El papel de la inmunidad innata en la obesidad / The role of innate immunity in obesity

La obesidad en México es un problema de salud preocupante por el incremento en la prevalencia en adultos y niños, y se considera un factor de riesgo para el desarrollo de resistencia a la insulina, así como de otras alteraciones metabólicas. En esta patología se ha observado un incremento en la expresión de los receptores tipo Toll (TLRs) en el adipocito, receptores con participación crucial en la respuesta inmune innata. Se propone que los TLRs están implicados en la inflamación sistémica y en el desarrollo de la resistencia a la insulina. La activación de los TLRs es mediada por ácidos grasos y su expresión está regulada por leptina, adiponectina y PPAR. El conocimiento de la función de los TLRs, tanto en la inflamación como en la diferenciación del adipocito es importante en la búsqueda de nuevos blancos terapéuticos antiinflamatorios que coadyuven en el tratamiento de la obesidad.

Obesity in Mexico is alarmingly increasing in prevalence in adults and children, and it is a risk factor for the development of insulin resistance, as well as, of other metabolic alterations. The discovery of the expression of the Toll-like receptors (TLRs) in adipocytes, suggests an important role in innate immunity. In different models of obesity, there has been observed an increase of TLRs expression in the fat tissue, therefore TLRs could be involved in systemic inflammation in this disease, and in the development of insulin resistance. TLR activation is mediated by fatty acids and their expression is regulated by leptin, adiponectin and PPARs. Knowledge of the role of TLRs in inflammation and adipocyte differentiation and their regulation, then it is important to try to develop new therapeutic anti-inflammatory targets that contribute in the treatment of obesity.

Motilidad intestinal y microflora / Intestinal motility and microflora

La microflora es el conjunto de colonias microbacterianas que cubren la superficie del tubo digestivo. Cada sujeto humano alberga unos 100 billones de colonias de unas 400 especies distintas, biodiversidad que facilita la vida y el desarrollo del conjunto. La concentración de bacterias va aumentando a lo largo del tubo digestivo, alcanzando concentraciones de 1012 UFC/ml. en el colon. La motilidad del intestino delgado es propulsiva con una fase de barrido que no permite el crecimiento de bacterias. Por el contrario, la motilidad del colon es muy lenta y no propulsiva durante el ayuno y el sueño. Sólo en vigilia y en período postprandial existen ondas de contracción de alta amplitud y rápidamente progresivas en dirección oral-anal. La interacción entre las bacterias presentes en el lumen y las ondas de contracción motora es muy difícil de evaluar. Este efecto se ha estudiado en base a los fármacos que alteran la motilidad y que al aumentar ésta, barren con la flora bacteriana presente. En ese sentido se sabe que el uso de cisaprida acelera el tránsito, reduciendo la densidad de bacterias metanogénicas con un aumento de la excreción de hidrógeno. En cambio, loperamida disminuye el tránsito, aumentando la flora metanogénica (hecho que representa lo que sucede a pacientes constipadas, que tienen flora mayoritariamente productora de metano). Conclusión: La interacción entre motilidad y flora bacteriana es compleja y está poco estudiada fundamentalmente debido a dificultades técnicas.

Microflora is the set of microbacterium colonies covering the digestive tract surface. Each human subject hosts ca. 100 billions of colonies of 400 different species, b23wiodiversity that facilitates life and development of the whole. Bacteria concentration increases throughout the digestive tract, reaching concentrations of 1012 CFU/ml in the colon. Motility of the small intestine is propulsive with a sweeping phase, allowing for the growth of bacteria. On the contrary, motility of the colon is very slow and non-propulsive during fasting and sleeping. Only during wakefulness and postprandial period there are wide-ranging and quickly progressive contraction waves in oral-anal direction. Interaction between bacteria present in lumen and the contraction waves is very hard to assess. This effect has been studied based on drugs that alter motility, and when it increases, they sweep the existing gut flora. In this sense, it is known that the use of cisapride accelerates the transit, reducing the density of methanogenic bacteria with an increase in the hydrogen excretion. On the other hand, loperamide slows down transit, causing an increase of the methanogenic flora (which represents what happens to constipated patients with flora that produces mainly methane). Conclusion: Interaction between motility and gut flora is complex and has not been enough studied mainly due to technical difficulties.

Modulação da ativação dos receptores ativados por proliferadores de peroxissoma (PPAR) e dos receptores X hepáticos (LXR) por LN´O IND. 2´ / Modulation of activity of peroxissome prolifetor-activated (PPAR) and liver X receptors(LXR) by LN´O IND. 2´

A atividade dos receptores ativados por proliferadores de peroxissoma (PPAR) e receptor X hepático (LXR) são regulados por ácidos graxos. Entretanto, o papel do LNO2, um produto endógeno da nitração do ácido linoléico por espécies reativas derivadas de óxido nítrico (•NO), na via de sinalização que regula a ativação destes receptores ainda não está elucidada. Assim, considerando a propriedade do LNO2 como doador de NO, nós investigamos a participação da via de sinalização p21Ras/Raf/ERK na ativação de PPAR e LXR por LNO2. Os resultados obtidos demonstraram que LNO2, na concentração de 0.01µM, foi um potente ativador de PPAR quando comparado ao ligante natural ácido linoléico, o qual apresentou ativação equivalente do PPAR na concentração de 0.01µM. O LN02, contudo não teve efeito na ativação de LXR. LNO2 foi um potente ativador de p21Ras quando comparado ao ácido linoléico. A ativação de Ras ocorreu após 5 minutos de incubação com LNO2 em células parentais. Entretanto, em células transfectadas com p21RasC118S, o LNO2 não foi capaz de ativar Ras. A ativação de Ras e PP AR foi dependente da liberação de NO a partir de LN02, o que foi evidenciado na presença de C-PTIO, um seqüestrador de NO. LNO2 ativou ERK, mas não demonstrou efeito relevante na ativação de p38 MAP kinase...

Cambios en los acidos grasos de membranas de Microbacterium esteraromaticum GNP-5 con diferentes temperaturas y osmolaridades / Changes in Membrane Fatty Acids of Microbacterium esteraromaticum GNP5 with Changes of Temperature and Osmolarity

Microbacterium esteraromaticum es un microorganismo que se aísla con frecuencia de landfarming o procesos de biorremediación de hidrocarburos en la meseta de la Patagonia central (Argentina) y se halla sometido a variaciones de temperatura y a cambios de salinidad que se producen naturalmente. Su adaptabilidad a esos cambios climáticos indujo al estudio de las modificaciones que se producen en su membrana celular para resistirlos. En este trabajo se estudió el efecto conjunto de la temperatura y la concentración de cloruro de sodio sobre la composición de los ácidos grasos de membrana en la cepa de Microbacterium esteraromaticum GNP5b. M. esteraromaticum utiliza, frente al incremento de la temperatura, la estrategia es aumentar la longitud de sus ácidos grasos de cadenas ramificada impar (17 átomos de carbono) con disminución de 15:0 anteiso, así como el porcentaje de ácidos grasos 15:0 iso (de mayor punto de fusión) a partir del respectivo anteiso. El aumento de la salinidad modifica la composición de ácidos grasos siguiendo patrones diferentes según sea la temperatura de incubación. A 14 y 28 °C incrementa los 15:0 iso y 17:0 iso en detrimento de sus homólogos anteiso. A 37 °C este grupo de ácidos grasos no sigue los mismos patrones anteriores. La longitud de cadena, expresada como el índice C15/C17, es errática con el aumento de la salinidad.

Citocinas, disfunção endotelial e resistência à insulina / Cytokines, endothelial dysfunction, and insulin resistance

A disfunção endotelial está associada a diversas alterações vasculares, como a aterosclerose, hipertensão arterial, hiperlipidemia e diabetes mellitus, que têm em comum a resistência à insulina (RI). Citocinas são proteínas de baixo peso molecular, com diversas funções metabólicas e endócrinas, que participam da inflamação e resposta do sistema imune. Várias dessas citocinas são consideradas como fatores de risco independentes para doenças da artéria coronária e cerebrovascular. As principais fontes de citocinas (adipocinas) são os tecidos adiposos subcutâneo e visceral. Assim, aumento da massa de tecido adiposo está associado com alterações da produção de adipocina com aumento da expressão de fator de necrose tumoral alfa (TNF-alfa), interleucina 6 (IL-6), inibidor do fator ativador de plasminogênio 1 (PAI-1), e diminuição da expressão de adiponectina no tecido adiposo. A condição pró-inflamatória associada a essas alterações sugere ligação entre RI e disfunção endotelial no estágio inicial do processo de aterosclerose, em indivíduos obesos e em pacientes diabéticos tipo 2. A redução da massa de tecido adiposo, por redução de peso associada a exercício físico, reduz TNF-alfa, IL-6 e PAI-1, aumenta adiponectina, e melhora tanto a sensibilidade à insulina quanto a função endotelial. A interação entre adipocinas e insulina no controle da função endotelial será discutida, bem como o conceito de que a alteração da secreção de adiponectinas na RI e/ou obesidade piora a função endotelial, além de diminuir ainda mais a sensibilidade à insulina.

Endothelial dysfunction is associated with several vascular conditions as atherosclerosis, hypertension, hyperlipidemia and diabetes mellitus. In all these conditions insulin resistance (IR) is present. Cytokines are low molecular weight proteins with several endocrine and metabolic functions that participate of inflammation and immune response. Several of these cytokines are independent risk factors for cerebrovascular and coronary artery disease. The major sources of cytokines (adipokines) are the visceral and subcutaneous adipose tissues. Thus, increased adipose tissue mass is associated with alteration in adipokine production as over expression of tumor necrosis factor alpha, interleukin 6, plasminogen activator inhibitor 1, and under expression of adiponectin in adipocite tissue. The pro-inflammatory status associated with these changes provides a potential link between IR and endothelial dysfunction, the early stage in the atherosclerotic process, in obese individuals, and type 2 diabetic patients. Reduction of adipose tissue mass through weight reduction in association with exercise reduces TNF-alpha, IL-6, and PAI-1, increases adiponectin, and is associated with improved insulin sensitivity and endothelial function. This review will focus on the evidence for regulation of endothelial function by insulin and the adypokines such as adyponectin, leptin, resistin, IL-6 and TNF-alpha. Interaction between insulin signaling and adypokines will be discussed, as well as the concept that aberrant adypokine secretion in IR and/or obesity impairs endothelial function and contributes further to reduce insulin sensitivity.

Effect of fatty acids on leukocyte function

Fatty acids have various effects on immune and inflammatory responses, acting as intracellular and intercellular mediators. Polyunsaturated fatty acids (PUFAs) of the omega-3 family have overall suppressive effects, inhibiting lymphocyte proliferation, antibody and cytokine production, adhesion molecule expression, natural killer cell activity and triggering cell death. The omega-6 PUFAs have both inhibitory and stimulatory effects. The most studied of these is arachidonic acid that can be oxidized to eicosanoids, such as prostaglandins, leukotrienes and thromboxanes, all of which are potent mediators of inflammation. Nevertheless, it has been found that many of the effects of PUFA on immune and inflammatory responses are not dependent on eicosanoid generation. Fatty acids have also been found to modulate phagocytosis, reactive oxygen species production, cytokine production and leukocyte migration, also interfering with antigen presentation by macrophages. The importance of fatty acids in immune function has been corroborated by many clinical trials in which patients show improvement when submitted to fatty acid supplementation. Several mechanisms have been proposed to explain fatty acid modulation of immune response, such as changes in membrane fluidity and signal transduction pathways, regulation of gene transcription, protein acylation, and calcium release. In this review, evidence is presented to support the proposition that changes in cell metabolism also play an important role in the effect of fatty acids on leukocyte functioning, as fatty acids regulate glucose and glutamine metabolism and mitochondrial depolarization

Mechanism of cAMP-induced H(+)-efflux of Dictyostelium cells: a role for fatty acids.

Aggregating Dictyostelium cells release protons when stimulated with cAMP. To find out whether the protons are generated by acidic vesicles or in the cytosol, we permeabilized the cells and found that this did not alter the cAMP-response. Proton efflux in intact cells was inhibited by preincubation with the V-type H(+) ATPase inhibitor concanamycin A and with the plasma membrane H(+) ATPase blocker miconazole. Surprisingly, miconazole also inhibited efflux in permeabilized cells, indicating that this type of H(+) ATPase is present on intracellular vesicles as well. Vesicular acidification was inhibited by miconazole and by concanamycin A, suggesting that the acidic vesicles contain both V-type and P-type H(+) ATPases. Moreover, concanamycin A and miconazole acted in concert, both in intact cells and in vesicles. The mechanism of cAMP-induced Ca2(+)-fluxes involves phospholipase A2 activity. Fatty acids circumvent the plasma membrane and stimulate vesicular Ca2(+)-efflux. Here we show that arachidonic acid elicited H(+)-efflux not only from intact cells but also from acidic vesicles. The target of regulation by arachidonic acid seemed to be the vesicular Ca2(+)-release channel.

Efecto inhibitorio del nonanoato de potasio y el fluoruro de sodio en la acidogenicidad de la placa dental humana in vitro / In vitro inhibitory effect of potassium nonanoate and sodium fluoride on acidogenity of human dental plaque

El ácido nonanoico es un ácido graso saturado de 9 carbonos el cual se ha demostrado reduce la aparición de caries de fisura en ratas cuando es incluido en la dieta (Hayes y Berkovitz, 1979). En 1979 Griffiths demostró que el nonanoato de potasio agregado en enjuagues con sacarosa inhibe la producción de ácidos por parte de la bacaterias de la placa dental en humanos. El objetivo de esta invesstigación fue estudiar el efecto de ácidos grasos y fluoruros en la producción de ácidos en placa dental de humanos in vitro. Para ello se recolectó placa dental en ayunas de 3 horas, en niños con caries activa y con edades comprendidas entre los 5 y 12 años. La producción de ácidos fue determinada por el método de titulación reportado por Hayes y Roberts (1980), luego de la adición de la glucosa exógena. Los resultados demostraron que a pH 7,4 el NK (3mM) y el NaF (13mM) produjeron una inhibición en la producción de ácidos en un 45 por ciento y 54,5 por ciento respectivamente, mientras que con la mezcla se observó un reducción de un 39 por ciento. A pH 5,5 el NK y el NaF a una concentración de 0,26mM produjeron una inhibición de 21,2 por ciento y 29,3 por ciento respectivamente y cuando se mezclaron esta inhibición se incrementó a 49,3 por ciento. Estos resultados sugieren que a pHs cercanos a la neutralidad (7,4) no hay efecto adhitivo del NK y el NaF, mientras que a pH ácido (5,5) la combinación de estos compuestos incrementó significativamente (p<0,01) su efectividad

Trans fatty acid isomers in human health and in the food industry

Trans fatty acids are unsaturated fatty acids with at least one double bond in the trans configuration. These fatty acids occur naturally in dairy and other natural fats and in some plants. However, industrial hydrogenation of vegetable or marine oils is largely the main source of trans fatty acids in our diet. The metabolic effect of trans isomers are today a matter of controversy generating diverse extreme positions in light of biochemical, nutritional, and epidemiological studies. Trans fatty acids also have been implicated in the etiology of various metabolic and functional disorders, but the main concern about its health effects arose because the structural similarity of these isomers to saturated fatty acids, the lack of specific metabolic functions, and its competition with essential fatty acids. The ingestion of trans fatty acids increases low density lipoprotein (LDL) to a degree similar to that of saturated fats, but it also reduces high density lipoproteins (HDL), therefore trans isomers are considered more atherogenic than saturated fatty acids. Trans isomers increase lipoprotein(a), a non-dietary-related risk of atherogenesis, to levels higher than the corresponding chain-length saturated fatty acid. There is little evidence that trans fatty acids are related to cancer risk at any of the major cancer sites. Considerable improvement has been obtained with respect to the metabolic effect of trans fatty acids due the development of analytical procedures to evaluate the different isomers in both biological and food samples. The oleochemical food industries have developed several strategies to reduce the trans content of hydrogenated oils, and now margarine and other hydrogenated-derived products containing low trans or virtually zero trans are available and can be obtained in the retail market. The present review provides an outline of the present status of trans fatty acids including origin, analytical procedures, estimated ingestion, metabolic effects, efforts to reduce trans isomers in our diet, and considerations for future prospects on trans isomers

Inhibition of two HMP shunt pathway enzymes by fatty acids and their CoA esters in developing human brain: role of fatty acid binding protein.

Inhibitory effects of fatty acids and their CoA esters on glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities of human fetal brain cytosol have been studied. Purified human fetal brain fatty acid binding protein reverses the inhibitory effects of palmitoyl-CoA and oleic acid on glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase activities in human fetal brain cytosol. This protein, when added alone, activates the enzymes. Levels of fatty acid binding proteins as well as the activities of these two HMP shunt pathway enzymes, which provide cofactors like NADPH for reductive biosynthesis, increase with gestation. These results indicate that a relationship exists between the high demand for fatty acids and synthesis of cofactors for lipid biosynthesis in developing brain.

The effects of fatty acids on lymphocyte functions

1. Lymphocytes play an important role in cell-mediated immunity and have been implicated in inflammatory and autoimmune diseases. 2. Unsaturated fatty acids, including oleic, linoleic, alpha-linolenic, arachidonic, eicosapentaenoic and docosahexaenoic acids, inhibit mitogen-stimulated lymphocyte proliferation in vitro. The inhibition of proliferation is dependent upon the concentration of fatty acid, the time during culture of fatty acid addition, the duration of exposure of the cells to the fatty acid and the chain length and degree of unsaturation of the fatty acid. 3. Unsaturated fatty acids suppress production of the immunoregulatory cytokine interleukin-2 by lymphocytes in vitro. 4. Triacylglycerols containing unsaturated fatty acids inhibit lymphocyte proliferation and natural killer cell activity in vitro. 5. Feeding weanling rats diets containing olive oil, evening primrose oil or fish oil results in suppression of lymphocyte proliferation. 6. Preliminary studies indicated that supplementation of the diet of healthy humans with fish oil-containing capsules suppresses lymphocyte proliferation and interleukin-2 production. 7. These effects, along with inhibitory effects upon the functions of other cells involved in the immune response, in particular monocytes and macrophages, indicate that certain unsaturated fatty acid-containing oils (particularly evening primrose oil and fish oil) may be of benefit in the treatment of inflammatory and autoimmune diseases

Efecto contraregulador del glucagon en la hiperinsulinemia inducida / Effect of glucagon in induced hyperinsulinem

Estudiando al glucagon como una alternativa en el tratamiento de la hiperinsulinemia el problema fue si el glucagon exogeno en condiciones de hiperinsulinemia inducida puede producir un efecto contraregulador al de la insulina en un grupo de ratas machos adultos de la Cepa Wistar. Se investigo el comportamiento dosis respuesta en diferentes tratamientos con insulina y glucagon dividiendo 40 ratas en cuatro grupos y aplicando un tratamiento a cada grupo. Las variables evaluadas fueron: Peptido C, glucagon, glucemia y acidos grasos libres plasmaticos. Se concluyo que existe suficiente diferencia en los resultados medios de los niveles de cada parametro analizado en los cuatro grupos.

Oncogene.

Recent studies have shown that activation of oncogenes, genes concerned with cell growth, and inactivation of anti-oncogenes may be responsible for uncontrolled cell proliferation leading to malignancy. These oncogenes code for products or proteins which are closely similar to growth factors or receptors of growth factors. Alterations in lipid metabolism in the form of excess formation of inositol triphosphate and relocation of protein kinase C, the second messengers of the mitotic process, can initiate cell division. Oncogenes can be activated by chromosomal aberrations induced by chemicals, viruses and drugs. The identification of oncogenes and their products may have relevance to the development of new therapeutic strategies in cancer.

Lipídios nutricionais e câncer mamário / Dietary lipids and mammary carcinogenesis

Os lípidios e ácidos graxos dietários interferem na estrutura e funçäo das membranas biológicas, nos níveis hormonais, no sistema imunológico e no reparo do ácido desoxirribonucléico (DNA). Estes efeitos podem estar relacionados com o desenvolvimento da carcinogênese mamária por mecanismos ainda pouco conhecidos. O aumento do consumo diário de lipídios está fortemente associado com o aumento da incidência e da mortalidade por câncer da mama como demonstrado em várias populaçöes humanas