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1.
Clin Investig Arterioscler ; 36(5): 286-298, 2024.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-38402026

RESUMO

INTRODUCTION: Cardiovascular calcification is an important public health issue with an unmeet therapeutic need. We had previously shown that lysyl oxidase (LOX) activity critically influences vascular wall smooth muscle cells (VSMCs) and valvular interstitial cells (VICs) calcification by affecting extracellular matrix remodeling. We have delved into the participation of LOX in atherosclerosis and vascular calcification, as well as in the mineralization of the aortic valve. METHODS: Immunohistochemical and expression studies were carried out in human atherosclerotic lesions and experimental models, valves from patients with aortic stenosis, VICs, and in a genetically modified mouse model that overexpresses LOX in CMLV (TgLOXCMLV). Hyperlipemia and atherosclerosis was induced in mice through the administration of adeno-associated viruses encoding a PCSK9 mutated form (AAV-PCSK9D374Y) combined with an atherogenic diet. RESULTS: LOX expression is increased in the neointimal layer of atherosclerotic lesions from human coronary arteries and in VSMC-rich regions of atheromas developed both in the brachiocephalic artery of control (C57BL/6J) animals transduced with PCSK9D374Y and in the aortic root of ApoE-/- mice. In TgLOXCMLV mice, PCSK9D374Y transduction did not significantly alter the enhanced aortic expression of genes involved in matrix remodeling, inflammation, oxidative stress and osteoblastic differentiation. Likewise, LOX transgenesis did not alter the size or lipid content of atherosclerotic lesions in the aortic arch, brachiocephalic artery and aortic root, but exacerbated calcification. Among lysyl oxidase isoenzymes, LOX is the most expressed member of this family in highly calcified human valves, colocalizing with RUNX2 in VICs. The lower calcium deposition and decreased RUNX2 levels triggered by the overexpression of the nuclear receptor NOR-1 in VICs was associated with a reduction in LOX. CONCLUSIONS: Our results show that LOX expression is increased in atherosclerotic lesions, and that overexpression of this enzyme in VSMC does not affect the size of the atheroma or its lipid content, but it does affect its degree of calcification. Further, these data suggest that the decrease in calcification driven by NOR-1 in VICs would involve a reduction in LOX. These evidences support the interest of LOX as a therapeutic target in cardiovascular calcification.


Assuntos
Estenose da Valva Aórtica , Aterosclerose , Modelos Animais de Doenças , Hipercolesterolemia , Camundongos Endogâmicos C57BL , Músculo Liso Vascular , Miócitos de Músculo Liso , Proteína-Lisina 6-Oxidase , Calcificação Vascular , Animais , Humanos , Aterosclerose/patologia , Aterosclerose/genética , Proteína-Lisina 6-Oxidase/metabolismo , Proteína-Lisina 6-Oxidase/genética , Camundongos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Calcificação Vascular/patologia , Calcificação Vascular/genética , Calcificação Vascular/etiologia , Calcificação Vascular/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Hipercolesterolemia/complicações , Estenose da Valva Aórtica/patologia , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/genética , Valva Aórtica/patologia , Valva Aórtica/metabolismo , Masculino , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Camundongos Transgênicos , Túnica Íntima/patologia , Túnica Íntima/metabolismo , Dieta Aterogênica/efeitos adversos
2.
Nutrients ; 13(11)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34836133

RESUMO

Bulbs from the Alliaceae family have been well-known and valued spices for thousands of years, not only for their unique flavor and aroma features, but also for their high nutritional and health-promoting values. Long-term or excessive consumption of these vegetables, especially raw garlic, can have side effects in the body (including in the digestive tract), causing a number of pathological changes in the intestinal wall; these changes lead, in turn, to its damage, dysfunction, and disorder development. Therefore, the aim of this study was to investigate the effect of the addition of freeze-dried vegetables from the Alliaceae family, i.e., garlic (Allium sativum L.), white onion, and red onion (Allium cepa L.) on the morphometric parameters (intestinal villi length, crypt depth, thickness of tunica mucosa, and the thickness of tunica muscle) of the jejunum of rats fed a semi-synthetic atherogenic diet (1% dietary cholesterol). In freeze-dried vegetables administered to rats, the contents of selected bioactive ingredients and their antioxidant potentials were determined. The effect of the onion vegetable supplements on growth parameters, serum lipid profile, plasma antioxidant potential, and the intestinal morphological parameters of rats loaded with cholesterol was determined. In an animal experiment, 30 male Wistar rats were divided into 5 diet groups, diet consumption and FER were studied. Supplementation of the atherogenic diet with vegetables improved the blood plasma lipid profiles and atherogenic indices, in a manner that was dependent on the type of supplementation used, with the best hypolipidemic and anti-atherosclerotic effects found in garlic use. The atherogenic diet, as well as the supplementation of this diet with the tested vegetables from the Alliaceae family, influenced the histological changes in the epithelium of the jejunum of rats. The damage to the intestinal mucosa was the greatest in animals fed an atherogenic diet supplemented with garlic. Bearing in mind that the desired beneficial therapeutic or prophylactic effects of onion vegetables (in particular garlic) in the course of various metabolic ailments (including atherosclerosis) are achieved during long-term supplementation, it is important to remember their possible cytotoxic effects (e.g., on the digestive tract) in order to achieve real benefits related to the supplementation with vegetables from the Alliaceae family.


Assuntos
Allium/efeitos adversos , Suplementos Nutricionais/efeitos adversos , Alho/efeitos adversos , Mucosa Intestinal/patologia , Jejuno/patologia , Animais , Dieta Aterogênica/efeitos adversos , Masculino , Ratos , Ratos Wistar , Verduras/efeitos adversos
3.
Am J Physiol Endocrinol Metab ; 321(5): E689-E701, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34632798

RESUMO

Inflammation and dyslipidemia are often present in polycystic ovary syndrome (PCOS). We determined the effect of saturated fat ingestion on circulating heat shock protein-70 (HSP-70) and mononuclear cell (MNC) toll-like receptor-2 (TLR2) gene expression, activator protein-1 (AP-1) activation, and matrix matalloproteinase-2 (MMP-2) protein in women with PCOS. Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity) participated in the study. HSP-70 was measured in serum and TLR2 mRNA and protein, AP-1 activation, and MMP-2 protein were quantified in MNC from blood drawn while fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood drawn while fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. In response to saturated fat ingestion, serum HSP-70, TLR2 gene expression, activated AP-1, and MMP-2 protein were greater in lean women with PCOS compared with lean controls and in women with PCOS and obesity compared with controls with obesity. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects of their respective weight classes. Lipid-stimulated proatherogenic inflammation marker responses were negatively correlated with ISOGTT and positively correlated with abdominal adiposity and HCG-stimulated androgen secretion. In PCOS, saturated fat ingestion stimulates proatherogenic inflammation independent of obesity. This effect is greater when PCOS is combined with obesity compared with obesity alone. Abdominal adiposity and hyperandrogenism may perpetuate proatherogenic inflammation.NEW & NOTEWORTHY This paper demonstrates that in polycystic ovary syndrome (PCOS), ingestion of saturated fat triggers a molecular pathway of inflammation known to drive atherogenesis. This effect is independent of obesity as it occurs in lean women with PCOS and not in lean ovulatory control subjects. Furthermore, the combined effects of PCOS and obesity are greater compared with obesity alone.


Assuntos
Aterosclerose/etiologia , Gorduras na Dieta/farmacologia , Ácidos Graxos/farmacologia , Inflamação/etiologia , Síndrome do Ovário Policístico/complicações , Adolescente , Adulto , Aterosclerose/patologia , Composição Corporal/efeitos dos fármacos , Dieta Aterogênica/efeitos adversos , Progressão da Doença , Feminino , Fatores de Risco de Doenças Cardíacas , Humanos , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Síndrome do Ovário Policístico/patologia , Adulto Jovem
4.
Physiol Genomics ; 53(5): 173-192, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33818129

RESUMO

Mice have provided critical mechanistic understandings of clinical traits underlying metabolic syndrome (MetSyn) and susceptibility to MetSyn in mice is known to vary among inbred strains. We investigated the diet- and strain-dependent effects on metabolic traits in the eight Collaborative Cross (CC) founder strains (A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ). Liver transcriptomics analysis showed that both atherogenic diet and host genetics have profound effects on the liver transcriptome, which may be related to differences in metabolic traits observed between strains. We found strain differences in circulating trimethylamine N-oxide (TMAO) concentration and liver triglyceride content, both of which are traits associated with metabolic diseases. Using a network approach, we identified a module of transcripts associated with TMAO and liver triglyceride content, which was enriched in functional pathways. Interrogation of the module related to metabolic traits identified NADPH oxidase 4 (Nox4), a gene for a key enzyme in the production of reactive oxygen species, which showed a strong association with plasma TMAO and liver triglyceride. Interestingly, Nox4 was identified as the highest expressed in the C57BL/6J and NZO/HILtJ strains and the lowest expressed in the CAST/EiJ strain. Based on these results, we suggest that there may be genetic variation in the contribution of Nox4 to the regulation of plasma TMAO and liver triglyceride content. In summary, we show that liver transcriptomic analysis identified diet- or strain-specific pathways for metabolic traits in the Collaborative Cross (CC) founder strains.


Assuntos
Camundongos de Cruzamento Colaborativo/genética , Camundongos de Cruzamento Colaborativo/metabolismo , Dieta , Fígado/fisiologia , Animais , Dieta Aterogênica/efeitos adversos , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Patrimônio Genético , Fígado/metabolismo , Metilaminas/sangue , Camundongos Endogâmicos C57BL , NADPH Oxidase 4/genética , Triglicerídeos/metabolismo
6.
Toxicol Appl Pharmacol ; 415: 115430, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33524446

RESUMO

Air pollutants may increase risk for cardiopulmonary disease, particularly in susceptible populations with metabolic stressors such as diabetes and unhealthy diet. We investigated effects of inhaled ozone exposure and high-cholesterol diet (HCD) in healthy Wistar and Wistar-derived Goto-Kakizaki (GK) rats, a non-obese model of type 2 diabetes. Male rats (4-week old) were fed normal diet (ND) or HCD for 12 weeks and then exposed to filtered air or 1.0 ppm ozone (6 h/day) for 1 or 2 days. We examined pulmonary, vascular, hematology, and inflammatory responses after each exposure plus an 18-h recovery period. In both strains, ozone induced acute bronchiolar epithelial necrosis and inflammation on histopathology and pulmonary protein leakage and neutrophilia; the protein leakage was more rapid and persistent in GK compared to Wistar rats. Ozone also decreased lymphocytes after day 1 in both strains consuming ND (~50%), while HCD increased circulating leukocytes. Ozone increased plasma thrombin/antithrombin complexes and platelet disaggregation in Wistar rats on HCD and exacerbated diet effects on serum IFN-γ, IL-6, KC-GRO, IL-13, and TNF-α, which were higher with HCD (Wistar>GK). Ex vivo aortic contractility to phenylephrine was lower in GK versus Wistar rats at baseline(~30%); ozone enhanced this effect in Wistar rats on ND. GK rats on HCD had higher aortic e-NOS and tPA expression compared to Wistar rats. Ozone increased e-NOS in GK rats on ND (~3-fold) and Wistar rats on HCD (~2-fold). These findings demonstrate ways in which underlying diabetes and HCD may exacerbate pulmonary, systemic, and vascular effects of inhaled pollutants.


Assuntos
Poluentes Atmosféricos/toxicidade , Aorta Torácica/efeitos dos fármacos , Colesterol na Dieta/toxicidade , Diabetes Mellitus Tipo 2/complicações , Dieta Aterogênica/efeitos adversos , Lesão Pulmonar/induzido quimicamente , Pulmão/efeitos dos fármacos , Ozônio/toxicidade , Doenças Vasculares/induzido quimicamente , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiopatologia , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Colesterol na Dieta/metabolismo , Citocinas/sangue , Diabetes Mellitus Tipo 2/sangue , Modelos Animais de Doenças , Mediadores da Inflamação/sangue , Exposição por Inalação , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/sangue , Lesão Pulmonar/patologia , Masculino , Necrose , Edema Pulmonar/sangue , Edema Pulmonar/induzido quimicamente , Edema Pulmonar/patologia , Ratos Wistar , Doenças Vasculares/sangue , Doenças Vasculares/fisiopatologia , Vasoconstrição/efeitos dos fármacos
7.
J Nutr ; 151(4): 902-910, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33561256

RESUMO

BACKGROUND: Epidemiologic studies suggest that fruit and vegetable (F&V) consumption is inversely associated with incidence of cardiovascular disease (CVD). However, evidence for causality is lacking, and the underlying mechanisms are not well understood. OBJECTIVES: We aimed to determine whether there is a causal relation between consuming high levels of F&V and prevention of atherosclerosis, the hallmark of CVD pathogenesis. Furthermore, the underlying mechanisms were determined. METHODS: Six-week-old male LDL receptor-knockout mice were randomly assigned to 3 diet groups (12 mice/group) for 20 wk: control (CON, 10% kcal fat, 0.20 g/kg cholesterol), atherogenic (Ath, 27% kcal fat, 0.55 g/kg cholesterol), and Ath supplemented with 15% F&V (Ath + FV) (equivalent to 8-9 servings/d in humans). F&V was added as a freeze-dried powder that was prepared from the 24 most commonly consumed F&Vs in the United States. Body weight, aortic atherosclerotic lesion area, hepatic steatosis area, serum lipid profile and proinflammatory cytokine TNF-α concentrations, gut microbiota, and liver TNF-α and fatty acid synthase (Fasn) mRNA concentrations were assessed. RESULTS: F&V supplementation did not affect weight gain. Mice fed the Ath + FV diet had a smaller aortic atherosclerotic lesion area (71.7% less) and hepatic steatosis area (80.7% less) than those fed the Ath diet (both P < 0.001) independent of impact on weight, whereas no difference was found between Ath + FV and CON groups in these 2 pathologic markers. Furthermore, F&V supplementation prevented Ath diet-induced dyslipidemia (high concentrations of serum TG and VLDL cholesterol and lower concentrations of HDL cholesterol), reduced serum TNF-α concentration (by 21.5%), suppressed mRNA expression of liver TNF-α and Fasn, and ameliorated Ath-induced gut microbiota dysbiosis. CONCLUSIONS: Our results indicate that consuming a large quantity and variety of F&Vs causally attenuates diet-induced atherosclerosis and hepatic steatosis in mice. These effects of F&Vs are associated with, and may be mediated through, improved atherogenic dyslipidemia, alleviated gut dysbiosis, and suppressed inflammation.


Assuntos
Aterosclerose/dietoterapia , Aterosclerose/prevenção & controle , Frutas , Receptores de LDL/deficiência , Verduras , Animais , Aterosclerose/etiologia , Dieta Aterogênica/efeitos adversos , Suplementos Nutricionais , Microbioma Gastrointestinal , Teste de Tolerância a Glucose , Fatores de Risco de Doenças Cardíacas , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Receptores de LDL/genética , Fator de Necrose Tumoral alfa/sangue , Aumento de Peso
8.
Drug Metab Dispos ; 49(1): 62-71, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33093018

RESUMO

Diet is an important factor for many diseases. Previous studies have demonstrated that several diets had remarkable effects on bile acid (BA) homeostasis, but no comprehensive information for both genders has been reported. Therefore, the current study characterized the nine most used laboratory animal diets fed to both genders of mice for a comparable evaluation of the topic. The results revealed that marked gender difference of BA homeostasis is ubiquitous in mice fed the various diets, and of the nine diets fed to mice, the atherogenic and calorie-restricted diets had the most marked effects on BA homeostasis, followed by the laboratory chow and essential fatty acid-deficient diets. More specifically, females had higher concentrations of total BAs in serum when fed six of the nine diets compared with male mice, and 26 of the 35 BA-related genes had marked gender difference in mice fed at least one diet. Although mice fed the calorie-restricted and atherogenic diets had increased BA, which was more pronounced in serum than liver, the intestinal farnesoid X nuclear receptor-fibroblast growth factor 15 axis changed in the opposite direction and resulted in different hepatic expression patterns of Cyp7a1 Compared with AIN-93M purified diet, higher hepatic expression of multidrug resistance-associated protein 3 was the only alteration in mice fed the laboratory chow diet. The other diets had little or no effect on BA concentrations in the liver and plasma or in the expression of BA-related genes. This study indicates that gender, the atherogenic diet, and the calorie-restricted diet have the most marked effects on BA homeostasis. SIGNIFICANCE STATEMENT: Previous evidence suggested that various diets have effect on bile acid (BA) homeostasis; however, it is not possible to directly compare these findings, as they are all from different studies. The current study was the first to systematically investigate the influence of the nine most used experimental mouse diets on BA homeostasis and potential mechanism in both genders of mice and indicates that gender, the atherogenic diet, and the calorie-restricted diet have the most marked effects on BA homeostasis, which will aid future investigations.


Assuntos
Ácidos e Sais Biliares/metabolismo , Restrição Calórica , Dieta Aterogênica , Regulação da Expressão Gênica/fisiologia , Fatores Sexuais , Transdução de Sinais/fisiologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Restrição Calórica/efeitos adversos , Restrição Calórica/métodos , Colesterol 7-alfa-Hidroxilase/metabolismo , Dieta/classificação , Dieta Aterogênica/efeitos adversos , Dieta Aterogênica/métodos , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Homeostase , Masculino , Camundongos , Receptores Citoplasmáticos e Nucleares/metabolismo
9.
J Ethnopharmacol ; 269: 113701, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33346028

RESUMO

ETHNOPHARMACOLOGY RELEVANCE: Schinus terebinthifolius is traditionally used for its anti inflammatory capacity, and indicated as a cardioprotective agent, whereas, its preventive effect against atherogenic diet fed (AD) induced metabolic disorders and the underlying mechanisms has not yet been explored. AIM OF THE STUDY: This study was undertaken to investigate the ameliorative role of Schinus terebinthifolius fruits extract (STFE) against cardiovascular problem, oxidative and inflammatory status related to obesity in rats fed an atherogenic diet. MATERIALS AND METHODS: The metabolites profile in STFE was evaluated using HPLC-DAD-ESI-QTOF-MS/MS analysis. In Wistar rats, atherogenic diet was added for 9 weeks to induce lipid accumulation simultaneously with STFE (50 mg/kg b. w) or saline treatment. Biochemical, oxidant, and inflammatory criteria together with hepatic and arterial integrity examination were assessed. RESULTS: A total of thirty three metabolites were identified using HPLC-DAD-ESI-QTOF-MS, among them masazino-flavanone was the major compound (2645.50 µg/g DW). The results indicated that STFE supplementation during 9 weeks (50 mg/kg b. w.) significantly attenuated the altered lipid profile by decreasing the levels of TC, TG, LDL-C and increasing the HDL-C content both in plasma and liver, when compared with the AD-group. The histological analysis using ORO staining revealed a decrease in the lipid droplet deposit in the cytoplasm of hepatocytes of STFE + AD group. The addition of STFE could improve the glycemic status of AD-treated rats by decreasing the glucose and insulin secretion, and ameliorating the hepatic glycogen synthesis. The harmful effects of atherogenic diet on hepatic oxidative stress indicators (MDA, PC, GSH, SOD, CAT, and GPx), biochemical markers (AST, ALT, LDH and ALP), and liver function, were found to be decreased by the addition of STFE. Moreover, the reduction of inflammatory markers (CRP, IL-6 and TNF-α), associated to alleviating of aortic oxidative stress and integrity, highlighted the positive anti-atherogenic effect of STFE. CONCLUSION: Overall, the pleiotropic protective effect observed with S. terebinthifolius fruits might be related to the presence of various bioactive compounds.


Assuntos
Anacardiaceae/química , Inflamação/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Doenças Vasculares/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Aorta/patologia , Aterosclerose/induzido quimicamente , Aterosclerose/tratamento farmacológico , Glicemia/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Dieta Aterogênica/efeitos adversos , Frutas/química , Inflamação/metabolismo , Insulina/sangue , Lipídeos/sangue , Fígado/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Glicogênio Hepático/metabolismo , Masculino , Doenças Metabólicas/metabolismo , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Fenóis/análise , Fenóis/química , Fenóis/isolamento & purificação , Extratos Vegetais/isolamento & purificação , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia
10.
Clin Transl Gastroenterol ; 11(9): e00234, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-33094961

RESUMO

INTRODUCTION: Endoscopic bariatric and metabolic therapies can potentially reproduce similar gastric and small intestinal anatomic and physiologic manipulations as Roux-en-Y gastric bypass. This proof of concept animal study was aimed to assess the feasibility, safety, efficacy, and impact on gastrointestinal physiology of combined intragastric balloons (IGB) and duodenal-jejunal bypass liner (DJBL) for the treatment of obesity. METHODS: Five Ossabaw pigs were fed a high-calorie diet to develop obesity and were randomly assigned to receive IGB or DJBL in sequence. The weight gain rate was calculated. Fasting and postprandial blood samples were drawn before any intervention (serving as the baseline group) and 1 month after second device insertion (serving as the combination group) to measure gut neurohormonal changes and metabolic parameters. RESULTS: Four pigs successfully received a sequential device insertion. One pig developed duodenal sleeve prolapse that was spontaneously resolved. One pig was early terminated because of developing a central line infection. The rate of weight gain in the combination group (0.63 ± 1.3 kg/wk) was significantly lower than the baseline group (1.96 ± 2.17 kg/wk) and numerically lower than after insertion of the IGB (1.00 ± 1.40 kg/wk) or the DJBL (0.75 ± 2.27 kg/wk) alone. A trend of higher postprandial glucagon-like peptide-1 was observed in the combination group compared with the baseline group. DISCUSSION: A combination of IGB and DJBL is feasible and well tolerated. A strategy of sequential use of these devices might offer a synergistic approach that can enhance weight loss and metabolic outcomes.


Assuntos
Cirurgia Bariátrica/instrumentação , Duodeno/cirurgia , Balão Gástrico , Jejuno/cirurgia , Obesidade Mórbida/cirurgia , Anastomose em-Y de Roux/instrumentação , Anastomose em-Y de Roux/métodos , Animais , Cirurgia Bariátrica/métodos , Terapia Combinada/instrumentação , Terapia Combinada/métodos , Dieta Aterogênica/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Estudos de Viabilidade , Peptídeo 1 Semelhante ao Glucagon/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Obesidade Mórbida/sangue , Obesidade Mórbida/etiologia , Obesidade Mórbida/metabolismo , Período Pós-Prandial , Estudo de Prova de Conceito , Suínos , Porco Miniatura , Redução de Peso
11.
Nutrients ; 12(7)2020 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-32708633

RESUMO

Hyperglycaemia has a toxic effect on blood vessels and promotes coronary artery disease. It is unclear whether the dysfunction caused by hyperglycaemia is blood vessel specific and whether the dysfunction is exacerbated following an atherogenic diet. Abdominal aorta, iliac, and mesenteric arteries were dissected from New Zealand White rabbits following either a 4-week normal or atherogenic diet (n = 6-12 per group). The arteries were incubated ex vivo in control or high glucose solution (20 mM or 40 mM) for 2 h. Isometric tension myography was used to determine endothelial-dependent vasodilation. The atherogenic diet reduced relaxation as measured by area under the curve (AUC) by 25% (p < 0.05), 17% (p = 0.06) and 40% (p = 0.07) in the aorta, iliac, and mesenteric arteries, respectively. In the aorta from the atherogenic diet fed rabbits, the 20 mM glucose altered EC50 (p < 0.05). Incubation of the iliac artery from atherogenic diet fed rabbits in 40 mM glucose altered EC50 (p < 0.05). No dysfunction occurred in the mesentery with high glucose incubation following either the normal or atherogenic diet. High glucose induced endothelial dysfunction appears to be blood vessel specific and the aorta may be the optimal artery to study potential therapeutic treatments of hyperglycaemia induced endothelial dysfunction.


Assuntos
Artérias , Dieta Aterogênica/efeitos adversos , Endotélio Vascular/fisiopatologia , Glucose/efeitos adversos , Hiperglicemia/etiologia , Doença Aguda , Animais , Doença da Artéria Coronariana/etiologia , Diabetes Mellitus/etiologia , Endotélio Vascular/metabolismo , Humanos , Técnicas In Vitro , Masculino , Relaxamento Muscular , Óxido Nítrico/metabolismo , Coelhos
12.
Nat Commun ; 11(1): 3766, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724076

RESUMO

Dipeptidyl peptidase-4 (DPP4) modulates inflammation by enzymatic cleavage of immunoregulatory peptides and through its soluble form (sDPP4) that directly engages immune cells. Here we examine whether reduction of DPP4 activity alters inflammation. Prolonged DPP4 inhibition increases plasma levels of sDPP4, and induces sDPP4 expression in lymphocyte-enriched organs in mice. Bone marrow transplantation experiments identify hematopoietic cells as the predominant source of plasma sDPP4 following catalytic DPP4 inhibition. Surprisingly, systemic DPP4 inhibition increases plasma levels of inflammatory markers in regular chow-fed but not in high fat-fed mice. Plasma levels of sDPP4 and biomarkers of inflammation are lower in metformin-treated subjects with type 2 diabetes (T2D) and cardiovascular disease, yet exhibit considerable inter-individual variation. Sitagliptin therapy for 12 months reduces DPP4 activity yet does not increase markers of inflammation or levels of sDPP4. Collectively our findings dissociate levels of DPP4 enzyme activity, sDPP4 and biomarkers of inflammation in mice and humans.


Assuntos
Doenças Cardiovasculares/imunologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/sangue , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inflamação/imunologia , Idoso , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/imunologia , Dieta Aterogênica/efeitos adversos , Dieta Hiperlipídica/efeitos adversos , Dipeptidil Peptidase 4/imunologia , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Modelos Animais de Doenças , Feminino , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Mediadores da Inflamação/análise , Mediadores da Inflamação/metabolismo , Masculino , Metformina/administração & dosagem , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/sangue , Isoformas de Proteínas/metabolismo , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/efeitos adversos
13.
J Nutr Biochem ; 79: 108337, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32018113

RESUMO

Atherogenic diet (AD) decreased bone density and increased serum cholesterol level in male mice, implying that cholesterol participates in bone loss. The aim of the present study was to identify the cells responsible for bone loss and evaluate the involved mechanism. AD resulted in increased number and surface of osteoclasts (OCs) with in vivo tartrate-resistant acid phosphatase (TRAP) staining, suggesting a critical role of OCs in cholesterol-induced bone loss. In vitro, cholesterol loading by oxidized low-density lipoprotein (oxLDL) increased the size and number of OCs as well as bone resorption activity, suggesting that cholesterol loading affects the number and activity of OCs. In contrast, cholesterol depletion by simvastatin decreased osteoclastogenesis and bone resorption. oxLDL stimulated osteoblasts (OBs) to increase expression of receptor activator of nuclear factor kappa-Β ligand (RANKL), resulting in increased OC formation when OBs were co-cultured with bone marrow derived macrophages. oxLDL increased expression of CD36 and liver X receptors (LXRα) in OCs as well as low density lipoprotein receptor (LDLR) and LXRα in OBs. These results suggest that CD36 and LXRα mediate the effect of oxLDL in OCs, whereas LDLR and LXRα mediate the effect of oxLDL in OBs. These findings demonstrate cholesterol-induced bone loss with increasing number and activity of OCs in mice, suggesting another harmful effect of cholesterol, a major cause of atherosclerosis.


Assuntos
Reabsorção Óssea/metabolismo , Dieta Aterogênica/efeitos adversos , Osteoclastos/metabolismo , Osteogênese/efeitos dos fármacos , Animais , Anticolesterolemiantes/farmacologia , Reabsorção Óssea/etiologia , Diferenciação Celular/efeitos dos fármacos , Colesterol/efeitos adversos , Colesterol/farmacologia , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoclastos/efeitos dos fármacos , Ligante RANK/metabolismo , Sinvastatina/farmacologia
14.
J Biochem Mol Toxicol ; 34(2): e22422, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31729780

RESUMO

M1 macrophages serve one edge as proinflammatory and M2 macrophages serve the other edge as an anti-inflammatory macrophage. It appears that a related "switch" in macrophage morphology may also happen in the course of atherosclerosis, which has not yet been elucidated. An atherogenic diet (AD) was given to rats, and induction of macrophage differentiation and the nuclear localization of nuclear factor-kappa B (NFκB) were investigated by Western blot and immunofluorescence. Chemokines were analyzed using an antibody array with 32 target proteins. M2 macrophage transformation was confirmed in diosgenin-treated aorta by immunofluorescence and was validated in vitro using THP-1 cells. MAC387 (macrophage marker) and NFκBp65 (inflammatory hub) were upregulated in oxidatively-modified low-density lipoprotein (OxyLDL) and AD-induced condition. Macrophage differentiation, which induced the formation of inflammatory mediators, was not significantly suppressed by the inhibition of NFκB using dexamethasone. M1 macrophage polarization was identified in OxyLDL-induced monocytes, which are proinflammatory in nature, whereas M2 macrophage polarization was noticed in diosgenin-treated monocytes, which exhibit anti-inflammatory properties. M1-and M2-specific chemokines were analyzed using chemokine antibody array. Furthermore, the expression of proinflammatory macrophage (M1) was noticed in AD-induced aorta and anti-inflammatory macrophage (M2) was observed in diosgenin-treated aorta. This is the first report where, unifying the mechanism of diosgenin as aan nti-atherosclerotic and the expression of M1 and M2 specific chemokines is shown by downregulating NFκB and not by preventing the differentiation of monocyte into a macrophage, but by allowing macrophage to differentiate into M2, which aids in preventing the atherosclerotic progression.


Assuntos
Aorta/metabolismo , Aterosclerose/metabolismo , Polaridade Celular , Citocinas/metabolismo , Diosgenina/farmacologia , Macrófagos/metabolismo , Extratos Vegetais/farmacologia , Fator de Transcrição RelA/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Antígenos CD36/genética , Antígenos CD36/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dexametasona/farmacologia , Dieta Aterogênica/efeitos adversos , Dioscorea/química , Diosgenina/uso terapêutico , Humanos , Lipoproteínas LDL/farmacologia , Masculino , Monócitos/metabolismo , Extratos Vegetais/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética
15.
Sci Rep ; 9(1): 16810, 2019 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-31728041

RESUMO

Lipotoxicity is a key player in the pathogenesis of nonalcoholic steatohepatitis (NASH), a progressive subtype of nonalcoholic fatty liver disease (NAFLD). In the present study, we combine histological, transcriptional and lipidomic approaches to dissociate common and specific alterations induced by two classical dietary NASH models (atherogenic (ATH) and methionine/choline deficient (MCD) diet) in C57BL/6J male mice. Despite a similar degree of steatosis, MCD-fed mice showed more pronounced liver damage and a worsened pro-inflammatory and pro-fibrogenic environment than ATH-fed mice. Regarding lipid metabolism, the ATH diet triggered hepatic counter regulatory mechanisms, while the MCD diet worsened liver lipid accumulation by a concomitant increase in lipid import and reduction in lipid export. Liver lipidomics revealed sphingolipid enrichment in both NASH models that was accompanied by an upregulation of the ceramide biosynthesis pathway and a significant rise in dihydroceramide levels. In contrast, the phospholipid composition was not substantially altered by the ATH diet, whereas the livers of MCD-fed mice presented a reduced phosphatidylcholine to phosphatidylethanolamine (PC/PE) ratio and a strong depletion in phospholipids containing the sum of 34-36 carbons in their fatty acid chains. Therefore, the assessment of liver damage at the histological and transcriptional level combined with a lipidomic analysis reveals sphingolipids as shared mediators in liver lipotoxicity and pathogenesis of NASH.


Assuntos
Aterosclerose/metabolismo , Dieta/efeitos adversos , Redes Reguladoras de Genes/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Esfingolipídeos/metabolismo , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Colina/química , Dieta Aterogênica/efeitos adversos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Lipidômica , Masculino , Metionina/deficiência , Camundongos , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Fosfatidilcolinas/metabolismo
16.
J Hum Hypertens ; 33(12): 844-855, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31636352

RESUMO

Metabolic syndrome (MetS) is a collection of pathological conditions associated with metabolic, pro-inflammatory, and prothrombotic states. MetS plays an essential role in the atherosclerotic process with associated clustering of risk factors which can increase the risk of atherogenic damage. There is an association between MetS components and the progression of atherosclerosis, which is the leading cause of cardiovascular deaths. This review was undertaken to assess the potential role of metabolic syndrome components, including oxidative stress, hypertension, hyperglycaemia and insulin resistance, obesity, dyslipidemia, chronic inflammation, physical inactivity, and atherogenic diet in the progression of atherosclerosis based on existing research.


Assuntos
Aterosclerose , Síndrome Metabólica , Aterosclerose/sangue , Aterosclerose/epidemiologia , Aterosclerose/fisiopatologia , Aterosclerose/terapia , Biomarcadores/sangue , Coagulação Sanguínea , Glicemia/metabolismo , Dieta Aterogênica/efeitos adversos , Progressão da Doença , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/fisiopatologia , Humanos , Hiperglicemia/sangue , Hiperglicemia/epidemiologia , Hiperglicemia/fisiopatologia , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Inflamação/sangue , Inflamação/epidemiologia , Inflamação/fisiopatologia , Mediadores da Inflamação/sangue , Resistência à Insulina , Lipídeos/sangue , Síndrome Metabólica/sangue , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/fisiopatologia , Síndrome Metabólica/terapia , Obesidade/sangue , Obesidade/epidemiologia , Obesidade/fisiopatologia , Estresse Oxidativo , Prognóstico , Medição de Risco , Fatores de Risco , Comportamento Sedentário
17.
Nutrients ; 11(10)2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581458

RESUMO

Serum uric acid (SUA) and apolipoprotein B (apoB) are markers of the risk of morbidity and mortality. However, no study has investigated their role, simultaneously with nutritional factors, on the risk of mortality. We calculated the dietary uricaemia score (DUS) and the dietary atherogenic score (DAS) and evaluated their associations with the risk of all-cause and cause-specific mortality. Data from the NHANES 1999-2010 study were used. Vital status through the 31 December 2011 was ascertained. Reduced rank regression models followed by stepwise linear regression analyses were applied on 39 macro/micronutrients to identify a dietary pattern most predictive of SUA (DUS) and apoB (DAS). Overall, 20,256 participants were included (mean age: 47.5 years; 48.7% men). DUS consists of 14 contributors (eight positive, six negative), whereas DAS consists of 23 contributors (six positive, 17 negative). An increasing risk of cause-specific mortality was found across the quartiles (Q) of DUS, i.e., participants with the highest score of DUS (Q4) had a greater risk of all-cause (hazard ratio (HR): 1.17, 95% confidence interval (CI): 1.07-1.30), cardiovascular disease (CVD) (HR: 1.36, 95%CI: 1.21-1.59) and cancer (HR: 1.06, 95%CI: 1.01-1.14) mortality compared with Q1. Similarly, participants at the highest DAS quartile had 25, 40 and 11% greater risk of all-cause, CVD and cancer mortality, respectively, compared with Q1. For the first time, we reported an underlying shared link between two atherosclerosis factors (SUA and apoB) and nutrients, as well as their joint adverse impact on all-cause and cause-specific mortality.


Assuntos
Aterosclerose/mortalidade , Dieta Aterogênica/mortalidade , Comportamento Alimentar , Hiperuricemia/mortalidade , Apolipoproteína B-100/sangue , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/etnologia , Biomarcadores/sangue , Causas de Morte , Dieta Aterogênica/efeitos adversos , Dieta Aterogênica/etnologia , Comportamento Alimentar/etnologia , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/diagnóstico , Hiperuricemia/etnologia , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia , Ácido Úrico/sangue
18.
Mediators Inflamm ; 2019: 6163130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31534437

RESUMO

Electronegative low-density lipoprotein (LDL(-)) has been found in the plasma of familial hypercholesterolemia and acute myocardial infarction and has been implicated in atherosclerosis and cardiovascular disease. However, less is known about the involvement of LDL(-) in atherosclerosis-related inflammation. This study aims at investigating the inducibility of LDL(-) by atherogenic diet in rabbits and at exploring the proinflammatory potential of the diet-induced LDL(-) in macrophages. Rabbits were fed with an atherogenic diet; LDL was isolated from plasma by NaBr density gradient ultracentrifugation and was then resolved into nLDL and LDL(-) by anion-exchange chromatography. Isolated nLDL and LDL(-) were directly used or incubated with 10 µM CuSO4 for 24 h to produce copper- (Cu-) ox-nLDL and Cu-ox-LDL(-). The effects of these LDLs on inflammation were evaluated in THP-1-derived macrophages. Macrophages were treated with nLDL, LDL(-), and extensively oxidized LDL (ox-LDL), then the levels of interleukin- (IL-) 1ß, IL-6, and tumor necrosis factor- (TNF-) α in a culture medium were determined by ELISA, and the levels of total and phosphorylated IκB, p65, p38, JNK, and ERK in cell lysates were determined by Western blotting. The LDL(-) induced significantly higher levels of IL-1ß, IL-6, and TNF-α in the medium. The levels of phosphorylated/total IκB, p65, p38, JNK, and ERK were also upregulated by LDL(-). In contrast, nLDL, Cu-ox-nLDL, and Cu-ox-LDL(-) exhibited much less effect. Knockdown of lectin-type oxidized LDL receptor- (LOX-) 1 resulted in significant reduction in LDL(-)-induced IL-1ß, IL-6, and TNF-α. In addition, these LDL(-) effects were also markedly attenuated by inhibition of NF-κB and ERK1/2. The data suggested that LDL(-) induced inflammation through LOX-1-, NF-κB-, and ERK1/2-dependent pathways. Taken together, our results show that rabbits fed with atherogenic diet produce a highly proinflammatory LDL(-) that is more potent in inducing inflammation than nLDL and extensively oxidize LDL in macrophages. The results thus provide a novel link between diet-induced hypercholesterolemia and inflammation.


Assuntos
Dieta Aterogênica/efeitos adversos , Interleucina-1beta/sangue , Lipoproteínas LDL/sangue , Macrófagos/metabolismo , Animais , Western Blotting , Linhagem Celular Tumoral , Humanos , Interleucina-6/sangue , Masculino , NF-kappa B/sangue , Coelhos , Células THP-1 , Fator de Necrose Tumoral alfa/sangue
19.
Nat Commun ; 10(1): 2631, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201301

RESUMO

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating a primary effect of sex chromosomes. Small intestine expression of enzymes involved in lipid absorption and chylomicron assembly are greater in XX male and female mice with higher intestinal lipids. Together, our results show that an XX sex chromosome complement promotes the bioavailability of dietary fat to accelerate atherosclerosis.


Assuntos
Transtornos 46, XX do Desenvolvimento Sexual/metabolismo , Aterosclerose/genética , Metabolismo dos Lipídeos/genética , Lipídeos/sangue , Cromossomo X/fisiologia , Transtornos 46, XX do Desenvolvimento Sexual/sangue , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Dieta Aterogênica/efeitos adversos , Modelos Animais de Doenças , Feminino , Hormônios Esteroides Gonadais/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Intestino Delgado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovário/metabolismo , Fatores Sexuais , Proteína da Região Y Determinante do Sexo/genética , Testículo/metabolismo
20.
Sci Rep ; 9(1): 8065, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147569

RESUMO

Vascular inflammation via T-cell-mediated immune responses has been shown to be critically involved in the pathogenesis of abdominal aortic aneurysm (AAA). T-cell coinhibitory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is known to act as a potent negative regulator of immune responses. However, the role of this molecule in the development of AAA remains completely unknown. We determined the effects of CTLA-4 overexpression on experimental AAA. We continuously infused CTLA-4 transgenic (CTLA-4-Tg)/apolipoprotein E-deficient (Apoe-/-) mice or control Apoe-/- mice fed a high-cholesterol diet with angiotensin II by implanting osmotic mini-pumps and evaluated the development of AAA. Ninety percent of angiotensin II-infused mice developed AAA, with 50% mortality because of aneurysm rupture. Overexpression of CTLA-4 significantly reduced the incidence (66%), mortality (26%), and diameter of AAA. These protective effects were associated with a decreased number of effector CD4+ T cells and the downregulated expression of costimulatory molecules CD80 and CD86, ligands for CTLA-4, on CD11c+ dendritic cells in lymphoid tissues. CTLA-4-Tg/Apoe-/- mice had reduced accumulation of macrophages and CD4+ T cells, leading to attenuated aortic inflammation, preserved vessel integrity, and decreased susceptibility to AAA and aortic rupture. Our findings suggest T-cell coinhibitory molecule CTLA-4 as a novel therapeutic target for AAA.


Assuntos
Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/imunologia , Ruptura Aórtica/imunologia , Aterosclerose/complicações , Antígeno CTLA-4/metabolismo , Angiotensina II/toxicidade , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/patologia , Aterosclerose/imunologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Dieta Aterogênica/efeitos adversos , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Camundongos Knockout para ApoE , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/metabolismo
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