TY  - JOUR
A1  - Li, Jian
A1  - Chen, You-Peng
A1  - Wang, Zi-Neng
A1  - Liu, Tie-Bin
A1  - Chen, Dan
A1  - Dong, Yun-Peng
A1  - Hocher, Berthold
T1  - A functional fetal HSD11B2[CA]n microsatellite polymorphism is associated with maternal serum cortisol concentrations in pregnant women
JF  - Kidney & blood pressure research : official organ of the Gesellschaft für Nephrologie
N2  - Background/Aims: Cortisol plays an important role during pregnancy. It controls maternal glucose metabolism and fetal development. Cortisol metabolism is partially controlled by the 11b-HSD2. This enzyme is expressed in the kidney and human placenta. The activity of the enzyme is partially controlled by functional polymorphisms: the HSD11B2[CA]n microsatellite polymorphism. The impact of this functional gene polymorphism on cortisol metabolism and potential effects on the newborn's is unknown so far. Methods: In the current prospective birth cohort study in southern Asia, we analyzed the association of the HSD11B2[CA]n microsatellite polymorphisms in 187 mothers and their newborn's on maternal and newborn's serum cortisol concentrations. Results: Using multivariable regression analyses considering known confounding ( gestational age, newborn's gender, the labor uterine contraction states and the timing during the day of blood taking), we showed that the fetal HSD11B2[CA]n microsatellite polymorphisms in the first intron was related to maternal cortisol concentration ( R2=0.26, B=96.27, p=0.007), whereas as the newborn's cortisol concentrations were independent of fetal and maternal HSD11B2[CA] n microsatellite polymorphism. Conclusions: Our study showed for the first time that the fetal HSD11B2[CA]n microsatellite polymorphism of the HSD11B2 gene in healthy uncomplicated human pregnancy is associated with maternal cortisol concentration. This indicates that fetal genes controlling cortisol metabolism may affect maternal cortisol concentration and hence physiology in healthy pregnant women.
KW  - Pregnancy
KW  - Placenta
KW  - Cortisol vertical bar metabolism
KW  - 11 beta-hydroxysteroid dehydrogenase 2
KW  - HSD11B2[CA]n polymorphism
Y1  - 2013
U6  - https://doi.org/10.1159/000355761
SN  - 1420-4096
SN  - 1423-0143
VL  - 38
IS  - 1
SP  - 132
EP  - 141
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Klein, Julia
A1  - Darvin, Maxim E.
A1  - Meinke, Martina C.
A1  - Schweigert, Florian J.
A1  - Müller, Kerstin E.
A1  - Lademann, Jürgen
T1  - Analyses of the correlation between dermal and blood carotenoids in female cattle by optical methods
JF  - Journal of biomedical optics
N2  - Herd health programs for the maintenance of welfare and productivity in cattle need efficient tools for monitoring the health of individual animals. Recent reports demonstrate that the oxidative status is related to various stress conditions in dairy cows. Biomarkers, among other carotenoids, could serve as indicators of stress originating from the environment (e.g., heat stress or sun radiation) or from the animal itself (e.g., disease). To date, only invasive in vitro tests are available to assess the oxidative status in cattle. The present study compares the results of optical noninvasive in vivo measurements of dermal carotenoids in cattle udder skin using an LED-based miniaturized spectroscopic system (MSS) with those obtained by photometric analysis of beta carotene in whole blood samples using a portable device. Correlations between the concentrations of dermal and blood carotenoids were calculated under consideration of the nutritional status of the animals. Significant correlation (R = 0.86) was found for cattle with a moderate to obese body condition. Thus, the blood and skin concentrations of the marker substance beta carotene are comparable under stable stress conditions of the cattle. This demonstrates that the MSS is suitable for noninvasive assessment of dermal carotenoid concentrations in cattle.
KW  - Raman spectroscopy
KW  - reflection spectroscopy
KW  - skin
KW  - antioxidants
KW  - free radicals
Y1  - 2013
U6  - https://doi.org/10.1117/1.JBO.18.6.061219
SN  - 1083-3668
VL  - 18
IS  - 6
PB  - SPIE
CY  - Bellingham
ER  - 
TY  - JOUR
A1  - Chaykovska, Lyubov
A1  - Alter, Markus L.
A1  - von Websky, Karoline
A1  - Hohmann, Margarete
A1  - Tsuprykov, Oleg
A1  - Reichetzeder, Christoph
A1  - Kutil, Barbara
A1  - Kraft, Robin
A1  - Klein, Thomas
A1  - Hocher, Berthold
T1  - Effects of telmisartan and linagliptin when used in combination on blood pressure and oxidative stress in rats with 2-kidney-1-clip hypertension
JF  - Journal of hypertension
N2  - Objective:To investigate the effects of linagliptin alone and in combination with the angiotensin II receptor blocker (ARB), telmisartan on blood pressure (BP), kidney function, heart morphology and oxidative stress in rats with renovascular hypertension.Methods:Fifty-seven male Wistar rats underwent unilateral surgical stenosis of the renal artery [2-kidney-1-clip (2k1c) method]. Animals were randomly divided into four treatment groups (n=14-18 per group) receiving: telmisartan (10mg/kg per day in drinking water), linagliptin (89ppm in chow), combination (linagliptin 89ppm+telmisartan 10mg/kg per day) or placebo. An additional group of 12 rats underwent sham surgery. BP was measured one week after surgery. Hypertensive animals entered a 16-week dosing period. BP was measured 2, 4, 8, 12 and 16 weeks after the initiation of treatment. Blood and urine were tested for assessment of kidney function and oxidative stress 6, 10, 14 and 18 weeks after surgery. Blood and urine sampling and organ harvesting were finally performed.Results:Renal stenosis caused an increase in meanSD systolic BP as compared with the sham group (157.7 +/- 29.3 vs. 106.2 +/- 20.5mmHg, respectively; P<0.001). Telmisartan alone and in combination with linagliptin, normalized SBP (111.1 +/- 24.3mmHg and 100.4 +/- 13.9mmHg, respectively; P<0.001 vs. placebo). Telmisartan alone and in combination with linagliptin significantly prevented cardiac hypertrophy, measured by heart weight and myocyte diameter. Renal function measured by cystatin C was not affected by 2k1c surgery. Telmisartan significantly increased plasma concentration of cystatin C. 2k1c surgery initiated fibrosis in both kidneys. Telmisartan promoted further fibrotic changes in the clipped kidney, as measured by protein expression of Col1a1 and histology for interstitial fibrosis and glomerulosclerosis. In non-clipped kidneys, telmisartan demonstrated antifibrotic properties, reducing Col1a1 protein expression. Plasma levels of oxidized low-density lipoprotein were higher in the placebo-treated 2k1c rats as compared to sham-operated animals. The increase was abolished by linagliptin alone (P=0.03 vs. placebo) and in combination with telmisartan (P=0.02 vs. placebo). Combination therapy also significantly reduced plasma concentration of carbonyl proteins (P=0.04 vs. placebo).Conclusion:Inhibition of type 4 dipeptidyl peptidase with linagliptin did not counter BP-lowering effects of ARB in 2k1c rats. Linagliptin reduced lipid and protein oxidation in 2k1c rats, and this effect was BP-independent.
KW  - 2k1c renovascular hypertension
KW  - blood pressure
KW  - DPP4 inhibition
KW  - linagliptin
KW  - oxidative stress
Y1  - 2013
U6  - https://doi.org/10.1097/HJH.0b013e3283649b4d
SN  - 0263-6352
SN  - 1473-5598
VL  - 31
IS  - 11
SP  - 2290
EP  - 2299
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Böhm, Andreas
A1  - Flößer, Anja
A1  - Ermler, Swen
A1  - Fender, Anke C.
A1  - Lüth, Anja
A1  - Kleuser, Burkhard
A1  - Schrör, Karsten
A1  - Rauch, Bernhard H.
T1  - Factor-Xa-induced mitogenesis and migration require sphingosine kinase activity and S1P formation in human vascular smooth muscle cells
JF  - Cardiovascular research
N2  - Sphingosine-1-phosphate (S1P) is a cellular signalling lipid generated by sphingosine kinase-1 (SPHK1). The aim of the study was to investigate whether the activated coagulation factor-X (FXa) regulates SPHK1 transcription and the formation of S1P and subsequent mitogenesis and migration of human vascular smooth muscle cells (SMC).
 FXa induced a time- (36 h) and concentration-dependent (330 nmol/L) increase of SPHK1 mRNA and protein expression in human aortic SMC, resulting in an increased synthesis of S1P. FXa-stimulated transcription of SPHK1 was mediated by the protease-activated receptor-1 (PAR-1) and PAR-2. In human carotid artery plaques, expression of SPHK1 was observed at SMC-rich sites and was co-localized with intraplaque FX/FXa content. FXa-induced SPHK1 transcription was attenuated by inhibitors of Rho kinase (Y27632) and by protein kinase C (PKC) isoforms (GF109203X). In addition, FXa rapidly induced the activation of the small GTPase Rho A. Inhibition of signalling pathways which regulate SPHK1 expression, inhibition of its activity or siRNA-mediated SPHK1 knockdown attenuated the mitogenic and chemotactic response of human SMC to FXa.
 These data suggest that FXa induces SPHK1 expression and increases S1P formation independent of thrombin and that this involves the activation of Rho A and PKC signalling. In addition to its key function in coagulation, this direct effect of FXa on human SMC may increase cell proliferation and migration at sites of vessel injury and thereby contribute to the progression of vascular lesions.
KW  - Factor-Xa
KW  - Atherosclerosis
KW  - Proliferation
KW  - Smooth muscle cells
KW  - Sphingosine kinase-1
Y1  - 2013
U6  - https://doi.org/10.1093/cvr/cvt112
SN  - 0008-6363
VL  - 99
IS  - 3
SP  - 505
EP  - 513
PB  - Oxford Univ. Press
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Jbeily, Nayla
A1  - Suckert, Iris
A1  - Gonnert, Falk A.
A1  - Acht, Benedikt
A1  - Bockmeyer, Clemens L.
A1  - Grossmann, Sascha D.
A1  - Blaess, Markus F.
A1  - Lüth, Anja
A1  - Deigner, Hans-Peter
A1  - Bauer, Michael
A1  - Claus, Ralf A.
T1  - Hyperresponsiveness of mice deficient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response
JF  - Journal of lipid research
N2  - Plasma secretion of acid sphingomyelinase is a hallmark of cellular stress response resulting in the formation of membrane embedded ceramide-enriched lipid rafts and the reorganization of receptor complexes. Consistently, decompartmentalization of ceramide formation from inert sphingomyelin has been associated with signaling events and regulation of the cellular phenotype. Herein, we addressed the question of whether the secretion of acid sphingomyelinase is involved in host response during sepsis. We found an exaggerated clinical course in mice genetically deficient in acid sphingomyelinase characterized by an increased bacterial burden, an increased phagocytotic activity, and a more pronounced cytokine storm. Moreover, on a functional level, leukocyte-endothelial interaction was found diminished in sphingomyelinase-deficient animals corresponding to a distinct leukocytes' phenotype with respect to rolling and sticking as well as expression of cellular surface proteins.(jlr) We conclude that hydrolysis of membrane-embedded sphingomyelin, triggered by circulating sphingomyelinase, plays a pivotal role in the first line of defense against invading microorganisms. This function might be essential during the early phase of infection leading to an adaptive response of remote cells and tissues.-Jbeily, N., I. Suckert, F. A. Gonnert, B. Acht, C. L. Bockmeyer, S. D. Grossmann, M. F. Blaess, A. Lueth, H.-P. Deigner, M. Bauer, and R. A. Claus. Hyperresponsiveness of mice deficient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response. J. Lipid Res. 2013. 54: 410-424.
KW  - sphingomyelin phosphodiesterase 1
KW  - inflammation
KW  - sepsis
KW  - gene expression
KW  - survival
KW  - leukocyte-endothelial interaction
KW  - trans-migration
KW  - organ failure
Y1  - 2013
U6  - https://doi.org/10.1194/jlr.M031625
SN  - 0022-2275
VL  - 54
IS  - 2
SP  - 410
EP  - 424
PB  - American Society for Biochemistry and Molecular Biology
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Lu, Yong-Ping
A1  - Zeng, De-Ying
A1  - Chen, You-Peng
A1  - Liang, Xu-Jing
A1  - Xu, Jie-Ping
A1  - Huang, Si-Min
A1  - Lai, Zhi-Wei
A1  - Wen, Wang-Rong
A1  - von Websky, Karoline
A1  - Hocher, Berthold
T1  - Low birth weight is associated with lower respiratory tract infections in children with hand, foot, and mouth disease
JF  - Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion
N2  - Background: Low birth weight (LBW) might be a risk factor for acquiring lower respiratory tract infections (LRTIs) associated with disease related complications in early childhood. HFMD, a frequent viral infection in southern China, is a leading cause of lower respiratory tract infections in children. We analyzed whether LBW is a risk factor for children with HFMD to develop lower respiratory tract infections.
 Methods: A total of 298 children with HFMD, admitted to a hospital in Qingyuan city, Guangdong province, were recruited. Demographic data and clinical parameters such as serum glucose level and inflammatory markers including peripheral white blood cell count, serum C-reactive protein, and erythrocyte sedimentation rate were routinely collected on admission. Birth weight data were derived from birth records.
 Results: Mean birth weight (BW) was 167 g lower in patients with HFMD and LRTIs as compared to patients with solely HFMD (p = 0.022) and the frequency of birth weight below the tenth percentile was significantly higher in patients with HFMD and LRTIs (p = 0.002).
 Conclusions: The results of the study show that low birth weight is associated with a higher incidence of lower respiratory tract infections in young children with HFMD.
KW  - hand
KW  - foot and mouth disease (HFMD)
KW  - low birth weight (LBW)
KW  - lower respiratory tract infections (LRTIs)
KW  - pneumonia
KW  - children
Y1  - 2013
U6  - https://doi.org/10.7754/Clin.Lab.2012.120725
SN  - 1433-6510
VL  - 59
IS  - 9-10
SP  - 985
EP  - 992
PB  - Clin Lab Publ., Verl. Klinisches Labor
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Espe, Katharina M.
A1  - Raila, Jens
A1  - Henze, Andrea
A1  - Blouin, Katja
A1  - Schneider, Andreas
A1  - Schmiedeke, Daniel
A1  - Krane, Vera
A1  - Pilz, Stefan
A1  - Schweigert, Florian J.
A1  - Hocher, Berthold
A1  - Wanner, Christoph
A1  - Drechsler, Christiane
T1  - Low plasma alpha-tocopherol concentrations and adverse clinical outcomes in diabetic hemodialysis patients
JF  - Clinical journal of the American Society of Nephrology
N2  - Background and objectives Trials with the antioxidant vitamin E have failed to show benefit in the general population. Considering the different causes of death in ESRD, this study investigated the association between plasma concentrations of alpha-tocopherol and specific clinical outcomes in diabetic hemodialysis patients.
 Design, settings, participants, & measurements In 1046 diabetic hemodialysis patients (participants of the German Diabetes and Dialysis Study), alpha-tocopherol was measured in plasma by reversed-phase HPLC. By Cox regression analyses, hazard ratios were determined for prespecified end points according to baseline plasma alpha-tocopherol levels: sudden death (n=134), myocardial infarction (n=172), stroke (n=89), combined cardiovascular events (n=398), fatal infection (n=107), and all-cause mortality (n=508).
 Results Patients had a mean age of 66 8 years, and mean plasma alpha-tocopherol level was 22.8+/-9.6 mu mol/L. Levels of alpha-tocopherol were highly correlated to triglycerides (r=0.63, P<0.001). Patients in the lowest alpha-tocopherol quartile had (in unadjusted analyses) a 79% higher risk of stroke and a 31% higher risk of all-cause mortality compared with patients in the highest quartile. The associations were attenuated after adjustment for confounders (hazard ratio(stroke)=1.56, 95% confidence interval=0.75-3.25; hazard ratio(mortality)=1.22, 95% confidence interval=0.89-1.69, respectively). There was no association between alpha-tocopherol and myocardial infarction, sudden death, or infectious death.
 Conclusions Plasma alpha-tocopherol concentrations were not independently associated with cardiovascular outcomes, infectious deaths, or all-cause mortality in diabetic hemodialysis patients. The lack of association can partly be explained by a confounding influence of malnutrition, which should be considered in the planning of trials to reduce cardiovascular risk in dialysis patients.
Y1  - 2013
U6  - https://doi.org/10.2215/CJN.04880511
SN  - 1555-9041
VL  - 8
IS  - 3
SP  - 452
EP  - 458
PB  - American Society of Nephrology
CY  - Washington
ER  - 
TY  - JOUR
A1  - Horikoshi, Momoko
A1  - Yaghootkar, Hanieh
A1  - Mook-Kanamori, Dennis O.
A1  - Sovio, Ulla
A1  - Taal, H. Rob
A1  - Hennig, Branwen J.
A1  - Bradfield, Jonathan P.
A1  - St Pourcain, Beate
A1  - Evans, David M.
A1  - Charoen, Pimphen
A1  - Kaakinen, Marika
A1  - Cousminer, Diana L.
A1  - Lehtimaki, Terho
A1  - Kreiner-Moller, Eskil
A1  - Warrington, Nicole M.
A1  - Bustamante, Mariona
A1  - Feenstra, Bjarke
A1  - Berry, Diane J.
A1  - Thiering, Elisabeth
A1  - Pfab, Thiemo
A1  - Barton, Sheila J.
A1  - Shields, Beverley M.
A1  - Kerkhof, Marjan
A1  - van Leeuwen, Elisabeth M.
A1  - Fulford, Anthony J.
A1  - Kutalik, Zoltan
A1  - Zhao, Jing Hua
A1  - den Hoed, Marcel
A1  - Mahajan, Anubha
A1  - Lindi, Virpi
A1  - Goh, Liang-Kee
A1  - Hottenga, Jouke-Jan
A1  - Wu, Ying
A1  - Raitakari, Olli T.
A1  - Harder, Marie N.
A1  - Meirhaeghe, Aline
A1  - Ntalla, Ioanna
A1  - Salem, Rany M.
A1  - Jameson, Karen A.
A1  - Zhou, Kaixin
A1  - Monies, Dorota M.
A1  - Lagou, Vasiliki
A1  - Kirin, Mirna
A1  - Heikkinen, Jani
A1  - Adair, Linda S.
A1  - Alkuraya, Fowzan S.
A1  - Al-Odaib, Ali
A1  - Amouyel, Philippe
A1  - Andersson, Ehm Astrid
A1  - Bennett, Amanda J.
A1  - Blakemore, Alexandra I. F.
A1  - Buxton, Jessica L.
A1  - Dallongeville, Jean
A1  - Das, Shikta
A1  - de Geus, Eco J. C.
A1  - Estivill, Xavier
A1  - Flexeder, Claudia
A1  - Froguel, Philippe
A1  - Geller, Frank
A1  - Godfrey, Keith M.
A1  - Gottrand, Frederic
A1  - Groves, Christopher J.
A1  - Hansen, Torben
A1  - Hirschhorn, Joel N.
A1  - Hofman, Albert
A1  - Hollegaard, Mads V.
A1  - Hougaard, David M.
A1  - Hyppoenen, Elina
A1  - Inskip, Hazel M.
A1  - Isaacs, Aaron
A1  - Jorgensen, Torben
A1  - Kanaka-Gantenbein, Christina
A1  - Kemp, John P.
A1  - Kiess, Wieland
A1  - Kilpelainen, Tuomas O.
A1  - Klopp, Norman
A1  - Knight, Bridget A.
A1  - Kuzawa, Christopher W.
A1  - McMahon, George
A1  - Newnham, John P.
A1  - Niinikoski, Harri
A1  - Oostra, Ben A.
A1  - Pedersen, Louise
A1  - Postma, Dirkje S.
A1  - Ring, Susan M.
A1  - Rivadeneira, Fernando
A1  - Robertson, Neil R.
A1  - Sebert, Sylvain
A1  - Simell, Olli
A1  - Slowinski, Torsten
A1  - Tiesler, Carla M. T.
A1  - Toenjes, Anke
A1  - Vaag, Allan
A1  - Viikari, Jorma S.
A1  - Vink, Jacqueline M.
A1  - Vissing, Nadja Hawwa
A1  - Wareham, Nicholas J.
A1  - Willemsen, Gonneke
A1  - Witte, Daniel R.
A1  - Zhang, Haitao
A1  - Zhao, Jianhua
A1  - Wilson, James F.
A1  - Stumvoll, Michael
A1  - Prentice, Andrew M.
A1  - Meyer, Brian F.
A1  - Pearson, Ewan R.
A1  - Boreham, Colin A. G.
A1  - Cooper, Cyrus
A1  - Gillman, Matthew W.
A1  - Dedoussis, George V.
A1  - Moreno, Luis A.
A1  - Pedersen, Oluf
A1  - Saarinen, Maiju
A1  - Mohlke, Karen L.
A1  - Boomsma, Dorret I.
A1  - Saw, Seang-Mei
A1  - Lakka, Timo A.
A1  - Koerner, Antje
A1  - Loos, Ruth J. F.
A1  - Ong, Ken K.
A1  - Vollenweider, Peter
A1  - van Duijn, Cornelia M.
A1  - Koppelman, Gerard H.
A1  - Hattersley, Andrew T.
A1  - Holloway, John W.
A1  - Hocher, Berthold
A1  - Heinrich, Joachim
A1  - Power, Chris
A1  - Melbye, Mads
A1  - Guxens, Monica
A1  - Pennell, Craig E.
A1  - Bonnelykke, Klaus
A1  - Bisgaard, Hans
A1  - Eriksson, Johan G.
A1  - Widen, Elisabeth
A1  - Hakonarson, Hakon
A1  - Uitterlinden, Andre G.
A1  - Pouta, Anneli
A1  - Lawlor, Debbie A.
A1  - Smith, George Davey
A1  - Frayling, Timothy M.
A1  - McCarthy, Mark I.
A1  - Grant, Struan F. A.
A1  - Jaddoe, Vincent W. V.
A1  - Jarvelin, Marjo-Riitta
A1  - Timpson, Nicholas J.
A1  - Prokopenko, Inga
A1  - Freathy, Rachel M.
T1  - New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism
JF  - Nature genetics
N2  - Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood(1). Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits(2). In an expanded genome-wide association metaanalysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism.
Y1  - 2013
U6  - https://doi.org/10.1038/ng.2477
SN  - 1061-4036
VL  - 45
IS  - 1
SP  - 76
EP  - U115
PB  - Nature Publ. Group
CY  - New York
ER  - 
TY  - JOUR
A1  - Neuschäfer-Rube, Frank
A1  - Pathe-Neuschäfer-Rube, A.
A1  - Hippenstiel, S.
A1  - Kracht, M.
A1  - Püschel, Gerhard Paul
T1  - NF-kB-dependent IL-8 induction by prostaglandin EP2 receptors EP1 and EP4
JF  - British journal of pharmacology : journal of The British Pharmacological Society
N2  - Background and Purpose Recent studies suggested a role for PGE2 in the expression of the chemokine IL-8. PGE2 signals via four different GPCRs, EP1-EP4. The role of EP1 and EP4 receptors for IL-8 induction was studied in HEK293 cells, overexpressing EP1 (HEK-EP1), EP4 (HEK-EP4) or both receptors (HEK-EP1 + EP4). Experimental Approach IL-8 mRNA and protein induction and IL-8 promoter and NF-?B activation were assessed in EP expressing HEK cells. Key Results In HEK-EP1 and HEK-EP1 + EP4 but not HEK or HEK-EP4 cells, PGE2 activated the IL-8 promoter and induced IL-8 mRNA and protein synthesis. Stimulation of HEK-EP1 + EP4 cells with an EP1-specific agonist activated IL-8 promoter and induced IL-8 mRNA and protein, whereas a specific EP4 agonist neither activated the IL-8 promoter nor induced IL-8 mRNA and protein synthesis. Simultaneous stimulation of HEK- EP1 + EP4 cells with both agonists activated IL-8 promoter and induced IL-8 mRNA to the same extent as PGE2. In HEK-EP1 + EP4 cells, PGE2-mediated IL-8 promoter activation and IL-8 mRNA induction were blunted by inhibition of I?B kinase. PGE2 activated NF-?B in HEK-EP1, HEK-EP4 and HEK-EP1 + EP4 cells. In HEK-EP1 + EP4 cells, simultaneous activation of both receptors was needed for maximal PGE2-induced NF-?B activation. PGE2-stimulated NF-?B activation by EP1 was blocked by inhibitors of PLC, calcium-signalling and Src-kinase, whereas that induced by EP4 was only blunted by Src-kinase inhibition. Conclusions and Implications These findings suggest that PGE2-mediated NF-?B activation by simultaneous stimulation of EP1 and EP4 receptors induces maximal IL-8 promoter activation and IL-8 mRNA and protein induction.
KW  - prostaglandin receptor
KW  - NF-?B
KW  - IL-8 transcription
KW  - signal transduction
Y1  - 2013
U6  - https://doi.org/10.1111/j.1476-5381.2012.02182.x
SN  - 0007-1188
VL  - 168
IS  - 3
SP  - 704
EP  - 717
PB  - Wiley-Blackwell
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Tepel, Martin
A1  - Armbruster, Franz Paul
A1  - Groen, Hans Juergen
A1  - Scholze, Alexandra
A1  - Reichetzeder, Christoph
A1  - Roth, Heinz Jürgen
A1  - Hocher, Berthold
T1  - Nonoxidized, biologically active parathyroid hormone determines mortality in hemodialysis patients
JF  - The journal of clinical endocrinology & metabolism
N2  - Background: It was shown that nonoxidized PTH (n-oxPTH) is bioactive, whereas the oxidation of PTH results in a loss of biological activity.
 Methods: In this study we analyzed the association of n-oxPTH on mortality in hemodialysis patients using a recently developed assay system.
 Results: Hemodialysis patients (224 men, 116 women) had a median age of 66 years. One hundred seventy patients (50%) died during the follow-up period of 5 years. Median n-oxPTH levels were higher in survivors (7.2 ng/L) compared with deceased patients (5.0 ng/L; P = .002). Survival analysis showed an increased survival in the highest n-oxPTH tertile compared with the lowest n-oxPTH tertile (chi(2), 14.3; P = 0008). Median survival was 1702 days in the highest n-oxPTH tertile, whereas it was only 453 days in the lowest n-oxPTH tertile. Multivariable-adjusted Cox regression showed that higher age increased odds for death, whereas higher n-oxPTH reduced the odds for death. Another model analyzing a subgroup of patients with intact PTH (iPTH) concentrations at baseline above the upper normal range of the iPTH assay (70 ng/L) revealed that mortality in this subgroup was associated with oxidized PTH but not with n-oxPTH levels.
 Conclusions: The predictive power of n-oxPTH and iPTH on the mortality of hemodialysis patients differs substantially. Measurements of n-oxPTH may reflect the hormone status more precisely. The iPTH-associated mortality is most likely describing oxidative stress-related mortality.
Y1  - 2013
U6  - https://doi.org/10.1210/jc.2013-2139
SN  - 0021-972X
SN  - 1945-7197
VL  - 98
IS  - 12
SP  - 4744
EP  - 4751
PB  - Endocrine Society
CY  - Chevy Chase
ER  - 
TY  - JOUR
A1  - Lotinun, Sutada
A1  - Kiviranta, Riku
A1  - Matsubara, Takuma
A1  - Alzate, Jorge A.
A1  - Neff, Lynn
A1  - Lüth, Anja
A1  - Koskivirta, Ilpo
A1  - Kleuser, Burkhard
A1  - Vacher, Jean
A1  - Vuorio, Eero
A1  - Horne, William C.
A1  - Baron, Roland
T1  - Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation
JF  - The journal of clinical investigation
N2  - Cathepsin K (CTSK) is secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption. Global deletion of Ctsk in mice decreases bone resorption, leading to osteopetrosis, but also increases the bone formation rate (BFR). To understand how Ctsk deletion increases the BFR, we generated osteoclast- and osteoblast-targeted Ctsk knockout mice using floxed Ctsk alleles. Targeted ablation of Ctsk in hematopoietic cells, or specifically in osteoclasts and cells of the monocyte-osteoclast lineage, resulted in increased bone volume and BFR as well as osteoclast and osteoblast numbers. In contrast, targeted deletion of Ctsk in osteoblasts had no effect on bone resorption or BFR, demonstrating that the increased BFR is osteoclast dependent. Deletion of Ctsk in osteoclasts increased their sphingosine kinase 1 (Sphk1) expression. Conditioned media from Ctsk-deficient osteoclasts, which contained elevated levels of sphingosine-l-phosphate (S1P), increased alkaline phosphatase and mineralized nodules in osteoblast cultures. An S1P(1,3) receptor antagonist inhibited these responses. Osteoblasts derived from mice with Ctsk-deficient osteoclasts had an increased RANKL/OPG ratio, providing a positive feedback loop that increased the number of osteoclasts. Our data provide genetic evidence that deletion of CTSK in osteoclasts enhances bone formation in vivo by increasing the generation of osteoclast-derived S1P.
Y1  - 2013
U6  - https://doi.org/10.1172/JCI64840
SN  - 0021-9738
VL  - 123
IS  - 2
SP  - 666
EP  - 681
PB  - American Society for Clinical Investigation
CY  - Ann Arbor
ER  - 
TY  - JOUR
A1  - Münzner, Matthias
A1  - Tuvia, Neta
A1  - Deutschmann, Claudia
A1  - Witte, Nicole
A1  - Tolkachov, Alexander
A1  - Valai, Atijeh
A1  - Henze, Andrea
A1  - Sander, Leif E.
A1  - Raila, Jens
A1  - Schupp, Michael
T1  - Retinol-binding protein 4 and its membrane receptor STRA6 control adipogenesis by regulating cellular retinoid homeostasis and retinoic acid receptor alpha activity
JF  - Molecular and cellular biology
N2  - Retinoids are vitamin A (retinol) derivatives and complex regulators of adipogenesis by activating specific nuclear receptors, including the retinoic acid receptor (RAR) and retinoid X receptor (RXR). Circulating retinol-binding protein 4 (RBP4) and its membrane receptor STRA6 coordinate cellular retinol uptake. It is unknown whether retinol levels and the activity of RAR and RXR in adipocyte precursors are linked via RBP4/STRA6. Here, we show that STRA6 is expressed in precursor cells and, dictated by the apo-and holo-RBP4 isoforms, mediates bidirectional retinol transport that controls RAR alpha activity and subsequent adipocyte differentiation. Mobilization of retinoid stores in mice by inducing RBP4 secretion from the liver activated RAR alpha signaling in the precursor cell containing the stromal-vascular fraction of adipose tissue. Retinol-loaded holo-RBP4 blocked adipocyte differentiation of cultured precursors by activating RAR alpha. Remarkably, retinol-free apo-RBP4 triggered retinol efflux that reduced cellular retinoids, RAR alpha activity, and target gene expression and enhanced adipogenesis synergistically with ectopic STRA6. Thus, STRA6 in adipocyte precursor cells links nuclear RAR alpha activity to the circulating RBP4 isoforms, whose ratio in obese mice was shifted toward limiting the adipogenic potential of their precursors. This novel cross talk identifies a retinoldependent metabolic function of RBP4 that may have important implications for the treatment of obesity.
Y1  - 2013
U6  - https://doi.org/10.1128/MCB.00221-13
SN  - 0270-7306
SN  - 1098-5549
VL  - 33
IS  - 20
SP  - 4068
EP  - 4082
PB  - American Society for Microbiology
CY  - Washington
ER  - 
TY  - JOUR
A1  - Schaper, Katrin
A1  - Dickhaut, Jeannette
A1  - Japtok, Lukasz
A1  - Kietzmann, Manfred
A1  - Mischke, Reinhard
A1  - Kleuser, Burkhard
A1  - Bäumer, Wolfgang
T1  - Sphingosine-1-phosphate exhibits anti-proliferative and anti-inflammatory effects in mouse models of psoriasis
JF  - Journal of dermatological scienc
N2  - Background: It has been indicated that the sphingolipid sphingosine-1-phosphate (SIP) restrains the ability of dendritic cells to migrate to lymph nodes. Furthermore SIP has been demonstrated to inhibit cell growth in human keratinocytes. However, only little is known about the effect of S1P in hyperproliferative and inflammatory in vivo models.
 Objective: In this study, locally acting SIP was explored in different experimental mouse models of psoriasis vulgaris.
 Methods: S1P and FTY720 were tested in the imiquimod-induced psoriasis mouse model, the mouse tail assay and a pilot study of the severe combined immunodeficiency mice (SCID).
 Results: In the imiquimod model the positive control diflorasone diacetate and S1P, but not FTY720 reduced the imiquimod-induced epidermal hyperproliferation of the ear skin. This effect was confirmed in the SCID model, where S1P treated skin from patients suffering from psoriasis showed a decrease in epidermal thickness compared to vehicle. In the imiquimod model, there was also significant inhibition of ear swelling and a moderate reduction of inflammatory cell influx and oedema formation in ear skin by SIP treatment. The inflammatory response on the back skin was, however, only reduced by diflorasone diacetate. In the mouse tail assay, the influence of S1P and FTY720 in stratum granulosum formation was tested compared to the positive control calcipotriol. Whereas topical administration of calcipotriol led to a low but significant increase of stratum granulosum, S1P and FTY720 lacked such an effect.
 Conclusion: Taken together, these results imply that topical administration of SIP might be a new option for the treatment of mild to moderate psoriasis lesions.
KW  - Imiquimod
KW  - Psoriasis
KW  - SCID mice
KW  - Sphingosine-1-phosphate
Y1  - 2013
U6  - https://doi.org/10.1016/j.jdermsci.2013.03.006
SN  - 0923-1811
VL  - 71
IS  - 1
SP  - 29
EP  - 36
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Hocher, Berthold
A1  - Sharkovska, Yuliya
A1  - Mark, Michael
A1  - Klein, Thomas
A1  - Pfab, Thiemo
T1  - The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats
JF  - International journal of cardiology
N2  - Background: Dipeptidylpeptidase-4 inhibition is reported to have beneficial effects on myocardial ischemia. Mechanisms might include a reduced degradation of stromal cell-derived factor-1 alpha with subsequent increased recruitment of circulating stem cells and/or incretin receptor-dependent pathways. This study evaluated the novel xanthine-based dipeptidylpeptidase-4 inhibitors linagliptin (BI 1356) and BI 14361 in cardiac ischemia.
 Methods: Male Wistar rats were pretreated with linagliptin or BI 14361 and subjected to ligation of the left anterior descending coronary artery for 30 min.
 Results: Dipeptidylpeptidase-4 inhibition significantly reduced the infarct size after 7 days (-27.7%, p<0.05) and 8 weeks (-18.0%, p<0.05). There was a significantly improved maximum rate of left ventricular pressure decline (dP/dt min) in linagliptin-treated animals 8 weeks after ischemia/reperfusion. Apart from that, treatment did not improve cardiac function as determined by echocardiography and cardiac catheterization. Immunohistological staining revealed an increased number of cells positive for stromal cell-derived factor-1 alpha, CXCR-4 and CD34 within and around the infarcted area of BI 14361-treated animals.
 Conclusions: Linagliptin and BI 14361 are able to reduce infarct size after myocardial ischemia. The immunohistological findings support the hypothesis that dipeptidylpeptidase-4 inhibition via reduced cleavage of stromal cell-derived factor-1 alpha might lead to an enhanced recruitment of CXCR-4+ circulating progenitor cells.
KW  - Dipeptidylpeptidase-4
KW  - Stromal cell-derived factor-1
KW  - Cardiac ischemia/reperfusion
KW  - Myocardial ischemia
KW  - Infarct size
KW  - Rats
Y1  - 2013
U6  - https://doi.org/10.1016/j.ijcard.2011.12.007
SN  - 0167-5273
VL  - 167
IS  - 1
SP  - 87
EP  - 93
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Gerecke, Christian
A1  - Mascher, Conny
A1  - Gottschalk, Uwe
A1  - Kleuser, Burkhard
A1  - Scholtka, Bettina
T1  - Ultrasensitive detection of unknown colon cancer-initiating mutations using the example of the adenomatous polyposis coli gene
JF  - Cancer prevention research
N2  - Detection of cancer precursors contributes to cancer prevention, for example, in the case of colorectal cancer. To record more patients early, ultrasensitive methods are required for the purpose of noninvasive precursor detection in body fluids. Our aim was to develop a method for enrichment and detection of known as well as unknown driver mutations in the Adenomatous polyposis coli (APC) gene. By coupled wild-type blocking (WTB) PCR and high-resolution melting (HRM), referred to as WTB-HRM, a minimum detection limit of 0.01% mutant in excess wild-type was achieved according to as little as 1 pg mutated DNA in the assay. The technique was applied to 80 tissue samples from patients with colorectal cancer (n = 17), adenomas (n = 50), serrated lesions (n = 8), and normal mucosa (n = 5). Any kind of known and unknown APC mutations (deletions, insertions, and base exchanges) being situated inside the mutation cluster region was distinguishable from wild-type DNA. Furthermore, by WTB-HRM, nearly twice as many carcinomas and 1.5 times more precursor lesions were identified to be mutated in APC, as compared with direct sequencing. By analyzing 31 associated stool DNA specimens all but one of the APC mutations could be recovered. Transferability of the WTB-HRM method to other genes was proven using the example of KRAS mutation analysis. In summary, WTB-HRM is a new approach for ultrasensitive detection of cancer-initiating mutations. In this sense, it appears especially applicable for noninvasive detection of colon cancer precursors in body fluids with excess wild-type DNA like stool. Cancer Prev Res; 6(9); 898-907. (C) 2013 AACR.
Y1  - 2013
U6  - https://doi.org/10.1158/1940-6207.CAPR-13-0145
SN  - 1940-6207
VL  - 6
IS  - 9
SP  - 898
EP  - 907
PB  - American Association for Cancer Research
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Carlsohn, Anja
A1  - Scharhag-Rosenberger, Friederike
A1  - Heydenreich, Juliane
A1  - Mayer, Frank
T1  - Vitamin-D-Status of athletes with higher UV-exposure during training
JF  - Ernährungs-Umschau : Forschung & Praxis
Y1  - 2013
SN  - 0174-0008
VL  - 60
IS  - 10
SP  - 174
EP  - 176
PB  - Umschau-Zeitschriftenverl.
CY  - Frankfurt, Main
ER  -