behaviour under batch binding conditions with these different polymer grafted Sepharose 6 Fast Flow sorbents at two different temperatures. In general, all sorbents exhibited greater affinity and adsorption capacity for bovine holo-lactoferrin at 50 °C compared to 20 °C. In addition, the affinity and adsorption capacity of bovine holo-lactoferrin with positively charged copolymer grafted Sepharose 6 Fast Flow chromatographic sorbents at 20 °C and 50 °C were much lower than that found for negatively charged copolymer grafted Sepharose 6 Fast Flow sorbents, whilst the opposite trend was found with bovine holo-transferrin due to differences in the surface charge properties of these two proteins, indicative of different separation selectivity. Furthermore, the structure of the side chains present in the grafted copolymer structure was found to affect the adsorption performance of both proteins at 20 °C and 50 °C.


Assuntos
Polímeros/química , Proteínas/química , Reologia , Sefarose/química , Temperatura , Resinas Acrílicas/síntese química , Resinas Acrílicas/química , Adsorção , Animais , Bovinos , Interações Hidrofóbicas e Hidrofílicas , Lactoferrina/química , Polimerização , Polímeros/síntese química , Transferrina/química
3.
Nature ; 583(7816): 425-430, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32612231

RESUMO

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability1-3. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins4,5. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport. Here we label hundreds of proteins constituting the mouse blood plasma proteome, and upon their systemic administration, study the BBB with its physiological ligand. We find that plasma proteins readily permeate the healthy brain parenchyma, with transport maintained by BBB-specific transcriptional programmes. Unlike IgG antibody, plasma protein uptake diminishes in the aged brain, driven by an age-related shift in transport from ligand-specific receptor-mediated to non-specific caveolar transcytosis. This age-related shift occurs alongside a specific loss of pericyte coverage. Pharmacological inhibition of the age-upregulated phosphatase ALPL, a predicted negative regulator of transport, enhances brain uptake of therapeutically relevant transferrin, transferrin receptor antibody and plasma. These findings reveal the extent of physiological protein transcytosis to the healthy brain, a mechanism of widespread BBB dysfunction with age and a strategy for enhanced drug delivery.


Assuntos
Envelhecimento/metabolismo , Envelhecimento/patologia , Barreira Hematoencefálica/metabolismo , Transcitose , Fosfatase Alcalina/metabolismo , Animais , Anticorpos/metabolismo , Transporte Biológico , Proteínas Sanguíneas/administração & dosagem , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/farmacocinética , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Saúde , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasma/metabolismo , Proteoma/administração & dosagem , Proteoma/metabolismo , Proteoma/farmacocinética , Receptores da Transferrina/imunologia , Transcrição Genética , Transferrina/metabolismo
4.
World J Emerg Surg ; 15(1): 41, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32605582

RESUMO

BACKGROUND: Iron metabolism and immune response to SARS-CoV-2 have not been described yet in intensive care patients, although they are likely involved in Covid-19 pathogenesis. METHODS: We performed an observational study during the peak of pandemic in our intensive care unit, dosing D-dimer, C-reactive protein, troponin T, lactate dehydrogenase, ferritin, serum iron, transferrin, transferrin saturation, transferrin soluble receptor, lymphocyte count and NK, CD3, CD4, CD8 and B subgroups of 31 patients during the first 2 weeks of their ICU stay. Correlation with mortality and severity at the time of admission was tested with the Spearman coefficient and Mann-Whitney test. Trends over time were tested with the Kruskal-Wallis analysis. RESULTS: Lymphopenia is severe and constant, with a nadir on day 2 of ICU stay (median 0.555 109/L; interquartile range (IQR) 0.450 109/L); all lymphocytic subgroups are dramatically reduced in critically ill patients, while CD4/CD8 ratio remains normal. Neither ferritin nor lymphocyte count follows significant trends in ICU patients. Transferrin saturation is extremely reduced at ICU admission (median 9%; IQR 7%), then significantly increases at days 3 to 6 (median 33%, IQR 26.5%, p value 0.026). The same trend is observed with serum iron levels (median 25.5 µg/L, IQR 69 µg/L at admission; median 73 µg/L, IQR 56 µg/L on days 3 to 6) without reaching statistical significance. Hyperferritinemia is constant during intensive care stay: however, its dosage might be helpful in individuating patients developing haemophagocytic lymphohistiocytosis. D-dimer is elevated and progressively increases from admission (median 1319 µg/L; IQR 1285 µg/L) to days 3 to 6 (median 6820 µg/L; IQR 6619 µg/L), despite not reaching significant results. We describe trends of all the abovementioned parameters during ICU stay. CONCLUSIONS: The description of iron metabolism and lymphocyte count in Covid-19 patients admitted to the intensive care unit provided with this paper might allow a wider understanding of SARS-CoV-2 pathophysiology.


Assuntos
Infecções por Coronavirus , Cuidados Críticos , Ferro/metabolismo , Linfócitos/imunologia , Pandemias , Pneumonia Viral , Idoso , Betacoronavirus/isolamento & purificação , Coagulação Sanguínea , Infecções por Coronavirus/sangue , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/terapia , Correlação de Dados , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Feminino , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Itália/epidemiologia , Contagem de Linfócitos/métodos , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Mortalidade , Pneumonia Viral/sangue , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Pneumonia Viral/terapia , Índice de Gravidade de Doença , Transferrina/análise
6.
PLoS Med ; 17(6): e1003091, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511251

RESUMO

BACKGROUND: Anemia is the most common and serious cancer-related complication. This study aimed to evaluate the efficacy of administration of ferric carboxymaltose without erythropoiesis-stimulating agents for treating anemia in cancer patients. Moreover, we identified the biomarkers of hemoglobin response to predict the need for iron therapy. METHODS AND FINDINGS: We enrolled patients with solid cancers who were treated at a single institute (Samsung Medical Center, South Korea), from April 2015 to July 2017, in this prospective single-arm Phase II clinical trial. Patients received intravenous ferric carboxymaltose (1,000 mg) infusion on the first day (visit 1) of treatment. The primary end point was the number of hemoglobin responders, defined as patients with an increase in hemoglobin level ≥ 1.0 g/dL from the baseline, a hemoglobin level ≥ 11.0 g/dL, or both, within an 8-week observation period (week 3, 6, or 8). Secondary end points included changes in transferrin saturation and levels of soluble transferrin receptors, hepcidin, erythropoietin, interleukin-6, and C-reactive protein (CRP) at each visit. Of the 103 recruited patients, 92 were eligible for analysis. The mean patient age was 57.3 ± 12.5 years, and 54.3% of the patients were women. The most common diagnoses were breast cancer (n = 23, 25.1%), lung cancer (n = 21, 22.9%), gastrointestinal cancer (n = 20, 20.9%), and lymphoma (n = 16, 17.7%). A hemoglobin response was observed in 36 (39.1%), 53 (57.6%), and 61 (66.3%) patients in the third, fifth, and eighth weeks, respectively. The mean increase in hemoglobin levels from the baseline to the end of treatment was 1.77 ± 1.30 g/dL. Baseline values of hepcidin (p = 0.008), total iron binding capacity (p = 0.014), ferritin (p = 0.048), and CRP (p = 0.044) were significantly different between the responder and nonresponder groups. Multiple logistic regression analysis for baseline anemia-related biochemical variable significantly associated with the hemoglobin response showed that only baseline hepcidin level was a significant factor for hemoglobin response (odds ratio = 0.95, 95% confidence interval 0.90-1.0, p = 0.045). Hemoglobin responders had significantly lower hepcidin levels than nonresponders (mean [±standard deviation], 13.45 [±14.71] versus 35.22 [±40.470 ng/ml]; p = 0.007). However, our analysis had some limitations such as the different patient characteristics in the studies that were included, institutional differences in the measurement of hepcidin level, and missing data on long-term safety. Therefore, our findings need further validation. CONCLUSIONS: Intravenous ferric carboxymaltose (1,000 mg) monotherapy increases hemoglobin levels without serious adverse events in patients with cancer. Hepcidin is a useful biomarker for predicting iron requirement in cancer patients. TRIAL REGISTRATION: Clinicaltrials.gov NCT02599012.


Assuntos
Anemia/tratamento farmacológico , Compostos Férricos/uso terapêutico , Maltose/análogos & derivados , Anemia/induzido quimicamente , Antineoplásicos/efeitos adversos , Biomarcadores/sangue , Eritropoetina/sangue , Feminino , Compostos Férricos/administração & dosagem , Hemoglobinas/análise , Hepcidinas/sangue , Humanos , Infusões Intravenosas , Masculino , Maltose/administração & dosagem , Maltose/uso terapêutico , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Projetos Piloto , República da Coreia , Transferrina/análise , Resultado do Tratamento
7.
Nat Commun ; 11(1): 2332, 2020 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-32393788

RESUMO

Fasting-mimicking diets delay tumor progression and sensitize a wide range of tumors to chemotherapy, but their therapeutic potential in combination with non-cytotoxic compounds is poorly understood. Here we show that vitamin C anticancer activity is limited by the up-regulation of the stress-inducible protein heme-oxygenase-1. The fasting-mimicking diet selectivity reverses vitamin C-induced up-regulation of heme-oxygenase-1 and ferritin in KRAS-mutant cancer cells, consequently increasing reactive iron, oxygen species, and cell death; an effect further potentiated by chemotherapy. In support of a potential role of ferritin in colorectal cancer progression, an analysis of The Cancer Genome Atlas Database indicates that KRAS mutated colorectal cancer patients with low intratumor ferritin mRNA levels display longer 3- and 5-year overall survival. Collectively, our data indicate that the combination of a fasting-mimicking diet and vitamin C represents a promising low toxicity intervention to be tested in randomized clinical trials against colorectal cancer and possibly other KRAS mutated tumors.


Assuntos
Ácido Ascórbico/farmacologia , Dieta , Jejum/fisiologia , Mutação/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Progressão da Doença , Heme Oxigenase-1/metabolismo , Humanos , Ferro/metabolismo , Camundongos Endogâmicos BALB C , Oxaliplatina/farmacologia , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Análise de Sobrevida , Transferrina/metabolismo
8.
Int J Nanomedicine ; 15: 2751-2764, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32368053

RESUMO

Introduction: A multifunctional redox- and pH-responsive polymeric drug delivery system is designed and investigated for targeted anticancer drug delivery to liver cancer. Methods: The nanocarrier (His-PAMAM-ss-PEG-Tf, HP-ss-PEG-Tf) is constructed based on generation 4 polyamidoamine dendrimer (G4 PAMAM). Optimized amount of histidine (His) residues is grafted on the surface of PAMAM to obtain enhanced pH-sensitivity and proton-buffering capacity. Disulfide bonds (ss) are introduced between PAMAM and PEG to reach accelerated intracellular drug release. Transferrin (Tf) was applied to achieve active tumor targeting. Doxorubicin (DOX) is loaded in the hydrophobic cavity of the nanocarrier to exert its anti-tumor effect. Results: The results obtained from in vitro and in vivo evaluation indicate that HP-ss-PEG-Tf/DOX complex has pH and redox dual-sensitive properties, and exhibit higher cellular uptake and cytotoxicity than the other control groups. Flow cytometry and confocal microscopy display internalization of HP-ss-PEG-Tf/DOX via clathrin mediated endocytosis and effective endosomal escape in HepG2 cancer cells. Additionally, cyanine 7 labeled HP-ss-PEG-Tf conjugate could quickly accumulate in the HepG2 tumor. Remarkably, HP-ss-PEG-Tf/DOX present superior anticancer activity, enhanced apoptotic activity and lower heart and kidney toxicity in vivo. Discussion: Thus, HP-ss-PEG-Tf is proved to be a promising candidate for effective targeting delivery of DOX into the tumor.


Assuntos
Antineoplásicos/administração & dosagem , Dendrímeros/química , Portadores de Fármacos/administração & dosagem , Nylons/química , Transferrina/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Dendrímeros/administração & dosagem , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Células Hep G2 , Histidina/química , Humanos , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos BALB C , Oxirredução , Polietilenoglicóis/química , Succinimidas/química , Transferrina/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Nanomedicine ; 15: 2841-2858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32425521

RESUMO

Introduction: Osthole (Ost) is a coumarin compound that strengthens hippocampal neurons and neural stem cells against Aß oligomer-induced neurotoxicity in mice, and is a potential drug for the treatment of Alzheimer's disease (AD). However, the effectiveness of the drug is limited by its solubility and bioavailability, as well as by the low permeability of the blood-brain barrier (BBB). In this study, a kind of transferrin-modified Ost liposomes (Tf-Ost-Lip) was constructed, which could improve the bioavailability and enhance brain targeting. Methods: Tf-Ost-Lip was prepared by thin-film hydration method. The ability of liposomal formulations to translocate across BBB was investigated using in vitro BBB model. And the protective effect of Tf-Ost-Lip was evaluated in APP-SH-SY5Y cells. In addition, we performed pharmacokinetics study and brain tissue distribution analysis of liposomal formulations in vivo. We also observed the neuroprotective effect of the varying formulations in APP/PS-1 mice. Results: In vitro studies reveal that Tf-Ost-Lip could increase the intracellular uptake of hCMEC/D3 cells and APP-SH-SY5Y cells, and increase the drug concentration across the BBB. Additionally, Tf-Ost-Lip was found to exert a protective effect on APP-SH-SY5Y cells. In vivo studies of pharmacokinetics and the Ost distribution in brain tissue indicate that Tf-Ost-Lip prolonged the cycle time in mice and increased the accumulation of Ost in the brain. Furthermore, Tf-Ost-Lip was also found to enhance the effect of Ost on the alleviation of Alzheimer's disease-related pathology. Conclusion: Transferrin-modified liposomes for delivery of Ost has great potential for AD treatment.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Barreira Hematoencefálica/efeitos dos fármacos , Cumarínicos/farmacologia , Lipossomos/farmacologia , Fármacos Neuroprotetores/farmacologia , Doença de Alzheimer/patologia , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Linhagem Celular , Cumarínicos/química , Cumarínicos/farmacocinética , Humanos , Lipossomos/química , Lipossomos/farmacocinética , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Polietilenoglicóis/química , Presenilina-1/genética , Ratos Sprague-Dawley , Distribuição Tecidual , Transferrina/química
10.
Diabetes Res Clin Pract ; 163: 108149, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32304796

RESUMO

AIMS: To assess the role of serum ferritin and transferrin with prevalent and incident type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) and whether these associations are independent of inflammatory markers and hepatic enzymes. METHODS: We analyzed data from 3,232 participants aged 20-81 years of the population-based Study of Health in Pomerania (SHIP) from Northeast Germany with a median follow-up time of 10.6 years. Logistic and Cox regression analyses were performed. RESULTS: Serum ferritin concentrations were associated with a higher prevalence of T2DM (total population OR: 1.16 [95% CI: 1.07, 1.26]; men OR: 1.18 [95% CI: 1.08, 1.30) and MetS (total population OR: 1.27 [95% CI: 1.16, 1.38]; men OR: 1.26 [95% CI: 1.15, 1.38]) in the total population and men independently of inflammatory markers and hepatic enzymes. In longitudinal analyses, baseline ferritin concentrations were associated with a higher risk of incident T2DM in women (HR: 1.38 [95% CI: 1.10, 1.71]), but not in men or in the total population and also with a higher risk of incident MetS (HR: 1.09 [95% CI: 1.01, 1.17]) in the total population. These longitudinal associations attenuated considerably after adjustment for hepatic enzymes but not inflammatory markers. Transferrin was not associated with any of the outcomes. CONCLUSIONS: Our results suggest a link between ferritin and T2DM and MetS, which might be partially explained by hepatic dysfunction.


Assuntos
Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Ferritinas/sangue , Ferro/metabolismo , Síndrome Metabólica/diagnóstico , Transferrina/metabolismo , Adulto , Feminino , Humanos , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos
11.
PLoS One ; 15(4): e0231057, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32240239

RESUMO

OBJECTIVES: Though elevated ferritin level and decreased lung function both predispose people to cardio-metabolic disease, few reports have investigated the association between them. Furthermore, it remains unclear whether the association reflects a change in iron stores or an epiphenomenon reflecting metabolic stress. Therefore, we looked for possible associations between ferritin, iron, and transferrin saturation (TSAT) and lung function to clarify the role of iron-related parameters in healthy men. METHODS: We conducted a cohort study of 42,927 healthy Korean men (mean age: 38.6 years). Percent predicted forced expiratory volume in one second (FEV1%) and forced vital capacity (FVC%) were categorized into quartiles. Adjusted odds ratios (aORs) and 95% confidence intervals (using the highest quartile as reference) were calculated for hyperferritinemia, high iron, and high TSAT after controlling for potential confounders. RESULTS: The median ferritin level was 199.8 (141.5-275.6) ng/mL. The prevalence of hyperferritinemia (defined as >300 ng/mL) was 19.3%. Subjects with hyperferritinemia had lower FEV1% and FVC% than those with normal ferritin level with a slight difference, but those were statistically significant (99.22% vs.99.61% for FEV1%, p = 0.015 and 98.43% vs. 98.87% for FVC, p = 0.001). However, FEV1/FVC ratio was not significantly different between groups (P = 0.797). Compared with the highest quartile, the aORs for hyperferritinemia across decreasing quartiles were 1.081 (1.005-1.163), 1.100 (1.007-1.200), and 1.140 (1.053-1.233) for FEV1% (p for trend = 0.007) and 1.094 (1.018-1.176), 1.101 (1.021-1.188), and 1.150 (1.056-1.252) for FVC% (p for trend = 0.001). However, neither FEV1% nor FVC% was associated with iron or TSAT. CONCLUSIONS: Hyperferritinemia was associated with decreased lung function in healthy Korean men, but iron and TSAT were not. Longitudinal follow-up studies are required to validate our findings.


Assuntos
Ferritinas/sangue , Ferro/sangue , Pulmão/fisiologia , Testes de Função Respiratória , Transferrina/metabolismo , Adulto , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Estudos Transversais , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , República da Coreia
12.
Klin Lab Diagn ; 65(5): 269-274, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32298541

RESUMO

The high frequency of herpes infection in children determines the need to search for new diagnostic markers, evaluate treatment efficacy and predict relapse of the disease. The purpose of the work is to assess the possibility of using biochemical analysis of oral fluid to assess the effectiveness of treatment of children with acute herpetic stomatitis. In the oral fluid and blood plasma of 28 children of patients with acute herpetic stomatitis in the dynamics of the disease, the content of total protein, proteins of the acute phase of inflammation, as well as the concentrations of calcium, magnesium, copper and zinc was determined spectrophotometrically. Oral fluid and blood plasma of 45 practically healthy children were used as a control. In acute herpetic stomatitis, the content of C-reactive protein, orosomucoid, α1-antitrypsin, ceruloplasmin, prealbumin and microalbumin, as well as magnesium, calcium and zinc, increases in the oral fluid of children, but the level of total protein and transferrin decreases. In this blood plasma, the level of ceruloplasmin, orosomucoid, C-reactive protein, α1-antitrypsin is higher, and zinc is lower than in healthy children. The copper content in the oral fluid and blood plasma of children increases with moderate herpetic stomatitis, and significantly decreases with severe herpetic stomatitis. The degree of changes in the content of the proteins of acute phase of inflammation and indicators of mineral metabolism of the oral fluid and blood plasma of children with a herpetic infection of the oral cavity correlates with the severity of the disease. Highly significant correlations were revealed when comparing the concentrations of proteins of the acute phase of inflammation, electrolytes between the oral fluid and the blood plasma of children with acute herpetic stomatitis. After treatment of children with acute herpetic stomatitis, the content of minerals and proteins of the acute phase of inflammation in the oral fluid returned to normal only with a mild disease severity. A method has been developed for evaluating the effectiveness of treatment of children with acute herpetic stomatitis by determining the content of minerals in the oral fluid. The ratio of copper to calcium in the oral fluid of children more than 45 should be considered an indicator of effective treatment of children with herpetic stomatitis.


Assuntos
Saliva/química , Estomatite Herpética/diagnóstico , Estomatite Herpética/terapia , Proteína C-Reativa , Cálcio , Ceruloplasmina , Criança , Cobre , Humanos , Minerais , Orosomucoide , Recidiva , Transferrina , Zinco , alfa 1-Antitripsina
13.
PLoS One ; 15(4): e0232125, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32324809

RESUMO

BACKGROUND: Few cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada. MATERIALS AND METHODS: We evaluated screening observations on women who participated between 2001-2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles. We defined ID using a stringent criterion: combined transferrin saturation <10% and serum ferritin <33.7 pmol/L (<15 µg/L). We compared ID prevalence in women of different race/ethnicity subgrouped by age and determined associations of p.C282Y and p.H63D to ID overall, and to ID in women ages 25-44 y with or without self-reported pregnancy. RESULTS: These 62,685 women included 27,079 whites, 17,272 blacks, 8,566 Hispanics, 7,615 Asians, 449 Pacific Islanders, 441 Native Americans, and 1,263 participants of other race/ethnicity. Proportions of women with ID were higher in Hispanics and blacks than whites and Asians. Prevalence of ID was significantly greater in women ages 25-54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity. In women ages ≥55 y, ID prevalence did not differ significantly across race/ethnicity. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy. CONCLUSIONS: ID prevalence was greater in Hispanic and black than white and Asian women ages 25-54 y. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy.


Assuntos
Anemia Ferropriva/epidemiologia , Grupos Étnicos/classificação , Ferritinas/sangue , Proteína da Hemocromatose/genética , Transferrina/análise , Adulto , Idoso , Anemia Ferropriva/genética , Anemia Ferropriva/metabolismo , Canadá/epidemiologia , Estudos Transversais , Grupos Étnicos/genética , Feminino , Humanos , Pessoa de Meia-Idade , Mutação , Prevalência , Estados Unidos/epidemiologia
14.
Proc Natl Acad Sci U S A ; 117(13): 7317-7325, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-32188787

RESUMO

Iron sequestration is a recognized innate immune mechanism against invading pathogens mediated by iron-binding proteins called transferrins. Despite many studies on antimicrobial activity of transferrins in vitro, their specific in vivo functions are poorly understood. Here we use Drosophila melanogaster as an in vivo model to investigate the role of transferrins in host defense. We find that systemic infections with a variety of pathogens trigger a hypoferremic response in flies, namely, iron withdrawal from the hemolymph and accumulation in the fat body. Notably, this hypoferremia to infection requires Drosophila nuclear factor κB (NF-κB) immune pathways, Toll and Imd, revealing that these pathways also mediate nutritional immunity in flies. Next, we show that the iron transporter Tsf1 is induced by infections downstream of the Toll and Imd pathways and is necessary for iron relocation from the hemolymph to the fat body. Consistent with elevated iron levels in the hemolymph, Tsf1 mutants exhibited increased susceptibility to Pseudomonas bacteria and Mucorales fungi, which could be rescued by chemical chelation of iron. Furthermore, using siderophore-deficient Pseudomonas aeruginosa, we discover that the siderophore pyoverdine is necessary for pathogenesis in wild-type flies, but it becomes dispensable in Tsf1 mutants due to excessive iron present in the hemolymph of these flies. As such, our study reveals that, similar to mammals, Drosophila uses iron limitation as an immune defense mechanism mediated by conserved iron-transporting proteins transferrins. Our in vivo work, together with accumulating in vitro studies, supports the immune role of insect transferrins against infections via an iron withholding strategy.


Assuntos
Proteínas de Drosophila/metabolismo , Ferro/metabolismo , Transferrina/metabolismo , Animais , Proteínas de Drosophila/imunologia , Drosophila melanogaster , Hemolinfa/imunologia , Hemolinfa/metabolismo , Imunidade Inata , Ferro/imunologia , NF-kappa B/metabolismo , Pseudomonas aeruginosa/metabolismo , Sideróforos/metabolismo , Transferrina/imunologia
15.
Nat Commun ; 11(1): 1262, 2020 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-32152269

RESUMO

Binding of biomolecules to crystal surfaces is critical for effective biological applications of crystalline nanomaterials. Here, we present the modulation of exposed crystal facets as a feasible approach to enhance specific nanocrystal-biomolecule associations for improving cellular targeting and nanomaterial uptake. We demonstrate that facet-engineering significantly enhances transferrin binding to cadmium chalcogenide nanocrystals and their subsequent delivery into cancer cells, mediated by transferrin receptors, in a complex biological matrix. Competitive adsorption experiments coupled with theoretical calculations reveal that the (100) facet of cadmoselite and (002) facet of greenockite preferentially bind with transferrin via inner-sphere thiol complexation. Molecular dynamics simulation infers that facet-dependent transferrin binding is also induced by the differential affinity of crystal facets to water molecules in the first solvation shell, which affects access to exposed facets. Overall, this research underlines the promise of facet engineering to improve the efficacy of crystalline nanomaterials in biological applications.


Assuntos
Proteínas de Transporte/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Transferrina/química , Adsorção , Fenômenos Biofísicos , Cádmio/química , Células HeLa , Humanos , Simulação de Dinâmica Molecular , Tamanho da Partícula , Receptores da Transferrina , Propriedades de Superfície , Difração de Raios X
16.
Oral Dis ; 26(3): 677-687, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31916654

RESUMO

OBJECTIVE: The purpose of the present study was to characterize the composition of the salivary microbiota and quantify salivary levels of inflammation-related proteins (neutrophil gelatinase-associated lipocalin [NGAL] and transferrin) in patients with psoriasis and compare data to those obtained in patients with periodontitis and orally healthy controls, respectively. MATERIALS AND METHODS: Stimulated saliva samples from patients with psoriasis (n = 27), patients with periodontitis (n = 58), and orally healthy controls (n = 52) were characterized by means of next-generation sequencing of the 16S rRNA gene. Salivary levels of NGAL and transferrin were quantified using immunoassays. RESULTS: Linear discriminant effect size analysis showed that 52 (22 psoriasis-associated and 30 periodontitis-associated) and 21 (8 psoriasis-associated and 13 orally healthy control-associated) bacterial taxa differentiated the salivary microbiota in patients with psoriasis from that of patients with periodontitis and orally healthy controls, respectively. Significantly lower mean salivary levels of NGAL (psoriasis: 996 [std. error 320], periodontitis: 2,072 [295], orally healthy controls: 2,551 [345] ng/ml, p < .0001) and transferrin (psoriasis: 4.37 [0.92], periodontitis: 7.25 [0.88], orally healthy controls: 10.02 [0.94] ng/ml, p < .0001) were identified in patients with psoriasis. CONCLUSIONS: Psoriasis associates with characteristics of the salivary microbiota and salivary levels of inflammation-related proteins, which are different from characteristics in patients with periodontitis and orally healthy controls, respectively.


Assuntos
Microbiota , Periodontite , Psoríase/microbiologia , Saliva/microbiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Inflamação , Lipocalina-2/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S , Transferrina/metabolismo
17.
18.
Nat Commun ; 11(1): 473, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980600

RESUMO

A variant at amino acid 47 in human TP53 exists predominantly in individuals of African descent. P47S human and mouse cells show increased cancer risk due to defective ferroptosis. Here, we show that this ferroptotic defect causes iron accumulation in P47S macrophages. This high iron content alters macrophage cytokine profiles, leads to higher arginase level and activity, and decreased nitric oxide synthase activity. This leads to more productive intracellular bacterial infections but is protective against malarial toxin hemozoin. Proteomics of macrophages reveal decreased liver X receptor (LXR) activation, inflammation and antibacterial defense in P47S macrophages. Both iron chelators and LXR agonists improve the response of P47S mice to bacterial infection. African Americans with elevated saturated transferrin and serum ferritin show higher prevalence of the P47S variant (OR = 1.68 (95%CI 1.07-2.65) p = 0.023), suggestive of its role in iron accumulation in humans. This altered macrophage phenotype may confer an advantage in malaria-endemic sub-Saharan Africa.


Assuntos
Ferro/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , África ao Sul do Saara , Afro-Americanos/genética , Animais , Infecções Bacterianas/etiologia , Infecções Bacterianas/genética , Infecções Bacterianas/metabolismo , Ferritinas/sangue , Ferroptose/efeitos dos fármacos , Ferroptose/genética , Ferroptose/fisiologia , Variação Genética , Hemeproteínas/toxicidade , Humanos , Listeriose/etiologia , Receptores X do Fígado/agonistas , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Malária/genética , Malária/metabolismo , Camundongos , Camundongos Transgênicos , Transferrina/metabolismo
19.
J Surg Oncol ; 121(5): 814-822, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31898327

RESUMO

INTRODUCTION: Considering the high morbimortality rate in oncologic surgeries of the gastrointestinal tract, especially in patients with malnutrition, the use of predictive tools is necessary, since preoperative strategies could improve postoperative outcomes. OBJECTIVES: To evaluate body composition by computed tomography and its association with morbimortality post esophagectomy and total gastrectomy. METHODS: Prospective cohort study (n = 80). Sociodemographic, diagnostic, treatment and postoperative data were collected. Anthropometric and biochemical (hemoglobin, transferrin, and albumin) data were evaluated. The muscle mass was calculated through two methods, the muscle mass index (MMI) and the psoas total area (PTA). For postoperative complications classification, the Clavien-Dindo scale was used. RESULTS: The prevalence of muscle depletion found was 33.8% by MMI and 61% by PTA (poor agreement, kappa = 0.25). Complication rates were 18.5% in gastrectomies and 50% in esophagectomies. No statistically significant difference was found between the presence of muscle depletion and complications. However, when stratified by surgery, a borderline association was found between the MMI and post esophagectomies complications (P = .05). CONCLUSION: Despite the high prevalence of muscle loss, it was not possible to correlate it with surgical outcomes for gastrectomies, but for esophagectomies, there may be relevance due to borderline association, although patients received nutritional therapy.


Assuntos
Composição Corporal , Esofagectomia/efeitos adversos , Gastrectomia/efeitos adversos , Sarcopenia/diagnóstico por imagem , Estudos de Coortes , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Complicações Pós-Operatórias , Prognóstico , Albumina Sérica , Tomografia Computadorizada por Raios X , Transferrina/análise
20.
J Biomed Nanotechnol ; 16(1): 85-100, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31996288

RESUMO

Plumbagin, a natural naphthoquinone from the officinal leadwort, has recently been shown to exert promising anti-cancer effects. However, its therapeutic use is hampered by its failure to specifically reach tumors after intravenous administration, without secondary effects on normal tissues. Its poor solubility in water and rapid elimination following in vivo administration further limit its potential use. We hypothesize that the entrapment of plumbagin within PEGylated PLGA nanoparticles conjugated with transferrin, whose receptors are overexpressed on many types of cancer cells, could lead to a selective delivery of the drug to tumors following intravenous administration and enhance its chemotherapeutic effects. The objectives of this study were therefore to prepare and characterize transferrin-conjugated, PEGylated PLGA nanoparticles entrapping plumbagin, and to assess their anti-cancer efficacy in vitro as well as in tumor-bearing mice. The intravenous administration of transferrin-conjugated PEGylated PLGA nanoparticles resulted in the complete suppression of 10% of B16-F10 tumors and regression of 30% of the tumors, with improvement of the animal survival compared to controls. The treatment was well tolerated by the animals. Transferrin-bearing PEGylated PLGA nanoparticles entrapping plumbagin are therefore highly promising therapeutic systems, able to lead to tumor regression and even suppression after intravenous administration without visible toxicity.


Assuntos
Nanopartículas , Animais , Linhagem Celular Tumoral , Camundongos , Naftoquinonas , Transferrina
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