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Chronic hypertension is a major risk factor for preeclampsia (PE), associated with significant maternal and neonatal morbidity. We previously demonstrated that pregnant stroke-prone spontaneously hypertensive rats (SHRSP) display a spontaneous PE-like phenotype with distinct placental, fetal, and maternal features. Here, we hypothesized that supplementation with alpha lipoic acid (ALA), a potent antioxidant, during early pregnancy could ameliorate the PE phenotype in this model. To test this hypothesis, timed pregnancies were established using 10 to 12-week-old SHRSP females (n = 19-16/group), which were assigned to two treatment groups: ALA (injected intraperitoneally with 25 mg/kg body weight ALA on gestation day (GD1, GD8, and GD12) or control, receiving saline following the same protocol. Our analysis of maternal signs showed that ALA prevented the pregnancy-dependent maternal blood pressure rise (GD14 blood pressure control 169.3 ± 19.4 mmHg vs. 146.1 ± 13.4 mmHg, p = 0.0001) and ameliorated renal function, as noted by the increased creatinine clearance and improved glomerular histology in treated dams. Treatment also improved the fetal growth restriction (FGR) phenotype, leading to increased fetal weights (ALA 2.19 ± 0.5 g vs. control 1.98 ± 0.3 g, p = 0.0074) and decreased cephalization indexes, indicating a more symmetric fetal growth pattern. This was associated with improved placental efficiency, decreased oxidative stress marker expression on GD14, and serum soluble fms-like tyrosine kinase 1 (sFlt1) levels on GD20. In conclusion, ALA supplementation mitigated maternal signs and improved placental function and fetal growth in SHRSP pregnancies, emerging as a promising therapy in pregnancies at high risk for PE.
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Type 2 diabetes (T2D) is a disease that occurs when cells do not respond normally to insulin, a condition called insulin resistance, which leads to high blood glucose levels. Although it can be treated pharmacologically, dietary habits beyond carbohydrate restriction can be highly relevant in the management of T2D. Emerging evidence supports the possibility that natural products (NPs) could contribute to managing blood glucose or counteract the undesirable effects of hyperglycemia and insulin resistance. This chapter summarizes the relevant preclinical evidence involving the flavonoid (-)-epicatechin (EC) in the optimization of glucose homeostasis, reducing insulin resistance and/or diabetes-associated disorders. Major effects of EC are observed on (i) intestinal functions, including digestive enzymes, glucose transporters, microbiota, and intestinal permeability, and (ii) redox homeostasis, including oxidative stress and inflammation. There is still a need for further clinical studies to confirm the in vitro and rodent data, allowing recommendations for EC, particularly in prediabetic and T2D patients. The collection of similar data and the lack of clinical evidence for EC is also applicable to other NPs.
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This review summarizes experimental evidence on the beneficial effects of ( -)-epicatechin (EC) attenuating major cardiometabolic risk factors, i.e., dyslipidemias, obesity (adipose tissue dysfunction), hyperglycemia (insulin resistance), and hypertension (endothelial dysfunction). Studies in humans are revised and complemented with experiments in animal models, and cultured cells, aiming to understand the molecular mechanisms involved in EC-mediated effects. Firstly, an assessment of EC metabolism gives relevance to both conjugated-EC metabolites product of host metabolism and microbiota-derived species. Integration and analysis of results stress the maintenance of redox homeostasis and mitigation of inflammation as relevant processes associated with cardiometabolic diseases. In these processes, EC appears having significant effects regulating NADPH oxidase (NOX)-dependent oxidant production, nitric oxide (NO) production, and energy homeostasis (mitochondrial biogenesis and function). The potential participation of cell membranes and membrane-bound receptors is also discussed in terms of direct molecular action of EC and EC metabolites reaching cells and tissues.
Assuntos
Fatores de Risco Cardiometabólico , Catequina/farmacologia , Animais , Catequina/química , Catequina/metabolismo , Catequina/uso terapêutico , Dislipidemias/tratamento farmacológico , Humanos , Hiperglicemia/tratamento farmacológico , Hipertensão/tratamento farmacológico , Obesidade/tratamento farmacológicoRESUMO
RESUMEN Introducción: Se desconoce el papel del anión cloruro en los efectos deletéreos del consumo excesivo de sal (NaCl) y si sus efectos son independientes de la presencia del sodio. Objetivo: Demostrar que tanto una sobrecarga de cloruro como una sobrecarga de sodio en la dieta producen efectos deletéreos, en forma independiente, sobre la presión arterial sistólica (PAS), la función renal y los marcadores de estrés oxidativo en el riñón. Materiales y métodos: Ratas Wistar macho fueron divididas en cuatro grupos (n = 8/grupo) y fueron alimentadas con diferentes dietas durante tres semanas: C: control (dieta estándar), NaCl: hipersódica-hiperclórica, Na: hipersódica sin cloruro, Cl: hiperclórica sin sodio. Se determinaron la presión arterial sistólica (PAS) y la función renal y en la corteza renal, se evaluó la producción de especies reactivas del ácido tiobarbitúrico (en inglés: TBARS) y la actividad y la expresión de las enzimas superóxido dismutasa (SOD), catalasa (CAT) y glutatión peroxidasa (GPx). Resultados: Al cabo de tres semanas, la PAS aumentó (*) en los dos grupos alimentados con cloruro. La excreción fraccional de sodio y de cloruro aumentó (*) en los grupos NaCl y Na. La diuresis y los TBARS en la corteza renal aumentaron (*) con las tres dietas, sin cambios en la actividad y en la expresión de SOD y CAT. La actividad de la GPx aumentó (*) en los dos grupos que recibieron cloruro; (*p < 0,05 vs C). Conclusión: Tanto la sobrecarga de sodio como la de cloruro se asocian a mayor estado oxidativo caracterizado por un incremento en la peroxidación lipídica en la corteza renal. Sin embargo, solo el exceso de cloruro se asocia a mayor actividad de la GPx y de la hipertensión, sin cambios en la excreción urinaria de cloruros, sugiriendo un mayor estado prooxidante renal en comparación con el grupo Na.
ABSTRACT Introduction: The role of the chloride anion on the deleterious effects of excessive consumption of salt (NaCl) and whether its effects are independent each other of the presence of sodium remains to date, unknown and unclear. Objective: To demonstrate that both a chloride overload and a sodium overload in the diet produce deleterious effects, by different mechanisms, on systolic blood pressure (SBP), renal function and markers of oxidative stress in the kidney. Materials and Methods: Male Wistar rats were divided into four groups (n = 8 / group) and fed with different diets for three weeks: C: control (standard diet), and diets: NaCl: hypersodic-hyperchloric; Na: hypersodic without chloride and Cl: hyperchloric without sodium. Systolic blood pressure (SBP) and renal function were determined, and the production of thiobarbituric acid reactive species (TBARS) and the activity and expression of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) enzymes were evaluated in renal cortex tissue. Results: SBP increased (*) in the two groups fed with chloride. The fractional excretion of sodium and chloride increased (*) in the NaCl and Na groups. increased (*) in the renal cortex with the three diets. No changes were observed in the activity and expression of SOD and CAT. GPx activity increased (*) in the two groups that received chloride; (* p <0.05 vs C). Conclusion: Both sodium and chloride overload are associated with a higher oxidative state characterized by an increase in lipid peroxidation in the renal cortex. However, compared with Na group, only chloride overload is associated with higher GPx activity and hypertension without any changes in urinary chloride excretion, suggesting a higher renal pro-oxidant state in this experimental group.
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High adipose tissue (AT) accumulation in the body increases the risk for many metabolic and chronic diseases. This work investigated the capacity of the flavonoid (-)-epicatechin to prevent undesirable modifications of AT in mice fed a high-fat diet. Studies were focused on thoracic aorta perivascular AT (taPVAT), which is involved in the control of blood vessel tone, among other functions. Male C57BL/6J mice were fed for 15 weeks a high-fat diet with or without added (-)-epicatechin (20 mg per kg body weight per d). In high-fat diet fed mice, (-)-epicatechin supplementation: (i) prevented the expansion of taPVAT, (ii) attenuated the whitening of taPVAT (according to the adipocyte morphology, diameter, and uncoupling-protein 1 (UCP-1) levels) and (iii) blunted the increase in plasma glucose and cholesterol. The observed taPVAT modifications were not associated with alterations in the aorta wall thickness, aorta tumor necrosis factor-alpha (TNF-α) and NADPH-oxidase 2 (NOX2) expression, and endothelial nitric oxide synthase (eNOS) phosphorylation levels. In summary, our results indicate (-)-epicatechin as a relevant bioactive protecting from the slow and silent development of metabolic and chronic diseases as they are associated with excessive fat intake.
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Tecido Adiposo/patologia , Aorta Torácica/patologia , Catequina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/efeitos adversos , Suplementos Nutricionais , Extratos Vegetais/farmacologia , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco , Animais , Aorta Torácica/metabolismo , Glicemia/metabolismo , Catequina/uso terapêutico , Colesterol/sangue , Gorduras na Dieta/administração & dosagem , Masculino , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Doenças Metabólicas/prevenção & controle , Camundongos Endogâmicos C57BL , NADPH Oxidase 2/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Obesidade/metabolismo , Obesidade/prevenção & controle , Extratos Vegetais/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Proteína Desacopladora 1/metabolismoRESUMO
The aim of this work was to evaluate the protective effects of (-)-epicatechin on the kidneys of NO-deprived rats. Male Sprague Dawley rats were divided into three groups: control (C), receiving water and standard diet; l-NAME (L), receiving a solution of N(ω)-nitro-l-arginine methyl ester (l-NAME) (360 mg l-1 in water) as a beverage and standard diet; and l-NAME-(-)-epicatechin (LE), receiving l-NAME solution as a beverage and standard diet supplemented with (-)-epicatechin (4 g kg-1 diet). The L-group showed altered kidney function parameters, evaluated based on plasma urea and creatinine. In parallel, kidney oxidative stress markers, i.e. superoxide anion production, malondialdehyde content, and 3-nitrotyrosine protein adducts, were significantly increased in the L group. In addition, l-NAME treatment induced modifications in kidney NO bioavailability determinants: increased expression of NOX subunits (p47phox, gp91phox, NOXO1, and NOX4) and lowered NOS activity. (-)-Epicatechin administration restored kidney function parameters, oxidative stress markers, expression of p47phox, gp91phox, and NOX4 and NOS activity to control values. These results indicate that (-)-epicatechin can mitigate NO-mediated impairment of kidney function, in part due to its capacity to modulate NOXs, NOSs, and consequently oxidative stress, and NO bioavailability.
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Catequina/farmacologia , Rim/efeitos dos fármacos , NG-Nitroarginina Metil Éster/efeitos adversos , Estresse Oxidativo , Substâncias Protetoras/farmacologia , Animais , Masculino , Malondialdeído/metabolismo , NADPH Oxidases/metabolismo , Óxido Nítrico/análise , Ratos , Ratos Sprague-Dawley , Superóxidos/metabolismoRESUMO
Inflammation involves the activation of redox-sensitive transcription factors, e.g., nuclear factor κB (NF-κB). Administration of (-)-epicatechin to high-fructose-fed rats prevented NF-κB activation and up-regulation of the NADPH oxidase 4 (NOX4) in the kidney cortex. These results add mechanistic insights into the action of (-)-epicatechin diminishing inflammatory responses.
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Catequina/metabolismo , Frutose/metabolismo , Córtex Renal/enzimologia , NADPH Oxidase 1/metabolismo , NADPH Oxidase 4/metabolismo , NF-kappa B/metabolismo , Animais , Córtex Renal/metabolismo , Masculino , NADPH Oxidase 1/genética , NADPH Oxidase 2/genética , NADPH Oxidase 2/metabolismo , NADPH Oxidase 4/genética , NF-kappa B/genética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismoRESUMO
This study investigated the effects of a quercetin-supplemented diet on the biochemical changes installed in the heart of NO-deficient rats in terms of oxidants production and NO bioavailability determinants. Sprague-Dawley rats were subjected to Nω-nitro-l-arginine methyl ester (l-NAME) treatment (360â¯mg/L l-NAME in the drinking water, 4â¯d) with or without supplementation with quercetin (4â¯g/kg diet). l-NAME administration led to increased blood pressure (BP) (30%), decreased nitric oxide synthase (NOS) activity (50%), and increases in NADPH oxidase (NOX)-dependent superoxide anion production (60%) and p47phox protein level (65%). The co-administration of quercetin prevented the increase in BP and the activation of NOX but did not modify the decrease in NOS activity caused by l-NAME. In addition, quercetin affected oxidative stress parameters as glutathione oxidation, and the activities of oxidant detoxifying enzymes superoxide dismutase, glutathione peroxidase, and catalase. Thus, quercetin administration counteracts l-NAME effects on NO bioavailability determinants in vivo, essentially through controlling NOX-mediated superoxide anion production.
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Antioxidantes/farmacologia , Inibidores Enzimáticos/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Quercetina/farmacologia , Animais , Antioxidantes/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Glutationa/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Hipertensão/prevenção & controle , Masculino , NG-Nitroarginina Metil Éster/administração & dosagem , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Quercetina/administração & dosagem , Ratos Sprague-Dawley , Superóxidos/metabolismoRESUMO
Metabolic syndrome is an array of closely metabolic disorders that includes glucose intolerance/insulin resistance, central obesity, dyslipidemia, and hypertension. Fructose, a highly lipogenic sugar, has profound metabolic effects in adipose tissue, and has been associated with the etiopathology of many components of the metabolic syndrome. In adipocytes, the enzyme 11 ß-HSD1 amplifies local glucocorticoid production, being a key player in the pathogenesis of central obesity and metabolic syndrome. 11 ß-HSD1 reductase activity is dependent on NADPH, a cofactor generated by H6PD inside the endoplasmic reticulum. Our focus was to explore the effect of fructose overload on epididymal white adipose tissue (EWAT) machinery involved in glucocorticoid production and NADPH and oxidants metabolism. Male Sprague-Dawley rats fed with a fructose solution (10% (w/v) in tap water) during 9 weeks developed some characteristic features of metabolic syndrome, such as hypertriglyceridemia, and hypertension. In addition, high levels of plasma and EWAT corticosterone were detected. Activities and expressions of H6PD and 11 ß-HSD1, NAPDH content, superoxide anion production, expression of NADPH oxidase 2 subunits, and indicators of oxidative metabolism were measured. Fructose overloaded rats showed an increased potential in oxidant production respect to control rats. In parallel, in EWAT from fructose overloaded rats we found higher expression/activity of H6PD and 11 ß-HSD1, and NADPH/NADP+ ratio. Our in vivo results support that fructose overload installs in EWAT conditions favoring glucocorticoid production through higher H6PD expression/activity supplying NADPH for enhanced 11 ß-HSD1 expression/activity, becoming this tissue a potential extra-adrenal source of corticosterone under these experimental conditions.
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Tecido Adiposo Branco/metabolismo , Corticosterona/metabolismo , Frutose/efeitos adversos , NADP/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Pressão Sanguínea , Peso Corporal , Corticosterona/sangue , Ingestão de Alimentos , Epididimo/efeitos dos fármacos , Epididimo/metabolismo , Frutose/metabolismo , Glucosefosfato Desidrogenase/metabolismo , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , NADPH Oxidase 2/metabolismo , Ratos Sprague-DawleyRESUMO
This work investigated the capacity of (-)-epicatechin to prevent the renal damage induced by LPS administration in rats. Male Sprague Dawley rats were fed for 4 days a diet without or with supplementation with (-)-epicatechin (80mg/kg BW/d), and subsequently i.p. injected with lipopolysaccharide (LPS). Six hours after injection, LPS-treated rats exhibited increased plasma creatinine and urea levels as indicators of impaired renal function. The renal cortex of the LPS-treated rats showed: i) increased expression of inflammatory molecules (TNF-α, iNOS and IL-6); ii) activation of several steps of NF-κB pathway; iii) overexpression of TLR4, and iv) higher superoxide anion production and lipid peroxidation index in association with increased levels of gp91phox and p47phox (NOX2) and NOX4. Pretreatment with dietary (-)-epicatechin prevented the adverse effects of LPS challenge essentially by inhibiting TLR4 upregulation and NOX activation and the consequent downstream events, e.g. NF-kB activation.