The vast majority of breast cancers are carcinomas that arise from mammary epithelial cells (MECs). One of the key early events in tumorigenic transformation is the ability of cells to overcome replicative senescence. However, the precise genetic changes that are responsible for this event in MECs is largely unknown. Here, we report that Bmi-1, originally identified as a c-Myc cooperating oncoprotein, can bypass senescence, extend the replicative life span, and immortalize MECs. Furthermore, Bmi-1 was overexpressed in immortal MECs and several breast cancer cell lines.
Forkhead box O (FOXO) transcription factors control diverse cellular functions, such as cell death, metabolism, and longevity. We analyzed FOXO3/FKHRL1 expression and subcellular localization in tumor sections of neuroblastoma patients and observed a correlation between nuclear FOXO3 and high caspase-8 expression. In neuroblastoma caspase-8 is frequently silenced by DNA methylation. Conditional FOXO3 activated caspase-8 gene expression but did not change the DNA-methylation pattern of regulatory sequences in the caspase-8 gene.
Laboratory Investigation; a Journal of Technical Methods and Pathology
The protective effect of heme oxygenase-1 (HO-1) expression in cardiovascular disease has been previously demonstrated using transgenic animal models in which HO-1 is constitutively overexpressed in the heart. However, the temporal requirements for protection by HO-1 induction relative to injury have not been investigated, but are essential to employ HO-1 as a therapeutic strategy in human cardiovascular disease states.
Research Communications in Chemical Pathology and Pharmacology
Methaqualone pretreatment for 3 or 6 days caused an induction of hepatic enzymes in the young male rat as measured by a reduction in hexobarbital-hypnosis. However, methaqualone pretreatment had no effect on the hexobarbital-hypnotic response in older male rats. Phenobarbital was a more potent enzyme inducer than methaqualone, and caused induction of liver enzymes in both age groups.
The Journal of Pharmacology and Experimental Therapeutics
The effect of methaqualone on the induction of hepatic enzymes was evaluated in rats and compared with that of phenobarbital by measuring effects on hexobarbital and methaqualone hypnosis, plasma and tissue levels of methaqualone, hepatic aniline hydroxylase and aminopyrine demethylase activity and warfarin-induced hypoprothrombinemia. Maximal reductions in hexobarbital hypnosis occurred 3 days after daily administration of 60 mg of methaqualone per kg per day.
Induction of hepatic propoxyphene N-demethylase and aniline hydroxylase activities resulted following repeated oral administration of 25, 50 and 100 mg d-propoxyphene hydrochloride per kg daily in the mouse over a six-day period. A significant elevation in both enzyme activities was noted after a single dose of propoxyphene (100 mg/kg). A dose-related response characterized the observed induction of each microsomal enzyme activity.
Archives Internationales De Pharmacodynamie Et De Thérapie
The interaction of four imidazole antimycotics clotrimazole, econazole, ketoconazole and miconazole with other drugs was studied in in vivo models known to reveal inhibition and induction of microsomal enzymes. In rats the duration of methohexital hypnosis and the prothrombin time prolongation induced by acenocoumarol were changed after oral administration of all four antimycotics. The oral ED50-values of miconazole, econazole and clotrimazole for prolongation of methohexital hypnosis in female rats (acute inhibiton of microsomal enzymes) were 3.55, 3.56 and 10.7 mg/kg.
Plasmodium berghei ANKA infected C57B1/6 mice develop cerebral malaria at a parasitaemia of 15-25%. When parasitaemia reached 10%, P. berghei infected mice were treated with artemether, chloroquine or clindamycin in order to prevent the occurrence of cerebral malaria. Artemether and chloroquine were highly efficient. Functional tests revealed that zymosan stimulated spleen cells from untreated mice with cerebral malaria showed a slight decrease in their capacity to produce reactive oxygen intermediates (ROI) when compared with naive mice.
Artemisinin drugs are of utmost importance in the treatment of malaria, because they represent the sole class of therapeutically used antimalarial drugs to which malaria parasites have not yet developed resistance. The major disadvantage of these medicines is the comparatively high recrudescence rate, which has been attributed to the remarkable decrease of artemisinin plasma concentrations during multiple dosing. Autoinduction of CYP2B6-mediated metabolism has been implicated as the underlying mechanism. So far, the molecular mechanism of induction by artemisinin has not been resolved.
Artemisinins induce drug metabolism through the activation of the pregnane X receptor (PXR) in vitro. Here, we report the resequencing and genotyping of PXR variants in 75 Vietnamese individuals previously characterized for CYP3A enzyme activity after artemisinin exposure. We identified a total of 31 PXR variants, including 5 novel single nucleotide polymorphisms (SNPs), and we identified significantly different allele frequencies relative to other ethnic groups.