TY  - JOUR
A1  - Gerecke, Christian
A1  - Scholtka, Bettina
A1  - Loewenstein, Yvonne
A1  - Fait, Isabel
A1  - Gottschalk, Uwe
A1  - Rogoll, Dorothee
A1  - Melcher, Ralph
A1  - Kleuser, Burkhard
T1  - Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer
JF  - Journal of cancer research and clinical oncology : official organ of the Deutsche Krebsgesellschaft
N2  - Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer.
 Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9).
 A high methylation frequency of VIM (55.6 %) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD).
 The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.
KW  - Epigenetic
KW  - DNA methylation
KW  - Colon cancer
KW  - Colitis
KW  - Gastrointestinal tract
KW  - Biomarker
Y1  - 2015
U6  - https://doi.org/10.1007/s00432-015-1972-8
SN  - 0171-5216
SN  - 1432-1335
VL  - 141
IS  - 12
SP  - 2097
EP  - 2107
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Schraplau, Anne
A1  - Schewe, Bettina
A1  - Neuschäfer-Rube, Frank
A1  - Ringel, Sebastian
A1  - Neuber, Corinna
A1  - Kleuser, Burkhard
A1  - Püschel, Gerhard Paul
T1  - Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital
JF  - Toxicology
N2  - Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR. (C) 2014 Elsevier Ireland Ltd. All rights reserved.
KW  - Endocrine disruption
KW  - Xenobesity
KW  - Aryl-hydrocarbon receptor
KW  - Cyp2b1
KW  - Thyroid hormone
KW  - UDP-glucuronosyltransferase
Y1  - 2015
U6  - https://doi.org/10.1016/j.tox.2014.12.004
SN  - 0300-483X
VL  - 328
SP  - 21
EP  - 28
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Sagu Tchewonpi, Sorel
A1  - Nso, Emmanuel Jong
A1  - Homann, Thomas
A1  - Kapseu, Cesar
A1  - Rawel, Harshadrai Manilal
T1  - Extraction and purification of beta-amylase from stems of Abrus precatorius by three phase partitioning
JF  - Food chemistry
N2  - The stems of Abrus precatorius were used to extract a beta-amylase enriched fraction. A three phase partitioning method and a Doehlert design with 3 variables (ratio of crude extract/t-butanol, the ammonium sulphate saturation and pH) were used. The data was fitted in a second-order polynomial model and the parameters were optimized to enrich beta-amylase. Experimental responses for the modulation were recovery of activity and the purification factor. The optimal conditions were: a ratio of crude extract/t-butanol of 0.87 (v/v), saturation in ammonium sulphate of 49.46% (w/v) and a pH of 5.2. An activity recovery of 156.2% and a purification factor of 10.17 were found. The enriched enzyme was identified as a beta-amylase and its molecular weight was 60.1 kDa. K-m and V-max values were 79.37 mg/ml and 5.13 U/ml, respectively and the highest activity was registered at a temperature of 70 degrees C and a pH between 6 and 6.5. A significant stabilization of the beta-amylase was observed up to 65 degrees C. (C) 2015 Elsevier Ltd. All rights reserved.
KW  - Purification
KW  - Beta-amylase
KW  - Abrus precatorius
KW  - Three phase partitioning
KW  - Doehlert design
Y1  - 2015
U6  - https://doi.org/10.1016/j.foodchem.2015.03.028
SN  - 0308-8146
SN  - 1873-7072
VL  - 183
SP  - 144
EP  - 153
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Kana-Sop, Marie Modestine
A1  - Gouado, Inocent
A1  - Achu, Mercy Bih
A1  - Van Camp, John
A1  - Zollo, Paul Henri Amvam
A1  - Schweigert, Florian J.
A1  - Oberleas, Donald
A1  - Ekoe, Tetanye
T1  - The Influence of Iron and Zinc Supplementation on the Bioavailability of Provitamin A Carotenoids from Papaya Following Consumption of a Vitamin A-Deficient Diet
JF  - Journal of nutritional science and vitaminology
N2  - Iron deficiency anemia, zinc and vitamin A deficiencies are serious public health problems in Cameroon, as in many developing countries. Local vegetables which are sources of provitamin A carotenoids (PACs) can be used to improve vitamin A intakes. However, traditional meals are often unable to cover zinc and iron needs. The aim of this study was to determine the bioavailability of 3 PACs (alpha-carotene, beta-carotene, and beta-cryptoxanthin) in young men, who were fed with a vitamin A-free diet and received iron and zinc supplementation. Twelve healthy participants were divided into three groups and were supplemented with elemental iron (20 mg of iron fumarate), 20 mg of zinc sulfate or iron + zinc (20 mg of iron in the morning and 20 mg of zinc in the evening) for 11 d. They were given a vitamin A- and PAC-free diet from the 6th to the 11th day, followed by a test meal containing 0.55 kg of freshly peeled papaya as a source of PACs. Blood samples were collected four times successively on the 11th day (the test meal day), at TO (just after the test meal), after 2 h (T2), after 4 h (T4) and after 7 h (T7). Ultracentrifugation was used to isolate serum chylomicrons. Retinol appearance and PAC postprandial concentrations were determined. The supplementation with zinc, iron and iron+zinc influenced the chylomicron appearance of retinol and PACs differently as reflected by retention times and maximum absorption peaks. Iron led to highest retinol levels in the chylomicron. Zinc and iron+zinc supplements were best for optimal intact appearance of alpha-carotene, beta-carotene and beta-cryptoxanthin respectively. Supplementation with iron led to the greatest bioavailability of PACs from papaya and its conversion to retinol.
KW  - micronutrient deficiencies
KW  - zinc/iron supplementation
KW  - carotenoids bioavailability
KW  - Cameroon
Y1  - 2015
SN  - 0301-4800
SN  - 1881-7742
VL  - 61
IS  - 3
SP  - 205
EP  - 214
PB  - Univ. of Tokyo Pr.
CY  - Tokyo
ER  - 
TY  - JOUR
A1  - Danquah, Ina
A1  - Dobrucky, C. Lydia
A1  - Frank, Laura K.
A1  - Henze, Andrea
A1  - Amoako, Yaw A.
A1  - Bedu-Addo, George
A1  - Raila, Jens
A1  - Schulze, Matthias Bernd
A1  - Mockenhaupt, Frank P.
A1  - Schweigert, Florian J.
T1  - Vitamin A: potential misclassification of vitamin A status among patients with type 2 diabetes and hypertension in urban Ghana
JF  - The American journal of clinical nutrition : a publication of the American Society for Nutrition, Inc.
N2  - Background: Sub-Saharan Africa is facing a double burden of malnutrition: vitamin A deficiency (VAD) prevails, whereas the nutrition-related chronic conditions type 2 diabetes (T2D) and hypertension are emerging. Serum retinol a VAD marker increases in kidney disease and decreases in inflammation, which can partly be attributed to alterations in the vitamin A transport proteins retinol-binding protein 4 (RBP4) and prealbumin. Kidney dysfunction and inflammation commonly accompany T2D and hypertension.
 Objective: Among urban Ghanaians, we investigated the associations of T2D and hypertension with serum retinol as well as the importance of kidney function and inflammation in this regard.
 Design: A hospital-based, case-control study in individuals for risk factors of T2D, hypertension, or both was conducted in Kumasi, Ghana (328 controls, 197 with T2D, 354 with hypertension, and 340 with T2D plus hypertension). In 1219 blood samples, serum retinol, RBP4, and prealbumin were measured. Urinary albumin and estimated glomerular filtration rate (eGFR) defined kidney function. C-reactive protein (CRP) >5 mg/L indicated inflammation. We identified associations of T2D and hypertension with retinol by linear regression and calculated the contribution of RBP4, prealbumin, urinary albumin, eGFR, and CRP to these associations as the percentages of the explained variance of retinol.
 Results: VAD (retinol <1.05 mu mol/L) was present in 10% of this predominantly female, middle-aged, overweight, and deprived population. Hypertension, but not T2D, was positively associated with retinol (beta: 0.12; 95% CI: 0.08, 0,17), adjusted for age, sex, socioeconomic factors, anthropometric measurements, and lifestyle. In addition to RBP4 (72%) and prealbumin (22%), the effect of increased retinol on individuals with hypertension was mainly attributed to impaired kidney function (eGFR: 30%; urinary albumin: 5%) but not to inflammation.
 Conclusions: In patients with hypertension, VAD might be underestimated because of increased serum retinol in the context of kidney dysfunction. Thus, the interpretation of serum retinol in sub-Saharan Africa should account for hypertension status.
KW  - hypertension
KW  - inflammation
KW  - kidney dysfunction
KW  - type 2 diabetes
KW  - vitamin A deficiency
Y1  - 2015
U6  - https://doi.org/10.3945/ajcn.114.101345
SN  - 0002-9165
SN  - 1938-3207
VL  - 102
IS  - 1
SP  - 207
EP  - 214
PB  - American Society for Nutrition, Inc.
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Zirafi, Onofrio
A1  - Kim, Kyeong-Ae
A1  - Ständker, Ludger
A1  - Mohr, Katharina B.
A1  - Sauter, Daniel
A1  - Heigele, Anke
A1  - Kluge, Silvia F.
A1  - Wiercinska, Eliza
A1  - Chudziak, Doreen
A1  - Richter, Rudolf
A1  - Möpps, Barbara
A1  - Gierschik, Peter
A1  - Vas, Virag
A1  - Geiger, Hartmut
A1  - Lamla, Markus
A1  - Weil, Tanja
A1  - Burster, Timo
A1  - Zgraja, Andreas
A1  - Daubeuf, Francois
A1  - Frossard, Nelly
A1  - Hachet-Haas, Muriel
A1  - Heunisch, Fabian
A1  - Reichetzeder, Christoph
A1  - Galzi, Jean-Luc
A1  - Perez-Castells, Javier
A1  - Canales-Mayordomo, Angeles
A1  - Jimenez-Barbero, Jesus
A1  - Gimenez-Gallego, Guillermo
A1  - Schneider, Marion
A1  - Shorter, James
A1  - Telenti, Amalio
A1  - Hocher, Berthold
A1  - Forssmann, Wolf-Georg
A1  - Bonig, Halvard
A1  - Kirchhoff, Frank
A1  - Münch, Jan
T1  - Discovery and Characterization of an Endogenous CXCR4 Antagonist
JF  - Cell reports
N2  - CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.
Y1  - 2015
U6  - https://doi.org/10.1016/j.celrep.2015.03.061
SN  - 2211-1247
VL  - 11
IS  - 5
SP  - 737
EP  - 747
PB  - Cell Press
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Maschirow, Laura
A1  - Khalaf, Kinda
A1  - Al-Aubaidy, Hayder A.
A1  - Jelinek, Herbert F.
T1  - Inflammation, coagulation, endothelial dysfunction and oxidative stress in prediabetes - Biomarkers as a possible tool for early disease detection for rural screening
JF  - Clinical biochemistry : official journal of the Canadian Society of Clinical Chemists
N2  - Objectives: This study aims to increase understanding of the connection between oxidative stress and inflammation in diabetes disease progression to provide a basis for investigating improved diagnostic possibilities, treatment and prevention of prediabetes.
 Design and methods: Differences in the level of biochemical markers of oxidative stress (erythrocyte GSH/GSSG and urinary 8-isoprostane), inflammation (CRP, IL-6), endothelial dysfunction (plasma homocysteine, urinary 8-hydroxy-2-deoxy-guanosine) and coagulation/fibrinolysis (C5a, D-Dimer) were determined in prediabetes and control subjects.
 Results: While no difference was found in the 8-isoprostane levels between the two groups, the erythrocyte GSH/GSSG ratio was significantly reduced in the prediabetes group compared to control, indicating increased oxidative stress in the prediabetic state. Both urinary 8-OHdG and surprisingly also plasma homocysteine were significantly elevated in the prediabetes group, indicating endothelial dysfunction. The inflammation markers were slightly elevated in the prediabetic subjects and the same trend was found for the coagulation/fibrinolysis markers C5a and D-Dimer. These results were however not significant.
 Conclusions: The small elevation of blood glucose levels in the prediabetic state may have a detectable influence on endothelial function as indicated by changes to 8-OHdG, indicating an increased DNA-damage and homocysteine release from endothelial cells. Increased oxidative stress as indicated by the reduced GSH/GSSG ratio is likely to be the link between the moderate hyperglycaemia in prediabetes and pathological changes in endothelial function, which in the long-term may promote atherogenesis and result in the development of cardiovascular disease. Early detection of prediabetes is essential to avoid diabetes development and the associated complications like cardiovascular disease. The GSH/GSSG ratio and biomarkers like urinary 8-OHdG and plasma homocysteine offer a possible tool for the assessment of prediabetes in prevention screenings. (C) 2015 The Authors. The Canadian Society of Clinical Chemists. Published by Elsevier Inc.
KW  - Prediabetes
KW  - Oxidative stress
KW  - Inflammation
KW  - Coagulation
KW  - Endothelial dysfunction
Y1  - 2015
U6  - https://doi.org/10.1016/j.clinbiochem.2015.02.015
SN  - 0009-9120
SN  - 1873-2933
VL  - 48
IS  - 9
SP  - 581
EP  - 585
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Satwiko, Muhammad Gahan
A1  - Ikeda, Koji
A1  - Nakayama, Kazuhiko
A1  - Yagi, Keiko
A1  - Hocher, Berthold
A1  - Hirata, Ken-Ichi
A1  - Emoto, Noriaki
T1  - Targeted activation of endothelin-1 exacerbates hypoxia-induced pulmonary hypertension
JF  - Biochemical and biophysical research communications
N2  - Pulmonary arterial hypertension (PAH) is a fatal disease that eventually results in right heart failure and death. Current pharmacologic therapies for PAH are limited, and there are no drugs that could completely cure PAH. Enhanced activity of endothelin system has been implicated in PAH severity and endothelin receptor antagonists have been used clinically to treat PAH. However, there is limited experimental evidence on the direct role of enhanced endothelin system activity in PAL-I. Here, we investigated the correlation between endothelin-1 (ET-1) and PAH using ET-1 transgenic (ETTG) mice. Exposure to chronic hypoxia increased right ventricular pressure and pulmonary arterial wall thickness in ETTG mice compared to those in wild type mice. Of note, ETTG mice exhibited modest but significant increase in right ventricular pressure and vessel wall thickness relative to wild type mice even under normoxic conditions. To induce severe PAH, we administered SU5416, a vascular endothelial growth factor receptor inhibitor, combined with exposure to chronic hypoxia. Treatment with SU5416 modestly aggravated hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial vessel wall thickening in ETTG mice in association with increased interleukin-6 expression in blood vessels. However, there was no sign of obliterative endothelial cell proliferation and plexiform lesion formation in the lungs. These results demonstrated that enhanced endothelin system activity could be a causative factor in the development of PAH and provided rationale for the inhibition of endothelin system to treat PAH. (C) 2015 Elsevier Inc. All rights reserved.
KW  - Pulmonary arterial hypertension
KW  - Endothelin
KW  - Hypoxia
KW  - SU5416
Y1  - 2015
U6  - https://doi.org/10.1016/j.bbrc.2015.08.002
SN  - 0006-291X
SN  - 1090-2104
VL  - 465
IS  - 3
SP  - 356
EP  - 362
PB  - Elsevier
CY  - San Diego
ER  - 
TY  - JOUR
A1  - Fruscalzo, Arrigo
A1  - Londero, Ambrogio P.
A1  - Driul, Lorenza
A1  - Henze, Andrea
A1  - Tonutti, Laura
A1  - Ceraudo, Maria
A1  - Zanotti, Giuseppe
A1  - Berni, Rodolfo
A1  - Schweigert, Florian J.
A1  - Raila, Jens
T1  - First trimester concentrations of the TTR-RBP4-retinol complex components as early markers of insulin-treated gestational diabetes mellitus
JF  - Clinical chemistry and laboratory medicine : journal of the Forum of the European Societies of Clinical Chemistry - the European Branch of the International Federation of Clinical Chemistry and Laboratory Medicine
N2  - Background: The objective of the study was to investigate the relationship between first trimester maternal serum levels of the TTR-RBP4-ROH complex components and the later insurgence of an altered glucose metabolism during pregnancy.
 Methods: Retrospective case control study including 96 patients between the 12th and 14th week of gestation, 32 that developed gestational diabetes mellitus (GDM), respectively, 21 non-insulin-treated (dGDM) and 11 insulin-treated (iGDM), 20 large for gestational age fetuses (LGA) without GDM and 44 patients with normal outcome as control. Serum concentrations of RBP4 and TTR were assessed by ELISA; serum concentration of ROH by reverse-phase high performance liquid chromatography (rpHPLC). The molecular heterogeneity of TTR and RBP4 was analyzed after immunoprecipitation by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS).
 Results: iGDM patients were characterized by reduced TTR, RBP4 and ROH compared to controls (respectively, iGDM vs. controls, mean +/- SD: TTR 3.96 +/- 0.89 mu mol/L vs. 4.68 +/- 1.21 mu mol/L, RBP4 1.13 +/- 0.25 mu mol/L vs. 1.33 +/- 0.38 mu mol/L and ROH 1.33 +/- 0.17 mu mol/L vs. 1.62 +/- 0.29 mu mol/L, p < 0.05). TTR containing Gly10 in place of Cys10 was lower in the iGDM group (p < 0.05) compared to controls. In the final logistic regression model ROH significantly predicted the diagnosis of iGDM (OR 0.93, 95% CI 0.87-0.98, p < 0.05).
 Conclusions: First trimester maternal serum ROH, RBP4 and TTR represent potential biomarkers associated with the development of iGDM.
KW  - first trimester
KW  - gestational diabetes mellitus (GDM)
KW  - insulin
KW  - large for gestational age fetus (LGA)
KW  - protein microheterogeneity
KW  - retinol (ROH)
KW  - serum retinol binding protein (RBP4)
KW  - transthyretin (TTR)
Y1  - 2015
U6  - https://doi.org/10.1515/cclm-2014-0929
SN  - 1434-6621
SN  - 1437-4331
VL  - 53
IS  - 10
SP  - 1643
EP  - 1651
PB  - De Gruyter
CY  - Berlin
ER  - 
TY  - JOUR
A1  - Luckert, Claudia
A1  - Hessel, Stefanie
A1  - Lenze, Dido
A1  - Lampen, Alfonso
T1  - Disturbance of gene expression in primary human hepatocytes by hepatotoxic pyrrolizidine alkaloids: A whole genome transcriptome analysis
JF  - Toxicology in vitro
N2  - 1,2-unsaturated pyrrolizidine alkaloids (PA) are plant metabolites predominantly occurring in the plant families Asteraceae and Boraginaceae. Acute and chronic PA poisoning causes severe hepatotoxicity. So far, the molecular mechanisms of PA toxicity are not well understood. To analyze its mode of action, primary human hepatocytes were exposed to a non-cytotoxic dose of 100 mu M of four structurally different PA: echimidine, heliotrine, senecionine, senkirkine. Changes in mRNA expression were analyzed by a whole genome microarray. Employing cut-off values with a vertical bar fold change vertical bar of 2 and a q-value of 0.01, data analysis revealed numerous changes in gene expression. In total, 4556, 1806, 3406 and 8623 genes were regulated by echimidine, heliotrine, senecione and senkirkine, respectively. 1304 genes were identified as commonly regulated. PA affected pathways related to cell cycle regulation, cell death and cancer development. The transcription factors TP53, MYC, NF kappa B and NUPR1 were predicted to be activated upon PA treatment. Furthermore, gene expression data showed a considerable interference with lipid metabolism and bile acid flow. The associated transcription factors FXR, LXR, SREBF1/2, and PPAR alpha/gamma/delta were predicted to be inhibited.
 In conclusion, though structurally different, all four PA significantly regulated a great number of genes in common. This proposes similar molecular mechanisms, although the extent seems to differ between the analyzed PA as reflected by the potential hepatotoxicity and individual PA structure. (C) 2015 Elsevier Ltd. All rights reserved.
KW  - Pyrrolizidine alkaloids
KW  - Transcriptomics
KW  - Gene expression
KW  - Hepatotoxicity
Y1  - 2015
U6  - https://doi.org/10.1016/j.tiv.2015.06.021
SN  - 0887-2333
VL  - 29
IS  - 7
SP  - 1669
EP  - 1682
PB  - Elsevier
CY  - Oxford
ER  -