RESUMEN
Atherosclerosis, a chronic inflammatory condition in which atheroma accumulates within the intima of the arterial wall, is a life-threatening manifestation of cardiovascular disease, due to atheroma rupture, chronic luminal narrowing and thrombosis. Current knowledge of the role of a protective immune response in atherosclerotic lesions has provided promising opportunities to develop new immunotherapeutic strategies. In particular, Tregs exert an atheroprotective role by releasing anti-inflammatory cytokines (IL-10/TGF-ß) and suppressing autoreactive T lymphocytes. In vivo animal experiments have shown that this can be achieved by developing vaccines that stimulate immunological tolerance to atheroma antigens. Here, we present an overview of the current knowledge of the proatherogenic immune response, and we discuss the strategies currently used as immunoregulatory therapy.
Lay abstract Atherosclerosis is a chronic inflammatory disease in which the wall of the artery develops abnormalities, and can lead to serious problems, including heart attack, stroke, or even death. Scientific evidence has shown that the immune system is involved in the development and progression of atherosclerosis. Understanding the role of protective immune response in atherosclerosis provided promising opportunities to develop approaches for prevention and treatment.
Asunto(s)
Aterosclerosis/inmunología , Aterosclerosis/terapia , Inmunoterapia/métodos , Animales , HumanosRESUMEN
Leishmaniasis is a public health disease that requires the development of more effective treatments and the identification of novel molecular targets. Since blocking the PI3K/AKT pathway has been successfully studied as an effective anticancer strategy for decades, we examined whether the same approach would also be feasible in Leishmania due to their high amount and diverse set of annotated proteins. Here, we used a best reciprocal hits protocol to identify potential protein kinase homologues in an annotated human PI3K/AKT pathway. We calculated their ligandibility based on available bioactivity data of the reported homologues and modelled their 3D structures to estimate the druggability of their binding pockets. The models were used to run a virtual screening method with molecular docking. We found and studied five protein kinases in five different Leishmania species, which are AKT, CDK, AMPK, mTOR and GSK3 homologues from the studied pathways. The compounds found for different enzymes and species were analysed and suggested as starting point scaffolds for the design of inhibitors. We studied the kinases' participation in protein-protein interaction networks, and the potential deleterious effects, if inhibited, were supported with the literature. In the case of Leishmania GSK3, an inhibitor of its human counterpart, prioritized by our method, was validated in vitro to test its anti-Leishmania activity and indirectly infer the presence of the enzyme in the parasite. The analysis contributes to improving the knowledge about the presence of similar signalling pathways in Leishmania, as well as the discovery of compounds acting against any of these kinases as potential molecular targets in the parasite.