TY - JOUR AU - Schirris, T.J.J. AU - Rossell, S.L. AU - Haas, R. de AU - Frambach, S.J.C.M. AU - Hoogstraten, C.A. AU - Renkema, G.H. AU - Beyrath, J.D. AU - Willems, P.H.G.M. AU - Huynen, M.A. AU - Smeitink, J.A.M. AU - Russel, F.G.M. AU - Notebaart, R.A. PY - 2021 UR - https://hdl.handle.net/2066/229007 AB - The majority of cellular energy is produced by the mitochondrial oxidative phosphorylation (OXPHOS) system. Failure of the first OXPHOS enzyme complex, NADH:ubiquinone oxidoreductase or complex I (CI), is associated with multiple signs and symptoms presenting at variable ages of onset. There is no approved drug treatment yet to slow or reverse the progression of CI-deficient disorders. Here, we present a comprehensive human metabolic network model of genetically characterized CI-deficient patient-derived fibroblasts. Model calculations predicted that increased cholesterol production, export, and utilization can counterbalance the surplus of reducing equivalents in patient-derived fibroblasts, as these pathways consume considerable amounts of NAD(P)H. We show that fibrates attenuated increased NAD(P)H levels and improved CI-deficient fibroblast growth by stimulating the production of cholesterol via enhancement of its cellular efflux. In CI-deficient (Ndufs4(-/-)) mice, fibrate treatment resulted in prolonged survival and improved motor function, which was accompanied by an increased cholesterol efflux from peritoneal macrophages. Our results shine a new light on the use of compensatory biological pathways in mitochondrial dysfunction which may lead to novel therapeutic interventions for mitochondrial diseases for which currently no cure exists. TI - Stimulation of cholesterol biosynthesis in mitochondrial complex I-deficiency lowers reductive stress and improves motor function and survival in mice SN - 0925-4439 IS - iss. 4 JF - Biochimica et biophysica acta. Molecular basis of disease VL - vol. 1867 DO - https://doi.org/10.1016/j.bbadis.2020.166062 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/229007/229007.pdf?sequence=1 ER - TY - JOUR AU - Lindic, M.M. AU - Zajonz, M. AU - Hebestreit, M.-L. AU - Schneider, M. AU - Meerts, W.L. AU - Schmitt, M. PY - 2020 UR - https://hdl.handle.net/2066/227161 TI - Determination of excited state dipole moments in solution via thermochromic methods SN - 2215-0161 SP - 1 JF - MethodsX VL - vol. 7 DO - https://doi.org/10.1016/j.mex.2020.101101 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/227161/227161.pdf?sequence=1 ER - TY - JOUR AU - Tooyserkani, R. AU - Lipinski, W.P. AU - Willemsen, B. AU - Lowik, D.W.P.M. PY - 2020 UR - https://hdl.handle.net/2066/225377 TI - Activation of cell-penetrating peptide fragments by disulfide formation EP - 1168 SN - 0939-4451 SP - 1161 JF - Amino Acids VL - vol. 52 PS - 8 p. DO - https://doi.org/10.1007/s00726-020-02880-x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/225377/225377.pdf?sequence=1 ER - TY - JOUR AU - Hebestreit, M.L. AU - Lartian, Hilda AU - Schneider, M. AU - Kuehnemuth, Ralf AU - Yareth Torres-Boy, America AU - Romero-Servin, Sergio AU - Meerts, W.L. AU - Schmitt, M. PY - 2020 UR - https://hdl.handle.net/2066/225073 TI - Structure and excited state dipole moments of oxygen containing heteroaromatics: 2,3-benzofuran EP - 7 SN - 0022-2860 SP - 1 JF - Journal of Molecular Structure VL - vol. 1210 DO - https://doi.org/10.1016/j.molstruc.2020.127992 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/225073/225073.pdf?sequence=1 ER - TY - JOUR AU - Luan, J. AU - Wang, D. AU - Wilson, D.A. PY - 2020 UR - https://hdl.handle.net/2066/226780 TI - Leveraging synthetic particles for communication: from passive to active systems EP - 21033 SN - 2040-3364 IS - iss. 41 SP - 21015 JF - Nanoscale VL - vol. 12 DO - https://doi.org/10.1039/d0nr05675h L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/226780/226780.pdf?sequence=1 ER - TY - JOUR AU - Prabhakara, K.H. AU - Shapaeva, T.B. AU - Davydova, M. AU - Zvezdin, A.K. AU - Davies, C.S. AU - Kirilyuk, A.I. AU - Rasing, T.H.M. AU - Kimel, A.V. PY - 2020 UR - https://hdl.handle.net/2066/227160 TI - Controlling magnetic domain wall velocity by femtosecond laser pulses EP - 20 SN - 0953-8984 IS - iss. 7 SP - 1 JF - Journal of Physics : Condensed Matter VL - vol. 33 DO - https://doi.org/10.1088/1361-648X/abc941 ER - TY - JOUR AU - Litjens, C.H.C. AU - Heuvel, J.M.W. van den AU - Russel, F.G.M. AU - Aarnoutse, R.E. AU - Brake, L.H.M. te AU - Koenderink, J.B. PY - 2020 UR - https://hdl.handle.net/2066/225349 AB - Single nucleotide polymorphisms in the OATP1B1 transporter have been suggested to partially explain the large interindividual variation in rifampicin exposure. HEK293 cells overexpressing wild-type (WT) or OATP1B1 variants *1b, *4, *5, and *15 were used to determine the in vitro rifampicin intrinsic clearance. For OATP1B1*5 and *15, a 36% and 42% reduction in intrinsic clearance, respectively, compared to WT was found. We consider that these differences in intrinsic clearance most likely have minor clinical implications. TI - Rifampicin Transport by OATP1B1 Variants SN - 0066-4804 IS - iss. 10 JF - Antimicrobial Agents and Chemotherapy VL - vol. 64 DO - https://doi.org/10.1128/AAC.00955-20 ER - TY - JOUR AU - Verscheijden, L.F.M. AU - Hattem, A.C. van AU - Pertijs, J.C.L.M. AU - Jongh, C.A. de AU - Verdijk, R.M. AU - Smeets, B. AU - Koenderink, J.B. AU - Russel, F.G.M. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225424 AB - When drugs exert their effects in the brain, linear extrapolation of doses from adults could be harmful for children as the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) function is still immature. More specifically, age-related variation in membrane transporters may impact brain disposition. As human data on brain transporter expression is scarce, age dependent [gestational age (GA), postnatal age (PNA), and postmenstrual age (PMA)] variation in immunohistochemical localization and staining intensity of the ABC transporters P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), and multidrug resistance-associated proteins 1, 2, 4, and 5 (MRP1/2/4/5) was investigated. Post mortem brain cortical and ventricular tissue was derived from 23 fetuses (GA range 12.9-39 weeks), 17 neonates (GA range 24.6-41.3 weeks, PNA range 0.004-3.5 weeks), 8 children (PNA range 0.1-3 years), and 4 adults who died from a wide variety of underlying conditions. In brain cortical BBB, immunostaining increased with age for Pgp and BCRP, while in contrast, MRP1 and MRP2 staining intensity appeared higher in fetuses, neonates, and children, as compared to adults. BCSFB was positively stained for Pgp, MRP1, and MRP2 and appeared stable across age, while BCRP was not detected. MRP4 and MRP5 were not detected in BBB or BCSFB. In conclusion, human BBB and BCSFB ABC membrane transporters show brain location and transporter-specific maturation. TI - Developmental patterns in human blood-brain barrier and blood-cerebrospinal fluid barrier ABC drug transporter expression EP - 273 SN - 0948-6143 IS - iss. 3 SP - 265 JF - Histochemistry and Cell Biology VL - vol. 154 DO - https://doi.org/10.1007/s00418-020-01884-8 ER - TY - JOUR AU - Smeets, N.J.L. AU - Litjens, C.H.C. AU - Heuvel, J.M.W. van den AU - Hove, H. AU - Broek, P.H.H. van den AU - Russel, F.G.M. AU - Koenderink, J.B. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225313 AB - BACKGROUND: Enalapril is often used in the treatment of cardiovascular diseases. Clinical data suggest that the urinary excretion of enalaprilat, the active metabolite of enalapril, is mediated by renal transporters. We aimed to identify enalaprilat specificity for renal proximal tubular transporters. METHODS: Baculovirus-transduced HEK293 cells overexpressing proximal tubular transporters were used to study enalaprilat cellular uptake. Uptake into cells overexpressing the basolateral transporters OCT2, OAT1, OAT2, or OAT3 and apical transporters OAT4, PEPT1, PEPT2, OCTN1, OCTN2, MATE1, MATE2k, and URAT1 was compared with mock-transduced control cells. Transport by renal efflux transporters MRP2, MPR4, P-gp, and BCRP was tested using a vesicular assay. Enalaprilat concentrations were measured using LC-MS/MS. RESULTS: Uptake of enalaprilat into cells expressing OAT3 as well as OAT4 was significantly higher compared to control cells. The enalaprilat affinity for OAT3 was 640 (95% CI: 520-770) µM. For OAT4, no reliable affinity constant could be determined using concentrations up to 3 mM. No transport was observed for other transporters. CONCLUSION: The affinity of enalaprilat for OAT3 and OAT4 was notably low compared to other substrates. Taking this affinity and clinically relevant plasma concentrations of enalaprilat and other OAT3 substrates into account, we believe that drug-drug interactions on a transporter level do not have a therapeutic consequence and will not require dose adjustments of enalaprilat itself or other OAT3 substrates. TI - Completing the Enalaprilat Excretion Pathway-Renal Handling by the Proximal Tubule SN - 1999-4923 IS - iss. 10 JF - Pharmaceutics VL - vol. 12 DO - https://doi.org/10.3390/pharmaceutics12100935 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/225313/225313.pdf?sequence=1 ER - TY - JOUR AU - Eliesen, G.A.M. AU - Drongelen, J. van AU - Hove, H. AU - Kooijman, N.I. AU - Broek, P.H. van den AU - Vries, A. De AU - Roeleveld, N. AU - Russel, F.G.M. AU - Greupink, R. PY - 2020 UR - https://hdl.handle.net/2066/220609 AB - Tumor necrosis factor (TNF) inhibitors are increasingly applied during pregnancy without clear knowledge of the impact on placenta and fetus. We assessed placental transfer and exposure to infliximab (n = 3) and etanercept (n = 3) in women with autoimmune diseases. Furthermore, we perfused healthy term placentas for 6 hours with 100 µg/mL infliximab (n = 4) or etanercept (n = 5). In pregnant women, infliximab transferred into cord blood but also entered the placenta (cord-to-maternal ratio of 1.6 ± 0.4, placenta-to-maternal ratio of 0.3 ± 0.1, n = 3). For etanercept, a cord-to-maternal ratio of 0.04 and placenta-to-maternal ratio of 0.03 was observed in one patient only. In ex vivo placenta perfusions, the extent of placental transfer did not differ between the drugs. Final concentrations in the fetal compartment for infliximab and etanercept were 0.3 ± 0.3 and 0.2 ± 0.2 µg/mL, respectively. However, in placental tissue, infliximab levels exceeded those of etanercept (19 ± 6 vs. 1 ± 3 µg/g, P < 0.001). In conclusion, tissue exposure to infliximab is higher than that of etanercept both in vivo as well as in ex vivo perfused placentas. However, initial placental transfer, as observed ex vivo, does not differ between infliximab and etanercept when administered in equal amounts. The difference in placental tissue exposure to infliximab and etanercept may be of clinical relevance and warrants further investigation. More specifically, we suggest that future studies should look into the occurrence of placental TNF inhibition and possible consequences thereof. TI - Assessment of Placental Disposition of Infliximab and Etanercept in Women With Autoimmune Diseases and in the Ex Vivo Perfused Placenta EP - 106 SN - 0009-9236 IS - iss. 1 SP - 99 JF - Clinical Pharmacology and Therapeutics VL - vol. 108 DO - https://doi.org/10.1002/cpt.1827 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220609/220609.pdf?sequence=1 ER - TY - JOUR AU - Freriksen, J.J.M. AU - Meijerhof, M. AU - Drongelen, J. van AU - Drenth, J.P.H. AU - Burger, D.M. AU - Russel, F.G.M. AU - Colbers, A. AU - Greupink, R. PY - 2020 UR - https://hdl.handle.net/2066/229071 TI - Transfer of daclatasvir and sofosbuvir's main metabolite, GS-331007, across the human placenta ex vivo EP - 943 SN - 0002-9378 IS - iss. 6 SP - 941 JF - American Journal of Obstetrics and Gynecology VL - vol. 223 DO - https://doi.org/10.1016/j.ajog.2020.08.107 ER - TY - JOUR AU - Bovee, Dominique M. AU - Visser, Wesley J. AU - Middel, Igor AU - Mik-van Egmond, Anneke De AU - Greupink, R. AU - Masereeuw, R. AU - Russel, F.G. AU - Zietse, Robert AU - Hoorn, Ewout J. PY - 2020 UR - https://hdl.handle.net/2066/217341 TI - A Randomized Trial of Distal Diuretics versus Dietary Sodium Restriction for Hypertension in Chronic Kidney Disease EP - 662 SN - 1046-6673 IS - iss. 3 SP - 650 JF - Journal of the American Society of Nephrology VL - vol. 31 DO - https://doi.org/10.1681/ASN.2019090905 ER - TY - JOUR AU - Freriksen, J.J.M. AU - Schalkwijk, S.J. AU - Colbers, A.P. AU - Abduljalil, K. AU - Russel, F.G.M. AU - Burger, D.M. AU - Greupink, R. PY - 2020 UR - https://hdl.handle.net/2066/220606 AB - Antiretroviral therapy during pregnancy reduces the risk of vertical HIV-1 transmission. However, drug dosing is challenging as pharmacokinetics (PK) may be altered during pregnancy. We combined a pregnancy physiologically-based pharmacokinetic (PBPK) modeling approach with data on placental drug transfer to simulate maternal and fetal exposure to dolutegravir (DTG). First, a PBPK model for DTG exposure in healthy volunteers was established based on physiological and DTG PK data. Next, the model was extended with a fetoplacental unit using transplacental kinetics obtained by performing ex vivo dual-side human cotyledon perfusion experiments. Simulations of fetal exposure after maternal dosing in the third trimester were in accordance with clinically observed DTG cord blood data. Furthermore, the predicted fetal trough plasma concentration (Ctrough ) following 50 mg q.d. dosing remained above the concentration that results in 90% of viral inhibition. Our integrated approach enables simulation of maternal and fetal DTG exposure, illustrating this to be a promising way to assess DTG PK during pregnancy. TI - Assessment of Maternal and Fetal Dolutegravir Exposure by Integrating Ex Vivo Placental Perfusion Data and Physiologically-Based Pharmacokinetic Modeling EP - 1361 SN - 0009-9236 IS - iss. 6 SP - 1352 JF - Clinical Pharmacology and Therapeutics VL - vol. 107 DO - https://doi.org/10.1002/cpt.1748 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220606/220606.pdf?sequence=1 ER - TY - JOUR AU - Verscheijden, L.F.M. AU - Zanden, T.M. van der AU - Bussel, L.P.M. van AU - Hoop-Sommen, M. de AU - Russel, F.G.M. AU - Johnson, T.N. AU - Wildt, S.N. de PY - 2020 UR - https://hdl.handle.net/2066/225414 AB - As chloroquine (CHQ) is part of the Dutch Centre for Infectious Disease Control coronavirus disease 2019 (COVID-19) experimental treatment guideline, pediatric dosing guidelines are needed. Recent pediatric data suggest that existing World Health Organization (WHO) dosing guidelines for children with malaria are suboptimal. The aim of our study was to establish best-evidence to inform pediatric CHQ doses for children infected with COVID-19. A previously developed physiologically-based pharmacokinetic (PBPK) model for CHQ was used to simulate exposure in adults and children and verified against published pharmacokinetic data. The COVID-19 recommended adult dosage regimen of 44 mg/kg total was tested in adults and children to evaluate the extent of variation in exposure. Based on differences in area under the concentration-time curve from zero to 70 hours (AUC(0-70h) ) the optimal CHQ dose was determined in children of different ages compared with adults. Revised doses were re-introduced into the model to verify that overall CHQ exposure in each age band was within 5% of the predicted adult value. Simulations showed differences in drug exposure in children of different ages and adults when the same body-weight based dose is given. As such, we propose the following total cumulative doses: 35 mg/kg (CHQ base) for children 0-1 month, 47 mg/kg for 1-6 months, 55 mg/kg for 6 months-12 years, and 44 mg/kg for adolescents and adults, not to exceed 3,300 mg in any patient. Our study supports age-adjusted CHQ dosing in children with COVID-19 in order to avoid suboptimal or toxic doses. The knowledge-driven, model-informed dose selection paradigm can serve as a science-based alternative to recommend pediatric dosing when pediatric clinical trial data is absent. TI - Chloroquine Dosing Recommendations for Pediatric COVID-19 Supported by Modeling and Simulation EP - 252 SN - 0009-9236 IS - iss. 2 SP - 248 JF - Clinical Pharmacology and Therapeutics VL - vol. 108 DO - https://doi.org/10.1002/cpt.1864 ER - TY - JOUR AU - Graumans, M.H.F. AU - Hoeben, W. AU - Russel, F.G.M. AU - Scheepers, P.T.J. PY - 2020 UR - https://hdl.handle.net/2066/218304 AB - There is a growing concern about pharmaceuticals entering the aquatic environment. Many of these compounds cannot be removed completely in sewage treatment plants. To remove these unwanted medicines from water, oxidative degradation techniques may complement the current purification steps. In this paper we studied the effect of advanced oxidation on the cytostatic drug cyclophosphamide (CP) by comparing thermal plasma activation with UV/H2O2 treatment. Plasma activated water (PAW) contains highly reactive oxygen and nitrogen species (RONS) as a result of electric gas discharges in air over water. CP solutions in tap water were oxidized over a period of 120 min and subsequently analyzed by LC-MS/MS to measure the compound degradation. Plasma activation was applied at 50, 100, or 150 W electric power input and UV/H2O2 treatment was carried out by the addition of H2O2 and placing an UV-C source above the test solution for immediate irradiation. The oxidative degradation of CP in PAW resulted in a complete degradation within 80 min at 150 W. CP was also completely degraded within 60 min applying UV/H2O2 oxidation. Both treatment techniques do induce different structural changes, demonstrating that CP is completely degraded in tap water. TI - Oxidative degradation of cyclophosphamide using thermal plasma activation and UV/H2O2 treatment in tap water SN - 0013-9351 JF - Environmental Research VL - vol. 182 DO - https://doi.org/10.1016/j.envres.2019.109046 ER - TY - JOUR AU - Frambach, S.J.C.M. AU - Haas, R. de AU - Smeitink, J.A.M. AU - Rongen, G.A.P.J.M. AU - Russel, F.G.M. AU - Schirris, T.J.J. PY - 2020 UR - https://hdl.handle.net/2066/218652 AB - Atherosclerosis is a leading cause of cardiovascular disease worldwide, and hypercholesterolemia is a major risk factor. Preventive treatments mainly focus on the effective reduction of low-density lipoprotein cholesterol, but their therapeutic value is limited by the inability to completely normalize atherosclerotic risk, probably due to the disease complexity and multifactorial pathogenesis. Consequently, high-density lipoprotein cholesterol gained much interest, as it appeared to be cardioprotective due to its major role in reverse cholesterol transport (RCT). RCT facilitates removal of cholesterol from peripheral tissues, including atherosclerotic plaques, and its subsequent hepatic clearance into bile. Therefore, RCT is expected to limit plaque formation and progression. Cellular cholesterol efflux is initiated and propagated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Their expression and function are expected to be rate-limiting for cholesterol efflux, which makes them interesting targets to stimulate RCT and lower atherosclerotic risk. This systematic review discusses the molecular mechanisms relevant for RCT and ABCA1 and ABCG1 function, followed by a critical overview of potential pharmacological strategies with small molecules to enhance cellular cholesterol efflux and RCT. These strategies include regulation of ABCA1 and ABCG1 expression, degradation, and mRNA stability. Various small molecules have been demonstrated to increase RCT, but the underlying mechanisms are often not completely understood and are rather unspecific, potentially causing adverse effects. Better understanding of these mechanisms could enable the development of safer drugs to increase RCT and provide more insight into its relation with atherosclerotic risk. SIGNIFICANCE STATEMENT: Hypercholesterolemia is an important risk factor of atherosclerosis, which is a leading pathological mechanism underlying cardiovascular disease. Cholesterol is removed from atherosclerotic plaques and subsequently cleared by the liver into bile. This transport is mediated by high-density lipoprotein particles, to which cholesterol is transferred via ATP-binding cassette transporters ABCA1 and ABCG1. Small-molecule pharmacological strategies stimulating these transporters may provide promising options for cardiovascular disease treatment. TI - Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment. EP - 190 SN - 0031-6997 IS - iss. 1 SP - 152 JF - Pharmacological Reviews VL - vol. 72 N1 - 1 januari 2020 DO - https://doi.org/10.1124/pr.119.017897 ER - TY - JOUR AU - Verscheijden, L.F.M. AU - Koenderink, J.B. AU - Johnson, T.N. AU - Wildt, S.N. de AU - Russel, F.G.M. PY - 2020 UR - https://hdl.handle.net/2066/220524 AB - Developmental changes in children can affect the disposition and clinical effects of a drug, indicating that scaling an adult dose simply down per linear weight can potentially lead to overdosing, especially in very young children. Physiologically-based pharmacokinetic (PBPK) models are compartmental, mathematical models that can be used to predict plasma drug concentrations in pediatric populations and acquire insight into the influence of age-dependent physiological differences on drug disposition. Pediatric PBPK models have generated attention in the last decade, because physiological parameters for model building are increasingly available and regulatory guidelines demand pediatric studies during drug development. Due to efforts from academia, PBPK model developers, pharmaceutical companies and regulatory authorities, examples are now available where clinical studies in children have been replaced or informed by PBPK models. However, the number of pediatric PBPK models and their predictive performance still lags behind that of adult models. In this review we discuss the general pediatric PBPK model principles, indicate the challenges that can arise when developing models, and highlight new applications, to give an overview of the current status and future perspective of pediatric PBPK modeling. TI - Physiologically-based pharmacokinetic models for children: Starting to reach maturation? SN - 0163-7258 JF - Pharmacology and Therapeutics. Part A: Chemotherapy, Toxicology and Metabolic Inhibitors VL - vol. 211 DO - https://doi.org/10.1016/j.pharmthera.2020.107541 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/220524/220524.pdf?sequence=1 ER - TY - JOUR AU - Hebestreit, M.L. AU - Henrichs, C. AU - Schneider, M. AU - Wilke, M. AU - Meerts, L. AU - Kruegler, D. AU - Schmitt, M. PY - 2019 UR - https://hdl.handle.net/2066/201985 TI - Structural changes upon electronic excitation in 1,2-dimethoxybenzene from rotationally resolved electronic spectroscopy of various isotopologues EP - 145 SN - 0022-2860 SP - 139 JF - Journal of Molecular Structure VL - vol. 1184 DO - https://doi.org/10.1016/j.molstruc.2019.01.074 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/201985/201985.pdf?sequence=1 ER - TY - JOUR AU - Men, Y. AU - Li, W. AU - Lebleu, C. AU - Sun, J. AU - Wilson, D.A. PY - 2019 UR - https://hdl.handle.net/2066/214643 TI - Tailoring Polymersome Shape Using the Hofmeister Effect SN - 1525-7797 JF - Biomacromolecules N1 - 17 september 2019 DO - https://doi.org/10.1021/acs.biomac.9b00924 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/214643/214643.pdf?sequence=1 ER - TY - JOUR AU - Sun, Jiawei AU - Mathesh Shanmugam, M. AU - Li, W. AU - Wilson, Daniela A. PY - 2019 UR - https://hdl.handle.net/2066/208623 TI - Enzyme-Powered Nanomotors with Controlled Size for Biomedical Applications EP - 10200 SN - 1936-0851 IS - iss. 9 SP - 10191 JF - ACS Nano VL - vol. 13 DO - https://doi.org/10.1021/acsnano.9b03358 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208623/208623.pdf?sequence=1 ER - TY - JOUR AU - Cremers, T.L. AU - Chefdeville, S. AU - Bakker, Joost M. AU - Meerts, L. AU - Meerakker, S.Y.T. van de PY - 2019 UR - https://hdl.handle.net/2066/202788 TI - Direct excitation of the spin-orbit forbidden X-2 pi(3/2) <- X-2 pi(1/2) transition in NO using the intra-cavity free electron laser FELICE SN - 0026-8976 JF - Molecular Physics DO - https://doi.org/10.1080/00268976.2019.1589008 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/202788/202788.pdf?sequence=1 ER - TY - JOUR AU - Ye, Yicheng AU - Luan, J. AU - Wang, Ming AU - Chen, Yongming AU - Wilson, D.A. AU - Peng, Fei AU - Tu, Yingfeng PY - 2019 UR - https://hdl.handle.net/2066/214599 AB - Abstract Delicate molecular and biological motors are tiny machines capable of achieving numerous vital tasks in biological processes. To gain a deeper understanding of their mechanism of motion, researchers from multiple backgrounds have designed and fabricated artificial micro- and nanomotors. These nano-/microscale motors can self-propel in solution by exploiting different sources of energy; thus showing tremendous potential in widespread applications. As one of the most common motor systems, Janus motors possess unique asymmetric structures and integrate different functional materials onto two sides. This review mainly focuses on the fabrication of different types of micro- and nanomotors based on Janus structures. Furthermore, some challenges still exist in the implementation of Janus motors in the biomedical field. With such common goals in mind, it is expected that the elaborate and multifunctional design of Janus motors will overcome their challenges in the near future. TI - Fabrication of Self-Propelled Micro- and Nanomotors Based on Janus Structures EP - 8680 SN - 0947-6539 IS - iss. 37 SP - 8663 JF - Chemistry : a European Journal VL - vol. 25 ER - TY - JOUR AU - Vriend, J. AU - Hoogstraten, C.A. AU - Venrooij, K.R. AU - Berge, B.T. van den AU - Govers, L.P. AU - Rooij, A.J.M. van AU - Huigen, M.C.D.G. AU - Schirris, T.J.J. AU - Russel, F.G.M. AU - Masereeuw (UU), R. AU - Wilmer, M.J.G. PY - 2019 UR - https://hdl.handle.net/2066/208820 TI - Organic anion transporters 1 and 3 influence cellular energy metabolism in renal proximal tubule cells EP - 1358 SN - 1431-6730 IS - iss. 10 SP - 1347 JF - Biological Chemistry VL - vol. 400 DO - https://doi.org/10.1515/hsz-2018-0446 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208820/208820.pdf?sequence=1 ER - TY - JOUR AU - Freriksen, J.J.M. AU - Seyen, M. van AU - Judd, A. AU - Gibb, D.M. AU - Collins, I.J. AU - Greupink, R. AU - Russel, F.G.M. AU - Drenth, J.P.H. AU - Colbers, A. AU - Burger, D.M. PY - 2019 UR - https://hdl.handle.net/2066/208830 AB - BACKGROUND: With the global efforts to eradicate hepatitis C virus (HCV), treatment during pregnancy is becoming a priority for research as this, and maternal cure should reduce vertical transmission. However, as information on the efficacy and safety of direct-acting antivirals (DAAs) in pregnancy is generally lacking, treatment of HCV infection during pregnancy is not currently recommended. AIM: To provide an overview of current knowledge regarding maternal exposure, placental handling and safety of DAAs during pregnancy and lactation METHODS: A literature search was performed focusing on the effect of pregnancy on maternal exposure to DAAs, the placental handling of DAAs, the safety of DAAs for mother and child during pregnancy and the safety of DAAs during lactation. RESULTS: Exposure to all DAAs studied is likely to be altered during pregnancy, mostly related to pregnancy-induced effects on drug absorption and metabolism. Although animal studies show that most DAAs are reported to cross the placenta and transfer into breast milk, most DAA combinations show a favourable safety profile. Because of the rapid viral decline after treatment initiation, and to avoid the critical period of organogenesis, treatment may be started at the end of the second trimester or early third trimester. CONCLUSIONS: Treatment of HCV infection during pregnancy is realistic, as DAAs are highly effective and treatment duration is relatively short. There is an urgent need to study DAAs during pregnancy and lactation to contribute to the goal of HCV elimination. TI - Review article: direct-acting antivirals for the treatment of HCV during pregnancy and lactation - implications for maternal dosing, foetal exposure, and safety for mother and child EP - 750 SN - 0269-2813 IS - iss. 7 SP - 738 JF - Alimentary Pharmacology & Therapeutics VL - vol. 50 DO - https://doi.org/10.1111/apt.15476 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208830/208830.pdf?sequence=1 ER - TY - JOUR AU - Oerlemans, A. AU - Verscheijden, L.F.M. AU - Mol, J.G.J. AU - Vermeulen, R.C.H. AU - Westerhout, J. AU - Roeleveld, N. AU - Russel, F.G.M. AU - Scheepers, P.T.J. PY - 2019 UR - https://hdl.handle.net/2066/208263 TI - Toxicokinetics of a urinary metabolite of tebuconazole following controlled oral and dermal administration in human volunteers EP - 2553 SN - 0340-5761 IS - iss. 9 SP - 2545 JF - Archives of Toxicology VL - vol. 93 DO - https://doi.org/10.1007/s00204-019-02523-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/208263/208263.pdf?sequence=1 ER - TY - JOUR AU - Schalkwijk, S.J. AU - Heine, R. ter AU - Colbers, A.P. AU - Capparelli, Edmund AU - Best, Brookie M. AU - Cressey, Tim R. AU - Greupink, R. AU - Russel, F.G. AU - Karlsson, Mats O. AU - Burger, D.M. PY - 2019 UR - https://hdl.handle.net/2066/207033 TI - Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling EP - 1356 SN - 0305-7453 IS - iss. 5 SP - 1348 JF - Journal of Antimicrobial Chemotherapy VL - vol. 74 DO - https://doi.org/10.1093/jac/dky567 ER - TY - JOUR AU - Verscheijden, L.F.M. AU - Koenderink, J.B. AU - Wildt, S.N. de AU - Russel, F.G.M. PY - 2019 UR - https://hdl.handle.net/2066/206439 AB - Different pediatric physiologically-based pharmacokinetic (PBPK) models have been described incorporating developmental changes that influence plasma drug concentrations. Drug disposition into cerebrospinal fluid (CSF) is also subject to age-related variation and can be further influenced by brain diseases affecting blood-brain barrier integrity, like meningitis. Here, we developed a generic pediatric brain PBPK model to predict CSF concentrations of drugs that undergo passive transfer, including age-appropriate parameters. The model was validated for the analgesics paracetamol, ibuprofen, flurbiprofen and naproxen, and for a pediatric meningitis population by empirical optimization of the blood-brain barrier penetration of the antibiotic meropenem. Plasma and CSF drug concentrations derived from the literature were used to perform visual predictive checks and to calculate ratios between simulated and observed area under the concentration curves (AUCs) in order to evaluate model performance. Model-simulated concentrations were comparable to observed data over a broad age range (3 months-15 years postnatal age) for all drugs investigated. The ratios between observed and simulated AUCs (AUCo/AUCp) were within 2-fold difference both in plasma (range 0.92-1.09) and in CSF (range 0.64-1.23) indicating acceptable model performance. The model was also able to describe disease-mediated changes in neonates and young children (<3m postnatal age) related to meningitis and sepsis (range AUCo/AUCp plasma: 1.64-1.66, range AUCo/AUCp CSF: 1.43-1.73). Our model provides a new computational tool to predict CSF drug concentrations in children with and without meningitis and can be used as a template model for other compounds that passively enter the CNS. TI - Development of a physiologically-based pharmacokinetic pediatric brain model for prediction of cerebrospinal fluid drug concentrations and the influence of meningitis SN - 1553-7358 IS - iss. 6 SP - e1007117 JF - Plos Computational Biology VL - vol. 15 DO - https://doi.org/10.1371/journal.pcbi.1007117 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/206439/206439.pdf?sequence=1 ER - TY - JOUR AU - Haas, R. de AU - Heltzel, L.C.M.W. AU - Tax, D. AU - Broek, P.H. van den AU - Steenbreker, H. AU - Verheij, M.M.M. AU - Russel, F.G.M. AU - Orr, A.L. AU - Nakamura, K. AU - Smeitink, J.A.M. PY - 2019 UR - https://hdl.handle.net/2066/215334 AB - The PTEN-induced putative kinase 1 knockout rat (Pink1(-/-)) is marketed as an established model for Parkinson's disease, characterized by development of motor deficits and progressive degeneration of half the dopaminergic neurons in the substantia nigra pars compacta by 8 months of age. In this study, we address our concerns about the reproducibility of the Pink1(-/-) rat model. We evaluated behavioural function, number of substantia nigra dopaminergic neurons and extracellular striatal dopamine concentrations by in vivo microdialysis. Strikingly, we and others failed to observe any loss of dopaminergic neurons in 8-month-old male Pink1(-/-) rats. To understand this variability, we compared key experimental parameters from the different studies and provide explanations for contradictory findings. Although Pink1(-/-) rats developed behavioural deficits, these could not be attributed to nigrostriatal degeneration as there was no loss of dopaminergic neurons in the substantia nigra and no changes in neurotransmitter levels in the striatum. To maximize the benefit of Parkinson's disease research and limit the unnecessary use of laboratory animals, it is essential that the research community is aware of the limits of this animal model. Additional research is needed to identify reasons for inconsistency between Pink1(-/-) rat colonies and why degeneration in the substantia nigra is not consistent. TI - To be or not to be pink(1): contradictory findings in an animal model for Parkinson's disease SN - 2632-1297 IS - iss. 1 SP - fcz016 JF - Brain Communications VL - vol. 1 DO - https://doi.org/10.1093/braincomms/fcz016 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/215334/215334.pdf?sequence=1 ER - TY - JOUR AU - Jin, S. AU - Sun, F. AU - Zou, Q. AU - Huang, J. AU - Zuo, Y. AU - Li, Y AU - Wang, S AU - Cheng, L. AU - Man, Y AU - Yang, F. AU - Li, J PY - 2019 UR - https://hdl.handle.net/2066/216056 AB - The purpose of this study was to fabricate a low-immunogenicity fish collagen (FC) and bioactive nanohydroxyapatite (n-HA) enhanced poly(lactide- co-glycolide) (PLGA) nanofibrous membrane for guided bone regeneration (GBR) via electrospinning. The physicochemical properties and morphology study revealed that FC and n-HA particles were homogeneously dispersed in the PLGA fibrous matrix. Notably, the formation of enhanced polymeric chain network due to the interaction between FC and PLGA significantly improved the tensile strength of the PLGA membrane. The incorporation of FC altered the degradation behavior of fibers and accelerated the degradation rate of the PLGA-based membranes. Moreover, the membranes exhibited favorable cytocompatibility with bone mesenchymal stem cells (BMSCs) and human gingiva fibroblasts (HGF) cells. More importantly, the optimized membrane satisfied the requirements of the 'Biological evaluation of medical devices' during the incipient biosafety evaluation. All the results indicate that this composite fibrous membrane exhibits significant potential for guided bone or tissue regeneration. TI - Fish Collagen and Hydroxyapatite Reinforced Poly(lactide- co-glycolide) Fibrous Membrane for Guided Bone Regeneration. EP - 2067 SN - 1525-7797 IS - iss. 5 SP - 2058 JF - Biomacromolecules VL - vol. 20 DO - https://doi.org/10.1021/acs.biomac.9b00267 ER - TY - JOUR AU - Zwartsen, A. AU - Litjens, C.H.C. AU - Hondebrink, L. AU - Heuvel, J van den AU - Greupink, R. AU - Russel, F.G.M. AU - Lange, D.W. de AU - Legler, J. AU - Koenderink, J.B. AU - Westerink, R.H. PY - 2019 UR - https://hdl.handle.net/2066/205470 AB - Many psychoactive substances affect the human dopamine (DA) reuptake transporter (hDAT). Polymorphisms in the encoding gene could affect the functionality of the transporter and consequently alter effects of psychotropic and recreational drugs. Recently, a T356 M single nucleotide polymorphism in the human SLC6A3 gene was described, which resulted in functional impairments of DA uptake. Therefore, we investigated the effects of 10 psychoactive substances (0.01-1000 muM)) on DA uptake in human embryonic kidney (HEK) 293 cells transiently overexpressing wildtype (WT) or T356 M hDAT. Our data shows that T356 M hDAT has a 3 times lower Vmax and a 3 times higher Km compared to WT hDAT. Additionally, all psychoactive substances inhibited DA uptake by T356 M and WT hDAT. The DA reuptake inhibitors (methylphenidate, cocaine, and bupropion) inhibited DA uptake by WT hDAT most potently, followed by amphetamine-type stimulants [4-fluoroamphetamine (4-FA), amphetamine and MDMA], selective serotonin reuptake inhibitors (SSRI; fluoxetine and citalopram) and arylcyclohexylamines [methoxetamine (MXE) and ketamine]. Compared to DA uptake by WT hDAT, bupropion, methylphenidate, cocaine, and MXE less potently inhibited DA uptake by T356 M hDAT, while citalopram more potently inhibited uptake. The differences in IC50 values between T356 M and WT hDAT were considerable (3-45 fold). As such, the presence of this polymorphism could affect treatment efficiency with these substances as well as susceptibly for toxicity and addiction for individuals carrying this polymorphism. TI - Differential effects of psychoactive substances on human wildtype and polymorphic T356M dopamine transporters (DAT) EP - 75 SN - 0300-483X SP - 69 JF - Toxicology VL - vol. 422 DO - https://doi.org/10.1016/j.tox.2019.04.012 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/205470/205470.pdf?sequence=1 ER - TY - JOUR AU - Weigand, K.M. AU - Schirris, T.J.J. AU - Houweling, Megan AU - Heuvel, J.M.W. van den AU - Koenderink, J.B. AU - Dankers, A.C.A. AU - Russel, F.G. AU - Greupink, R. PY - 2019 UR - https://hdl.handle.net/2066/202078 TI - Uremic solutes modulate hepatic bile acid handling and induce mitochondrial toxicity EP - 61 SN - 0887-2333 SP - 52 JF - Toxicology in Vitro VL - vol. 56 DO - https://doi.org/10.1016/j.tiv.2019.01.003 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/202078/202078.pdf?sequence=1 ER - TY - JOUR AU - Roucou, A. AU - Kleiner, Isabelle AU - Goubet, Manuel AU - Bteich, Sabath AU - Mouret, Gael AU - Bocquet, Robin AU - Meerts, L. AU - Cuisset, A. PY - 2018 UR - https://hdl.handle.net/2066/191477 TI - Towards the Detection of Explosive Taggants: Microwave and Millimetre-Wave Gas-Phase Spectroscopies of 3-Nitrotoluene EP - 1067 SN - 1439-4235 IS - iss. 9 SP - 1056 JF - Chemphyschem VL - vol. 19 DO - https://doi.org/10.1002/cphc.201701266 ER - TY - JOUR AU - Schneider, M. AU - Hebestreit, M.L. AU - Lindic, Mirko Matthias AU - Parsian, Hilda AU - Yareth Torres-Boy, America AU - Alvarez-Valtierra, L. AU - Meerts, L. AU - Kuehnemuth, Ralf AU - Schmitt, M. PY - 2018 UR - https://hdl.handle.net/2066/197185 TI - Rotationally resolved electronic spectroscopy of 3-cyanoindole and the 3-cyanoindole-water complex EP - 23452 SN - 1463-9076 IS - iss. 36 SP - 23441 JF - PCCP Physical Chemistry Chemical Physics VL - vol. 20 DO - https://doi.org/10.1039/c8cp04020f L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/197185/197185.pdf?sequence=1 ER - TY - JOUR AU - Lindic, Mirko Matthias AU - Zajonz, Matthias AU - Hebestreit, M.L. AU - Schneider, M. AU - Meerts, L. AU - Schmitt, M. PY - 2018 UR - https://hdl.handle.net/2066/195558 TI - Excited state dipole moments of anisole in gas phase and solution EP - 219 SN - 1010-6030 SP - 213 JF - Journal of Photochemistry and Photobiology. A, Chemistry VL - vol. 365 DO - https://doi.org/10.1016/j.jphotochem.2018.07.047 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/195558/195558.pdf?sequence=1 ER - TY - JOUR AU - Men, Y. AU - Tu, Y. AU - Li, W. AU - Peng, Fei AU - Wilson, Daniela A. PY - 2018 UR - https://hdl.handle.net/2066/194794 TI - Poly(ionic liquid)s Based Brush Type Nanomotor EP - 11 SN - 2072-666X IS - iss. 7 SP - 1 JF - Micromachines VL - vol. 9 PS - 11 p. DO - https://doi.org/10.3390/mi9070364 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194794/194794.pdf?sequence=1 ER - TY - JOUR AU - Schneider, M. AU - Wilke, M. AU - Hebestreit, M.L. AU - Henrichs, C. AU - Meerts, W.L. AU - Schmitt, M. PY - 2018 UR - https://hdl.handle.net/2066/183437 TI - Excited-State Dipole Moments and Transition Dipole Orientations of Rotamers of 1,2-, 1,3-, and 1,4-Dimethoxybenzene. EP - 318 SN - 1439-4235 IS - iss. 3 SP - 307 JF - Chemphyschem VL - vol. 19 DO - http://dx.doi.org/10.1002/cphc.201701095 ER - TY - JOUR AU - Evers, R. AU - Piquette-Miller, M. AU - Polli, J.W. AU - Russel, F.G.M. AU - Sprowl, J.A. AU - Tohyama, K. AU - Ware, J.A. AU - Wildt, S.N. de AU - Xie, W AU - Brouwer, K.L.R. PY - 2018 UR - https://hdl.handle.net/2066/200052 AB - Drug transporters are critically important for the absorption, distribution, metabolism, and excretion (ADME) of many drugs and endogenous compounds. Therefore, disruption of these pathways by inhibition, induction, genetic polymorphisms, or disease can have profound effects on overall physiology, drug pharmacokinetics, drug efficacy, and toxicity. This white paper provides a review of changes in transporter function associated with acute and chronic disease states, describes regulatory pathways affecting transporter expression, and identifies opportunities to advance the field. TI - Disease-Associated Changes in Drug Transporters May Impact the Pharmacokinetics and/or Toxicity of Drugs: A White Paper From the International Transporter Consortium EP - 915 SN - 0009-9236 IS - iss. 5 SP - 900 JF - Clinical Pharmacology and Therapeutics VL - vol. 104 DO - https://doi.org/10.1002/cpt.1115 ER - TY - JOUR AU - Brake, L.H.M. te AU - Knegt, G.J. de AU - Steenwinkel, J.E. de AU - Dam, T.J.P. van AU - Burger, D.M. AU - Russel, F.G.M. AU - Crevel, R. van AU - Koenderink, J.B. AU - Aarnoutse, R. PY - 2018 UR - https://hdl.handle.net/2066/190648 AB - Insight into drug transport mechanisms is highly relevant to the efficacious treatment of tuberculosis (TB). Major problems in TB treatment are related to the transport of antituberculosis (anti-TB) drugs across human and mycobacterial membranes, affecting the concentrations of these drugs systemically and locally. Firstly, transporters located in the intestines, liver, and kidneys all determine the pharmacokinetics and pharmacodynamics of anti-TB drugs, with a high risk of drug-drug interactions in the setting of concurrent use of antimycobacterial, antiretroviral, and antidiabetic agents. Secondly, human efflux transporters limit the penetration of anti-TB drugs into the brain and cerebrospinal fluid, which is especially important in the treatment of TB meningitis. Finally, efflux transporters located in the macrophage and Mycobacterium tuberculosis cell membranes play a pivotal role in the emergence of phenotypic tolerance and drug resistance, respectively. We review the role of efflux transporters in TB drug disposition and evaluate the promise of efflux pump inhibition from a novel holistic perspective. TI - The Role of Efflux Pumps in Tuberculosis Treatment and Their Promise as a Target in Drug Development: Unraveling the Black Box EP - 291 SN - 0362-1642 SP - 271 JF - Annual review of pharmacology and toxicology VL - vol. 58 DO - https://doi.org/10.1146/annurev-pharmtox-010617-052438 ER - TY - JOUR AU - Dekker, Douwe AU - Dorresteijn, M.J. AU - Welzen, M.E.B. AU - Timman, S.T. AU - Pickkers, P. AU - Burger, D.M. AU - Smits, P. AU - Wagener, F.A.D.T.G. AU - Russel, F.G.M. PY - 2018 UR - https://hdl.handle.net/2066/187828 TI - Parenteral bilirubin in healthy volunteers: a reintroduction in translational research EP - 279 SN - 0306-5251 IS - iss. 2 SP - 268 JF - British Journal of Clinical Pharmacology VL - vol. 84 DO - https://doi.org/10.1111/bcp.13458 ER - TY - JOUR AU - Notenboom, Sylvia AU - Weigand, K.M. AU - Proost, Johannes H. AU - Lipzig, Marola M.H. van AU - Steeg, E. Van de AU - Broek, P.H.H. van den AU - Greupink, R. AU - Russel, F.G. AU - Groothuis, G.M. PY - 2018 UR - https://hdl.handle.net/2066/189813 TI - Development of a mechanistic biokinetic model for hepatic bile acid handling to predict possible cholestatic effects of drugs EP - 184 SN - 0928-0987 SP - 175 JF - European Journal of Pharmaceutical Sciences VL - vol. 115 DO - https://doi.org/10.1016/j.ejps.2018.01.007 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/189813/189813.pdf?sequence=1 ER - TY - JOUR AU - Nieskens, T.T.G. AU - Peters, J.G.P. AU - Dabaghie, D. AU - Korte, D. AU - Jansen, K. AU - Asbeck, A.H. van AU - Tavraz, N.N. AU - Friedrich, T. AU - Russel, F.G.M. AU - Masereeuw, R. AU - Wilmer, M.J.G. PY - 2018 UR - https://hdl.handle.net/2066/193213 AB - Cisplatin is a cytostatic drug used for treatment of solid organ tumors. The main adverse effect is organic cation transporter 2 (OCT2)-mediated nephrotoxicity, observed in 30% of patients. The contribution of other renal drug transporters is elusive. Here, cisplatin-induced toxicity was evaluated in human-derived conditionally immortalized proximal tubule epithelial cells (ciPTEC) expressing renal drug transporters, including OCT2 and organic anion transporters 1 (OAT1) or 3 (OAT3). Parent ciPTEC demonstrated OCT2-dependent cisplatin toxicity (TC50 34 +/- 1 muM after 24-hour exposure), as determined by cell viability. Overexpression of OAT1 and OAT3 resulted in reduced sensitivity to cisplatin (TC50 45 +/- 6 and 64 +/- 11 muM after 24-hour exposure, respectively). This effect was independent of OAT-mediated transport, as the OAT substrates probenecid and diclofenac did not influence cytotoxicity. Decreased cisplatin sensitivity in OAT-expressing cells was associated directly with a trend toward reduced intracellular cisplatin accumulation, explained by reduced OCT2 gene expression and activity. This was evaluated by Vmax of the OCT2-model substrate ASP(+) (23.5 +/- 0.1, 13.1 +/- 0.3, and 21.6 +/- 0.6 minutes(-1) in ciPTEC-parent, ciPTEC-OAT1, and ciPTEC-OAT3, respectively). Although gene expression of cisplatin efflux transporter multidrug and toxin extrusion 1 (MATE1) was 16.2 +/- 0.3-fold upregulated in ciPTEC-OAT1 and 6.1 +/- 0.7-fold in ciPTEC-OAT3, toxicity was unaffected by the MATE substrate pyrimethamine, suggesting that MATE1 does not play a role in the current experimental set-up. In conclusion, OAT expression results in reduced cisplatin sensitivity in renal proximal tubule cells, explained by reduced OCT2-mediated uptake capacity. In vitro drug-induced toxicity studies should consider models that express both OCT and OAT drug transporters. TI - Expression of Organic Anion Transporter 1 or 3 in Human Kidney Proximal Tubule Cells Reduces Cisplatin Sensitivity EP - 599 SN - 0090-9556 IS - iss. 5 SP - 592 JF - Drug Metabolism and Disposition VL - vol. 46 DO - https://doi.org/10.1124/dmd.117.079384 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/193213/193213.pdf?sequence=1 ER - TY - JOUR AU - Freriksen, J.J.M. AU - Feyaerts, D. AU - Broek, P.H.H. van den AU - Heijden, O.W.H. van der AU - Drongelen, J. van AU - Hamersvelt, H.W. van AU - Russel, F.G. AU - Molen, R.G. van der AU - Greupink, R. PY - 2018 UR - https://hdl.handle.net/2066/191930 TI - Placental disposition of the immunosuppressive drug tacrolimus in renal transplant recipients and in ex vivo perfused placental tissue EP - 248 SN - 0928-0987 SP - 244 JF - European Journal of Pharmaceutical Sciences VL - vol. 119 DO - https://doi.org/10.1016/j.ejps.2018.04.017 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/191930/191930.pdf?sequence=1 ER - TY - JOUR AU - Schalkwijk, S.J. AU - Buaben, A.O. AU - Freriksen, J.J.M. AU - Colbers, A.P. AU - Burger, D.M. AU - Greupink, R. AU - Russel, F.G.M. PY - 2018 UR - https://hdl.handle.net/2066/191932 TI - Prediction of Fetal Darunavir Exposure by Integrating Human Ex-Vivo Placental Transfer and Physiologically Based Pharmacokinetic Modeling EP - 716 SN - 0312-5963 IS - iss. 6 SP - 705 JF - Clinical Pharmacokinetics VL - vol. 57 DO - https://doi.org/10.1007/s40262-017-0583-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/191932/191932.pdf?sequence=1 ER - TY - JOUR AU - Allard, N.A.E. AU - Schirris, T.J.J. AU - Verheggen, R.J. AU - Russel, F.G.M. AU - Rodenburg, R.J.T. AU - Smeitink, J.A.M. AU - Hopman, M.T.E. AU - Timmers, S. PY - 2018 UR - https://hdl.handle.net/2066/187834 TI - Statins Affect Skeletal Muscle Performance: Evidence for Disturbances in Energy Metabolism EP - 84 SN - 0021-972X IS - iss. 1 SP - 75 JF - Journal of Clinical Endocrinology and Metabolism VL - vol. 103 DO - https://doi.org/10.1210/jc.2017-01561 ER - TY - JOUR AU - Vriend, J. AU - Nieskens, T.T.G. AU - Vormann, Marianne K. AU - Berge, Bartholomeus T. van den AU - Heuvel, Angelique van den AU - Russel, F.G.M. AU - Masereeuw, R. AU - Wilmer, M.J.G. PY - 2018 UR - https://hdl.handle.net/2066/194259 TI - Screening of Drug-Transporter Interactions in a 3D Microfluidic Renal Proximal Tubule on a Chip SN - 1550-7416 IS - iss. 5 JF - Aaps Journal VL - vol. 20 DO - https://doi.org/10.1208/s12248-018-0247-0 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/194259/194259.pdf?sequence=1 ER - TY - JOUR AU - Schalkwijk, S.J. AU - Heine, R. ter AU - Colbers, A. AU - Huitema, Alwin D.R. AU - Denti, Paolo AU - Dooley, Kelly E. AU - Greupink, R. AU - Russel, F.G.M. AU - Mirochnick, Mark AU - Burger, D.M. PY - 2018 UR - https://hdl.handle.net/2066/197395 TI - A Mechanism-Based Population Pharmacokinetic Analysis Assessing the Feasibility of Efavirenz Dose Reduction to 400 mg in Pregnant Women EP - 1433 SN - 0312-5963 IS - iss. 11 SP - 1421 JF - Clinical Pharmacokinetics VL - vol. 57 DO - https://doi.org/10.1007/s40262-018-0642-9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/197395/197395.pdf?sequence=1 ER - TY - JOUR AU - Oerlemans, A. AU - Dael, M.F.P. van AU - Vermeulen, R.C.H. AU - Russel, F.G. AU - Scheepers, P.T.J. PY - 2018 UR - https://hdl.handle.net/2066/198244 TI - Urine collection methods for non-toilet-trained children in biological monitoring studies: Validation of a disposable diaper for characterization of tebuconazole exposure EP - 206 SN - 0378-4274 SP - 201 JF - Toxicology Letters VL - vol. 298 DO - https://doi.org/10.1016/j.toxlet.2018.09.018 ER - TY - JOUR AU - Yauw, S.T.K. AU - Lomme, R.M.L.M. AU - Broek, P.H.H. van den AU - Greupink, R. AU - Russel, F.G.M. AU - Goor, H. van PY - 2018 UR - https://hdl.handle.net/2066/195656 AB - Background: Diclofenac increases the risk of anastomotic leakage, but the underlying mechanism is unknown. As diclofenac is excreted largely as biliary metabolites, the aim of this study was to determine the effect of these metabolites on intestinal anastomoses. Methods: This was a randomized controlled blinded experiment using 210 male Wistar rats to assess the effect of 'diclofenac bile' on the anastomotic complication score, leak rate and anastomotic strength following oral and parenteral administration of diclofenac. Bile duct and duodenal catheterization techniques were used for diversion and replacement of bile, and biliary diclofenac metabolites were determined. Results: Replacement of control bile with diclofenac bile resulted in higher anastomotic complication scores (P = 0.006) and leakage in five of 18 animals, compared with one of 18 controls (P = 0.089). In turn, following oral diclofenac administration, replacement of diclofenac bile with control bile reduced anastomotic complications (P = 0.016). The leak rate was seven of 15 versus 13 of 17 without replacement (P = 0.127). After intramuscular administration of diclofenac, the reduction in anastomotic complications was not significant when bile was replaced with control bile (P = 0.283), but it was significant when bile was drained without replacement (P = 0.025). Diclofenac metabolites in bile peaked within 2 h after administration. Administration of diclofenac bile resulted in nearly undetectable plasma levels of diclofenac (mean(s.d.) 0.01(0.01) mug/ml) after 120 min. Following oral diclofenac, bile replacement with control bile did not affect the plasma concentration of diclofenac (0.12(0.08) mug/ml versus 0.10(0.05) mug/ml with diclofenac bile; P = 0.869). Conclusion: Altered bile composition as a result of diclofenac administration increases the ileal anastomotic complication rate in rats. TI - Experimental study of diclofenac and its biliary metabolites on anastomotic healing EP - 228 SN - 2474-9842 IS - iss. 4 SP - 220 JF - BJS Open VL - vol. 2 DO - https://doi.org/10.1002/bjs5.63 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/195656/195656.pdf?sequence=1 ER - TY - JOUR AU - Schneider, M. AU - Wilke, M. AU - Hebestreit, M.L. AU - Ruiz-Santoyo, J.A. AU - Alvarez-Valtierra, L. AU - Yi, J.T. AU - Meerts, W.L. AU - Pratte, D.W. AU - Schmitt, M. PY - 2017 UR - https://hdl.handle.net/2066/177424 TI - Rotationally resolved electronic spectroscopy of the rotamers of 1,3-dimethoxybenzene EP - 21372 SN - 1463-9076 IS - iss. 32 SP - 21364 JF - PCCP Physical Chemistry Chemical Physics VL - vol. 19 DO - http://dx.doi.org/10.1039/c7cp04401a ER - TY - JOUR AU - Roucou, A. AU - Dhont, G. AU - Cuisset, A. AU - Martin-Drumel, M.A. AU - Thorwirth, S. AU - Fontanari, D. AU - Meerts, W.L. PY - 2017 UR - https://hdl.handle.net/2066/177397 TI - High resolution study of the v(2) and v(5) rovibrational fundamental bands of thionyl chloride: Interplay of an evolutionary algorithm and a line-by-line analysis EP - 13 SN - 0021-9606 IS - iss. 5 SP - 1 JF - Journal of Chemical Physics VL - vol. 147 PS - 13 p. DO - https://doi.org/10.1063/1.4996655 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/177397/177397.pdf?sequence=1 ER - TY - JOUR AU - Velden, M van der AU - Bilos, A. AU - Heuvel, J.M. van den AU - Rijpma, S.R. AU - Hurkmans, E.G.E. AU - Sauerwein, R.W. AU - Russel, F.G.M. AU - Koenderink, J.B. PY - 2017 UR - https://hdl.handle.net/2066/182160 AB - BACKGROUND: Malaria, HIV/AIDS, and tuberculosis endemic areas show considerable geographical overlap, leading to incidence of co-infections. This requires treatment with multiple drugs, potentially causing adverse drug-drug interactions (DDIs). As anti-malarials are generally positively charged at physiological pH, they are likely to interact with human organic cation transporters 1 and 2 (OCT1 and OCT2). These transporters are involved in the uptake of drugs into hepatocytes and proximal tubule cells for subsequent metabolic conversion or elimination. This efflux of cationic drugs from hepatocytes and proximal tubule cells into bile and urine can be mediated by multidrug and toxin extrusion 1 and 2-K (MATE1 and MATE2-K) transporters, respectively. METHODS: Here, the interaction of anti-malarials with these transporters was studied in order to predict potential DDIs. Using baculovirus-transduced HEK293 cells transiently expressing human OCT1, OCT2, MATE1 and MATE2K uptake and inhibition was studied by a range of anti-malarials. RESULTS: Amodiaquine, proguanil, pyrimethamine and quinine were the most potent inhibitors of 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP) transport, a known substrate of OCT1/2, resulting in half maximal inhibitory concentrations (IC50) of 11, 13, 1.6, and 3.4 microM, respectively. Only quinine had a drug-drug index higher than the cut-off value of 0.1 for OCT2, therefore, in vivo pharmacokinetic studies focusing on DDIs involving this compound and other OCT2-interacting drugs are warranted. Furthermore, proguanil appeared to be a substrate of OCT1 and OCT2 with affinities of 8.1 and 9.0 microM, respectively. Additionally, MATE1 and MATE2-K were identified as putative transport proteins for proguanil. Finally, its metabolite cycloguanil was also identified as an OCT1, OCT2, MATE1 and MATE2-K substrate. CONCLUSION: Anti-malarials can reduce OCT1 and OCT2 transport activity in vitro. Furthermore, proguanil and cycloguanil were found to be substrates of OCT1, OCT2, MATE1 and MATE2-K, highlighting the importance of these transporters in distribution and excretion. As these compounds shares substrate overlap with metformin DDIs can be anticipated during concurrent treatment. TI - Proguanil and cycloguanil are organic cation transporter and multidrug and toxin extrusion substrates SN - 1475-2875 IS - iss. 1 JF - Malaria Journal VL - vol. 16 DO - https://doi.org/10.1186/s12936-017-2062-y L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/182160/182160.pdf?sequence=1 ER - TY - JOUR AU - Huuskonen, A. AU - Kurri, M. AU - Holleman, I. PY - 2016 UR - https://hdl.handle.net/2066/159334 TI - Improved analysis of solar signals for differential reflectivity monitoring EP - 3192 SN - 1867-8548 IS - iss. 7 SP - 3183 JF - Atmospheric Measurement Techniques VL - vol. 9 DO - http://dx.doi.org/10.5194/amt-9-3183-2016 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/159334/159334.pdf?sequence=1 ER - TY - JOUR AU - Gozalpour, E. AU - Wilmer, M.J.G. AU - Bilos, A. AU - Masereeuw, R. AU - Russel, F.G. AU - Koenderink, J.B. PY - 2016 UR - https://hdl.handle.net/2066/170844 AB - Digitalis-like compounds (DLCs), the ancient medication of heart failure and Na,K-ATPase inhibitors, are characterized by their toxicity. Drug-drug interactions (DDIs) at absorption and excretion levels play a key role in their toxicity, hence, knowledge about the transporters involved might prevent these unwanted interactions. In the present study, the transport of fourteen DLCs with human P-glycoprotein (P-gp; ABCB1) was studied using a liquid chromatography-mass spectrometry (LC-MS) quantification method. DLC transport by P-gp overexpressing Madin-Darby canine kidney (MDCK) and immortalized human renal cells (ciPTEC) was compared to vesicular DLC transport. Previously, we identified convallatoxin as a substrate using membrane vesicles overexpressing P-gp; however, we could not measure transport of other DLCs in this assay (Gozalpour et al., 2014a). Here, we showed that lipophilic digitoxin, digoxigenin, strophanthidin and proscillaridin A are P-gp substrates in cellular accumulation assays, whereas the less lipophilic convallatoxin was not. P-gp function in the cellular accumulation assays depends on the entrance of lipophilic compounds by passive diffusion, whereas the vesicular transport assay is more appropriate for hydrophilic substrates. In conclusion, we identified digitoxin, digoxigenin, strophanthidin and proscillaridin A as P-gp substrates using cellular accumulation assays and recognized lipophilicity as an important factor in selecting a suitable transport assay. TI - Heterogeneous transport of digitalis-like compounds by P-glycoprotein in vesicular and cellular assays EP - 145 SN - 0887-2333 SP - 138 JF - Toxicology in Vitro VL - vol. 32 DO - http://dx.doi.org/10.1016/j.tiv.2015.12.009 ER - TY - JOUR AU - Colbers, A. AU - Greupink, R. AU - Litjens, C. AU - Burger, D.M. AU - Russel, F.G.M. PY - 2016 UR - https://hdl.handle.net/2066/170832 TI - Physiologically Based Modelling of Darunavir/Ritonavir Pharmacokinetics During Pregnancy EP - 396 SN - 0312-5963 IS - iss. 3 SP - 381 JF - Clinical Pharmacokinetics VL - vol. 55 DO - https://doi.org/10.1007/s40262-015-0325-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/170832/170832.pdf?sequence=1 ER - TY - JOUR AU - Schalkwijk, S.J. AU - Greupink, R. AU - Colbers, A.P. AU - Wouterse, A.C. AU - Verweij, V.G.M. AU - Drongelen, J. van AU - Teulen, M.J.A. AU - Oetelaar, D. van den AU - Burger, D.M. AU - Russel, F.G. PY - 2016 UR - https://hdl.handle.net/2066/168052 AB - OBJECTIVES: Data on fetal exposure to antiretroviral agents during pregnancy are important to estimate their potential for prevention of mother-to-child transmission (PMTCT) and possible toxicity. For the recently developed HIV integrase inhibitor dolutegravir, clinical data on fetal disposition are not yet available. Dual perfusion of a single placental lobule (cotyledon) provides a useful ex vivo model to predict the in vivo maternal-to-fetal transfer of this drug. The aim of this study was to estimate the transfer of dolutegravir across the human term placenta, using a dual-perfusion cotyledon model. METHODS: After cannulation of the cotyledons (n = 6), a fetal circulation of 6 mL/min and maternal circulation of 12 mL/min were initiated. The perfusion medium consisted of Krebs-Henseleit buffer (pH = 7.2-7.4) supplemented with 10.1 mM glucose, 30 g/L human serum albumin and 0.5 mL/L heparin 5000IE. Dolutegravir was administered to the maternal circulation ( approximately 4.2 mg/L) and analysed by UPLC-MS/MS. RESULTS: After 3 h of perfusion, the mean +/- SD fetal-to-maternal (FTM) concentration ratio of dolutegravir was 0.6 +/- 0.2 and the mean +/- SD concentrations in the maternal and fetal compartments were 2.3 +/- 0.4 and 1.3 +/- 0.3 mg/L, respectively. CONCLUSIONS: Dolutegravir crosses the blood-placental barrier with a mean FTM concentration ratio of 0.6. Compared with other antiretroviral agents, placental transfer of dolutegravir is moderate to high. These data suggest that dolutegravir holds clinical potential for pre-exposure prophylaxis and consequently PMTCT, but also risk of fetal toxicity. TI - Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human cotyledon perfusion model EP - 483 SN - 0305-7453 IS - iss. 2 SP - 480 JF - Journal of Antimicrobial Chemotherapy VL - vol. 71 DO - https://doi.org/10.1093/jac/dkv358 ER - TY - JOUR AU - Schalkwijk, S.J. AU - Feiterna-Sperling, C. AU - Weizsacker, K. AU - Colbers, A. AU - Buhrer, C. AU - Greupink, R. AU - Russel, F.G.M. AU - Burger, D.M. PY - 2016 UR - https://hdl.handle.net/2066/170835 TI - Substantially lowered dolutegravir exposure in a treatment-experienced perinatally HIV-1-infected pregnant woman EP - 2001 SN - 0269-9370 IS - iss. 12 SP - 1999 JF - Aids VL - vol. 30 DO - https://doi.org/10.1097/QAD.0000000000001123 ER - TY - JOUR AU - Schalkwijk, S.J. AU - Colbers, A. AU - Konopnicki, D. AU - Greupink, R. AU - Russel, F.G. AU - Burger, D.M. PY - 2016 UR - https://hdl.handle.net/2066/170842 TI - First reported use of elvitegravir and cobicistat during pregnancy EP - 808 SN - 0269-9370 IS - iss. 5 SP - 807 JF - Aids VL - vol. 30 DO - https://doi.org/10.1097/QAD.0000000000000976 ER - TY - GEN AU - Huuskonen, A. AU - Kurri, M. AU - Holleman, I. PY - 2016 UR - https://hdl.handle.net/2066/159706 AB - This dataset contains the underlying data that are used in the figures of the article 'Improved analysis of solar signals for differential reflectivity monitoring' published in Atmospheric Measurement Techniques. The Finnish Meteorological Institute (FMI) operates a network of 10 C-band Doppler weather radars, of which nine radars are polarimetric. Every 15 min the radars perform a 30 12-elevation volume scan between 0.3 and 45◦ elevations, where 6 elevations up to 9◦ are scanned in single–PRF with 570 Hz, and then 6 elevations starting from 2 up to 45◦ in dual–PRF. Every 5 min the first 6 of these 12 elevations are repeated. The dataset contain analyses of so-called 'sunhits' that are detected in the polar volume data produced by the Finnish radars. Datasets are ascii text files where each line represents a datapoint, the content is described in separate 'Readme' files. The data files are best understood when they are read alongside the accompanying article by Huuskonen, Kurri, and Holleman entitled "Improved analysis of solar signals for differential reflectivity monitoring" in Atmos. Meas. Tech., 9, 3183-3192, 2016 (doi:10.5194/amt-9-3183-2016). PB - DANS EASY TI - Improved analysis of solar signals for differential reflectivity monitoring DO - https://doi.org/10.17026/dans-zrx-jyjt ER - TY - JOUR AU - Brand, J.A. van den AU - Mutsaers, H.A. AU - Zuilen, A.D. van AU - Blankestijn, P.J. AU - Broek, P.H.H. van den AU - Russel, F.G.M. AU - Masereeuw, R. AU - Wetzels, J.F.M. PY - 2016 UR - https://hdl.handle.net/2066/170838 AB - BACKGROUND: To date, over 150 possible uremic solutes have been listed, but their role in the progression of CKD is largely unknown. Here, the association between a selected panel of uremic solutes and progression in CKD patients was investigated. METHODS: Patients from the MASTERPLAN study, a randomized controlled trial in CKD patients with a creatinine clearance between 20 and 70 ml/min per 1.73m2, were selected based on their rate of eGFR decline during the first five years of follow-up. They were categorized as rapid (decline >5 ml/min per year) or slow progressors. Concentrations of eleven uremic solutes were obtained at baseline and after one year of follow-up. Logistic regression was used to compare the odds for rapid to slow progression by uremic solute concentrations at baseline. Variability in uremic solute levels was assessed using scatter plots, and limits of variability were calculated. RESULTS: In total, 40 rapidly and 40 slowly progressing patients were included. Uremic solutes were elevated in all patients compared to reference values for healthy persons. The serum levels of uremic solutes were not associated with rapid progression. Moreover, we observed substantial variability in solute levels over time. CONCLUSIONS: Elevated concentrations of uremic solutes measured in this study did not explain differences in rate of eGFR decline in CKD patients, possibly due to lack of power as a result of the small sample size, substantial between patient variability, and variability in solute concentrations over time. The etiology of intra-individual variation in uremic solute levels remains to be elucidated. TI - Uremic Solutes in Chronic Kidney Disease and Their Role in Progression SN - 1932-6203 IS - iss. 12 JF - PLoS One VL - vol. 11 DO - https://doi.org/10.1371/journal.pone.0168117 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/170838/170838.pdf?sequence=1 ER - TY - JOUR AU - El Messaoudi, S. AU - Russel, F.G. AU - Colbers, A. AU - Bandell, C.C. AU - Broek, P.H.H. van den AU - Burger, D.M. AU - Rongen, G.A. AU - Riksen, N.P. PY - 2016 UR - https://hdl.handle.net/2066/170836 AB - PURPOSE: Concomitant treatment with the glucose-lowering drug metformin and the platelet aggregation inhibitor dipyridamole often occurs in patients with type 2 diabetes mellitus who have suffered a cerebrovascular event. The gastrointestinal uptake of metformin is mediated by the human equilibrative nucleoside transporter 4 (ENT4), which is inhibited by dipyridamole in preclinical studies. We hypothesized that dipyridamole lowers the plasma exposure to metformin. METHODS: Eighteen healthy volunteers (mean age 23 years; 9 male) were randomized in an open-label crossover study. Subjects were allocated to treatment with metformin 500 mg twice daily in combination with dipyridamole slow-release 200 mg twice daily or to metformin alone for 4 days. After a washout period of 10 days, the volunteers were crossed over to the alternative treatment arm. Blood samples were collected during a 10-h period after intake of the last metformin dose. The primary endpoint was the area under the plasma concentration-time curve (AUC0-12h) and the maximum plasma metformin concentration (C max). RESULTS: In healthy subjects, dipyridamole did not significantly affect Cmax nor AUC0-12h of metformin under steady-state conditions. CONCLUSIONS: Previous in vitro studies report that dipyridamole inhibits the ENT4 transporter that mediates gastrointestinal uptake of metformin. In contrast, co-administration of dipyridamole at therapeutic dosages to healthy volunteers does not have a clinically relevant effect on metformin plasma steady-state exposure. This observation is reassuring for patients who are treated with this combination of drugs. TI - The effect of dipyridamole on the pharmacokinetics of metformin: a randomized crossover study in healthy volunteers EP - 730 SN - 0031-6970 IS - iss. 6 SP - 725 JF - European Journal of Clinical Pharmacology VL - vol. 72 DO - https://doi.org/10.1007/s00228-016-2039-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/170836/170836.pdf?sequence=1 ER - TY - JOUR AU - Garsen, M. AU - Rops, L.W.M.M. AU - Dijkman, H.B. AU - Willemsen, B.K. AU - Kuppevelt, T.H. van AU - Russel, F.G.M. AU - Rabelink, T.J. AU - Berden, J.H. AU - Reinheckel, T. AU - Vlag, J. van der PY - 2016 UR - https://hdl.handle.net/2066/170839 AB - Proteinuria is one of the first clinical signs of diabetic nephropathy and an independent predictor for the progression to renal failure. Cathepsin L, a lysosomal cysteine protease, can be involved in the development of proteinuria by degradation of proteins that are important for normal podocyte architecture, such as the CD2-associated protein, synaptopodin, and dynamin. Cathepsin L also activates heparanase, a heparan sulfate endoglycosidase previously shown to be crucial for the development of diabetic nephropathy. Here, we evaluated the exact mode of action of cathepsin L in the development of proteinuria in streptozotocin-induced diabetes. Cathepsin L-deficient mice, in contrast to their wild-type littermates, failed to develop albuminuria, mesangial matrix expansion, tubulointerstitial fibrosis, and renal macrophage influx and showed a normal renal function. In wild-type mice the early development of albuminuria correlated with the activation of heparanase and loss of heparan sulfate expression, whereas loss of synaptopodin expression and podocyte damage occurred at a later stage. Thus, cathepsin L is causally involved in the pathogenesis of experimental diabetic nephropathy. Most likely, cathepsin L-dependent heparanase activation is crucial for the development of albuminuria and renal damage. TI - Cathepsin L is crucial for the development of early experimental diabetic nephropathy EP - 1022 SN - 2157-1724 IS - iss. 5 SP - 1012 JF - Kidney International. Supplement VL - vol. 90 DO - https://doi.org/10.1016/j.kint.2016.06.035 ER - TY - JOUR AU - Rijpma, S.R. AU - Velden, M. van der AU - Annoura, T. AU - Matz, J.M. AU - Kenthirapalan, S. AU - Kooij, T.W. AU - Matuschewski, K. AU - Gemert, G.J.A. van AU - Vegte-Bolmer, M.G. van de AU - Siebelink-Stoter, R. AU - Graumans, W. AU - Ramesar, J. AU - Klop, O. AU - Russel, F.G. AU - Sauerwein, R.W. AU - Janse, C.J. AU - Franke-Fayard, B.M. AU - Koenderink, J.B. PY - 2016 UR - https://hdl.handle.net/2066/170840 AB - Multidrug resistance (MDR) proteins belong to the B subfamily of the ATP Binding Cassette (ABC) transporters, which export a wide range of compounds including pharmaceuticals. In this study, we used reverse genetics to study the role of all seven Plasmodium MDR proteins during the life cycle of malaria parasites. Four P. berghei genes (encoding MDR1, 4, 6 and 7) were refractory to deletion, indicating a vital role during blood stage multiplication and validating them as potential targets for antimalarial drugs. Mutants lacking expression of MDR2, MDR3 and MDR5 were generated in both P. berghei and P. falciparum, indicating a dispensable role for blood stage development. Whereas P. berghei mutants lacking MDR3 and MDR5 had a reduced blood stage multiplication in vivo, blood stage growth of P. falciparum mutants in vitro was not significantly different. Oocyst maturation and sporozoite formation in Plasmodium mutants lacking MDR2 or MDR5 was reduced. Sporozoites of these P. berghei mutants were capable of infecting mice and life cycle completion, indicating the absence of vital roles during liver stage development. Our results demonstrate vital and dispensable roles of MDR proteins during blood stages and an important function in sporogony for MDR2 and MDR5 in both Plasmodium species. TI - Vital and dispensable roles of Plasmodium multidrug resistance transporters during blood- and mosquito-stage development EP - 91 SN - 0950-382X IS - iss. 1 SP - 78 JF - Molecular Microbiology VL - vol. 101 DO - https://doi.org/10.1111/mmi.13373 ER - TY - JOUR AU - Rijpma, S.R. AU - Velden, M. van der AU - Gonzalez-Pons, M. AU - Annoura, T. AU - Schaijk, B.C.L. van AU - Gemert, G.J.A. van AU - Heuvel, J.M.W. van den AU - Ramesar, J. AU - Chevalley-Maurel, S. AU - Ploemen, I.H. AU - Khan, S.M. AU - Franetich, J.F. AU - Mazier, D. AU - Wilt, J.H.W. de AU - Serrano, A.E. AU - Russel, F.G. AU - Janse, C.J. AU - Sauerwein, R.W. AU - Koenderink, J.B. AU - Franke-Fayard, B.M. PY - 2016 UR - https://hdl.handle.net/2066/170829 AB - Multidrug resistance-associated proteins (MRPs) belong to the C-family of ATP-binding cassette (ABC) transport proteins and are known to transport a variety of physiologically important compounds and to be involved in the extrusion of pharmaceuticals. Rodent malaria parasites encode a single ABC transporter subfamily C protein, whereas human parasites encode two: MRP1 and MRP2. Although associated with drug resistance, their biological function and substrates remain unknown. To elucidate the role of MRP throughout the parasite life cycle, Plasmodium berghei and Plasmodium falciparum mutants lacking MRP expression were generated. P. berghei mutants lacking expression of the single MRP as well as P. falciparum mutants lacking MRP1, MRP2 or both proteins have similar blood stage growth kinetics and drug-sensitivity profiles as wild type parasites. We show that MRP1-deficient parasites readily invade primary human hepatocytes and develop into mature liver stages. In contrast, both P. falciparum MRP2-deficient parasites and P. berghei mutants lacking MRP protein expression abort in mid to late liver stage development, failing to produce mature liver stages. The combined P. berghei and P. falciparum data are the first demonstration of a critical role of an ABC transporter during Plasmodium liver stage development. TI - Multidrug ATP-binding cassette transporters are essential for hepatic development of Plasmodium sporozoites EP - 383 SN - 1462-5814 IS - iss. 3 SP - 369 JF - Cellular Microbiology VL - vol. 18 DO - https://doi.org/10.1111/cmi.12517 ER - TY - JOUR AU - Velden, M van der AU - Rijpma, S.R. AU - Verweij, V. AU - Gemert, G.J.A. van AU - Chevalley-Maurel, S. AU - Vegte-Bolmer, M. van de AU - Franke-Fayard, B.M. AU - Russel, F.G.M. AU - Janse, C.J. AU - Sauerwein, R.W. AU - Koenderink, J.B. PY - 2016 UR - https://hdl.handle.net/2066/170833 AB - Whole parasite immunization strategies employing genetically attenuated parasites (GAP), which arrest during liver-stage development, have been applied successfully for induction of sterile malaria protection in rodents. Recently, we generated a Plasmodium berghei GAP-lacking expression of multidrug resistance-associated protein (MRP2) (PbDeltamrp2) that was capable of partial schizogony in hepatocytes but showed complete growth arrest. Here, we investigated the protective efficacy after intravenous (IV) immunization of BALB/c and C57BL/6J mice with PbDeltamrp2 sporozoites. Low-dose immunization using 400 PbDeltamrp2 sporozoites induced 100% sterile protection in BALB/c mice after IV challenge with 10,000 wild-type sporozoites. In addition, almost full protection (90%) was obtained after three immunizations with 10,000 sporozoites in C57BL/6J mice. Parasite liver loads in nonprotected PbDeltamrp2-challenged C57BL/6J mice were reduced by 86% +/- 5% on average compared with naive control mice. The mid-to-late arresting PbDeltamrp2 GAP was equipotent in induction of protective immunity to the early arresting PbDeltab9Deltaslarp GAP. The combined data support a clear basis for further exploration of Plasmodium falciparum parasites lacking mrp2 as a suitable GAP vaccine candidate. TI - Protective Efficacy Induced by Genetically Attenuated Mid-to-Late Liver-Stage Arresting Plasmodium berghei Deltamrp2 Parasites EP - 382 SN - 0002-9637 IS - iss. 2 SP - 378 JF - American Journal of Tropical Medicine and Hygiene VL - vol. 95 DO - https://doi.org/10.4269/ajtmh.16-0226 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/170833/170833.pdf?sequence=1 ER - TY - JOUR AU - Rijpma, S.R. AU - Velden, M. van der AU - Bilos, A. AU - Jansen, R.S. AU - Mahakena, S. AU - Russel, F.G. AU - Sauerwein, R.W. AU - Wetering, K. van de AU - Koenderink, J.B. PY - 2016 UR - https://hdl.handle.net/2066/170847 AB - Multidrug resistance-associated proteins (MRP) of Plasmodium falciparum have been associated with altered drug sensitivity. Knowledge on MRP substrate specificity is indispensible for the characterization of resistance mechanisms and identifying its physiological roles. An untargeted metabolomics approach detected decreased folate concentrations in red blood cells infected with schizont stage parasites lacking expression of MRP1. Furthermore, a tenfold decrease in sensitivity toward the folate analog methotrexate was detected for parasites lacking MRP1. PfMRP1 is involved in the export of folate from parasites into red blood cells and is therefore a relevant factor for efficient malaria treatment through the folate pathway. TI - MRP1 mediates folate transport and antifolate sensitivity in Plasmodium falciparum EP - 492 SN - 1873-3468 IS - iss. 4 SP - 482 JF - FEBS Letters VL - vol. 590 DO - https://doi.org/10.1002/1873-3468.12079 ER - TY - JOUR AU - Haas, R. de AU - Russel, F.G. AU - Smeitink, J.A. PY - 2016 UR - https://hdl.handle.net/2066/170843 AB - Leigh disease (LD) is one of the clinical phenotypes of mitochondrial OXPHOS disorders and also known as sub-acute necrotizing encephalomyelopathy. The disease has an incidence of 1 in 77,000 live births. Symptoms typically begin early in life and prognosis for LD patients is poor. Currently, no clinically effective treatments are available. Suitable animal and cellular models are necessary for the understanding of the neuropathology and the development of successful new therapeutic strategies. In this study we used the Ndufs4 knockout (Ndufs4(-/-)) mouse, a model of mitochondrial complex I deficiency. Ndusf4(-/-) mice exhibit progressive neurodegeneration, which closely resemble the human LD phenotype. When dissecting behavioral abnormalities in animal models it is of great importance to apply translational tools that are clinically relevant. To distinguish gait abnormalities in patients, simple walking tests can be assessed, but in animals this is not easy. This study is the first to demonstrate automated CatWalk gait analysis in the Ndufs4(-/-) mouse model. Marked differences were noted between Ndufs4(-/-) and control mice in dynamic, static, coordination and support parameters. Variation of walking speed was significantly increased in Ndufs4(-/-) mice, suggesting hampered and uncoordinated gait. Furthermore, decreased regularity index, increased base of support and changes in support were noted in the Ndufs4(-/-) mice. Here, we report the ability of the CatWalk system to sensitively assess gait abnormalities in Ndufs4(-/-) mice. This objective gait analysis can be of great value for intervention and drug efficacy studies in animal models for mitochondrial disease. TI - Gait analysis in a mouse model resembling Leigh disease EP - 198 SN - 0166-4328 SP - 191 JF - Behavioural Brain Research VL - vol. 296 DO - https://doi.org/10.1016/j.bbr.2015.09.006 ER - TY - JOUR AU - Wilke, J. AU - Wilke, M. AU - Brand, C. van den AU - Meerts, W.L. AU - Schmitt, M. PY - 2016 UR - https://hdl.handle.net/2066/161416 TI - On the Additivity of Molecular Fragment Dipole Moments of 5-Substituted Indole Derivatives EP - 2743 SN - 1439-4235 IS - iss. 17 SP - 2736 JF - Chemphyschem VL - vol. 17 DO - http://dx.doi.org/10.1002/cphc.201600420 ER - TY - JOUR AU - Burnell, E.E. AU - de Lange, C.A. AU - Meerts, W.L. PY - 2016 UR - https://hdl.handle.net/2066/161388 TI - Communication: Molecular gears EP - 10 SN - 0021-9606 IS - iss. 9 SP - 5 JF - Journal of Chemical Physics VL - vol. 145 DO - https://doi.org/10.1063/1.4962221 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/161388/161388.pdf?sequence=1 ER - TY - JOUR AU - Wilke, J. AU - Wilke, M. AU - Meerts, W.L. AU - Schmitt, M. PY - 2016 UR - https://hdl.handle.net/2066/156895 TI - Determination of ground and excited state dipole moments via electronic Stark spectroscopy: 5-methoxyindole EP - 19 SN - 0021-9606 IS - iss. 4 SP - 10 JF - Journal of Chemical Physics VL - vol. 144 DO - https://doi.org/10.1063/1.4940689 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/156895/156895.pdf?sequence=1 ER - TY - JOUR AU - Brake, L.H. te AU - Russel, F.G. AU - Heuvel, J.J.T.M. AU - Knegt, G.J. de AU - Steenwinkel, J.E. de AU - Burger, D.M. AU - Aarnoutse, R.E. AU - Koenderink, J.B. PY - 2016 UR - https://hdl.handle.net/2066/167529 AB - BACKGROUND: Multiple-drug therapy for tuberculosis (TB) and TB-associated co-morbidity increase the likelihood of drug-drug interactions (DDIs). Inhibition of membrane transporters is an important mechanism underlying DDIs. In this study, we assessed the in vitro inhibitory potential of currently used first and second-line TB drugs and of proposed mycobacterial efflux pump inhibitors (EPIs) on the major ABC transporters relevant to drug transport, namely P-gp, BCRP, BSEP and MRP1-5. METHODS: Membrane vesicles isolated from transporter-overexpressing HEK293 cells were used to study the inhibitory action of TB drugs and EPIs on the transport of model substrates [(3)H]-NMQ (P-gp); [(3)H]-E1S (BCRP); [(3)H]-TCA (BSEP); [(3)H]-E217betaG (MRP1, 3 and 4) and [(3)H]-MTX (MRP2 and 5). RESULTS: A strong inhibition (IC50 value <15 muM) was observed for clofazimine (P-gp, BCRP and MRP1), thioridazine (BCRP), timcodar (P-gp, BSEP and MRP1) and SQ109 (P-gp and BCRP). Rifampicin inhibited all transporters, but less potently. CONCLUSIONS: Co-administration of clofazimine, thioridazine, timcodar, SQ109 and possibly rifampicin with drugs that are substrates for the inhibited transporters may lead to DDIs. The mycobacterial EPIs potently inhibited a wider range of human ABC transporters than previously reported. These vesicular transport data are especially valuable considering the current emphasis on development of TB drug regimens. TI - Inhibitory potential of tuberculosis drugs on ATP-binding cassette drug transporters EP - 157 SN - 1472-9792 SP - 150 JF - Tuberculosis VL - vol. 96 DO - https://doi.org/10.1016/j.tube.2015.08.004 ER - TY - JOUR AU - Brake, L.H.M. te AU - Heuvel, J.M.W. van den AU - Buaben, A.O. AU - Crevel, R. van AU - Bilos, A. AU - Russel, F.G. AU - Aarnoutse, R.E. AU - Koenderink, J.B. PY - 2016 UR - https://hdl.handle.net/2066/167530 AB - It is largely unknown if simultaneous administration of tuberculosis (TB) drugs and metformin leads to drug-drug interactions (DDIs). Disposition of metformin is determined by organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs). Thus, any DDIs would primarily be mediated via these transporters. This study aimed to assess the in vitro inhibitory effects of TB drugs (rifampin, isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin, and linezolid) on metformin transport and whether TB drugs are also substrates themselves of OCTs and MATEs. HEK293 cells overexpressing OCT1, OCT2, OCT3, MATE1, and MATE2K were used to study TB drug-mediated inhibition of [14C]metformin uptake and to test if TB drugs are transporter substrates. Metformin uptake was determined by quantifying [14C]metformin radioactivity, and TB drug uptake was analyzed using liquid chromatography-tandem mass spectrometry. DDI indices were calculated (plasma maximum concentrations [Cmax]/50% inhibitory concentrations [IC50]), and based on the literature, a cutoff of >0.1 was assumed to warrant further in vivo investigation. Moxifloxacin was the only TB drug identified as a potent inhibitor (DDI index of >0.1) of MATE1- and MATE2K-mediated metformin transport, with IC50s of 12 muM (95% confidence intervals [CI], 5.1 to 29 muM) and 7.6 muM (95% CI, 0.2 to 242 muM), respectively. Of all TB drugs, only ethambutol appeared to be a substrate of OCT1, OCT2, OCT3, MATE1, and MATE2K. MATE1-mediated ethambutol uptake was inhibited strongly (DDI index of >0.1) by moxifloxacin (IC50, 12 muM [95% CI, 3.4 to 43 muM]). Our findings provide a mechanistic basis for DDI predictions concerning ethambutol. According to international guidelines, an in vivo interaction study is warranted for the observed in vitro interaction between ethambutol and moxifloxacin. TI - Moxifloxacin Is a Potent In Vitro Inhibitor of OCT- and MATE-Mediated Transport of Metformin and Ethambutol EP - 7114 SN - 0066-4804 IS - iss. 12 SP - 7105 JF - Antimicrobial Agents and Chemotherapy VL - vol. 60 DO - https://doi.org/10.1128/AAC.01471-16 ER - TY - JOUR AU - Lempers, V.J. AU - Heuvel, J.J.M.W. van den AU - Russel, F.G. AU - Aarnoutse, R.E. AU - Burger, D.M. AU - Bruggemann, R.J. AU - Koenderink, J.B. PY - 2016 UR - https://hdl.handle.net/2066/170845 AB - Inhibition of ABC transporters is a common mechanism underlying drug-drug interactions (DDIs). We determined the inhibitory potential of antifungal drugs currently used for invasive fungal infections on ABC transporters P-glycoprotein (P-gp), MRP1 to MRP5, BCRP, and BSEP in vitro Membrane vesicles isolated from transporter-overexpressing HEK 293 cells were used to investigate the inhibitory potential of antifungal drugs (250 muM) on transport of model substrates. Concentration-inhibition curves were determined if transport inhibition was >60%. Fifty percent inhibitory concentrations (IC50s) for P-gp and BCRP were both 2 muM for itraconazole, 5 and 12 muM for hydroxyitraconazole, 3 and 6 muM for posaconazole, and 3 and 11 muM for isavuconazole, respectively. BSEP was strongly inhibited by itraconazole and hydroxyitraconazole (3 and 17 muM, respectively). Fluconazole and voriconazole did not inhibit any transport for >60%. Micafungin uniquely inhibited all transporters, with strong inhibition of MRP4 (4 muM). Anidulafungin and caspofungin showed strong inhibition of BCRP (7 and 6 muM, respectively). Amphotericin B only weakly inhibited BCRP-mediated transport (127 muM). Despite their wide range of DDIs, azole antifungals exhibit selective inhibition on efflux transporters. Although echinocandins display low potential for clinically relevant DDIs, they demonstrate potent in vitro inhibitory activity. This suggests that inhibition of ABC transporters plays a crucial role in the inexplicable (non-cytochrome P450-mediated) DDIs with antifungal drugs. TI - Inhibitory Potential of Antifungal Drugs on ATP-Binding Cassette Transporters P-Glycoprotein, MRP1 to MRP5, BCRP, and BSEP EP - 3379 SN - 0066-4804 IS - iss. 6 SP - 3372 JF - Antimicrobial Agents and Chemotherapy VL - vol. 60 DO - https://doi.org/10.1128/AAC.02931-15 ER - TY - JOUR AU - Burnell, E.E. AU - Weber, A.C.J. AU - Dong, R.Y. AU - Meerts, W.L. AU - Lange, C.A. de PY - 2015 UR - https://hdl.handle.net/2066/140115 TI - A model-free temperature-dependent conformational study of n-pentane in nematic liquid crystals SN - 0021-9606 IS - iss. 2 JF - Journal of Chemical Physics VL - vol. 142 DO - http://dx.doi.org/10.1063/1.4904822 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/140115/140115.pdf?sequence=1 ER - TY - JOUR AU - Burnell, E.E. AU - Weber, A.C.J. AU - Dong, R.Y. AU - Meerts, W.L. AU - Lange, C.A. de PY - 2015 UR - https://hdl.handle.net/2066/149476 TI - A model-free temperature-dependent conformational study of n-pentane in nematic liquid crystals (vol 142, 024904, 2015) SN - 0021-9606 IS - iss. 8 JF - Journal of Chemical Physics VL - vol. 142 DO - http://dx.doi.org/10.1063/1.4913425 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/149476/149476.pdf?sequence=1 ER - TY - JOUR AU - Weber, A.C.J. AU - Burnell, E.E. AU - Meerts, W.L. AU - Lange, C.A. de AU - Dong, R.Y. AU - Muccioli, L. AU - Pizzirusso, A. AU - Zannoni, C. PY - 2015 UR - https://hdl.handle.net/2066/144918 TI - Communication: Molecular dynamics and H-1 NMR of n-hexane in liquid crystals SN - 0021-9606 IS - iss. 1 JF - Journal of Chemical Physics VL - vol. 143 DO - http://dx.doi.org/10.1063/1.4923253 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/144918/144918.pdf?sequence=1 ER - TY - JOUR AU - Wijngaarden, J. van AU - Desmond, D. AU - Meerts, W.L. PY - 2015 UR - https://hdl.handle.net/2066/144985 TI - Analysis of high resolution FTIR spectra from synchrotron sources using evolutionary algorithms EP - 113 SN - 0022-2852 SP - 107 JF - Journal of Molecular Spectroscopy VL - vol. 315 DO - https://doi.org/10.1016/j.jms.2015.04.002 ER - TY - JOUR AU - Schirris, T.J.J. AU - Ritschel, T. AU - Bilos, A. AU - Smeitink, J. AU - Russel, F.G.M. PY - 2015 UR - https://hdl.handle.net/2066/152742 AB - Statins are cholesterol-lowering drugs that have proven to be effective in lowering the risk of major cardiovascular events. Although well tolerated, statin-induced myopathies are the most common side effects. Compared to their pharmacologically active acid form, statin lactones are more potent inducers of toxicity. They can be formed by glucuronidation mediated by uridine 5'-diphospho-glucuronosyltransferases (UGTs), but a systematic characterization of subtype specificity and kinetics of lactonization is lacking. Here, we demonstrate for six clinically relevant statins that only UGT1A1, 1A3, and 2B7 contribute significantly to their lactonization. UGT1A3 appeared to have the highest lactonization capacity with marked differences in statin conversion rates: pitavastatin >> atorvastatin > cerivastatin > lovastatin > rosuvastatin (simvastatin not converted). Using in silico modeling we could identify a probable statin interaction region in the UGT binding pocket. Polymorphisms in these regions of UGT1A1, 1A3, and 2B7 may be a contributing factor in statin-induced myopathies, which could be used in personalization of statin therapy with improved safety. TI - Statin Lactonization by Uridine 5'-Diphospho-glucuronosyltransferases (UGTs) EP - 4055 SN - 1543-8384 IS - iss. 11 SP - 4048 JF - Molecular Pharmaceutics VL - vol. 12 DO - https://doi.org/10.1021/acs.molpharmaceut.5b00474 ER - TY - JOUR AU - Schirris, T.J.J. AU - Ritschel, T. AU - Renkema, G.H. AU - Willems, P.H. AU - Smeitink, J. AU - Russel, F.G. PY - 2015 UR - https://hdl.handle.net/2066/153404 AB - Cannabinoid receptor 1 (CB1R) antagonists appear to be promising drugs for the treatment of obesity, however, serious side effects have hampered their clinical application. Rimonabant, the first in class CB1R antagonist, was withdrawn from the market because of psychiatric side effects. This has led to the search for more peripherally restricted CB1R antagonists, one of which is ibipinabant. However, this 3,4-diarylpyrazoline derivative showed muscle toxicity in a pre-clinical dog study with mitochondrial dysfunction. Here, we studied the molecular mechanism by which ibipinabant induces mitochondrial toxicity. We observed a strong cytotoxic potency of ibipinabant in C2C12 myoblasts. Functional characterization of mitochondria revealed increased cellular reactive oxygen species generation and a decreased ATP production capacity, without effects on the catalytic activities of mitochondrial enzyme complexes I-V or the complex specific-driven oxygen consumption. Using in silico off-target prediction modelling, combined with in vitro validation in isolated mitochondria and mitoplasts, we identified adenine nucleotide translocase (ANT)-dependent mitochondrial ADP/ATP exchange as a novel molecular mechanism underlying ibipinabant-induced toxicity. Minor structural modification of ibipinabant could abolish ANT inhibition leading to a decreased cytotoxic potency, as observed with the ibipinabant derivative CB23. Our results will be instrumental in the development of new types of safer CB1R antagonists. TI - Mitochondrial ADP/ATP exchange inhibition: a novel off-target mechanism underlying ibipinabant-induced myotoxicity SN - 2045-2322 JF - Scientific Reports VL - vol. 5 DO - https://doi.org/10.1038/srep14533 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153404/153404.pdf?sequence=1 ER - TY - JOUR AU - Poppel, P.C.M. van AU - Breedveld, P. AU - Abbink, E.J. AU - Roelofs, H. AU - Heerde, W.L. van AU - Smits, P. AU - Lin, W. AU - Tan, A.H. AU - Russel, F.G.M. AU - Donders, R. AU - Tack, C.J.J. AU - Rongen, G.A.P.J.M. PY - 2015 UR - https://hdl.handle.net/2066/153925 TI - Salvia Miltiorrhiza Root Water-Extract (Danshen) Has No Beneficial Effect on Cardiovascular Risk Factors. A Randomized Double-Blind Cross-Over Trial SN - 1932-6203 IS - iss. 7 JF - PLoS One VL - vol. 10 DO - https://doi.org/10.1371/journal.pone.0128695 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/153925/153925.PDF?sequence=1 ER - TY - JOUR AU - Biesterbos, J.W.H. AU - Beckmann, G. AU - Wel, L. van AU - Anzion, R.B.M. AU - Goetz, N. von AU - Dudzina, T. AU - Roeleveld, N. AU - Ragas, A.M.J. AU - Russel, F.G.M. AU - Scheepers, P.T.J. AU - Anzion, R.B. AU - Russel, F.G. PY - 2015 UR - https://hdl.handle.net/2066/140057 AB - Consumers who use personal care products (PCPs) are internally exposed to some of the organic components present of which some may be detected in exhaled air when eliminated. The aim of this study was the quantitative determination of octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) in end-exhaled air to study dermal absorption of substances in PCPs. We exposed the forearm of fifteen healthy volunteers for 60min to pure D4 or D5 and to commercial products containing D4 and D5. Inhalation uptake was kept to a minimum by keeping the forearm in a flow cabinet during dermal exposure and supplying filtered air to the breathing zone of the volunteer during the post-exposure period. End-exhaled air was collected using a breath sampler (Bio-VOC), transferred to carbograph multi-bed adsorbent tubes and analyzed by thermal desorption gas chromatography mass spectrometry (TD-GC-MS). In the end-exhaled air of non-exposed volunteers background concentrations of D4 (0.8-3.5ng/L) and D5 (0.8-4.0ng/L) were observed. After exposing the volunteers, the level of D4 and D5 in end-exhaled air did not or barely exceed background concentrations. At t=90min, a sharp increase of the D4/D5 concentration in end-exhaled air was observed, which we attributed to the inhalation of the substances during a toilet visit without using inhalation protection devices. When this visit was taken out of the protocol, the sharp increase disappeared. Overall, the results of our study indicate that dermal absorption of D4 and D5 contributes only marginally to internal exposure following dermal applications. As in our study inhalation is the primary route of entry for these compounds, we conclude that its risk assessment should focus on this particular exposure route. TI - Aggregate dermal exposure to cyclic siloxanes in personal care products: Implications for risk assessment TI - Aggregate dermal exposure to cyclic siloxanes in personal care products: implications for risk assessment EP - 239 SN - 0160-4120 SP - 231 JF - Environment International VL - vol. 74 DO - https://doi.org/10.1016/j.envint.2014.10.017 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/140057/140057pos.pdf?sequence=3 ER - TY - JOUR AU - Huuskonen, A. AU - Kurri, M. AU - Hohti, H. AU - Beekhuis, H. AU - Leijnse, H. AU - Holleman, I. PY - 2014 UR - https://hdl.handle.net/2066/135848 TI - Radar Performance Monitoring Using the Angular Width of the Solar Image EP - 1712 SN - 0739-0572 IS - iss. 8 SP - 1704 JF - Journal of Atmospheric and Oceanic Technology VL - vol. 31 DO - http://dx.doi.org/10.1175/JTECH-D-13-00246.1 ER - TY - JOUR AU - Huuskonen, A. AU - Saltikoff, E. AU - Holleman, I. PY - 2014 UR - https://hdl.handle.net/2066/135854 TI - The Operational Weather Radar Network in Europe EP - 907 SN - 0003-0007 IS - iss. 6 SP - 897 JF - Bulletin of the American Meteorological Society VL - vol. 95 DO - http://dx.doi.org/10.1175/BAMS-D-12-00216.1 ER - TY - JOUR AU - El-Sheikh, A.A.K. AU - Koenderink, J.B. AU - Wouterse, A.C. AU - Broek, P.H.H. van den AU - Verweij, V.G.M. AU - Masereeuw, R. AU - Russel, F.G. PY - 2014 UR - https://hdl.handle.net/2066/136697 AB - Mycophenolic acid (MPA) is an immunosuppressant used in transplant rejection, often in combination with cyclosporine (CsA) and tacrolimus (Tac). The drug is cleared predominantly via the kidneys, and 95% of the administered dose appears in urine as 7-hydroxy mycophenolic acid glucuronide (MPAG). The current study was designed to unravel the renal excretory pathway of MPA and MPAG, and their potential drug-drug interactions. The role of multidrug resistance protein (MRP) 2 and MRP4 in MPA disposition was studied using human embryonic kidney 293 (HEK293) cells overexpressing the human transporters, and in isolated, perfused kidneys of Mrp2-deficient rats and Mrp4-deficient mice. Using these models, we identified MPA as substrate of MRP2 and MRP4, whereas its MPAG appeared to be a substrate of MRP2 only. CsA inhibited MPAG transport via MRP2 for 50% at 8 muM (P < 0.05), whereas Tac had no effect. This was confirmed by cell survival assays, showing a 10-fold increase in MPA cytotoxicity (50% reduction in cell survival changed from 12.2 +/- 0.3 muM to 1.33 +/- 0.01 muM by MPA + CsA; P < 0.001) and in perfused kidneys, showing a 50% reduction in MPAG excretion (P < 0.05). The latter effect was observed in Mrp2-deficient animals as well, supporting the importance of Mrp2 in MPAG excretion. CsA, but not Tac, inhibited MPA glucuronidation by rat kidney homogenate and human uridine 5'-diphospho-glucuronosyltransferase-glucuronosyltransferase 1A9 (P < 0.05 and P < 0.01, respectively). We conclude that MPA is a substrate of both MRP2 and MRP4, but MRP2 is the main transporter involved in renal MPAG excretion. In conclusion, CsA, but not Tac, influences MPA clearance by inhibiting renal MPA glucuronidation and MRP2-mediated MPAG secretion. TI - Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid: interaction with cyclosporine and tacrolimus EP - 56 SN - 1931-5244 IS - iss. 1 SP - 46 JF - Translational Research VL - vol. 164 DO - http://dx.doi.org/10.1016/j.trsl.2014.01.006 ER - TY - JOUR AU - Swelm, R.P.L. van AU - Kramers, C. AU - Masereeuw, R. AU - Russel, F.G.M. PY - 2014 UR - https://hdl.handle.net/2066/138858 TI - Application of urine proteomics for biomarker discovery in drug-induced liver injury EP - 841 SN - 1040-8444 IS - iss. 10 SP - 823 JF - Critical Reviews in Toxicology VL - vol. 44 DO - http://dx.doi.org/10.3109/10408444.2014.931341 ER - TY - JOUR AU - Biesterbos, J.W.H. AU - Beckmann, G. AU - Anzion, R.B.M. AU - Ragas, A.M.J. AU - Russel, F.G. AU - Scheepers, P.T.J. AU - Anzion, R.B. PY - 2014 UR - https://hdl.handle.net/2066/130485 AB - Octamethylcyclotetrasiloxane (D4) and decamethylpentasiloxane (D5) are used as ingredients for personal care products (PCPs). Because of the use of these PCPs, consumers are exposed daily to D4 and D5. A sensitive analytical method was developed for analysis of D4 and D5 in end-exhaled air by thermal desorption gas chromatography mass spectrometry (TD-GC-MS), to determine the internal dose for consumer exposure assessment. Fifteen consumers provided end-exhaled air samples that were collected using Bio-VOC breath samplers and subsequently transferred to automatic thermal desorption (ATD) tubes. Prior to use, the ATD tubes were conditioned for a minimum of 4 h at 350 degrees C. The TD unit and auto sampler were coupled to a GC-MS using electron ionization. Calibration was performed using 0-10 ng/muL solutions of D4/D5 and (13)C-labeled D4/D5 as internal standards. The ions monitored were m/z 281 for D4, 355 for D5, 285 for (13)C-labeled D4, and 360 for (13)C-labeled D5. The addition of internal standard reduced the coefficient of variation from 30.8% to 9.5% for D4 and from 37.8% to 12.5% for D5. The limit of quantification was 2.1 ng/L end-exhaled air for D4 and 1.4 ng/L end-exhaled air for D5. With this method, cyclic siloxanes (D4 and D5) can be quantified in end-exhaled air at concentrations as low as background levels observed in the general population. TI - Sensitive method for quantification of octamethylcyclotetrasiloxane (d4) and decamethylcyclopentasiloxane (d5) in end-exhaled air by thermal desorption gas chromatography mass spectrometry EP - 5799 SN - 0003-2670 IS - iss. 12 SP - 5794 JF - Analytica Chimica Acta VL - vol. 86 PS - 6 p. DO - https://doi.org/10.1021/ac5004695 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/130485/130485.pdf?sequence=1 ER - TY - JOUR AU - Lundvig, D.M.S. AU - Scharstuhl, A. AU - Cremers, N.A.J. AU - Pennings, S.W.C. AU - Paske, J. Te AU - Rheden, R. van AU - Breda, C. van Run-van AU - Regan, R.F. AU - Russel, F.G.M. AU - Carels, C.E.L. AU - Maltha, J.C. AU - Wagener, F.A.D.T.G. PY - 2014 UR - https://hdl.handle.net/2066/137751 AB - Impaired wound healing can lead to scarring, and aesthetical and functional problems. The cytoprotective haem oxygenase (HO) enzymes degrade haem into iron, biliverdin and carbon monoxide. HO-1 deficient mice suffer from chronic inflammatory stress and delayed cutaneous wound healing, while corneal wound healing in HO-2 deficient mice is impaired with exorbitant inflammation and absence of HO-1 expression. This study addresses the role of HO-2 in cutaneous excisional wound healing using HO-2 knockout (KO) mice. Here, we show that HO-2 deficiency also delays cutaneous wound closure compared to WT controls. In addition, we detected reduced collagen deposition and vessel density in the wounds of HO-2 KO mice compared to WT controls. Surprisingly, wound closure in HO-2 KO mice was accompanied by an inflammatory response comparable to WT mice. HO-1 induction in HO-2 deficient skin was also similar to WT controls and may explain this protection against exaggerated cutaneous inflammation but not the delayed wound closure. Proliferation and myofibroblast differentiation were similar in both two genotypes. Next, we screened for candidate genes to explain the observed delayed wound closure, and detected delayed gene and protein expression profiles of the chemokine (C-X-C) ligand-11 (CXCL-11) in wounds of HO-2 KO mice. Abnormal regulation of CXCL-11 has been linked to delayed wound healing and disturbed angiogenesis. However, whether aberrant CXCL-11 expression in HO-2 KO mice is caused by or is causing delayed wound healing needs to be further investigated. TI - Delayed cutaneous wound closure in HO-2 deficient mice despite normal HO-1 expression EP - 2498 SN - 1582-4934 IS - iss. 12 SP - 2488 JF - Journal of Cellular and Molecular Medicine VL - vol. 18 DO - https://doi.org/10.1111/jcmm.12389 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/137751/137751.pdf?sequence=1 ER - TY - JOUR AU - Weber, A.C. AU - Dong, R.Y. AU - Meerts, W.L. AU - Yang, Xuan AU - Burnell, E.E. PY - 2013 UR - https://hdl.handle.net/2066/123845 TI - Nmr of short-chain hydrocarbons in nematic and smectic a liquid crystals EP - 9234 SN - 1089-5639 IS - iss. 38 SP - 9224 JF - The Journal of Physical Chemistry A VL - vol. 117 DO - http://dx.doi.org/10.1021/jp404315t ER - TY - JOUR AU - Grimminck, D.L.A.G. AU - Meerten, B. van AU - Verkuijlen, M.H.W. AU - Eck, E.R.H. van AU - Meerts, W.L. AU - Kentgens, A.P.M. PY - 2013 UR - https://hdl.handle.net/2066/103315 TI - Easy-going deconvolution: Automated mqmas nmr spectrum analysis based on a model with analytical crystallite excitation efficiencies EP - 124 SN - 1090-7807 SP - 116 JF - Journal of Magnetic Resonance VL - vol. 228 DO - http://dx.doi.org/10.1016/j.jmr.2012.12.012 ER - TY - JOUR AU - Grimminck, D.L.A.G. AU - Meerten, B. van AU - Verkuijlen, M.H.W. AU - Eck, E.R.H. van AU - Meerts, W.L. AU - Kentgens, A.P.M. PY - 2013 UR - https://hdl.handle.net/2066/111488 TI - EASY-GOING deconvolution: Automated MQMAS NMR spectrum on a model with analytical crystallite excitation efficiencies EP - 124 SN - 1090-7807 SP - 116 JF - Journal of Magnetic Resonance VL - vol. 228 DO - http://dx.doi.org/10.1016/j.jmr.2012.12.012 ER - TY - JOUR AU - Beusekom, C.D. van AU - Heuvel, J.J.M.W. van den AU - Koenderink, J.B. AU - Schrickx, J.A. AU - Russel, F.G.M. PY - 2013 UR - https://hdl.handle.net/2066/126115 TI - The feline bile salt export pump: a structural and functional comparison with canine and human Bsep/BSEP. SN - 1746-6148 IS - iss. 1 SP - 259 JF - BMC Veterinary Research VL - vol. 9 DO - http://dx.doi.org/10.1186/1746-6148-9-259 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/126115/126115.pdf?sequence=1 ER - TY - JOUR AU - Dokter, A.M. AU - Akesson, S. AU - Beekhuis, H. AU - Bouten, W. AU - Buurma, L. AU - van Gasteren, H. AU - Holleman, I. PY - 2013 UR - https://hdl.handle.net/2066/135817 TI - Twilight ascents by common swifts, Apus apus, at dawn and dusk: acquisition of corientation cues EP - 552 SN - 0003-3472 SP - 545 JF - Animal Behaviour VL - vol. 85 DO - http://dx.doi.org/10.1016/j.anbehav.2012.12.006 ER - TY - JOUR AU - Holleman, I. AU - Huuskonen, A. PY - 2013 UR - https://hdl.handle.net/2066/135815 TI - Analytical formulas for refraction of radiowaves from exoatmospheric sources EP - 231 SN - 0048-6604 SP - 226 JF - Radio Science VL - vol. 48 DO - http://dx.doi.org/10.1002/rds.20030 ER - TY - JOUR AU - Dokter, A.M. AU - Shamoun-Baranes, J. AU - Kemp, M.U. AU - Tijm, S. AU - Holleman, I. PY - 2013 UR - https://hdl.handle.net/2066/135816 TI - High altitude bird migration at temperate latitudes: a synoptic perspective on wind assistance SN - 1932-6203 JF - PLoS One VL - vol. 8 DO - http://dx.doi.org/10.1371/journal.pone.0052300 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/135816/135816.pdf?sequence=1 ER - TY - JOUR AU - Wagener, F.A.D.T.G. AU - Dankers, A.C.A. AU - Summeren, F. van AU - Scharstuhl, A. AU - Heuvel, J.J.M.W. van den AU - Koenderink, J.B. AU - Pennings, S.W.C. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2013 UR - https://hdl.handle.net/2066/111350 AB - Heme is the functional group of diverse hemoproteins and crucial for many cellular processes. However, heme is increasingly recognized as a culprit for a wide variety of pathologies, including sepsis, malaria, and kidney failure. Excess of free heme can be detrimental to tissues by mediating oxidative and inflammatory injury. Protective mechanisms against free heme are therefore pivotal for cellular survival. We postulated that overexpression of Heme Oxygenase-1 (HO-1) and Breast Cancer Resistance Protein (BCRP) would protect against heme-induced cytotoxicity. HO-1 is a heme-degrading enzyme generating carbon monoxide, iron, and biliverdin/bilirubin, while BCRP is a heme efflux transporter. Human embryonic kidney cells were transduced using a baculovirus system as a novel strategy to efficiently overexpress HO-1 and BCRP. Exposing cells to heme resulted in a dose-dependent increase in reactive oxygen species formation, DNA damage and cell death. Heme-induced cell death was significantly attenuated when cells overexpressed HO-1, BCRP, or both. The protective effects of HO-1 overexpression were most pronounced, while co-treatment with the HO-activity inhibitor tin mesoporphyrin reversed these protective effects. Also cells treated with the anti-oxidants N-acetylcysteine or HO-effector molecule bilirubin showed protection against heme insults, which may explain the increased protection by HO-1 compared to BCRP. In conclusion, both HO-1 and BCRP protect against heme-induced toxicity and may thus form novel therapeutic targets for heme-mediated pathologies. TI - Heme Oxygenase-1 and Breast Cancer Resistance Protein Protect Against Heme-induced Toxicity EP - 2707 SN - 1381-6128 IS - iss. 15 SP - 2698 JF - Current Pharmaceutical Design VL - vol. 19 ER - TY - JOUR AU - Gozalpour, E. AU - Wittgen, H.G.M. AU - Heuvel, J.M.W. van den AU - Greupink, R. AU - Russel, F.G.M. AU - Koenderink, J.B. PY - 2013 UR - https://hdl.handle.net/2066/111359 AB - Digitalis-like compounds (DLCs), or cardiac glycosides, are produced and sequestered by certain plants and animals as a protective mechanism against herbivores or predators. Currently, the DLCs digoxin and digitoxin are used in the treatment of cardiac congestion and some types of cardiac arrhythmia, despite a very narrow therapeutic index. P-glycoprotein (P-gp; ABCB1) is the only known ATP-dependent efflux transporter that handles digoxin as a substrate. Ten alanine mutants of human P-gp drug-binding amino acids-Leu(65), Ile(306), Phe(336), Ile(340), Phe(343), Phe(728), Phe(942), Thr(945), Leu(975), and Val(982)-were generated and expressed in HEK293 cells with a mammalian baculovirus system. The uptake of [(3)H]-N-methyl-quinidine (NMQ), the P-gp substrate in vesicular transport assays, was determined. The mutations I306A, F343A, F728A, T945A, and L975A abolished NMQ transport activity of P-gp. For the other mutants, the apparent affinities for six DLCs (cymarin, digitoxin, digoxin, peruvoside, proscillaridin A, and strophanthidol) were determined. The affinities of digoxin, proscillaridin A, peruvoside, and cymarin for mutants F336A and I340A were decreased two- to fourfold compared with wild type, whereas that of digitoxin and strophanthidol did not change. In addition, the presence of a hydroxyl group at position 12beta seems to reduce the apparent affinity when the side chain of Phe(336) and Phe(942) is absent. Our results showed that a delta-lactone ring and a sugar moiety at 3beta of the steroid body are favorable for DLC binding to P-gp. Moreover, DLC inhibition is increased by hydroxyl groups at positions 5beta and 19, whereas inhibition is decreased by those at positions 1beta, 11alpha, 12beta, and 16beta. The understanding of the P-gp-DLC interaction improves our insight into DLCs toxicity and might enhance the replacement of digoxin with other DLCs that have less adverse drug effects. TI - Interaction of digitalis-like compounds with p-glycoprotein EP - 511 SN - 1096-6080 IS - iss. 2 SP - 502 JF - Toxicological Sciences VL - vol. 131 DO - http://dx.doi.org/10.1093/toxsci/kfs307 ER - TY - JOUR AU - Biesterbos, J.W.H. AU - Dudzina, T. AU - Delmaar, C.J. AU - Bakker, M.I. AU - Russel, F.G.M. AU - Goetz, N. von AU - Scheepers, P.T.J. AU - Roeleveld, N. PY - 2013 UR - https://hdl.handle.net/2066/111458 AB - Complete information regarding the use of personal care products (PCPs) by consumers is limited, but such information is crucial for realistic consumer exposure assessment. To fill this gap, a database was created with person-oriented information regarding usage patterns and circumstances of use for 32 different PCPs. Out of 2700 potential participants from the Netherlands, 516 men and women completed a digital questionnaire. The prevalence of use varied by gender, age, level of education and skin type. A high frequency of use was observed for some products (e.g. lip care products), while toothpaste, deodorant and day cream were generally used once or twice a day. The frequency of use for other PCPs varied over a wide range. The amounts of use varied largely between and within different product groups. Body lotion, sunscreen and after sun lotion were often applied on adjacent body parts. The majority of PCPs were applied in the morning, but some products, such as night cream and after sun, were predominantly applied in the evening or night. As expected, the participants used several PCPs simultaneously. The database yields important personalized exposure factors which can be used in aggregate consumer exposure assessment for substances that are components of PCPs. TI - Usage patterns of personal care products: Important factors for exposure assessment EP - 17 SN - 0278-6915 SP - 8 JF - Food and Chemical Toxicology VL - vol. 55 DO - http://dx.doi.org/10.1016/j.fct.2012.11.014 ER - TY - JOUR AU - Swarts, H.G.P. AU - Weigand, K.M. AU - Venselaar, H. AU - Maagdenberg, A.M. van den AU - Russel, F.G.M. AU - Koenderink, J.B. PY - 2013 UR - https://hdl.handle.net/2066/125451 AB - Familial hemiplegic migraine (FHM) is a monogenic variant of migraine with aura. One of the three known causative genes, ATP1A2, which encodes the alpha2 isoform of Na,K-ATPase, causes FHM type 2 (FHM2). Over 50 FHM2 mutations have been reported, but most have not been characterized functionally. Here we study the molecular mechanism of Na,K-ATPase alpha2 missense mutations. Mutants E700K and P786L inactivate or strongly reduce enzyme activity. Glutamic acid 700 is located in the phosphorylation (P) domain and the mutation most likely disrupts the salt bridge with Lysine 35, thereby destabilizing the interaction with the actuator (A) domain. Mutants G900R and E902K are present in the extracellular loop at the interface of the alpha and beta subunit. Both mutants likely hamper the interaction between these subunits and thereby decrease enzyme activity. Mutants E174K, R548C and R548H reduce the Na(+) and increase the K(+) affinity. Glutamic acid 174 is present in the A domain and might form a salt bridge with Lysine 432 in the nucleotide binding (N) domain, whereas Arginine 548, which is located in the N domain, forms a salt bridge with Glutamine 219 in the A domain. In the catalytic cycle, the interactions of the A and N domains affect the K(+) and Na(+) affinities, as observed with these mutants. Functional consequences were not observed for ATP1A2 mutations found in two sporadic hemiplegic migraine cases (Y9N and R879Q) and in migraine without aura (R51H and C702Y). TI - Familial hemiplegic migraine mutations affect Na,K-ATPase domain interactions EP - 2179 SN - 0925-4439 IS - iss. 12 SP - 2173 JF - Biochimica et Biophysica Acta. Molecular Basis of Disease VL - vol. 1832 DO - http://dx.doi.org/10.1016/j.bbadis.2013.08.003 ER - TY - JOUR AU - El-Sheikh, A.A.K. AU - Greupink, R. AU - Wortelboer, H.M. AU - Heuvel, J.J.M.W. van den AU - Schreurs, M. AU - Koenderink, J.B. AU - Masereeuw, R. AU - Russel, F.G.M. PY - 2013 UR - https://hdl.handle.net/2066/125987 AB - Renal proximal tubule transporters can play a key role in excretion, pharmacokinetic interactions, and toxicity of immunosuppressant drugs. Basolateral organic anion transporters (OATs) and apical multidrug resistance-associated proteins (MRPs) contribute to the active tubular uptake and urinary efflux of these drugs, respectively. We studied the interaction of 12 immunosuppressants with OAT1- and OAT3-mediated [(3)H]-methotrexate (MTX) uptake in cells, and adenosine triphosphate-dependent [(3)H]-MTX transport in membrane vesicles isolated from human embryonic kidney 293 cells overexpressing human MRP2 and MRP4. Our results show that at a clinically relevant concentration of 10 muM, mycophenolic acid inhibited both OAT1- and OAT3-mediated [(3)H]-MTX uptake. Cytarabine, vinblastine, vincristine, hydrocortisone, and mitoxantrone inhibited only OAT1, whereas tacrolimus, azathioprine, dexamethasone, cyclosporine, and 6-mercaptopurine had no effect on both transporters. Cyclophosphamide stimulated OAT1, but did not affect OAT3. With regard to the apical efflux transporters, mycophenolic acid, cyclophosphamide, hydrocortisone, and tacrolimus inhibited MRP2 and MRP4, whereas mitoxantrone and dexamethasone stimulated [(3)H]-MTX transport by both transporters. Cyclosporine, vincristine, and vinblastine inhibited MRP2 only, whereas 6-mercaptopurine inhibited MRP4 transport activity only. Cytarabine and azathioprine had no effect on either transporter. In conclusion, we charted comprehensively the differences in inhibitory action of various immunosuppressive agents against the 4 key renal anion transporters, and we provide evidence that immunosuppressant drugs can modulate OAT1-, OAT3-, MRP2-, and MRP4-mediated transport of MTX to different extents. The data provide a better understanding of renal mechanisms underlying drug-drug interactions and nephrotoxicity concerning combination regimens with these compounds in the clinic. TI - Interaction of immunosuppressive drugs with human organic anion transporter (OAT) 1 and OAT3, and multidrug resistance-associated protein (MRP) 2 and MRP4 EP - 409 SN - 1931-5244 IS - iss. 6 SP - 398 JF - Translational Research VL - vol. 162 DO - http://dx.doi.org/10.1016/j.trsl.2013.08.003 ER - TY - JOUR AU - Greupink, R. AU - Schreurs, M. AU - Benne, M.S. AU - Huisman, M.T. AU - Russel, F.G.M. PY - 2013 UR - https://hdl.handle.net/2066/136174 AB - We studied if the clinical pharmacokinetics and drug-drug interactions (DDIs) of the sulfonylurea-derivative glibenclamide can be simulated via a physiologically-based pharmacokinetic modeling approach. To this end, a glibenclamide PBPK-model was build in Simcyp using in vitro physicochemical and biotransformation data of the drug, and was subsequently optimized using plasma disappearance data observed after i.v. administration. The model was validated against data observed after glibenclamide oral dosing, including DDIs. We found that glibenclamide pharmacokinetics could be adequately modeled if next to CYP metabolism an active hepatic uptake process was assumed. This hepatic uptake process was subsequently included in the model in a non-mechanistic manner. After an oral dose of 0.875 mg predicted Cmax and AUC were 39.7 (95% CI:37.0-42.7)ng/mL and 108 (95% CI: 96.9-120)ng/mLh, respectively, which is in line with observed values of 43.6 (95% CI: 37.7-49.5)ng/mL and 133 (95% CI: 107-159)ng/mLh. For a 1.75 mg oral dose, the predicted and observed values were 82.5 (95% CI:76.6-88.9)ng/mL vs 91.1 (95% CI: 67.9-115.9) for Cmax and 224 (95% CI: 202-248) vs 324 (95% CI: 197-451)ng/mLh for AUC, respectively. The model correctly predicted a decrease in exposure after rifampicin pre-treatment. An increase in glibenclamide exposure after clarithromycin co-treatment was predicted, but the magnitude of the effect was underestimated because part of this DDI is the result of an interaction at the transporter level. Finally, the effects of glibenclamide and fluconazol co-administration were simulated. Our simulations indicated that co-administration of this potent CYP450 inhibitor will profoundly increase glibenclamide exposure, which is in line with clinical observations linking the glibenclamide-fluconazol combination to an increased risk of hypoglycemia. In conclusion, glibenclamide pharmacokinetics and its CYP-mediated DDIs can be simulated via PBPK-modeling. In addition, our data underline the relevance of modeling transporters on a full mechanistic level to further improve pharmacokinetic and DDI predictions of this sulfonylurea-derivative. TI - Semi-mechanistic physiologically-based pharmacokinetic modeling of clinical glibenclamide pharmacokinetics and drug-drug-interactions EP - 828 SN - 0928-0987 IS - iss. 5 SP - 819 JF - European Journal of Pharmaceutical Sciences VL - vol. 49 DO - http://dx.doi.org/10.1016/j.ejps.2013.06.009 ER - TY - JOUR AU - Dankers, A.C.A. AU - Roelofs, M.J. AU - Piersma, A.H. AU - Sweep, C.G.J. AU - Russel, F.G.M. AU - Berg, M. van den AU - Duursen, M.B. van AU - Masereeuw, R. PY - 2013 UR - https://hdl.handle.net/2066/125412 AB - Endocrine-disrupting chemicals (EDCs) are considered to cause testicular toxicity primarily via interference with steroid hormone function. Alternatively, EDCs could possibly exert their effects by interaction with ATP-binding cassette (ABC) transporters that are expressed in the blood-testis barrier. In this study, we investigated the effects of bisphenol A (BPA), tetrabromobisphenol A (TBBPA), bis(2-ethylhexyl) phthalate, mono(2-ethylhexyl) phthalate, perfluorooctanoic acid (PFOA), and perfluorooctanesulfonic acid (PFOS) on breast cancer resistance protein (BCRP), multidrug resistance proteins 1 and 4 (MRP1 and MRP4), and P-glycoprotein (P-gp) using membrane vesicles overexpressing these transporters. BPA solely inhibited BCRP activity, whereas TBBPA, PFOA, and PFOS inhibited all transporters tested. No effect was observed for the phthalates. Using transporter-overexpressing Madin-Darby canine kidney cells, we show that BPA and PFOA, but not TBBPA, are transported by BCRP, whereas none of the compounds were transported by P-gp. To investigate the toxicological implications of these findings, testosterone secretion and expression of steroidogenic genes were determined in murine Leydig (MA-10) cells upon exposure to the selected EDCs. Only BPA and TBBPA concentration dependently increased testosterone secretion by MA-10 cells to 6- and 46-fold of control levels, respectively. Inhibition of the Mrp's by MK-571 completely blocked testosterone secretion elicited by TBBPA, which could not be explained by coinciding changes in expression of steroidogenic genes. Therefore, we hypothesize that transporter-mediated efflux of testosterone precursors out of MA-10 cells is inhibited by TBBPA resulting in higher availability for testosterone production. Our data show the toxicological and clinical relevance of ABC transporters in EDC risk assessment related to testicular toxicity. TI - Endocrine Disruptors Differentially Target ATP-Binding Cassette Transporters in the Blood-Testis Barrier and Affect Leydig Cell Testosterone Secretion In Vitro EP - 391 SN - 1096-6080 IS - iss. 2 SP - 382 JF - Toxicological Sciences VL - vol. 136 DO - https://doi.org/10.1093/toxsci/kft198 ER - TY - JOUR AU - Dankers, A.C.A. AU - Mutsaers, H.A.M. AU - Dijkman, H.B.P.M. AU - Heuvel, L.P.W.J. van den AU - Hoenderop, J.G.J. AU - Sweep, C.G.J. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2013 UR - http://repository.ubn.ru.nl/handle/2066/127304 AB - Hyperuricemia is related to a variety of pathologies, including chronic kidney disease (CKD). However, the pathophysiological mechanisms underlying disease development are not yet fully elucidated. Here, we studied the effect of hyperuricemia on tryptophan metabolism and the potential role herein of two important uric acid efflux transporters, multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Hyperuricemia was induced in mice by treatment with the uricase inhibitor oxonic acid, confirmed by the presence of urate crystals in the urine of treated animals. A transport assay, using membrane vesicles of cells overexpressing the transporters, revealed that uric acid inhibited substrate-specific transport by BCRP at clinically relevant concentrations (calculated IC50 value: 365+/-13muM), as was previously reported for MRP4. Moreover, we identified kynurenic acid as a novel substrate for MRP4 and BCRP. This finding was corroborated by increased plasma levels of kynurenic acid observed in Mrp4(-/-) (107+/-19nM; P=0.145) and Bcrp(-/-) mice (133+/-10nM; P=0.0007) compared to wild type animals (71+/-11nM). Hyperuricemia was associated with >1.5 fold increase in plasma kynurenine levels in all strains. Moreover, hyperuricemia led to elevated plasma kynurenic acid levels (128+/-13nM, P=0.005) in wild type mice but did not further increase kynurenic acid levels in knockout mice. Based on our results, we postulate that elevated uric acid levels hamper MRP4 and BCRP functioning, thereby promoting the retention of other potentially toxic substrates, including kynurenic acid, which could contribute to the development of CKD. TI - Hyperuricemia influences tryptophan metabolism via inhibition of multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP) EP - 1722 SN - 0925-4439 IS - iss. 10 SP - 1715 JF - Biochimica et Biophysica Acta. Molecular Basis of Disease VL - vol. 1832 DO - https://doi.org/10.1016/j.bbadis.2013.05.002 ER - TY - JOUR AU - Swelm, R.P.L. van AU - Laarakkers, C.M. AU - Kooijmans-Otero, M.E. AU - Jong, E.M.G.J. de AU - Masereeuw, R. AU - Russel, F.G.M. PY - 2013 UR - https://hdl.handle.net/2066/119233 AB - Hepatic fibrosis is an adverse drug reaction of methotrexate (MTX) seen after long-term use in psoriasis patients. Currently, patients are monitored for MTX-induced hepatic fibrosis by performing liver biopsy, which is risky and burdensome for the patient, or by measuring plasma procollagen type III aminopeptide (PIIINP), which is not conclusive. The objective of this study was to identify novel predictive and preferably non-invasive biomarkers to monitor psoriasis patients for MTX-induced hepatic fibrosis. Urine samples were collected from 60 psoriasis patients treated with MTX and divided into two categories: low cumulative dose (< 1500 mg MTX) and high cumulative dose (> 1500 mg). Urinary proteins were profiled using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and identified using electrospray ionization LTQ. In urine of psoriasis patients with high cumulative MTX dose multiple proteins were identified that are associated with hepatic fibrosis, such as N-cadherin, inter-alpha-trypsin inhibitor heavy chain H4, haptoglobin and serotransferrin. These proteins may be candidate urinary biomarkers to monitor MTX-induced hepatic fibrosis. In conclusion, urinary proteome analysis identified a profile of potentially predictive biomarkers for MTX-induced hepatic fibrosis in psoriasis patients with high cumulative dose of MTX. TI - Biomarkers for methotrexate-induced liver injury: urinary protein profiling of psoriasis patients EP - 224 SN - 0378-4274 IS - iss. 3 SP - 219 JF - Toxicology Letters VL - vol. 221 DO - https://doi.org/10.1016/j.toxlet.2013.06.234 ER - TY - JOUR AU - Swelm, R.P.L. van AU - Laarakkers, C.M. AU - Pertijs, J.C.L.M. AU - Verweij, V.G.M. AU - Masereeuw, R. AU - Russel, F.G.M. PY - 2013 UR - https://hdl.handle.net/2066/117320 AB - Diclofenac (DF) is a widely used non-steroidal anti-inflammatory drug for the treatment of rheumatic disorders, but is often associated with liver injury. We applied urinary proteomic profiling using MALDI-TOF MS to identify biomarkers for DF-induced hepatotoxicity in mice. Female CH3/HeOUJIco mice were treated with 75mg/kg bw DF by oral gavage and 24h urine was collected. Proteins identified in urine of DF-treated mice included epidermal growth factor, transthyretin, kallikrein, clusterin, fatty acid binding protein 1 and urokinase, which are related to liver regeneration but also to kidney injury. Both organs showed enhanced levels of oxidative stress (TBARS, p<0.01). Kidney injury was confirmed by histology and increased Kim1 and Il-6 mRNA expression levels (p<0.001 and p<0.01). Liver histology and plasma ALT levels in DF-treated mice were not different from control, but mRNA expression of Stat3 (p<0.001) and protein expression of PCNA (p<0.05) were increased, indicating liver regeneration. In conclusion, urinary proteome analysis revealed that DF treatment in mice induced kidney and liver injury. Within 24h, however, the liver was able to recover by activating tissue regeneration processes. Hence, the proteins found in urine of DF-treated mice represent kidney damage rather than hepatic injury. TI - Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice EP - 149 SN - 0041-008X IS - iss. 2 SP - 141 JF - Toxicology and Applied Pharmacology VL - vol. 269 DO - https://doi.org/10.1016/j.taap.2013.03.005 ER - TY - JOUR AU - Weber, A.C.J. AU - Pizzirusso, A. AU - Muccioli, L. AU - Zannoni, C. AU - Meerts, W.L. AU - Lange, C.A. de AU - Burnell, E.E. PY - 2012 UR - https://hdl.handle.net/2066/103327 TI - Efficient analysis of highly complex nuclear magnetic resonance spectra of flexible solutes in ordered liquids by using molecular dynamics SN - 0021-9606 IS - iss. 17 JF - Journal of Chemical Physics VL - vol. 136 DO - http://dx.doi.org/10.1063/1.4705271 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/103327/103327.pdf?sequence=1 ER - TY - JOUR AU - Wittgen, H.G.M. AU - Greupink, R. AU - Heuvel, J.J.M.W. van den AU - Broek, P.H.H. van den AU - Dinter-Heidorn, H. AU - Koenderink, J.B. AU - Russel, F.G.M. PY - 2012 UR - https://hdl.handle.net/2066/107834 AB - Although the CB1 receptor antagonist/inverse agonist rimonabant has positive effects on weight loss and cardiometabolic risk factors, neuropsychiatric side effects have prompted researchers to develop peripherally acting derivatives. Here, we investigated for a series of 3,4-diarylpyrazoline CB1 receptor antagonists if transport by the brain efflux transporter P-gp could be used as a selection criterion in the development of such drugs. All 3,4-diarylpyrazolines and rimonabant inhibited P-gp transport activity in membrane vesicles isolated from HEK293 cells overexpressing the transporter, but only the 1,1-dioxo-thiomorpholino analogue 23 exhibited a reduced accumulation (-38 +/- 2%) in these cells, which could be completely reversed by the P-gp/BCRP inhibitor elacridar. In addition, 23 appeared to be a BCRP substrate, whereas rimonabant was not. In rats, the in vivo brain/plasma concentration ratio of 23 was significantly lower than for rimonabant (0.4 +/- 0.1 vs 6.2 +/- 1.6, p < 0.001). Coadministration of elacridar resulted in an 11-fold increase of the brain/plasma ratio for 23 (p < 0.01) and only 1.4-fold for rimonabant (p < 0.05), confirming the involvement of P-gp and possibly BCRP in limiting the brain entrance of 23 in vivo. In conclusion, these data support the conception that efflux via transporters such as P-gp and BCRP can limit the brain penetration of CB1 receptor antagonists, and that this property could be used in the development of peripheral antagonists. TI - Exploiting transport activity of p-glycoprotein at the blood-brain barrier for the development of peripheral cannabinoid type 1 receptor antagonists. EP - 1360 SN - 1543-8384 IS - iss. 5 SP - 1351 JF - Molecular Pharmaceutics VL - vol. 9 DO - http://dx.doi.org/10.1021/mp200617z ER - TY - JOUR AU - Weigand, K.M. AU - Swarts, H.G.P. AU - Fedosova, N.U. AU - Russel, F.G.M. AU - Koenderink, J.B. PY - 2012 UR - https://hdl.handle.net/2066/108799 AB - Digitalis-like compounds (DLCs), specific inhibitors of Na,K-ATPase, are implicated in cellular signaling. Exposure of cell cultures to ouabain, a well-known DLC, leads to up- or down regulation of various processes and involves activation of Src kinase. Since Na,K-ATPase is the only known target for DLC binding an in vitro experimental setup using highly purified Na,K-ATPase from pig kidney and commercially available recombinant Src was used to investigate the mechanism of coupling between the Na,K-ATPase and Src. Digoxin was used as a representative DLC for inhibition of Na,K-ATPase. The activation of Src kinase was measured as the degree of its autophosphorylation. It was observed that in addition to digoxin, Src activation was dependent on concentrations of other specific ligands of Na,K-ATPase: Na(+), K(+), vanadate, ATP and ADP. The magnitude of the steady-state ATPase activity therefore seemed to affect Src activation. Further experiments with an ATP regenerating system showed that the ATP/ADP ratio determined the extent of Src activation. Thus, our model system which represents the proposed very proximal part of the Na,K-ATPase-Src signaling cascade, shows that Src kinase activity is regulated by both ATP and ADP concentrations and provides no evidence for a direct interaction between Na,K-ATPase and Src. TI - Na,K-ATPase activity modulates Src activation: A role for ATP/ADP ratio. EP - 1273 SN - 0005-2736 IS - iss. 5 SP - 1269 JF - Biochimica et Biophysica Acta. Biomembranes VL - vol. 1818 N1 - 1 mei 2012 DO - http://dx.doi.org/10.1016/j.bbamem.2012.01.015 ER - TY - JOUR AU - Masereeuw, R. AU - Russel, F.G.M. PY - 2012 UR - https://hdl.handle.net/2066/109335 AB - The ATP-binding cassette transport proteins (ABC transporters) represent important determinants of drug excretion. Protective or excretory tissues where these transporters mediate substrate efflux include the kidney proximal tubule. Regulation of the transport proteins in this tissue requires elaborate signaling pathways, including genetic, epigenetic, nuclear receptor mediated, posttranscriptional gene regulation involving microRNAs, and non-genomic (kinases) pathways triggered by hormones and/or growth factors. This review discusses current knowledge on regulatory pathways for ABC transporters in kidney proximal tubules, with a main focus on P-glycoprotein, multidrug resistance proteins 2 and 4, and breast cancer resistance protein. Insight in these processes is of importance because variations in transporter activity due to certain (disease) conditions could lead to significant changes in drug efficacy or toxicity. TI - Regulatory pathways for ATP-binding cassette transport proteins in kidney proximal tubules EP - 894 SN - 1550-7416 IS - iss. 4 SP - 883 JF - Aaps Journal VL - vol. 14 DO - http://dx.doi.org/10.1208/s12248-012-9404-z ER - TY - JOUR AU - Wittgen, H.G.M. AU - Heuvel, J.J.M.W. van den AU - Broek, P.H.H. van den AU - Siissalo, S. AU - Groothuis, G.M. AU - Graaf, I.A. de AU - Koenderink, J.B. AU - Russel, F.G.M. PY - 2012 UR - https://hdl.handle.net/2066/110039 AB - Coumarin (1,2-benzopyrone) is a natural compound that has been used as a fragrance in the food and perfume industry and could have therapeutic usefulness in the treatment of lymphedema and different types of cancer. Several previous pharmacokinetic studies of coumarin have been performed in humans, which revealed extensive first-pass metabolism of the compound. 7-Hydroxycoumarin (7-HC) and its glucuronide (7-HC-G) are the main metabolites formed in humans, and via this route, 80 to 90% of the absorbed coumarin is excreted into urine, mainly as 7-HC-G. Active transport processes play a role in the urinary excretion of 7-HC-G; however, until now, the transporters involved remained to be elucidated. In this study, we investigated whether the efflux transporters multidrug resistance-associated proteins (MRP)1-4, breast cancer resistance protein, or P-glycoprotein play a role in 7-HC and 7-HC-G transport. For this purpose, we measured uptake of the metabolites into membrane vesicles overexpressing these transporters. Our results showed that 7-HC is not transported by any of the efflux transporters tested, whereas 7-HC-G was a substrate of MRP3 and MRP4. These results are in line with the pharmacokinetic profile of coumarin and suggest that MRP3 and MRP4 are the main transporters involved in the excretion of the coumarin metabolite 7-HC-G from liver and kidney. TI - Transport of the coumarin metabolite 7-hydroxycoumarin glucuronide is mediated via multidrug resistance-associated proteins 3 and 4. EP - 1079 SN - 0090-9556 IS - iss. 6 SP - 1076 JF - Drug Metabolism and Disposition VL - vol. 40 N1 - 1 juni 2012 DO - http://dx.doi.org/10.1124/dmd.111.044438 ER - TY - JOUR AU - Engbersen, R.H.G. AU - Masereeuw, R. AU - Gestel, M.A. van AU - Siero, H.L.M. AU - Moons, M.M. AU - Smits, P. AU - Russel, F.G.M. PY - 2012 UR - https://hdl.handle.net/2066/110913 AB - Sulfonylurea drugs exert their insulinotropic action by inhibiting ATP-sensitive potassium channels in the pancreas. However, these channels are also expressed in myocardial and vascular smooth muscle, implicating possible detrimental cardiovascular effects. Aim of the present study was to investigate the inhibitory potency of various widely used sulfonylurea drugs in resistance arteries. Isolated mesenteric and renal resistance arteries mounted in a myograph and isolated perfused kidneys were used to measure drug responses. Pinacidil induced a dose-dependent relaxation of phenylephrine preconstricted mesenteric and renal arteries (pEC(50)=6.10 +/- 0.01 and 5.66 +/- 0.03, respectively). Schild plot analysis of pinacidil relaxation curves in mesenteric arteries in the presence of sulfonylurea antagonists revealed the following order of potency: glimepiride (pA(2)=7.22) >/= glibenclamide (pA(2)=7.05) > glipizide (pA(2)=5.25) > gliclazide (pA(2)=4.31). The effects of glibenclamide in renal arteries were comparable. Furthermore, glibenclamide produced similar constrictive properties in isolated renal arteries as in isolated perfused whole kidneys. We conclude that sulfonylurea drugs exert differential effects on vascular smooth muscle K(ATP) channels. Our results suggest that glibenclamide and glimepiride will interact with these channels at therapeutic concentrations. TI - Differential effects of sulfonylurea derivatives on vascular ATP-sensitive potassium channels. EP - 79 SN - 0014-2999 IS - iss. 1-3 SP - 75 JF - European Journal of Pharmacology VL - vol. 681 DO - http://dx.doi.org/10.1016/j.ejphar.2012.02.006 ER - TY - JOUR AU - Greupink, R. AU - Nabuurs, S.B. AU - Zarzycka, B. AU - Verweij, V.G.M. AU - Monshouwer, M. AU - Huisman, M.T. AU - Russel, F.G.M. PY - 2012 UR - https://hdl.handle.net/2066/108286 AB - Na(+)-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1) is the main transporter facilitating the hepatic uptake of bile acids from the circulation. Consequently, the interaction of xenobiotics, including therapeutic drugs, with the bile acid binding pocket of NTCP could lead to impairment of hepatic bile acid uptake. We pursued a 3D-pharmacophore approach to model the NTCP substrate and inhibitor specificity and investigated whether it is possible to identify compounds with intrinsic NTCP inhibitory properties. Based on known endogenous NTCP substrates, a 3D-pharmacophore model was built, which was subsequently used to screen two virtual libraries together containing the structures of 10 million compounds. Studies with Chinese hamster ovary cells overexpressing human NTCP, human hepatocytes, ex vivo perfused rat livers, and bile duct-cannulated rats were conducted to validate the activity of the virtual screening hits. Modeling yielded a 3D-pharmacophore, consisting of two hydrogen bond acceptors and three hydrophobic features. Six out of 10 structurally diverse compounds selected in the first virtual screening procedure significantly inhibited taurocholate uptake in the NTCP overexpressing cells. For the most potent inhibitor identified, an anthraquinone derivative, this finding was confirmed in human hepatocytes and perfused rat livers. Subsequent structure and activity relationship studies with analogs of this derivative indicated that an appropriate distance between hydrogen bond acceptor features and presence of one or two negative charges appear critical for a successful NTCP interaction. In conclusion, pharmacophore modeling was successfully used to identify compounds that inhibit NTCP. Our approach represents an important first step toward the in silico flagging of potential cholestasis-inducing molecules. TI - In Silico Identification of Potential Cholestasis-Inducing Agents via Modeling of Na+-Dependent Taurocholate Cotransporting Polypeptide Substrate Specificity. EP - 48 SN - 1096-6080 IS - iss. 1 SP - 35 JF - Toxicological Sciences VL - vol. 129 N1 - 1 september 2012 DO - https://doi.org/10.1093/toxsci/kfs188 ER - TY - JOUR AU - Wittgen, H.G.M. AU - Heuvel, J.M.W. van den AU - Krieger, E. AU - Schaftenaar, G. AU - Russel, F.G.M. AU - Koenderink, J.B. PY - 2012 UR - https://hdl.handle.net/2066/103615 AB - Multidrug resistance-associated protein 4 (MRP4) is a membrane transporter that mediates the cellular efflux of a wide range of anionic drugs and endogenous molecules. MRP4 transport can influence the pharmacokinetics of drugs and their metabolites, therefore more knowledge about the molecular determinants important for its transport function would be of relevance. Here, we substituted amino acids Phe(368), Trp(995), and Arg(998) with conservative or non-conservative residues, and determined the effect on transport of the model substrates estradiol 17-beta-d-glucuronide (E(2)17betaG), cyclic guanosine monophosphate (cGMP), methotrexate (MTX), and folic acid into membrane vesicles isolated from baculovirus transduced HEK293 cells overexpressing the mutant MRP4 proteins. This revealed that all Arg(998) mutations appeared to be deleterious, whereas the effect of a Phe(368) or Trp(995) replacement was dependent on the amino acid introduced and the substrate studied. Substitution of Phe(368) with Trp (F368W) induced a gain-of-function of E(2)17betaG transport and a loss-of-function of MTX transport, which could not be attributed to an altered substrate binding. Moreover, we did not observe any modification in ATP or ADP handling for F368W. These results, in combination with docking of substrates in a homology model of MRP4 in the inward- and outward-facing conformation, suggest that Phe(368) and Trp(995) do not play an important role in the initial binding of substrates. They, however, might interact with the substrates during rearrangement of helixes for substrate translocation, funneling the substrates to the exit site in the outward-facing conformation. TI - Phenylalanine 368 of multidrug resistance-associated protein 4 (MRP4/ABCC4) plays a crucial role in substrate-specific transport activity. EP - 373 SN - 0006-2952 IS - iss. 3 SP - 366 JF - Biochemical Pharmacology VL - vol. 84 DO - https://doi.org/10.1016/j.bcp.2012.04.012 ER - TY - JOUR AU - Swelm, R.P.L. van AU - Laarakkers, J.M.M. AU - van der Kuur, E.C. AU - Morava, E. AU - Wevers, R.A. AU - Augustijn, K.D. AU - Touw, D.J. AU - Sandel, M.H. AU - Masereeuw, R. AU - Russel, F.G.M. PY - 2012 UR - https://hdl.handle.net/2066/108207 AB - Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced by acetaminophen (APAP). Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw) followed by 24 h urine collection. Doses of >/=275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT) values (p<0.0001). Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001), including superoxide dismutase 1 (SOD1), carbonic anhydrase 3 (CA3) and calmodulin (CaM), as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001) in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury. TI - Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice SN - 1932-6203 IS - iss. 11 JF - PLoS One VL - vol. 7 DO - https://doi.org/10.1371/journal.pone.0049524 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/108207/108207.pdf?sequence=1 ER - TY - JOUR AU - Breuer, M.E. AU - Willems, P.H.G.M. AU - Russel, F.G.M. AU - Koopman, W.J.H. AU - Smeitink, J.A.M. PY - 2012 UR - https://hdl.handle.net/2066/108693 AB - The biologist Lewis Thomas once wrote: "my mitochondria comprise a very large proportion of me. I cannot do the calculation, but I suppose there is almost as much of them in sheer dry bulk as there is the rest of me". As humans, or indeed as any mammal, bird, or insect, we contain a specific molecular makeup that is driven by vast numbers of these miniscule powerhouses residing in most of our cells (mature red blood cells notwithstanding), quietly replicating, living independent lives and containing their own DNA. Everything we do, from running a marathon to breathing, is driven by these small batteries, and yet there is evidence that these molecular energy sources were originally bacteria, possibly parasitic, incorporated into our cells through symbiosis. Dysfunctions in these organelles can lead to debilitating, and sometimes fatal, diseases of almost all the bodies' major organs. Mitochondrial dysfunction has been implicated in a wide variety of human disorders either as a primary cause or as a secondary consequence. To better understand the role of mitochondrial dysfunction in human disease, a multitude of pharmacologically induced and genetically manipulated animal models have been developed showing to a greater or lesser extent the clinical symptoms observed in patients with known and unknown causes of the disease. This review will focus on diseases of the brain and spinal cord in which mitochondrial dysfunction has been proven or is suspected and on animal models that are currently used to study the etiology, pathogenesis and treatment of these diseases. TI - Modeling mitochondrial dysfunctions in the brain: from mice to men. EP - 210 SN - 0141-8955 IS - iss. 2 SP - 193 JF - Journal of Inherited Metabolic Disease VL - vol. 35 N1 - 1 maart 2012 DO - https://doi.org/10.1007/s10545-011-9375-8 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/108693/108693.pdf?sequence=1 ER - TY - JOUR AU - Dankers, A.C.A. AU - Sweep, C.G.J. AU - Pertijs, J.C.L.M. AU - Verweij, V.G.M. AU - Heuvel, J.J.M.W. van den AU - Koenderink, J.B. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2012 UR - https://hdl.handle.net/2066/108532 AB - Breast cancer resistance protein (BCRP) is known for its protective function against the toxic effects of exogenous compounds. In addition to this, a role in the transport of endogenous compounds has been described. Since BCRP in the plasma membrane was shown to be regulated by sex steroids, we investigated the presence and possible role of BCRP in steroid hormone-producing organs. Therefore, the presence and localization of Bcrp was investigated in endocrine organs of wild-type mice. Furthermore, the interaction of various steroid hormones with human BCRP activity was studied. Quantitative PCR revealed Bcrp mRNA in the pituitary and adrenal glands, pancreas, ovary, testis and adipose tissue. Immunohistochemistry revealed the presence of Bcrp in the cortex of the adrenal gland and in plasma membranes of adipocytes. In the pituitary gland, pancreas, ovary and testis, Bcrp was mainly located in the capillaries. The interaction between BCRP and 12 steroid hormones was studied using membrane vesicles of HEK293-BCRP cells. Estradiol, testosterone, progesterone and androstenedione inhibited BCRP-mediated uptake of (3)H-estrone sulphate (E(1)S) most potently, with calculated inhibitory constant (Ki) values of 5.0 +/- 0.2, 36 +/- 14, 14.7 +/- 1.3 and 217 +/- 13 muM, respectively. BCRP function was attenuated non-competitively, which implies an allosteric inhibition of BCRP-mediated E(1)S transport by these steroids. In conclusion, localization of Bcrp in endocrine organs together with the efficient allosteric inhibition of the efflux pump by steroid hormones are suggestive for a role for BCRP in steroid hormone regulation. TI - Localization of breast cancer resistance protein (Bcrp) in endocrine organs and inhibition of its transport activity by steroid hormones. EP - 563 SN - 0302-766X IS - iss. 2 SP - 551 JF - Cell and Tissue Research VL - vol. 349 N1 - 1 augustus 2012 DO - https://doi.org/10.1007/s00441-012-1417-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/108532/108532.pdf?sequence=1 ER - TY - JOUR AU - Brand, C. van den AU - Meerts, W.L. AU - Schmitt, M. PY - 2011 UR - https://hdl.handle.net/2066/91899 TI - How and why do transition dipole moment orientations depend on conformer structure? EP - 9619 SN - 1089-5639 IS - iss. 34 SP - 9612 JF - The Journal of Physical Chemistry A VL - vol. 115 PS - 7 p. DO - http://dx.doi.org/10.1021/jp200492s ER - TY - JOUR AU - Burnell, E.E. AU - Weber, A.C.J. AU - Lange, C.A. de AU - Meerts, W.L. AU - Dong, R.Y. PY - 2011 UR - https://hdl.handle.net/2066/92134 TI - Nuclear magnetic resonance study of alkane conformational statistics EP - 234506-10 SN - 0021-9606 IS - iss. 23 SP - 234506-1 JF - Journal of Chemical Physics VL - vol. 135 DO - http://dx.doi.org/10.1063/1.3665139 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/92134/92134.pdf?sequence=1 ER - TY - CHAP AU - Schmitt, M. AU - Meerts, W.L. PY - 2011 UR - https://hdl.handle.net/2066/92282 PB - [S.l.] : John Wiley and Sons TI - Rotationally resolved electronic spectroscopy and automatic assignment techniques using evolutionary SN - 9780470749593 SP - 1345 CT - Quack, M.; Merkt, F. (ed.), Handbook of high resolution spectroscopy DO - http://dx.doi.org/10.1002/9780470749593 ER - TY - JOUR AU - Thi, B.C.V. AU - Brand, C. van den AU - Meerts, W.L. AU - Schmitt, M. PY - 2011 UR - https://hdl.handle.net/2066/92283 TI - Rotationally resolved electronic spectroscopy of 1,4-benzodioxan: The anomeric effect in the ground and electronically excited state EP - 2041 SN - 1439-4235 IS - iss. 10 SP - 2035 JF - Chemphyschem VL - vol. 12 PS - 7 p. DO - http://dx.doi.org/10.1002/cphc.201000576 ER - TY - JOUR AU - Oeltermann, O. AU - Brand, C. van den AU - Meerts, W.L. AU - Tatchen, J. AU - Schmitt, M. PY - 2011 UR - https://hdl.handle.net/2066/92284 TI - Rotationally resolved electronic spectroscopy of 2,3-bridged indole derivatives: Tetrahydrocarbazole EP - 8 SN - 0022-2860 IS - iss. 1-3 SP - 2 JF - Journal of Molecular Structure VL - vol. 993 PS - 7 p. DO - http://dx.doi.org/10.1016/j.molstruc.2011.01.029 ER - TY - JOUR AU - Yi, J.T. AU - Brand, C. van den AU - Wollenhaupt, M. AU - Pratt, D.W. AU - Meerts, W.L. AU - Schmitt, M. PY - 2011 UR - https://hdl.handle.net/2066/92285 TI - Rotationally resolved electronic spectroscopy of biomolecules in the gas phase. Melatonin EP - 122 SN - 0022-2852 IS - iss. 1-2 SP - 115 JF - Journal of Molecular Spectroscopy VL - vol. 268 PS - 8 p. DO - http://dx.doi.org/10.1016/j.jms.2011.04.004 ER - TY - JOUR AU - Grimminck, D. AU - Polman, B.J.W. AU - Kentgens, A.P.M. AU - Meerts, W.L. PY - 2011 UR - https://hdl.handle.net/2066/91742 TI - Easy-going deconvolution: Combining accurate simulation and evolutionary algorithms for fast deconvolution of solid-state quadrupolar nmr spectra EP - 120 SN - 1090-7807 IS - iss. 2 SP - 114 JF - Journal of Magnetic Resonance VL - vol. 211 PS - 6 p. DO - http://dx.doi.org/10.1016/j.jmr.2011.04.009 ER - TY - JOUR AU - Boogaard, M.H.W.A. van den AU - Swelm, R.P.L. van AU - Russel, F.G.M. AU - Heemskerk, S. AU - Hoeven, J.G. van der AU - Masereeuw, R. AU - Pickkers, P. PY - 2011 UR - https://hdl.handle.net/2066/92532 TI - Urinary protein profiling in hyperactive delirium and non-delirium cardiac surgery ICU patients EP - 13 SN - 1477-5956 SP - 13 JF - Proteome Science VL - vol. 9 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/92532/92532.pdf?sequence=1 ER - TY - JOUR AU - Wittgen, H.G.M. AU - Heuvel, J.J.M.W. van den AU - Broek, P.H. van den AU - Dinter-Heidorn, H. AU - Koenderink, J.B. AU - Russel, F.G.M. PY - 2011 UR - https://hdl.handle.net/2066/91615 TI - Cannabinoid type 1 receptor antagonists modulate transport activity of multidrug resistance-associated proteins MRP1, MRP2, MRP3, and MRP4 EP - 1302 SN - 0090-9556 IS - iss. 7 SP - 1294 JF - Drug Metabolism and Disposition VL - vol. 39 DO - http://dx.doi.org/10.1124/dmd.110.037812 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/91615/91615.pdf?sequence=1 ER - TY - JOUR AU - Greupink, R. AU - Dillen, L. AU - Monshouwer, M. AU - Huisman, M.T. AU - Russel, F.G.M. PY - 2011 UR - https://hdl.handle.net/2066/91944 TI - Interaction of fluvastatin with the liver-specific Na(+)-dependent taurocholate cotransporting polypeptide (NTCP) EP - 496 SN - 0928-0987 IS - iss. 4 SP - 487 JF - European Journal of Pharmaceutical Sciences VL - vol. 44 DO - http://dx.doi.org/10.1016/j.ejps.2011.09.009 ER - TY - JOUR AU - Prevoo, B. AU - Miller, D.S. AU - Water, F.M. van de AU - Wever, K.E. AU - Russel, F.G.M. AU - Flik, G. AU - Masereeuw, R. PY - 2011 UR - https://hdl.handle.net/2066/92256 TI - Rapid, nongenomic stimulation of multidrug resistance protein 2 (Mrp2) activity by glucocorticoids in renal proximal tubule EP - 371 SN - 0022-3565 IS - iss. 1 SP - 362 JF - Journal of Pharmacology and Experimental Therapeutics VL - vol. 338 DO - http://dx.doi.org/10.1124/jpet.111.179689 ER - TY - JOUR AU - Lipciuc, M.L. AU - Rakitzis, T.P. AU - Meerts, W.L. AU - Groenenboom, G.C. AU - Janssen, M.H.M. PY - 2011 UR - https://hdl.handle.net/2066/92507 TI - Towards the complete experiment: Measurement of s((1)d(2)) polarization in correlation with single rotational states of co(j) from the photodissociation of oriented ocs(v(2)=1 vertical bar jlm=111) EP - 8559 SN - 1463-9076 IS - iss. 18 SP - 8549 JF - PCCP Physical Chemistry Chemical Physics VL - vol. 13 DO - https://doi.org/10.1039/c0cp02671a L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/92507/92507.pdf?sequence=1 ER - TY - JOUR AU - Rennings, A.J.M. AU - Russel, F.G.M. AU - Li, Y. AU - Deen, P.M.T. AU - Masereeuw, R. AU - Tack, C.J.J. AU - Smits, P. PY - 2011 UR - https://hdl.handle.net/2066/92219 TI - Preserved response to diuretics in rosiglitazone-treated subjects with insulin resistance: a randomized double-blind placebo-controlled crossover study EP - 594 SN - 0009-9236 IS - iss. 4 SP - 587 JF - Clinical Pharmacology and Therapeutics VL - vol. 89 DO - https://doi.org/10.1038/clpt.2010.360 ER - TY - JOUR AU - Grimminck, D. AU - Vasa, S.K. AU - Meerts, W.L. AU - Kentgens, A.P.M. AU - Brinkmann, A. PY - 2011 UR - https://hdl.handle.net/2066/91743 TI - Easy-going dumbo on-spectrometer optimisation of phase modulated homonuclear decoupling sequences in solid-state nmr EP - 191 SN - 0009-2614 IS - iss. 4-6 SP - 186 JF - Chemical Physics Letters VL - vol. 509 PS - 5 p. DO - https://doi.org/10.1016/j.cplett.2011.04.079 ER - TY - JOUR AU - Malik, D.A. AU - Eppink, A.T.J.B. AU - Meerts, W.L. AU - Kimel, A.V. AU - Kirilyuk, Andrei AU - Rasing, T.H.M. AU - Zande, W.J. van der PY - 2011 UR - https://hdl.handle.net/2066/92526 TI - Ultrafast coherent control of angular momentum during a one-photon excitation SN - 1050-2947 IS - iss. 4 JF - Physical Review (A) . General Physics VL - vol. 84 DO - https://doi.org/10.1103/PhysRevA.84.043404 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/92526/92526.pdf?sequence=1 ER - TY - JOUR AU - Tjalsma, H. AU - Laarakkers, C.M. AU - Swelm, R.P. van AU - Theurl, M. AU - Theurl, I. AU - Kemna, E.H.J.M. AU - Burgt, Y.E. van der AU - Venselaar, H. AU - Dutilh, B.E. AU - Russel, F.G.M. AU - Weiss, G. AU - Masereeuw, R. AU - Fleming, R.E. AU - Swinkels, D.W. PY - 2011 UR - https://hdl.handle.net/2066/92029 AB - The mouse is a valuable model for unravelling the role of hepcidin in iron homeostasis, however, such studies still report hepcidin mRNA levels as a surrogate marker for bioactive hepcidin in its pivotal function to block ferroportin-mediated iron transport. Here, we aimed to assess bioactive mouse Hepcidin-1 (Hep-1) and its paralogue Hepcidin-2 (Hep-2) at the peptide level. To this purpose, fourier transform ion cyclotron resonance (FTICR) and tandem-MS was used for hepcidin identification, after which a time-of-flight (TOF) MS-based methodology was exploited to routinely determine Hep-1 and -2 levels in mouse serum and urine. This method was biologically validated by hepcidin assessment in: i) 3 mouse strains (C57Bl/6; DBA/2 and BABL/c) upon stimulation with intravenous iron and LPS, ii) homozygous Hfe knock out, homozygous transferrin receptor 2 (Y245X) mutated mice and double affected mice, and iii) mice treated with a sublethal hepatotoxic dose of paracetamol. The results showed that detection of Hep-1 was restricted to serum, whereas Hep-2 and its presumed isoforms were predominantly present in urine. Elevations in serum Hep-1 and urine Hep-2 upon intravenous iron or LPS were only moderate and varied considerably between mouse strains. Serum Hep-1 was decreased in all three hemochromatosis models, being lowest in the double affected mice. Serum Hep-1 levels correlated with liver hepcidin-1 gene expression, while acute liver damage by paracetamol depleted Hep-1 from serum. Furthermore, serum Hep-1 appeared to be an excellent indicator of splenic iron accumulation. In conclusion, Hep-1 and Hep-2 peptide responses in experimental mouse agree with the known biology of hepcidin mRNA regulators, and their measurement can now be implemented in experimental mouse models to provide novel insights in post-transcriptional regulation, hepcidin function, and kinetics. TI - Mass spectrometry analysis of hepcidin peptides in experimental mouse models SN - 1932-6203 IS - iss. 3 JF - PLoS One VL - vol. 6 DO - https://doi.org/10.1371/journal.pone.0016762 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/92029/92029.pdf?sequence=1 ER - TY - JOUR AU - Mutsaers, R. AU - Heuvel, L.P. van den AU - Ringens, L.H. AU - Dankers, A.C.A. AU - Russel, F.G.M. AU - Wetzels, J.F.M. AU - Hoenderop, J.G.J. AU - Masereeuw, R. PY - 2011 UR - https://hdl.handle.net/2066/92531 AB - During chronic kidney disease (CKD), there is a progressive accumulation of toxic solutes due to inadequate renal clearance. Here, the interaction between uremic toxins and two important efflux pumps, viz. multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP) was investigated. Membrane vesicles isolated from MRP4- or BCRP-overexpressing human embryonic kidney cells were used to study the impact of uremic toxins on substrate specific uptake. Furthermore, the concentrations of various uremic toxins were determined in plasma of CKD patients using high performance liquid chromatography and liquid chromatography/tandem mass spectrometry. Our results show that hippuric acid, indoxyl sulfate and kynurenic acid inhibit MRP4-mediated [3H]-methotrexate ([3H]-MTX) uptake (calculated Ki values: 2.5 mM, 1 mM, 25 µM, respectively) and BCRP-mediated [3H]-estrone sulfate ([3H]-E1S) uptake (Ki values: 4 mM, 500 µM and 50 µM, respectively), whereas indole-3-acetic acid and phenylacetic acid reduce [3H]-MTX uptake by MRP4 only (Ki value: 2 mM and IC50 value: 7 mM, respectively). In contrast, p-cresol, p-toluenesulfonic acid, putrescine, oxalate and quinolinic acid did not alter transport mediated by MRP4 or BCRP. In addition, our results show that hippuric acid, indole-3-acetic acid, indoxyl sulfate, kynurenic acid and phenylacetic acid accumulate in plasma of end-stage CKD patients with mean concentrations of 160 µM, 4 µM, 129 µM, 1 µM and 18 µM, respectively. Moreover, calculated Ki values are below the maximal plasma concentrations of the tested toxins. In conclusion, this study shows that several uremic toxins inhibit active transport by MRP4 and BCRP at clinically relevant concentrations. TI - Uremic toxins inhibit transport by breast cancer resistance protein and multidrug resistance protein 4 at clinically relevant concentrations SN - 1932-6203 IS - iss. 4 JF - PLoS One VL - vol. 6 DO - https://doi.org/10.1371/journal.pone.0018438 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/92531/92531.pdf?sequence=1 ER - TY - JOUR AU - Schreuder, M.F. AU - Bueters, R.R.G. AU - Huigen, M.C. AU - Russel, F.G.M. AU - Masereeuw, R. AU - Heuvel, L.P.W.J. van den PY - 2011 UR - https://hdl.handle.net/2066/91750 TI - Effect of drugs on renal development EP - 217 SN - 1555-9041 IS - iss. 1 SP - 212 JF - Clinical Journal of the American Society of Nephrology VL - vol. 6 DO - https://doi.org/10.2215/CJN.04740510 ER - TY - JOUR AU - Copsel, S.N. AU - Garcia, C. AU - Diez, F. AU - Vermeulem, M. AU - Baldi, A. AU - Bianciotti, L.G. AU - Russel, F.G.M. AU - Shayo, C. AU - Davio, C. PY - 2011 UR - https://hdl.handle.net/2066/92098 TI - Multidrug resistance protein 4 (MRP4/ABCC4) regulates cAMP cellular levels and controls human leukemia cell proliferation and differentiation EP - 6988 SN - 0021-9258 IS - iss. 9 SP - 6979 JF - Journal of Biological Chemistry VL - vol. 286 DO - https://doi.org/10.1074/jbc.M110.166868 ER - TY - JOUR AU - Knijn, P.J. AU - Bentum, P.J.M. van AU - Eck, E.R.H. van AU - Fang, C.M. AU - Grimminck, D.L.A.G. AU - Groot, R.A. de AU - Havenith, R.W.A. AU - Marsman, M. AU - Meerts, W.L. AU - Wijs, G.A. de AU - Kentgens, A.P.M. PY - 2010 UR - https://hdl.handle.net/2066/84343 TI - A solid-state NMR and DFT study of compositional modulations in AlxGa1-xAs EP - 11535 SN - 1463-9076 IS - iss. 37 SP - 11517 JF - PCCP Physical Chemistry Chemical Physics VL - vol. 12 PS - 19 p. DO - http://dx.doi.org/10.1039/c003624b ER - TY - JOUR AU - Weber, A.C.J. AU - Lange, C.A. de AU - Meerts, W.L. AU - Burnell, E.E. PY - 2010 UR - https://hdl.handle.net/2066/83912 TI - The butane condensed matter conformational problem EP - 262 SN - 0009-2614 IS - iss. 4-6 SP - 257 JF - Chemical Physics Letters VL - vol. 496 PS - 6 p. DO - http://dx.doi.org/10.1016/j.cplett.2010.07.014 ER - TY - JOUR AU - Lange, C.A. de AU - Meerts, W.L. AU - Weber, A.C.J. AU - Burnell, E.E. PY - 2010 UR - https://hdl.handle.net/2066/84048 TI - Scope and limitations of accurate structure determination of solutes dissolved in liquid crystals EP - 5887 SN - 1089-5639 IS - iss. 18 SP - 5878 JF - The Journal of Physical Chemistry A VL - vol. 114 PS - 10 p. DO - http://dx.doi.org/10.1021/jp1004264 ER - TY - JOUR AU - Gengeliczki, Z. AU - Callahan, M.P. AU - Svadlenak, N. AU - Pongor, C.I. AU - Sztáray, B. AU - Meerts, W.L. AU - Nachtigallová, D. AU - Hobza, P. AU - Barbatti, M. AU - Lischka, H. AU - De Vries, M.S. PY - 2010 UR - https://hdl.handle.net/2066/84203 TI - Effect of substituents on the excited-state dynamics of the modified DNA bases 2,4-diaminopyrimidine and 2,6-diaminopurine EP - 5388 SN - 1463-9076 IS - iss. 20 SP - 5375 JF - PCCP Physical Chemistry Chemical Physics VL - vol. 12 PS - 14 p. DO - http://dx.doi.org/10.1039/b917852j L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/84203/84203.pdf?sequence=1 ER - TY - JOUR AU - Just, G.M.P. AU - Rupper, P. AU - Miller, T.A. AU - Meerts, W.L. PY - 2010 UR - https://hdl.handle.net/2066/84396 TI - High-resolution cavity ringdown spectroscopy of the jet-cooled propyl peroxy radical c3h7o2 EP - 4782 SN - 1463-9076 IS - iss. 18 SP - 4773 JF - PCCP Physical Chemistry Chemical Physics VL - vol. 12 PS - 10 p. DO - http://dx.doi.org/10.1039/b924323b ER - TY - JOUR AU - Masereeuw, R. AU - Russel, F.G.M. PY - 2010 UR - https://hdl.handle.net/2066/87699 AB - One of most important functions of the kidney concerns the clearance of endogenous waste products, exogenously administered drugs as well as environmental exposures. In addition to glomerular filtration, active tubular secretion is an efficient mechanism for extracting compounds from the circulation and excreting them into the urinary compartment, and it presents one of the determinants of a drug's pharmacokinetic behavior. The renal proximal tubules are equipped with a range of transporters, which can be roughly divided into a system for organic anions and one for organic cations, each consisting of multiple carriers with overlapping substrate specificities that cooperate in basolateral drug uptake and luminal excretion. Drug transporters are often involved in clinically significant drug-drug interactions, leading to unexpected changes in drug plasma levels. Similar effects may be observed for the interaction of drugs with endogenous substrates and food components. Furthermore, disease states could affect the expression and/or function of transport systems as well, mainly through regulation of gene transcription. Finally, inter-individual variability and gender differences exist in the expression of drug transporters, which affect overall renal drug handling. This review highlights recent knowledge of the renal organic anion system with special reference to the therapeutic implications associated with variations in transporter activity and drug interactions. TI - Therapeutic implications of renal anionic drug transporters. EP - 216 SN - 0163-7258 IS - iss. 2 SP - 200 JF - Pharmacology and Therapeutics. Part A: Chemotherapy, Toxicology and Metabolic Inhibitors VL - vol. 126 N1 - 1 mei 2010 DO - http://dx.doi.org/10.1016/j.pharmthera.2010.02.007 ER - TY - JOUR AU - Brand, C. van den AU - Oeltermann, O. AU - Pratt, D. AU - Weinkauf, R. AU - Meerts, W.L. AU - Zande, W.J. van der AU - Kleinermanns, K. AU - Schmitt, M. PY - 2010 UR - https://hdl.handle.net/2066/84093 TI - Rotationally resolved electronic spectroscopy of 5-methoxyindole SN - 0021-9606 IS - iss. 2 SP - 024303 JF - Journal of Chemical Physics VL - vol. 133 PS - 11 p. DO - http://dx.doi.org/10.1063/1.3459128 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/84093/84093.pdf?sequence=1 ER - TY - JOUR AU - Heemskerk, S. AU - Peters, J.G.P. AU - Louisse, J. AU - Sagar, S. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2010 UR - https://hdl.handle.net/2066/89462 AB - During endotoxemia, the ATP-dependent drug efflux pump P-glycoprotein (Abcb1/P-gp) is upregulated in kidney proximal tubule epithelial cells. The signaling pathway through which lipopolysaccharide (LPS) or tumor necrosis factor-alpha (TNF-alpha) regulates P-gp expression and activity was investigated further in the present study. Exposure of rat kidney proximal tubule cells to TNF-alpha alone or TNF-alpha and LPS increased P-gp gene and protein expression levels and efflux activity, suggesting de novo P-gp synthesis. Upon exposure to TNF-alpha in combination with LPS, P-gp activity in renal proximal tubule cells is increased under influence of nitric oxide (NO) produced by inducible NO synthase. Upon exposure to TNF-alpha alone, P-gp upregulation seems to involve TLR4 activation and nuclear factor kappaB (NF-kappaB) translocation, a pathway that is likely independent of NO. These findings indicate that at least two pathways regulate P-gp expression in the kidney during endotoxemia. TI - Regulation of P-glycoprotein in renal proximal tubule epithelial cells by LPS and TNF-alpha. EP - 525180 SN - 1110-7243 SP - 525180 JF - Journal of Biomedicine and Biotechnology VL - vol. 2010 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/89462/89462.pdf?sequence=1 ER - TY - JOUR AU - Wagener, F.A.D.T.G. AU - Scharstuhl, A. AU - Tyrrell, R.M. AU - Hoff, J.W. Von den AU - Jozkowicz, A. AU - Dulak, J. AU - Russel, F.G.M. AU - Kuijpers-Jagtman, A.M. PY - 2010 UR - https://hdl.handle.net/2066/87830 AB - Wound healing is an intricate process requiring the concerted action of keratinocytes, fibroblasts, endothelial cells, and macrophages. Here, we review the literature on normal wound healing and the pathological forms of wound healing, such as hypertrophic or excessive scar formation, with special emphasis on the heme-heme oxygenase (HO) system and the versatile effector molecules that are formed after HO-mediated heme degradation. Excessive scar formation following wounding is thought to relate to prolonged oxidative and inflammatory stress in the skin. Evidence is accumulating that the heme-HO system forms a novel and important target in the control of wound healing. Heme-protein derived heme can act as a potent oxidative and inflammatory stress inducer, and excess levels of heme may thus contribute to delayed resolution of oxidative and inflammatory insults in the skin. This emphasizes the need for a timely reduction of the levels of heme. Heme-binding proteins, heme transporters, and the heme degrading protein, HO, form therefore a necessary defense. Deficiencies in these defense proteins or a disturbed redox status, as in diabetic patients, may render individuals more prone to heme-induced deleterious effects. A better understanding of the heme-heme oxygenase system as target during wound healing may result in novel strategies to reduce scar formation. TI - The heme-heme oxygenase system in wound healing; implications for scar formation. EP - 1585 SN - 1389-4501 IS - iss. 12 SP - 1571 JF - Current Drug Targets VL - vol. 11 N1 - 1 december 2010 ER - TY - JOUR AU - Koenderink, J.B. AU - Kavishe, R.A. AU - Rijpma, S.R. AU - Russel, F.G.M. PY - 2010 UR - https://hdl.handle.net/2066/89009 AB - Expanding drug resistance could become a major problem in malaria treatment, as only a limited number of effective antimalarials are available. Drug resistance has been associated with single nucleotide polymorphisms and an increased copy number of multidrug resistance protein 1 (MDR1), an ATP-binding cassette (ABC) protein family member. Many ABC transport proteins are membrane transporters that actively translocate a wide range of structurally and functionally diverse amphipathic compounds. The Plasmodium falciparum ABC family consists of 16 members and current knowledge of their physiological function and contribution to antimalarial drug resistance is limited. Here, we give an overview of the Plasmodium ABC family members with reference to their possible role in multidrug resistance. TI - The ABCs of multidrug resistance in malaria. EP - 446 SN - 1471-4922 IS - iss. 9 SP - 440 JF - Trends in Parasitology VL - vol. 26 N1 - 1 september 2010 DO - https://doi.org/10.1016/j.pt.2010.05.002 ER - TY - JOUR AU - Loo-Bouwman, C.A. Van AU - Naber, T.H. AU - Breemen, R.B. van AU - Zhu, D. AU - Dicke, H. AU - Siebelink, E. AU - Hulshof, P.J. AU - Russel, F.G.M. AU - Schaafsma, G. AU - West, C.E. PY - 2010 UR - https://hdl.handle.net/2066/87496 AB - The objective was to quantify the vitamin A equivalency of beta-carotene in two diets using a dual-isotope dilution technique and the apparent beta-carotene absorption as measured by the oral-faecal balance technique. Seventeen healthy adults with an ileostomy completed the 4-week diet-controlled, cross-over intervention study. Each subject followed both diets for 2 weeks: a diet containing vegetables low in beta-carotene content with supplemental beta-carotene in salad dressing oil ('oil diet'; mean beta-carotene intake 3.1 mg/d) and a diet containing vegetables and fruits high in beta-carotene content ('mixed diet'; mean beta-carotene intake 7.6 mg/d). Daily each subject consumed a mean of 190 microg [13C10]beta-carotene and 195 microg [13C10]retinyl palmitate in oil capsules. The vitamin A equivalency of beta-carotene was calculated as the dose-corrected ratio of [13C5]retinol to [13C10]retinol in serum. Apparent absorption of beta-carotene was determined with oral-faecal balance. Isotopic data quantified a vitamin A equivalency of [13C10]beta-carotene in oil of 3.6:1 (95 % CI 2.8, 4.6) regardless of dietary matrices differences. The apparent absorption of (labelled and dietary) beta-carotene from the 'oil diet' (30 %) was 1.9-fold higher than from the 'mixed diet' (16 %). This extrinsic labelling technique can measure precisely the vitamin A equivalency of beta-carotene in oil capsules, but it does not represent the effect of different dietary matrices. TI - Vitamin A equivalency and apparent absorption of beta-carotene in ileostomy subjects using a dual-isotope dilution technique. EP - 1843 SN - 0007-1145 IS - iss. 12 SP - 1836 JF - British Journal of Nutrition VL - vol. 103 N1 - 1 juni 2010 DO - https://doi.org/10.1017/S0007114509993849 ER - TY - JOUR AU - Huls, M. AU - Schoeber, J.P.H. AU - Verfaillie, C.M. AU - Luttun, A. AU - Ulloa-Montoya, F. AU - Menke, A.L. AU - Bolderen, L.R. van AU - Woestenenk, R.M. AU - Merkx, G.F.M. AU - Wetzels, J.F.M. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2010 UR - https://hdl.handle.net/2066/88153 AB - The kidney has a high capacity to regenerate after ischemic injury via several mechanisms, one of which involves bone marrow-derived (stem) cells. The ATP binding cassette transporters, P-glycoprotein and breast cancer resistance protein, are determinants for the enriched stem and progenitor cell fraction in bone marrow. Because they are upregulated after acute kidney injury, we hypothesized that both efflux pumps may play a role in protecting against renal injury. Surprisingly, transporter-deficient mice were protected against ischemia-induced renal injury. To further study this, bone marrow from irradiated wild-type mice was reconstituted by bone marrow from wild-type, P-glycoprotein- or breast cancer resistance protein-deficient mice. Four weeks later, kidney injury was induced and its function evaluated. Significantly more bone marrow-derived cells were detected in kidneys grafted with transporter-deficient bone marrow. A gender mismatch study suggested that cell fusion of resident tubular cells with bone marrow cells was unlikely. Renal function analyses indicated an absence of renal damage following ischemia-reperfusion in animals transplanted with transporter-deficient bone marrow. When wild-type bone marrow was transplanted in breast cancer resistance protein-deficient mice this protection is lost. Furthermore, we demonstrate that transporter-deficient bone marrow contained significantly more monocytes, granulocytes, and early outgrowth endothelial progenitor cells. TI - Deficiency of either P-glycoprotein or breast cancer resistance protein protect against acute kidney injury. EP - 1208 SN - 0963-6897 IS - iss. 9 SP - 1195 JF - Cell Transplantation VL - vol. 19 DO - https://doi.org/10.3727/096368910X504478 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/88153/88153.pdf?sequence=1 ER - TY - JOUR AU - Wilmer, M.J.G. AU - Saleem, M.A. AU - Masereeuw, R. AU - Ni, L. AU - Velden, T.J.A.M. van der AU - Russel, F.G.M. AU - Mathieson, P.W. AU - Monnens, L.A.H. AU - Heuvel, L.P.W.J. van den AU - Levtchenko, E.N. PY - 2010 UR - https://hdl.handle.net/2066/89888 AB - Reabsorption of filtered solutes from the glomerular filtrate and excretion of waste products and xenobiotics are the main functions of the renal proximal tubular (PT) epithelium. A human PT cell line expressing a range of functional transporters would help to augment current knowledge in renal physiology and pharmacology. We have established and characterized a conditionally immortalized PT epithelial cell line (ciPTEC) obtained by transfecting and subcloning cells exfoliated in the urine of a healthy volunteer. The PT origin of this line has been confirmed morphologically and by the expression of aminopeptidase N, zona occludens 1, aquaporin 1, dipeptidyl peptidase IV and multidrug resistance protein 4 together with alkaline phosphatase activity. ciPTEC assembles in a tight monolayer with limited diffusion of inulin-fluorescein-isothiocyanate. Concentration and time-dependent reabsorption of albumin via endocytosis has been demonstrated, together with sodium-dependent phosphate uptake. The expression and activity of apical efflux transporter p-glycoprotein and of baso-lateral influx transporter organic cation transporter 2 have been shown in ciPTEC. This established human ciPTEC expressing multiple endogenous organic ion transporters mimicking renal reabsorption and excretion represents a powerful tool for future in vitro transport studies in pharmacology and physiology. TI - Novel conditionally immortalized human proximal tubule cell line expressing functional influx and efflux transporters. EP - 457 SN - 0302-766X IS - iss. 2 SP - 449 JF - Cell and Tissue Research VL - vol. 339 N1 - 1 februari 2010 DO - https://doi.org/10.1007/s00441-009-0882-y ER - TY - JOUR AU - Huls, M. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2009 UR - https://hdl.handle.net/2066/75680 AB - ATP binding cassette (ABC) transporters are ATP-dependent membrane proteins predominantly expressed in excretory organs, such as the liver, intestine, blood-brain barrier, blood-testes barrier, placenta, and kidney. Here, they play an important role in the absorption, distribution, and excretion of drugs, xenobiotics, and endogenous compounds. In addition, the ABC transporters, P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2), are highly expressed in a population of primitive stem cells: the side population (SP). SP cells were originally discovered in bone marrow by their capacity to exclude rhodamine 123 and Hoechst dye 33342; however, extensive research also revealed their presence in other nonhematopoietic tissues. The expression levels of BCRP and P-gp are tightly controlled and may determine the differentiation of SP cells toward other more specialized cell types. Although their exact function in these cells is still not clear, they may protect the cells by pumping out toxicants and harmful products of oxidative stress. Transplantation studies in animals revealed that bone marrow-derived SP cells contribute to organ repopulation and tissue repair after damage, e.g., in liver and heart. The role of SP cells in regeneration of damaged kidney segments is not yet clarified. This review focuses on the role of ABC transporters in tissue defense and regeneration, with specific attention to P-gp and BCRP in organ regeneration and repair. TI - The role of ATP binding cassette transporters in tissue defense and organ regeneration. EP - 9 SN - 0022-3565 IS - iss. 1 SP - 3 JF - Journal of Pharmacology and Experimental Therapeutics VL - vol. 328 PS - 7 p. DO - http://dx.doi.org/10.1124/jpet.107.132225 ER - TY - JOUR AU - Kavishe, R.A. AU - Heuvel, J.M.W. van den AU - Vegte-Bolmer, M.G. van de AU - Luty, A.J.F. AU - Russel, F.G.M. AU - Koenderink, J.B. PY - 2009 UR - https://hdl.handle.net/2066/76045 AB - BACKGROUND: The spread of drug resistance has been a major obstacle to the control of malaria. The mechanisms underlying drug resistance in malaria seem to be complex and multigenic. The current literature on multiple drug resistance against anti-malarials has documented PfMDR1, an ATP-binding cassette (ABC) protein, as an important determinant of resistance. In the Plasmodium falciparum genome, there are several ABC transporters some of which could be putative drug transporting proteins. In order to understand the molecular mechanisms underlying drug resistance, characterization of these transporters is essential. The aim of this study was to characterize and localize putative ABC transporters. METHODS: In the plasmoDB database, 16 members of the P. falciparum ABC family can be identified, 11 of which are putative transport proteins. A phylogenetic analysis of the aligned NBDs of the PfABC genes was performed. Antibodies against PfMRP1 (PfABCC1), PfMRP2 (PfABCC2), and PfMDR5 (PfABCB5) were generated, affinity purified and used in immunocytochemistry to localize the proteins in the asexual stages of the parasite. RESULTS: The ABC family members of P. falciparum were categorized into subfamilies. The ABC B subfamily was the largest and contained seven members. Other family members that could be involved in drug transport are PfABCC1, PfABCC2, PfABCG1, and PfABCI3. The expression and localization of three ABC transport proteins was determined. PfMRP1, PfMRP2, and PfMDR5 are localized to the plasma membrane in all asexual stages of the parasite. CONCLUSION: In conclusion, 11 of the 16 ABC proteins in the P. falciparum genome are putative transport proteins, some of which might be involved in drug resistance. Moreover, it was demonstrated that three of these proteins are expressed on the parasite's plasma membrane. TI - Localization of the ATP-binding cassette (ABC) transport proteins PfMRP1, PfMRP2, and PfMDR5 at the Plasmodium falciparum plasma membrane. EP - 205 SN - 1475-2875 SP - 205 JF - Malaria Journal VL - vol. 8 PS - 1 p. L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/76045/76045.pdf?sequence=1 ER - TY - JOUR AU - Heemskerk, S. AU - Masereeuw, R. AU - Moesker, O. AU - Bouw, M.P.W.J.M. AU - Hoeven, J.G. van der AU - Peters, W.H.M. AU - Russel, F.G.M. AU - Pickkers, P. PY - 2009 UR - https://hdl.handle.net/2066/75218 AB - OBJECTIVE: Alkaline phosphatase (AP) attenuates inflammatory responses by lipopolysaccharide detoxification and may prevent organ damage during sepsis. To investigate the effect of AP in patients with severe sepsis or septic shock on acute kidney injury. DESIGN AND SETTING: A multicenter double-blind, randomized, placebo-controlled phase IIa study (2:1 ratio). PATIENTS: Thirty-six intensive care unit patients (20 men/16 women, mean age 58 +/- 3 years) with a proven or suspected Gram-negative bacterial infection, >or=2 systemic inflammatory response syndrome criteria (<24 hours), and <12 hours end-organ dysfunction onset were included. INTERVENTION: An initial bolus intravenous injection (67.5 U/kg body weight) over 10 minutes of AP or placebo, followed by continuous infusion (132.5 U/kg) over the following 23 hours and 50 minutes. MEASUREMENTS AND MAIN RESULTS: Median plasma creatinine levels declined significantly from 91 (73-138) to 70 (60-92) micromol/L only after AP treatment. Pathophysiology of nitric oxide (NO) production and subsequent renal damage were assessed in a subgroup of 15 patients. A 42-fold induction (vs. healthy subjects) in renal inducible NO synthase expression was reduced by 80% +/- 5% after AP treatment. In AP-treated patients, the increase in cumulative urinary NO metabolite excretion was attenuated, whereas the opposite occurred after placebo. Reduced excretion of NO metabolites correlated with the proximal tubule injury marker glutathione S-transferase A1-1 in urine, which decreased by 70 (50-80)% in AP-treated patients compared with an increase by 200 (45-525)% in placebo-treated patients. CONCLUSIONS: In severe sepsis and septic shock, infusion of AP inhibits the upregulation of renal inducible NO synthase, leading to subsequent reduced NO metabolite production, and attenuated tubular enzymuria. This mechanism may account for the observed improvement in renal function. TI - Alkaline phosphatase treatment improves renal function in severe sepsis or septic shock patients. EP - 23, e1 SN - 0090-3493 IS - iss. 2 SP - 417 JF - Critical Care Medicine VL - vol. 37 DO - http://dx.doi.org/10.1097/CCM.0b013e31819598af ER - TY - JOUR AU - Loo-Bouwman, C.A. Van AU - West, C.E. AU - Breemen, R.B. van AU - Zhu, D. AU - Siebelink, E. AU - Versloot, P. AU - Hulshof, P.J. AU - Lieshout, M. van AU - Russel, F.G.M. AU - Schaafsma, G. AU - Naber, A.H.J. PY - 2009 UR - https://hdl.handle.net/2066/75576 AB - Data on the vitamin A equivalency of beta-carotene in food are inconsistent. We quantified the vitamin A equivalency (microg) of beta-carotene in two diets using the dual-isotope dilution technique and the oral-faecal balance technique. A diet-controlled, cross-over intervention study was conducted in twenty-four healthy adults. Each subject followed two diets for 3 weeks each: a diet containing vegetables low in beta-carotene with supplemental beta-carotene in salad dressing oil ('oil diet') and a diet containing vegetables and fruits high in beta-carotene ('mixed diet'). During all 6 weeks, each subject daily consumed a mean of 55 (sd 0.5) microg [13C10]beta-carotene and 55 (sd 0.5) microg [13C10]retinyl palmitate in oil capsules. The vitamin A equivalency of beta-carotene was calculated as the dose-corrected ratio of [13C5]retinol to [13C10]retinol in serum and from apparent absorption by oral-faecal balance. Isotopic data quantified a vitamin A equivalency of [13C10]beta-carotene in oil of 3.4 microg (95 % CI 2.8, 3.9), thus the bio-efficacy of the beta-carotene in oil was 28 % in the presence of both diets. However, data from oral-faecal balance estimated vitamin A equivalency as 6:1 microg (95 % CI 4, 7) for beta-carotene in the 'oil diet'. beta-Carotene in the 'oil diet' had 2.9-fold higher vitamin A equivalency than beta-carotene in the 'mixed diet'. In conclusion, this extrinsic labelling technique cannot measure effects of mixed vegetables and fruits matrices, but can measure precisely the vitamin A equivalency of the beta-carotene in oil capsules. TI - Vitamin A equivalency of beta-carotene in healthy adults: limitation of the extrinsic dual-isotope dilution technique to measure matrix effect. EP - 1845 SN - 0007-1145 IS - iss. 12 SP - 1837 JF - British Journal of Nutrition VL - vol. 101 DO - https://doi.org/10.1017/S0007114508131762 ER - TY - JOUR AU - Scharstuhl, A. AU - Mutsaers, H.A.M. AU - Pennings, S.W.C. AU - Szarek, W.A. AU - Russel, F.G.M. AU - Wagener, F.A.D.T.G. PY - 2009 UR - https://hdl.handle.net/2066/75426 AB - Fibroblast apoptosis plays a crucial role in normal and pathological scar formation and therefore we studied whether the putative apoptosis-inducing factor curcumin affects fibroblast apoptosis and may function as a novel therapeutic. We show that 25-microM curcumin causes fibroblast apoptosis and that this could be inhibited by co-administration of antioxidants N-acetyl-l-cysteine (NAC), biliverdin or bilirubin, suggesting that reactive oxygen species (ROS) are involved. This is supported by our observation that 25-microM curcumin caused the generation of ROS, which could be completely blocked by addition of NAC or bilirubin. Since biliverdin and bilirubin are downstream products of heme degradation by heme oxygenase (HO), it has been suggested that HO-activity protects against curcumin-induced apoptosis. Interestingly, exposure to curcumin maximally induced HO-1 protein and HO-activity at 10-15 microM, whereas, at a concentration of >20-microM curcumin HO-1-expression and HO-activity was negligible. NAC-mediated inhibition of 25-microM curcumin-induced apoptosis was demonstrated to act in part via restored HO-1-induction, since the rescuing effect of NAC could be reduced by inhibiting HO-activity. Moreover pre-induction of HO-1 using 5-microM curcumin protected fibroblasts against 25-microM curcumin-induced apoptosis. On a functional level, fibroblast-mediated collagen gel contraction, an in vitro wound contraction model, was completely prevented by 25-microM curcumin, while this could be reversed by co-incubation with NAC, an effect that was also partially HO-mediated. In conclusion, curcumin treatment in high doses (>25 microM) may provide a novel way to modulate pathological scar formation through the induction of fibroblast apoptosis, while antioxidants, HO-activity and its effector molecules act as a possible fine-tuning regulator. TI - Curcumin-induced fibroblast apoptosis and in vitro wound contraction are regulated by antioxidants and heme oxygenase: implications for scar formation. EP - 725 SN - 1582-4934 IS - iss. 4 SP - 712 JF - Journal of Cellular and Molecular Medicine VL - vol. 13 DO - https://doi.org/10.1111/j.1582-4934.2008.00339.x L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/75426/75426.pdf?sequence=1 ER - TY - JOUR AU - Heemskerk, S. AU - Wouterse, A.C. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2008 UR - https://hdl.handle.net/2066/71089 AB - In the kidney, P-glycoprotein (Abcb1), an ATP-driven drug efflux pump, plays an important role in the detoxification of proximal tubule cells through the excretion of cationic and amphipathic organic compounds. We recently found that NO, produced by renal inducible NO synthase (iNOS), is involved in an up-regulation of P-glycoprotein during endotoxemia in rats. In the present study, we investigated the functional consequences of endotoxemia on the renal handling of rhodamine 123 by using isolated perfused rat kidneys. Wistar Hannover rats were injected intraperitoneally with 5 mg/kg body weight lipopolysaccharide (LPS) or with both LPS and the iNOS inhibitor, aminoguanidine. Despite an increased P-glycoprotein expression, we found a diminished urinary rhodamine 123 clearance 12 h after LPS (P<0.001). In addition, we found a diminished perfusate clearance (P<0.05) for rhodamine 123 after LPS treatment, suggesting a predominant role of influx carriers in urinary rhodamine 123 excretion. We examined the expression levels of organic cation transporter 1 (Slc22a1/Oct1) and Slc22a2/Oct2. Both appeared to be down-regulated at the mRNA and protein level, 12 h after LPS. Co-administration of aminoguanidine attenuated the down-regulation of both Oct1 and Oct2 protein expression and reversed the decrease in rhodamine 123 clearance (P<0.001). These findings indicate that NO, produced by iNOS, is responsible for a down-regulation of the influx carriers, Oct1 and Oct2. TI - Nitric oxide down-regulates the expression of organic cation transporters (OCT) 1 and 2 in rat kidney during endotoxemia. EP - 397 SN - 0014-2999 IS - iss. 2-3 SP - 390 JF - European Journal of Pharmacology VL - vol. 584 PS - 8 p. DO - http://dx.doi.org/10.1016/j.ejphar.2008.02.006 ER - TY - JOUR AU - Heemskerk, S. AU - Haren, F.M. van AU - Foudraine, N.A. AU - Peters, W.H.M. AU - Hoeven, J.G. van der AU - Russel, F.G.M. AU - Masereeuw, R. AU - Pickkers, P. PY - 2008 UR - https://hdl.handle.net/2066/71022 AB - OBJECTIVE: We previously demonstrated that upregulation of renal inducible nitric oxide synthase (iNOS) is associated with proximal tubule injury during systemic inflammation in humans. In this study we investigated the short-term effect of methylene blue (MB), an inhibitor of the NO pathway, on kidney damage and function in septic shock patients. DESIGN AND SETTING: A prospective clinical study conducted in an intensive care unit. PATIENTS: Nine patients (four men, five women, mean age 71 +/- 3 years) with confirmed or suspected bacterial infection and with refractory septic shock defined as a mean arterial pressure < or = 70 mmHg despite norepinephrine infusion > or = 0.2 microg/kg per minute. INTERVENTIONS: A 4 h continuous intravenous infusion of 1 mg/kg MB per hour. MEASUREMENTS AND RESULTS: The urinary excretion of NO metabolites decreased with median 90% (range 75-95%) from baseline to 6 h after MB administration. The first 24 h creatinine clearance improved by 51% (18-173%) after MB treatment but was still strongly impaired. During the first 6 h after the start of MB treatment both the urinary excretion of cytosolic glutathione S-transferase A1-1 and P1-1, markers for proximal and distal tubule damage, respectively, decreased by 45% (10-70%) and 70% (40-85) vs. baseline. After termination of the MB infusion the NO metabolites and markers of tubular injury returned to pretreatment levels. CONCLUSIONS: In septic patients with refractory shock short-term infusion of MB is associated with a decrease in NO production and an attenuation of the urinary excretion of renal tubular injury markers. TI - Short-term beneficial effects of methylene blue on kidney damage in septic shock patients. EP - 354 SN - 0342-4642 IS - iss. 2 SP - 350 JF - Intensive Care Medicine VL - vol. 34 DO - http://dx.doi.org/10.1007/s00134-007-0867-9 ER - TY - JOUR AU - Vegt, E. AU - Eerd-Vismale, J.E.M. van AU - Eek, A. AU - Oyen, W.J.G. AU - Wetzels, J.F.M. AU - Jong, M. de AU - Russel, F.G.M. AU - Masereeuw, R. AU - Gotthardt, M. AU - Boerman, O.C. PY - 2008 UR - https://hdl.handle.net/2066/71199 AB - In most types of peptide receptor radionuclide therapy, the maximum activity dose that can be administered is limited by high and persistent renal retention of the radiolabeled peptides, which is, at least partly, mediated by the megalin receptor. Several agents that interfere with renal reabsorption of radiolabeled peptides have been identified (e.g., lysine, arginine, succinylated gelatin solution), but none of these inhibit renal reabsorption completely. Albumin, a naturally abundant megalin ligand, might be a safe and potent alternative. In this study, we analyzed the effects of albumin and fragments of albumin (FRALB) on the renal reabsorption of (111)In-diethylenetriaminepentaacetic acid (DTPA)-d-Phe(1)-octreotide ((111)In-octreotide), [Lys(40)(aminohexoic acid-DTPA-(111)In)NH(2)]-exendin-4 ((111)In-exendin), and (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-Glu(1)-minigastrin ((111)In-minigastrin). METHODS: The effects of albumin and FRALB on megalin-associated binding of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin were assessed in vitro using rat yolk sac epithelial (BN16) cells. In vivo, uptake and localization of (111)In-albumin and (111)In-FRALB in the kidneys of Wistar rats were determined, as well as the effect of lysine, succinylated gelatin solution, albumin, and FRALB on the kidney uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin. RESULTS: FRALB significantly reduced binding and uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin by BN16 cells. In rats, renal uptake of (111)In-labeled FRALB was significantly higher than that of (111)In-labeled intact albumin (P<0.001). FRALB administration effectively reduced renal uptake of (111)In-octreotide, (111)In-exendin, and (111)In-minigastrin. Administration of 1-2 mg of FRALB reduced renal uptake of (111)In-octreotide as efficiently as 80 mg of lysine. CONCLUSION: Renal uptake of (111)In-octreotide and other radiolabeled peptides in rats can be effectively reduced by administration of albumin fragments. Additional studies to identify the albumin fragments responsible for inhibition of renal peptide uptake are warranted. TI - Reducing renal uptake of radiolabeled peptides using albumin fragments. EP - 1511 SN - 0161-5505 IS - iss. 9 SP - 1506 JF - The Journal of Nuclear Medicine (1978) VL - vol. 49 PS - 6 p. DO - http://dx.doi.org/10.2967/jnumed.108.053249 ER - TY - JOUR AU - Bodde, E.W.H. AU - Boerman, O.C. AU - Russel, F.G.M. AU - Mikos, A.G. AU - Spauwen, P.H.M. AU - Jansen, J.A. PY - 2008 UR - https://hdl.handle.net/2066/70710 AB - The healing of large bone defects can be improved by osteogenic bone graft substitutes, due to growth factor inclusion. A sustained release of these growth factors provides more efficient bioactivity when compared with burst release and might reduce the dose required for bone regeneration, which is desirable for socioeconomical and safety reasons. In this study, we compared different rhBMP-2 loadings in a sustained release system of CaP cement and PLGA-microparticles and were able to couple kinetic to biological activity data. Fifty-two rats received a critical-size cranial defect, which was left open or filled with the cement composites. The implants consisted of plain, high, and five-fold lower dose rhBMP-2 groups. Implantation time was 4 and 12 weeks. Longitudinal in vivo release was monitored by scintigraphic imaging of (131)I-labeled rhBMP-2. Quantitative analysis of the scintigraphic images revealed a sustained release of (131)I-rhBMP-2 for both doses, with different release profiles between the two loadings. However, around 70% of the initial dose was retained in both implant formulations. Although low amounts of rhBMP-2 were released (2.4 +/- 0.8 mug in 5 weeks), histology showed defect bridging in the high-dose implants. Release out of the low-dose implants was not sufficient to enhance bone formation. Implant degradation was limited in all formulations, but was mainly seen in the high-dose group. Low amounts of sustained released rhBMP-2 were sufficient to bridge critically sized defects. A substantial amount of rhBMP-2 was retained in the implants because of the slow release rate and the limited degradation. TI - The kinetic and biological activity of different loaded rhBMP-2 calcium phosphate cement implants in rats. EP - 791 SN - 1549-3296 IS - iss. 3 SP - 780 JF - Journal of Biomedical Materials Research Part A VL - vol. 87 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/70710/70710.pdf?sequence=1 ER - TY - JOUR AU - Wagener, F.A.D.T.G. AU - Toonen, E.J.M. AU - Wigman, L. AU - Fransen, J. AU - Creemers, M.C.W. AU - Radstake, T.R.D.J. AU - Coenen, M.J.H. AU - Barrera Rico, P. AU - Riel, P.L.C.M. van AU - Russel, F.G.M. PY - 2008 UR - https://hdl.handle.net/2066/70109 AB - OBJECTIVE: The guanine-thymidine (GT)n repeat in the HMOX1 promoter determines the level of induction of the heme-degrading enzyme heme oxygenase 1 (HO-1), which protects against inflammatory and oxidative stress. In individuals with short (GT)n repeats (where n < 25; SS genotype), higher levels of HO-1 activity are induced more rapidly than in those with long (GT)n repeats (where n > or = 25; LL genotype). Recently, it was demonstrated that HO-1 activity protects against the onset of rheumatoid arthritis (RA). The aim of this study was to determine whether the (GT)n-repeat length within the HMOX1 promoter region is associated with RA disease severity and radiographic joint damage. METHODS: A cohort of 325 well-characterized RA patients and 273 controls was investigated by DNA fragment-length analysis for the association of (GT)n repeats in the HMOX1 promoter region with RA disease susceptibility and severity. RESULTS: Although no significant differences in genotype or allele frequency were found between controls and RA patients, the odds ratios corresponded well to those in the previously described cohort. Among patients, those carrying the SS genotype had a more favorable radiographic outcome over 9 years than those carrying the LL genotype. This was unexpected since no differences in disease activity were found between the genotypes or alleles. CONCLUSION: Patients with the SS genotype have a better long-term radiographic outcome despite poor prognostic markers at baseline and despite disease activity at followup similar to that of patients with the LL genotype. This suggests that the HMOX1/HO-1 system is involved in the uncoupling of disease activity and joint damage and may provide a novel target for the treatment of RA. TI - HMOX1 promoter polymorphism modulates the relationship between disease activity and joint damage in rheumatoid arthritis. EP - 3393 SN - 0004-3591 IS - iss. 11 SP - 3388 JF - Arthritis and Rheumatism VL - vol. 58 PS - 6 p. DO - https://doi.org/10.1002/art.23970 ER - TY - JOUR AU - Sassi, Y. AU - Lipskaia, L. AU - Vandecasteele, G. AU - Nikolaev, V.O. AU - Hatem, S.N. AU - Cohen Aubart, F. AU - Russel, F.G.M. AU - Mougenot, N. AU - Vrignaud, C. AU - Lechat, P. AU - Lompre, A.M. AU - Hulot, J.S. PY - 2008 UR - https://hdl.handle.net/2066/70676 AB - The second messengers cAMP and cGMP can be degraded by specific members of the phosphodiesterase superfamily or by active efflux transporters, namely the multidrug resistance-associated proteins (MRPs) MRP4 and MRP5. To determine the role of MRP4 and MRP5 in cell signaling, we studied arterial SMCs, in which the effects of cyclic nucleotide levels on SMC proliferation have been well established. We found that MRP4, but not MRP5, was upregulated during proliferation of isolated human coronary artery SMCs and following injury of rat carotid arteries in vivo. MRP4 inhibition significantly increased intracellular cAMP and cGMP levels and was sufficient to block proliferation and to prevent neointimal growth in injured rat carotid arteries. The antiproliferative effect of MRP4 inhibition was related to PKA/CREB pathway activation. Here we provide what we believe to be the first evidence that MRP4 acts as an independent endogenous regulator of intracellular cyclic nucleotide levels and as a mediator of cAMP-dependent signal transduction to the nucleus. We also identify MRP4 inhibition as a potentially new way of preventing abnormal VSMC proliferation. TI - Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation. EP - 2757 SN - 0021-9738 IS - iss. 8 SP - 2747 JF - Journal of Clinical Investigation VL - vol. 118 PS - 11 p. DO - https://doi.org/10.1172/JCI35067 ER - TY - JOUR AU - El-Sheikh, A.A.K. AU - Masereeuw, R. AU - Russel, F.G.M. PY - 2008 UR - https://hdl.handle.net/2066/69190 AB - By utilizing filtration, active secretion and reabsorption processes, the kidney can conserve essential nutrients, and eliminate drugs and potentially toxic compounds. Active uptake of organic anions and cations across the basolateral membrane, and their extrusion into the urine across the brush border membrane mainly takes place in the renal proximal tubule cells, and is facilitated via a range of substrate-specific tubular transporters. Many drugs and their phase II conjugates are anionic compounds, and therefore renal organic anion transporters are important determinants of their distribution and elimination. Competition for renal excretory transporters may cause drugs to accumulate in the body leading to toxicity, which is a potential hazard of concomitant drug administration. Here, we present a brief update on the most prominent human proximal tubule organic anion transporters, which either belong to the ATP-binding cassette (ABC) or the solute carrier transporter (SLC) families. We focus on the participation of the individual transporters in renal anionic drug elimination, in an attempt to understand their overall biological and pharmacological significance, hoping to inspire further studies in the renal transporters field. TI - Mechanisms of renal anionic drug transport. EP - 255 SN - 0014-2999 IS - iss. 2-3 SP - 245 JF - European Journal of Pharmacology VL - vol. 585 PS - 11 p. DO - https://doi.org/10.1016/j.ejphar.2008.02.085 ER - TY - JOUR AU - Huls, M. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2008 UR - https://hdl.handle.net/2066/69695 AB - Acute kidney injury (AKI) is a frequent clinical problem with a high mortality rate, generally caused by ischemic insults. Nevertheless, the kidney has a remarkably high capacity to regenerate after ischemic injury. Tubular cells can restore renal function by proliferation and dedifferentiation into a mesenchymal cell type, but also stem cells residing in bone marrow may contribute. We compiled a protocol from several published methods to study the contribution of bone marrow-derived cells to renal regeneration. Bone marrow was isolated from donor FVB mice and labeled with enhanced green fluorescent protein (eGFP) through adenovirus transduction. After cell sorting, eGFP-labeled cells were transplanted in sublethally irradiated recipient FVB mice. Four weeks after transplantation, we provoked AKI in mice by inducing unilateral ischemic-reperfusion injury for 30 min. Seven days after the injury, eGFP-positive bone marrow-derived cells were clearly detectable in ischemic kidney tissue, and they contribute to the regeneration of approximately 10% of proximal tubular mass. In this review the advantages and shortcomings of our procedure are critically discussed and compared with other methods described. TI - Insights into the role of bone marrow-derived stem cells in renal repair. EP - 110 SN - 1420-4096 IS - iss. 2 SP - 104 JF - Kidney & Blood Pressure Research VL - vol. 31 PS - 7 p. DO - https://doi.org/10.1159/000121387 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/69695/69695.pdf?sequence=1 ER - TY - JOUR AU - El-Sheikh, A.A.K. AU - Heuvel, J.J.M.W. van den AU - Koenderink, J.B. AU - Russel, F.G.M. PY - 2008 UR - https://hdl.handle.net/2066/70432 AB - BACKGROUND AND PURPOSE: The xanthine oxidase inhibitors allopurinol and oxypurinol are used to treat hyperuricaemia, whereas loop and thiazide diuretics can cause iatrogenic hyperuricaemia. Some uricosuric drugs and salicylate have a bimodal action on urate renal excretion. The mechanisms of action of these hypo- and hyperuricaemic drugs on the handling of urate in renal tubules have not been fully elucidated. Recently, we identified the multidrug resistance protein (MRP) 4 as a luminal efflux transporter for urate in the proximal tubule. EXPERIMENTAL APPROACH: Here, we studied the effect of these drugs on [(14)C]urate transport using human embryonic kidney 293 cells overexpressing human MRP4 and in membrane vesicles isolated from these cells. KEY RESULTS: Allopurinol stimulated MRP4-mediated cellular urate efflux and allopurinol and oxypurinol both markedly stimulated urate transport by MRP4 in membrane vesicles. Bumetanide and torasemide had no effect, whereas furosemide, chlorothiazide, hydrochlorothiazide, salicylate, benzbromarone and sulfinpyrazone inhibited urate transport, at concentrations ranging from nanomolar up to millimolar. Probenecid stimulated urate transport at 0.1 microM and inhibited transport at higher concentrations. CONCLUSIONS AND IMPLICATIONS: These data suggest that inhibition of MRP4-mediated urate efflux by furosemide and thiazide diuretics could have an important function in their hyperuricaemic mechanisms. Furthermore, stimulation of MRP4-mediated renal urate efflux could be a new mechanism in the hypouricaemic action of allopurinol and oxypurinol. In conclusion, MRP4 may provide a potential target for drugs affecting urate homoeostasis, which needs to be further evaluated in vivo. TI - Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4. EP - 1075 SN - 0007-1188 IS - iss. 7 SP - 1066 JF - British Journal of Pharmacology VL - vol. 155 PS - 10 p. DO - https://doi.org/10.1038/bjp.2008.343 ER - TY - JOUR AU - Russel, F.G.M. AU - Koenderink, J.B. AU - Masereeuw, R. PY - 2008 UR - https://hdl.handle.net/2066/70675 AB - Multidrug resistance protein (MRP) 4 is a member of the MRP/ABCC subfamily of ATP-binding cassette transporters, which are capable of pumping a wide variety of endogenous and xenobiotic organic anionic compounds out of the cell. In addition to its role in the body distribution and renal excretion of a wide variety of antiviral, cytostatic, antibiotic and cardiovascular drugs, MRP4/ABCC4 has the remarkable ability to transport molecules involved in cellular signalling. These molecules include cyclic nucleotides, eicosanoids, urate and conjugated steroids. The unique structure, regulation and dual localisation of MRP4 in polarised cells could be connected with a key function in cellular protection and extracellular signalling pathways. This review focuses on recent insights into the versatile transport function of MRP4 and its potential as a new therapeutic target to modulate various pathophysiological signalling processes. TI - Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. EP - 207 SN - 0165-6147 IS - iss. 4 SP - 200 JF - Trends in Pharmacological Sciences VL - vol. 29 PS - 8 p. DO - https://doi.org/10.1016/j.tips.2008.01.006 ER - TY - JOUR AU - Huls, M. AU - Brown, C.D. AU - Windass, A.S. AU - Sayer, R. AU - Heuvel, J.J.M.W. van den AU - Heemskerk, S. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2008 UR - https://hdl.handle.net/2066/70782 AB - The Breast Cancer Resistance Protein (BCRP/ABCG2) is a transporter restricting absorption and enhancing excretion of many compounds including anticancer drugs. This transporter is highly expressed in many tissues; however, in human kidney, only the mRNA was found in contrast to the mouse kidney, where the transporter is abundant. In bcrp/abcg2((-/-)) mice, the expression of two sterol transporter genes, abcg5 and abcg8, was strongly increased in the kidney, perhaps as a compensatory mechanism to upregulate efflux. We found using immunohistochemical analysis clear localization of BCRP/ABCG2 to the proximal tubule brush border membrane of the human kidney comparable to that of other ABC transporters such as P-glycoprotein/ABCB1, MRP2/ABCC2, and MRP4/ABCC4. Hoechst 33342 dye efflux from primary human proximal tubule cells was significantly reduced by the BCRP/ABCG2 inhibitors fumitremorgin C and nelfinavir. Our study shows that in addition to other apical ABC transporters, BCRP/ABCG2 may be important in renal drug excretion. TI - The breast cancer resistance protein transporter ABCG2 is expressed in the human kidney proximal tubule apical membrane. EP - 225 SN - 2157-1724 IS - iss. 2 SP - 220 JF - Kidney International. Supplement VL - vol. 73 DO - https://doi.org/10.1038/sj.ki.5002645 ER - TY - JOUR AU - El-Sheikh, A.A.K. AU - Heuvel, J.J.M.W. van den AU - Krieger, E. AU - Russel, F.G.M. AU - Koenderink, J.B. PY - 2008 UR - https://hdl.handle.net/2066/70256 AB - Multidrug resistance protein (MRP) 4 transports a variety of endogenous and xenobiotic organic anions. MRP4 is widely expressed in the body and specifically localized to the renal apical proximal tubule cell membrane, where it mediates the excretion of these compounds into urine. To characterize the MRP4 substrate-binding site, the amino acids Phe368, Phe369, Glu374, Arg375, and Glu378 of transmembrane helix 6, and Arg998 of helix 12, localized in the intracellular half of the central pore, were mutated into the corresponding amino acids of MRP1 and MRP2. Membrane vesicles isolated from human embryonic kidney 293 cells overexpressing these mutants showed significantly reduced methotrexate (MTX) and cGMP transport activity compared with vesicles that expressed wild-type MRP4. The only exception was substitution of Arg375 with serine, which had no effect on cGMP transport but significantly decreased the affinity of MTX. Substitution of the same amino acid with a positively charged lysine returned the MTX affinity to that of the wild type. Furthermore, MTX inhibition of MRP4-mediated cGMP transport was noncompetitive, and the inhibition constant was increased by introduction of the R375S mutation. A homology model of MRP4 showed that Arg375 and Arg998 face right into the central aqueous pore of MRP4. We conclude that positively charged amino acids in transmembrane helices 6 and 12 contribute to the MRP4 substrate-binding pocket. TI - Functional role of arginine 375 in transmembrane helix 6 of multidrug resistance protein 4 (MRP4/ABCC4). EP - 971 SN - 0026-895X IS - iss. 4 SP - 964 JF - Molecular Pharmacology VL - vol. 74 PS - 8 p. DO - https://doi.org/10.1124/mol.107.043661 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/70256/70256.pdf?sequence=1 ER - TY - JOUR AU - Bartels-Stringer, M. AU - Verpalen, J.T.M. AU - Wetzels, J.F.M. AU - Russel, F.G.M. AU - Kramers, C. PY - 2007 UR - https://hdl.handle.net/2066/34571 AB - It has now been firmly established that, not only ischemia/reperfusion, but also cold itself causes damage during kidney transplantation. Iron chelators or anti-oxidants applied during the cold plus rewarming phase are able to prevent this damage. At present, it is unknown if these measures act only during the cold, or whether application during the rewarming phase also prevents damage. We aimed to study this after cold normoxic and hypoxic conditions. LLC-PK1 cells were incubated at 4 degrees C in Krebs-Henseleit buffer for 6 or 24h, followed by 18 or 6h rewarming, respectively. Cold preservation was performed under both normoxic (95% air/5% CO2) and hypoxic (95% N2/5% CO2) conditions. The iron chelator 2,2'-DPD (100 microM), anti-oxidants BHT (20 microM) or sibilinin (200 microM), and xanthine oxidase inhibitor allopurinol (100 microM) were added during either cold preservation plus rewarming, or rewarming alone. Cell damage was assessed by LDH release (n=3-9). Addition of 2,2'-DPD and BHT during cold hypoxia plus rewarming did, but during rewarming alone did not prevent cell damage. When added during rewarming after 6h cold normoxic incubation, BHT and 2,2'-DPD inhibited rewarming injury compared to control (p<0.05). Allopurinol did not prevent cell damage in any experimental set-up. Our data show that application of iron chelators or anti-oxidants during the rewarming phase protects cells after normoxic but not hypoxic incubation. Allopurinol had no effect. Since kidneys are hypoxic during transplantation, measures aimed at preventing cold-induced and rewarming injury should be taken during the cold. TI - Iron chelation or anti-oxidants prevent renal cell damage in the rewarming phase after normoxic, but not hypoxic cold incubation. EP - 264 SN - 0011-2240 IS - iss. 3 SP - 258 JF - Cryobiology VL - vol. 54 DO - http://dx.doi.org/10.1016/j.cryobiol.2007.02.004 ER - TY - JOUR AU - Water, F.M. van de AU - Boleij, J.M. AU - Peters, J.G.P. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2007 UR - https://hdl.handle.net/2066/35029 AB - The activity of P-glycoprotein (Pgp/MDR1/ABCB1) and multidrug resistance proteins (MRP/ABCC) influence the pharmacokinetics and bioavailability of many drugs. Few suitable cell lines for the study of drug transport exist. Additional non-human cell lines may help clarify species differences and contribute to the current knowledge of drug transport. The aim of the present study was to characterize three rat epithelial cell lines for transporter expression and activity. Transporter expression was assessed in intestinal IEC-6 and renal GERP and NRK-52E cells using RT-PCR and Western blot analysis. Pgp and Mrp transport activity were analyzed by measuring calcein accumulation and glutathione-S-bimane efflux, respectively. The three cell lines showed Pgp expression and Pgp-dependent transport, both decreasing with culture time after reaching confluency. Besides Pgp, cells expressed Mrp1, Mrp3, Mrp4, and Mrp5, while Mrp2 and Mrp6 were absent. In addition, they showed temperature- and Mrp-dependent efflux of glutathione-S-bimane. Exposure to a panel of different inhibitors showed that this efflux was probably mediated by Mrp4. In conclusion, the three rat epithelial cell lines investigated showed Pgp and Mrp expression and transport. Mrp dependent transport was most likely mediated by Mrp4. In future, these cell lines may be used as in vitro models to study drug transport. TI - Characterization of P-glycoprotein and multidrug resistance proteins in rat kidney and intestinal cell lines. EP - 44 SN - 0928-0987 IS - iss. 1 SP - 36 JF - European Journal of Pharmaceutical Sciences VL - vol. 30 DO - https://doi.org/10.1016/j.ejps.2006.09.008 ER - TY - JOUR AU - El-Sheikh, A.A.K. AU - Heuvel, J.J.M.W. van den AU - Koenderink, J.B. AU - Russel, F.G.M. PY - 2007 UR - https://hdl.handle.net/2066/34599 AB - Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) in the treatment of inflammatory diseases as well as malignancies. Especially at high MTX dosages, severe adverse effects with this combination may occur, usually resulting from an impaired renal elimination. It has been shown that the mechanism of this interaction cannot be fully attributed to inhibition of basolateral MTX uptake in renal proximal tubules. Here, we studied the effect of various NSAIDs on MTX transport in membrane vesicles isolated from cells overexpressing the proximal tubular apical efflux transporters human multidrug resistance protein (MRP) 2/ABCC2 and MRP4/ABCC4. MTX was transported by MRP2 and MRP4 with Km values of 480 +/- 90 and 220 +/- 70 microM, respectively. The inhibitory potency of the NSAIDs was generally higher against MRP4- than MRP2-mediated MTX transport, with therapeutically relevant IC50 values, ranging from approximately 2 microM to 1.8 mM. Salicylate, piroxicam, ibuprofen, naproxen, sulindac, tolmetin, and etodolac inhibited MRP2- and MRP4-mediated MTX transport according to a one-site competition model. In some cases, more complex interaction patterns were observed. Inhibition of MRP4 by diclofenac and MRP2 by indomethacin and ketoprofen followed a two-site competition model. Phenylbutazone stimulated MRP2 and celecoxib MRP4 transport at low concentrations and inhibited both transporters at high concentration. Our data suggest that the inhibition by NSAIDs of renal MTX efflux via MRP2 and MRP4 is a potential new site and mechanism contributing to the overall interaction between these drugs. TI - Interaction of nonsteroidal anti-inflammatory drugs with multidrug resistance protein (MRP) 2/ABCC2- and MRP4/ABCC4-mediated methotrexate transport. EP - 235 SN - 0022-3565 IS - iss. 1 SP - 229 JF - Journal of Pharmacology and Experimental Therapeutics VL - vol. 320 DO - https://doi.org/10.1124/jpet.106.110379 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/34599/34599.pdf?sequence=1 ER - TY - JOUR AU - Huls, M. AU - Kramers, C. AU - Levtchenko, E.N. AU - Wilmer, M.J.G. AU - Dijkman, H.B.P.M. AU - Kluijtmans, L.A.J. AU - Hoorn, J.W. van der AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2007 UR - https://hdl.handle.net/2066/36285 AB - The multidrug resistance gene 1 product, P-glycoprotein (P-gp), is expressed in several excretory organs, including the apical membrane of proximal tubules. After inducing acute renal failure, P-gp expression is upregulated and this might be a protective function by pumping out toxicants and harmful products of oxidative stress. We characterized renal function of P-gp knockout mice and studied its consequences in renal ischemic damage. Compared with wild-type mice, knockout mice have a lower glomerular filtration rate and renal plasma flow. An augmented urinary excretion of sodium, numerous amino acids, calcium, glucose, and low molecular weight proteins was observed along with an increased diuresis. A higher lithium plasma clearance in the knockout mice suggested proximal tubular dysfunction. Electron microscopy showed mitochondrial abnormalities in proximal tubular cells that could account for decreased adenosine triphosphate levels in the cortex. After inducing ischemia, wild-type mice showed a decrease in creatinine clearance and severe proximal tubular necrosis. In contrast, knockout mice had no signs of tubular damage. Our data indicate that P-gp knockout mice have impaired renal function but are protected against ischemic renal injury. TI - P-glycoprotein-deficient mice have proximal tubule dysfunction but are protected against ischemic renal injury. EP - 1241 SN - 2157-1724 IS - iss. 10 SP - 1233 JF - Kidney International. Supplement VL - vol. 72 DO - https://doi.org/10.1038/sj.ki.5002522 ER - TY - JOUR AU - Vanhoutte, K.J.A. AU - Laarakkers, C.M. AU - Marchiori, E. AU - Pickkers, P. AU - Wetzels, J.F.M. AU - Willems, J.L. AU - Heuvel, L.P.W.J. van den AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2007 UR - https://hdl.handle.net/2066/35077 AB - BACKGROUND: Urine proteomics is one of the key emerging technologies to discover new biomarkers for renal disease, which may be used in the early diagnosis, prognosis and treatment of patients. In the present study, we validated surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) for biomarker discovery in patients with mild ischaemic kidney injury. METHODS: We used first-morning mid-stream urine samples from healthy volunteers, and from intensive care unit patients we collected urine 12-24 h after coronary artery bypass graft (CABG) surgery. Samples of 50 volunteers were mixed to establish a reference sample (master pool). Urine samples were analysed with constant creatinine levels. RESULTS: The average intra- and interchip variation was found to be in the normal experimental range (CV of 10 to 30%). Computational analysis revealed (i) low intra-individual day-to-day variation in individual healthy volunteers; (ii) high concordance between the master pool sample and individual samples. Machine learning techniques for classification of CABG condition vs healthy patients showed that (iii) in the 3-20 kDa range, the joint activity of four protein peaks effectively discriminated the two classes, (iv) in the 20-70 kDa range, a single m/z marker was sufficient to achieve perfect separation. CONCLUSIONS: Our results substantiate the effectiveness of Seldi-TOF MS-based computational analysis as a tool for discovering potential biomarkers in urine samples associated with early renal injury. TI - Biomarker discovery with SELDI-TOF MS in human urine associated with early renal injury: evaluation with computational analytical tools. EP - 2943 SN - 0931-0509 IS - iss. 10 SP - 2932 JF - Nephrology, Dialysis, Transplantation VL - vol. 22 DO - https://doi.org/10.1093/ndt/gfm170 ER - TY - JOUR AU - Heemskerk, S. AU - Koppen, A. van AU - Broek, L. van den AU - Poelen, G.J.M. AU - Wouterse, A.C. AU - Dijkman, H.B.P.M. AU - Russel, F.G.M. AU - Masereeuw, R. PY - 2007 UR - https://hdl.handle.net/2066/35309 AB - Nitric oxide (NO) is an important regulator of renal transport processes. In the present study, we investigated the role of NO, produced by inducible NO synthase (iNOS), in the regulation of renal ATP-binding cassette (ABC) transporters in vivo during endotoxemia. Wistar-Hannover rats were injected with lipopolysaccharide (LPS(+)) alone or in combination with the iNOS inhibitor, aminoguanidine. Controls received detoxified LPS (LPS(-)). After LPS(+), proximal tubular damage and a reduction in renal function were observed. Furthermore, iNOS mRNA and protein, and the amount of NO metabolites in plasma and urine, increased compared to the LPS(-) group. Coadministration with aminoguanidine resulted in an attenuation of iNOS induction and reduction of renal damage. Gene expression of 20 ABC transporters was determined. After LPS(+), a clear up-regulation in Abca1, Abcb1/P-glycoprotein (P-gp), Abcb11/bile salt export pump (Bsep), and Abcc2/multidrug resistance protein (Mrp2) was found, whereas Abcc8 was down-regulated. Up-regulation of Abcc2/Mrp2 was accompanied by enhanced calcein excretion. Aminoguanidine attenuated the effects on transporter expression. Our data indicate that NO, produced locally by renal iNOS, regulates the expression of ABC transporters in vivo. Furthermore, we showed, for the first time, expression and subcellular localization of Abcb11/Bsep in rat kidney. TI - Nitric oxide differentially regulates renal ATP-binding cassette transporters during endotoxemia. EP - 934 SN - 0031-6768 IS - iss. 2 SP - 321 JF - Pflügers Archiv : European Journal of Physiology VL - vol. 454 DO - https://doi.org/10.1007/s00424-007-0210-x ER - TY - JOUR AU - Jurdik, E. AU - Hohlfeld, J. AU - Etteger, A.F. van AU - Toonen, A.J. AU - Meerts, W.L. AU - van Kempen, H. AU - Rasing, T.H.M. PY - 2002 UR - https://hdl.handle.net/2066/92610 TI - Performance optimization of an external enhancement resonator for optical second-harmonic generation EP - 1667 SN - 0740-3224 IS - iss. 7 SP - 1660 JF - Journal of the Optical Society of America B-Optical Physics VL - vol. 19 DO - https://doi.org/10.1364/JOSAB.19.001660 ER - TY - JOUR AU - Remmers, K. AU - Satink, R.G. AU - Helden, G.J. von AU - Piest, H. AU - Meijer, G.J.M. AU - Meerts, W.L. PY - 2000 UR - https://hdl.handle.net/2066/98958 TI - Gas-phase infrared spectroscopy on the lowest triplet state of the pyrazine-argon complex EP - 202 SN - 0009-2614 IS - iss. 3-5 SP - 197 JF - Chemical Physics Letters VL - vol. 317 DO - http://dx.doi.org/10.1016/S0009-2614(99)01387-1 ER - TY - JOUR AU - Smaalen, S. Van AU - Dinnebier, R.E. AU - Milletich, R. AU - Kunz, M. AU - Holleman, I. AU - Helden, G.J. von AU - Meijer, G.J.M. PY - 2000 UR - https://hdl.handle.net/2066/98953 TI - Compressibility of co intercalated c-60 crystals EP - 286 SN - 0009-2614 IS - iss. 3-4 SP - 283 JF - Chemical Physics Letters VL - vol. 319 ER - TY - JOUR AU - Tomaselli, M. AU - Knecht, D.W. AU - Holleman, I. AU - Meijer, G.J.M. AU - Meier, B.H. PY - 2000 UR - https://hdl.handle.net/2066/98955 TI - Evidence for orientational tunneling of co intercalated in c-60: A nuclear magnetic resonance study EP - 5144 SN - 0021-9606 IS - iss. 13 SP - 5141 JF - Journal of Chemical Physics VL - vol. 113 DO - http://dx.doi.org/10.1063/1.1312866 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98955/98955.pdf?sequence=1 ER - TY - JOUR AU - Holleman, I. AU - Helden, G.J. von AU - Avoird, A. van der AU - Meijer, G.J.M. PY - 1999 UR - https://hdl.handle.net/2066/98964 TI - An infrared study on co intercalated in solid c-60 EP - 2139 SN - 0021-9606 IS - iss. 4 SP - 2129 JF - Journal of Chemical Physics VL - vol. 110 DO - http://dx.doi.org/10.1063/1.477822 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98964/98964.pdf?sequence=1 ER - TY - JOUR AU - Holleman, I. AU - Robyr, P. AU - Kentgens, A.P.M. AU - Meier, B.H. AU - Meijer, G.J. PY - 1999 UR - https://hdl.handle.net/2066/76609 TI - Motion of CO molecules in solid C-60 probed by solid-state NMR EP - 207 SN - 0002-7863 IS - iss. 1 SP - 199 JF - Journal of the American Chemical Society VL - vol. 121 PS - 9 p. DO - http://dx.doi.org/10.1021/ja982503z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/76609/76609.pdf?sequence=1 ER - TY - JOUR AU - Holleman, I. AU - Robyr, P. AU - Kentgens, A.P.M. AU - Meier, B.H. AU - Meijer, G.J.M. PY - 1999 UR - https://hdl.handle.net/2066/98973 TI - Motion of co molecules in solid c-60 probed by solid-state nmr EP - 207 SN - 0002-7863 IS - iss. 1 SP - 199 JF - Journal of the American Chemical Society VL - vol. 121 DO - http://dx.doi.org/10.1021/ja982503z L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98973/98973.pdf?sequence=1 ER - TY - JOUR AU - Helden, G.J. von AU - Holleman, I. AU - Meijer, G.J.M. AU - Sartakov, B. PY - 1999 UR - https://hdl.handle.net/2066/98969 TI - Excitation of c-60 using a chirped free electron laser EP - 52 SN - 1094-4087 IS - iss. 2 SP - 46 JF - Optics Express VL - vol. 4 DO - http://dx.doi.org/10.1364/OE.4.000046 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98969/98969.pdf?sequence=1 ER - TY - JOUR AU - Helden, G.J. von AU - Holleman, I. AU - Putter, M. AU - Roij, A.J.A. van AU - Meijer, G.J.M. PY - 1999 UR - https://hdl.handle.net/2066/98970 TI - Infrared resonance enhanced multi-photon ionization spectroscopy of c-84 EP - 176 SN - 0009-2614 IS - iss. 2 SP - 171 JF - Chemical Physics Letters VL - vol. 299 DO - http://dx.doi.org/10.1016/S0009-2614(98)01259-7 ER - TY - JOUR AU - Holleman, I. AU - Helden, G.J. von AU - Avoird, A. van der AU - Meijer, G.J.M. PY - 1998 UR - https://hdl.handle.net/2066/98978 TI - Dynamics of co molecules in solid c-60 as a function of cavity size EP - 4902 SN - 0031-9007 IS - iss. 22 SP - 4899 JF - Physical Review Letters VL - vol. 80 DO - http://dx.doi.org/10.1103/PhysRevLett.80.4899 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98978/98978.pdf?sequence=1 ER - TY - JOUR AU - Smaalen, S. Van AU - Dinnebier, R.E. AU - Schnelle, W. AU - Holleman, I. AU - Helden, G.J. von AU - Meijer, G.J.M. PY - 1998 UR - https://hdl.handle.net/2066/98981 TI - Phase transitions of co-intercalated c-60 crystals EP - 307 SN - 0295-5075 IS - iss. 3 SP - 302 JF - Europhysics Letters VL - vol. 43 DO - http://dx.doi.org/10.1209/epl/i1998-00356-y ER - TY - JOUR AU - Helden, G.J. von AU - Holleman, I. AU - Putter, M. AU - Meijer, G.J.M. PY - 1998 UR - https://hdl.handle.net/2066/98982 TI - Photochemistry of solid c-60 with tunable infrared radiation EP - 167 SN - 0947-8396 IS - iss. 2 SP - 161 JF - Applied Physics a : Materials Science & Processing VL - vol. 67 DO - http://dx.doi.org/10.1007/s003390050755 ER - TY - JOUR AU - Smaalen, S. Van AU - Dinnebier, R. AU - Holleman, I. AU - Helden, G.J. von AU - Meijer, G.J.M. PY - 1998 UR - https://hdl.handle.net/2066/98984 TI - Rotational order in co-intercalated c-60 crystals EP - 6324 SN - 1098-0121 IS - iss. 11 SP - 6321 JF - Physical Review. B, Condensed Matter and Materials Physics VL - vol. 57 DO - http://dx.doi.org/10.1103/PhysRevB.57.6321 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98984/98984.pdf?sequence=1 ER - TY - JOUR AU - Helden, G.J. von AU - Holleman, I. AU - Roij, A.J.A. van AU - Knippels, G.M.H. AU - Meer, A.F.G. van der AU - Meijer, G.J.M. PY - 1998 UR - https://hdl.handle.net/2066/98985 TI - Shedding new light on thermionic electron emission of fullerenes EP - 1828 SN - 0031-9007 IS - iss. 9 SP - 1825 JF - Physical Review Letters VL - vol. 81 DO - http://dx.doi.org/10.1103/PhysRevLett.81.1825 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98985/98985.pdf?sequence=1 ER - TY - JOUR AU - Berg, G.J.B. Van den AU - Heuvel, D.J. Van den AU - Poluektov, O.G. AU - Holleman, I. AU - Meijer, G.J.M. AU - Groenen, E.J.J. PY - 1998 UR - https://hdl.handle.net/2066/98983 TI - Pulsed endor studies at 95 ghz of the triplet state of c-13(60) EP - 45 SN - 1090-7807 IS - iss. 1 SP - 39 JF - Journal of Magnetic Resonance VL - vol. 131 DO - http://dx.doi.org/10.1006/jmre.1997.1343 ER - TY - JOUR AU - Helden, G.J. von AU - Holleman, I. AU - Putter, M. AU - Meijer, G.J.M. PY - 1998 UR - https://hdl.handle.net/2066/98980 TI - Ir spectroscopy on gas-phase molecules with a free electron laser EP - 217 SN - 0168-583X IS - iss. 1-4 SP - 211 JF - Nuclear Instruments & Methods in Physics Research Section B-Beam Interactions with Materials and Atoms VL - vol. 144 DO - http://dx.doi.org/10.1016/S0168-583X(98)00358-9 ER - TY - JOUR AU - Jurdik, E. AU - Bentivegna, F. AU - Petukhov, A.V. AU - Meerts, W.L. AU - Rasing, T.H.M. AU - Kempen, H. van PY - 1998 UR - https://hdl.handle.net/2066/92670 TI - Deposition of magnetic nanostructures of atomic lithography: Semiclassical simulation EP - 196 SN - 0003-4169 SP - 195 JF - Annales de Physique VL - vol. 23 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/92670/92670.pdf?sequence=1 ER - TY - JOUR AU - Holleman, I. AU - Helden, G.J. von AU - Olthof, E.H.T. AU - Bentum, P.J.M. van AU - Engeln, R. AU - Nachtegaal, G.H. AU - Kentgens, A.P.M. AU - Meier, B.H. AU - Avoird, A. van der AU - Meijer, G.J.M. PY - 1997 UR - https://hdl.handle.net/2066/98994 TI - Rovibrational motion of co in solid c-60 EP - 1141 SN - 0031-9007 IS - iss. 6 SP - 1138 JF - Physical Review Letters VL - vol. 79 DO - http://dx.doi.org/10.1103/PhysRevLett.79.1138 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98994/98994.pdf?sequence=1 ER - TY - JOUR AU - Helden, G.J. von AU - Holleman, I. AU - Knippels, G.M.H. AU - Meer, A.F.G. van der AU - Meijer, G.J.M. PY - 1997 UR - https://hdl.handle.net/2066/98991 TI - Infrared resonance enhanced multiphoton ionization of fullerenes EP - 5237 SN - 0031-9007 IS - iss. 26 SP - 5234 JF - Physical Review Letters VL - vol. 79 DO - http://dx.doi.org/10.1103/PhysRevLett.79.5234 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/98991/98991.pdf?sequence=1 ER - TY - JOUR AU - Warntjes, J.B.M. AU - Holleman, I. AU - Meijer, G.J.M. AU - Groenen, E.J.J. PY - 1996 UR - https://hdl.handle.net/2066/99006 TI - Photoluminescence of molecular c-70 at 1.5k. On the nature of the lowest excited states EP - 501 SN - 0009-2614 IS - iss. 4-5 SP - 495 JF - Chemical Physics Letters VL - vol. 261 DO - http://dx.doi.org/10.1016/0009-2614(96)00995-5 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99006/99006.pdf?sequence=1 ER - TY - JOUR AU - Boogaarts, M.G.H. AU - Holleman, I. AU - Jongma, R.T. AU - Parker, D.H. AU - Meijer, G.J.M. AU - Even, U. PY - 1996 UR - https://hdl.handle.net/2066/99002 TI - High rydberg states of dabco: Spectroscopy, ionization potential, and comparison with mass analyzed threshold ionization EP - 4364 SN - 0021-9606 IS - iss. 12 SP - 4357 JF - Journal of Chemical Physics VL - vol. 104 DO - https://doi.org/10.1063/1.471186 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99002/99002.pdf?sequence=1 ER - TY - JOUR AU - Holleman, I. AU - Boogaarts, M.G.H. AU - Bentum, P.J.M. van AU - Meijer, G.J.M. PY - 1995 UR - https://hdl.handle.net/2066/99013 TI - Production and characterization of crystalline c-13(60) EP - 171 SN - 0009-2614 IS - iss. 1-3 SP - 165 JF - Chemical Physics Letters VL - vol. 240 DO - http://dx.doi.org/10.1016/0009-2614(95)00511-2 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99013/99013.pdf?sequence=1 ER - TY - JOUR AU - Boonman, M.E.J. AU - Loosdrecht, P.H.M. van AU - Bethune, D.S. AU - Holleman, I. AU - Meijer, G.J.M. AU - Bentum, P.J.M. van PY - 1995 UR - https://hdl.handle.net/2066/99008 TI - High-frequency electron-spin-resonance in er-m-at-c-2n EP - 326 SN - 0921-4526 IS - iss. 1-4 SP - 323 JF - Physica B - Condensed Matter VL - vol. 211 DO - http://dx.doi.org/10.1016/0921-4526(94)01050-B L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99008/99008.pdf?sequence=1 ER - TY - JOUR AU - Heuvel, D.J. Van den AU - Berg, G.J.B. Van den AU - Groenen, E.J.J. AU - Schmidt, J. AU - Holleman, I. AU - Meijer, G.J.M. PY - 1995 UR - https://hdl.handle.net/2066/99009 TI - Lowest excited singlet-state of c-60 - a vibronic analysis of the fluorescence EP - 11649 SN - 0022-3654 IS - iss. 30 SP - 11644 JF - Journal of Physical Chemistry VL - vol. 99 DO - http://dx.doi.org/10.1021/j100030a004 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99009/99009.pdf?sequence=1 ER - TY - JOUR AU - Jongma, R.T. AU - Boogaarts, M.G.H. AU - Holleman, I. AU - Meijer, G.J.M. PY - 1995 UR - https://hdl.handle.net/2066/99014 TI - Trace gas-detection with cavity ring down spectroscopy EP - 2828 SN - 0034-6748 IS - iss. 4 SP - 2821 JF - Review of Scientific Instruments VL - vol. 66 DO - https://doi.org/10.1063/1.1145562 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99014/99014.pdf?sequence=1 ER - TY - JOUR AU - Holleman, I. AU - Boogaarts, M.G.H. AU - Meijer, G.J.M. PY - 1994 UR - https://hdl.handle.net/2066/99020 TI - Endohedral fullerene research EP - 546 SN - 0165-0513 IS - iss. 12 SP - 543 JF - Recueil des Travaux Chimiques des Pays-Bas VL - vol. 113 ER - TY - JOUR AU - Meijer, G.J.M. AU - Berden, G. AU - Meerts, W.L. AU - Hunziker, H.E. AU - Vries, M.S. De AU - Wendt, H.R. PY - 1992 UR - https://hdl.handle.net/2066/99045 TI - Spectroscopy on triphenylamine and its vanderwaals complexes EP - 222 SN - 0301-0104 IS - iss. 2 SP - 209 JF - Chemical Physics VL - vol. 163 DO - http://dx.doi.org/10.1016/0301-0104(92)87104-H L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99045/99045.pdf?sequence=1 ER - TY - JOUR AU - Versluis, M. AU - Boogaarts, M. AU - Kleindouwel, R. AU - Thus, B. AU - Dejongh, W. AU - Braam, A. AU - Termeulen, J.J. AU - Meerts, W.L. AU - Meijer, G.J.M. PY - 1992 UR - https://hdl.handle.net/2066/99038 TI - Laser-induced fluorescence imaging in a 100 kw natural-gas flame EP - 170 SN - 0721-7269 IS - iss. 2 SP - 164 JF - Applied Physics B. Photophysics and Laser Chemistry VL - vol. 55 DO - http://dx.doi.org/10.1007/BF00324069 L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99038/99038.pdf?sequence=1 ER - TY - JOUR AU - Meijer, G.J.M. AU - Heinze, J. AU - Meerts, W.L. AU - Termeulen, J.J. PY - 1989 UR - https://hdl.handle.net/2066/99065 TI - High-resolution spectroscopy on the a-similar-1b1(0, 6, 0) - x-similar-1a1(0, 0, 0) transition in sicl2 EP - 263 SN - 0022-2852 IS - iss. 1 SP - 251 JF - Journal of Molecular Spectroscopy VL - vol. 138 DO - http://dx.doi.org/10.1016/0022-2852(89)90115-X L1 - https://repository.ubn.ru.nl/bitstream/handle/2066/99065/99065.pdf?sequence=1 ER -