TASK DEFINITION: Given a passage, construct a question on the basis of the information present in the passage. Construct the question in such a way that (i) it is unambiguous, (ii) it is answerable from the passage, (iii) its answer is unique (iv) it answer uses text phrases from the passage. Avoid creating questions that (i) can't be answered correctly without actually understanding the passage and (ii) uses the same words or phrases given in the passage.
PROBLEM: Vascular endothelial growth factor (VEGF) has been well documented to stimulate cell proliferation and differentiation; however, we have observed that copper (Cu)-induced regression of heart hypertrophy was VEGF-dependent. The present study was undertaken to test the hypothesis that Cu causes alterations in the distribution of VEGF receptors (VEGFRs) in hypertrophic cardiomyocytes so that it switches the signalling pathway from stimulation of cell growth to reversal of cell hypertrophy.', 'Primary cultures of neonatal rat cardiomyocytes were exposed to phenylephrine (PE) at a final concentration of 100 microM in cultures for 48 h to induce cell hypertrophy. The hypertrophic cardiomyocytes were exposed to copper sulfate at a final concentration of 5 microM in cultures for 24 h with a concomitant presence of PE. Flow cytometry, gene silencing, and ELISA procedures were used to analyse the changes in VEGFRs and their relationship with regression of cardiomyocyte hypertrophy. Cu did not change the concentration of VEGF in culture media, but increased the ratio of VEGFR-1 to VEGFR-2 two-fold. Gene silencing of VEGFR-2, in the absence of Cu addition, reversed PE-induced cardiomyocyte hypertrophy, which was suppressed by an anti-VEGF antibody. Gene silencing of VEGFR-1 blocked Cu-induced regression of cell hypertrophy and decreased the activity of cGMP-dependent protein kinase-1 (PKG-1). A PKG-1 antagonist, Rp-8-pCPT-cGMPS, blocked both Cu- and VEGFR-2 gene silencing-induced regression of cardiomyocyte hypertrophy.

SOLUTION: Is copper-induced regression of cardiomyocyte hypertrophy associated with enhanced vascular endothelial growth factor receptor-1 signalling pathway?

PROBLEM: The antidepressant drug fluoxetine (FLU) is considered in the group of selective serotonine re-uptake inhibitors. Its distribution in brain and binding to human brain glutathione S-transferase-π (GST-π) have been shown. FLU can cross blood brain barrier and placenta, accumulate in fetus and may cause congenital malformations.', 'To elucidate the interaction of placental GST-π with FLU.', 'First, concentration-dependent inhibition of human placental GST-π was evaluated by using different FLU concentrations and then 0.3125, 0.625, 1.25, 2.5 and 5\u2009mM FLU concentrations were chosen and tested while keeping GSH concentration constant and 1-chloro-2,4-dinitrobenzene (CDNB) concentration varied and vice versa. The data were evaluated with different kinetic models and Statistica 9.00 for Windows.', 'The Vm, at variable [CDNB] (142\u2009±\u200916\u2009U/mg protein) was 3 times higher than the Vm obtained at variable [GSH] (49\u2009±\u20094\u2009U/mg protein). On the other hand, the Km for CDNB was ∼10 times higher than the Km for GSH (1.99\u2009±\u20090.36\u2009mM versus 0.21\u2009±\u20090.06\u2009mM). The IC50 value for FLU was 8.6\u2009mM. Both at constant [CDNB] and variable [GSH] and at constant [GSH] and variable [CDNB] the inhibition types were competitive with the Ki values of 5.62\u2009±\u20094.37 and 8.09\u2009±\u20091.27\u2009mM, respectively.

SOLUTION: Does fluoxetine-induced toxicity result in human placental glutathione S-transferase-π ( GST-π ) dysfunction?

PROBLEM: Targeted metabolomic and transcriptomic approaches were used to evaluate the relationship between skeletal muscle metabolite signatures, gene expression profiles and clinical outcomes in response to various exercise training interventions. We hypothesised that changes in mitochondrial metabolic intermediates would predict improvements in clinical risk factors, thereby offering novel insights into potential mechanisms.', 'Subjects at risk of metabolic disease were randomised to 6\xa0months of inactivity or one of five aerobic and/or resistance training programmes (n\u2009=\u2009112). Pre/post-intervention assessments included cardiorespiratory fitness ([Formula: see text]), serum triacylglycerols (TGs) and insulin sensitivity (SI). In this secondary analysis, muscle biopsy specimens were used for targeted mass spectrometry-based analysis of metabolic intermediates and measurement of mRNA expression of genes involved in metabolism.', 'Exercise regimens with the largest energy expenditure produced robust increases in muscle concentrations of even-chain acylcarnitines (median 37-488%), which correlated positively with increased expression of genes involved in muscle uptake and oxidation of fatty acids. Along with free carnitine, the aforementioned acylcarnitine metabolites were related to improvements in [Formula: see text], TGs and SI (R\u2009=\u20090.20-0.31, p\u2009<\u20090.05). Muscle concentrations of the tricarboxylic acid cycle intermediates succinate and succinylcarnitine (R\u2009=\u20090.39 and 0.24, p\u2009<\u20090.05) emerged as the strongest correlates of SI.

SOLUTION:
Do metabolite signatures of exercise training in human skeletal muscle relate to mitochondrial remodelling and cardiometabolic fitness?