Identification of transcription factors and coactivators affected by dibutylphthalate interactions in fetal rat testes.

Previous analysis of in utero dibutylphthalate (DBP)-exposed fetal rat testes indicated that DBP's antiandrogenic effects were mediated, in part, by indirect inhibition of steroidogenic factor 1 (SF1), suggesting that peroxisome proliferator-activated receptor alpha (PPARα) might be involved through coactivator (CREB-binding protein [CBP]) sequestration. To test this hypothesis, we have performed chromatin immunoprecipitation (ChIP) microarray analysis to assess the DNA binding of PPARα, SF1, CBP, and RNA polymerase II in DBP-induced testicular maldevelopment target genes. Pathway analysis of expression array data in fetal rat testes examined at gestational day (GD) 15, 17, or 19 indicated that lipid metabolism genes regulated by SF1 and PPARα, respectively, were overrepresented, and the time dependency of changes to PPARα-regulated lipid metabolism genes correlated with DBP-mediated repression of SF1-regulated steroidogenesis genes.

Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo.

Mouse nongenotoxic hepatocarcinogens phenobarbital (PB) and chlordane induce hepatomegaly characterized by hypertrophy and hyperplasia. Increased cell proliferation is implicated in the mechanism of tumor induction. The relevance of these tumors to human health is unclear.

Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1-NRF2 pathway, and not the BACH1-NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds.

To better understand the role of transcription factor NF-E2-related factor (NRF) 2 in the human and its contribution to cancer chemoprevention, we have knocked down its negative regulators, Kelch-like ECH-associated protein 1 (KEAP1) and broad-complex, tramtrack and bric à brac and cap'n'collar homology 1 (BACH1), in HaCaT keratinocytes. Whole-genome microarray revealed that knockdown of KEAP1 resulted in 23 messenger RNAs (mRNAs) being up-regulated > or = 2.0-fold.

Phase I clinical trial of oral curcumin: biomarkers of systemic activity and compliance.

Curcumin, a polyphenolic antioxidant derived from a dietary spice, exhibits anticancer activity in rodents and in humans. Its efficacy appears to be related to induction of glutathione S-transferase enzymes, inhibition of prostaglandin E(2) (PGE(2)) production, or suppression of oxidative DNA adduct (M(1)G) formation. We designed a dose-escalation study to explore the pharmacology of curcumin in humans.

Cyclooxygenase-2 expression is a novel prognostic factor in malignant mesothelioma.

Malignant mesothelioma (MM) is a fatal tumor of increasing incidence, which is resistant to current therapy. Cyclooxygenase-2 (COX-2) plays an important role in solid tumor growth, invasiveness, and angiogenesis, in part through the synthesis of prostaglandins such as prostaglandin E(2) (PGE(2)). In a prospective study, we evaluated COX-2 expression in snap-frozen, surgically resected MM tissue specimens using immunohistochemistry and semiquantitative Western blotting.