@article{ShahidManchiSlunskyetal.2017, author = {Shahid, Muhammad and Manchi, G. and Slunsky, Pavel and Naseer, O. and Fatima, A. and Leo, B. and Raila, Jens}, title = {A systemic review of existing serological possibilities to diagnose canine osteoarthritis with a particular focus on extracellular matrix proteoglycans and protein}, series = {Polish journal of veterinary sciences : PJVS : the journal of Committee of Veterinary Sciences of Polish Academy of Sciences and University of Warmia and Mazury in Olsztyn}, volume = {20}, journal = {Polish journal of veterinary sciences : PJVS : the journal of Committee of Veterinary Sciences of Polish Academy of Sciences and University of Warmia and Mazury in Olsztyn}, number = {1}, publisher = {De Gruyter}, address = {Berlin}, issn = {1505-1773}, doi = {10.1515/pjvs-2017-0024}, pages = {189 -- 201}, year = {2017}, abstract = {Extra-cellular matrix (ECM) components are important and their stabilization is significant in maintaining normal healthy joint environment. In osteoarthritis (OA), ECM components are altered and indicate disease progression. The joint ECM is composed of proteoglycans (aggrecan, perlecan,inter α-trypsin inhibitor), glycoproteins (fibronectin, lubricin, COMP) and collagen types (most abundantly collagen type II) which represent structural and functional transformation during disease advancement. ECM investigation revealed significant biomarkers of OA that could be used as a diagnostic and therapeutic tool in different canine orthopedic diseases. This review deliberates our current findings of how the components of ECM change at the molecular level during disease progression in canine OA.}, language = {en} } @article{LuHasanZengetal.2017, author = {Lu, Yong-Ping and Hasan, Ahmed A. and Zeng, Shufei and Hocher, Berthold}, title = {Plasma ET-1 concentrations are elevated in pregnant women with hypertension - meta-analysis of clinical studies}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, volume = {42}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, number = {4}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000482004}, pages = {654 -- 663}, year = {2017}, abstract = {Background/Aims: The ET system might be involved in the pathogenesis of hypertensive disorders during pregnancy. The objective is to analyse the impact of ET-1 in hypertensive pregnant women by a strict meta-analysis of published human clinical studies. Methods: Based on the principle of Cochrane systematic reviews, Cohort studies in PubMed (Medline), Google Scholar and China Biological Medicine Database (CBM-disc) designed to identify the role of endothelin-1 (ET-1) in the pathophysiology of gestational hypertension and preeclampsia were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95\% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects model. Results: Sixteen published cohort studies including 1739 hypertensive cases and 409 controls were used in the meta-analysis. ET-1 plasma concentrations were higher in hypertensive pregnant women as compared to the controls (mean difference between groups: 19.02 [15.60～22.44], P < 0.00001,). These finding were driven by severity of hypertension and/or degree of proteinuria. Conclusion: Plasma ET-1 concentrations are elevated in hypertensive disorders during human pregnancy. In particular women with preeclampsia (hypertensive pregnant women with proteinuria) have substantially elevated plasma ET-1 concentration as compared to pregnant women with normal blood pressure.}, language = {en} } @article{FayyazJaptokSchumacheretal.2017, author = {Fayyaz, Susann and Japtok, Lukasz and Schumacher, Fabian and Wigger, Dominik and Schulz, Tim Julius and Haubold, Kathrin and Gulbins, Erich and V{\"o}ller, Heinz and Kleuser, Burkhard}, title = {Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {43}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000480470}, pages = {445 -- 456}, year = {2017}, abstract = {Background/Aims: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6). Methods: The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Results: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). Conclusion: LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.}, language = {en} } @article{NeuberSchumacherGulbinsetal.2017, author = {Neuber, Corinna and Schumacher, Fabian and Gulbins, Erich and Kleuser, Burkhard}, title = {Mass Spectrometric Determination of Fatty Aldehydes Exemplified by Monitoring the Oxidative Degradation of (2E)-Hexadecenal in HepG2 Cell Lysates}, series = {Lipidomics}, volume = {125}, journal = {Lipidomics}, publisher = {Humana Press}, address = {Totowa}, isbn = {978-1-4939-6946-3}, issn = {0893-2336}, doi = {10.1007/978-1-4939-6946-3_10}, pages = {147 -- 158}, year = {2017}, abstract = {Within the last few decades, liquid chromatography-mass spectrometry (LC-MS) has become a preferred method for manifold issues in analytical biosciences, given its high selectivity and sensitivity. However, the analysis of fatty aldehydes, which are important components of cell metabolism, remains challenging. Usually, chemical derivatization prior to MS detection is required to enhance ionization efficiency. In this regard, the coupling of fatty aldehydes to hydrazines like 2,4-dinitrophenylhydrazine (DNPH) is a common approach. Additionally, hydrazones readily react with fatty aldehydes to form stable derivatives, which can be easily separated using high-performance liquid chromatography (HPLC) and subsequently detected by MS. Here, we exemplarily present the quantification of the long-chain fatty aldehyde (2E)-hexadecenal, a break-down product of the bioactive lipid sphingosine 1-phosphate (S1P), after derivatization with 2-diphenylacetyl-1,3-indandione-1-hydrazone (DAIH) via isotope-dilution HPLC-electrospray ionization-quadrupole/time-of-flight (ESI-QTOF) MS. Moreover, we show that the addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) as a coupling agent allows for simultaneous determination of fatty aldehydes and fatty acids as DAIH derivatives. Taking advantage of this, we describe in detail how to monitor the degradation of (2E)-hexadecenal and the concurrent formation of its oxidation product (2E)-hexadecenoic acid in lysates of human hepatoblastoma (HepG2) cells within this chapter.}, language = {en} } @article{SchwiebsThomasKleuseretal.2017, author = {Schwiebs, Anja and Thomas, Dominique Jeanette and Kleuser, Burkhard and Pfeilschifter, Josef and Radeke, Heinfried H.}, title = {Nuclear translocation of SGPP-1 and decrease of SGPL-1 activity contribute to sphingolipid rheostat regulation of inflammatory dendritic cells}, series = {Mediators of inflammation}, journal = {Mediators of inflammation}, publisher = {Hindawi Publishing Corp.}, address = {London}, issn = {0962-9351}, doi = {10.1155/2017/5187368}, pages = {10}, year = {2017}, abstract = {A balanced sphingolipid rheostat is indispensable for dendritic cell function and survival and thus initiation of an immune response. Sphingolipid levels are dynamically maintained by the action of sphingolipid enzymes of which sphingosine kinases, S1P phosphatases (SGPP-1/2) and S1P lyase (SGPL-1), are pivotal in the balance of S1P and sphingosine levels. In this study, we present that SGPP-1 and SGPL-1 are regulated in inflammatory dendritic cells and contribute to S1P fate. TLR-dependent activation caused SGPL-1 protein downregulation with subsequent decrease of enzymatic activity by two-thirds. In parallel, confocal fluorescence microscopy revealed that endogenous SGPP-1 was expressed in nuclei of naive dendritic cells and was translocated into the cytoplasmatic compartment upon inflammatory stimulation resulting in dephosphorylation of S1P. Mass spectrometric determination showed that a part of the resulting sphingosine was released from the cell, increasing extracellular levels. Another route of diminishing intracellular S1P was possibly taken by its export via ATP-binding cassette transporter C1 which was upregulated in array analysis, while the S1P transporter, spinster homolog 2, was not relevant in dendritic cells. These investigations newly describe the sequential expression and localization of the endogenous S1P regulators SGPP-1 and SGPL-1 and highlight their contribution to the sphingolipid rheostat in inflammation.}, language = {en} } @article{HoehnJerniganJaptoketal.2017, author = {Hoehn, Richard S. and Jernigan, Peter L. and Japtok, Lukasz and Chang, Alex L. and Midura, Emily F. and Caldwell, Charles C. and Kleuser, Burkhard and Lentsch, Alex B. and Edwards, Michael J. and Gulbins, Erich and Pritts, Timothy A.}, title = {Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation}, series = {Annals of surgery : a monthly review of surgical science and practice}, volume = {265}, journal = {Annals of surgery : a monthly review of surgical science and practice}, number = {1}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0003-4932}, doi = {10.1097/SLA.0000000000001648}, pages = {218 -- 226}, year = {2017}, abstract = {Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion. Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion. Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units. Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice. Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood.}, language = {en} } @misc{YangDarkoHuangetal.2017, author = {Yang, Xiaoping and Darko, Kwame Oteng and Huang, Yanjun and He, Caimei and Yang, Huansheng and He, Shanping and Li, Jianzhong and Li, Jian and Hocher, Berthold and Yin, Yulong}, title = {Resistant starch regulates gut microbiota}, series = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, volume = {42}, journal = {Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology}, number = {1}, publisher = {Karger}, address = {Basel}, issn = {1015-8987}, doi = {10.1159/000477386}, pages = {306 -- 318}, year = {2017}, abstract = {Starch is one of the most popular nutritional sources for both human and animals. Due to the variation of its nutritional traits and biochemical specificities, starch has been classified into rapidly digestible, slowly digestible and resistant starch. Resistant starch has its own unique chemical structure, and various forms of resistant starch are commercially available. It has been found being a multiple-functional regulator for treating metabolic dysfunction. Different functions of resistant starch such as modulation of the gut microbiota, gut peptides, circulating growth factors, circulating inflammatory mediators have been characterized by animal studies and clinical trials. In this mini-review, recent remarkable progress in resistant starch on gut microbiota, particularly the effect of structure, biochemistry and cell signaling on nutrition has been summarized, with highlights on its regulatory effect on gut microbiota.}, language = {en} } @article{HeLiuLuetal.2017, author = {He, Jing and Liu, Zhi-Wei and Lu, Yong-Ping and Li, Tao-Yuan and Liang, Xu-Jing and Arck, Petra and Huang, Si-Min and Hocher, Berthold and Chen, You-Peng}, title = {A systematic review and meta-analysis of influenza a virus infection during pregnancy associated with an increased risk for stillbirth and low birth weight}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, volume = {42}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000477221}, pages = {232 -- 243}, year = {2017}, abstract = {Background/Aims: Impaired pregnancy outcomes, such as low birth weight are associated with increased disease risk in later life, however little is known about the impact of common infectious diseases during pregnancy on birth weight. The study had two aims: a) to investigate risk factors of influenza virus infection during pregnancy, and b) to analyze the impact of influenza virus infection on pregnancy outcome, especially birth weight. Methods: Prospective and retrospective observational studies found in PubMed, MEDLINE, Embase, Google Scholar, and WangFang database were included in this meta analysis. Data of included studies was extracted and analyzed by the RevMan software. Results: Pregnant women with anemia (P=0.004, RR=1.46, 95\% CI: 1.13-1.88), obesity (P<0.00001, RR=1.35, 95\% CI: 1.25-1.46) and asthma (P<0.00001, RR=1.99, 95\% CI: 1.67-2.37) had higher rates of influenza virus infection. Regarding birth outcomes, influenza A virus infection did not affect the likelihood for cesarean section. Mothers with influenza had a higher rate of stillbirth (P=0.04, RR=2.36, 95\% CI: 1.05-5.31), and their offspring had low 5-minute APGR Scores (P=0.009, RR=1.39, 95\% CI: 1.08-1.79). Furthermore, the rate for birth weight < 2500g (P=0.04, RR=1.71, 95\% CI: 1.03-2.84) was increased. Conclusion: Results of this study showed that anemia, asthma and obesity during pregnancy are risk factors influenza A virus infection during pregnancy. Moreover, gestational influenza A infection impairs pregnancy outcomes and increases the risk for low birth weight, a known risk factor for later life disease susceptibility.}, language = {en} } @article{ReichetzederHeunischvonEinemetal.2017, author = {Reichetzeder, Christoph and Heunisch, Fabian and von Einem, Gina-Franziska and Tsuprykov, Oleg and Kellner, Karl-Heinz and Dschietzig, Thomas and Kretschmer, Axel and Hocher, Berthold}, title = {Pre-interventional kynurenine predicts medium-term outcome after contrast media exposure due to coronary angiography}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, volume = {42}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000477222}, pages = {244 -- 256}, year = {2017}, abstract = {Background/Aims: Contrast induced acute kidney injury (CI-AKI) remains a serious complication of contrast media enhanced procedures like coronary angiography. There is still a lack of established biomarkers that help to identify patients at high risk for short and long-term complications. The aim of the current study was to evaluate plasma kynurenine as a predictive biomarker for CI-AKI and long-term complications, measured by the combined endpoint "major adverse kidney events" (MAKE) up to 120 days after CM application. Methods: In this prospective cohort study 245 patients undergoing coronary angiography were analyzed. Blood samples were obtained at baseline, 24h and 48h after contrast media (CM) application to diagnose CI-AKI. Patients were followed for 120 days for adverse clinical events including death, the need for dialysis, and a doubling of plasma creatinine. Occurrence of any of these events was summarized in the combined endpoint MAKE. Results: Preinterventional plasma kynurenine was not associated with CI-AKI. Patients who later developed MAKE displayed significantly increased preinterventional plasma kynurenine levels (p<0.0001). ROC analysis revealed that preinterventional kynurenine is highly predictive for MAKE (AUC=0.838; p<0.0001). The optimal cutoff was found at >= 3.5 mu mol/L. Using this cutoff, the Kaplan-Meier estimator demonstrated that concentrations of plasma kynurenine >= 3.5 mu mol/L were significantly associated with a higher prevalence of MAKE until follow up (p<0.0001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. Conclusion: Preinterventional plasma kynurenine might serve as a highly predictive biomarker for MAKE up to 120 days after coronary angiography.}, language = {en} } @article{XuLuHasanetal.2017, author = {Xu, Mei and Lu, Yong-Ping and Hasan, Ahmed A. and Hocher, Berthold}, title = {Plasma ET-1 concentrations are elevated in patients with hypertension meta-analysis of clinical studies}, series = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, volume = {42}, journal = {Kidney \& blood pressure research : official organ of the Gesellschaft f{\"u}r Nephrologie ; official organ of the Deutsche Liga zur Bek{\"a}mpfung des Hohen Blutdruckes e.V., Deutsche Hypertonie-Gesellschaft}, number = {2}, publisher = {Karger}, address = {Basel}, issn = {1420-4096}, doi = {10.1159/000477572}, pages = {304 -- 313}, year = {2017}, abstract = {Background/Aims: A recent study revealed that global overexpression of ET-1 causes a slight reduction in systemic blood pressure. Moreover, heterozygous ET-1 knockout mice are hypertensive. The role of ET-1 in human hypertension was so far not addressed by a strict meta-analysis of published human clinical studies. Methods: We included studies published between January 1, 1990 and February 28, 2017. We included case control studies analyzing untreated essential hypertension or hypertensive patients where antihypertensive medication was discontinued for at least two weeks. Based on the principle of Cochrane systematic reviews, case control studies (CCSs) in PubMed (Medline) and Google Scholar designed to identify the role of endothelin-1 (ET-1) in the pathophysiological of hypertension were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95\% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects models. Results: Eleven studies fulfilling our in-and exclusion criteria were eligible for this meta-analysis. These studies included 450 hypertensive patients and 328 controls. Our meta-analysis revealed that ET-1 plasma concentrations were higher in hypertensive patients as compared to the control patients [mean difference between groups 1.57 pg/mL, 95\%Ci [0.47 similar to 2.68, P = 0.005]. These finding were driven by patients having systolic blood pressure higher than 160 mmHg and diastolic blood pressure higher than 100 mmHg. Conclusions: This meta-analysis showed that hypertensive patients do have elevated plasma ET-1 concentrations. This finding is driven by those patients with high systolic/diastolic blood pressure. Given that the ET-1 gene did not appear in any of the whole genome association studies searching for hypertension associated gene loci, it is very likely that the elevated plasma ET-1 concentrations in hypertensive patients are secondary to hypertension and may reflect endothelial cell damage.}, language = {en} } @article{GereckeEdlichGiulbudagianetal.2017, author = {Gerecke, Christian and Edlich, Alexander and Giulbudagian, Michael and Schumacher, Fabian and Zhang, Nan and Said, Andre and Yealland, Guy and Lohan, Silke B. and Neumann, Falko and Meinke, Martina C. and Ma, Nan and Calderon, Marcelo and Hedtrich, Sarah and Schaefer-Korting, Monika and Kleuser, Burkhard}, title = {Biocompatibility and characterization of polyglycerol-based thermoresponsive nanogels designed as novel drug-delivery systems and their intracellular localization in keratinocytes}, series = {Nanotoxicology}, volume = {11}, journal = {Nanotoxicology}, publisher = {Routledge, Taylor \& Francis Group}, address = {Abingdon}, issn = {1743-5390}, doi = {10.1080/17435390.2017.1292371}, pages = {267 -- 277}, year = {2017}, abstract = {Novel nanogels that possess the capacity to change their physico-chemical properties in response to external stimuli are promising drug-delivery candidates for the treatment of severe skin diseases. As thermoresponsive nanogels (tNGs) are capable of enhancing penetration through biological barriers such as the stratum corneum and are taken up by keratinocytes of human skin, potential adverse consequences of their exposure must be elucidated. In this study, tNGs were synthesized from dendritic polyglycerol (dPG) and two thermoresponsive polymers. tNG_dPG_tPG are the combination of dPG with poly(glycidyl methyl ether-co-ethyl glycidyl ether) (p(GME-co-EGE)) and tNG_dPG_pNIPAM the one with poly(N-isopropylacrylamide) (pNIPAM). Both thermoresponsive nanogels are able to incorporate high amounts of dexamethasone and tacrolimus, drugs used in the treatment of severe skin diseases. Cellular uptake, intracellular localization and the toxicological properties of the tNGs were comprehensively characterized in primary normal human keratinocytes (NHK) and in spontaneously transformed aneuploid immortal keratinocyte cell line from adult human skin (HaCaT). Laser scanning confocal microscopy revealed fluorescently labeled tNGs entered into the cells and localized predominantly within lysosomal compartments. MTT assay, comet assay and carboxy-H2DCFDA assay, demonstrated neither cytotoxic or genotoxic effects, nor any induction of reactive oxygen species of the tNGs in keratinocytes. In addition, both tNGs were devoid of eye irritation potential as shown by bovine corneal opacity and permeability (BCOP) test and red blood cell (RBC) hemolysis assay. Therefore, our study provides evidence that tNGs are locally well tolerated and underlines their potential for cutaneous drug delivery.}, language = {en} } @article{SahleGereckeKleuseretal.2017, author = {Sahle, Fitsum Feleke and Gerecke, Christian and Kleuser, Burkhard and Bodmeier, Roland}, title = {Formulation and comparative in vitro evaluation of various dexamethasone-loaded pH-sensitive polymeric nanoparticles intended for dermal applications}, series = {International Journal of Pharmaceutics}, volume = {516}, journal = {International Journal of Pharmaceutics}, number = {1-2}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0378-5173}, doi = {10.1016/j.ijpharm.2016.11.029}, pages = {21 -- 31}, year = {2017}, abstract = {pH-sensitive nanoparticles have a great potential for dermal and transfollicular drug delivery. In this study, pH-sensitive, dexamethasone-loaded Eudragit (R) L 100, Eudragit (R) L 100-55, Eudragit (R) S 100, HPMCP-50, HPMCP-55 and cellulose acetate phthalate nanoparticles were prepared by nanoprecipitation and characterized. The pH-dependent swelling, erosion, dissolution and drug release kinetics were investigated in vitro using dynamic light scattering and Franz diffusion cells, respectively. Their toxicity potential was assessed by the ROS and MTT assays. 100-700 nm nanoparticles with high drug loading and entrapment efficiency were obtained. The nanoparticles bear no toxicity potential. Cellulose phthalates nanoparticles were more sensitive to pH than acrylates nanoparticles. They dissolved in 10 mM pH 7.5 buffer and released > 80\% of the drug within 7 h. The acrylate nanoparticles dissolved in 40 mM pH 7.5 buffer and released 65-70\% of the drug within 7 h. The nanoparticles remained intact in 10 and 40 mM pH 6.0 buffers (HPMCP nanoparticles dissolved in 40 mM pH 6.0 buffer) and released slowly. The nanoparticles properties could be modulated by blending the different polymers. In conclusion, various pH-sensitive nanoparticles that could release differently on the skin surface and dissolve and release in the hair follicles were obtained.}, language = {en} } @article{HeunischChaykovskavonEinemetal.2017, author = {Heunisch, Fabian and Chaykovska, Lyubov and von Einem, Gina and Alter, Markus and Dschietzig, Thomas and Kretschmer, Axel and Kellner, Karl-Heinz and Hocher, Berthold}, title = {ADMA predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus undergoing coronary angiography}, series = {Medicine}, volume = {96}, journal = {Medicine}, number = {6}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, issn = {0025-7974}, doi = {10.1097/MD.0000000000006065}, pages = {7}, year = {2017}, abstract = {Asymmetric dimethylarginine (ADMA) is a competitive inhibitor of the nitric oxide (NO)-synthase and a biomarker of endothelial dysfunction (ED). ED plays an important role in the pathogenesis of contrast-induced nephropathy (CIN). The aim of our study was to evaluate serum ADMA concentration as a biomarker of an acute renal damage during the follow-up of 90 days after contrast medium (CM) application. Blood samples were obtained from 330 consecutive patients with diabetes mellitus or mild renal impairment immediately before, 24 and 48 hours after the CM application for coronary angiography. The patients were followed for 90 days. The composite endpoints were major adverse renal events (MARE) defined as occurrence of death, initiation of dialysis, or a doubling of serum creatinine concentration. Overall, ADMA concentration in plasma increased after CM application, although, there was no differences between ADMA levels in patients with and without CIN. ADMA concentration 24 hours after the CM application was predictive for dialysis with a specificity of 0.889 and sensitivity of 0.653 at values higher than 0.71 mu mol/L (area under the curve: 0.854, 95\% confidential interval: 0.767-0.941, P<0.001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. 24 hours after the CM application, ADMA concentration in plasma was predictive for MARE with a specificity of 0.833 and sensitivity of 0.636 at a value of more than 0.70 mu mol/L (area under the curve: 0.750, 95\% confidence interval: 0.602-0.897, P=0.004). Multivariate logistic regression analysis confirmed that ADMA and anemia were significant predictors of MARE. Further analysis revealed that increased ADMA concentration in plasma was highly significant predictor of MARE in patients with CIN. Moreover, patients with CIN and MARE had the highest plasma ADMA levels 24 hours after CM exposure in our study cohort. The impact of ADMA on MARE was independent of such known CIN risk factors as anemia, pre-existing renal failure, pre-existing heart failure, and diabetes. ADMA concentration in plasma is a promising novel biomarker of major contrast-induced nephropathy-associated events 90 days after contrast media exposure.}, language = {en} } @article{TaylorGoodaleRaabetal.2017, author = {Taylor, Vivien and Goodale, Britton and Raab, Andrea and Schwerdtle, Tanja and Reimer, Ken and Conklin, Sean and Karagas, Margaret R. and Francesconi, Kevin A.}, title = {Human exposure to organic arsenic species from seafood}, series = {The science of the total environment : an international journal for scientific research into the environment and its relationship with man}, volume = {580}, journal = {The science of the total environment : an international journal for scientific research into the environment and its relationship with man}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0048-9697}, doi = {10.1016/j.scitotenv.2016.12.113}, pages = {266 -- 282}, year = {2017}, abstract = {Seafood, including finfish, shellfish, and seaweed, is the largest contributor to arsenic (As) exposure in many human populations. In contrast to the predominance of inorganic As in water and many terrestrial foods, As in marine-derived foods is present primarily in the form of organic compounds. To date, human exposure and toxicological assessments have focused on inorganic As, while organic As has generally been considered to be nontoxic. However, the high concentrations of organic As in seafood, as well as the often complex As speciation, can lead to complications in assessing As exposure from diet. In this report, we evaluate the presence and distribution of organic As species in seafood, and combined with consumption data, address the current capabilities and needs for determining human exposure to these compounds. The analytical approaches and shortcomings for assessing these compounds are reviewed, with a focus on the best practices for characterization and quantitation. Metabolic pathways and toxicology of two important classes of organic arsenicals, arsenolipids and arsenosugars, are examined, as well as individual variability in absorption of these compounds. Although determining health outcomes or assessing a need for regulatory policies for organic As exposure is premature, the extensive consumption of seafood globally, along with the preliminary toxicological profiles of these compounds and their confounding effect on assessing exposure to inorganic As, suggests further investigations and process-level studies on organic As are needed to fill the current gaps in knowledge.}, language = {en} } @article{MarschallKroepflJensenetal.2017, author = {Marschall, Talke Anu and Kroepfl, Nina and Jensen, Kenneth Bendix and Bornhorst, Julia and Meermann, B. and K{\"u}hnelt, Doris and Schwerdtle, Tanja}, title = {Tracing cytotoxic effects of small organic Se species in human liver cells back to total cellular Se and Se metabolites}, series = {Metallomics}, volume = {9}, journal = {Metallomics}, publisher = {Royal Society of Chemistry}, address = {Cambridge}, issn = {1756-5901}, doi = {10.1039/c6mt00300a}, pages = {268 -- 277}, year = {2017}, abstract = {Small selenium (Se) species play a major role in the metabolism, excretion and dietary supply of the essential trace element selenium. Human cells provide a valuable tool for investigating currently unresolved issues on the cellular mechanisms of Se toxicity and metabolism. In this study, we developed two isotope dilution inductively coupled plasma tandem-mass spectrometry based methods and applied them to human hepatoma cells (HepG2) in order to quantitatively elucidate total cellular Se concentrations and cellular Se species transformations in relation to the cytotoxic effects of four small organic Se species. Species-and incubation time-dependent results were obtained: the two major urinary excretion metabolites trimethylselenonium (TMSe) and methyl-2-acetamido-2-deoxy-1-seleno-beta- D-galactopyranoside (SeSugar 1) were taken up by the HepG2 cells in an unmodified manner and did not considerably contribute to the Se pool. In contrast, Se-methylselenocysteine (MeSeCys) and selenomethionine (SeMet) were taken up in higher amounts, they were largely incorporated by the cells (most likely into proteins) and metabolized to other small Se species. Two new metabolites of MeSeCys, namely gamma-glutamyl-Se-methylselenocysteine and Se-methylselenoglutathione, were identified by means of HPLC-electrospray-ionization-Orbitrap-MS. They are certainly involved in the (de-) toxification modes of Se metabolism and require further investigation.}, language = {en} } @misc{DoegeSchumacherBalzusetal.2017, author = {D{\"o}ge, Nadine and Schumacher, Fabian and Balzus, Benjamin and Colombo, Miriam and Hadam, Sabrina and Rancan, Fiorenza and Blume-Peytavi, Ulrike and Kleuser, Burkhard and Bodmeier, Roland and Vogt, Annika}, title = {Particle- based formulations and controlled skin barrier disruption have a signifi cant impact on the delivery and penetration kinetics of dexamethasone as assessed in an ex vivo microdialysis}, series = {Journal der Deutschen Dermatologischen Gesellschaft}, volume = {15}, journal = {Journal der Deutschen Dermatologischen Gesellschaft}, publisher = {Wiley}, address = {Berlin}, issn = {1610-0379}, pages = {182 -- 182}, year = {2017}, abstract = {Preclinical assessment of penetration not only in intact, but also in barrier-disrupted skin is important to explore the surplus value of novel drug delivery systems, which can be specifically designed for diseased skin. Here, we characterized physical and chemical barrier disruption protocols for short-term ex vivo skin cultures with regard to structural integrity, physiological and biological parameters. Further, we compared the penetration of dexamethasone (Dex) in different nanoparticle-based formulations in stratum corneum, epidermis and dermis extracts of intact vs. barrier-disrupted skin as well as by dermal microdialysis at 6, 12 and 24 hours after topical application. Dex was quantified by liquid-chromatography - tandem-mass spectrometry (LC-MS/MS). Simultaneously, we investigated the Dex efficacy by interleukin (IL) analysis. Tape-stripping (TS) and 4 hours sodium lauryl sulfate 5 \% (SLS) exposure were identified as highly effective barrier disruption methods assessed by reproducible transepidermal water loss (TEWL) changes and IL-6/8 increase which was more pronounced in SLS-treated skin. The barrier state has also a significant impact on the Dex penetration kinetics: for all formulations, TS highly increased dermal Dex concentration despite the fact that nanocrystals quickly and effectively penetrated both, intact and barrier-disrupted skin reaching significantly higher dermal Dex concentration after 6 hours compared to Dex cream. The surplus value of encapsulation in ethyl cellulose nanocarriers could mostly be observed when applied on intact skin, in general showing a delayed Dex penetration. Estimation of cytokines was limited due to the trauma caused by probe insertion. In summary, ex vivo human skin is a highly interesting short-term preclinical model for the analysis of penetration and efficacy of novel drug delivery systems.}, language = {en} } @article{BoenickHuschekRawel2017, author = {B{\"o}nick, Josephine and Huschek, Gerd and Rawel, Harshadrai Manilal}, title = {Determination of wheat, rye and spelt authenticity in bread by targeted peptide biomarkers}, series = {Journal of Food Composition and Analysis}, volume = {58}, journal = {Journal of Food Composition and Analysis}, publisher = {Elsevier}, address = {San Diego}, issn = {0889-1575}, doi = {10.1016/j.jfca.2017.01.019}, pages = {82 -- 91}, year = {2017}, abstract = {Adulteration of food and mislabeled products in global market is a major financial and reputational risk for food manufacturers and trade companies. Consequently, there is a necessity to develop analytical methods to meet these issues. An analytical strategy to check the authenticity of wheat, spelt and rye addition in bread products was developed based on database research, in silico digestion confirming peptide specificity and finally quantification by liquid chromatography-tandem mass spectrometry analysis. Peptide markers for wheat (SQQQISQQPQQLPQQQQIPQQPQQF; QQHQIPQQPQQFPQQQQF and QPHQPQQPYPQQ), spelt (ASIVVGIGGQ; SQQPGQIIPQQPQQPSPL) and rye (LPQSHKQHVGQGAL; AQVQGIIQPQQL and QQFPQQPQQSFPQQPQQPVPQQPL) were identified, verified by protein Basic Local Alignment Search Tool and database research and used for quantification in bread. The specific use of multi-reaction monitoring transitions of selected peptides permitted the identification of closely related species wheat and spelt. Other cereal species (emmer, einkorn, barley, maize, rye and oat) were also checked. The target peptides were quantified at different levels using own reference baked products (bread) after in-solution chymotryptic digestion. Sensitivity of the identification was 0.5-1\% using flour-based (0-25\%) matrix calibration and the analytical recovery in bread was 80-125\%. The analytical strategy described here supplies an emerging, independent and flexible tool in controlling the labeling of bread.}, language = {en} } @article{BalzusSahleHoenzkeetal.2017, author = {Balzus, Benjamin and Sahle, Fitsum Feleke and H{\"o}nzke, Stefan and Gerecke, Christian and Schumacher, Fabian and Hedtrich, Sarah and Kleuser, Burkhard and Bodmeier, Roland}, title = {Formulation and ex vivo evaluation of polymeric nanoparticles for controlled delivery of corticosteroids to the skin and the corneal epithelium}, series = {European journal of pharmaceutics and biopharmaceutics : EJPB ; official journal of the International Association for Pharmaceutical Technology}, volume = {115}, journal = {European journal of pharmaceutics and biopharmaceutics : EJPB ; official journal of the International Association for Pharmaceutical Technology}, publisher = {Elsevier}, address = {Amsterdam}, issn = {0939-6411}, doi = {10.1016/j.ejpb.2017.02.001}, pages = {122 -- 130}, year = {2017}, abstract = {Controlled delivery of corticosteroids using nanoparticles to the skin and corneal epithelium may reduce their side effects and maximize treatment effectiveness. Dexamethasone-loaded ethyl cellulose, Eudragit® RS and ethyl cellulose/Eudragit® RS nanoparticles were prepared by the solvent evaporation method. Dexamethasone release from the polymeric nanoparticles was investigated in vitro using Franz diffusion cells. Drug penetration was also assessed ex vivo using excised human skin. Nanoparticle toxicity was determined by MTT and H2DCFDA assays. Eudragit® RS nanoparticles were smaller and positively charged but had a lower dexamethasone loading capacity (0.3-0.7\%) than ethyl cellulose nanoparticles (1.4-2.2\%). By blending the two polymers (1:1), small (105 nm), positively charged (+37 mV) nanoparticles with sufficient dexamethasone loading (1.3\%) were obtained. Dexamethasone release and penetration significantly decreased with decreasing drug to polymer ratio and increased when Eudragit® RS was blended with ethyl cellulose. Ex vivo, drug release and penetration from the nanoparticles was slower than a conventional cream. The nanoparticles bear no toxicity potentials except ethyl cellulose nanoparticles had ROS generation potential at high concentration. In conclusion, the nanoparticles showed great potential to control the release and penetration of corticosteroids on the skin and mucus membrane and maximize treatment effectiveness.}, language = {en} } @article{McVeyKimTabuchietal.2017, author = {McVey, Mark J. and Kim, Michael and Tabuchi, Arata and Srbely, Victoria and Japtok, Lukasz and Arenz, Christoph and Rotstein, Ori and Kleuser, Burkhard and Semple, John W. and Kuebler, Wolfgang M.}, title = {Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets}, series = {American journal of physiology : Lung cellular and molecular physiology}, volume = {312}, journal = {American journal of physiology : Lung cellular and molecular physiology}, number = {5}, publisher = {American Physiological Society}, address = {Bethesda}, issn = {1040-0605}, doi = {10.1152/ajplung.00317.2016}, pages = {625 -- 637}, year = {2017}, abstract = {Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1-5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.}, language = {en} } @article{FruscalzoFrommerLonderoetal.2017, author = {Fruscalzo, Arrigo and Frommer, Julia-Marie and Londero, Ambrogio P. and Henze, Andrea and Schweigert, Florian J. and Nofer, Jerzy-Roch and Steinhard, Johannes and Klockenbusch, Walter and Schmitz, Ralf and Raila, Jens}, title = {First trimester TTR-RBP4-ROH complex and angiogenic factors in the prediction of small for gestational age infant's outcome}, series = {Archives of gynecology and obstetrics}, volume = {295}, journal = {Archives of gynecology and obstetrics}, publisher = {Springer}, address = {Heidelberg}, issn = {0932-0067}, doi = {10.1007/s00404-017-4338-4}, pages = {1157 -- 1165}, year = {2017}, abstract = {To study the role of the TTR-RBP4-ROH complex components (transthyretin, serum retinol binding protein, retinol) and of angiogenic factors PlGF (placental growth factor) and sFlt-1 (soluble fms-like tyrosine kinase-1) in pregnancies complicated by small for gestational age infants (SGA). Case control study conducted on maternal serum collected between 11 + 0 to 13 + 6 weeks of gestation. TTR, RBP4, ROH, PlGF and sFlt-1 were measured in SGA patients (birth weight < 10\%) who delivered at term (n = 37) and before 37 weeks of gestation (n = 17) and in a matched control group with uneventful pregnancies (n = 37). We found decreased RBP4 in SGA patients that delivered fetuses < 3\% and in fetuses delivered after the 37 weeks of gestation compared to controls [1.50 (95\% CI 1.40-1.75) vs 1.62 (95\% CI 1.47-1.98), p < 0.05]. Further, we found lower PlGF and sFlt-1 concentrations in SGA that delivered before 37 weeks of gestation compared to controls (respectively, PIGF and sFlt-1: 39.7 pg/ml (95\% CI 32.3-66.3) vs 62.9 pg/ml (95\% CI 45.2-78.4) and 906 pg/ml (95\% CI 727-1626) vs 1610 pg/ml (95\% CI 1088-212), p < 0.05). First trimester maternal serum RBP4 and angiogenic factors PlGF and sFlt-1 can differently predict the timing of delivery of pregnancies complicated by SGA fetuses.}, language = {en} }