No marked adverse effects in renal function were observed in animals treated with MEL alone or CA alone, but evidence related to nephrotoxicity was noted in rats administered MC. Renal calculi and increased kidney weights were found in rats 7 d after daily oral administration of MC. Blood urea nitrogen (BUN) and creatinine were significantly elevated in the high dose MC groups at 100x or 1000x. In addition, elevated numbers of white blood cells (WBC), neutrophils, and lymphocytes in vivo and increased levels of prostaglandin E2 (PGE2) in vitro were found in the MC group. Based on these data, the NOAEL (no-observed-adverse-effect AZD1480 mw level)

for nephrotoxicity for MC was estimated to be 3.15 mg/kg body weight (bw)/d (MEL) plus 2.5 mg/kg bw/d (CA). If a safety factor of 1000 or more were applied to NOAEL, tolerable daily intake (TDI) would be 0.00315 and 0.0025 mg/kg/d or less for MEL and CA, respectively, which is far below the TDI

of 0.2 mg/kg/d set by World Health Organization (WHO). In addition, in vitro cytotoxicity assays showed that the ACHN human renal adenocarcinoma cell line was more sensitive to MEL, CA, and MC than the MDCK canine kidney epithelial cell line. The 24-h half maximal inhibitory concentration (IC50) values for MEL (4792, 2792 g/ml) were less than those of CA (9890, 6725 g/ml, respectively) in MDCK and PKA activator ACHN cell lines, suggesting that MEL may be more cytotoxic than CA. Furthermore, the 24-h IC50 value for MC was found to be 208 g/ml in ACHN cells. Data suggest that NOAELs based upon acute

nephrotoxic parameters for MC were low, which might require further reassessment of the current TDI.”
“In the brain, the stress system plays an important role in motivating continued alcohol use and relapse. The neuropeptide substance P and the neurokinin-1 receptor (NK1R) are involved in the stress response and drug reward systems. Recent findings have shown that the binding of ligands to NK1Rs decreases the self-administration of alcohol in mice. We examined the effect of an artificial microRNA (amiRNA) on the functional expression of NK1R in mouse brains. Lentiviruses expressing either an amiRNA PLEKHM2 targeting the NK1R (amiNK1R) or a negative control amiRNA (amiNC) were injected into mouse brains. Four weeks after amiRNA injection, we found that amiNK1R decreased the voluntary alcohol consumption compared to mice injected with amiNC. We also observed that NK1R expression was reduced in the hippocampus. RNA interference is an effective approach to regulate the expression of specific behavior-related genes. Our results support the potential use of amiRNA as a therapeutic agent for the treatment of alcohol dependence. (C) 2010 Elsevier Ireland Ltd. All rights reserved.”
“Toxicometabolomics of urinary biomarkers for human gastric cancer in a mouse model was investigated using 1H-nuclear magnetic resonance (NMR) spectroscopy.