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1.
Vet Sci ; 10(2)2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36851425

RESUMO

Red blood cell (RBC) transfusion is associated with recipient inflammation and infection, which may be triggered by excessive circulating iron. Iron chelation following transfusion may reduce these risks. The aim of this study was to evaluate the effect of deferoxamine on circulating iron and inflammation biomarkers over time and in vitro growth of Escherichia coli (E. coli) following RBC transfusion in dogs with atraumatic hemorrhage. Anesthetized dogs were subject to atraumatic hemorrhage and transfusion of RBCs, then randomized to receive either deferoxamine or saline placebo of equivalent volume (n = 10 per group) in a blinded fashion. Blood was sampled before hemorrhage and then 2, 4, and 6 h later. Following hemorrhage and RBC transfusion, free iron increased in all dogs over time (both p < 0.001). Inflammation biomarkers interleukin-6 (IL6), CXC motif chemokine-8 (CXCL8), interleukin-10 (IL10), and keratinocyte-derived chemokine (KC) increased in all dogs over time (all p < 0.001). Logarithmic growth of E. coli clones within blood collected 6 h post-transfusion was not different between groups. Only total iron-binding capacity was different between groups over time, being significantly increased in the deferoxamine group at 2 and 4 h post-transfusion (both p < 0.001). In summary, while free iron and inflammation biomarkers increased post-RBC transfusion, deferoxamine administration did not impact circulating free iron, inflammation biomarkers, or in vitro growth of E. coli when compared with placebo.

2.
Sci Rep ; 12(1): 1199, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-35075227

RESUMO

Kidney iron deposition may play a role in the progression of tubulointerstitial injury during chronic kidney disease. Here, we studied the molecular mechanisms of kidney iron loading in experimental focal segmental glomerulosclerosis (FSGS) and investigated the effect of iron-reducing interventions on disease progression. Thy-1.1 mice were injected with anti-Thy-1.1 monoclonal antibody (mAb) to induce proteinuria. Urine, blood and tissue were collected at day (D)1, D5, D8, D15 and D22 after mAb injection. Thy-1.1 mice were subjected to captopril (CA), iron-deficient (ID) diet or iron chelation (deferoxamine; DFO). MAb injection resulted in significant albuminuria at all time points (p < 0.01). Kidney iron loading, predominantly in distal tubules, increased in time, along with urinary kidney injury molecule-1 and 24p3 concentration, as well as kidney mRNA expression of Interleukin-6 (Il-6) and Heme oxygenase-1 (Ho-1). Treatment with CA, ID diet or DFO significantly reduced kidney iron deposition at D8 and D22 (p < 0.001) and fibrosis at D22 (p < 0.05), but not kidney Il-6. ID treatment increased kidney Ho-1 (p < 0.001). In conclusion, kidney iron accumulation coincides with progression of tubulointerstitial injury in this model of FSGS. Reduction of iron loading halts disease progression. However, targeted approaches to prevent excessive kidney iron loading are warranted to maintain the delicate systemic and cellular iron balance.


Assuntos
Glomerulosclerose Segmentar e Focal/metabolismo , Ferro/metabolismo , Túbulos Renais Distais/metabolismo , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Captopril/uso terapêutico , Desferroxamina/uso terapêutico , Modelos Animais de Doenças , Feminino , Glomerulosclerose Segmentar e Focal/dietoterapia , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Masculino , Camundongos , Receptores de Superfície Celular/metabolismo , Sideróforos/uso terapêutico
3.
Am J Physiol Renal Physiol ; 316(3): F606-F614, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30623722

RESUMO

In physiological conditions, circulating iron can be filtered by the glomerulus and is almost completely reabsorbed by the tubular epithelium to prevent urinary iron wasting. Increased urinary iron concentrations have been associated with renal injury. However, it is not clear whether increased urinary iron concentrations in patients are the result of increased glomerular iron filtration and/or insufficient tubular iron reabsorption and if these processes contribute to renal injury. We measured plasma and urine iron parameters and urinary tubular injury markers in healthy human subjects ( n = 20), patients with systemic iron overload ( n = 20), and patients with renal tubular dysfunction ( n = 18). Urinary iron excretion parameters were increased in both patients with systemic iron overload and tubular dysfunction, whereas plasma iron parameters were only increased in patients with systemic iron overload. In patients with systemic iron overload, increased urinary iron levels were associated with elevated circulating iron, as indicated by transferrin saturation (TSAT), and increased body iron, as suggested by plasma ferritin concentrations. In patients with tubular dysfunction, enhanced urinary iron and transferrin excretion were associated with distal tubular injury as indicated by increased urinary glutathione S-transferase pi 1-1 (GSTP1-1) excretion. In systemic iron overload, elevated urinary iron and transferrin levels were associated with increased injury to proximal tubules, indicated by increased urinary kidney injury marker 1 (KIM-1) excretion. Our explorative study demonstrates that both glomerular filtration of elevated plasma iron levels and insufficient tubular iron reabsorption could increase urinary iron excretion and cause renal injury.


Assuntos
Taxa de Filtração Glomerular/fisiologia , Sobrecarga de Ferro/metabolismo , Ferro/urina , Rim/metabolismo , Adulto , Feminino , Humanos , Sobrecarga de Ferro/urina , Rim/fisiopatologia , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/fisiopatologia , Masculino
4.
Ned Tijdschr Geneeskd ; 154: A1038, 2010.
Artigo em Holandês | MEDLINE | ID: mdl-20719010

RESUMO

A 36-year old female patient who had had iron deficiency anaemia since her childhood showed no clear response to oral iron treatment. Elevated serum hepcidin levels were found after excluding other causes of iron deficiency. This is in contrast to what is expected in iron deficiency anaemia and indicates a primary defect in hepcidin regulation. Indeed, in the search for a defect in genes coding for hepcidin-regulating proteins the patient was found to be compound heterozygous for two different mutations in the TMPRSS6 gene. This leads to a dysfunctional matriptase-2 protein for which the gene codes. Consequently, liver cells cannot inhibit hepcidin production in the presence of low serum iron levels. High hepcidin levels result in less iron being absorbed from the bowel than is necessary for erythropoiesis. Therefore, patients with matriptase-2 deficiency respond poorly to oral iron treatment and have to be treated with intravenous iron.


Assuntos
Anemia Ferropriva/enzimologia , Anemia Ferropriva/genética , Peptídeos Catiônicos Antimicrobianos/sangue , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Adulto , Anemia Ferropriva/tratamento farmacológico , Feminino , Hepcidinas , Humanos , Ferro/uso terapêutico , Mutação/genética , Linhagem , Falha de Tratamento
5.
J Cell Mol Med ; 13(9B): 3091-102, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18774956

RESUMO

Heme oxygenase-1 (HO-1) contribution to iron homeostasis has been postulated, because it facilitates iron recycling by liberating iron mostly from heme catabolism. This enzyme also appears to be responsible for the resolution of inflammatory conditions. In a patient with HO-1 deficiency, inflammation and dysregulation of body iron homeostasis, including anemia and liver and kidney hemosiderosis, are evidenced. Here we postulated that HO-1 is critical in the regulation of ferroportin, the major cellular iron exporter, and hepcidin, the key regulator of iron homeostasis central in the pathogenesis of anemia of inflammation. Our current experiments in human THP-1 monocytic cells indicate a HO-1-induced iron-mediated surface-ferroportin expression, consistent with the role of HO-1 in iron recycling. Surprisingly, we observed low hepcidin levels in the HO-1-deficient patient, despite the presence of inflammation and hemosiderosis, both inducers of hepcidin. Instead, we observed highly increased soluble transferrin receptor levels. This suggests that the decreased hepcidin levels in HO-1 deficiency reflect the increased need for iron in the bone marrow due to the anaemia. Using human hepatoma cells, we demonstrate that HO-activity did not have a direct modulating effect on expression of HAMP, the gene that encodes for hepcidin. Therefore, we argue that the decreased iron recycling may, in part, have contributed to the low hepcidin levels. These findings indicate that dysregulation of iron homeostasis in HO-1 deficiency is the result of both defective iron recycling and erythroid activity-associated inhibition of hepcidin expression. This study therefore shows a crucial role for HO-1 in maintaining body iron balance.


Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Heme Oxigenase-1/deficiência , Ferro/metabolismo , Monócitos/metabolismo , Anemia/patologia , Animais , Peptídeos Catiônicos Antimicrobianos/metabolismo , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Sobrevivência Celular , Fluoresceínas/metabolismo , Hepcidinas , Humanos , Inflamação , Ferro/química , Rim/patologia , Fígado/patologia , Camundongos
7.
Clin Chem ; 50(11): 1986-93, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15364883

RESUMO

BACKGROUND: Results in previous qualitative studies of the association of the apoptosis inhibitor survivin with prognosis of breast cancer patients have been contradictory. METHODS: Survivin mRNA was measured by quantitative TaqMan reverse transcription-PCR in 275 breast cancer tissues from patients with operable tumors and was correlated with established clinicopathologic factors, relapse-free survival [(RFS); 102 events], and overall survival [(OS); 81 events]. RESULTS: High survivin mRNA concentrations were found mainly in tissues from younger patients and in high-grade cancer tissues. High survivin concentrations were most strongly associated with estrogen receptor- or progesterone receptor-negative tumors. In univariate Cox regression analysis for RFS, survivin concentrations were significantly associated with poor prognosis with a hazard ratio (HR) of 1.99 (95% confidence interval, 1.31-3.02; P = 0.001) for every 10-fold increase in expression. For OS, a significant contribution of survivin to poor prognosis was found with a HR of 2.76 (1.67-4.55; P <0.001). Multivariate analyses were performed including established clinicopathologic factors. For RFS, age (P = 0.027), nodal category (P <0.001), and survivin [HR = 1.78 (1.18-2.68); P = 0.006] contributed significantly to the model. For OS, only nodal category (P <0.001) and survivin [HR = 3.05 (1.83-5.10); P <0.001] were significant. CONCLUSION: Survivin demonstrates a strong, independent, association with poor prognosis. Survivin might be used as a new marker to stratify breast cancer patients for more optimal treatment modalities, or it could be a promising new target for therapy.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Proteínas Associadas aos Microtúbulos/análise , Intervalo Livre de Doença , Feminino , Humanos , Proteínas Inibidoras de Apoptose , Proteínas Associadas aos Microtúbulos/genética , Análise Multivariada , Proteínas de Neoplasias , RNA Mensageiro/análise , Análise de Regressão , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Medição de Risco , Taxa de Sobrevida , Survivina
8.
Hum Mutat ; 19(5): 554-9, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11968088

RESUMO

Novel fluorescent oligonucleotides that contain a 3' minor groove binding group (MGB) hybridize to single-stranded targets with increased sequence-specificity compared to ordinary DNA probes. This reduces non-specific probe hybridization and results in low background fluorescence during the 5' nuclease PCR assay (TaqMan, Applied Biosystems, Foster City, CA). We developed a method for closed-tube genotyping using two allele-specific MGB probes labeled with different fluorophores in one reaction. After PCR, tubes were transported to a fluorescence plate-reader for analysis of fluorescence. Common spreadsheet software was used for automated genotype assignment. As an example, DNA samples from 172 hemochromatosis patients were selected and tested for molecular defects in the HFE gene, i.e., mutations in codon 63 and 282. Tight genotype clusters were observed for both codons and results with MGB probes were identical to conventional genotyping (PCR + restriction-fragment-length-polymorphism). We show that this fast and easy method can be used for large-scale (high-throughput) genetic studies but also for routine molecular diagnostics without post-PCR manipulation of amplicons or the need for real-time quantitative PCR machines. Hum Mutat 19:554-559, 2002.


Assuntos
DNA de Cadeia Simples/metabolismo , Proteínas de Membrana , Sondas de Oligonucleotídeos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Alelos , Códon/genética , Análise Mutacional de DNA/métodos , DNA de Cadeia Simples/isolamento & purificação , Genes MHC Classe I/genética , Genótipo , Antígenos HLA/genética , Hemocromatose/genética , Proteína da Hemocromatose , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Pessoa de Meia-Idade , Conformação de Ácido Nucleico , Hibridização de Ácido Nucleico/métodos , Sondas de Oligonucleotídeos/isolamento & purificação , Fosfatos Açúcares/química , Fosfatos Açúcares/metabolismo
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