Benefits and risks of the hormetic effects of dietary isothiocyanates on cancer prevention

The isothiocyanate (ITC) sulforaphane (SFN) was shown at low levels (1-5 µM) to promote cell proliferation to 120-143% of the controls in a number of human cell lines, whilst at high levels (10-40 µM) it inhibited such cell proliferation. Similar dose responses were observed for cell migration, i.e. SFN at 2.5 µM increased cell migration in bladder cancer T24 cells to 128% whilst high levels inhibited cell migration. This hormetic action was also found in an angiogenesis assay where SFN at 2.5 µM promoted endothelial tube formation (118% of the control), whereas at 10-20 µM it caused significant inhibition. The precise mechanism by which SFN influences promotion of cell growth and migration is not known, but probably involves activation of autophagy since an autophagy inhibitor, 3-methyladenine, abolished the effect of SFN on cell migration. Moreover, low doses of SFN offered a protective effect against free-radical mediated cell death, an effect that was enhanced by co-treatment with selenium. These results suggest that SFN may either prevent or promote tumour cell growth depending on the dose and the nature of the target cells. In normal cells, the promotion of cell growth may be of benefit, but in transformed or cancer cells it may be an undesirable risk factor. In summary, ITCs have a biphasic effect on cell growth and migration. The benefits and risks of ITCs are not only determined by the doses, but are affected by interactions with Se and the measured endpoint

Evaluation of a new arterial pressure-based cardiac output device requiring no external calibration

<p>Abstract</p> <p>Background</p> <p>Several techniques have been discussed as alternatives to the intermittent bolus thermodilution cardiac output (CO_PAC) measurement by the pulmonary artery catheter (PAC). However, these techniques usually require a central venous line, an additional catheter, or a special calibration procedure. A new arterial pressure-based cardiac output (CO_AP) device (FloTrac™, Vigileo™; Edwards Lifesciences, Irvine, CA, USA) only requires access to the radial or femoral artery using a standard arterial catheter and does not need an external calibration. We validated this technique in critically ill patients in the intensive care unit (ICU) using CO_PACas the method of reference.</p> <p>Methods</p> <p>We studied 20 critically ill patients, aged 16 to 74 years (mean, 55.5 ± 18.8 years), who required both arterial and pulmonary artery pressure monitoring. CO_PACmeasurements were performed at least every 4 hours and calculated as the average of 3 measurements, while CO_APvalues were taken immediately at the end of bolus determinations. Accuracy of measurements was assessed by calculating the bias and limits of agreement using the method described by Bland and Altman.</p> <p>Results</p> <p>A total of 164 coupled measurements were obtained. Absolute values of CO_PACranged from 2.80 to 10.80 l/min (mean 5.93 ± 1.55 l/min). The bias and limits of agreement between CO_PACand CO_APfor unequal numbers of replicates was 0.02 ± 2.92 l/min. The percentage error between CO_PACand CO_APwas 49.3%. The bias between percentage changes in CO_PAC(ΔCO_PAC) and percentage changes in CO_AP(ΔCO_AP) for consecutive measurements was -0.70% ± 32.28%. CO_PACand CO_APshowed a Pearson correlation coefficient of 0.58 (<it>p </it>< 0.01), while the correlation coefficient between ΔCO_PACand ΔCO_APwas 0.46 (<it>p </it>< 0.01).</p> <p>Conclusion</p> <p>Although the CO_APalgorithm shows a minimal bias with CO_PACover a wide range of values in an inhomogeneous group of critically ill patients, the scattering of the data remains relative wide. Therefore, the used algorithm (V 1.03) failed to demonstrate an acceptable accuracy in comparison to the clinical standard of cardiac output determination.</p

Targets of drugs are generally, and targets of drugs having side effects are specifically good spreaders of human interactome perturbations

Network-based methods are playing an increasingly important role in drug design. Our main question in this paper was whether the efficiency of drug target proteins to spread perturbations in the human interactome is larger if the binding drugs have side effects, as compared to those which have no reported side effects. Our results showed that in general, drug targets were better spreaders of perturbations than non-target proteins, and in particular, targets of drugs with side effects were also better spreaders of perturbations than targets of drugs having no reported side effects in human protein-protein interaction networks. Colorectal cancer-related proteins were good spreaders and had a high centrality, while type 2 diabetes-related proteins showed an average spreading efficiency and had an average centrality in the human interactome. Moreover, the interactome-distance between drug targets and disease-related proteins was higher in diabetes than in colorectal cancer. Our results may help a better understanding of the network position and dynamics of drug targets and disease-related proteins, and may contribute to develop additional, network-based tests to increase the potential safety of drug candidates.Comment: 49 pages, 2 figures, 2 tables, 10 supplementary figures, 13 supplementary table

Isotropic magnetization response of electrodeposited nanocrystalline Ni–W alloy nanowire arrays

Isotropic magnetization response was demonstrated in electrodeposited nanocrystalline Ni–15 % W alloy nanowire arrays, which can be applied to nanoscale magnetic field sensors. The Ni–W alloy nanowire arrays were electrochemically synthesized on a nanochannel template electrode from an aqueous electrolytic solution. X-ray and electron diffraction patterns revealed that Ni–15 % W alloy deposits were composed of ultrafine crystal grains with a supersaturated solid solution phase. The magnetization of the Ni–15 % W alloy thin films reached saturation at around 2.5 kOe in a perpendicular direction to the film plane, whereas the pure Ni thin films hardly magnetized in the perpendicular direction. On the contrary, Ni–15 % W alloy nanowire arrays were easily magnetized, and reach saturation at around 1.0 kOe, even in a perpendicular direction to the array film plane that corresponds to the long-axis direction of the alloy nanowires

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits

The voltage-sensitive dye RH421 detects a Na⁺,K⁺-ATPase conformational change at the membrane surface

© 2017 Elsevier B.V. RH421 is a voltage-sensitive fluorescent styrylpyridinium dye which has often been used to probe the kinetics of Na+,K+-ATPase partial reactions. The origin of the dye's response has up to now been unclear. Here we show that RH421 responds to phosphorylation of the Na+,K+-ATPase by inorganic phosphate with a fluorescence increase. Analysis of the kinetics of the fluorescence response indicates that the probe is not detecting phosphorylation itself but rather a shift in the protein's E1/E2 conformational equilibrium induced by preferential phosphate binding to and phosphorylation of enzyme in the E2 conformation. Molecular dynamics simulations of crystal structures in lipid bilayers indicate some change in the protein's hydrophobic thickness during the E1-E2 transition, which may influence the dye response. However, the transition is known to involve significant rearrangement of the protein's highly charged lysine-rich cytoplasmic N-terminal sequence. Using poly-L-lysine as a model of the N-terminus, we show that an analogous response of RH421 to the E1 → E2P conformational change is produced by poly-L-lysine binding to the surface of the Na+,K+-ATPase-containing membrane fragments. Thus, it seems that the prime origin of the RH421 fluorescence response is a change in the interaction of the protein's N-terminus with the surrounding membrane. Quantum mechanical calculations of the dye's visible absorption spectrum give further support to this conclusion. The results obtained indicate that membrane binding and release of the N-terminus of the Na+,K+-ATPase α-subunit are intimately involved in the protein's catalytic cycle and could represent an effective site of regulation