The methyl ester of rosuvastatin elicited an endothelium-independent and 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent relaxant effect in rat aorta

The relaxant effect of the methyl ester of rosuvastatin was evaluated on aortic rings from male Wistar rats (250-300 g, 6 rats for each experimental group) with and without endothelium precontracted with 1.0 µM phenylephrine. The methyl ester presented a slightly greater potency than rosuvastatin in relaxing aortic rings, with log IC50 values of -6.88 and -6.07 M, respectively. Unlike rosuvastatin, the effect of its methyl ester was endothelium-independent. Pretreatment with 10 µM indomethacin did not inhibit, and pretreatment with 1 mM mevalonate only modestly inhibited the relaxant effect of the methyl ester. Nω-nitro-L-arginine methyl ester (L-NAME, 10 µM), the selective nitric oxide-2 (NO-2) inhibitor 1400 W (10 µM), tetraethylammonium (TEA, 10 mM), and cycloheximide (10 µM) partially inhibited the relaxant effect of the methyl ester on endothelium-denuded aortic rings. However, the combination of TEA plus either L-NAME or cycloheximide completely inhibited the relaxant effect. Inducible NO synthase (NOS-2) was only present in endothelium-denuded aortic rings, as demonstrated by immunoblot with methyl ester-treated rings. In conclusion, whereas rosuvastatin was associated with a relaxant effect dependent on endothelium and hydroxymethylglutaryl coenzyme A reductase in rat aorta, the methyl ester of rosuvastatin exhibited an endothelium-independent and only slightly hydroxymethylglutaryl coenzyme A reductase-dependent relaxant effect. Both NO produced by NOS-2 and K+ channels are involved in the relaxant effect of the methyl ester of rosuvastatin.

WT-1 mRNA expression is modulated by nitric oxide availability and Hsp70 interaction after neonatal unilateral ureteral obstruction

Wilms tumor gene 1 (wt-1), a key regulator of mesenchymal-epithelial transformation, is downregulated during congenital obstructive nephropathy, leading to apoptosis. There is a functional interaction between WT-1 and inducible nitric oxide synthase (iNOS). In this regard, we reported that after neonatal unilateral ureteral obstruction, rosuvastatin prevents apoptosis through an increase in nitric oxide bioavailability, which in turn is linked to higher Hsp70 expression. Hence, the goal of this study was to determine whether a nitric oxide/Hsp70 interaction is involved in changes in WT-1 mRNA expression after ureteral obstruction. Neonatal rats submitted to experimental ureteral obstruction were treated with either vehicle or rosuvastatin for 14 days. Decreased nitric oxide and iNOS/Hsp70 expression associated wit h WT-1 low expression was shown in obstructed kidneys. Apoptosis was induced and it was associated with an increased Bax/BcL2 ratio. Conversely, iNOS/Hsp70 upregulation and an increased WT-1 mRNA expression, without an apoptotic response, were observed in the cortex of obstructed kidneys of rosuvastatin-treated rats. Nitric oxide also modulated Hsp70 and WT-1 mRNA expression in MDCK cells. Finally, in vivo experiments with nitric oxide modulators support our hypothesis that WT-1 mRNA expression is associated with nitric oxide level. Results suggest that rosuvastatin may modulate WT-1 mRNA expression through renal nitric oxide bioavailability, preventing neonatal obstruction-induced apoptosis associated with Hsp70 interaction.

Implications of dibenzyl trisulphide for disease treatment based on its mode of action / Implicaciones del trisulfuro de dibencilo para el tratamiento de enfermedades a partir de su modo de acción

Studies conducted on the secondary metabolite (natural product), dibenzyl trisulphide (DTS), which was isolated from the sub-tropical shrub Petiveria alliacea (guinea hen weed, anamu) [Phytolaccaceae] have shown tremendous pharmaceutical promise as a drug prototype. This is now reflected in the development of the broad spectrum anti-cancer molecule, fluorapacin (bis(4-fluorobenzyl) trisulphide) which has an excellent safety profile. The mode of action elucidated for DTS is the mitogen activated protein extracellular regulated kinases 1 and 2 (MAPKinases ERK 1 and ERK 2). The MAPKinase signal transduction biochemical pathways are important in the regulation of a wide range of cellular processes which are important in disease establishment. These processes include: cancer cell proliferation, nerve repair, memory enhancement, autoimmune diseases, which are linked to thymic cell involution and bone marrow functions, cerebrovascular and cardiovascular diseases. In addition to the MAPkinase signal transduction mode of action, DTS also prevents the denaturation of serum albumin which is a feature of nonsteroidal anti-inflammatory drugs, thus supporting the molecule's possible role in the treatment of inflammatory ageing diseases.

Los estudios realizados sobre el metabolito secundario (producto natural), trisulfuro de dibencilo (TSD), que fue aislado del arbusto subtropical Petiveria alliacea (hierba de guinea, anamú) [Phytolaccaceae] muestran que se trata de una tremenda promesa farmacéutica como prototipo de droga. Esto se refleja actualmente en el desarrollo de la molécula anticancerígena de amplio espectro, la fluorapacina (bis (4-fluorobencilo) trisulfuro) que posee un excelente perfil de seguridad. El modo de acción para el TSD se explica partiendo de las proteínas quinasas 1 y 2 activadas por mitógenos y reguladas por señales extracelulares (Quinasas MAP ERK 1 y ERK 2). Las vías bioquímicas de transducción de la señal de la quinasa MAP, son importantes en la regulación de una amplia variedad de procesos celulares, importantes a la hora de determinar una enfermedad. Dichos procesos comprenden: la proliferación de la célula cancerosa, la reparación de nervios, el mejoramiento de la memoria, y las enfermedades autoinmunes, vinculadas con la involución tímica y las funciones de la médula, las enfermedades cerebrovasculares y cardiovasculares. Además del modo de acción de las transducción de señales de la quinasa MAP, el TSD previene también la desnaturalización de la albúmina sérica, lo cual constituye una característica de las drogas anti-inflamatorias no esferoidales, apoyando así el posible papel de las moléculas en el tratamiento de las enfermedades inflamatorias en el proceso de envejecimiento.

Efectos pleiotrópicos de las estatinas: [revisión] / Pleiotropic effects of statins: [review]

Results of numerous epidemiologic studies indicate that elevated serum cholesterol, especially the LDL fraction, is a major cause of coronary heart disease (CHD). Epidemiologic and angiographic evidence from primary and secondary prevention studies involving several HMG-CoA reducíase inhibitors (statins) indicate that decreasing elevated serum cholesterol concentration (specifically LDL-cholesterol) can reduce the incidence of CHD and/or progression of atherosclerosis and results in a decrease in associated morbidity and mortality. It has been estimated that each 1 percent reduction in LDL-cholesterol concentration may result in a 1 percent decrease in the incidence of CHD. Furthermore, an analysis of pooled data from primary and secondary prevention studies found that treatment with a statin for a median duration of 5.4 years was associated with a 31 percent and 21 percent reduction in the risk of major coronary events and total mortality, respectively. This paper deals with the pharmacology of statins, specially with the pleiotropic effects ofthese drugs.