No abstract

Capsaicin, a pungent ingredient of hot peppers, causes excitation of small sensory neurons, and thereby produces severe pain. A nonselective cation channel activated by capsaicin has been identified in sensory neurons and a cDNA encoding the channel has been cloned recently. However, an endogenous activator of the receptor has not yet been found. In this study, we show that several products of lipoxygenases directly activate the capsaicinactivated channel in isolated membrane patches of sensory neurons. Among them, 12-and 15-(S)-hydroperoxyeicosatetraenoic acids, 5-and 15-(S)-hydroxyeicosatetraenoic acids, and leukotriene B4 possessed the highest potency. The eicosanoids also activated the cloned capsaicin receptor (VR1) expressed in HEK cells. Prostaglandins and unsaturated fatty acids failed to activate the channel. These results suggest a novel signaling mechanism underlying the pain sensory transduction.

The clinical and public health significance of non-alcoholic fatty liver disease (NAFLD) is not well established. We investigate the long-term impact of NAFLD on mortality. This analysis utilizes the National Health and Nutrition Examination Survey conducted in 1988–1994 and subsequent follow-up data for mortality through December 31, 2006. NAFLD was defined by ultrasonographic detection of hepatic steatosis in the absence of other known liver diseases. The presence and severity of hepatic fibrosis in subjects with NAFLD was determined by the NAFLD fibrosis score (NFS), the AST-platelet ratio index (APRI), and the FIB-4 score. Out of 11,154 participants, 34.0% had NAFLD - the majority (71.7%) had NFS consistent with lack of significant fibrosis (NFS < −1.455), whereas 3.2% had a score indicative of advanced fibrosis (NFS > 0.676). After a median follow-up of 14.5 years, NAFLD was not associated with higher mortality (age- and sex-adjusted hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.93–1.19). In contrast, there was a progressive increase in mortality with advancing fibrosis scores. Compared to subjects without fibrosis, those with a high probability of advanced fibrosis had a 69% increase in mortality (HR 1.69 (95% CI 1.09–2.63) for NFS, 1.85 (1.02–3.37) for APRI, 1.66 (0.98–2.82) for FIB-4) after adjustment for other known predictors of mortality. These increases in mortality were almost entirely from cardiovascular causes (HR 3.46 (95% CI 1.91–6.25) for NFS, 2.53 (1.33–4.83) for APRI, 2.68 (1.44–4.99) for FIB-4). Conclusions Ultrasonography-diagnosed NAFLD is not associated with increased mortality. However, advanced fibrosis as determined by non-invasive fibrosis marker panels is a significant predictor of mortality, mainly from cardiovascular causes, independent of other known factors.

Two-pore-domain potassium (K(+)) channels are substrates for resting K(+) currents in neurons. They are major targets for endogenous modulators, as well as for clinically important compounds such as volatile anesthetics. In the current study, we report on the CNS distribution in the rat and mouse of mRNA encoding seven two-pore-domain K(+) channel family members: TASK-1 (KCNK3), TASK-2 (KCNK5), TASK-3 (KCNK9), TREK-1 (KCNK2), TREK-2 (KCNK10), TRAAK (KCNK4), and TWIK-1 (KCNK1). All of these genes were expressed in dorsal root ganglia, and for all of the genes except TASK-2, there was a differential distribution in the CNS. For TASK-1, highest mRNA accumulation was seen in the cerebellum and somatic motoneurons. TASK-3 was much more widely distributed, with robust expression in all brain regions, with particularly high expression in somatic motoneurons, cerebellar granule neurons, the locus ceruleus, and raphe nuclei and in various nuclei of the hypothalamus. TREK-1 was highest in the striatum and in parts of the cortex (layer IV) and hippocampus (CA2 pyramidal neurons). mRNA for TRAAK also was highest in the cortex, whereas expression of TREK-2 was primarily restricted to the cerebellar granule cell layer. There was widespread distribution of TWIK-1, with highest levels in the cerebellar granule cell layer, thalamic reticular nucleus, and piriform cortex. The differential expression of each of these genes likely contributes to characteristic excitability properties in distinct populations of neurons, as well as to diversity in their susceptibility to modulation.