overall performance and predictive value of these met


overall performance and predictive value of these methods was then examined by testing a training set of 10 compounds, including known developmental neurotoxicants and compounds not considered to be neurotoxic. The classification of the selected compounds as either neurotoxic or non-neurotoxic, based on the effects observed in zebrafish embryos and larvae, was compared to available mammalian data and an overall concordance of 90% was achieved. Furthermore, the specificity of the selected endpoints for DNT was evaluated as well as the potential similarities between zebrafish and mammals with regard to mechanisms of action for the selected compounds. Although further studies, including the screening of a large testing set of compounds are required, we suggest that the proposed methods with zebrafish embryos and larvae might be valuable alternatives for animal testing for the screening and prioritization of compounds Torin 2 manufacturer for DNT. (C) 2013 Elsevier Inc.

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“Salvinorin A, the primary psychoactive derivative of the hallucinogenic herb Salvia divinorum, is a potent and highly selective kappa-opioid receptor (KOR) agonist. Several recent studies, however, have suggested endocannabinoid system mediation of Silmitasertib some of its effects.

This study represents a systematic examination of this hypothesis.

Salvinorin A was isolated from S. divinorum and was evaluated check details in a battery of in vitro and in vivo procedures designed to detect cannabinoid activity, including CB(1) receptor radioligand and [(35)S]GTP gamma S binding, calcium flux assay, in vivo cannabinoid

screening tests, and drug discrimination.

Salvinorin A did not bind to nor activate CB(1) receptors. In vivo salvinorin A produced pronounced hypolocomotion and antinociception (and to a lesser extent, hypothermia). These effects were blocked by the selective KOR antagonist, JDTic, but not by the CB(1) receptor antagonist rimonabant. Interestingly, however, rimonabant attenuated KOR activation stimulated by U69,593 in a [(35)S]GTP gamma S assay. Salvinorin A did not substitute for Delta(9)-tetrahydrocannabinol (THC) in mice trained to discriminate THC.

These findings suggest that similarities in the pharmacological effects of salvinorin A and those of cannabinoids are mediated by its activation of KOR rather than by any direct action of salvinorin A on the endocannabinoid system. Further, the results suggest that rimonabant reversal of salvinorin A effects in previous studies may be explained in part by rimonabant attenuation of KOR activation.”
“The tissue microenvironment in chronic lymphocytic leukemia (CLL) has an increasingly recognized role in disease progression, but the molecular mechanisms of cross talk between CLL cells and their microenvironment remain incompletely defined.

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