Caracterización de los efectos biológicos de los polifenoles en la inflamación y el metabolismo : nuevas perspectivas nutricionales

La obesidad es quizá la enfermedad más frecuente en todo el mundo. Tanto es así que la OMS la califica de pandemia. Todo el exceso de energía que ingerimos se almacena en el tejido adiposo, diseñado específicamente para llevar a cabo tal función. Pero el exceso puede llegar a ser tanto, que el tejido adiposo se ve sobrepasado y debe derivar la grasa que no puede almacenar a otros tejidos como el hígado, el páncreas y el músculo, que no están preparados para tal fin. El estrés celular que esto supone, se acompaña de una respuesta inflamatoria y metabólica alteradas en múltiples tipos celulares. Por otro lado, un estés celular moderado es normal, y no por ello perjudicial. Por ejemplo, el ejercicio físico puede suponer un estrés importante en algunos tipos celulares, pero no por ello deja de ser saludable. Algunas moléculas capaces de producir estrés celular, como los tóxicos, se comportan de forma parecida. A dosis muy bajas, pueden proporcionar efectos beneficiosos; es lo que se conoce como hormesis. Las plantas sintetizan diferentes tipos de moléculas para defenderse del estrés que produce la sequía o las plagas entre otras agresiones. Los humanos, al comernos las plantas, somos capaces de aprovechar el estrés que sufren utilizando los compuestos que sintetizan. La idea de que una especie se aproveche del estrés de otra especie, es lo que trata de explicar la hipótesis de la xenohormesis. Los polifenoles son un tipo de compuestos horméticos. En esta Tesis hemos desarrollado técnicas analíticas para la caracterización de los compuestos presentes en extractos acuosos de plantas y hemos evaluado los efectos biológicos del consumo de extractos acuosos ricos en polifenoles de Hibiscussabdariffay Aspalathuslinearis (rooibos).Obesity is perhaps the most common disease worldwide. The WHO qualify it as a pandemic disease. The excess of energy ingested is stored in adipose tissue, specifically designed to perform this function. But too much can be therefore, that adipose tissue is overwhelmed and must derive the excess of fat to other tissues such as liver, pancreas and muscle, which are not prepared for this purpose. The concomitant cellular stress generated, is accompanied by an altered metabolic and inflammatory response in multiple cell types. On the other hand, a moderate cell stress is normal, and does not have to be harmful. For example, exercise can cause a significant stress in some cell types, but not for that isunhealthy. Some molecules that can produce cellular stress, such as toxic, have similar behavior. Used at very low doses, can provide beneficial effects, it is what is known as hormesis. Plants synthesize different types of molecules to defend against the stress of drought or pests among other attacks. When humans eat plants, are able to benefit this stress experienced by plants by using the synthesized compounds. The idea that a specie will take advantage of the stress of another specie, is what the hypothesis of xenohormesistry to explain. Polyphenols are a class of hermetic compounds. In this Thesis we have developed analytical techniques for the characterization of the compounds present in aqueous extracts of plants and assessed the biological effects of consumption of polyphenol-rich aqueous extracts from Hibiscus sabdariffa and Aspalathuslinearis (rooibos)

Methodological constraints in interpreting serum paraoxonase-1 activity measurements: an example from a study in HIV-infected patients

<p>Abstract</p> <p>Background</p> <p>Paraoxonase-1 (PON1) is an antioxidant enzyme that attenuates the production of the monocyte chemoattractant protein-1 (MCP-1) <it>in vitro</it>. Although oxidation and inflammation are closely related processes, the association between PON1 and MCP-1 has not been completely characterised due, probably, to that the current use of synthetic substrates for PON1 measurement limits the interpretation of the data. In the present study, we explored the relationships between the circulating levels of PON1 and MCP-1 in human immunodeficiency virus-infected patients in relation to the multifunctional capabilities of PON1.</p> <p>Methods</p> <p>We measured selected variables in 227 patients and in a control group of 409 participants. Serum PON1 esterase and lactonase activities were measured as the rates of hydrolysis of paraoxon and of 5-(thiobutyl)-butyrolactone, respectively. Oxidised LDL and MCP-1 concentrations were determined by enzyme-linked immunosorbent assay. High-density lipoproteins cholesterol, apolipoprotein A-I, and C-reactive protein concentrations were measured by standard automated methods.</p> <p>Results</p> <p>There were significant relationships between PON1 activity and several indices of oxidation and inflammation in control subjects and in infected patients. However, these relationships varied not only with disease status but also on the type of substrate used for PON1 measurement.</p> <p>Conclusion</p> <p>The present study is a cautionary tale highlighting that results of clinical studies on PON1 may vary depending on the methods used as well as the disease studied. Until more specific methods using physiologically-akin substrates are developed for PON1 measurement, we suggest the simultaneous employment of at least two different substrates in order to improve the reliability of the results obtained.</p

Beneficial Effects of Proanthocyanidins on Intestinal Permeability and Its Relationship with Inflammation

The intestinal barrier is constantly exposed to potentially harmful environmental factors including food components and bacterial endotoxins. When the intestinal barrier function and immune homeostasis are compromised, inflammatory conditions may be developed and impact overall health. Evidence from experimental animal and cell-culture studies suggests that exposure of intestinal mucosa to proanthocyanidin-rich plant products may contribute to maintain the barrier function and to ameliorate the inflammation present in prevalent pathologies such as diet-induced obesity and inflammatory bowel disease. In this review, we aim to update the current knowledge on the bioactivity of PACs in experimental models of altered intestinal permeability and in humans, emphasizing the beneficial effects of grape-seed proanthocyanidin extracts in intestinal health and giving insights into the subjacent biochemical and molecular mechanism

Treatment of hypertriglyceridemia and HIV: fenofibrate-induced changes in the expression of chemokine genes in circulating leukocytes

Fenofibrate changed the expression of chemokine genes in circulating leukocytes of HIV-infected patients with hypertriglyceridemia. The data suggest that fenofibrate when effective in the treatment of lipoprotein abnormalities, may act as a modulator of systemic inflammation. This particular action, therefore, may also influence the clinical course of the disease

PPARs in Regulation of Paraoxonases: Control of Oxidative Stress and Inflammation Pathways

The paraoxonase (PON) group of enzymes, composed of PON1, PON2, and PON3, play an important role in decreasing oxidative stress by degrading lipid peroxides. PON1 synthesis is upregulated by PPAR. Several pharmacological compounds (acting as antioxidants and, hence, atheroprotective) stimulate both PPAR activity and PON1 expression. Recent evidence suggests that PON1 and the monocyte chemoattractant protein-1 (MCP-1) are involved in coordinating the inflammatory response in damaged tissues; PPAR may be central in the regulation of these biochemical pathways. This article reviews the state of knowledge on PON1 biochemistry and function, the influence of genetic variation, and the regulation of PON1 expression by pharmaceutical compounds that increase PPAR activity. We also describe recent lines of evidence suggesting links between PON1 and MCP-1 and how their production may be regulated by PPAR

Differential effects of a cafeteria diet and GSPE preventive treatments on the enterohormone secretions of aged vs. young female rats

Grape seed derived procyanidins (GSPE) have been shown to effectively prevent intestinal disarrangements induced by a cafeteria diet in young rats. However, little is known about the effects of procyanidins and cafeteria diet on enterohormone secretion in aged rats, as the ageing processes modify these effects. To study these effects in aged rats, we subjected 21-month-old and young 2-month-old female rats to two sub-chronic preventive GSPE treatments. After three months of cafeteria diet administration, we analysed the basal and stimulated secretion and mRNA expression of CCK, PYY and GLP-1, caecal SCFA and intestinal sizes. We found that the effects of a cafeteria diet on the basal duodenal CCK secretion are age dependent. GLP-1 in the ileum was not modified regardless of the rat's age, and GSPE preventive effects differed in the two age groups. GSPE pre-treatment reduced GLP-1, PYY and ChgA in mRNA in aged ileum tissue, while the cafeteria diet increased these in aged colon. The GSPE treatments only modified low-abundance SCFAs. The cafeteria diet in aged rats increases the caecum size differently from that in young rats and GSPE pre-treatment prevents this increase. Therefore, ageing modifies nutrient sensing, and the cafeteria diet acts mainly on the duodenum and colon, while procyanidins have a larger effect on the ileum.info:eu-repo/semantics/publishedVersio

Decreased paraoxonase-1 activity is associated with alterations of high-density lipoprotein particles in chronic liver impairment

<p>Abstract</p> <p>Background</p> <p>Paraoxonase-1 (PON1), a lactonase synthesized by the liver, circulates in blood bound to high-density lipoproteins (HDL). This enzyme is thought to degrade oxidized phospholipids and play an important role in the organism's antioxidant and anti-inflammatory system. Chronic liver diseases are characterized by decreased serum PON1 activity. The aim of the present study was to investigate the compositional changes in HDL that could influence PON1 activity in liver impairment.</p> <p>Methods</p> <p>The study was performed in samples from five patients with advanced liver cirrhosis and with preserved renal function, chosen on the basis of having low serum PON1 activity and high serum PON1 concentration. As a control group, we accessed five healthy volunteers from among our hospital staff. Lipid and protein compositional analysis of lipoprotein particles were done by high-performance liquid chromatography, gel electrophoresis, and Western-Blot.</p> <p>Results</p> <p>HDL particles from cirrhotic patients had an increased phospholipid content that was inversely correlated to PON1 activity. The HDL particles contained high levels of PON1 that corresponded, in part, to an immunoreactive protein of high molecular weight (55 kDa) not present in control subjects. This protein was identified as glycosylated PON1 and was also present in biopsies from patients with steatosis and from rats with CCl₄-induced hepatic impairment. These changes were associated with an increased plasma concentration of markers of oxidative stress, inflammation and fibrogenesis.</p> <p>Conclusion</p> <p>Abnormalities in the composition of lipids and proteins of HDL particles, including PON1 glycosylation, are associated with the decrease in serum PON1 activity in patients with liver disease. These alterations may adversely affect the protective role of HDL against oxidative stress and inflammation in these patients.</p

The Deleterious Influence of Tenofovir-Based Therapies on the Progression of Atherosclerosis in HIV-Infected Patients

We investigated the potential differential effects of antiretroviral therapies on unbalanced chemokine homeostasis and on the progression of atherosclerosis in HIV-infected patients. A two-year prospective study was performed in 67 consecutive HIV-infected patients initiating antiretroviral therapy with abacavir/lamivudine or tenofovir/emtricitabine. Circulating levels of inflammatory biomarkers, progression of subclinical atherosclerosis and expression levels of selected chemokines genes in circulating leukocytes were assessed. Control subjects showed significantly lower plasma concentrations of CRP, tPA, IL-6, and MCP-1 than HIV-infected patients at a baseline. After two years of followup, the observed decreases in plasma inflammatory biomarker levels were only significant for MCP-1, tPA, and IL-6. The decrease in plasma MCP-1 concentration was associated with the progression of atherosclerosis, and this effect was negligible only in patients receiving TDF-based therapy. Multivariate analysis confirmed that treatment with TDF was positively and significantly associated with a higher likelihood of subclinical atherosclerosis progression. However, the expression levels of selected genes in blood cells only showed associations with the viral load and total and HDL-cholesterol levels. Current antiretroviral treatments may partially attenuate the influence of HIV infection on certain inflammatory pathways, though patients receiving TDF therapy must be carefully monitored with respect to the presence and/or progression of atherosclerosis

Modulation of food intake by differential TAS2R stimulation in rat

Metabolic surgery modulates the enterohormone profile, which leads, among other effects, to changes in food intake. Bitter taste receptors (TAS2Rs) have been identified in the gastrointestinal tract and specific stimulation of these has been linked to the control of ghrelin secretion. We hypothesize that optimal stimulation of TAS2Rs could help to modulate enteroendocrine secretions and thus regulate food intake. To determine this, we have assayed the response to specific agonists for hTAS2R5, hTAS2R14 and hTAS2R39 on enteroendocrine secretions from intestinal segments and food intake in rats. We found that hTAS2R5 agonists stimulate glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK), and reduce food intake. hTAS2R14 agonists induce GLP1, while hTASR39 agonists tend to increase peptide YY (PYY) but fail to reduce food intake. The effect of simultaneously activating several receptors is heterogeneous depending on the relative affinity of the agonists for each receptor. Although detailed mechanisms are not clear, bitter compounds can stimulate differentially enteroendocrine secretions that modulate food intake in rats

HIV-1/HAART-Related Lipodystrophy Syndrome (HALS) Is Associated with Decreased Circulating sTWEAK Levels

Background and Objectives Obesity and HIV-1/HAART-associated lipodystrophy syndrome (HALS) share clinical, pathological and mechanistic features. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine that plays an important role in obesity and related diseases. We sought to explore the relationship between HALS and circulating levels of soluble (s) TWEAK and its scavenger receptor sCD163. Methods This was a cross-sectional multicenter study of 120 HIV-1-infected patients treated with a stable HAART regimen; 56 with overt HALS and 64 without HALS. Epidemiological and clinical variables were determined. Serum levels of sTWEAK and sCD163 levels were measured by ELISA. Results were analyzed with Student's t-test, Mann-Whitney U and χ2 test. Pearson and Spearman correlation were used to estimate the strength of association between variables. Results Circulating sTWEAK was significantly decreased in HALS patients compared with non-HALS patients (2.81±0.2 vs. 2.94±0.28 pg/mL, p = 0.018). No changes were observed in sCD163 levels in the studied cohorts. On multivariate analysis, a lower log sTWEAK concentration was independently associated with the presence of HALS (OR 0.027, 95% CI 0.001-0.521, p = 0.027). Conclusions HALS is associated with decreased sTWEAK levels