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1.
Inflammation ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31858317

RESUMO

The inflammasome is responsible for maturation of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) contributing to the inflammatory process in atherosclerosis. It is shown here that an electronegative low-density lipoprotein [LDL (-)] apoB-100 mimetic peptide can activate the transcriptional and posttranslational signs needed for complete inflammasome activation. This peptide, named p2C7, can activate the Toll-like receptor 4 (TLR4) that induces NF-κB activation and the transcription of inflammasome components. After blocking TLR4 with a neutralizing antibody, inflammasome component (NLRP3, CASP1, and ASC) and IL1b and IL18 gene downregulation occurred in human-derived macrophages stimulated with p2C7 or LDL (-). Moreover, the posttranslational signal was activated by the interaction between p2C7 and the lectin-type oxidized LDL receptor 1 (LOX-1), as demonstrated by the induction of caspase-1 cleavage in macrophages. The blockage of either TLR4 or LOX-1 decreased IL-1ß and IL-18 secretion by human-derived macrophages as both pathways are necessary for complete inflammasome activation. These findings suggest a mechanism by which macrophages transduce the pro-inflammatory signal provided by LDL (-) ApoB-100 and its mimetic peptides to activate the inflammasome protein complex what may be relevant for the inflammatory process in atherosclerosis.

2.
Biomolecules ; 9(8)2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31434316

RESUMO

The electronegative low-density lipoprotein, LDL (-), is an endogenously modified LDL subfraction with cytotoxic and proinflammatory actions on endothelial cells, monocytes, and macrophages contributing to the progression of atherosclerosis. In this study, epitopes of LDL (-) were mapped using a phage display library of peptides and monoclonal antibodies reactive to this modified lipoprotein. Two different peptide libraries (X6 and CX8C for 6- and 8-amino acid-long peptides, respectively) were used in the mapping. Among all tested peptides, two circular peptides, P1A3 and P2C7, were selected based on their high affinities for the monoclonal antibodies. Small-angle X-ray scattering analysis confirmed their structures as circular rings. P1A3 or P2C7 were quickly internalized by bone marrow-derived murine macrophages as shown by confocal microscopy. P2C7 increased the expression of TNFα, IL-1 ß and iNOS as well as the secretion of TNFα, CCL2, and nitric oxide by murine macrophages, similar to the responses induced by LDL (-), although less intense. In contrast, P1A3 did not show pro-inflammatory effects. We identified a mimetic epitope associated with LDL (-), the P2C7 circular peptide, that activates macrophages. Our data suggest that this conformational epitope represents an important danger-associated molecular pattern of LDL (-) that triggers proinflammatory responses.

3.
Nutrire Rev. Soc. Bras. Aliment. Nutr ; 42: 1-8, Dec. 2017. tab
Artigo em Inglês | LILACS | ID: biblio-881179

RESUMO

BACKGROUND: Cardiovascular diseases constitute the main death cause worldwide resulting from a combination of genetic and lifestyle factors, and the prevalence among younger individuals has increased. It is important to early identify changes in lipid profile and the influence of genetic variations in specific genes on the individual patterns of lipid profile. Thus, the aim of this study was to verify the relationship of polymorphisms in PPAR-gamma gene (PPARG−rs1801282−Pro12Ala) and in apolipoprotein E gene (APOE−rs429358 + rs7412, determinants of the APOE2, APOE3, or APOE4 genotypes) with lipid profile of adolescents under cardiovascular risk factors. METHODS: This was a cross-sectional study with 115 adolescents aged 10­19 years, which presented cardiovascular risk factors. The students were evaluated regarding socioeconomic, anthropometric, biochemical, genetic, and dietetic variables. Student'sttest or Mann-Whitney test were applied to the analysis of the genotypes. Multiple linear regression analysis was performed to determine the variables that most influenced the lipid profile. RESULTS: Adolescents carrying PPARG Ala allele showed higher serum triglycerides (p= 0.0423) and very low-density lipoprotein (p= 0.0410) levels when compared to those carrying the wild genotype. For the APOE polymorphism, it was observed a trend of higher triglycerides (p= 0.0712) and very low-density lipoprotein (p= 0.0758) levels in the adolescents carrying the E4 allele when compared to those who did not carry this allele. CONCLUSION: The polymorphisms PPARGrs1801282 andAPOErs429358 + rs7412 seem to be related to the development of lipid profile alterations in adolescents.


Assuntos
Humanos , Masculino , Feminino , Adolescente , Apolipoproteínas E/genética , Polimorfismo Genético , PPAR gama/genética , Dislipidemias/genética , Sobrepeso/genética
4.
Cardiorenal Med ; 7(4): 334-341, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29118772

RESUMO

Background: Chronic kidney disease (CKD) patients develop metabolic acidosis when approaching stages 3 and 4, a period in which accelerated atherogenesis may ensue. Studies in vitro show that low pH may increase low-density lipoprotein (LDL) oxidation, suggesting a role for chronic metabolic acidosis in atherosclerosis. The present study attempted to evaluate the effects of conservative care using oral sodium bicarbonate (NaHCO3) supplementation on the electronegative LDL [LDL(-)], a minimally oxidized LDL, plasma levels in CKD patients. Methods: Thirty-one CKD patients were followed by a multidisciplinary team during 15 months of care in which 1.0 mmol/kg/day oral NaHCO3 supplementation was first given in the third month. Blood samples were collected 3 months before the initiation of oral NaHCO3 supplementation (T1), at the time of the beginning of supplementation (T2), and thereafter, each 4 months (T3, T4 and T5) until month 15 of care. Blood parameters and LDL(-) were measured from these collections. Results: After 12 months of conservative care, creatinine clearance (MDRD) was kept stable, and serum bicarbonate (HCO3-) increased from 20.5 ± 2.9 to 22.6 ± 1.1 mM (p < 0.003). LDL(-) plasma levels declined from 4.5 ± 3.3 to 2.1 ± 0.9 U/L (p < 0.007) after reaching mean serum HCO3- levels of 22.6 ± 1.1 mM. Conclusions: Conservative care using oral NaHCO3 supplementation was able to stabilize renal function and decrease serum levels of LDL(-), a modified proatherogenic lipoprotein, only when mean serum HCO3- levels approached 22 mM. This study constitutes evidence that alkali therapy, in addition to its beneficial effect on renal disease progression, might serve as a preventive strategy to attenuate atherogenesis in CKD patients.

5.
Eur J Pharm Biopharm ; 107: 120-9, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27378286

RESUMO

Atherosclerosis is a chronic inflammatory disease responsible for the majority of cases of myocardial infarction and ischemic stroke. The electronegative low-density lipoprotein, a modified subfraction of native LDL, is pro-inflammatory and plays an important role in atherogenesis. To investigate the effects of a nanoformulation (scFv anti-LDL(-)-MCMN-Zn) containing a scFv reactive to LDL(-) on the inhibition of atherosclerosis, its toxicity was evaluated in vitro and in vivo and further it was also administered weekly to LDL receptor knockout mice. The scFv anti-LDL(-)-MCMN-Zn nanoformulation did not induce cell death in RAW 264.7 macrophages and HUVECs. The 5mg/kg dose of scFv anti-LDL(-)-MCMN-Zn did not cause any typical signs of toxicity and it was chosen for the evaluation of its atheroprotective effect in Ldlr(-/-) mice. This nanoformulation significantly decreased the atherosclerotic lesion area at the aortic sinus, compared with that in untreated mice. In addition, the Il1b mRNA expression and CD14 protein expression were downregulated in the atherosclerotic lesions at the aortic arch of Ldlr(-/-) mice treated with scFv anti-LDL(-)-MCMN-Zn. Thus, the scFv anti-LDL(-)-MCMN-Zn nanoformulation inhibited the progression of atherosclerotic lesions, indicating its potential use in a future therapeutic strategy for atherosclerosis.


Assuntos
Aterosclerose/prevenção & controle , Lipoproteínas LDL/imunologia , Receptores de LDL/fisiologia , Anticorpos de Cadeia Única/imunologia , Animais , Linhagem Celular , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/genética
6.
Nutrients ; 8(1)2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26797632

RESUMO

BACKGROUND: Cardiovascular disease is the leading cause of worldwide morbidity and mortality. Several studies have demonstrated that specific probiotics affect the host's metabolism and may influence the cardiovascular disease risk. OBJECTIVES: The aim of this study was to investigate the influence of an isoflavone-supplemented soy product fermented with Enterococcus faecium CRL 183 and Lactobacillus helveticus 416 on cardiovascular risk markers in moderately hypercholesterolemic subjects. DESIGN: Randomized placebo-controlled double-blind trial Setting: São Paulo State University in Araraquara, SP, Brazil. PARTICIPANTS: 49 male healthy men with total cholesterol (TC) >5.17 mmol/L and <6.21 mmol/L Intervention: The volunteers have consumed 200 mL of the probiotic soy product (group SP-10(10) CFU/day), isoflavone-supplemented probiotic soy product (group ISP-probiotic plus 50 mg of total isoflavones/100 g) or unfermented soy product (group USP-placebo) for 42 days in a randomized, double-blind study. MAIN OUTCOME MEASURES: Lipid profile and additional cardiovascular biomarkers were analyzed on days 0, 30 and 42. Urine samples (24 h) were collected at baseline and at the end of the experiment so as to determine the isoflavones profile. RESULTS: After 42 days, the ISP consumption led to improved total cholesterol, non-HDL-C (LDL + IDL + VLDL cholesterol fractions) and electronegative LDL concentrations (reduction of 13.8%, 14.7% and 24.2%, respectively, p < 0.05). The ISP and SP have prevented the reduction of HDL-C level after 42 days. The C-reactive protein and fibrinogen levels were not improved. The equol production by the ISP group subjects was inversely correlated with electronegative LDL concentration. CONCLUSIONS: The results suggest that a regular consumption of this probiotic soy product, supplemented with isoflavones, could contribute to reducing the risk of cardiovascular diseases in moderately hypercholesterolemic men, through the an improvement in lipid profile and antioxidant properties.


Assuntos
Suplementos Nutricionais , Hipercolesterolemia/dietoterapia , Isoflavonas/administração & dosagem , Lipídeos/sangue , Probióticos/administração & dosagem , Alimentos de Soja/microbiologia , Adulto , Antioxidantes/administração & dosagem , Biomarcadores/sangue , Biomarcadores/urina , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/efeitos dos fármacos , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/complicações , Isoflavonas/urina , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Int J Endocrinol ; 2015: 146816, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26089875

RESUMO

We investigated the potential of a panel of 22 biomarkers to predict the presence of coronary artery disease (CAD) in type 2 diabetes mellitus (DM2) patients. The study enrolled 96 DM2 patients with (n = 75) and without (n = 21) evidence of CAD. We assessed a biochemical profile that included 22 biomarkers: total cholesterol, LDL, HDL, LDL/HDL, triglycerides, glucose, glycated hemoglobin, fructosamine, homocysteine, cysteine, methionine, reduced glutathione, oxidized glutathione, reduced glutathione/oxidized glutathione, L-arginine, asymmetric dimethyl-L-arginine, symmetric dimethyl-L-arginine, asymmetric dimethyl-L-arginine/L-arginine, nitrate plus nitrite, S-nitrosothiols, nitrotyrosine, and n-acetyl-ß-glucosaminidase. Prediction models were built using logistic regression models. We found that eight biomarkers (methionine, nitratate plus nitrite, n-acetyl-ß-glucosaminidase, BMI, LDL, HDL, reduced glutathione, and L-arginine/asymmetric dimethyl-L-arginine) along with gender and BMI were significantly associated with the odds of CAD in DM2. These preliminary findings support the notion that emerging biochemical markers might be used for CAD prediction in patients with DM2. Our findings warrant further investigation with large, well-designed studies.

8.
PLoS One ; 10(6): e0130893, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26098914

RESUMO

AMP-activated protein kinase (AMPK) maintains energy homeostasis by suppressing cellular ATP-consuming processes and activating catabolic, ATP-producing pathways such as fatty acid oxidation (FAO). The transcription factor peroxisome proliferator-activated receptor δ (PPARδ) also affects fatty acid metabolism, stimulating the expression of genes involved in FAO. To question the interplay of AMPK and PPARδ in human macrophages we transduced primary human macrophages with lentiviral particles encoding for the constitutively active AMPKα1 catalytic subunit, followed by microarray expression analysis after treatment with the PPARδ agonist GW501516. Microarray analysis showed that co-activation of AMPK and PPARδ increased expression of FAO genes, which were validated by quantitative PCR. Induction of these FAO-associated genes was also observed upon infecting macrophages with an adenovirus coding for AMPKγ1 regulatory subunit carrying an activating R70Q mutation. The pharmacological AMPK activator A-769662 increased expression of several FAO genes in a PPARδ- and AMPK-dependent manner. Although GW501516 significantly increased FAO and reduced the triglyceride amount in very low density lipoproteins (VLDL)-loaded foam cells, AMPK activation failed to potentiate this effect, suggesting that increased expression of fatty acid catabolic genes alone may be not sufficient to prevent macrophage lipid overload.


Assuntos
3-Hidroxiacil-CoA Desidrogenases/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA C-Aciltransferase/metabolismo , Isomerases de Ligação Dupla Carbono-Carbono/metabolismo , Enoil-CoA Hidratase/metabolismo , Regulação da Expressão Gênica/fisiologia , Macrófagos/metabolismo , PPAR delta/metabolismo , Racemases e Epimerases/metabolismo , Análise de Variância , Western Blotting , Primers do DNA/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Análise em Microsséries , Mutagênese Sítio-Dirigida , Consumo de Oxigênio , Plasmídeos/genética , Pironas/farmacologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiazóis/farmacologia , Tiofenos/farmacologia
9.
J Control Release ; 209: 207-18, 2015 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-25931305

RESUMO

We report the in vitro release profile and comparative pharmacokinetics and biodistribution of a new peroxisome proliferator-activated receptor-γ agonist and cyclooxygenase inhibitor (Lyso-7) free or associated to poly(D,L-lactic acid) nanocapsules (NC) after intravenous administration in mice. Lyso-7 pertains to the class of insulin-sensitizing agents that shows potential beneficial effects in diabetes therapy. Monodispersed Lyso-7 NC with a mean diameter of 273 nm with high encapsulation efficiency (83%) were obtained. Lyso-7 dissolution rate was reduced (2.6-fold) upon loading in NC. The pharmacokinetic parameters were determined using a non-compartmental approach. In comparison with Lyso-7 in solution, the plasma-AUC increased 14-fold, the mean residence time 2.6-fold and the mean half-life (t1/2) 1.5-fold for Lyso-7-NC; the Lyso-7 plasma clearance, distribution volume and elimination rate were reduced 13, 10 and 1.4 fold, respectively, which indicates higher retention of encapsulated Lyso-7 in the blood compartment. Upon association with NC, organ exposure to Lyso-7 was higher in the heart (3.6-fold), lung (2.8-fold), spleen (2.3-fold), kidney (2-fold) and liver (1.8-fold) compared to Lyso-7 in solution. The analysis of whole data clearly indicates that body exposure to Lyso-7 was enhanced and the general toxicity reduced upon nanoencapsulation, allowing further evaluation of Lyso-7 in nonclinical and clinical studies.


Assuntos
Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/farmacocinética , Indóis/administração & dosagem , Indóis/farmacocinética , Nanocápsulas/administração & dosagem , PPAR gama/agonistas , Tiazolidinedionas/administração & dosagem , Tiazolidinedionas/farmacocinética , Animais , Inibidores de Ciclo-Oxigenase/sangue , Inibidores de Ciclo-Oxigenase/química , Eritrócitos/efeitos dos fármacos , Feminino , Hemólise/efeitos dos fármacos , Indóis/sangue , Indóis/química , Rim/metabolismo , Fígado/metabolismo , Pulmão/metabolismo , Camundongos , Miocárdio/metabolismo , Nanocápsulas/química , Nanocápsulas/ultraestrutura , Tamanho da Partícula , Baço/metabolismo , Propriedades de Superfície , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Distribuição Tecidual
10.
PLoS One ; 10(3): e0119830, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25785441

RESUMO

OBJECTIVE: Statins treatment may modify the levels of zinc and selenium, minerals that can improve vascular function and reduce oxidative damage and inflammation in atherosclerotic patients. This study aimed to evaluate the effects of rosuvastatin, alone or associated with zinc and selenium supplementation, on lipid profile, antioxidant enzymes and mineral status in coronary artery disease patients. MATERIAL AND METHODS: A double-blind randomized clinical trial was performed in which patients (n = 76) were treated with 10 mg rosuvastatin over 4 months associated or not with zinc (30 mg/d) and selenium (150 µg/d) supplementation. The following parameters were analyzed before and after the intervention: anthropometric measurements, lipid profile, high sensitivity C-reactive protein (hs-CRP), electronegative low density lipoprotein (LDL(-)) concentrations, activities of glutathione peroxidase (GPx), superoxide dismutase (SOD), zinc and selenium concentrations in blood plasma and erythocytes. Significance was determined using an α of 5% (two-tailed). RESULTS: We found that rosuvastatin therapy was efficient in reducing total cholesterol, LDL-cholesterol, non-HDL cholesterol, triglycerides, and hs-CRP independently of mineral supplementation. Neither treatment was associated with significant changes in LDL(-). Similarly, the antioxidant enzymes GPx and SOD activity were unchanged by treatments. Neither treatment was associated with significant differences in concentrations of zinc or selenium in blood plasma and erythocytes of studied groups. CONCLUSION: Rosuvastatin treatment did not affect zinc and selenium levels in coronary artery disease patients. The zinc and selenium supplementation at doses used in this study did not change lipid profile or SOD and GPx activity in patients receiving rosuvastatin. Further studies should be focused on testing alternative doses and supplements in different populations to contribute for a consensus on the ideal choice of antioxidants to be used as possible complementary therapies in atherosclerotic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01547377.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Hipolipemiantes/farmacologia , Rosuvastatina Cálcica/farmacologia , Selênio/farmacologia , Zinco/farmacologia , Proteína C-Reativa/metabolismo , Suplementos Nutricionais , Feminino , Glutationa Peroxidase/sangue , Humanos , Lipídeos/sangue , Lipoproteínas LDL/sangue , Masculino , Selênio/sangue , Estatísticas não Paramétricas , Superóxido Dismutase/sangue , Resultado do Tratamento , Zinco/sangue
11.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-31190

RESUMO

We investigated the potential of a panel of 22 biomarkers to predict the presence of coronary artery disease (CAD) in type 2diabetes mellitus (DM2) patients. The study enrolled 96 DM2 patients with (n = 75) and without (n = 21) evidence of CAD.We assessed a biochemical profile that included 22 biomarkers: total cholesterol, LDL, HDL, LDL/HDL, triglycerides, glucose,glycated hemoglobin, fructosamine, homocysteine, cysteine, methionine, reduced glutathione, oxidized glutathione, reducedglutathione/oxidized glutathione, L-arginine, asymmetric dimethyl-L-arginine, symmetric dimethyl-L-arginine, asymmetricdimethyl-L-arginine/L-arginine, nitrate plus nitrite, S-nitrosothiols, nitrotyrosine, and n-acetyl-𝛽-glucosaminidase. Predictionmodels were built using logistic regression models.We found that eight biomarkers (methionine, nitratate plus nitrite, n-acetyl-𝛽-glucosaminidase, BMI, LDL, HDL, reduced glutathione, and L-arginine/asymmetric dimethyl-L-arginine) along with gender andBMI were significantly associated with the odds of CAD in DM2. These preliminary findings support the notion that emergingbiochemical markers might be used for CAD prediction in patients with DM2. Our findings warrant further investigation withlarge, well-designed studies. (AU)


Assuntos
Doença da Artéria Coronariana , Diabetes Mellitus , Infarto
12.
Artigo em Inglês | Sec. Est. Saúde SP, SESSP-IDPCPROD, Sec. Est. Saúde SP | ID: ses-31195

RESUMO

We investigated the potential of a panel of 22 biomarkers to predict the presence of coronary artery disease (CAD) in type 2diabetes mellitus (DM2) patients. The study enrolled 96 DM2 patients with (n = 75) and without (n = 21) evidence of CAD.We assessed a biochemical profile that included 22 biomarkers: total cholesterol, LDL, HDL, LDL/HDL, triglycerides, glucose,glycated hemoglobin, fructosamine, homocysteine, cysteine, methionine, reduced glutathione, oxidized glutathione, reducedglutathione/oxidized glutathione, L-arginine, asymmetric dimethyl-L-arginine, symmetric dimethyl-L-arginine, asymmetricdimethyl-L-arginine/L-arginine, nitrate plus nitrite, S-nitrosothiols, nitrotyrosine, and n-acetyl-𝛽-glucosaminidase. Predictionmodels were built using logistic regression models.We found that eight biomarkers (methionine, nitratate plus nitrite, n-acetyl-𝛽-glucosaminidase, BMI, LDL, HDL, reduced glutathione, and L-arginine/asymmetric dimethyl-L-arginine) along with gender andBMI were significantly associated with the odds of CAD in DM2. These preliminary findings support the notion that emergingbiochemical markers might be used for CAD prediction in patients with DM2. Our findings warrant further investigation withlarge, well-designed studies. (AU)


Assuntos
Biomarcadores Farmacológicos , Doença da Artéria Coronariana , Diabetes Mellitus
13.
Biotechnol Prog ; 30(5): 1206-13, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24911875

RESUMO

Experimental studies on atherosclerosis are crucial for investigating its pathophysiology, defining new therapeutic targets, and developing new drugs and diagnostic tools. Thus, many imaging markers have been developed and introduced in experimental studies. The main advantage of these new tools is that they allow the noninvasive diagnosis of atherosclerotic vascular disease. Here, we describe the cloning, expression, purification, and stabilization of a chimeric protein specifically designed to probe cells and tissues for the presence of LDL(-), a relevant marker of atherosclerosis. The DNA sequence that encodes the anti-LDL(-) scFv, previously obtained from a hybridoma secreting an anti-LDL(-) monoclonal antibody, was inserted into the bacterial vector pET-28a(+) in tandem with a DNA sequence encoding GFP. The recombinant protein was expressed in high yields in E. coli as inclusion bodies. The applicability of GFP-scFv was assessed by ELISA, which determined its affinity for LDL(-) and confocal microscopy, that showed macrophage uptake of the protein along with LDL(-). In conclusion, our data suggest that the anti-LDL(-) GFP-scFv chimeric protein could be useful in studies on atherogenesis as well as for developing diagnostic tools for atherosclerosis.


Assuntos
Biomarcadores/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Lipoproteínas LDL/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Anticorpos de Cadeia Única/metabolismo , Animais , Aterosclerose/metabolismo , Linhagem Celular Tumoral , Endocitose , Escherichia coli/metabolismo , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/farmacocinética , Camundongos , Imagem Molecular/métodos , Ligação Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacocinética , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/farmacocinética
14.
J Trace Elem Med Biol ; 28(2): 194-199, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24560278

RESUMO

BACKGROUND: Statins have multiple antiatherosclerotic effects, but can reduce blood plasma concentrations of minerals, including zinc. As zinc possesses antiinflammatory and antioxidant effects, low zinc status can promote injuries or inadequate tissue repair in endothelial cells. Metallothionein (MT) expression might modulate responses induced by statins in patients with atherosclerosis. However, research regarding mineral status and the use of statins is scarce. This study evaluated the effects of zinc supplementation on zinc status and expression of the zinc-dependent MT1F and MT2A genes in patients with atherosclerosis treated with rosuvastatin. METHODS: A double-blind, randomized clinical trial was performed with 54 participants treated with 10mg rosuvastatin for 4 months with or without zinc supplementation (30mg/day). Diet, lipid profile, high-sensitivity reactive protein C (hs-CRP), plasma and erythrocyte zinc concentrations, erythrocyte superoxide dismutase (SOD) activity, and MT1F and MT2A genes expression were analyzed before and after intervention. RESULTS: Rosuvastatin therapy was effective in reducing low- and non-high-density lipoprotein, total cholesterol, triglycerides, and hs-CRP levels, independent of zinc supplementation. Additionally, zinc treatment had no effect on SOD enzyme activity (P=0.201), plasma (P>0.671) and erythrocyte (P>0.123) zinc concentrations, or the pattern of MT1F and MT2A genes expression (P=0.088 and P=0.229, respectively). CONCLUSIONS: The effectiveness of rosuvastatin treatment is independent of the effects of zinc supplementation. Moreover, rosuvastatin treatment did not have a significant impact on zinc status or MT1F and MT2A genes expression in patients with atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Suplementos Nutricionais , Fluorbenzenos/uso terapêutico , Pirimidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Zinco/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria , Biomarcadores/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Metalotioneína/genética , Metalotioneína/metabolismo , Pessoa de Meia-Idade , Dados de Sequência Molecular , Placebos , Rosuvastatina Cálcica
15.
J Nutr Sci Vitaminol (Tokyo) ; 59(2): 100-7, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23727639

RESUMO

Obesity has increased in children and adolescents. What is reflected in the early occurrence of cardiometabolic alterations, like hypertension and type 2 diabetes, where the oxLDL formation is stimulated. Various studies have shown that plasma α-tocopherol (α-TP) can protect LDL against oxidation. Nevertheless, the action of plasma α-TP in cardiovascular diseases remains controversial. We conducted a cross-sectional study to evaluate plasma α-TP and its impact on the concentration of LDL(-). Adolescents (n=150) of both sexes were classified into three groups: healthy weight (HW; 50%), overweight (OV; 22%), and obese (OB; 28%). Lipid profile, LDL(-), anti-oxLDL and anti-LDL(-) antibodies, CRP (ELISA) and plasma α-TP (HPLC) were analyzed. Demographic, anthropometric, and food intake data were evaluated. Crude and energy-adjusted intake of vitamin E in the OB group were higher than in the HW group (p<0.001). Crude and energy-adjusted vitamin E intakes were not correlated with plasma α-TP (r=-0.07; p=0.412 and r=-0.064; p=0.467, respectively). Subjects in the OB group had higher TC and LDL-C and lower HDL-C than in the HW and OV groups. C-reactive protein and anti-oxLDL antibodies changed as a function of BMI. The impact of obesity was reinforced by high values for LDL(-) and low content of plasma α-TP in comparison with the HW (p<0.001) and OV groups (p=0.03). This negative profile was maintained for the ratio between α-TP and TC or LDL-C. Plasma α-TP, α-TP/TC and α-TP/LDL-C were negatively associated with LDL(-) and other cardiometabolic risk factors (BMI, WC, AC and anti-oxLDL). Our results demonstrate that obesity in adolescents is associated with high levels of LDL(-) and low plasma α-TP content.


Assuntos
LDL-Colesterol/sangue , Obesidade/sangue , alfa-Tocoferol/sangue , Adolescente , Antropometria , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Criança , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Proteínas na Dieta/administração & dosagem , Ingestão de Energia , Feminino , Humanos , Hipertensão/sangue , Hipertensão/etiologia , Lipoproteínas LDL/sangue , Masculino , Obesidade/complicações , Sobrepeso/sangue , Sobrepeso/complicações , Fatores de Risco , Inquéritos e Questionários
16.
Ren Fail ; 35(5): 680-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23650973

RESUMO

Despite the fact that low plasma zinc (Zn) levels play important roles in the oxidative stress, the relationships between lipid peroxidation and inflammation biomarkers with low plasma Zn levels have not been investigated in chronic kidney disease (CKD) patients. The aim of this study was to evaluate the Zn plasma levels, electronegative LDL [LDL(-)] levels, and inflammation markers as predictors of cardiovascular (CV) mortality in hemodialysis (HD) patients. Forty-five HD patients (28 men, 54.2 ± 12.7 years, 62.2 ± 51.4 months on dialysis and BMI 24.3 ± 4.1 kg/m(2)) were studied and compared to 20 healthy individuals (9 men, 51.6 ± 15.6 years, BMI 25.2 ± 3.9 kg/m(2)) and followed for 24 months to investigate the risks for CV mortality. LDL(-) levels were measured by ELISA, plasma Zn levels by atomic absorption spectrophotometry, C-reactive protein (CRP) level by immunoturbidimetric method, and tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein-1 (MCP-1), and plasminogen activator inhibitor-1 (PAI-1) levels by a multiplex assay kit. HD patients presented low plasma Zn levels (54.9 ± 16.1 µg/dL) and high-LDL(-) (0.18 ± 0.12 U/L) and TNF-α (5.5 ± 2.2 pg/mL) levels when compared to healthy subjects (78.8 ± 9.4µ g/dL, 0.10 ± 0.08U/L, 2.4 ± 1.1 pg/mL, respectively, p < 0.05). Zn plasma levels were negatively correlated to TNF-α (r = -0.49; p = 0.0001) and LDL(-) (r = -0.33; p = 0.008). During the 2 years, 24.4% of the patients died, all due to CV disease. Analysis by the Cox model showed that high CRP, TNF-α, IL-6 levels, and long duration of HD were significant predictors of mortality. In conclusion, reduced Zn levels were associated with lipid peroxidation and inflammation, and we confirm here in a Brazilian cohort of HD patients that inflammation markers are strong predictors of CV death.


Assuntos
Doenças Cardiovasculares/sangue , Falência Renal Crônica/sangue , Peroxidação de Lipídeos , Lipoproteínas LDL/sangue , Zinco/sangue , Adulto , Idoso , Brasil/epidemiologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/mortalidade , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/mortalidade , Masculino , Pessoa de Meia-Idade , Diálise Renal , Fatores de Risco
17.
Arq. bras. cardiol ; 100(5): 404-411, maio 2013. ilus, tab
Artigo em Português | LILACS | ID: lil-675601

RESUMO

FUNDAMENTO: Hiperglicemia na fase aguda do infarto do miocárdio é importante fator prognóstico. Entretanto, sua fisiopatologia não está completamente elucidada. OBJETIVO: Analisar simultaneamente correlação entre hiperglicemia e marcadores bioquímicos relacionados ao estresse,metabolismo glicídico e lipídico, coagulação, inflamação e necrose miocárdica. MÉTODOS: Oitenta pacientes com infarto agudo do miocárdio foram incluídos prospectivamente. Os parâmetros analisados foram: glicose, hormônios do estresse (cortisol e norepinefrina), fatores do metabolismo glicídico [hemoglobina glicada (HbA1c), insulina], lipoproteínas (colesterol total, LDL, HDL, LDL eletronegativa minimamente modificada e adiponectina), glicerídeos (triglicérides, VLDL e ácido graxo), fatores da coagulação (fator VII, fibrinogênio,inibidor do ativador do plasminogênio-1), inflamação (proteína C reativa ultrassensível) e necrose miocárdica (CK-MB e troponina). Variáveis contínuas foram convertidas em graus de pertinência por intermédio de lógica fuzzy. RESULTADOS: Houve correlação significativa entre hiperglicemia e metabolismo glicídico (p < 0,001), lipoproteínas (p = 0,03) e fatores de necrose (p = 0,03). Na análise multivariada, somente metabolismo glicídico (OR = 4,3; IC = 2,1-68,9 e p < 0,001) e necrose miocárdica (OR = 22,5; IC = 2-253 e p = 0,012) mantiveram correlação independente e significativa.Para análise da influência da história de diabetes mellitus , modelo de regressão, incluindo somente pacientes sem diabetes mellitus foi desenvolvido, e os resultados não alteraram. Finalmente, no modelo ajustado para idade, sexo e variáveis clínicas(história de diabetes mellitus, hipertensão arterial e dislipidemia), três variáveis mantiveram associação significativa e independente com hiperglicemia: metabolismo glicídico (OR = 24,1; IC = 4,8-122,1 e p < 0,001) necrose miocárdica (OR = 21,9; IC = 1,3-360,9 e p = 0,03) e história de DM (OR = 27, IC = 3,7-195,7 e p = 0,001). CONCLUSÃO: Marcadores do metabolismo glicídico e necrose miocárdica foram os melhores preditores de hiperglicemia em pacientes com infarto agudo do miocárdio.


BACKGROUND: Hyperglycemia in the acute phase of myocardial infarction is an important prognostic factor. However, its pathophysiology is not fully understood. OBJECTIVE: To analyze simultaneously the correlation between hyperglycemia and biochemical markers related to stress, glucose and lipid metabolism, coagulation, inflammation, and myocardial necrosis. METHODS Eighty patients with acute myocardial infarction were prospectively included. The following parameters were analyzed: blood glucose; stress hormones (cortisol and norepinephrine); glucose metabolism factors [glycated hemoglobin (HbA1c); insulin]; lipoproteins (total cholesterol, LDL, HDL, minimally modified electronegative LDL, and adiponectin); glycerides (triglycerides, VLDL and fatty acids); coagulation factors (factor VII, fibrinogen, plasminogen activator inhibitor-1); inflammation (high-sensitivity C reactive protein); and myocardial necrosis (CK-MB and troponin). Continuous variables were converted into degrees of relevance using fuzzy logic. RESULTS: Significant correlation was observed between hyperglycemia and glucose metabolism (p < 0.001), lipoproteins (p = 0.03), and necrosis factors (p = 0.03). In the multivariate analysis, only glucose metabolism (OR = 4.3; CI = 2.1-68.9; and p < 0.001) and myocardial necrosis (OR = 22.5; CI = 2-253; and p = 0.012) showed independent and significant correlation. For the analysis of the influence of history of diabetes mellitus, a regression model including only patients without diabetes mellitus was developed, and the results did not change. Finally, in the model adjusted for age, gender, and clinical variables (history of diabetes mellitus, hypertension and dyslipidemia), three variables maintained a significant and independent association with hyperglycemia: glucose metabolism (OR = 24.1; CI = 4.8-122.1; and p < 0.001), myocardial necrosis (OR = 21.9; CI = 1.3-360.9; and p = 0.03), and history of DM (OR = 27; CI = 3.7-195.7; and p = 0.001). CONCLUSION: Glucose metabolism and myocardial necrosis markers were the best predictors of hyperglycemia in patients with acute myocardial infarction.


Assuntos
Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Diabetes Mellitus/diagnóstico , Hiperglicemia/diagnóstico , Infarto do Miocárdio/sangue , Troponina/sangue , Biomarcadores/sangue , Coagulação Sanguínea/fisiologia , Creatina Quinase Forma MB/sangue , Diabetes Mellitus/sangue , Métodos Epidemiológicos , Hemoglobina A Glicada/análise , Hiperglicemia/sangue , Inflamação/sangue , Insulina/sangue , Lipoproteínas/sangue , Infarto do Miocárdio/patologia , Necrose , Estresse Fisiológico/fisiologia
18.
Arq Bras Cardiol ; 100(5): 404-11, 2013 May.
Artigo em Inglês, Português | MEDLINE | ID: mdl-23598457

RESUMO

BACKGROUND: Hyperglycemia in the acute phase of myocardial infarction is an important prognostic factor. However, its pathophysiology is not fully understood. OBJECTIVE: To analyze simultaneously the correlation between hyperglycemia and biochemical markers related to stress, glucose and lipid metabolism, coagulation, inflammation, and myocardial necrosis. METHODS Eighty patients with acute myocardial infarction were prospectively included. The following parameters were analyzed: blood glucose; stress hormones (cortisol and norepinephrine); glucose metabolism factors [glycated hemoglobin (HbA1c); insulin]; lipoproteins (total cholesterol, LDL, HDL, minimally modified electronegative LDL, and adiponectin); glycerides (triglycerides, VLDL and fatty acids); coagulation factors (factor VII, fibrinogen, plasminogen activator inhibitor-1); inflammation (high-sensitivity C reactive protein); and myocardial necrosis (CK-MB and troponin). Continuous variables were converted into degrees of relevance using fuzzy logic. RESULTS: Significant correlation was observed between hyperglycemia and glucose metabolism (p < 0.001), lipoproteins (p = 0.03), and necrosis factors (p = 0.03). In the multivariate analysis, only glucose metabolism (OR = 4.3; CI = 2.1-68.9; and p < 0.001) and myocardial necrosis (OR = 22.5; CI = 2-253; and p = 0.012) showed independent and significant correlation. For the analysis of the influence of history of diabetes mellitus, a regression model including only patients without diabetes mellitus was developed, and the results did not change. Finally, in the model adjusted for age, gender, and clinical variables (history of diabetes mellitus, hypertension and dyslipidemia), three variables maintained a significant and independent association with hyperglycemia: glucose metabolism (OR = 24.1; CI = 4.8-122.1; and p < 0.001), myocardial necrosis (OR = 21.9; CI = 1.3-360.9; and p = 0.03), and history of DM (OR = 27; CI = 3.7-195.7; and p = 0.001). CONCLUSION: Glucose metabolism and myocardial necrosis markers were the best predictors of hyperglycemia in patients with acute myocardial infarction.


Assuntos
Diabetes Mellitus/diagnóstico , Hiperglicemia/diagnóstico , Infarto do Miocárdio/sangue , Troponina/sangue , Biomarcadores/sangue , Coagulação Sanguínea/fisiologia , Creatina Quinase Forma MB/sangue , Diabetes Mellitus/sangue , Métodos Epidemiológicos , Feminino , Hemoglobina A Glicada/análise , Humanos , Hiperglicemia/sangue , Inflamação/sangue , Insulina/sangue , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Necrose , Estresse Fisiológico/fisiologia
19.
J Clin Endocrinol Metab ; 97(8): E1353-62, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22564665

RESUMO

CONTEXT: Periodontitis is the most common lytic disease of bone and is recognized as a common complication of diabetes. Lipid peroxidation (LPO) is increased in diabetes and may be related to modulation of the inflammatory response. LPO levels in patients with diabetes and periodontal disease have not been evaluated. OBJECTIVE: The aim of this study was to evaluate the levels of LPO and its correlation with periodontal status and inflammatory cytokines in type 2 diabetic and nondiabetic patients. DESIGN AND SETTING: This is a cross-sectional study involving Brazilian patients recruited at the State University of São Paulo. PATIENTS: The sample comprised 120 patients divided into four groups based upon diabetic and dyslipidemic status: poorly controlled diabetics with dyslipidemia, well-controlled diabetics with dyslipidemia, normoglycemic individuals with dyslipidemia, and healthy individuals. MAIN OUTCOME MEASURES: Blood analyses were carried out for fasting plasma glucose, glycated hemoglobin, and lipid profile. Periodontal examinations were performed, and gingival crevicular fluid was collected. LPO levels were evaluated by measuring oxidized low-density lipoprotein (ELISA) and malondialdehyde (HPLC). Cytokines were evaluated by the multiplex bead technique. RESULTS: LPO evaluated by malondialdehyde in plasma and gingival crevicular fluid was significantly increased in diabetes groups. Significant correlations between LPO markers and periodontal parameters indicate a direct relationship between these levels and the severity of inflammation and secretion of inflammatory cytokines, particularly in diabetic patients. CONCLUSION: These findings suggest an important association for LPO with the severity of the local inflammatory response to bacteria and the susceptibility to periodontal disease in diabetic patients.


Assuntos
Diabetes Mellitus Tipo 2/complicações , Inflamação/etiologia , Peroxidação de Lipídeos , Doenças Periodontais/metabolismo , Adulto , Estudos Transversais , Feminino , Líquido do Sulco Gengival/química , Humanos , Interleucina-6/análise , Masculino , Malondialdeído/análise , Pessoa de Meia-Idade , Análise de Regressão , Fator de Necrose Tumoral alfa/análise
20.
Clin Chim Acta ; 413(1-2): 291-7, 2012 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-22037508

RESUMO

BACKGROUND: Electronegative low-density lipoprotein (LDL-) promotes atherosclerosis through inflammatory and immunologic mechanisms that lead to the production of anti-LDL(-) autoantibodies and to the subsequent formation of immune complexes (IC) and macrophage foam cells. We described the development and validation of an ELISA for the quantification of free anti-LDL(-) autoantibodies and an ELISA for the quantification of IC consisting of LDL(-)-bound IgG in human plasma. METHODS: LDL(-) purified from human plasma, and anti-LDL(-) monoclonal antibody Fab fragments were adsorbed onto ELISA plates to capture anti-LDL(-) autoantibodies and IC-LDL(-), respectively. The performance characteristics of both ELISAs, including the limits of detection and quantification, accuracy and inter- and intra-assay precision were evaluated. Linearity, interference and stability tests were also performed. RESULTS: The calibration range of the anti-LDL(-) assay was 0.004-0.125 mU/l and plasma demonstrated a dilutional linearity when diluted 1:100, 1:200, 1:400 and 1:800. The calibration range of the IC-LDL(-) assay was 0.06-4 U/l, and plasma demonstrated a dilutional linearity when diluted 1:12.5, 1:25, 1:50 and 1:100. Both ELISAs showed intra- and inter-assay precision and recovery within the required limits for immunoassays. CONCLUSION: These ELISAs can be used in clinical studies and for the biochemical investigation of atherosclerosis. In addition, they will enable the comprehensive evaluation of the importance of bound or free autoantibodies against LDL(-) in this disease.


Assuntos
Autoanticorpos/sangue , Imunoensaio/métodos , Lipoproteínas LDL/imunologia , Calibragem , Eletroforese em Gel de Ágar , Ensaio de Imunoadsorção Enzimática , Humanos , Limite de Detecção
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