Transcription factor NF-kappaB regulation of renal fibrosis during ureteral obstruction

BACKGROUND: Oxycodone is metabolized in the liver by means of O-demethylation to form oxymorphone in a reaction catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). This enzyme is expressed as 2 phenotypes (extensive and poor metabolizers). Several drugs are metabolized by CYP2D6, and clinically relevant drug interactions may occur. The aim of this study was to evaluate the role of oxymorphone in mediating the opioid effects of oxycodone by means of blocking CYP2D6 with quinidine. METHODS: Ten healthy extensive metabolizers were administered 20 mg controlled-release oxycodone after premedication with placebo or 200 mg quinidine in this randomized, double-blind crossover study. A dose of 100 mg quinidine was administered 6 hours later. Plasma opioid concentrations, subjective pharmacodynamic ratings, and psychomotor function were assessed for 24 hours after drug administration. RESULTS: No oxymorphone was detected at any time after quinidine premedication in 8 of 10 subjects. Plasma oxycodone (difference not significant) and noroxycodone (P < .01) concentrations were greater after quinidine pretreatment. Prevention of the production of oxymorphone by quinidine did not affect the psychomotor or subjective drug effects of oxycodone. No difference in number of adverse effects was observed after the 2 pretreatments. CONCLUSIONS: A significant reduction in plasma oxymorphone levels did not substantially alter the pharmacodynamic effects of oxycodone. Analgesia was not evaluated because pain was not present.     

Topoisomerase poisons activate the transcription factor NF-kappaB in ACH-2 and CEM cells

The nuclear factor kappaB (NF-kappaB) is involved in T cell activation and enhances HIV-1 gene expression. It is activated in response to numerous stimuli, including oxidative stress. Oxidative stress damages membrane lipids, proteins and nucleic acids. We have shown previously that oxidative DNA damage generated by photosensitization could trigger activation of NF-kappaB. We now show that a series of topoisomerase poisons (actinomycin D, camptothecin, daunomycin and etoposide) also activate NF-kappaB (NFKB1/RelA dimer) in ACH-2 and CEM cells. This activation is inhibited by pyrrolidine dithiocarbamate. In ACH-2 cells latently infected by HIV-1, camptothecin, daunomycin and etoposide are able to enhance virus production. Since topoisomerase poisons cause the formation of single- and double-strand breaks in DNA, these lesions might be capable of triggering NF-kappaB activation. Indeed, DNA damaging agents generating adducts (trans-platin and 4-nitroquinoline 1-oxide) and/or crosslinks in DNA (cisplatin and mitomycin C) do not or only weakly activate NF-kappaB in T cell lines.     

Modulation of transcription factor NF-kappaB by enantiomers of the nonsteroidal drug ibuprofen

In a sample of 463 high school students, 43% reported being the victim of either sexual violence or severe physical violence by peers in the past year. Perpetrators were more likely to be known rather than unknown to the victim, or to be dating/ex-dating partners, and 70% of those who experienced violence by peers were girls. Findings support a view of high school peer violence that encompasses relationship, gender, effects on the victim, and beliefs about both male role power and personal power.     

Yersinia enterocolitica impairs activation of transcription factor NF-kappaB: involvement in the induction of programmed cell death and in the suppression of the macrophage tumor necrosis factor alpha production

Advanced glycation endproducts (AGEs) have been implicated in the pathophysiology of coronary heart disease in ageing, diabetes and renal disease. Competitive enzyme-linked immunosorbent assays (ELISAs) have been developed to measure these compounds in serum, but as recognition of AGEs is both carrier protein- and antibody-dependent standardisation is problematic. We report here on another barrier to standardization, as yet unrecognised. During the development of an AGE ELISA, we found that serum samples did not dilute in parallel to AGE standards or each other. This finding was confirmed by recovery studies that showed over-recovery of AGEs at high serum concentrations, but under-recovery at high dilutions of serum in assay buffer. We developed an inhibition assay to detect factors in serum capable of interacting directly with AGEs immobilised on microtitre plates. Binding of these factors prevented recognition of AGEs by a CML monoclonal antibody and a polyclonal anti-AGE antibody, and was neither sugar- nor carrier protein-dependent. We detected the presence of this factor in all human sera tested and also in foetal calf serum. Pre-incubation of sera with AGEs or heat-treatment at 56 degrees C for 30 min. significantly reduced this binding. We are currently investigating the nature of this factor and the possibility that it may be complement. The effect of this factor on immunoassays for AGEs can only be detected by performing parallelism and recovery studies and we suggest the use of the method referred to in this paper to aid interpretation of parallelism data.     

Helenalin, an anti-inflammatory sesquiterpene lactone from Arnica, selectively inhibits transcription factor NF-kappaB

The cyclin-dependent kinase, proliferating cell nuclear antigen, and stress-activated protein kinase/c-jun NH2 terminal kinase inhibitor p21WAF1/CIP1 can induce G1 arrest, and its expression coincides with the cessation of replication in many systems. We examined expression of p21 during the early stages of carbon tetrachloride intoxication in the mouse liver and observed a dramatic increase in p21 RNA levels between 4 and 8 h after administration. p21 expression, visualized by in situ hybridization, is induced in pericentral hepatocytes before carbon tetrachloride-induced necrosis. Examination of c-fos and c-myc expression patterns confirm that these immediate-early genes are induced in similar regions of the mouse liver. p21 induction is not dependent on p53; we observed similar levels and localization of p21 in wild-type and p53 null animals. Immunohistochemical localization of p21 and CCAAT/enhancer-binding protein expression shows that p21 protein accumulation is limited to a subset of CCAAT/enhancer-binding protein-positive hepatocytes. A second peak of periportal and intermediate zone-specific p21 gene expression, appearing 1-2 days after injection, is also p53 independent and may represent cell cycle checkpoints or postmitotic growth arrest. Sporadic p21 expression was also detected in pairs of hepatocytes distributed throughout the liver acini in healthy animals. Together, these data suggest several roles for p21 in the liver in response to toxicity, regeneration, and growth inhibition.