For many years, cardiovascular disease (CVD) has been the leading cause of death around the world. Often associated with CVD are comorbidities such as obesity, abnormal lipid profiles and insulin resistance. Insulin is a key hormone that functions as a regulator of cellular metabolism in many tissues in the human body. Insulin resistance is defined as a decrease in tissue response to insulin stimulation thus insulin resistance is characterized by defects in uptake and oxidation of glucose, a decrease in glycogen synthesis, and, to a lesser extent, the ability to suppress lipid oxidation. Literature widely suggests that free fatty acids are the predominant substrate used in the adult myocardium for ATP production, however, the cardiac metabolic network is highly flexible and can use other substrates, such as glucose, lactate or amino acids. During insulin resistance, several metabolic alterations induce the development of cardiovascular disease. For instance, insulin resistance can induce an imbalance in glucose metabolism that generates chronic hyperglycemia, which in turn triggers oxidative stress and causes an inflammatory response that leads to cell damage. Insulin resistance can also alter systemic lipid metabolism which then leads to the development of dyslipidemia and the well-known lipid triad: (1) high levels of plasma triglycerides, (2) low levels of high-density lipoprotein, and (3) the appearance of small dense low-density lipoproteins. This triad, along with endothelial dysfunction, which can also be induced by aberrant insulin signaling, contribute to atherosclerotic plaque formation. Regarding the systemic consequences associated with insulin resistance and the metabolic cardiac alterations, it can be concluded that insulin resistance in the myocardium generates damage by at least three different mechanisms: (1) signal transduction alteration, (2) impaired regulation of substrate metabolism, and (3) altered delivery of substrates to the myocardium. The aim of this review is to discuss the mechanisms associated with insulin resistance and the development of CVD. New therapies focused on decreasing insulin resistance may contribute to a decrease in both CVD and atherosclerotic plaque generation.

Artemisinins are the most important class of antimalarial drugs. They specifically inhibit PfATP6, a SERCA-type ATPase of Plasmodium falciparum. Here we show that a single amino acid in transmembrane segment 3 of SERCAs can determine susceptibility to artemisinin. An L263E replacement of a malarial by a mammalian residue abolishes inhibition by artemisinins. Introducing residues found in other Plasmodium spp. also modulates artemisinin sensitivity, suggesting that artemisinins interact with the thapsigargin-binding cleft of susceptible SERCAs.

The GLUT2 glucose transporter and the K-ATP-sensitive potassium channels have been implicated as an integral part of the glucose-sensing mechanism in the pancreatic islet b cells. The expression of GLUT2 and K-ATP channels in the hypothalamic region suggest that they are also involved in a sensing mechanism in this area. The hypothalamic glial cells, known as tanycytes a and b, are specialized ependymal cells that bridge the cerebrospinal fluid and the portal blood of the median eminence. We used immunocytochemistry, in situ hybridization and transport analyses to demonstrate the glucose transporters expressed in tanycytes. Confocal microscopy using specific antibodies against GLUT1 and GLUT2 indicated that both transporters are expressed in a and b tanycytes. In addition, primary cultures of mouse hypothalamic tanycytes were found to express both GLUT1 and GLUT2 transporters. Transport studies, including 2-deoxyglucose and fructose uptake in the presence or absence of inhibitors, indicated that these transporters are functional in cultured tanycytes. Finally, our analyses indicated that tanycytes express the K-ATP channel subunit Kir6.1 in vitro. As the expression of GLUT2 and K-ATP channel is linked to glucose-sensing mechanisms in pancreatic b cells, we postulate that tanycytes may be responsible, at least in part, for a mechanism that allows the hypothalamus to detect changes in glucose concentrations.

The glucose transporters (GLUT/SLC2A) are members of the major facilitator superfamily. Here, we generated a three-dimensional model for Glut1 using a two-step strategy: 1), GlpT structure as an initial homology template and 2), evolutionary homology using glucose-6-phosphate translocase as a template. The resulting structure (PDB No. 1SUK) exhibits a water-filled passageway communicating the extracellular and intracellular domains, with a funnel-like exofacial vestibule (infundibulum), followed by a 15 A-long x 8 A-wide channel, and a horn-shaped endofacial vestibule. Most residues which, by mutagenesis, are crucial for transport delimit the channel, and putative sugar recognition motifs (QLS, QLG) border both ends of the channel. On the outside of the structure there are two positively charged cavities (one exofacial, one endofacial) delimited by ATP-binding Walker motifs, and an exofacial large side cavity of yet unknown function. Docking sites were found for the glucose substrate and its inhibitors: glucose, forskolin, and phloretin at the exofacial infundibulum; forskolin, and phloretin at an endofacial site next to the channel opening; and cytochalasin B at a positively charged endofacial pocket 3 A away from the channel. Thus, 1SUK accounts for practically all biochemical and mutagenesis evidence, and provides clues for the transport process.

Mesenchymal stem cells (MSCs) are adult multipotent stem cells that are able to differentiate into multiple specialized cell types including osteocytes, adipocytes, and chondrocytes. MSCs exert different functions in the body and have recently been predicted to have a major clinical/therapeutic potential. However, the mechanisms of self-renewal and tissue regeneration are not completely understood. It has been shown that the biological effect depends mainly on its paracrine action. Furthermore, it has been reported that the secretion of soluble factors and the release of extracellular vesicles, such as exosomes, could mediate the cellular communication to induce cell-differentiation/self-renewal. This review provides an overview of MSC-derived exosomes in promoting angiogenicity and of the clinical relevance in a therapeutic approach.