Intestinal Adaptation to Repeated Exposure of Flavonoid-rich Foods: In Vitro and Clinical Data

Interest in application of flavonoids for chronic disease prevention has grown significantly, but the low oral bioavailability of these compounds from acute doses is commonly highlighted as a limitation when considering their biological significance. Still, the impact of broad dietary patterns such as repeated exposure on flavonoid’s absorption, metabolism, and eventual efficacy is critical to consider since evidence suggests that their bioavailability may be enhanced with repeated exposure. To fill this gap in knowledge, this dissertation will focus on three major areas including characterization of flavonoid metabolites, in addition to use of in vitro models and clinical work to test the effect of repeated exposure on flavonoid bioavailability. Though flavan-3-ols undergo Phase II metabolism in humans and rodents, researchers have generally not been able to utilize fully characterized standards for these metabolites. Thus, collaborators synthesized flavan-3-ols metabolites after which liquid chromatography/time-of-flight mass spectrometry (LC-TOF-MS) and nuclear magnetic resonance (NMR) spectroscopy were used to characterize their structure and match the synthesized metabolites to those found in rodent plasma. To explore changes occurring in the upper small intestine from flavonoid repeated exposure, Caco-2 cells were differentiated in the presence of isolated flavan-3-ols, green tea, grape seed, or blackberry extracts. EGCG and EC pretreatment altered formation rate of Phase II metabolites, in addition, green tea and grape seed extract pretreatment both resulted in increased flavan-3-ol transport. In contrast, blackberry extract pretreated monolayers displayed decreased transport of phenolic compounds. Finally, alterations in mRNA expression of select transport and metabolizing genes were observed in cells pretreated with blackberry extract. To determine if flavonoid absorption changes with repeated exposure to blackberry in humans, a controlled feeding study was performed to assess the effect of three-week daily blackberry exposure on flavonoid pharmacokinetics. The results showed increased plasma AUC of peonidin glucoside after blackberry treatment in lean volunteers. Accumulation of total anthocyanins in urine was greater in the lean group after blackberry exposure. This difference may be driven by increased Phase II anthocyanin metabolites since there was greater accumulation of anthocyanin metabolites in urine in the lean group after blackberry exposure. Taken together, these data suggest that the small intestine may be a key regulator of the observed adaptive phenomena occurring in vivo. These results demonstrate that there is both differential transport, absorption, and metabolism of flavonoids, including select flavonoids and phenolic acids, after repeated exposure to flavonoid-rich blackberry and that this response appears to differ with BMI. These studies provide a basis for future work on the effect of chronic flavonoid exposure on their bioavailability and metabolism in a range of interventions

A chemical survey of exoplanets with ARIEL

Thousands of exoplanets have now been discovered with a huge range of masses, sizes and orbits: from rocky Earth-like planets to large gas giants grazing the surface of their host star. However, the essential nature of these exoplanets remains largely mysterious: there is no known, discernible pattern linking the presence, size, or orbital parameters of a planet to the nature of its parent star. We have little idea whether the chemistry of a planet is linked to its formation environment, or whether the type of host star drives the physics and chemistry of the planet’s birth, and evolution. ARIEL was conceived to observe a large number (~1000) of transiting planets for statistical understanding, including gas giants, Neptunes, super-Earths and Earth-size planets around a range of host star types using transit spectroscopy in the 1.25–7.8 μm spectral range and multiple narrow-band photometry in the optical. ARIEL will focus on warm and hot planets to take advantage of their well-mixed atmospheres which should show minimal condensation and sequestration of high-Z materials compared to their colder Solar System siblings. Said warm and hot atmospheres are expected to be more representative of the planetary bulk composition. Observations of these warm/hot exoplanets, and in particular of their elemental composition (especially C, O, N, S, Si), will allow the understanding of the early stages of planetary and atmospheric formation during the nebular phase and the following few million years. ARIEL will thus provide a representative picture of the chemical nature of the exoplanets and relate this directly to the type and chemical environment of the host star. ARIEL is designed as a dedicated survey mission for combined-light spectroscopy, capable of observing a large and well-defined planet sample within its 4-year mission lifetime. Transit, eclipse and phase-curve spectroscopy methods, whereby the signal from the star and planet are differentiated using knowledge of the planetary ephemerides, allow us to measure atmospheric signals from the planet at levels of 10–100 part per million (ppm) relative to the star and, given the bright nature of targets, also allows more sophisticated techniques, such as eclipse mapping, to give a deeper insight into the nature of the atmosphere. These types of observations require a stable payload and satellite platform with broad, instantaneous wavelength coverage to detect many molecular species, probe the thermal structure, identify clouds and monitor the stellar activity. The wavelength range proposed covers all the expected major atmospheric gases from e.g. H2O, CO2, CH4 NH3, HCN, H2S through to the more exotic metallic compounds, such as TiO, VO, and condensed species. Simulations of ARIEL performance in conducting exoplanet surveys have been performed – using conservative estimates of mission performance and a full model of all significant noise sources in the measurement – using a list of potential ARIEL targets that incorporates the latest available exoplanet statistics. The conclusion at the end of the Phase A study, is that ARIEL – in line with the stated mission objectives – will be able to observe about 1000 exoplanets depending on the details of the adopted survey strategy, thus confirming the feasibility of the main science objectives.Peer reviewedFinal Published versio