I began my studies under the direction of Professor Alberto Sols investigating the effect of protein interactions in the regulation of carbohydrate metabolism. Later I continued my post-doctoral training at the University of Oxford and at the Faculty of Medicine of UCL (Brussels). As an independent researcher I worked and collaborate with Dr Peter J Parker at Cancer United Kingdom (London) and Carleton University in Ottawa, investigating the role of protein kinase C on the energy metabolism of tumor cells. Since 1997 I focused on the study of the pathophysiology of inflammatory processes, investigating their contribution in processes as diverse as liver regeneration, septic shock and myocarditis. In this context, I studied the role of reactive oxygen and nitrogen species, including nitric oxide, on the regulation of liver regeneration after partial hepatectomy as well as on macrophage activation and its role in heart diseases after sepsis, heart attack or infectious and autoimmune myocarditis, demonstrating its role in the process of remodeling of the extracellular matrix. The study area of the inflammatory response in the liver has allowed our group to characterize important mechanisms in liver regeneration after chronic or acute injury, or after partial hepatectomy. We have shown how caveolin 1 has a relevant role in the regulation of liver regeneration providing signals that are essential for the commitment of hepatocyte growth, so that it fits the organ size for the required physiological functions, including signals linked to aggression by oncogenic agents (associated with inflammation). This work has helped to clarify conflicting precedent data in which caveolin-1 appeared to be an essential requirement for liver regeneration. Our group has shown that those data were associated with an epiphenomenon associated to the metabolic dependence of the liver and that, contrary to the initially published results, the lack of caveolin 1 suppresses proliferative brakes that eventually can contribute to various forms of liver disease, which has been studied in depth by our group. In the last decade we have also worked in the regulation of inflammation as a common pathophysiological process, from inception to resolution, and applied this knowledge to understand the pathogenesis of processes that are relevant in cardiovascular diseases. Thus, we have shown for the first time how bioactive lipids derived from cyclooxygenase and/or lipooxygenase are involved in resolution of several cardiovascular pathologies. In atherogenesis, these molecules modulate macrophage viability and this is a critical step in the regulation of the innate response. Briefly, lipoxin A4 and its derivatives, through a mechanism operated by plasma membrane receptors, inhibit apoptosis and induce macrophage autophagy. This is important because, (1) these molecules are synthesized by the macrophage itself in the course of the pro-inflammatory response without requiring precursors requiring intercellular trafficking; (2) modulate Nrf-2-dependent gene expression that mediates adaptation to oxidative stress, a signature of the activated innate immune response; (3) delay macrophage apoptosis until the resolution is completed, avoiding necrosis and necroptosis-related alterations; and (4) generate a response that ensures autophagic concatenation of pro-resolution activities, both through lipids derived from omega-6 PUFAs (lipoxins) and omega-3 (resolvins and maresins) polyunsaturated fatty acids. Under the viewpoint of the molecular mechanisms that govern the metabolic profiling of macrophages and their impact on the cell function we have demonstrated the basic principles associated to the metabolic adaptation of macrophages depending on their functional proinflammatory polarization (M1) or anti-inflammatory and pro-resolution (M2a/b). These works use techniques intended to provide fluxomics and metabolomics maps associated to the functional polarization. These approaches allowed us to assess the different energy flows used by the macrophage as a function of the distinct metabolic precursors. We demonstrated that, regardless of the nature of macrophage activation, they always use the glycolytic pathway to generate most of the ATP required for any phenotype of polarization. What has been interesting from these studies is to check that the metabolic fluxes are qualitatively identical along the different phenotypes analyzed, but what makes the difference among them is the intensity of the fluxes, being especially glycolysis which provides the energy supply to these cells in both normoxic and hypoxic, the latter a typical condition of inflammatory environments. The second conclusion of this study was to assess that the use of substrates through the TCA/OXPHOS pathway is a feature of the M2 polarization, while in M1 cells it is repressed (both in humans and rodent cells) below control levels. The use of these routes, which is important in pathological contexts where oxygen is limiting are mainly directed towards anaplerotic purposes. Finally, we have concluded that HIF-1alpha did not exert the preponderant role that the in vitro studies show, being replaced by HIF-2alpha in animals in which this gene is deleted. These works have been positioned the group in a relevant position in the field of the metabolic regulation of macrophage function associated to its polarization. As evidence of this, these works have been cited more than 140 times in high impact journals in the field of immunobiology. As an extension of these studies, the diagnosing of atherogenesis requires imaging techniques to identify the presence of ‘active’ plates, i.e. recruiting macrophages and other cell types following an atherogenic event. In collaboration with the group of Dr. J Narula (Mount Sinai Med School, NY) we tried different positron emission tomography (PET)-based tracers to improve the imaging based on the classic fluorodeoxyglucose (FDG) incorporation that offers low resolution levels. One of the most promising new substrates to characterize macrophage signatures is the uptake of fluoro-deoxymannose that provides a significant increase in the intracellular burden signal. Our group identified the mechanisms by which this mannose mark exceeds widely that of glucose, allowing a significant increase in the quality and specificity of the PET image without affecting costs, toxicity or detection mechanism. This work has opened new perspectives for the characterization of alternative molecules to FDG tracers of atherogenesis, with a clear application to biomedical imaging. These studies have been conducted in rodents, rabbits and are being implemented in humans. With a cost of € 5-10 for each administration in humans and an increase up to 3 times in the signal vs. noise ratio, represent a valid alternative for the athero detection. The study of molecules derived from natural products with anti-inflammatory activity is a subject of broad translational interest. However, surprisingly little is known regarding the molecular mechanisms involved. Chemical series derived from acanthoic acid exhibit potent anti-inflammatory action and we showed that they selectively activate the nuclear receptor LXR. By examining the mechanisms that mediate the pharmacological actions of these molecules we saw that they also selectively activate two isoforms of PI3K in the macrophage. The recapitulation of these data provides for the first time a series of molecules (from natural products) that simultaneously activate a nuclear receptor (LXR) and PI3K, both converging in suppressing macrophage inflammatory genes. The work has paid an editorial in the journal BIOL CHEM from the CELL group.