[Nutrigenetics: potentials and applications in cardiovascular diseases and associated risk factors]. / Potenciales de la nutrigenética en el abordaje y tratamiento de enfermedades cardiovasculares y factores de riesgo asociados.

Introduction: From nutrigenetics, the genetic variation to dietary response, it is possible to understand and modulate the clinical response conditioned by the genotype by the diet. Objetive: to explore the bibliographic evidence on the potential of nutrigenetics in the approach and treatment of cardiovascular diseases (CVD) and associated risk factors. Materials and methods: a systematic search was carried out in the electronic databases MEDLINE, EMBASE and Google Scholar. Those articles that contained the keywords or a combination of them, during 1990-2019, from both experimental and observational studies, were included. Results: 49 articles were included, classified according to the main molecular pathways involved in the etiopathogenesis of CVD. Although a wide diversity of genetic variants was found that confer susceptibility to CVD and risk factors such as obesity, dyslipidemia and arterial hypertension, there is little consistency in the publication of replication studies. Conclusions: the knowledge of genetic variants allows the personalization of the diet, which can be complemented with other healthy recommendations associated with the lifestyle. More studies in large populations and meta-analyzes are necessary to unequivocally show the gene-nutrient relationship.

Introducción: A partir de la nutrigenética, estudio del efecto que la variación genética tiene sobre la respuesta individual a la dieta, es posible comprender y modular la respuesta clínica condicionada por el genotipo por la dieta. Objetivo: explorar la evidencia bibliográfica sobre los potenciales de la nutrigenética en el abordaje y tratamiento de las enfermedades cardiovasculares (ECV) y factores de riesgo asociados. Materiales y métodos: se realizó una búsqueda sistemática de publicaciones en bases de datos electrónicas MEDLINE, EMBASE y Google Scholar. Se incluyeron aquellos artículos que contenían las palabras claves o una combinación de ellas, durante 1990-2019, tanto de estudios experimentales como observacionales. Resultados: 49 artículos fueron incluidos, clasificados de acuerdo a las principales vías moleculares involucradas en la etiopatogenia de las ECV. Si bien se encontró una amplia diversidad de variantes genéticas que confieren susceptibilidad para las ECV y factores de riesgo como obesidad, dislipemia e hipertensión arterial, se observó poca consistencia en la publicación de estudios de replicación. Conclusiones: el conocimiento de variantes genéticas permite la personalización de la dieta, que puede complementarse con otras recomendaciones saludables asociadas al estilo de vida. Son necesarios más estudios en grandes poblaciones y metaanálisis que muestren de manera inequívoca la relación gen-nutriente.

Molecular Basis of the Beneficial Actions of Resveratrol.

Resveratrol modulates the transcription factor NF-κB, cytochrome P450 isoenzyme CYP1A1, expression and activity of cyclooxygenase (COX) enzymes, Fas/Fas ligand mediated apoptosis, p53, mTOR and cyclins and various phospho-diesterases resulting in an increase in cytosolic cAMP levels. Cyclic AMP, in turn, activates Epac1/CaMKKß/AMPK/SIRT1/PGC-1α pathway that facilitates increased oxidation of fatty acids, mitochondrial respiration and their biogenesis and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α (TNF-α), interleukin-17 (IL-17) and other pro-inflammatory molecules and inhibits expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) that may explain its anti-inflammatory actions. Polyunsaturated fatty acids (PUFAs) and their anti-inflammatory metabolites lipoxin A4, resolvins, protectins and maresins have a significant role in obesity, type 2 diabetes mellitus (T2DM), metabolic syndrome and cancer. We observed that PUFAs (especially arachidonic acid, AA) and BDNF (brain-derived neurotrophic factor) protect against the cytotoxic actions of alloxan, streptozotocin, benzo(a)pyrene (BP) and doxorubicin. Thus, there is an overlap in the beneficial actions of resveratrol, PUFAs and BDNF suggesting that these molecules may interact and augment synthesis and action of each other. This is supported by the observation that resveratrol and PUFAs modulate gut microbiota and influence stem cell proliferation and differentiation. Since resveratrol is not easily absorbed from the gut it is likely that it may act on endocannabinoid and light, odor, and taste receptors located in the gut, which, in turn, convey their messages to the various organs via vagus nerve.

Associations between major dietary patterns and biomarkers of endothelial dysfunction in two urban midsized cities in Argentina.

OBJECTIVE: We examined whether dietary patterns (DPS) are associated with endothelial dysfunction (ED) markers in an Argentinian population. RESEARCH METHODS & PROCEDURES: The sample in this cross-sectional study was derived from 1,983 subjects from two mid-sized cities in Argentina who were involved in the CESCAS I Study. To define DP, a food-frequency questionnaire was applied. In a subsample randomly selected from the primary cohort, serum concentrations of C-reactive protein (hs-CRP), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble E selectin (sSELE) were determined. Correlations and multiple linear regression models were used to assess the relation between each quartile of DP adherence score and ED markers (Q1 lowest adherence; Q4 highest adherence). RESULTS: Three DPs were identified: Traditional (TDP), Prudent (PDP), and Convenience and processed (CDP). TDP was characterized by higher intake of refined grains, red meat, whole fat dairy products, vegetable oils, and "mate", a traditional South American infused drink; PDP was characterized by higher intake of vegetables, fruit, low-fat dairy products, whole grains, and legumes; and CDP consisted mainly of processed meat, snacks, pizza, and "empanadas", a stuffed bread served baked or fried. Lower scores (Q2, Q3) in TDP were inversely associated with concentrations of sSELE (P < 0.0001 and P < 0.05, respectively). In PDP, higher scores were inversely associated with hs-CRP, whereas lower scores showed a positive relation with sSELE (P < 0.05). Contrariwise, higher scores in CDP were directly associated with sSELE concentrations (P < 0.05). CONCLUSION: Adherence for each DP identified is differentially related to ED markers in the studied population.

Cooking methods and the formation of PhIP (2-Amino, 1-methyl, 6-phenylimidazo[4,5-b] pyridine) in the crust of the habitually consumed meat in Argentina.

Content of carcinogenic molecules like, 2-Amino, 1-methyl, 6-phenylimidazo[4,5-b] pyridine in meals is one of the main mutagenic substances formed during meat cooking, and it can be used as a dietary exposure marker. Our objective was to estimate the amount of PhIP consumed from habitual Argentinean diet, rich in red meats, comparing different cooking procedures and meat type. Samples (n = 240) of lean and fatty beef, chicken, pork, and fish were cooked using different methods: griddle, grill, sauté pan, and oven. Samples were: Overcooked, or cooked with a microbiologically suitable or "healthy technique" (HT). The PhIP was determined by HPLC-MS. Meats cooked using HT formed little crust amounts and PhIP was below the detection levels. In overcooked meats, large amounts of crust were formed in lean meats, fatty beef, fatty chicken and baked pork. PhIP was measured in lean meats sauted or cooked on a griddle, a method reaching temperatures until 250 °C.It was estimated that Argentine people eats about 12,268.0 ng/day of PhIP being these values above those tolerated limits for total dietary heterocyclic amines in some developed countries. Hence, cooking small meat portions, at medium temperature, avoiding prolonged cooking and preferring baked lean meats could be recommended as a healthier habit.

Beneficial action of resveratrol: How and why?

Flavonoid resveratrol modulates the transcription factor NF-κB; inhibits the cytochrome P450 isoenzyme CYP1 A1; suppresses the expression and activity of cyclooxygenase enzymes; and modulates Fas/Fas-ligand-mediated apoptosis, p53, mammalian target of rapamycin, and cyclins and various phosphodiesterases. This increases the cytosolic cAMP that activates Epac1/CaMKKß/AMPK/SIRT1/PGC-1α pathway, which in turn facilitates increased oxidation of fatty acids, mitochondrial biogenesis, mitochondrial respiration, and gluconeogenesis. Resveratrol triggers apoptosis of activated T cells and suppresses tumor necrosis factor-α, interluekin-17 (IL-17), and other proinflammatory molecules, and thus is of benefit in autoimmune diseases. In addition, resveratrol inhibits expression of hypoxia-inducible factor-1α and vascular endothelial growth factor, explaining its effective action against cancer. Brain-derived neurotrophic factor (BDNF) that is involved in the pathogenesis of obesity, type 2 diabetes mellitus, and metabolic syndrome is also altered in depression, schizophrenia, bipolar disorder, and autism. We noted that BDNF protects against cytotoxic actions of alloxan, streptozotocin, and benzo(a)pyrene. Resveratrol prevents bisphenol A-induced autism, type 2 diabetes mellitus, and metabolic syndrome, suggesting that it may augment BDNF synthesis and action. We also observed that BDNF levels are low in type 2 diabetes mellitus and that BDNF enhances production of antiinflammatory lipid, lipoxin A4, whose levels are low in diabetes mellitus. Thus, resveratrol may augment production of lipoxin A4. Resveratrol alters gut microbiota and influences stem cell proliferation and differentiation. These pleiotropic actions of resveratrol may explain the multitude of its actions and benefits.

Polyunsaturated fatty acids and gliomas: a critical review of experimental, clinical, and epidemiologic data.

Certain polyunsaturated fatty acids (PUFAs) called essential fatty acids (EFAs) cannot be biosynthesized by the body and hence, need to be obtained from diet. These PUFAs and their metabolites have multiple physiological functions that are altered in tumor cells due to a decreased expression of Δdelta-6-desaturase, which is an essential step in their metabolism. As a result, tumor cells would be protected from the toxic effect caused by free radicals, one product of EFA metabolism. EFAs have been proposed to have therapeutic potential in the treatment of glioblastoma. Gliomas are the most common primary tumors of the central nervous system in children and adults. High-grade gliomas remain a therapeutic challenge in neuro-oncology because there is no treatment that achieves a significant improvement in survival. Novel therapeutic strategies that use PUFAs for the treatment of gliomas have been assessed in cell cultures, rodent glioma models, and humans, with encouraging results. Here we review the latest progress made in the field.

Dietary patterns and risk of urinary tract tumors: a multilevel analysis of individuals in rural and urban contexts.

INTRODUCTION: Bladder cancer is the fourth most frequently diagnosed malignancy in males in Córdoba, Argentina. The evidence regarding an association between urinary tract tumors and dietary factors still remains controversial. Argentina has particular dietary habits, which have already been associated with cancer occurrence. PURPOSES: (a) To estimate the association of typical dietary patterns in Argentina on the occurrence of urinary tract tumors and (b) to assess the urban-rural context of residence and cancer occurrence dependency. METHODS: A case-control study of urinary tract tumors (n = 123, 41/82 cases/controls) was performed in Córdoba Province (Argentina), 2006-2011. A two-level logistic regression model was fitted, taking into account rural-urban residence. An exhaustive probabilistic sensitivity analysis (bias analysis) was performed. RESULTS: Southern Cone pattern, characterized by red meat, starchy vegetables and wine consumptions (OR 1.75 high versus low level of adherence to the pattern), and a medium adherence to a high-sugar drinks pattern, with high loadings for soft drinks (OR 2.55), were associated with increasing risk of urinary tract tumors. High adherence to the latter pattern was inversely associated (OR 0.72). The occurrence of urinary tract tumors was also linked to place of residence (urban-rural), explaining more than 20% of outcome variability and improving the above risk estimations. CONCLUSIONS: A high intake of red meat, starchy vegetables and wine, and a moderate intake of high-sugar drinks seem to be associated with increased risk of urinary tract tumors, with differences related to the context of residence.

Dietary habits and prostate cancer prevention: a review of observational studies by focusing on South America.

There exist several works considering the association between diet and prostate cancer (PC) risk, but the issue is largely unsettled. This article systematically reviews the epidemiological studies on diet and risk of PC focusing on those carried out in countries of South America. There is some suggestion that dairy products, red meat, processed meat, α-linolenic fatty acids, as well as dietary patterns characterized by higher intakes of red and processed meat, eggs, and grains may play some role in the development of PC. There is no clear association with the intake of vegetables and fruits, lycopene, fats, and different types of fatty acids. The evidence on diet and PC is therefore inconclusive in general and specifically in South America. Particular attention must be paid to the study of cancer risk in some countries of South America because of the singularly risky dietary pattern consumed by its population.

Basic aspects of tumor cell fatty acid-regulated signaling and transcription factors.

This article reviews the current knowledge and experimental research about the mechanisms by which fatty acids and their derivatives control specific gene expression involved during carcinogenesis. Changes in dietary fatty acids, specifically the polyunsaturated fatty acids of the ω-3 and ω-6 families and some derived eicosanoids from lipoxygenases, cyclooxygenases, and cytochrome P-450, seem to control the activity of transcription factor families involved in cancer cell proliferation or cell death. Their regulation may be carried out either through direct binding to DNA as peroxisome proliferator-activated receptors or via modulation in an indirect manner of signaling pathway molecules (e.g., protein kinase C) and other transcription factors (nuclear factor kappa B and sterol regulatory element binding protein). Knowledge of the mechanisms by which fatty acids control specific gene expression may identify important risk factors for cancer and provide insight into the development of new therapeutic strategies for a better management of whole body lipid metabolism.

Is insulin resistance a disorder of the brain?

There is reasonable evidence to suggest that insulin resistance may have its origins in the hypothalamus. Insulin secretion is regulated by sympathetic and parasympathetic nervous systems and modulates the concentrations of hypothalamic neuropeptides and monoaminergic neurotransmitters, and, in return, hypothalamic monoamines regulate the secretion of insulin by pancreatic beta cells. A lesion of the ventromedial hypothalamus produces all the features of the metabolic syndrome including insulin resistance and hyperinsulinemia. These and other evidence suggest that insulin resistance may very well be a disease of the brain.

L-arginine, NO and asymmetrical dimethylarginine in hypertension and type 2 diabetes.

Both hypertension and type 2 diabetes mellitus are common and there are no reliable markers either to predict their development or complications. High fat diet and carbohydrate-rich diet enhance serum asymmetrical dimethylarginine (ADMA) levels, an endogenous inhibitor of nitric oxide synthesis. ADMA levels are elevated in patients with hypertension, poor control of hyperglycemia, diabetic microangiopathy and macroangiopathy and dyslipidemia. One of the earliest signs of vascular dysfunction and insulin resistance, which are present in hypertension and type 2 diabetes mellitus, is an elevation in serum ADMA levels. Displacing plasma ADMA by oral supplementation of L-arginine restores endothelial dysfunction by augmenting endothelial nitric oxide generation. Strict control of hyperglycemia decreases serum ADMA levels. These and other studies suggest that serum ADMA levels could be used to predict the development of hypertension and type 2 diabetes mellitus in those who are at high-risk to develop these diseases.

Role of PUFAs, the precursors of endocannabinoids, in human obesity and type 2 diabetes.

Polyunsaturated fatty acids (PUFAs) serve as precursors of the endocannabinoids (ECs) that are bioactive lipids molecules. Recent studies revealed that ECs participate in several physiological and pathological processes including obesity and type 2 diabetes mellitus. Here we review the experimental and clinical aspects of the role of endocannabinoids in obesity and type 2 diabetes mellitus and the modification of the endocannabinoids by exogenously administered PUFAs. Based on these evidences, we propose that the endocannabinoid system (ECS) can be modulated by exogenous manipulation of PUFAs that could help in the prevention and management of human diseases such as obesity, metabolic syndrome and type 2 diabetes mellitus.

Cancer mortality in Córdoba, Argentina, 1986-2006: an age-period-cohort analysis.

AIMS AND BACKGROUND: Cancer is the second main cause of death in Argentina, surpassed only by cardiovascular disease. However, analytical approaches isolating some of the known effects, such as age at death, period of death and birth cohort, have never been performed in cancer mortality studies in Argentina. The aim of this study was to analyze cancer mortality trends in a representative region of the country, the Córdoba province (1986-2006). METHODS AND STUDY DESIGN: Overall age-standardized (world population) mortality rates for cancer (all sites) were computed by a direct method. Joinpoint regression was fitted to the age-standardized mortality rates for both sexes to provide estimated and 95% confidence intervals of the annual percentage changes. The effects of age (15 age groups), period of death (1986-90, 1991-95, 1996-00 or 2001-06), and birth cohort (18 overlapping 10-year birth cohorts) covariates on mortality rates were estimated using a sequentially fitted Poisson regression model. RESULTS: During the study period, 102,737 people died of cancer in Córdoba, with the age-standardized mortality rates decreasing from 139.3 to 118.7/100,000 person-years. Although this reduction was more noticeable in men, the joinpoint regression model showed a significant change of the age-standardized mortality rates after 1996 in both sexes. Age-period-cohort analysis suggested that the cancer mortality trends may be linked with a strong age effect and a moderate or mild period and cohort effect, related to sex and place of residence. CONCLUSIONS: Based on the observed cohort effect, it may be argued that there has been a lower exposure level to some risk factors, such as diet and other environmental factors, in Cordoba over the last decades.

Colorectal cancer mortality trends in Córdoba, Argentina.

BACKGROUND: Colorectal cancer is a leading cause of death worldwide for men and women, and one of the most commonly diagnosed in Córdoba, Argentina. The aim of this work was to provide an up-to-date approach to descriptive epidemiology of colorectal cancer in Córdoba throughout the estimation of mortality trends in the period 1986-2006, using Joinpoint and age-period-cohort (APC) models. METHODS: Age-standardized (world population) mortality rates (ASMR), overall and truncated (35-64 years), were calculated and Joinpoint regression performed to compute the estimated annual percentage changes (EAPC). Poisson sequential models were fitted to estimate the effect of age (11 age groups), period (1986-1990, 1991-1995, 1996-2000 or 2001-2006) and cohort (13 ten-years cohorts overlapping each other by five-years) on colorectal cancer mortality rates. RESULTS: ASMR showed an overall significant decrease (EAPC -0.9 95%CI: -1.7, -0.2) for women, being more noticeable from 1996 onwards (EAPC -2.1 95%CI: -4.0, -0.1). Age-effect showed an important rise in both sexes, but more evident in males. Birth cohort- and period effects reflected increasing and decreasing tendencies for men and women, respectively. CONCLUSIONS: Differences in mortality rates were found according to sex and could be related to age-period-cohort effects linked to the ageing process, health care and lifestyle. Further research is needed to elucidate the specific age-, period- and cohort-related factors.