Two separate experiments were performed to determine the effect of acute resistive exercise on postexercise energy expenditure in male subjects previously trained in resistive exercise. In experiment 1, after measurement of their resting metabolic rate (RMR) at 0700 h and their ingestion of a standardized meal at 0800 h, seven subjects (age range 22-40 yr) beginning at 1400 h completed a 90-min weight-lifting protocol. Postexercise metabolic rate (PEMR) was measured continuously for 2 h after exercise and compared with a preexercise baseline. RMR was measured the following morning 15 h after completion of the workout. In experiment 2, six different men (age range 20-35 yr) completed a similar experimental protocol as well as a control condition on a separate day in which metabolic rate was measured for 2 h after a period of quiet sitting. For both experiments, PEMR remained elevated for the entire 2-h measured recovery period, with the average oxygen consumption for the last 6 min elevated by 11-12%. RMR measured the morning after exercise was 9.4% higher in experiment 1 and 4.7% higher in experiment 2 than on the previous day. In experiment 2, the postabsorptive respiratory exchange ratio was significantly lower the morning after the exercise bout. Strenuous resistive exercise may elevate PEMR for a prolonged period and may enhance postexercise lipid oxidation.

Since the discovery of cisplatin more than 40 years ago and its clinical introduction in the 1970s an enormous amount of research has gone into elucidating the mechanism of action of cisplatin on tumor cells. With a novel cell biosensor chip system allowing continuous monitoring of respiration, glycolysis, and impedance we followed cisplatin treatment of different cancer cell lines in real-time. Our measurements reveal a first effect on respiration, in all cisplatin treated cell lines, followed with a significant delay by interference with glycolysis in HT-29, HCT-116, HepG2, and MCF-7 cells but not in the cisplatin-resistant cell line MDA-MB-231. Most strikingly, cell death started in all cisplatin-sensitive cell lines within 8 to 11 h of treatment, indicating a clear time frame from exposure, first response to cisplatin lesions, to cell fate decision. The time points of most significant changes were selected for more detailed analysis of cisplatin response in the breast cancer cell line MCF-7. Phosphorylation of selected signal transduction mediators connected with cellular proliferation, as well as changes in gene expression, were analyzed in samples obtained directly from sensor chips at the time points when changes in glycolysis and impedance occurred.Our online cell biosensor measurements reveal for the first time the time scale of metabolic response until onset of cell death under cisplatin treatment, which is in good agreement with models of p53-mediated cell fate decision.

Adverse drug reactions are a relevant cause of emergency department visits, accounting for 6.5% of the total visits in this study, and often lead to hospital admission. The ADRED (Adverse Drug Reactions in Emergency Departments) study, which is now being conducted, is intended to shed further light on their causes, patient risk factors, and potential avoidability.

Neural stem cells (NSCs) generate new neurons in vivo and in vitro throughout adulthood and therefore are physiologically and clinically relevant. Unveiling the mechanisms regulating the lineage progression from NSCs to newborn neurons is critical for the transition from basic research to clinical application. However, the direct analysis of NSCs and their progeny is still elusive due to the problematic identification of the cells. We here describe the isolation of highly purified genetically unaltered NSCs and transit-amplifying precursors (TAPs) from the adult subependymal zone (SEZ). Using this approach we show that a primary cilium and high levels of epidermal growth factor receptor (EGFR) at the cell membrane characterize quiescent and cycling NSCs, respectively. However, we also observed non-ciliated quiescent NSCs and NSCs progressing into the cell cycle without up-regulating EGFR expression. Thus, the existence of NSCs displaying distinct molecular and structural conformations provides more flexibility to the regulation of quiescence and cell cycle progression.

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Green tea polyphenols may contribute to the prevention of cancer and other diseases. To learn more about the pharmacokinetics and interindividual variation of green tea polyphenols after oral intake in humans we performed a population nutrikinetic study of standardized green tea extract. 84 healthy participants took green tea extract capsules standardized to 150 mg epigallocatechin-gallate (EGCG) twice a day for 5 days. On day 5 catechin plasma concentrations were analyzed using non-compartmental and population pharmacokinetic methods. A strong between-subject variability in catechin pharmacokinetics was found with maximum plasma concentrations varying more than 6-fold. The AUCs of EGCG, EGC and ECG were 877.9 (360.8–1576.5), 35.1 (8.0–87.4), and 183.6 (55.5–364.6) h*μg/L respectively, and the elimination half lives were 2.6 (1.8–3.8), 3.9 (0.9–10.7) and 1.8 (0.8–2.9) h, respectively. Genetic polymorphisms in genes of the drug transporters MRP2 and OATP1B1 could at least partly explain the high variability in pharmacokinetic parameters. The observed variability in catechin plasma levels might contribute to interindividual variation in benefical and adverse effects of green tea polyphenols. Our data could help to gain a better understanding of the causes of variability of green tea effects and to improve the design of studies on the effects of green tea polyphenols in different health conditions.Trial registration: ClinicalTrials.gov: NCT01360320

Zonation of metabolic activities within specific structures and cell types is a phenomenon of liver organization and ensures complementarity of variant liver functions like protein production, glucose homeostasis and detoxification. To analyze damage and regeneration of liver tissue in response to a toxic agent, expression of liver specific enzymes was analyzed by in situ hybridization in mouse over a 6 days time course following carbon tetrachloride (CCl4) injection. CCl4 mixed with mineral oil was administered to BALB/c mice by intraperitoneal injection, and mice were sacrificed at different time points post injection. Changes in the expression of albumin (Alb), arginase (Arg1), glutaminase 2 (Gls2), Glutamine synthetase (Gs), glucose-6-phosphatase (G6pc), glycogen synthase 2 (Gys2), Glycerinaldehyd-3-phosphat-Dehydrogenase (Gapdh), Cytochrom p450 2E1 (Cyp2e1) and glucagon receptor (Gcgr) genes in the liver were studied by in situ hybridization and qPCR. We observed significant changes in gene expression of enzymes involved in nitrogen and glucose metabolism and their local distribution following CCl4 injury. We also found that Cyp2e1, the primary metabolizing enzyme for CCl4, was strongly expressed in the pericentral zone during recovery. Furthermore, cells in the damaged area displayed distinct gene expression profiles during the analyzed time course and showed complete recovery with strong albumin production 6 days after CCl4 injection. Our results indicate that despite severe damage, liver cells in the damaged area do not simply die but instead display locally adjusted gene expression supporting damage response and recovery.

Regulatory Smads (R-Smads), Smad1/5/8 and Smad2/3, are the central mediators of TGFβ and BMP signaling pathways. Here, we screened indirubin derivatives, known kinase inhibitors, and observed strong interference with BMP signaling. We found that indirubin derivative E738 inhibited both TGFβ and BMP pathways through ubiquitin-proteasome-mediated depletion of total R-Smad pools, although phospho-R-Smad levels were initially stabilized by GSK3β and cyclin-dependent kinase inhibition. E738 also enhanced p38 and JNK phosphorylation, involved in Smad-independent TGFβ/BMP signaling. Additionally, using a small siRNA screen, we showed that depletion of ubiquitin proteases USP9x and USP34 significantly reduced total R-Smad levels, mimicking E738 treatment. In fact, both USP9x and USP34 levels were significantly reduced in E738-treated cells. Our findings not only describe the complex activity profile of the indirubin derivative E738, but also reveal a mechanism for controlling TGFβ/BMP signaling, the control of R-Smad protein levels through deubiquitination.