Atherosclerosis and cancer are chronic diseases considered two of the main causes of death all over the world. Taking into account that both diseases are multifactorial, they share not only several important molecular pathways but also many ethiological and mechanistical processes from the very early stages of development up to the advanced forms in both pathologies. Factors involved in their progression comprise genetic alterations, inflammatory processes, uncontrolled cell proliferation and oxidative stress, as the most important ones. The fact that external effectors such as an infective process or a chemical insult have been proposed to initiate the transformation of cells in the artery wall and the process of atherogenesis, emphasizes many similarities with the progression of the neoplastic process in cancer. Deregulation of cell proliferation and therefore cell cycle progression, changes in the synthesis of important transcription factors as well as adhesion molecules, an alteration in the control of angiogenesis and the molecular similarities that follow chronic inflammation, are just a few of the processes that become part of the phenomena that closely correlates atherosclerosis and cancer. The aim of the present study is therefore, to provide new evidence as well as to discuss new approaches that might promote the identification of closer molecular ties between these two pathologies that would permit the recognition of atherosclerosis as a pathological process with a very close resemblance to the way a neoplastic process develops, that might eventually lead to novel ways of treatment.

An elevated level of plasma uric acid has been widely recognized as a risk factor for non-alcoholic fatty liver disease (NAFLD), where oxidative stress and inflammation play an important role in the pathophysiology of the disease. Although the complete molecular mechanisms involved remain unknown, while under physiological conditions uric acid presents antioxidant properties, hyperuricemia has been linked to oxidative stress, chronic low-grade inflammation, and insulin resistance, basic signs of NAFLD. Employing in vivo experimentation, we aim to investigate whether a high-fat diet rich in cholesterol (HFD), modifies the metabolism of purines in close relationship to molecular events associated with the development of NAFLD. In vitro experiments employing HepG2 cells are also carried out to study the phenomenon of oxidative stress. Adult male rabbits were fed for 8 weeks an HFD to induce NAFLD. At the beginning of the experiment and every 15 d until the completion of the study, plasma levels of lipids, lipoproteins, and uric acid were measured. Liver tissue was isolated, and histology performed followed by the biochemical determination of hypoxanthine, protein expression of xanthine oxidoreductase (XOR) by western blot analysis, and xanthine oxidase (XO) activity using an enzymatic kinetic assay. Furthermore, we employed in vitro experimentation studying HepG2 cells to measure the effect of hypoxanthine and H2O2 upon the production of radical oxygen species (ROS), XO activity, and cell viability. Hepatic tissue from rabbits fed the HFD diet showed signs of NAFLD associated with an increased ROS concentration and an altered purine metabolism characterized by the increase in hypoxanthine, together with an apparent equilibrium displacement of XOR towards the xanthine dehydrogenase (XDH) isoform of the enzyme. This protein shift visualized by a western blot analysis, associated with an increase in plasma uric acid and hepatocyte hypoxanthine could be understood as a compensatory series of events secondary to the establishment of oxidative stress associated with the chronic establishment of fatty liver disease.

The complex pathophysiology of sepsis makes it a syndrome with limited therapeutic options and a high mortality rate. Gram-negative bacteria containing lipopolysaccharides (LPS) in their outer membrane correspond to the most common cause of sepsis. Since the gut is considered an important source of LPS, intestinal damage has been considered a cause and a consequence of sepsis. Although important in the maintenance of the intestinal epithelial cell homeostasis, the microbiota has been considered a source of LPS. Recent studies have started to shed light on how sepsis is triggered by dysbiosis, and an increased inflammatory state of the intestinal epithelial cells, expanding the understanding of the gut-liver axis in sepsis. Here, we review the gut-liver interaction in Gram-negative sepsis, exploring the mechanisms of LPS inactivation, including the recently described contribution of an isoform of the cholesteryl-ester transfer protein (CETPI). Although several key questions remain to be answered when the pathophysiology of sepsis is reviewed, new contributions coming to light exploring the way LPS might be inactivated in vivo, suggest that new applications might soon reach the clinical setting.

Metabolic overload by saturated fatty acids (SFA), which comprises β-cell function, and impaired glucose-stimulated insulin secretion are frequently observed in patients suffering from obesity and type 2 diabetes mellitus. The increase of intracellular Ca²⁺ triggers insulin granule release, therefore several mechanisms regulate Ca²⁺ efflux within the β-cells, among others, the plasma membrane Ca²⁺-ATPase (PMCA). In this work, we describe that lipotoxicity mediated mainly by the saturated palmitic acid (PA) (16C) is associated with loss of protein homeostasis (proteostasis) and potentially cell viability, a phenomenon that was induced to a lesser extent by stearic (18C), myristic (14C) and lauric (12C) acids. PA was localized on endoplasmic reticulum, activating arms of the unfolded protein response (UPR), as also promoted by lipopolysaccharides (LPS)-endotoxins. In particular, our findings demonstrate an alteration in PMCA1/4 expression caused by PA and LPS which trigger the UPR, affecting not only insulin release and contributing to β-cell mass reduction, but also increasing reactive nitrogen species. Nonetheless, stearic acid (SA) did not show these effects. Remarkably, the proteolytic degradation of PMCA1/4 prompted by PA and LPS was avoided by the action of monounsaturated fatty acids such as oleic and palmitoleic acid. Oleic acid recovered cell viability after treatment with PA/LPS and, more interestingly, relieved endoplasmic reticulum (ER) stress. While palmitoleic acid improved the insulin release, this fatty acid seems to have more relevant effects upon the expression of regulatory pumps of intracellular Ca²⁺. Therefore, chain length and unsaturation of fatty acids are determinant cues in proteostasis of β-cells and, consequently, on the regulation of calcium and insulin secretion.

Purpose of Review The purpose of this review is to focus on the outcome of recent antioxidant interventions using synthetic and naturally occurring molecules established as adjuvant strategies to lipid-lowering or anti-inflammatory therapies designed to reduce the risk of cardiovascular disease. Recent Findings To date, accumulated evidence regarding oxidation as a pro-atherogenic factor indicates that redox biochemical events involved in atherogenesis are indeed a very attractive target for the management of cardiovascular disease in the clinic. Nevertheless, although evidence indicates that redox reactions are important in the initiation and progression of atherosclerosis, oxidation with a pro-atherogenic context does not eliminate the fact that oxidation participates in many cases as an essential messenger of important cellular signaling pathways. Therefore, disease management and therapeutic goals require not only high-precision and high-sensitivity methods to detect in plasma very low amounts of reducing and oxidizing molecules but also a much better understanding of the normal processes and metabolic pathways influenced and/or controlled by oxidative stress. As several methodologies have been specifically described for the quantification of the total antioxidant capacity and the oxidation state of diverse biological systems, a successful way to carefully study how redox reactions influence atherosclerosis can be achieved. Summary Since there is still a lack of standardization with many of these methods, clinical trials studying antioxidant capacity have been difficult to compare and therefore difficult to use in order to reach a conclusion. We believe a comprehensive analysis of new knowledge and its relationship with the presence of plasma antioxidants and their reducing capacity will undoubtedly open new ways to understand and develop new therapeutic pathways in the fight not only against atherosclerosis but also against other degenerative diseases.