Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism.

BACKGROUND AND OBJECTIVES: Bile acids (BAs) traversing the enterohepatic circulation (EHC) influence important metabolic pathways. By determining individual serum BAs in relation to markers of metabolic activity, we explored how diurnal variations in their EHC relate to hepatic metabolism in normal humans. METHODS: Serum BAs, fibroblast growth factor 19 (FGF19), lipoproteins, glucose/insulin and markers of cholesterol and BA syntheses were monitored for 32 h in 8 healthy males. Studies were conducted at basal state and during initiation of cholestyramine treatment, with and without atorvastatin pretreatment. Time series cross-correlation analysis, Bayesian structural model and Granger causality test were applied. RESULTS: Bile acids synthesis dominated daytime, and cholesterol production at night. Conjugated BAs peaked after food intake, with subsequent FGF19 elevations. BA synthesis was reduced following conjugated BA and FGF19 peaks. Cholestyramine reduced conjugated BAs and FGF19, and increased BA and cholesterol production; the latter effects attenuated by atorvastatin. The relative importance of FGF19 vs. conjugated BAs in this feedback inhibition could not be discriminated. Unconjugated BAs displayed one major peak late at night/early morning that was unrelated to FGF19 and BA synthesis, and abolished by cholestyramine. The normal suppression of serum triglycerides, glucose and insulin observed at night was attenuated by cholestyramine. CONCLUSIONS: Conjugated and unconjugated BAs have asynchronous rhythms of EHC in humans. Postprandial transintestinal flux of conjugated BAs increases circulating FGF19 levels and suppresses BA synthesis. Unconjugated BAs peak late at night, indicating a non-postprandial diurnal change in human gut microflora, the physiological implications of which warrants further study.

A Mathematical Modeling Approach to Understanding the Effect of Anti-Interleukin Therapy on Eosinophils.

Emerging T-helper type 2 (Th2 ) cytokine-based asthma therapies, such as tralokinumab, lebrikizumab (anti-interleukin (IL)-13), and mepolizumab (anti-IL-5), have shown differences in their blood eosinophil (EOS) response. To better understand these effects, we developed a mathematical model of EOS dynamics. For the anti-IL-13 therapies, lebrikizumab and tralokinumab, the model predicted an increase of 30% and 10% in total and activated EOS in the blood, respectively, and a decrease in the total and activated EOS in the airways. The model predicted a rapid decrease in total and activated EOS levels in blood and airways for the anti-IL-5 therapy mepolizumab. All model-based predictions were consistent with published clinical observations. The modeling approach provided insights into EOS response after treatment with Th2 -targeted therapies, and supports the hypothesis that an increase in blood EOS after anti-IL-13 therapy is part of the pharmacological action of these therapies.

[Kinetic properties of peroxidase from intact and virus-infected tobacco leaves]. / Kineticheskie svoistva peroksidazy, vydelennoi iz zdorovykh i zarazhennykh virusami rastenii tabaka.

The kinetic properties of peroxidase from tobacco leaves (var. Xanthie and Samsun) infected with various viruses (TMV, Xt and Xy, were compared. The enzyme from intact plant grown under similar conditions was used as control. The pH dependencies of the peroxidase activity for o-dianisidine peroxidation in infected and control plants were identical. Viral infection produces a dramatic effect on the kinetic properties of the enzyme: the KM values for o-dianisidine were decreased by 20-40% and those for H2O2 - by 30-40% in the case of the Samsun var. infected with TMV and Xanthie var. infected with a highly virulent strain of potato X-virus. The decrease of these values in plants infected with a weakly virulent strain of the virus was insignificant.

[Activity, isoenzyme composition, thermostability and molecular weight of peroxidase from intact and virus infected tobacco plant leaves]. / Aktivnost, izofermentnyi spektp, termostabil'nost' i molekuliarnyi vec peroksidazy, vydelennoi iz zdorovykh i zarazhennykh virusami rastenii tabaka.

The enzyme peroxidase was isolated from the leaves of the tobacco plant Xanthi (intact and infected with weakly (XY) and highly (XT) pathogenic strains of potato X-virus) and partially purified. The original extract (the 30,000 g supernatant) was purified by ammonium sulfate at 30--80% of saturation and by gel filtration through Sephadex G-25 and G-100 in 0.05 M tris-HCl buffer, pH 7.4 containing 17% sucrose. Disc electrophoresis revealed that both intact and infected plants contain 10 isoperoxidases. The electrophoregrams of isoenzymes from infected plants with the Rf values of 0.1, 0.48, 0.53 and 0.59 stained with benzidine produced a more intensive colouring as compared to the corresponding isoenzymes from intact plants. The total enzymatic activity for the plants infected with the XY and XT strains made up to 180% and 240% of that for the intact plants, respectively. The molecular weights of the peroxidase isoenzymes were found to be the same and equal to 40,000. Study of the thermostability at 60 degrees C and pH 7.0 showed that after 90 min the enzyme activity was 12.4% and 5.1% of the original one in intact and infected plants, respectively. The data obtained suggest that the activity, thermostability and synthesis of some peroxidase isoenzymes in tobacco plant leaves are affected by viral infection.