Botanical drugs, synergy, and network pharmacology: forth and back to intelligent mixtures

For centuries the science of pharmacognosy has dominated rational drug development until it was gradually substituted by target-based drug discovery in the last fifty years. Pharmacognosy stems from the different systems of traditional herbal medicine and its "reverse pharmacology" approach has led to the discovery of numerous pharmacologically active molecules and drug leads for humankind. But do botanical drugs also provide effective mixtures? Nature has evolved distinct strategies to modulate biological processes, either by selectively targeting biological macromolecules or by creating molecular promiscuity or polypharmacology (one molecule binds to different targets). Widely claimed to be superior over monosubstances, mixtures of bioactive compounds in botanical drugs allegedly exert synergistic therapeutic effects. Despite evolutionary clues to molecular synergism in nature, sound experimental data are still widely lacking to support this assumption. In this short review, the emerging concept of network pharmacology is highlighted, and the importance of studying ligand-target networks for botanical drugs is emphasized. Furthermore, problems associated with studying mixtures of molecules with distinctly different pharmacodynamic properties are addressed. It is concluded that a better understanding of the polypharmacology and potential network pharmacology of botanical drugs is fundamental in the ongoing rationalization of phytotherapy.

Comparison of the immediate effects of gaseous ozone and chlorhexidine gel on bacteria in cavitated carious lesions in children in vivo

Clinical application of ozone gas has been shown to arrest the progression of dentinal caries in children. In this study, we compare the immediate effects of gaseous ozone and chlorhexidine gel on bacteria in cavitated carious lesions in children. Forty children, each with at least two open occlusal carious lesions, were enrolled in the study. Two teeth were chosen randomly. In one lesion, overlying soft biological material was removed, whilst the other lesion was not excavated. Cavities were rinsed with sterile water and dried with air. A standardised sample was taken from the mesial part of each lesion. Then, gaseous ozone (HealOzone) or 1% chlorhexidine gel (Corsodyl) was applied for 30 s on both lesions of 20 children each, and a second sample was taken from the distal part of each lesion. The anaerobic microbiota was cultivated; the number of colony forming units was calculated per milligram sample. The two-sided paired t test showed no significant (P > 0.05) differences in the reduction of total bacterial counts per milligram comparing samples before and after ozone or chlorhexidine application. The tests also showed no statistically significant difference whether the superficial decayed dentine had been removed before ozone or with chlorhexidine treatment or not. It can be concluded that gaseous ozone or chlorhexidine gel application for 30 s to deep occlusal carious cavities had no significant immediate antimicrobial effects whether the superficial decayed layers dentine were removed or not.

Perceptual and processing differences between physical and dichorhinic odor mixtures

Perceptual integration of sensory input from our two nostrils has received little attention in comparison to lateralized inputs for vision and hearing. Here, we investigated whether a binary odor mixture of eugenol and l-carvone (smells of cloves and caraway) would be perceived differently if presented as a mixture in one nostril (physical mixture), vs. the same two odorants in separate nostrils (dichorhinic mixture). In parallel, we investigated whether the different types of presentation resulted in differences in olfactory event-related potentials (OERP). Psychophysical ratings showed that the dichorhinic mixtures were perceived as more intense than the physical mixtures. A tendency for shift in perceived quality was also observed. In line with these perceptual changes, the OERP showed a shift in latencies and amplitudes for early (more "sensory") peaks P1 and N1 whereas no significant differences were observed for the later (more "cognitive") peak P2. The results altogether suggest that the peripheral level is a site of interaction between odorants. Both psychophysical ratings and, for the first time, electrophysiological measurements converge on this conclusion.

Flux and resident injection in gaseous advection experiments

The occurrence of gaseous pollutants in soils has stimulated many experimental activities, including forced ventilation in the field as well as laboratory transport experiments with gases. The dispersion coefficient in advective-dispersive gas phase transport is often dominated by molecular diffusion, which leads to a large overall dispersivity gamma. Under such conditions it is important to distinguish between flux and resident modes of solute injection and detection. The influence of the inlet type oil the macroscopic injection mode was tested in two series of column experiments with gases at different mean flow velocities nu. First we compared infinite resident and flux injections, and second, semi-infinite resident and flux injections. It is shown that the macroscopically apparent injection condition depends on the geometry of the inlet section. A reduction of the cross-sectional area of the inlet relative to that of the column is very effective in excluding the diffusive solute input, thus allowing us to use the solutions for a flux Injection also at rather low mean flow velocities nu. If the whole cross section of a column is exposed to a large reservoir like that of ambient air, a semi-infinite resident injection is established, which can be distinguished from a flux injection even at relatively high velocities nu, depending on the mechanical dispersivity of the porous medium.

Gaseous radiocarbon measurements of small samples

Radiocarbon dating by means of accelerator mass spectrometry (AMS) is a well-established method for samples containing carbon in the milligram range. However, the measurement of small samples containing less than 50 lg carbon often fails. It is difficult to graphitise these samples and the preparation is prone to contamination. To avoid graphitisation, a solution can be the direct measurement of carbon dioxide. The MICADAS, the smallest accelerator for radiocarbon dating in Zurich, is equipped with a hybrid Cs sputter ion source. It allows the measurement of both, graphite targets and gaseous CO2 samples, without any rebuilding. This work presents experiences dealing with small samples containing 1-40 lg carbon. 500 unknown samples of different environmental research fields have been measured yet. Most of the samples were measured with the gas ion source. These data are compared with earlier measurements of small graphite samples. The performance of the two different techniques is discussed and main contributions to the blank determined. An analysis of blank and standard data measured within years allowed a quantification of the contamination, which was found to be of the order of 55 ng and 750 ng carbon (50 pMC) for the gaseous and the graphite samples, respectively. For quality control, a number of certified standards were measured using the gas ion source to demonstrate reliability of the data.

Sublimation of ice–tholins mixtures: A morphological and spectro-photometric study

Sublimation, the direct transition from solid to gas phase, is a process responsible for shaping and changing the reflectance properties of many Solar System surfaces. In this study, we have characterized the evolution of the structure/texture and of the visible and near-infrared (VIS–NIR) spectral reflectance of surfaces made of water ice mixed with analogues of complex extraterrestrial organic matter, named tholins, under low temperature (<-70° C) and pressure (10-⁵mbar) conditions. The experiments were carried out in the SCITEAS simulation setup recently built as part of the Laboratory for Outflow Studies of Sublimating Materials (LOSSy) at the University of Bern (Pommerol, A. et al. [2015a]. Planet. Space Sci. 109–110, 106–122). As the water ice sublimated, we observed in situ the formation of a sublimation lag deposit made of a water-free porous (>90% porosity) network of organic filaments on top of the ice. The temporal evolution of the tholins and water ice spectral features (reflectance at the absorption bands wavelengths, red slope, from 0.40 to 1.90lm) are analyzed throughout the sublimation of the samples. We studied how different mixtures of tholins with water (0.1 wt.% tholins as coating or inclusions within the water particles), and different ice particle sizes (4.5 ± 2.5 or 67 ± 31lm) influence the morphological and spectral evolutions of the samples. The sublimation of the ice below the mantle produces a gas flow responsible for the ejection of mm to cm-sized fragments of the deposit in outbursts-like events. The results show remarkable differences between these samples in term of mantle structure, speed of mantle building, rates and surface area of mantle ejections. These data provide useful references for interpreting remote-sensing observations of icy Solar System surfaces, in particular the activity of comet nuclei where sublimation of organic-rich ices and deposition of organic-dust particles likely play a major role. Consequently, the data presented here could be of high interest for the interpretation of Rosetta, and also New Horizons, observations.

Future water quality monitoring--adapting tools to deal with mixtures of pollutants in water resource management.

Environmental quality monitoring of water resources is challenged with providing the basis for safeguarding the environment against adverse biological effects of anthropogenic chemical contamination from diffuse and point sources. While current regulatory efforts focus on monitoring and assessing a few legacy chemicals, many more anthropogenic chemicals can be detected simultaneously in our aquatic resources. However, exposure to chemical mixtures does not necessarily translate into adverse biological effects nor clearly shows whether mitigation measures are needed. Thus, the question which mixtures are present and which have associated combined effects becomes central for defining adequate monitoring and assessment strategies. Here we describe the vision of the international, EU-funded project SOLUTIONS, where three routes are explored to link the occurrence of chemical mixtures at specific sites to the assessment of adverse biological combination effects. First of all, multi-residue target and non-target screening techniques covering a broader range of anticipated chemicals co-occurring in the environment are being developed. By improving sensitivity and detection limits for known bioactive compounds of concern, new analytical chemistry data for multiple components can be obtained and used to characterise priority mixtures. This information on chemical occurrence will be used to predict mixture toxicity and to derive combined effect estimates suitable for advancing environmental quality standards. Secondly, bioanalytical tools will be explored to provide aggregate bioactivity measures integrating all components that produce common (adverse) outcomes even for mixtures of varying compositions. The ambition is to provide comprehensive arrays of effect-based tools and trait-based field observations that link multiple chemical exposures to various environmental protection goals more directly and to provide improved in situ observations for impact assessment of mixtures. Thirdly, effect-directed analysis (EDA) will be applied to identify major drivers of mixture toxicity. Refinements of EDA include the use of statistical approaches with monitoring information for guidance of experimental EDA studies. These three approaches will be explored using case studies at the Danube and Rhine river basins as well as rivers of the Iberian Peninsula. The synthesis of findings will be organised to provide guidance for future solution-oriented environmental monitoring and explore more systematic ways to assess mixture exposures and combination effects in future water quality monitoring.

Cerebral Gaseous Microemboli are Detectable During Continuous Venovenous Hemodialysis in Critically Ill Patients: An Observational Pilot Study

BACKGROUND Continuous venovenous hemodialysis (CVVHD) may generate microemboli that cross the pulmonary circulation and reach the brain. The aim of the present study was to quantify (load per time interval) and qualify (gaseous vs. solid) cerebral microemboli (CME), detected as high-intensity transient signals, using transcranial Doppler ultrasound. MATERIALS AND METHODS Twenty intensive care unit (ICU group) patients requiring CVVHD were examined. CME were recorded in both middle cerebral arteries for 30 minutes during CVVHD and a CVVHD-free interval. Twenty additional patients, hospitalized for orthopedic surgery, served as a non-ICU control group. Statistical analyses were performed using the Mann-Whitney U test or the Wilcoxon matched-pairs signed-rank test, followed by Bonferroni corrections for multiple comparisons. RESULTS In the non-ICU group, 48 (14.5-169.5) (median [range]) gaseous CME were detected. In the ICU group, the 67.5 (14.5-588.5) gaseous CME detected during the CVVHD-free interval increased 5-fold to 344.5 (59-1019) during CVVHD (P<0.001). The number of solid CME was low in all groups (non-ICU group: 2 [0-5.5]; ICU group CVVHD-free interval: 1.5 [0-14.25]; ICU group during CVVHD: 7 [3-27.75]). CONCLUSIONS This observational pilot study shows that CVVHD was associated with a higher gaseous but not solid CME burden in critically ill patients. Although the differentiation between gaseous and solid CME remains challenging, our finding may support the hypothesis of microbubble generation in the CVVHD circuit and its transpulmonary translocation toward the intracranial circulation. Importantly, the impact of gaseous and solid CME generated during CVVHD on brain integrity of critically ill patients currently remains unknown and is highly debated.