Browsing by Subject "ABSORPTION"

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  • Koivusalo, Antti; Mutanen, Annika; Nissinen, Markku; Gylling, Helena; Pakarinen, Mikko (2019)
    Objectives: We elucidated pathophysiology of pediatric gallstone disease by assessing liver expression of bile transporters in relation to bile acids and surrogates of cholesterol absorption and synthesis in serum and gallstones. Methods: RNA expression of canalicular bile transporters in liver biopsies from 32 pediatric gallstone patients and from 6 liver donors (controls) was measured by qRT-PCR (quantitative real-time reverse transcription polymerase chain reaction). Concentrations of cholesterol and precursors, plant sterols and bile acids in gallstones, and in serum of the patients and 82 healthy children were measured. Primary outcomes were the difference in RNA expressions and serum sterol profiles between patients and controls. Results: Cholesterol stones (CS; n = 15) contained cholesterol >42% and pigment stones (PS; n = 17)
  • Simonen, P.; Li, S.; Chua, N. K.; Lampi, A-M; Piironen, V.; Lommi, J.; Sinisalo, J.; Brown, A. J.; Ikonen, E.; Gylling, H. (2020)
    Background We have earlier reported that amiodarone, a potent and commonly used antiarrhythmic drug increases serum desmosterol, the last precursor of cholesterol, in 20 cardiac patients by an unknown mechanism. Objective Here, we extended our study to a large number of cardiac patients of heterogeneous diagnoses, evaluated the effects of combining amiodarone and statins (inhibitors of cholesterol synthesis at the rate-limiting step of hydroxy-methyl-glutaryl CoA reductase) on desmosterol levels and investigated the mechanism(s) by which amiodarone interferes with the metabolism of desmosterol using in vitro studies. Methods and Results We report in a clinical case-control setting of 236 cardiac patients (126 with and 110 without amiodarone treatment) that amiodarone medication is accompanied by a robust increase in serum desmosterol levels independently of gender, age, body mass index, cardiac and other diseases, and the use of statins. Lipid analyses in patient samples taken before and after initiation of amiodarone therapy showed a systematic increase of desmosterol upon drug administration, strongly arguing for a direct causal link between amiodarone and desmosterol accumulation. Mechanistically, we found that amiodarone resulted in desmosterol accumulation in cultured human cells and that the compound directly inhibited the 24-dehydrocholesterol reductase (DHCR24) enzyme activity. Conclusion These novel findings demonstrate that amiodarone blocks the cholesterol synthesis pathway by inhibiting DHCR24, causing a robust accumulation of cellular desmosterol in cells and in the sera of amiodarone-treated patients. It is conceivable that the antiarrhythmic potential and side effects of amiodarone may in part result from inhibition of the cholesterol synthesis pathway.
  • Simonen, Piia; Lehtonen, Jukka; Gylling, Helena; Kupari, Markku (2016)
    Background and aims: Patients with cardiac sarcoidosis (CS) suffer from myocardial inflammation, but atherosclerosis is not infrequent in these patients. However, the classical atherosclerotic risk factors, such as perturbed serum lipids and whole-body cholesterol metabolism, remain unravelled in CS. Methods: We assessed serum non-cholesterol sterols, biomarkers of whole-body cholesterol synthesis and cholesterol absorption efficiency, with gas-liquid chromatography in 39 patients with histologically verified CS and in an age-adjusted random population sample (n = 124). Results: CS was inactive or responding to treatment in all patients. Concentrations of serum, LDL, and HDL cholesterol and serum triglycerides were similar in CS patients and in control subjects. Cholesterol absorption markers were higher in CS patients than in controls (eg serum campesterol to cholesterol ratio in CS 246 +/- 18 vs in controls 190 +/- 8 10(2) x mu mol/mmol of cholesterol, p = 0.001). Cholesterol synthesis markers were lower in CS patients than in controls (eg serum lathosterol to cholesterol ratio in CS 102 +/- 8 vs in controls 195 +/- 5 10(2) x mu mol/mmol of cholesterol, p = 0.000). In CS patients, cholesterol absorption markers significantly correlated with plasma prohormone brain natriuretic peptide (proBNP), a marker of hemodynamic load. Conclusion: High cholesterol absorption efficiency, which is suggested to be atherogenic, characterized the metabolic profile of cholesterol in CS patients. The association between cholesterol absorption efficiency and plasma proBNP concentration, which suggests a link between inflammation, cholesterol homeostasis, and hemodynamic load, warrants further studies in order to confirm this finding and to reveal the underlying mechanisms. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Sporre, Moa K.; O'Connor, Ewan J.; Håkansson, Nina; Thoss, Anke; Swietlicki, Erik; Petäjä, Tuukka (2016)
    Cloud retrievals from the Moderate Resolution Imaging Spectroradiometer (MODIS) instruments aboard the satellites Terra and Aqua and the Visible Infrared Imaging Radiometer Suite (VIIRS) instrument aboard the Suomi-NPP satellite are evaluated using a combination of ground-based instruments providing vertical profiles of clouds. The ground-based measurements are obtained from the Atmospheric Radiation Measurement (ARM) programme mobile facility, which was deployed in Hyytiala, Finland, between February and September 2014 for the Biogenic Aerosols - Effects on Clouds and Climate (BAECC) campaign. The satellite cloud parameters cloud top height (CTH) and liquid water path (LWP) are compared with ground-based CTH obtained from a cloud mask created using lidar and radar data and LWP acquired from a multi-channel microwave radiometer. Clouds from all altitudes in the atmosphere are investigated. The clouds are diagnosed as single or multiple layer using the ground-based cloud mask. For single-layer clouds, satellites overestimated CTH by 326 (14 %) on average. When including multilayer clouds, satellites underestimated CTH by on average 169 m (5.8 %). MODIS collection 6 overestimated LWP by on average 13 g m(-2) (11 %). Interestingly, LWP for MODIS collection 5.1 is slightly overestimated by Aqua (4.56 %) but is underestimated by Terra (14.3 %). This underestimation may be attributed to a known issue with a drift in the reflectance bands of the MODIS instrument on Terra. This evaluation indicates that the satellite cloud parameters selected show reasonable agreement with their ground-based counterparts over Finland, with minimal influence from the large solar zenith angle experienced by the satellites in this high-latitude location.
  • Ramsay, Eva; del Amo, Eva M.; Toropainen, Elisa; Tengvall-Unadike, Unni; Ranta, Veli-Pekka; Urtti, Arto; Ruponen, Marika (2018)
    On the surface of the eye, both the cornea and conjunctiva are restricting ocular absorption of topically applied drugs, but barrier contributions of these two membranes have not been systemically compared. Herein, we studied permeability of 32 small molecular drug compounds across an isolated porcine cornea and built a quantitative structure-property relationship (QSPR) model for the permeability. Corneal drug permeability (data obtained for 25 drug molecules) showed a 52-fold range in permeability (0.09-4.70x10(-6) cm/s) and the most important molecular descriptors in predicting the permeability were hydrogen bond donor, polar surface area and halogen ratio. Corneal permeability values were compared to their conjunctival drug permeability values. Ocular drug bioavailability and systemic absorption via conjunctiva were predicted for this drug set with pharmacokinetic calculations. Drug bioavailability in the aqueous humour was simulated to be <5% and trans-conjunctival systemic absorption was 34-79% of the dose. Loss of drug across the conjunctiva to the blood circulation restricts significantly ocular drug bioavailability and, therefore, ocular absorption does not increase proportionally with the increasing corneal drug permeability.
  • Saarinen, Harri Juhani; Sittiwet, Chaiyasit; Simonen, Piia; Nissinen, Markku J.; Stenman, Ulf-Håkan; Gylling, Helena; Palomäki, Ari (2018)
    We have earlier reported the reduction of total cholesterol low-density lipoprotein (LDL) cholesterol and oxidized LDL caused by short-term modification of diet with cold-pressed turnip rapeseed oil (CPTRO) instead of butter. The aim of this supplementary study was to determine whether the beneficial effects resulted from altered cholesterol metabolism during the intervention. Thirty-seven men with metabolic syndrome (MetS) completed an open, randomized and balanced crossover study. Subjects' usual diet was supplemented with either 37.5 g of butter or 35 mL of CPTRO for 6-8 weeks. Otherwise normal dietary habits and physical activity were maintained without major variations. Serum non-cholesterol sterols were assayed with gas-liquid chromatography and used as surrogate markers of whole-body cholesterol synthesis and absorption efficiency. Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration was analyzed with Quantikine ELISA Immunoassay. Serum cholesterol synthesis markers and serum cholestanol (absorption marker), all as ratios to cholesterol, did not differ between the periods. Serum campesterol and sitosterol ratios to cholesterol were significantly increased after the administration of CPTRO resulting from the increased intake of 217 mg/day of plant sterols in CPTRO. Serum PCSK9 concentration did not differ between CPTRO and butter periods. The reduction in serum cholesterol by 7.2% after consumption of rapeseed oil could not be explained by changes in cholesterol absorption, synthesis or PCSK9 metabolism in MetS.
  • Kari, Elina; Merkouriadi, Ioanna; Walve, Jakob; Leppäranta, Matti; Kratzer, Susanne (2018)
    Seasonal sea ice cover reduces wind-driven mixing and allows for under-ice stratification to develop. These under-ice plumes are a common phenomenon in the seasonal sea ice zone. They stabilize stratification and concentrate terrestrial runoff in the top layer, transporting it further offshore than during ice-free seasons. In this study, the effect of sea ice on spring stratification is investigated in Himmerfjärden bay in the NW Baltic Sea. Distinct under-ice plumes were detected during long ice seasons. The preconditions for the development of the under-ice plumes are described as well as the typical spatial and temporal dimensions of the resulting stratification patterns. Furthermore, the effect of the under-ice plume on the timing of the onset and the maximum of the phytoplankton spring bloom were investigated, in terms of chlorophyll-a (Chl-a) concentrations. At the head of the bay, bloom onset was delayed on average by 18 days in the event of an under-ice plume. However, neither the maximum concentration of Chl-a nor the timing of the Chl-a maximum were affected, implying that the growth period was shorter with a higher daily productivity. During this period from spring bloom onset to maximum Chl-a, the diatom biomass was higher and Mesodinium rubrum biomass was lower in years with under-ice plumes compared to years without under-ice plumes. Our results thus suggest that the projected shorter ice seasons in the future will reduce the probability of under-ice plume development, creating more dynamic spring bloom conditions. These dynamic conditions and the earlier onset of the spring bloom seem to favor the M. rubrum rather than diatoms.
  • Brandão, L. P. M.; Brighenti, L. S.; Staehr, P. A.; Asmala, E.; Massicotte, P.; Tonetta, D.; Barbosa, F. A. R.; Pujoni, D.; Bezerra-Neto, J. F. (2018)
    Despite the increasing understanding about differences in carbon cycling between temperate and tropical freshwater systems, our knowledge on the importance of organic matter (OM) pools on light absorption properties in tropical lakes is very scarce. We performed a factorial mesocosm experiment in a tropical lake (Minas Gerais, Brazil) to evaluate the effects of increased concentrations of al-lochthonous and autochthonous OM, and differences in light availability on the light absorption characteristics of chromophoric dissolved organic matter (CDOM). Autochthonous OM deriving from phytoplankton (similar to Chl a) was stimulated by addition of nutrients, while OM from degradation of terrestrial leaves increased allochthonous OM, and neutral shading was used to manipulate light availability. Effects of the additions and shading on DOC, Chl a, nutrients, total suspended solid concentrations (TSM) and spectral CDOM absorption were monitored every 3 days. CDOM quality was characterized by spectral indices (S250-450, S275-295, S350-450, S-R and SUVA(254)). Effects of carbon sources and shading on the spectral CDOM absorption was investigated through principal component (PCA) and redundancy (RDA) analyses. The two different OM sources affected CDOM quality very differently and shading had minor effects on OM levels, but significant effects on OM quality, especially in combination with nutrient additions. Spectral indices (S250-450 and S-R) were mostly affected by allochthonous OM addition. The PCA showed that enrichment by allochthonous carbon had a strong effect on the CDOM spectra in the range between 300 and 400 nm, while the increase in autochthonous carbon increased absorption at wavelengths below 350 nm. Our study shows that small inputs of allochthonous OM can have large effects on the spectral light absorption compared to large production of autochthonous OM, with important implications for carbon cycling in tropical lakes.
  • Heilkkinen, Emma M.; Auriola, Seppo; Ranta, Veli-Pekka; Demarais, Nicholas J.; Grey, Angus C.; del Amo, Eva M.; Toropainen, Elisa; Vellonen, Kati-Sisko; Urtti, Arto; Ruponen, Marika (2019)
    Lens is the avascular tissue in the eye between the aqueous humor and vitreous. Drug binding to the lens might affect ocular pharmacokinetics, and the binding may also have a pharmacological role in drug-induced cataract and cataract treatment. Drug distribution in the lens has been studied in vitro with many compounds; however, the experimental methods vary, no detailed information on distribution between the lens sublayers exist, and the partition coefficients are reported rarely. Therefore, our objectives were to clarify drug localization in the lens layers and establish partition coefficients for a wide range of molecules. Furthermore, we aimed to illustrate the effect of lenticular drug binding on overall ocular drug pharmacokinetics. We studied the distribution of 16 drugs and three fluorescent dyes in whole porcine lenses in vitro with imaging mass spectrometry and fluorescence microscopy techniques. Furthermore, we determined lens/buffer partition coefficients with the same experimental setup for 28 drugs with mass spectrometry. Finally, the effect of lenticular binding of drugs on aqueous humor drug exposure was explored with pharmacokinetic simulations. After 4 h, the drugs and the dyes distributed only to the outermost lens layers (capsule and cortex). The lens/buffer partition coefficients for the drugs were low, ranging from 0.05 to 0.8. On the basis of the pharmacokinetic simulations, a high lens-aqueous humor partition coefficient increases drug exposure in the lens but does not significantly alter the pharmacokinetics in the aqueous humor. To conclude, the lens seems to act mainly as a physical barrier for drug distribution in the eye, and drug binding to the lens affects mainly the drug pharmacokinetics in the lens.
  • Chacon-Tanarro, A.; Pineda, J. E.; Caselli, P.; Bizzocchi, L.; Gutermuth, R. A.; Mason, B. S.; Gomez-Ruiz, A.; Harju, J.; Devlin, M.; Dicker, S. R.; Mroczkowski, T.; Romero, C. E.; Sievers, J.; Stanchfield, S.; Offner, S.; Sanchez-Argueelles, D. (2019)
    Context. The study of dust emission at millimeter wavelengths is important to shed light on the dust properties and physical structure of pre-stellar cores, the initial conditions in the process of star and planet formation. Aims. Using two new continuum facilities, AzTEC at the Large Millimeter Telescope Alfonso Serrano and MUSTANG-2 at the Green Bank Observatory, we aim to detect changes in the optical properties of dust grains as a function of radius for the well-known pre-stellar core L1544. Methods. We determined the emission profiles at 1.1 and 3.3 mm and examine whether they can be reproduced in terms of the current best physical models for L1544. We also made use of various tools to determine the radial distributions of the density, temperature, and dust opacity in a self-consistent manner. Results. We find that our observations cannot be reproduced without invoking opacity variations. New temperature and density profiles, as well as opacity variations across the core, have been derived with the new data. The opacity changes are consistent with the expected variations between uncoagulated bare grains, toward the outer regions of the core, and grains with thick ice mantles, toward the core center. A simple analytical grain growth model predicts the presence of grains of similar to 3-4 mu m within the central 2000 au for the new density profile.
  • Miettinen, Helena E.; Rönö, Kristiina; Koivusalo, Saila; Stach-Lempinen, Beata; Pöyhönen-Alho, Maritta; Eriksson, Johan G.; Hiltunen, Timo P.; Gylling, Helena (2014)
  • Ding, A. J.; Huang, X.; Nie, W.; Sun, J. N.; Kerminen, V. -M.; Petäjä, T.; Su, H.; Cheng, Y. F.; Yang, X. -Q.; Wang, M. H.; Chi, X. G.; Wang, J. P.; Virkkula, A.; Guo, W. D.; Yuan, J.; Wang, S. Y.; Zhang, R. J.; Wu, Y. F.; Song, Y.; Zhu, T.; Zilitinkevich, S.; Kulmala, M.; Fu, C. B. (2016)
    Aerosol-planetary boundary layer (PBL) interactions have been found to enhance air pollution in megacities in China. We show that black carbon (BC) aerosols play the key role in modifying the PBL meteorology and hence enhancing the haze pollution. With model simulations and data analysis from various field observations in December 2013, we demonstrate that BC induces heating in the PBL, particularly in the upper PBL, and the resulting decreased surface heat flux substantially depresses the development of PBL and consequently enhances the occurrences of extreme haze pollution episodes. We define this process as the dome effect of BC and suggest an urgent need for reducing BC emissions as an efficient way to mitigate the extreme haze pollution in megacities of China.
  • Fung, Pak L.; Zaidan, Martha A.; Timonen, Hilkka; Niemi, Jarkko V.; Kousa, Anu; Kuula, Joel; Luoma, Krista; Tarkoma, Sasu; Petäjä, Tuukka; Kulmala, Markku; Hussein, Tareq (2021)
    Air quality prediction with black-box (BB) modelling is gaining widespread interest in research and industry. This type of data-driven models work generally better in terms of accuracy but are limited to capture physical, chemical and meteorological processes and therefore accountability for interpretation. In this paper, we evaluated different white-box (WB) and BB methods that estimate atmospheric black carbon (BC) concentration by a suite of observations from the same measurement site. This study involves data in the period of 1st January 2017–31st December 2018 from two measurement sites, from a street canyon site in Mäkelänkatu and from an urban background site in Kumpula, in Helsinki, Finland. At the street canyon site, WB models performed (R² = 0.81–0.87) in a similar way as the BB models did (R² = 0.86–0.87). The overall performance of the BC concentration estimation methods at the urban background site was much worse probably because of a combination of smaller dynamic variability in the BC values and longer data gaps. However, the difference in WB (R²= 0.44–0.60) and BB models (R² = 0.41–0.64) was not significant. Furthermore, the WB models are closer to physics-based models, and it is easier to spot the relative importance of the predictor variable and determine if the model output makes sense. This feature outweighs slightly higher performance of some individual BB models, and inherently the WB models are a better choice due to their transparency in the model architecture. Among all the WB models, IAP and LASSO are recommended due to its flexibility and its efficiency, respectively. Our findings also ascertain the importance of temporal properties in statistical modelling. In the future, the developed BC estimation model could serve as a virtual sensor and complement the current air quality monitoring.
  • Baghirov, Habib; Karaman, Didem; Viitala, Tapani; Duchanoy, Alain; Lou, Yan-Ru; Mamaeva, Veronika; Pryazhnikov, Evgeny; Khiroug, Leonard; Davies, Catharina de Lange; Sahlgren, Cecilia; Rosenholm, Jessica M. (2016)
    Drug delivery into the brain is impeded by the blood-brain-barrier (BBB) that filters out the vast majority of drugs after systemic administration. In this work, we assessed the transport, uptake and cytotoxicity of promising drug nanocarriers, mesoporous silica nanoparticles (MSNs), in in vitro models of the BBB. RBE4 rat brain endothelial cells and Madin-Darby canine kidney epithelial cells, strain II, were used as BBB models. We studied spherical and rod-shaped MSNs with the following modifications: bare MSNs and MSNs coated with a poly (ethylene glycol)-poly(ethylene imine) (PEG-PEI) block copolymer. In transport studies, MSNs showed low permeability, whereas the results of the cellular uptake studies suggest robust uptake of PEG-PEI-coated MSNs. None of the MSNs showed significant toxic effects in the cell viability studies. While the shape effect was detectable but small, especially in the real-time surface plasmon resonance measurements, coating with PEG-PEI copolymers clearly facilitated the uptake of MSNs. Finally, we evaluated the in vivo detectability of one of the best candidates, i.e. the copolymer-coated rod-shaped MSNs, by two-photon in vivo imaging in the brain vasculature. The particles were clearly detectable after intravenous injection and caused no damage to the BBB. Thus, when properly designed, the uptake of MSNs could potentially be utilized for the delivery of drugs into the brain via transcellular transport.
  • Luetjohann, Dieter; Björkhem, Ingemar; Friedrichs, Silvia; Kerksiek, Anja; Lovgren-Sandblom, Anita; Geilenkeuser, Wolf-Jochen; Ahrends, Robert; Andrade, Isabel; Ansorena, Diana; Astiasaran, Iciar; Baila-Rueda, Lucia; Barriuso, Bianca; Becker, Susen; Bretillon, Lionel; Browne, Richard W.; Caccia, Claudio; Ceglarek, Uta; Cenarro, Ana; Crick, Peter J.; Fauler, Günter; Garcia-Llatas, Guadalupe; Gray, Robert; Griffiths, William J.; Gylling, Helena; Harding, Scott; Helmschrodt, Christin; Iuliano, Luigi; Janssen, Hans-Gerd; Jones, Peter; Kaipiainen, Leena; Kannenberg, Frank; Jesus Lagarda, Maria; Leoni, Valerio; Lottenberg, Ana Maria; MacKay, Dylan S.; Matysik, Silke; McDonald, Jeff; Menendez-Carreno, Maria; Myrie, Semone B.; Nunes, Valeria Sutti; Ostlund, Richard E.; Polisecki, Eliana; Ramos, Fernando; Rideout, Todd C.; Schaefer, Ernst J.; Schmitz, Gerd; Wang, Yuqin; Zerbinati, Chiara; Diczfalusy, Ulf; Schött, Hans-Frieder (2019)
    Serum concentrations of lathosterol, the plant sterols campesterol and sitosterol and the cholesterol metabolite 5 alpha-cholestanol are widely used as surrogate markers of cholesterol synthesis and absorption, respectively. Increasing numbers of laboratories utilize a broad spectrum of well-established and recently developed methods for the determination of cholesterol and non-cholesterol sterols (NCS). In order to evaluate the quality of these measurements and to identify possible sources of analytical errors our group initiated the first international survey for cholesterol and NCS. The cholesterol and NCS survey was structured as a two-part survey which took place in the years 2013 and 2014. The first survey part was designed as descriptive, providing information about the variation of reported results from different laboratories. A set of two lyophilized pooled sera (A and B) was sent to twenty laboratories specialized in chromatographic lipid analysis. The different sterols were quantified either by gas chromatography-flame ionization detection, gas chromatography- or liquid chromatography-mass selective detection. The participants were requested to determine cholesterol and NCS concentrations in the provided samples as part of their normal laboratory routine. The second part was designed as interventional survey. Twenty-two laboratories agreed to participate and received again two different lyophilized pooled sera (C and D). In contrast to the first international survey, each participant received standard stock solutions with defined concentrations of cholesterol and NCS. The participants were requested to use diluted calibration solutions from the provided standard stock solutions for quantification of cholesterol and NCS. In both surveys, each laboratory used its own internal standard (5 alpha-cholestane, epicoprostanol or deuterium labelled sterols). Main outcome of the survey was, that unacceptably high interlaboratory variations for cholesterol and NCS concentrations are reported, even when the individual laboratories used the same calibration material. We discuss different sources of errors and recommend all laboratories analysing cholesterol and NCS to participate in regular quality control programs.
  • Tikkanen, Alli; Pierrot, Estelle; Deng, Feng; Sanchez, Virginia Barras; Hagström, Marja; Koenderink, Jan B.; Kidron, Heidi (2020)
    Food additives are compounds that are added to food and beverage to improve the taste, color, preservation, or composition. Generally, food additives are considered safe for human use due to safety evaluations conducted by food safety authorities and high safety margins applied to permitted usage levels. However, the interaction potential of food additives with simultaneously administered medication has not received much attention. Even though many food additives are poorly absorbed into systemic circulation, high concentrations could exist in the intestinal lumen, making intestinal drug transporters, such as the uptake transporter organic anion transporting polypeptide 2B1 (OATP2B1), a possible site of food additive-drug interactions. In the present work, we aimed to characterize the interaction of a selection of 25 food additives including colorants, preservatives, and sweeteners with OATP2B1 in vitro. In human embryonic kidney 293 (HEK293) cells transiently overexpressing OATP2B1 or control, uptake of dibromofluorescein was studied with and without 50 mu M food additive at pH 7.4. As OATP2B1 displays substrate- and pH-dependent transport functions and the intraluminal pH varies along the gastrointestinal tract, we performed the studies also at pH 5.5 using estrone sulfate as an OATP2B1 substrate. Food additives that inhibited OATP2B1-mediated substrate transport by >= 50% were subjected to dose-response studies. Six colorants were identified and validated as OATP2B1 inhibitors at pH 5.5, but only three of these were categorized as inhibitors at pH 7.4. One sweetener was validated as an inhibitor under both assay conditions, whereas none of the preservatives exhibited >= 50% inhibition of OATP2B1-mediated transport. Extrapolation of computed inhibitory constants (K-i values) to estimations of intestinal food additive concentrations implies that selected colorants could inhibit intestinal OATP2B1 also in vivo. These results suggest that food additives, especially colorants, could alter the pharmacokinetics of orally administered OATP2B1 substrate drugs, although further in vivo studies are warranted to understand the overall clinical consequences of the findings.
  • Seidelmann, Sara B.; Feofanova, Elena; Yu, Bing; Franceschini, Nora; Claggett, Brian; Kuokkanen, Mikko; Puolijoki, Hannu; Ebeling, Tapani; Perola, Markus; Salomaa, Veikko; Shah, Amil; Coresh, Josef; Selvin, Elizabeth; MacRae, Calum A.; Cheng, Susan; Boerwinkle, Eric; Solomon, Scott D. (2018)
    BACKGROUND Loss-of-function mutations in the SGLT1 (sodium/glucose co-transporter-1) gene result in a rare glucose/galactose malabsorption disorder and neonatal death if untreated. In the general population, variants related to intestinal glucose absorption remain uncharacterized. OBJECTIVES The goat of this study was to identify functional SGLT1 gene variants and characterize their clinical consequences. METHODS Whole exome sequencing was performed in the ARIC (Atherosclerosis Risk in Communities) study participants enrolled from 4 U.S. communities. The association of functional, nonsynonymous substitutions in SGLT1 with 2-h oral glucose tolerance test results was determined. Variants related to impaired glucose tolerance were studied, and Mendelian randomization analysis of cardiometabotic outcomes was performed. RESULTS Among 5,687 European-American subjects (mean age 54 +/- 6 years; 47% mate), those who carried a haplotype of 3 missense mutations (frequency of 6.7%)-Asn51Ser, Ala411Thr, and His615Gln-had lower 2-h glucose and odds of impaired glucose tolerance than noncarriers (beta-coefficient: -8.0; 95% confidence interval [CI]: -12.7 to -3.3; OR: 0.71; 95% CI: 0.59 to 0.86, respectively). The association of the haplotype with oral glucose tolerance test results was consistent in a replication sample of 2,791 African-American subjects (beta = -16.3; 95% CI: -36.6 to 4.1; OR: 0.39; 95% CI: 0.17 to 0.91) and an external European-Finnish population sample of 6,784 subjects (beta = -3.2; 95% CI: -6.4 to 0.02; OR: 0.81; 95% CI: 0.68 to 0.98). Using a Mendelian randomization approach in the index cohort, the estimated 25-year effect of a reduction of 20 mg/dl in 2-h glucose via SGLT1 inhibition would be reduced prevalent obesity (OR: 0.43; 95% CI: 0.23 to 0.63), incident diabetes (hazard ratio [HR]: 0.58; 95% CI: 0.35 to 0.81), heart failure (HR: 0.53; 95% CI: 0.24 to 0.83), and death (HR: 0.66; 95% CI: 0.42 to 0.90). CONCLUSIONS Functionally damaging missense variants in SGLT1 protect from diet-induced hyperglycemia in multiple populations. Reduced intestinal glucose uptake may protect from long-term cardiometabolic outcomes, providing support for therapies that target SGLT1 function to prevent and treat metabolic conditions. (C) 2018 Published by Elsevier on behalf of the American College of Cardiology Foundation.
  • Carley, Eoin P.; Hayes, Laura A.; Murray, Sophie A.; Morosan, Diana E.; Shelley, Warren; Vilmer, Nicole; Gallagher, Peter T. (2019)
    Solar flares often involve the acceleration of particles to relativistic energies and the generation of high-intensity bursts of radio emission. In some cases, the radio bursts can show periodic or quasiperiodic intensity pulsations. However, precisely how these pulsations are generated is still subject to debate. Prominent theories employ mechanisms such as periodic magnetic reconnection, magnetohydrodynamic (MHD) oscillations, or some combination of both. Here we report on high-cadence (0.25 s) radio imaging of a 228 MHz radio source pulsating with a period of 2.3 s during a solar flare on 2014-April-18. The pulsating source is due to an MHD sausage mode oscillation periodically triggering electron acceleration in the corona. The periodic electron acceleration results in the modulation of a loss-cone instability, ultimately resulting in pulsating plasma emission. The results show that a complex combination of MHD oscillations and plasma instability modulation can lead to pulsating radio emission in astrophysical environments.
  • Gylling, Helena; Strandberg, Timo E.; Kovanen, Petri T.; Simonen, Piia (2020)
    Atherosclerotic cardiovascular diseases (ASCVDs) cause every fifth death worldwide. However, it is possible to prevent the progression of ASCVDs by reducing circulating concentrations of low-density lipoprotein cholesterol (LDL-C). Recent large meta-analyses demonstrated that by reducing the dietary intake of saturated fat and cholesterol, it is possible to reduce the risk of ASCVD events. Plant stanols, as fatty-acid esters, were developed as a dietary adjunct to reduce LDL-C levels as part of a heart-healthy diet. They reduce cholesterol absorption so that less cholesterol is transported to the liver, and the expression of LDL receptors is upregulated. Ultimately, LDL-C concentrations are reduced on average by 9-12% by consuming 2-3 g of plant stanol esters per day. In this review, we discuss recent information regarding the prevention of ASCVDs with a focus on dietary means. We also present new estimates on the effect of plant stanol ester consumption on LDL-C levels and the risk of ASCVD events. Plant stanol esters as part of a heart-healthy diet plausibly offer a means to reduce the risk of ASCVD events at a population level. This approach is not only appropriate for subjects with a high risk of ASCVD, but also for subjects at an apparently lower risk to prevent subclinical atherosclerosis.