RESUMEN
The gold-catalyzed reaction of 2-en-4-ynones with alkynylsilanes provides fully substituted allene derivatives bearing furyl and silyl groups. This transformation would involve generation of a gold furyl carbene intermediate, which regioselectively undergoes a nucleophilic attack by the alkynylsilane at the electrophilic carbene carbon atom with the formation of a ß-gold vinyl cation species. The subsequent release of the gold catalyst, accompanied by a 1,2-silyl shift, leads to the formation of tetrasubstituted allene products.
RESUMEN
Psoriasis is a chronic systemic inflammatory disease associated with a higher incidence of cardiovascular disease, especially in patients with moderate to severe psoriasis. It has been estimated that severe psoriasis confers a 25% increase in relative risk of cardiovascular disease, regardless of traditional risk factors. Although the underlying pathogenic mechanisms relating psoriasis to increased cardiovascular risk are not clear, atherosclerosis is emerging as a possible link between skin and vascular affection. The hypothesis that the inflammatory cascade activated in psoriasis contributes to the atherosclerotic process provides the underlying basis to suggest that an anti-inflammatory therapy that improved atherosclerosis would also reduce the risk of MACEs. In this sense, the introduction of biological drugs which specifically target cytokines implicated in the inflammatory cascade have increased the expectations of control over the cardiovascular comorbidity present in psoriasis patients, however, their role in vascular damage processes remains controversial. The aim of this paper is to review the mechanistic link between psoriasis and cardiovascular disease development, as well as analyzing which of the biological treatments could also reduce the cardiovascular risk in these patients, fueling a growing debate on the modification of the general algorithm of treatment.
RESUMEN
The cardiovascular toxicity of Abacavir is related to its purinergic structure. Purinergic P2X7-receptors (P2X7R), characterized by activation by high concentrations of ATP and with high plasticity, seem implicated. We appraise the nature of the interplay between Abacavir and P2X7R in generating vascular inflammation. The effects of Abacavir on leukocyte-endothelium interactions were compared with those of its metabolite carbovir triphosphate (CBV-TP) or ATP in the presence of apyrase (ATP-ase) or A804598 (P2X7R-antagonist). CBV-TP and ATP levels were evaluated by HPLC, while binding of Abacavir, CBV-TP and ATP to P2X7R was assessed by radioligand and docking studies. Hypersensitivity studies explored a potential allosteric action of Abacavir. Clinical concentrations of Abacavir (20 µmol/L) induced leukocyte-endothelial cell interactions by specifically activating P2X7R, but the drug did not show affinity for the P2X7R ATP-binding site (site 1). CBV-TP levels were undetectable in Abacavir-treated cells, while those of ATP were unaltered. The effects of Abacavir were Apyrase-dependent, implying dependence on endogenous ATP. Exogenous ATP induced a profile of proinflammatory actions similar to Abacavir, but was not entirely P2X7R-dependent. Docking calculations suggested ATP-binding to sites 1 and 2, and Abacavir-binding only to allosteric site 2. A combination of concentrations of Abacavir (1 µmol/L) and ATP (0.1 µmol/L) that had no effect when administered separately induced leukocyte-endothelium interactions mediated by P2X7R and involving Connexin43 channels. Therefore, Abacavir acts as a positive allosteric modulator of P2X7R, turning low concentrations of endogenous ATP themselves incapable of stimulating P2X7R into a functional proinflammatory agonist of the receptor.
