@article{NeuschaeferRubeLieskeKunaetal.2014,
  author    = {Neuschaefer-Rube, Frank and Lieske, Stefanie and Kuna, Manuela and Henkel, Janin and Perry, Rachel J. and Erion, Derek M. and Pesta, Dominik and Willmes, Diana M. and Brachs, Sebastian and von Loeffelholz, Christian and Tolkachov, Alexander and Schupp, Michael and Pathe-Neuschaefer-Rube, Andrea and Pfeiffer, Andreas F. H. and Shulman, Gerald I. and P{\"u}schel, Gerhard Paul and Birkenfeld, Andreas L.},
  title     = {The mammalian INDY homolog is induced by CREB in a rat model of type 2 diabetes},
  series = {Diabetes : a journal of the American Diabetes Association},
  volume    = {63},
  journal   = {Diabetes : a journal of the American Diabetes Association},
  number    = {3},
  publisher = {American Diabetes Association},
  address   = {Alexandria},
  issn      = {0012-1797},
  pages     = {1048 -- 1057},
  year      = {2014},
  language  = {en}
}
@article{PastukhovSchwalmZangemeisterWittkeetal.2014,
  author    = {Pastukhov, Oleksandr and Schwalm, Stephanie and Zangemeister-Wittke, Uwe and Fabbro, Doriano and Bornancin, Frederic and Japtok, Lukasz and Kleuser, Burkhard and Pfeilschifter, Josef and Huwiler, Andrea},
  title     = {The ceramide kinase inhibitor NVP-231 inhibits breast and lung cancer cell proliferation by inducing M phase arrest and subsequent cell death},
  series = {British journal of pharmacology : journal of The British Pharmacological Society},
  volume    = {171},
  journal   = {British journal of pharmacology : journal of The British Pharmacological Society},
  number    = {24},
  publisher = {Wiley-Blackwell},
  address   = {Hoboken},
  issn      = {0007-1188},
  doi       = {10.1111/bph.12886},
  pages     = {5829 -- 5844},
  year      = {2014},
  abstract  = {Background and PurposeCeramide kinase (CerK) catalyzes the generation of ceramide-1-phosphate which may regulate various cellular functions, including inflammatory reactions and cell growth. Here, we studied the effect of a recently developed CerK inhibitor, NVP-231, on cancer cell proliferation and viability and investigated the role of cell cycle regulators implicated in these responses. Experimental ApproachThe breast and lung cancer cell lines MCF-7 and NCI-H358 were treated with increasing concentrations of NVP-231 and DNA synthesis, colony formation and cell death were determined. Flow cytometry was performed to analyse cell cycle distribution of cells and Western blot analysis was used to detect changes in cell cycle regulator expression and activation. Key ResultsIn both cell lines, NVP-231 concentration-dependently reduced cell viability, DNA synthesis and colony formation. Moreover it induced apoptosis, as measured by increased DNA fragmentation and caspase-3 and caspase-9 cleavage. Cell cycle analysis revealed that NVP-231 decreased the number of cells in S phase and induced M phase arrest with an increased mitotic index, as determined by increased histone H3 phosphorylation. The effect on the cell cycle was even more pronounced when NVP-231 treatment was combined with staurosporine. Finally, overexpression of CerK protected, whereas down-regulation of CerK with siRNA sensitized, cells for staurosporine-induced apoptosis. Conclusions and ImplicationsOur data demonstrate for the first time a crucial role for CerK in the M phase control in cancer cells and suggest its targeted inhibition, using drugs such as NVP-231, in combination with conventional pro-apoptotic chemotherapy.},
  language  = {en}
}
@article{PewznerJungTabazavarehGrassmeetal.2014,
  author    = {Pewzner-Jung, Yael and Tabazavareh, Shaghayegh Tavakoli and Grassme, Heike and Becker, Katrin Anne and Japtok, Lukasz and Steinmann, Joerg and Joseph, Tammar and Lang, Stephan and Tuemmler, Burkhard and Schuchman, Edward H. and Lentsch, Alex B. and Kleuser, Burkhard and Edwards, Michael J. and Futerman, Anthony H. and Gulbins, Erich},
  title     = {Sphingoid long chain bases prevent lung infection by Pseudomonas aeruginosa},
  series = {EMBO molecular medicine},
  volume    = {6},
  journal   = {EMBO molecular medicine},
  number    = {9},
  publisher = {Wiley-Blackwell},
  address   = {Hoboken},
  issn      = {1757-4676},
  doi       = {10.15252/emmm.201404075},
  pages     = {1205 -- 1214},
  year      = {2014},
  abstract  = {Cystic fibrosis patients and patients with chronic obstructive pulmonary disease, trauma, burn wound, or patients requiring ventilation are susceptible to severe pulmonary infection by Pseudomonas aeruginosa. Physiological innate defense mechanisms against this pathogen, and their alterations in lung diseases, are for the most part unknown. We now demonstrate a role for the sphingoid long chain base, sphingosine, in determining susceptibility to lung infection by P.aeruginosa. Tracheal and bronchial sphingosine levels were significantly reduced in tissues from cystic fibrosis patients and from cystic fibrosis mouse models due to reduced activity of acid ceramidase, which generates sphingosine from ceramide. Inhalation of mice with sphingosine, with a sphingosine analog, FTY720, or with acid ceramidase rescued susceptible mice from infection. Our data suggest that luminal sphingosine in tracheal and bronchial epithelial cells prevents pulmonary P.aeruginosa infection in normal individuals, paving the way for novel therapeutic paradigms based on inhalation of acid ceramidase or of sphingoid long chain bases in lung infection.},
  language  = {en}
}
@article{PieperWeheBornhorstetal.2014,
  author    = {Pieper, Imke and Wehe, Christoph A. and Bornhorst, Julia and Ebert, Franziska and Leffers, Larissa and Holtkamp, Michael and Hoeseler, Pia and Weber, Till and Mangerich, Aswin and Buerkle, Alexander and Karst, Uwe and Schwerdtle, Tanja},
  title     = {Mechanisms of Hg species induced toxicity in cultured human astrocytes: genotoxicity and DNA-damage response},
  series = {Metallomics : integrated biometal science},
  volume    = {6},
  journal   = {Metallomics : integrated biometal science},
  number    = {3},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {1756-5901},
  doi       = {10.1039/c3mt00337j},
  pages     = {662 -- 671},
  year      = {2014},
  abstract  = {The toxicologically most relevant mercury (Hg) species for human exposure is methylmercury (MeHg). Thiomersal is a common preservative used in some vaccine formulations. The aim of this study is to get further mechanistic insight into the yet not fully understood neurotoxic modes of action of organic Hg species. Mercury species investigated include MeHgCl and thiomersal. Additionally HgCl2 was studied, since in the brain mercuric Hg can be formed by dealkylation of the organic species. As a cellular system astrocytes were used. In vivo astrocytes provide the environment necessary for neuronal function. In the present study, cytotoxic effects of the respective mercuricals increased with rising alkylation level and correlated with their cellular bioavailability. Further experiments revealed for all species at subcytotoxic concentrations no induction of DNA strand breaks, whereas all species massively increased H2O2-induced DNA strand breaks. This co- genotoxic effect is likely due to a disturbance of the cellular DNA damage response. Thus, at nanomolar, sub-cytotoxic concentrations, all three mercury species strongly disturbed poly(ADP-ribosyl)ation, a signalling reaction induced by DNA strand breaks. Interestingly, the molecular mechanism behind this inhibition seems to be different for the species. Since chronic PARP-1 inhibition is also discussed to sacrifice neurogenesis and learning abilities, further experiments on neurons and in vivo studies could be helpful to clarify whether the inhibition of poly(ADP-ribosyl) ation contributes to organic Hg induced neurotoxicity.},
  language  = {en}
}
@article{PrueferSchuchardtToelleetal.2014,
  author    = {Pruefer, Jasmin and Schuchardt, Mirjam and Toelle, Markus and Pruefer, Nicole and Hoehne, Matthias and Zidek, Walter and van der Giet, Markus},
  title     = {Harmful effects of the azathioprine metabolite 6-mercaptopurine in vascular cells: Induction of mineralization},
  series = {PLoS one},
  volume    = {9},
  journal   = {PLoS one},
  number    = {7},
  publisher = {PLoS},
  address   = {San Fransisco},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0101709},
  pages     = {8},
  year      = {2014},
  abstract  = {Vascular mineralization contributes to the high cardiovascular morbidity and mortality in patients who suffer from chronic kidney disease and in individuals who have undergone solid organ transplantation. The immunosuppressive regimen used to treat these patients appears to have an impact on vascular alterations. The effect of 6-mercaptopurine (6-MP) on vascular calcification has not yet been determined. This study investigates the effect of 6-MP on vascular mineralization by the induction of trans-differentiation of rat vascular smooth muscle cells in vitro. 6-MP not only induces the expression of osteochondrocyte-like transcription factors and proteins but also activates alkaline phosphatase enzyme activity and produces calcium deposition in in vitro and ex vivo models. These processes are dependent on 6-MP-induced production of reactive oxygen species, intracellular activation of mitogen-activated kinases and phosphorylation of the transcription factor Cbfa1. Furthermore, the metabolic products of 6-MP, 6-thioguanine nucleotides and 6-methyl-thio-inosine monophosphate have major impacts on cellular calcification. These data provide evidence for a possible harmful effect of the immunosuppressive drug 6-MP in vascular diseases, such as arteriosclerosis.},
  language  = {en}
}
@article{PutraNeuberReichetzederetal.2014,
  author    = {Putra, Sulistyo Emantoko Dwi and Neuber, Corinna and Reichetzeder, Christoph and Hocher, Berthold and Kleuser, Burkhard},
  title     = {Analysis of genomic DNA methylation levels in human placenta using liquid Chromatography-Electrospray ionization tandem mass spectrometry},
  series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  volume    = {33},
  journal   = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology},
  number    = {4},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1015-8987},
  doi       = {10.1159/000358666},
  pages     = {945 -- 952},
  year      = {2014},
  abstract  = {Background: DNA-methylation is a common epigenetic tool which plays a crucial role in gene regulation and is essential for cell differentiation and embryonic development. The placenta is an important organ where gene activity can be regulated by epigenetic DNA modifications, including DNA methylation. This is of interest as, the placenta is the interface between the fetus and its environment, the mother. Exposure to environmental toxins and nutrition during pregnancy may alter DNA methylation of the placenta and subsequently placental function and as a result the phenotype of the offspring. The aim of this study was to develop a reliable method to quantify DNA methylation in large clinical studies. This will be a tool to analyze the degree of DNA methylation in the human placenta in relationship to clinical readouts. Methods: Liquid chromatography-electrospray ionization/multi-stage mass spectrometry (LC-ESI/MS/MS) technique was used for the quantification of the 5dmC/dG ratio in placentas from 248 healthy pregnancies. We were able to demonstrate that this method is a reliable and stable way to determine global placental DNA methylation in large clinical trials. Results/Conclusion: The degree of placental DNA methylation seen in our pilot study varies substantially from 2\% to 5\%. The clinical implications of this variation need to be demonstrated in adequately powered large studies.},
  language  = {en}
}
@article{PutraTsuprykovVonWebskyetal.2014,
  author    = {Putra, Sulistyo Emantoko Dwi and Tsuprykov, Oleg and Von Websky, Karoline and Ritter, Teresa and Reichetzeder, Christoph and Hocher, Berthold},
  title     = {Dealing with large sample sizes: comparison of a new one spot dot blot method to western blot},
  series = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  volume    = {60},
  journal   = {Clinical laboratory : the peer reviewed journal for clinical laboratories and laboratories related to blood transfusion},
  number    = {11},
  publisher = {Clin Lab Publ., Verl. Klinisches Labor},
  address   = {Heidelberg},
  issn      = {1433-6510},
  doi       = {10.7754/Clin.Lab.2014.140317},
  pages     = {1871 -- 1877},
  year      = {2014},
  abstract  = {Background: Western blot is the gold standard method to determine individual protein expression levels. However, western blot is technically difficult to perform in large sample sizes because it is a time consuming and labor intensive process. Dot blot is often used instead when dealing with large sample sizes, but the main disadvantage of the existing dot blot techniques, is the absence of signal normalization to a housekeeping protein. Methods: In this study we established a one dot two development signals (ODTDS) dot blot method employing two different signal development systems. The first signal from the protein of interest was detected by horseradish peroxidase (HRP). The second signal, detecting the housekeeping protein, was obtained by using alkaline phosphatase (AP). Results: Inter-assay results variations within ODTDS dot blot and western blot and intra-assay variations between both methods were low (1.04 - 5.71\%) as assessed by coefficient of variation. Conclusions: ODTDS dot blot technique can be used instead of western blot when dealing with large sample sizes without a reduction in results accuracy.},
  language  = {en}
}
@article{RailaSchweigertKohn2014,
  author    = {Raila, Jens and Schweigert, Florian J. and Kohn, Barbara},
  title     = {Relationship between urinary Tamm-Horsfall protein excretion and renal function in dogs with naturally occurring renal disease},
  series = {Veterinary clinical pathology},
  volume    = {43},
  journal   = {Veterinary clinical pathology},
  number    = {2},
  publisher = {Wiley-Blackwell},
  address   = {Hoboken},
  issn      = {0275-6382},
  doi       = {10.1111/vcp.12143},
  pages     = {261 -- 265},
  year      = {2014},
  abstract  = {Background Tamm-Horsfall protein (THP) is physiologically excreted in urine, but little is known about the role of THP in the diagnosis of renal disease in dogs. Objective The aim of this study was to evaluate to which extent naturally occurring renal disease affects the urinary excretion of THP. Methods Dogs were divided into 5 groups according to plasma creatinine concentration, urinary protein-to-creatinine ratio (UP/UC), and exogenous plasma creatinine clearance (P-ClCr) rates: Group A (healthy control dogs; n=8), nonazotemic and nonproteinuric dogs, with P-ClCr rates > 90mL/min/m2; group B (n=25), nonazotemic and nonproteinuric dogs with reduced P-ClCr rates (51-89mL/min/m2); group C (n=7), nonazotemic but proteinuric dogs with P-ClCr rates 53-98mL/min/m2; group D (n=8), azotemic and borderline proteinuric dogs (P-ClCr rates: 22-45mL/min/m2); and group E (n=15), azotemic and proteinuric dogs (not tested for P-ClCr). THP was measured by quantitative Western blot analysis, and the ratio of THP-to-urinary creatinine (THP/UC) was calculated. Results The THP/UC concentrations were not different among dogs of groups A-D, but were reduced in dogs of group E (P<.001). THP/UC correlated negatively with serum creatinine (P<.01) and UP/UC (P<.01), but was not significantly associated with P-ClCr. Conclusions Decreased levels of THP/UC were present in moderately to severely azotemic and proteinuric dogs. This suggests tubular injury in these dogs and that THP might be useful as urinary marker to study the pathogenesis of renal disease.},
  language  = {en}
}
@article{ReichetzederChenFoelleretal.2014,
  author    = {Reichetzeder, Christoph and Chen, Hong and Foeller, Michael and Slowinski, Torsten and Li, Jian and Chen, You-Peng and Lang, Florian and Hocher, Berthold},
  title     = {Maternal vitamin D deficiency and fetal programming - lessons learned from humans and mice},
  series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie},
  volume    = {39},
  journal   = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie},
  number    = {4},
  publisher = {Karger},
  address   = {Basel},
  issn      = {1420-4096},
  doi       = {10.1159/000355809},
  pages     = {315 -- 329},
  year      = {2014},
  abstract  = {Background/Aims: Cardiovascular disease partially originates from poor environmental and nutritional conditions in early life. Lack of micronutrients like 25 hydroxy vitamin D-3 (25OHD) during pregnancy may be an important treatable causal factor. The present study explored the effect of maternal 25OHD deficiency on the offspring. Methods: We performed a prospective observational study analyzing the association of maternal 25OHD deficiency during pregnancy with birth outcomes considering confounding. To show that vitamin D deficiency may be causally involved in the observed associations, mice were set on either 25OHD sufficient or insufficient diets before and during pregnancy. Growth, glucose tolerance and mortality was analyzed in the F1 generation. Results: The clinical study showed that severe 25OHD deficiency was associated with low birth weight and low gestational age. ANCOVA models indicated that established confounding factors such as offspring sex, smoking during pregnancy and maternal BMI did not influence the impact of 25OHD on birth weight. However, there was a significant interaction between 25OHD and gestational age. Maternal 25OHD deficiency was also independently associated with low APGAR scores 5 minutes postpartum. The offspring of 25OHD deficient mice grew slower after birth, had an impaired glucose tolerance shortly after birth and an increased mortality during follow-up. Conclusions: Our study demonstrates an association between maternal 25OHD and offspring birth weight. The effect of 25OHD on birth weight seems to be mediated by vitamin D controlling gestational age. Results from an animal experiment suggest that gestational 25OHD insufficiency is causally linked to adverse pregnancy outcomes. Since birth weight and prematurity are associated with an adverse cardiovascular outcome in later life, this study emphasizes the need for novel monitoring and treatment guidelines of vitamin D deficiency during pregnancy.},
  language  = {en}
}
@inproceedings{ReichetzederPaschvonWebskyetal.2014,
  author    = {Reichetzeder, Christoph and Pasch, A. and von Websky, Karoline and Tsuprykov, Oleg and Klein, T. and Hocher, Berthold},
  title     = {The DPP-4 inhibitor linagliptin increases plasma fetuin-A concentrations in a rat model of uraemic calcification},
  series = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  volume    = {57},
  booktitle = {Diabetologia : journal of the European Association for the Study of Diabetes (EASD)},
  publisher = {Springer},
  address   = {New York},
  issn      = {0012-186X},
  pages     = {S522 -- S522},
  year      = {2014},
  language  = {en}
}
@misc{ReichetzederTsuprykovHocher2014,
  author    = {Reichetzeder, Christoph and Tsuprykov, Oleg and Hocher, Berthold},
  title     = {Endothelin receptor antagonists in clinical research - Lessons learned from preclinical and clinical kidney studies},
  series = {Life sciences : molecular, cellular and functional basis of therapy},
  volume    = {118},
  journal   = {Life sciences : molecular, cellular and functional basis of therapy},
  number    = {2},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0024-3205},
  doi       = {10.1016/j.lfs.2014.02.025},
  pages     = {141 -- 148},
  year      = {2014},
  abstract  = {Endothelin receptor antagonists (ETRAs) are approved for the treatment of pulmonary hypertension and scleroderma-related digital ulcers. The efforts to approve this class of drugs for renal indications, however, failed so far. Preclinical studies were promising. Transgenic overexpression of ET-1 or ET-2 in rodents causes chronic renal failure. Blocking the ET system was effective in the treatment of renal failure in rodent models. However, various animal studies indicate that blocking the renal tubular ETAR and ETBR causes water and salt retention partially mediated via the epithelial sodium transporter in tubular cells. ETRAs were successfully tested clinically in renal indications in phase 2 trials for the treatment of diabetic nephropathy. They showed efficacy in terms of reducing albumin excretion on top of guideline based background therapy (RAS blockade). However, these promising results could not be translated to successful phase Ill trials so far. The spectrum of serious adverse events was similar to other phase III trials using ETRAs. Potential underlying reasons for these failures and options to solve these issues are discussed. In addition preclinical and clinical studies suggest caution when addressing renal patient populations such as patients with hepatorenal syndrome, patients with any type of cystic kidney disease and patients at risk of contrast media induced nephropathy. The lessons learned in renal indications are also important for other potential promising indications of ETRAs like cancer and heart failure. (C) 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).},
  language  = {en}
}
@phdthesis{Schmiedchen2014,
  author    = {Schmiedchen, Bettina},
  title     = {Vitamin D and its linkage between chronic kidney disease and cardiovascular integrity},
  pages     = {113},
  year      = {2014},
  language  = {en}
}
@article{ScholzeLiuPedersenetal.2014,
  author    = {Scholze, Alexandra and Liu, Ying and Pedersen, Lise and Xia, Shengqiang and Roth, Heinz J. and Hocher, Berthold and Rasmussen, Lars Melholt and Tepel, Martin},
  title     = {Soluble alpha-Klotho and its relation to kidney function and fibroblast growth factor-23},
  series = {The journal of clinical endocrinology \& metabolism},
  volume    = {99},
  journal   = {The journal of clinical endocrinology \& metabolism},
  number    = {5},
  publisher = {Endocrine Society},
  address   = {Washington},
  issn      = {0021-972X},
  doi       = {10.1210/jc.2013-4171},
  pages     = {E855 -- E861},
  year      = {2014},
  abstract  = {Context: Relations between fibroblast growth factor-23 (FGF-23), soluble alpha-klotho (s-alpha-klotho), and kidney function in chronic kidney disease (CKD) are still unclear. Especially the role of s-alpha-klotho requires further study. Objectives: Our objectives were to analyze the relation of s-alpha-klotho to estimated glomerular filtration rate (eGFR), FGF-23, and other parameters of calcium-phosphate metabolism and to investigate the response of s-alpha-klotho to cholecalciferol. Patients, Design, and Setting: Twenty-four CKD (stage 1-5) patients participated in this 8-week randomized controlled trial (vitamin D and chronic renal insufficiency). Interventions: Interventions included 40 000 IU cholecalciferol or placebo weekly. Main Outcome Measure: S-alpha-klotho was determined by ELISA with antihuman klotho antibodies 67G3 and 91F1. Results: For all patients, s-alpha-klotho concentrations did not differ between CKD stages. When patients were subdivided based on FGF-23 concentrations, a positive association of s-alpha-klotho with eGFR became apparent in patients with lower than median FGF-23 concentrations but not in those above median value. Patients with s-alpha-klotho below 204 pg/mL showed higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase compared with patients with higher s-alpha-klotho. Treatment with cholecalciferol significantly increased 1,25-dihydroxyvitamin D. The increase of FGF-23 had only borderline significance. There was no significant effect of high-dose cholecalciferol administration for 8 weeks on plasma s-alpha-klotho. Conclusions: CKD patients with s-alpha-klotho below 204 pg/mL had higher age, lower phosphate clearance, and lower bone-specific alkaline phosphatase. An association of s-alpha-klotho with eGFR was observed only in the presence of close to normal, but not high, FGF-23 concentrations. Cholecalciferol treatment did not change s-alpha-klotho concentrations.},
  language  = {en}
}
@inproceedings{ScholzePetersenHocheretal.2014,
  author    = {Scholze, Alexandra and Petersen, Lise and Hocher, Berthold and Rasmussen, Lars M. and Tepel, Martin},
  title     = {Role of fibroblast growth factor-23 and soluble alpha klotho in chronic kidney disease},
  series = {Nephrology, dialysis, transplantation},
  volume    = {29},
  booktitle = {Nephrology, dialysis, transplantation},
  publisher = {Oxford Univ. Press},
  address   = {Oxford},
  issn      = {0931-0509},
  pages     = {120 -- 121},
  year      = {2014},
  language  = {en}
}
@article{SharkovskaReichetzederAlteretal.2014,
  author    = {Sharkovska, Yuliya and Reichetzeder, Christoph and Alter, Markus L. and Tsuprykov, Oleg and Bachmann, Sebastian and Secher, Thomas and Klein, Thomas and Hocher, Berthold},
  title     = {Blood pressure and glucose independent renoprotective effects of dipeptidyl peptidase-4 inhibition in a mouse model of type-2 diabetic nephropathy},
  series = {Journal of hypertension},
  volume    = {32},
  journal   = {Journal of hypertension},
  number    = {11},
  publisher = {Lippincott Williams \& Wilkins},
  address   = {Philadelphia},
  issn      = {0263-6352},
  doi       = {10.1097/HJH.0000000000000328},
  pages     = {2211 -- 2223},
  year      = {2014},
  abstract  = {Background: Despite the beneficial effects of type 4 dipeptidyl peptidase (DPP-4) inhibitors on glucose levels, its effects on diabetic nephropathy remain unclear. Method: This study examined the long-term renoprotective effects of DPP-4 inhibitor linagliptin in db/db mice, a model of type 2 diabetes. Results were compared with the known beneficial effects of renin-angiotensin system blockade by enalapril. Ten-week-old male diabetic db/db mice were treated for 3 months with either vehicle (n = 10), 3 mg linagliptin/kg per day (n = 8), or 20 mg enalapril/kg per day (n = 10). Heterozygous db/m mice treated with vehicle served as healthy controls (n = 8). Results: Neither linagliptin nor enalapril had significant effects on the parameters of glucose metabolism or blood pressure in diabetic db/db mice. However, linagliptin treatment reduced albuminuria and attenuated kidney injury. In addition, expression of podocyte marker podocalyxin was normalized. We also analysed DPP-4 expression by immunofluorescence in human kidney biopsies and detected upregulation of DPP-4 in the glomeruli of patients with diabetic nephropathy, suggesting that our findings might be of relevance for human kidney disease as well. Conclusion: Treatment with DPP-4 inhibitor linagliptin delays the progression of diabetic nephropathy damage in a glucose-independent and blood-pressure-independent manner. The observed effects may be because of the attenuation of podocyte injury and inhibition of myofibroblast transformation.},
  language  = {en}
}
@article{SicKrausMadletal.2014,
  author    = {Sic, Heiko and Kraus, Helene and Madl, Josef and Flittner, Karl-Andreas and von Muenchow, Audrey Lilly and Pieper, Kathrin and Rizzi, Marta and Kienzler, Anne-Kathrin and Ayata, Korcan and Rauer, Sebastian and Kleuser, Burkhard and Salzer, Ulrich and Burger, Meike and Zirlik, Katja and Lougaris, Vassilios and Plebani, Alessandro and Roemer, Winfried and Loeffler, Christoph and Scaramuzza, Samantha and Villa, Anna and Noguchi, Emiko and Grimbacher, Bodo and Eibel, Hermann},
  title     = {Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis},
  series = {The journal of allergy and clinical immunology},
  volume    = {134},
  journal   = {The journal of allergy and clinical immunology},
  number    = {2},
  publisher = {Elsevier},
  address   = {New York},
  issn      = {0091-6749},
  doi       = {10.1016/j.jaci.2014.01.037},
  pages     = {420 -- +},
  year      = {2014},
  abstract  = {Background: Five different G protein-coupled sphingosine-1-phosphate (S1P) receptors (S1P1-S1P5) regulate a variety of physiologic and pathophysiologic processes, including lymphocyte circulation, multiple sclerosis (MS), and cancer. Although B-lymphocyte circulation plays an important role in these processes and is essential for normal immune responses, little is known about S1P receptors in human B cells. Objective: To explore their function and signaling, we studied B-cell lines and primary B cells from control subjects, patients with leukemia, patients with S1P receptor inhibitor-treated MS, and patients with primary immunodeficiencies. Methods: S1P receptor expression was analyzed by using multicolor immunofluorescence microscopy and quantitative PCR. Transwell assays were used to study cell migration. S1P receptor internalization was visualized by means of time-lapse imaging with fluorescent S1P receptor fusion proteins expressed by using lentiviral gene transfer. B-lymphocyte subsets were characterized by means of flow cytometry and immunofluorescence microscopy. Results: Showing that different B-cell populations express different combinations of S1P receptors, we found that S1P1 promotes migration, whereas S1P4 modulates and S1P2 inhibits S1P1 signals. Expression of CD69 in activated B lymphocytes and B cells from patients with chronic lymphocytic leukemia inhibited S1P-induced migration. Studying B-cell lines, normal B lymphocytes, and B cells from patients with primary immunodeficiencies, we identified Bruton tyrosine kinase, beta-arrestin 2, LPS-responsive beige-like anchor protein, dedicator of cytokinesis 8, and Wiskott-Aldrich syndrome protein as critical signaling components downstream of S1P1. Conclusion: Thus S1P receptor signaling regulates human B-cell circulation and might be a factor contributing to the pathology of MS, chronic lymphocytic leukemia, and primary immunodeficiencies.},
  language  = {en}
}
@article{TaleshiSeidlerEgdalJensenetal.2014,
  author    = {Taleshi, Mojtaba S. and Seidler-Egdal, Rune K. and Jensen, Kenneth Bendix and Schwerdtle, Tanja and Francesconi, Kevin A.},
  title     = {Synthesis and Characterization of Arsenolipids: Naturally Occurring Arsenic Compounds in Fish and Algae},
  series = {Organometallics},
  volume    = {33},
  journal   = {Organometallics},
  number    = {6},
  publisher = {American Chemical Society},
  address   = {Washington},
  issn      = {0276-7333},
  doi       = {10.1021/om4011092},
  pages     = {1397 -- 1403},
  year      = {2014},
  abstract  = {Arsenic-containing lipids (arsenolipids) are natural products present in fish and algae. Because these compounds occur in foods, there is considerable interest in their human toxicology. We report the synthesis and characterization of seven arsenic-containing lipids, including six natural products. The compounds comprise dimethylarsinyl groups attached to saturated long-chain hydrocarbons (three compounds), saturated long-chain fatty acids (two compounds), and monounsaturated long chain fatty acids (two compounds). The arsenic group was introduced through sodium dimethylarsenide or bis(dimethylarsenic) oxide. The latter route provided higher and more reproducible yields, and consequently, this pathway was followed to synthesize six of the seven compounds. Mass spectral properties are described to assist in the identification of these compounds in natural samples. The pure synthesized arsenolipids will be used for in vitro experiments with human cells to test their uptake, biotransformation, and possible toxic effects.},
  language  = {en}
}
@article{TuKagaGerickeetal.2014,
  author    = {Tu, Vo Anh and Kaga, Atsushi and Gericke, Karl-Heinz and Watanabe, Naoharu and Narumi, Tetsuo and Toda, Mitsuo and Brueckner, Bernhard and Baldermann, Susanne and Mase, Nobuyuki},
  title     = {Synthesis and characterization of quantum dot nanoparticles bound to the plant volatile precursor of Hydroxy-apo-10'-carotenal},
  series = {The journal of organic chemistry},
  volume    = {79},
  journal   = {The journal of organic chemistry},
  number    = {15},
  publisher = {American Chemical Society},
  address   = {Washington},
  issn      = {0022-3263},
  doi       = {10.1021/jo500605c},
  pages     = {6808 -- 6815},
  year      = {2014},
  abstract  = {This study is focused on the synthesis and characterization of hydroxy-apo-10'-carotenal/quantum dot (QD) conjugates aiming at the in vivo visualization of beta-ionone, a carotenoid-derived volatile compound known for its important contribution to the flavor and aroma of many fruits, vegetables, and plants. The synthesis of nanoparticles bound to plant volatile precursors was achieved via coupling reaction of the QD to C-27-aldehyde which was prepared from alpha-ionone via 12 steps in 2.4\% overall yield. The formation of the QD-conjugate was confirmed by measuring its fluorescence spectrum to observe the occurrence of fluorescence resonance energy transfer.},
  language  = {en}
}
@article{UhrBuchholzHomannetal.2014,
  author    = {Uhr, Linda and Buchholz, Tina and Homann, Thomas and Huschek, Gerd and Rawel, Harshadrai Manilal},
  title     = {Targeted proteomics-based analysis of technical enzymes from fungal origin in baked products},
  series = {Journal of cereal science},
  volume    = {60},
  journal   = {Journal of cereal science},
  number    = {2},
  publisher = {Elsevier},
  address   = {London},
  issn      = {0733-5210},
  doi       = {10.1016/j.jcs.2014.04.007},
  pages     = {440 -- 447},
  year      = {2014},
  abstract  = {The application of technical enzymes is a potential tool in modulating the dough and baking quality of cereal products. No endogenous amylases (alpha- and beta-forms) are present in mature wheat grains; they may be synthesized or activated during germination. Hence, microbial alpha-amylases are added to the dough, being resistant to the endogenous alpha-amylase/trypsin inhibitors. Here, we report on the initial identification of two technical enzymes from a commercial sample based on an in-gel tryptic digestion coupled with MALDI-MS analysis. The primary component of the protein fraction with 51.3 kDa was alpha-amylase from Aspergillus species. A second major protein with 24.8 kDa was identified as endo-1,4-xylanase from Thermomyces lanuginosus. In the following experimental work up, a targeted proteomics approach utilizing the combination of specific proteolytic digestion of the added amylase and xylanase in wheat flour, dough or baked products, solid phase extraction of released peptides and their detection using LC-MS/MS was optimized. The targeted (MRM) MS/MS peptide signals showed that the peptide "ALSSALHER" (MW = 983) originating from amylase and "GWNPGLNAR" (MW = 983) from xylanase can be used to identify the corresponding technical enzymes added. Consequently, locally available baked products were tested and found to contain these enzymes as supplementary ingredients. (C) 2014 Elsevier Ltd. All rights reserved.},
  language  = {en}
}
@article{UnterbergLeffersHuebneretal.2014,
  author    = {Unterberg, Marlies and Leffers, Larissa and Huebner, Florian and Humpf, Hans-Ulrich and Lepikhov, Konstantin and Walter, Joern and Ebert, Franziska and Schwerdtle, Tanja},
  title     = {Toxicity of arsenite and thio-DMA(V) after long-term (21 days) incubation of human urothelial cells: cytotoxicity, genotoxicity and epigenetics},
  series = {Toxicology research},
  volume    = {3},
  journal   = {Toxicology research},
  number    = {6},
  publisher = {Royal Society of Chemistry},
  address   = {Cambridge},
  issn      = {2045-452X},
  doi       = {10.1039/c4tx00036f},
  pages     = {456 -- 464},
  year      = {2014},
  abstract  = {This study aims to further mechanistically understand toxic modes of action after chronic inorganic arsenic exposure. Therefore long-term incubation studies in cultured cells were carried out, to display chronically attained changes, which cannot be observed in the generally applied in vitro short-term incubation studies. Particularly, the cytotoxic, genotoxic and epigenetic effects of an up to 21 days incubation of human urothelial (UROtsa) cells with pico- to nanomolar concentrations of iAs(III) and its metabolite thio-DMA(V) were compared. After 21 days of incubation, cytotoxic effects were strongly enhanced in the case of iAs(III) and might partly be due to glutathione depletion and genotoxic effects on the chromosomal level. These results are in strong contrast to cells exposed to thio-DMA(V). Thus, cells seemed to be able to adapt to this arsenical, as indicated among others by an increase in the cellular glutathione level. Most interestingly, picomolar concentrations of both iAs(III) and thio-DMA(V) caused global DNA hypomethylation in UROtsa cells, which was quantified in parallel by 5-medC immunostaining and a newly established, reliable, high resolution mass spectrometry (HRMS)-based test system. This is the first time that epigenetic effects are reported for thio-DMA(V); iAs(III) induced epigenetic effects occur in at least 8000 fold lower concentrations as reported in vitro before. The fact that both arsenicals cause DNA hypomethylation at really low, exposure-relevant concentrations in human urothelial cells suggests that this epigenetic effect might contribute to inorganic arsenic induced carcinogenicity, which for sure has to be further investigated in future studies.},
  language  = {en}
}
@article{VignonZellwegerRelleRahnenfuehreretal.2014,
  author    = {Vignon-Zellweger, Nicolas and Relle, Katharina and Rahnenfuehrer, Jan and Schwab, Karima and Hocher, Berthold and Theuring, Franz},
  title     = {Endothelin-1 overexpression and endothelial nitric oxide synthase knock-out induce different pathological responses in the heart of male and female mice},
  series = {Life sciences : molecular, cellular and functional basis of therapy},
  volume    = {118},
  journal   = {Life sciences : molecular, cellular and functional basis of therapy},
  number    = {2},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0024-3205},
  doi       = {10.1016/j.lfs.2013.12.003},
  pages     = {219 -- 225},
  year      = {2014},
  abstract  = {Aims: The nitric oxide and endothelin systems are key components of a local paracrine hormone network in the heart. We previously reported that diastolic dysfunction observed in mice lacking the endothelial nitric oxide synthase (eNOS-/-) can be prevented by a genetic overexpression of ET-1. Sexual dimorphisms have been reported in both ET-1 and NO systems. Particularly, eNOS-/- mice present sex related phenotypic differences. Main methods: We used the ET-1 transgenic (ET+/+), eNOS-/-, and crossbred ET+/+ eNOS-/- mice, and wild type controls. We measured cardiac function by heart catheterization. Cardiac ventricles were collected for histological and molecular profiling. Key findings: We report here that (i) the level of ET-1 expression in eNOS-/- mice was elevated in males but not in females. (ii) Left ventricular end-diastolic blood pressure was higher in male eNOS-/- mice than in females. (ii) eNOS-/- males but not females developed cardiomyocyte hypertrophy. (iv) Perivascular fibrosis of intra-cardiac arteries developed in female ET+/+ and eNOS-/- mice but not in males. Additionally, (v) the cardiac expression of metalloprotease-9 was higher in eNOS-/- males compared to females. Finally, (vi) cardiac proteome analysis revealed that the protein abundance of the oxidative stress related enzyme superoxide dismutase presented with sexual dimorphism in eNOS-/- and ET+/+ mice. Significance: These results indicate that the cardiac phenotypes of ET-1 transgenic mice and eNOS knockout mice are sex specific. Since both systems are key players in the pathogenesis of cardiovascular diseases, our findings might be important in the context of gender differences in patients with such diseases. (C) 2013 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).},
  language  = {en}
}
@article{YamamotoBaldermannYoshikawaetal.2014,
  author    = {Yamamoto, Masayoshi and Baldermann, Susanne and Yoshikawa, Keisuke and Fujita, Akira and Mase, Nobuyuki and Watanabe, Naoharu},
  title     = {Determination of volatile compounds in four commercial samples of japanese green algae using solid phase microextraction gas chromatography mass spectrometry},
  series = {The ScientificWorld journal},
  journal   = {The ScientificWorld journal},
  publisher = {Hindawi Publishing Corp.},
  address   = {New York},
  issn      = {1537-744X},
  doi       = {10.1155/2014/289780},
  pages     = {8},
  year      = {2014},
  abstract  = {Green algae are of great economic importance. Seaweed is consumed fresh or as seasoning in Japan. The commercial value is determined by quality, color, and flavor and is also strongly influenced by the production area. Our research, based on solid phase microextraction gas chromatography mass spectrometry (SPME-GC-MS), has revealed that volatile compounds differ intensely in the four varieties of commercial green algae. Accordingly, 41 major volatile compounds were identified. Heptadecene was the most abundant compound from Okayama (Ulva prolifera), Tokushima (Ulva prolifera), and Ehime prefecture (Ulva linza). Apocarotenoids, such as ionones, and their derivatives were prominent volatiles in algae from Okayama (Ulva prolifera) and Tokushima prefecture (Ulva prolifera). Volatile, short chained apocarotenoids are among the most potent flavor components and contribute to the flavor of fresh, processed algae, and algae-based products. Benzaldehyde was predominant in seaweed from Shizuoka prefecture (Monostroma nitidum). Multivariant statistical analysis (PCA) enabled simple discrimination of the samples based on their volatile profiles. This work shows the potential of SPME-GC-MS coupled with multivariant analysis to discriminate between samples of different geographical and botanical origins and form the basis for development of authentication methods of green algae products, including seasonings.},
  language  = {en}
}
@article{YangLaiDengetal.2014,
  author    = {Yang, Fang and Lai, Xinlong and Deng, Li and Liu, Xiaoxiao and Li, Jian and Zeng, Shuixiu and Zhang, Cheng and Hocher, Carl-Friedrich and Hocher, Berthold},
  title     = {Association of endothelin-1 gene polymorphisms with the clinical phenotype in primary nephrotic syndrome of children},
  series = {Life sciences : molecular, cellular and functional basis of therapy},
  volume    = {118},
  journal   = {Life sciences : molecular, cellular and functional basis of therapy},
  number    = {2},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0024-3205},
  doi       = {10.1016/j.lfs.2014.04.010},
  pages     = {446 -- 450},
  year      = {2014},
  abstract  = {Aims:This study aims to investigate the relationship between plasma endothelin-1 (ET-1) concentrations, ET-1 gene polymorphisms in loci rs5370, rs1630736, 3A/4A and clinical features of primary nephrotic syndrome (NS) in children. Materials and methods: Thirty-six children with primary NS were selected as case group, and 94 healthy children were selected as control group. All subjects were genotyped for three single nucleotide polymorphisms (SNPs) (rs5370, rs10478694 [3A4A) and rs 1630736) in the ET-1 gene by gene sequencing. The plasma ET-1 concentrations were measured using a radio-immunoassay. Key findings: Plasma ET-1 concentrations were higher in NS patients (P = 0.007) as compared to healthy children. The allele frequencies between control and NS patients were significantly different only with respect to the rs10478694 SNP of the ET-1 gene. The allele frequencies between control and NS patients for the rs5370 SNP showed a trend towards difference (P = 0.057). Plasma cholesterol in NS patients is associated with both: the Cl genotype in locus rs5370 and the 3A4A genotype in locus rs10478694 (P < 0.05 in both cases). Significance: The ET systems might play a disease modifying role in pediatric NS. Plasma cholesterol, a hallmark of NS. seems to be associated with genetic variations within the human ET-1 gene. (C) 2014 Elsevier Inc. All rights reserved.},
  language  = {en}
}