Exercise and inflammation-related epigenetic modifications: focus on DNA methylation.

Epigenetics is the study of mitotically or meiotically heritable phenotypes that occur as a result of modifications to DNA, thereby regulating gene expression independently of changes in base sequence due to manipulation of the chromatin structure. These modifications occur through a variety of mechanisms, such as DNA methylation, post-translational histone modifications, and non-coding RNAs, and can cause transcriptional suppression or activation depending on the location within the gene. Environmental stimuli, such as diet and exercise, are thought to be able to regulate these mechanisms, with inflammation as a probable contributory factor. Research into these areas is still in its infancy however. This review will focus on DNA methylation in the context of inflammation (both pro- and anti-inflammatory processes) and exercise. The complexity and relative shortcomings of some existing techniques for studying epigenetics will be highlighted, and recommendations for future study approaches made.

Host recognition by pathogenic fungi through plant flavonoids.

A common characteristic among fungal pathogens of plants is that each specializes on a narrow range of specific plants as hosts. One adaptation to a specific host plant is the recognition of the host's chemicals which can be used to trigger genes or developmental pathways needed for pathogenesis. The production of characteristic flavonoids by plants, particularly those exuded from roots by legumes, appear to be used as signals for various microbes, including symbionts as well as pathogens. Nectria haematococca MPVI (anamorph: Fusarium solani) is a soil-borne pathogen of garden pea (Pisum sativum) which serves as a useful model in studying host flavonoid recognition. This fungus displays flavonoid induction of specific pathogenicity genes as well as stimulation of development needed for pathogenesis. Here, we summarize the study of flavonoid-inducible signal pathways which regulate these trait, through identification of transcription factors and regulatory components which control these responses. The characterization of the components a pathogen uses to specifically recognize its host provides insights into the host adaptation process at the molecular level.

Cytochrome P450 2C9 catalyzes indomethacin O-demethylation in human liver microsomes.

Indomethacin is a widely used nonsteroidal anti-inflammatory drug. We studied the human cytochrome P450 (CYP) isoform responsible for indomethacin O-demethylation, the major metabolic pathway for indomethacin. For indomethacin O-demethylase activities, the KM value was 34.6 +/- 5.4 muM and the Vmax value was 14.1 +/- 3.9 pmol/mg/min in human liver microsomes (N = 4). Indomethacin O-demethylase activity in human liver microsomes was competitively inhibited by sulfaphenazole, (S)-warfarin, and tolbutamide and was not affected by alpha-naphthoflavone, (S)-mephenytoin, or erythromycin. Indomethacin O-demethylase activities in microsomes from nine human livers were significantly correlated with tolbutamide hydroxylase activities (r = 0.750, p < 0.05) and not with (S)-mephenytoin 4'-hydroxylase activities. When the capacity for indomethacin O-demethylation in microsomes of B lymphoblastoid cells expressing human CYPs was investigated at an indomethacin concentration of 5 microM, cDNA-expressed CYP2C9 exhibited 6-fold greater activity than did CYP2C19. At an indomethacin concentration of 50 microM, cDNA-expressed CYP1A2 and CYP2D6 also exhibited slight activities. The KM values were 9.9 +/- 1.2 and 117.1 +/- 13.8 microM and the Vmax values were 0.33 +/- 0.05 and 0.24 +/- 0.04 pmol/min/pmol CYP in microsomes with cDNA-expressed CYP2C9 and CYP2C19, respectively (N = 4). Considering the 16-fold higher intrinsic clearance of CYP2C9, compared with that of CYP2C19, and these expression levels in human livers, the contribution of CYP2C19 to indomethacin O-demethylation was considered to be negligible. Indomethacin appears to be O-demethylated exclusively by CYP2C9 in humans.

Formation of catechol estrogens by intestinal bacterial demethylation of 2-methoxyestrone.

The intestinal bacterial metabolism of 2-methoxyestrone was studied by incubation in the isolated coecum from rats. Following isolation of estrogens by a combination of ion-exchange and ligand-exchange chromatography, the metabolites were identified by gas chromatography-mass spectrometry. The two main reactions were oxidoreduction at C-17 and extensive demethylation at C-2. Thus, the demethylation of 2-methoxyestrogens known to occur in vivo may be due to the action of microbial enzymes. The study also shows that the intestinal microflora is capable of converting biologically inactive into active steroid hormones.