Effects of the L-tyrosine-derived bacterial metabolite p-cresol on colonic and peripheral cells.

Specific families of bacteria present within the intestinal luminal content produce p-cresol from L-tyrosine. Although the hosts do not synthesize p-cresol, they can metabolize this compound within their colonic mucosa and liver leading to the production of co-metabolites including p-cresyl sulfate (p-CS) and p-cresyl glucuronide (p-CG). p-Cresol and its co-metabolites are recovered in the circulation mainly conjugated to albumin, but also in their free forms that are excreted in the urine. An increased dietary protein intake raises the amount of p-cresol recovered in the feces and urine, while fecal excretion of p-cresol is diminished by a diet containing undigestible polysaccharides. p-Cresol in excess is genotoxic for colonocytes. In addition, in these cells, this bacterial metabolite decreases mitochondrial oxygen consumption, while increasing the anion superoxide production. In chronic kidney disease (CKD), marked accumulation of p-cresol and p-CS in plasma is measured, and in renal tubular cells, p-cresol and p-CS increase oxidative stress, affect mitochondrial function, and lead to cell death, strongly suggesting that these 2 compounds act as uremic toxins that aggravate CKD progression. p-Cresol and p-CS are also suspected to play a role in the CKD-associated adverse cardiovascular events, since they affect endothelial cell proliferation and migration, decrease the capacity of endothelial wound repair, and increase the senescence of endothelial cells. Finally, the fact that concentration of p-cresol is transiently increased in young autistic children biological fluids, and that intraperitoneal injection of p-cresol in animal models induces some behavioral characteristics observed in the autism spectrum disorders (ASD), raise the view that p-cresol may possibly represent one of the components involved in ASD etiology. Further pre-clinical and clinical studies are obviously needed to determine if the lowering of p-cresol and/or p-CS circulating concentrations, by dietary and/or pharmacological means, would allow, by itself or in combination with other interventions, to improve CKD progression and associated cardiovascular outcomes, as well as some neurological outcomes in children with an early diagnosis of autism.

Prostaglandin-independent effects of aspirin on cell cycle and putrescine synthesis in human colon carcinoma cells.

Aspirin consumption has been reported to be able to reduce colorectal cancer risk in humans and in animal models of colon carcinogenesis. Although the mechanism involved in such an effect is not yet clear, both prostaglandin-dependent and -independent effects have been proposed. Using HT-29 Glc(-/+)cells, which originate from a human colon adenocarcinoma, we demonstrated in this study a dose-dependent effect of millimolar concentration of aspirin on cell growth that was concomitant with a rapid accumulation of the cells in the G0/G1 phase, followed by an accumulation in the G2/M phase and by a minor increase in the proportion of cells undergoing nuclear condensation. Cell membrane integrity and cell release into the culture medium were not affected by this treatment. The aspirin effects were apparently unrelated to prostaglandin biosynthesis inhibition, since although these cells were found to express high levels of cyclooxygenase 1 (COX-1) and low levels of COX-2 proteins, they did not produce any measurable net amounts of prostaglandins, based on both utilization of radiolabelled arachidonic acid and the radioimmunoassay of prostaglandins E2 and F2 alpha. In contrast, we identified polyamine biosynthesis as a cellular target of aspirin, since the treatment of HT-29 Glc(-/+) cells with aspirin reduced the flux of L-ornithine through ornithine decarboxylase, an effect that could not be explained by an acute action of the drug on the ornithine decarboxylase catalytic activity. Since polyamine biosynthesis is strictly necessary for HT-29 cell growth, our data suggest that reduced flux through ornithine decarboxylase may participate in the antiproliferative activity of aspirin towards colonic tumoral cells. It is concluded that in HT-29 Glc(-/+) cells that are not functional for prostaglandin production, aspirin can affect cell growth, cell cycle, and polyamine biosynthesis without affecting cell membrane integrity.

Glycerokinase activity in brown and white adipose tissues of cold-adapted obese Zucker rats.

Glycerokinase activity was measured in the brown and white adipose tissues compared with that in the liver obese Zucker rats adapted or not adapted to cold. In white adipose tissue total activity was low but higher in the fa/fa rats than in the Fa/ones; cold adaptation did not modify this activity. In brown adipose tissue specific activity was higher than in white; specific activity was twice as high in the fa/fa rats than in the Fa/-. Cold-adaptation induced an increase in the activity in the Fa rats and a decrease in the fa/fa rats. The results are discussed with regard to the cold-induced increase in the energetic efficiency of the tissue.