Anna Hernández-Aguilera

Abstract: Obesity is not necessarily a predisposing factor for disease. It is the handling of fat and/or excessive energy intake that encompasses the linkage of inflammation, oxidation, and metabolism to the deleterious effects associated with the continuous excess of food ingestion. The roles of cytokines and insulin resistance in excessive energy intake have been studied extensively. Tobacco use and obesity accompanied by an unhealthy diet and physical inactivity are the main factors that underlie noncommunicable diseases. The implication is that the management of energy or food intake, which is the main role of mitochondria, is involved in the most common diseases. In this study, we highlight the importance of mitochondrial dysfunction in the mutual relationships between causative conditions. Mitochondria are highly dynamic organelles that fuse and divide in response to environmental stimuli, developmental status, and energy requirements. These organelles act to supply the cell with ATP and to synthesise key molecules in the processes of inflammation, oxidation, and metabolism. Therefore, energy sensors and management effectors are determinants in the course and development of diseases. Regulating mitochondrial function may require a multifaceted approach that includes drugs and plant-derived phenolic compounds with antioxidant and anti-inflammatory activities that improve mitochondrial biogenesis and act to modulate the AMPK/mTOR pathway.

Abstract: BACKGROUND: Chemokines can block viral entry by interfering with HIV co-receptors and are recognised mediators of atherosclerosis development. A number of experimental drugs that inhibit HIV entry arrest the development of atherosclerosis in animal models. We hypothesised that the expression of chemokine receptors in circulating leukocytes is associated with the rate of atherosclerosis progression in HIV-infected patients. METHODS: The increase in intima-media thickness during a 2-year follow-up was used to classify HIV-infected patients (n = 178) as progressors (n = 142) or non-progressors (n = 36) with respect to atherosclerosis. Logistic regression was used to assess variables associated with atherosclerosis progression. Mutations in the CCR5Delta32, CCR2 64I, and CX3CR1 (T280M and V249I) co-receptors as well as the levels of CCR5, CXCR4, CX3CR1, and CCR2 mRNA expression in circulating leukocytes were analysed as independent variables. RESULTS: Among the baseline variables, only genetic variants explained the dichotomous outcome. The expression of CCR2 and CXCR4 did not discriminate between progressors and non-progressors. Conversely, CCR5 and CX3CR1 expression was higher in not only progressors but also patients with detectable viral load. The logistic regression, however, demonstrated a significant role for CCR5 expression as a predictor of atherosclerosis progression (B = 2.1, OR = 8.1, p = 0.04) and a negligible effect for CXC3R1 and CCR2 expression. CONCLUSIONS: Available CCR5 antagonists should be investigated for their potential to delay the course of atherosclerosis in HIV-infected patients.

Abstract: BACKGROUND: The relevance of the association between inflammation and atrial fibrillation (AF) is not firmly established. The clinical importance is considerable because inflammation is usually not targeted as a treatment option, minimizing a probable benefit. MATERIALS AND METHODS: We have used a case-control study with a Mendelian randomization rationale to assess whether proposed risk factors that have a genetic component and are readily detected in circulating blood are causally related to AF. The studied variables were C-reactive protein (CRP) and a representative of the chemokine system, the monocyte chemoattractant protein-1 (CCL2). RESULTS: Plasma CRP and CCL2 concentrations were significantly higher in AF patients than in the unaffected population. However, when segregated between paroxysmal and permanent, the difference for CRP was only observed in patients with a permanent condition. Plasma CCL2 was raised in both subgroups. Confounding factors were carefully considered, and multivariable analyses revealed that circulating CCL2 was significant and CRP was negligible to explain the presence of AF. The duration of the episode also bore a significant predictive value. Odd ratios for AF as a function of genotype did not differ from 1·0 for any of the individual CRP and CCL2 polymorphisms, or any combinations. CONCLUSIONS: Elevated plasma CRP concentration per se does not increase atrial fibrillation risk. Values obtained for CCL2 suggest that inflammation is probably a consequence of AF. Our data also suggest that the effect of the duration of the episode should be further studied in the assessment of the actual role of inflammation.

Abstract: Aging can be viewed as a quasi-programmed phenomenon driven by the overactivation of the nutrient-sensing mTOR gerogene. mTOR-driven aging can be triggered or accelerated by a decline or loss of responsiveness to activation of the energy-sensing protein AMPK, a critical gerosuppressor of mTOR. The occurrence of age-related diseases, therefore, reflects the synergistic interaction between our evolutionary path to sedentarism, which chronically increases a number of mTOR activating gero-promoters (e.g., food, growth factors, cytokines and insulin) and the "defective design" of central metabolic integrators such as mTOR and AMPK. Our laboratories at the Bioactive Food Component Platform in Spain have initiated a systematic approach to molecularly elucidate and clinically explore whether the "xenohormesis hypothesis," which states that stress-induced synthesis of plant polyphenols and many other phytochemicals provides an environmental chemical signature that upregulates stress-resistance pathways in plant consumers, can be explained in terms of the reactivity of the AMPK/mTOR-axis to so-called xenohormetins. Here, we explore the AMPK/mTOR-xenohormetic nature of complex polyphenols naturally present in extra virgin olive oil (EVOO), a pivotal component of the Mediterranean style diet that has been repeatedly associated with a reduction in age-related morbid conditions and longer life expectancy. Using crude EVOO phenolic extracts highly enriched in the secoiridoids oleuropein aglycon and decarboxymethyl oleuropein aglycon, we show for the first time that (1) the anticancer activity of EVOO secoiridoids is related to the activation of anti-aging/cellular stress-like gene signatures, including endoplasmic reticulum (ER) stress and the unfolded protein response, spermidine and polyamine metabolism, sirtuin-1 (SIRT1) and NRF2 signaling; (2) EVOO secoiridoids activate AMPK and suppress crucial genes involved in the Warburg effect and the self-renewal capacity of "immortal" cancer stem cells; (3) EVOO secoiridoids prevent age-related changes in the cell size, morphological heterogeneity, arrayed cell arrangement and senescence-associated β-galactosidase staining of normal diploid human fibroblasts at the end of their proliferative lifespans. EVOO secoiridoids, which provide an effective defense against plant attack by herbivores and pathogens, are bona fide xenohormetins that are able to activate the gerosuppressor AMPK and trigger numerous resveratrol-like anti-aging transcriptomic signatures. As such, EVOO secoiridoids constitute a new family of plant-produced gerosuppressant agents that molecularly "repair" the aimless (and harmful) AMPK/mTOR-driven quasi-program that leads to aging and aging-related diseases, including cancer.

Abstract: Chronic, non-acute inflammation is behind conditions that represent most of the disease burden in humans and is clearly linked to immune and metabolic mechanisms. The convergence of pathways involving the immune response, oxidative stress, increased circulating lipids and aberrant insulin signaling results in CCL2-associated macrophage recruitment and altered energy metabolism. The CCL2/CCR2 pathway and the energy sensor AMP-activated protein kinase (AMPK) are attractive therapeutic targets as a part of preventive management of disease. Several effects of polyphenols are useful in this scenario, including a reduction in the activities of cytokines and modulation of cellular metabolism through histone deacetylase inhibitors, AMPK activators, calorie-restriction mimetics or epigenetic regulators. Research is currently underway to develop orally active drugs with these effects, but it is convenient to examine more closely what we are eating. If a lack of relevance in terms of toxicity and substantial effectiveness are confirmed, plant-derived components may provide useful druggable components and dietary supplements. We consider therapeutic actions as a combination of synergistic and/or antagonistic interactions in a multi-target strategy. Hence, improvement in food through enrichment with polyphenols with demonstrated activity may represent a major advance in the design of diets with both industrial and sanitary value.