Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 14 de 14
Filtrar
1.
Cytokine ; 91: 38-43, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27997859

RESUMO

Neutrophil gelatinase-associated lipocalin (NGAL) is increasingly regarded as a biomarker of acute kidney injury, or kidney injury in general, but the stimuli responsible for its production are incompletely understood. This study tested the relationship between the pro-inflammatory cytokine interleukin-1ß (IL-1ß) and both circulating and renal NGAL, using chronic subcutaneous infusion of IL-1ß in mice and tissue culture of renal cell lines. Following a 14-day subcutaneous infusion of vehicle or IL-1ß (10ng/h) in male C57Bl/6 mice, a striking positive correlation (r2=0.94; P<0.01) was observed between plasma IL-1ß and NGAL concentrations. NGAL was markedly increased in the kidneys of IL-1ß-infused mice compared with vehicle-treated mice, both at the protein and mRNA level, indicating increased local as well as systemic production of NGAL. Immunohistochemical staining revealed prominent increases of NGAL in the proximal tubular epithelium of IL-1ß infused mice. These effects occurred in the absence of overt renal injury, with plasma creatinine concentration not significantly different between groups. Further showing that IL-1ß has a direct effect on NGAL production by tubular epithelial cells, exposure of a proximal tubular cell line (HK-2 cells) and a cortical collecting duct principal cell line (mpkCCD cells) to IL-1ß for 24h produced a significant increase of NGAL mRNA levels (>30-fold). These data indicate IL-1ß serves as a powerful stimulus for renal production of NGAL.


Assuntos
Injúria Renal Aguda/imunologia , Interleucina-1beta/imunologia , Túbulos Renais Proximais/imunologia , Lipocalina-2/imunologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Linhagem Celular Transformada , Humanos , Túbulos Renais Proximais/patologia , Camundongos
2.
Am J Physiol Renal Physiol ; 309(4): F305-17, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26062878

RESUMO

While there is evidence that sex hormones influence multiple systems involved in salt and water homeostasis, the question of whether sex hormones regulate aquaporin-2 (AQP2) and thus water handling by the collecting duct has been largely ignored. Accordingly, the present study investigated AQP2 expression, localization and renal water handling in intact and ovariectomized (OVX) female rats, with and without estradiol or progesterone replacement. OVX resulted in a significant increase in urine osmolality and increase in p256-AQP2 in the renal cortex at 7 days post-OVX, as well as induced body weight changes. Relative to OVX alone, estradiol repletion produced a significant increase in urine output, normalized urinary osmolality and reduced both total AQP2 (protein and mRNA) and p256-AQP2 expression, whereas progesterone repletion had little effect. Direct effects of estradiol on AQP2 mRNA and protein levels were further tested in vitro using the mpkCCD principal cell line. Estradiol treatment of mpkCCD cells reduced AQP2 at both the mRNA and protein level in the absence of deamino-8-d-AVP (dDAVP) and significantly blunted the dDAVP-induced increase in AQP2 at the protein level only. We determined that mpkCCD and native mouse collecting ducts express both estrogen receptor (ER)α and ERß and that female mice lacking ERα displayed significant increases in AQP2 protein compared with wild-type littermates, implicating ERα in mediating the inhibitory effect of estradiol on AQP2 expression. These findings suggest that changes in estradiol levels, such as during menopause or following reproductive surgeries, may contribute to dysregulation of water homeostasis in women.


Assuntos
Aquaporina 2/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios , Túbulos Renais Coletores/efeitos dos fármacos , Osmorregulação/efeitos dos fármacos , Animais , Aquaporina 2/genética , Linhagem Celular , Regulação para Baixo , Ingestão de Líquidos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Receptor alfa de Estrogênio/deficiência , Receptor alfa de Estrogênio/genética , Feminino , Túbulos Renais Coletores/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Concentração Osmolar , Ovariectomia , Fosforilação , Progesterona/farmacologia , Transporte Proteico , RNA Mensageiro/metabolismo , Ratos Wistar , Fatores de Tempo , Micção/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacos
3.
Neurobiol Dis ; 71: 34-42, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25014023

RESUMO

Disruption of redox homeostasis is a prominent feature in the pathogenesis of Huntington's disease (HD). Selenium an essential element nutrient that modulates redox pathways and has been reported to provide protection against both acute neurotoxicity (e.g. methamphetamine) and chronic neurodegeneration (e.g. tauopathy) in mice. The objective of our study was to investigate the effect of sodium selenite, an inorganic form of selenium, on behavioral, brain degeneration and biochemical outcomes in the N171-82Q Huntington's disease mouse model. HD mice, which were supplemented with sodium selenite from 6 to 14 weeks of age, demonstrated increased motor endurance, decreased loss of brain weight, decreased mutant huntingtin aggregate burden and decreased brain oxidized glutathione levels. Biochemical studies revealed that selenite treatment reverted HD-associated changes in liver selenium and plasma glutathione in N171-82Q mice and had effects on brain selenoprotein transcript expression. Further, we found decreased brain selenium content in human autopsy brain. Taken together, we demonstrate a decreased selenium phenotype in human and mouse HD and additionally show some protective effects of selenite in N171-82Q HD mice. Modification of selenium metabolism results in beneficial effects in mouse HD and thus may represent a therapeutic strategy.


Assuntos
Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Proteínas do Tecido Nervoso/genética , Fármacos Neuroprotetores/uso terapêutico , Ácido Selenioso/uso terapêutico , Selênio/sangue , Expansão das Repetições de Trinucleotídeos/genética , Adulto , Animais , Modelos Animais de Doenças , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Feminino , Humanos , Proteína Huntingtina , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Análise de Sobrevida , Fatores de Tempo
4.
Hum Mol Genet ; 21(12): 2768-78, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22422767

RESUMO

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that has an extracellular bilobed venus flytrap domain (VFTD) predicted to contain five calcium (Ca(2+))-binding sites. To elucidate the structure-function relationships of the VFTD, we investigated 294 unrelated probands with familial hypocalciuric hypercalcaemia (FHH), neonatal severe primary hyperparathyroidism (NSHPT) or autosomal dominant hypocalcaemic hypercalciuria (ADHH) for CaSR mutations and performed in vitro functional expression studies and three-dimensional modelling of mutations involving the VFTD. A total of 70 different CaSR mutations were identified: 35 in FHH, 10 in NSHPT and 25 in ADHH patients. Furthermore, a CaSR variant (Glu250Lys) was identified in FHH and ADHH probands and demonstrated to represent a functionally neutral polymorphism. NSHPT was associated with a large proportion of truncating CaSR mutations that occurred in the homozygous or compound heterozygous state. Thirty-four VFTD missense mutations were identified, and 18 mutations were located within 10 Å of one or more of the predicted Ca(2+)-binding sites, particularly at the VFTD cleft, which is the principal site of Ca(2+) binding. Mutations of residues 173 and 221, which are located at the entrance to the VFTD cleft binding site, were associated with both receptor activation (Leu173Phe and Pro221Leu) and inactivation (Leu173Pro and Pro221Gln), thereby highlighting the importance of these residues for entry and binding of Ca(2+) by the CaSR. Thus, these studies of disease-associated CaSR mutations have further elucidated the role of the VFTD cleft region in Ca(2+) binding and the function of the CaSR.


Assuntos
Hipercalcemia/genética , Hipocalcemia/genética , Mutação , Receptores de Detecção de Cálcio/genética , Sítios de Ligação/genética , Cálcio/química , Cálcio/metabolismo , Genótipo , Células HEK293 , Humanos , Hiperparatireoidismo , Recém-Nascido , Modelos Moleculares , Taxa de Mutação , Mutação de Sentido Incorreto , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores de Detecção de Cálcio/química , Receptores de Detecção de Cálcio/metabolismo
5.
Ann Clin Biochem ; 58(5): 528-536, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34096326

RESUMO

BACKGROUND: Measurement of procollagen type I N-terminal propeptide (PINP) concentration in serum reflects the rate of type I collagen synthesis and can therefore be used as a bone formation marker. There are two methods of PINP quantification; the first measures the trimeric propeptide (intact PINP) and the second measures both the trimeric and monomeric propeptides (total PINP). Trimeric PINP is excreted via hepatic endothelial cells, whereas monomeric PINP is cleared renally. Therefore, in renal failure, the total assay has a positive bias with respect to the intact assay, due to monomeric PINP accumulation. The aim of this study was to compare the performance of both assays across all stages of chronic kidney disease. METHODS: Serum was taken from male (n = 111) and female (n = 105) patients attending a metabolic bone clinic, and these were partitioned into stages of chronic kidney disease 1-5. Each serum sample was analysed using the Roche electrochemiluminescence immunoassay for total PINP and the Immunodiagnostic Systems chemiluminescence immunoassay for intact PINP. RESULTS: Passing-Bablok regression analysis comparing both methods showed that with advancing chronic kidney disease there was a proportional positive bias affecting the total assay when compared with the intact assay. This proportional positive bias was statistically significant for chronic kidney disease stages 3b, 4 and 5. CONCLUSIONS: Based on this method comparison study, usage of the total PINP assay should be avoided in chronic kidney disease stages 3b, 4 and 5 (eGFR ≤44 mL/min/1.73 m2) and instead an intact assay used as the total assay overestimates PINP concentrations due to monomeric PINP accumulation.


Assuntos
Osteogênese , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue , Insuficiência Renal Crônica/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
Lipids Health Dis ; 6: 26, 2007 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-17908332

RESUMO

UNLABELLED: Lipoprotein(a) is an independent risk factor for Ischaemic Heart Disease (IHD) in the general population. There are conflicting reports in the extent of its association with IHD among subjects with Type 2 diabetes mellitus (T2DM). The aim was to determine the concentration of Lp(a) and its relationship with other lipids parameters among Omani T2DM subjects with and without IHD. An over-night fasting blood sample from 221 T2DM subjects (86 females and 135 males) and 156 non-diabetics (69 females and 87 males) aged 30-70 years (as control) was taken for lipid profile studies. RESULTS: Lp(a) was significantly lower (p = 0.012) among T2DM subjects 0.123(1.12) g/L compared to non-diabetics 0.246 (1.18)g/L, irrespective of gender.A significant correlation (Spearman correlation, P = 0.047) was revealed between Lp(a) and IHD among Omani T2DM subjects. The proportions of T2DM subjects with IHD and an Lp(a) >0.3 g/L was higher compared to T2DM without IHD irrespective of gender, for women 42% vs. 27% and for men 17.5 vs. 8%, respectively.A significant negative correlation existed between Lp(a) and triglycerides (r = 0.41, P = 0.002) among T2DM subjects. In contrast, a significant positive correlation existed between Lp(a) and LDL-chol among the non-diabetic subjects. Women had significantly higher Lp(a) concentration compared to men ( 0.30 Vs. 0.16 g/L, P < 0.0001) irrespective of the diabetic status. CONCLUSION: Lp(a) is an independent risk factor for IHD among Omani T2DM subjects. Lp(a) concentration was significantly lower and negatively correlated with triglycerides among Omani diabetic compared to non-diabetic subjects.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Lipoproteína(a)/sangue , Isquemia Miocárdica/sangue , Triglicerídeos/sangue , Adulto , Idoso , Estudos de Casos e Controles , Interpretação Estatística de Dados , Diabetes Mellitus Tipo 2/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/etiologia , Fatores de Risco
7.
Lipids Health Dis ; 6: 19, 2007 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-17683612

RESUMO

BACKGROUND: ApolipoproteinA1 (apoA1) is the major apoprotein constituent of high-density-lipoprotein(HDL). The relationship of apoA1 -75 bp(M1-) allele polymorphism with lipoprotein phenotype and cardiovascular disease (CVD) remain unclear. Overnight fasting blood samples were collected from a cohort of high-risk Omani population, 90 non-diabetic subjects and 149 type 2 diabetes mellitus (T2DM) subjects for genotype and phenotype studies. RESULTS: The M1+ and M1- alleles frequencies were 0.808 and 0.192 for M1+ and M1-, respectively, comparable to the frequency of apoA1 (M1+ and M1-) amongst a healthy Omani population, 0.788 and 0.212, respectively. The frequencies of the hetero- and homozygous subjects for the MspI polymorphism at -75 (M1-) of the apoA1 gene were in Hardy-Weinberg equilibrium. The mean Lp(a) concentration was significantly higher(P = 0.02) in subjects carrying M1- allele compared to M1+ allele of the APOA1 gene with an odd ratio of 2.3(95% CI, 1.13-14.3), irrespective of gender and the diabetic status. CONCLUSION: ApolipoproteinA1-75 G/A (M1-) polymorphism is relatively common and is positively associated with Lp(a) and therefore, may confer a potential risk for cardiovascular disease (CVD).


Assuntos
Apolipoproteína A-I/genética , Aterosclerose/genética , Lipoproteína(a)/genética , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Adenina , Apolipoproteína A-I/sangue , Frequência do Gene , Triagem de Portadores Genéticos , Predisposição Genética para Doença , Genótipo , Guanina , Homozigoto , Humanos , Lipoproteína(a)/sangue , Regiões Promotoras Genéticas , Fatores de Risco , Triglicerídeos/sangue
8.
Nutr Rev ; 75(6): 456-470, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28505363

RESUMO

Context: Accumulation of brain iron is linked to aging and protein-misfolding neurodegenerative diseases. High iron intake may influence important brain health outcomes in later life. Objective: The aim of this systematic review was to examine evidence from animal and human studies of the effects of high iron intake or peripheral iron status on adult cognition, brain aging, and neurodegeneration. Data Sources: MEDLINE, Scopus, CAB Abstracts, the Cochrane Central Register of Clinical Trials, and OpenGrey databases were searched. Study Selection: Studies investigating the effect of elevated iron intake at all postnatal life stages in mammalian models and humans on measures of adult brain health were included. Data Extraction: Data were extracted and evaluated by two authors independently, with discrepancies resolved by discussion. Neurodegenerative disease diagnosis and/or behavioral/cognitive, biochemical, and brain morphologic findings were used to study the effects of iron intake or peripheral iron status on brain health. Risk of bias was assessed for animal and human studies. PRISMA guidelines for reporting systematic reviews were followed. Results: Thirty-four preclinical and 14 clinical studies were identified from database searches. Thirty-three preclinical studies provided evidence supporting an adverse effect of nutritionally relevant high iron intake in neonates on brain-health-related outcomes in adults. Human studies varied considerably in design, quality, and findings; none investigated the effects of high iron intake in neonates/infants. Conclusions: Human studies are needed to verify whether dietary iron intake levels used in neonates/infants to prevent iron deficiency have effects on brain aging and neurodegenerative disease outcomes.


Assuntos
Envelhecimento/efeitos dos fármacos , Cognição/efeitos dos fármacos , Ferro da Dieta/administração & dosagem , Ferro da Dieta/efeitos adversos , Anemia Ferropriva/sangue , Anemia Ferropriva/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Bases de Dados Factuais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Ferro/sangue , Deficiências de Ferro , Metanálise como Assunto , Estado Nutricional , Estudos Observacionais como Assunto , Viés de Publicação , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco
9.
Sci Rep ; 7(1): 12821, 2017 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-28993663

RESUMO

Proteins involved in iron homeostasis have been identified as biomarkers for lupus nephritis, a serious complication of systemic lupus erythematosus (SLE). We tested the hypothesis that renal iron accumulation occurs and contributes to renal injury in SLE. Renal non-heme iron levels were increased in the (New Zealand Black x New Zealand White) F1 (NZB/W) mouse model of lupus nephritis compared with healthy New Zealand White (NZW) mice in an age- and strain-dependent manner. Biodistribution studies revealed increased transferrin-bound iron accumulation in the kidneys of albuminuric NZB/W mice, but no difference in the accumulation of non-transferrin bound iron or ferritin. Transferrin excretion was significantly increased in albuminuric NZB/W mice, indicating enhanced tubular exposure and potential for enhanced tubular uptake following filtration. Expression of transferrin receptor and 24p3R were reduced in tubules from NZB/W compared to NZW mice, while ferroportin expression was unchanged and ferritin expression increased, consistent with increased iron accumulation and compensatory downregulation of uptake pathways. Treatment of NZB/W mice with the iron chelator deferiprone significantly delayed the onset of albuminuria and reduced blood urea nitrogen concentrations. Together, these findings suggest that pathological changes in renal iron homeostasis occurs in lupus nephritis, contributing to the development of kidney injury.


Assuntos
Albuminúria/metabolismo , Quelantes de Ferro/farmacologia , Ferro/metabolismo , Rim/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Albuminúria/urina , Animais , Deferiprona/farmacologia , Modelos Animais de Doenças , Proteínas de Ligação ao Ferro/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Lúpus Eritematoso Sistêmico/urina , Camundongos , Distribuição Tecidual/efeitos dos fármacos , Transferrina/urina
10.
London J Prim Care (Abingdon) ; 7(2): 15-22, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26217398

RESUMO

BACKGROUND: Over recent years there has been increased interest in the disease burden associated with vitamin D deficiency. This, combined with recognition that the prevalence of vitamin D deficiency is high in the UK, has led to increased requests for vitamin D assessment from primary care clinicians. SETTING: A primary care cohort in Liverpool. QUESTION: How has the usefulness of vitamin D testing changed over time in identifying deficiency? METHODS: Vitamin D results from primary care practices in Liverpool were collected between 2007 and 2012, inclusive. Results were allocated to six cohorts based on year of request and each was grouped into three categories (adequate, insufficient and deficient). RESULTS: Vitamin D results of 9460 (74%) first tests and 3263 (26%) retests were analysed. Total number of requests increased 11-fold, from 503 in 2007 to 5552 in 2012. Overall 42% of first-test results were deficient (< 30 nmol). With each incremental year, more cases of vitamin D deficiency were detected - but the odds of detecting vitamin D deficiency decreased. CONCLUSIONS: An exponential increase in the number of vitamin D requests was observed over this six-year period. Although more patients with vitamin deficiency were identified, the increased number of tests represents a significant cost to health services. Moreover, the practice of retesting too soon after treatment can be inappropriate. There is a need to develop clear guidance for assessing vitamin D status in primary care.

11.
PLoS One ; 8(10): e77023, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24146952

RESUMO

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine-encoding CAG expansion in the huntingtin gene. Iron accumulates in the brains of HD patients and mouse disease models. However, the cellular and subcellular sites of iron accumulation, as well as significance to disease progression are not well understood. We used independent approaches to investigate the location of brain iron accumulation. In R6/2 HD mouse brain, synchotron x-ray fluorescence analysis revealed iron accumulation as discrete puncta in the perinuclear cytoplasm of striatal neurons. Further, perfusion Turnbull's staining for ferrous iron (II) combined with transmission electron microscope ultra-structural analysis revealed increased staining in membrane bound peri-nuclear vesicles in R6/2 HD striatal neurons. Analysis of iron homeostatic proteins in R6/2 HD mice revealed decreased levels of the iron response proteins (IRPs 1 and 2) and accordingly decreased expression of iron uptake transferrin receptor (TfR) and increased levels of neuronal iron export protein ferroportin (FPN). Finally, we show that intra-ventricular delivery of the iron chelator deferoxamine results in an improvement of the motor phenotype in R6/2 HD mice. Our data supports accumulation of redox-active ferrous iron in the endocytic / lysosomal compartment in mouse HD neurons. Expression changes of IRPs, TfR and FPN are consistent with a compensatory response to an increased intra-neuronal labile iron pool leading to increased susceptibility to iron-associated oxidative stress. These findings, together with protection by deferoxamine, support a potentiating role of neuronal iron accumulation in HD.


Assuntos
Doença de Huntington/metabolismo , Ferro/metabolismo , Neurônios/metabolismo , Animais , Corpo Estriado/metabolismo , Corpo Estriado/patologia , Desferroxamina/administração & dosagem , Desferroxamina/farmacologia , Modelos Animais de Doenças , Feminino , Doença de Huntington/fisiopatologia , Doença de Huntington/prevenção & controle , Injeções Intraventriculares , Proteína 1 Reguladora do Ferro/metabolismo , Proteína 2 Reguladora do Ferro/metabolismo , Masculino , Camundongos , Receptores da Transferrina/metabolismo , Transferrina/metabolismo
14.
J Med Case Rep ; 1: 51, 2007 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-17629933

RESUMO

BACKGROUND: Severe hypertriglyceridaemia (HTG) is uncommon but most prevalent in subjects with type 2 diabetes mellitus (T2DM) and excess ethanol intake. CASE PRESENTATION: We describe a case of a middle age male (53 y) presenting to the emergency room with acute atypical central chest pain and severe HTG in the absence of evidence of overt ischaemic heart disease (IHD). Admission ECG and EET (exercise tolerance test) were negative for reversible ischaemic changes. His admission glucose was 12.2 mmol/l, triglycerides (TG) were 103 mmol/l, total cholesterol 37 mmol/l. Cardiac Troponin T could not be measured on three occasions but CK MB mass was normal at 3 mug/l. The patient was started on Bezafibrate 400 mg OD, Simvastatin 20 mg nocte, Omacor (Omega-3 fish oil) 1 gm bd and Metformin 500 mg tds. Four weeks after admission, lipid and liver profiles showed remarkable improvement, TG 2.9 mmol/l, Tchol 6.3 mmol/l and HDLc 1.5 mmol/l, ALAT and GGT were normal. CONCLUSION: A case report of severe hypertriglyceridaemia with atypical presentation demonstrate the role of combined lipid modifying agents in lowering triglycerides and cholesterol as well as improving liver enzymes.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA