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Leyendecker M.,Leibniz Institute For Umweltmedizinische Forschung Iuf | Korsten P.,Universitatsmedizin Gottingen | Reinehr R.,Heinrich Heine University Dusseldorf | Speckmann B.,Heinrich Heine University Dusseldorf | And 6 more authors.
Hormone and Metabolic Research | Year: 2011

The phosphoinositide 3-kinase (PI3 K)/Akt pathway controls the activity of a number of proteins important in the regulation of apoptosis and cell proliferation. FoxO (forkhead box, class O) transcription factors, substrates of the Ser/Thr kinase Akt, control the expression of several target genes that are crucial to the defense against oxidative stress, the regulation of cell cycle, and apoptosis in mammalian cells. Here, expression of ceruloplasmin (CP), the major copper-containing protein in blood released by the liver, was investigated. We observed a significant downregulation of CP mRNA levels after insulin treatment in H4IIE rat hepatoma cells. The PI3K inhibitor wortmannin counteracted this insulin effect on CP mRNA levels, indicating that the PI3K/Akt cascade is involved in the regulation of CP expression. Stimulation of FoxO1 was induced in H4IIE rat hepatoma cells expressing a conditionally active FoxO1 construct, resulting in significant upregulation of CP mRNA levels. This upregulation was prevented in the presence of insulin. In parallel, mRNAs of established FoxO target genes were analyzed: like CP mRNA, selenoprotein P and glucose 6-phosphatase mRNAs were upregulated by FoxO1, which was prevented by insulin. The same effects of insulin on CP mRNA levels were detected in primary rat hepatocytes. Furthermore, CP release into cell culture media was analyzed with primary hepatocytes and found to be attenuated by insulin. In line with its insulin-mimetic effects on cultured cells, Cu2+ imitated the effect of insulin on CP expression and caused a downregulation of CP mRNA levels in rat hepatoma cells. © Georg Thieme Verlag KG Stuttgart - New York. Source


Heinrich J.,Helmholtz Center Munich | Bruske I.,Helmholtz Center Munich | Schnappinger M.,Helmholtz Center Munich | Standl M.,Helmholtz Center Munich | And 20 more authors.
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz | Year: 2012

Numerous chronic diseases in childhood and adulthood have their origins in perinatal life and are potentially influenced by trans-generational epigenetic processes. Therefore, prospective birth cohorts can substantially contribute to our knowledge about the etiology of diseases including modifiable risk factors. The two population-based German birth cohorts GINIplus and LISAplus aim to describe the natural course of chronic diseases and intermediate phenotypes in childhood and its determinants, and to identify potential genetic effect modifications. In the mid-1990s, 5,991 (GINIplus) and 3,097 (LISAplus) healthy, term newborns were recruited for long-term follow-up in four regions of Germany. The follow-up rate for the first 10 years was about 55%. We analyzed the growth and development of overweight, infections and allergic diseases, mental and oral health, metabolic and inflammatory parameters and the role of potential risk factors including genetics. The results of these two birth cohorts substantially contribute to the current knowledge about the natural course of these health parameters. These data were included in many international projects and consortia for purposes of international comparisons of prevalence and consistency of findings, and to increase the power of the analyses. © Springer-Verlag 2012. Source


Von Berg A.,Klinik fur Kinder und Jugendmedizin | Filipiak-Pittroff B.,Klinik fur Kinder und Jugendmedizin | Kramer U.,Leibniz Institute For Umweltmedizinische Forschung Iuf | Link E.,Leibniz Institute For Umweltmedizinische Forschung Iuf | And 8 more authors.
Allergologie | Year: 2012

In the complex interaction between certain environmental factors and genetic disposition, the early allergen exposure plays a major role in the development of allergic diseases. In aiming to reduce the allergen burden for the infant at risk during early infancy, cow milk protein hydrolysate infant formulas (hypoallergenic infant formulas) are appropriate alternatives to breastfeeding for primary allergy prevention. The German Infant Nutritional Intervention- Program (GINI) was supported for the first 3 years of the study by the German Ministry for Education and Research (BMBF) (FKZ 01 EE 9401-4). It is a birth cohort which was primarily scheduled until the children were 3 years old. The aim of the prospective, randomised, double-blind intervention study was to investigate the impact of different cow milk protein hydrolysate infant formulas in the first 4 - 6 months on the development of allergic diseases in children at risk due to at least one parent or biological sibling with a history of an allergic disease. The allocation to one of the 4 intervention formulas (partial whey hydrolysate, extensive whey hydrolysate, extensive casein hydrolysate or standard cow's milk formula) was randomised and stratified by family history (single/biparental) and the respective obstetric clinic. Recruitment was carried out by the three clinical centers (Research Institute Marien-Hospital Wesel, Children's Department, Ludwigs-Maximilians-University München and Children's Department Technical University München) in 18 obstetric clinics between 01.09.1995 and 30.06.1998. Along with the intervention study a non-interventional, complementary observational cohort of children with or without allergy risk was recruited and followed by annual self-reporting parental questionnaires. The GINI intervention study (GINI-I, N = 2.252) and the non-interventional observation study (GINI-NI, N = 3.739) are combined in the population-based GINIplus study (see article J. Heinrich et al. in this journal). The results of the GINI intervention study confirm that, cow milk protein hydrolysate infant formulas have a preventive effect on allergic manifestation compared with a standard cow milk formula, until school age. However, the dimension of the effect is different between the formulas. This effect, which is mainly driven by the effect on atopic eczema, develops in the first months of life and persists without rebound. In the formula-groups the cumulative incidence of atopic eczema until school age is reduced between 26% and 45% compared with standard cow milk formula. A beneficial effect of the hydrolysate formulas on the respiratory manifestations asthma and rhinoconjunctivitis, however, could not be shown. By comparing the GINI-intervention and non-intervention arm of the GINIplus study it was demonstrated, that a family history for allergy doubles the risk for eczema in the offspring. Early intervention with cow milk protein hydrolysate infant formulas is able to substantially compensate this risk for eczema until the age of 6 years. In contrast, by randomisation to standard cow milk formula this risk showed a trend towards a higher incidence compared with children at risk from the non-intervention group. Thus, the results of the GINIplus study have contributed to answer some of the controversially discussed questions. © 2012Dustri-Verlag Dr. Karl Feistle. Source


von Berg A.,Klinik fur Kinder und Jugendmedizin | Filipiak-Pittroff B.,Klinik fur Kinder und Jugendmedizin | Kramer U.,Leibniz Institute For Umweltmedizinische Forschung Iuf | Link E.,Leibniz Institute For Umweltmedizinische Forschung Iuf | And 8 more authors.
Pravention und Rehabilitation | Year: 2012

In the complex interaction between certain environmental factors and genetic disposition, the early allergen exposure plays a major role in the development of allergic diseases. In aiming to reduce the allergen burden for the infant at risk during early infancy, cow milk protein hydrolysate infant formulas (hypoallergenic infant formulas) are appropriate alternatives to breastfeeding for primary allergy prevention. The German Infant Nutritional Intervention- Program (GINI) was supported for the first 3 years of the study by the German Ministry for Education and Research (BMBF) (FKZ 01 EE 9401-4). It is a birth cohort which was primarily scheduled until the children were 3 years old. The aim of the prospective, randomised, double-blind intervention study was to investigate the impact of different cow milk protein hydrolysate infant formulas in the first 4 - 6 months on the development of allergic diseases in children at risk due to at least one parent or biological sibling with a history of an allergic disease. The allocation to one of the 4 intervention formulas (partial whey hydrolysate, extensive whey hydrolysate, extensive casein hydrolysate or standard cow's milk formula) was randomised and stratified by family history (single/biparental) and the respective obstetric clinic. Recruitment was carried out by the three clinical centers (Research Institute Marien-Hospital Wesel, Children's Department, Ludwigs-Maximilians-University München and Children's Department Technical University München) in 18 obstetric clinics between 01.09.1995 and 30.06.1998. Along with the intervention study a non-interventional, complementary observational cohort of children with or without allergy risk was recruited and followed by annual self-reporting parental questionnaires. The GINI intervention study (GINI-I, N = 2.252) and the non-interventional observation study (GINI-NI, N = 3.739) are combined in the population-based GINIplus study. The results of the GINI intervention study confirm that, cow milk protein hydrolysate infant formulas have a preventive effect on allergic manifestation compared with a standard cow milk formula, until school age. However, the dimension of the effect is different between the formulas. This effect, which is mainly driven by the effect on atopic eczema, develops in the first months of life and persists without rebound. In the formula-groups the cumulative incidence of atopic eczema until school age is reduced between 26% and 45% compared with standard cow milk formula. A beneficial effect of the hydrolysate formulas on the respiratory manifestations asthma and rhinoconjunctivitis, however, could not be shown. By comparing the GINI-intervention and non-intervention arm of the GINIplus study it was demonstrated, that a family history for allergy doubles the risk for eczema in the offspring. Early intervention with cow milk protein hydrolysate infant formulas is able to substantially compensate this risk for eczema until the age of 6 years. In contrast, by randomisation to standard cow milk formula this risk showed a trend towards a higher incidence compared with children at risk from the non-intervention group. Thus, the results of the GINIplus study have contributed to answer some of the controversially discussed questions. © 2012 Dustri-Verlag Dr. Karl Feistle. Source


Ale-Agha N.,Leibniz Institute For Umweltmedizinische Forschung Iuf | Albrecht C.,Leibniz Institute For Umweltmedizinische Forschung Iuf | Klotz L.-O.,Leibniz Institute For Umweltmedizinische Forschung Iuf | Klotz L.-O.,University of Alberta
Biological Chemistry | Year: 2010

The aim of this study was to investigate whether fine and ultrafine carbon black (fC and ufC), and fine and ultrafine silica (fS, ufS) particles affect gap junctional intercellular communication (GJIC) in rat lung epithelial cells. Exposure of cells to subcytotoxic doses of ufC, fS and ufS resulted in a 63%, 59% and 77% reduction of GJIC, respectively, as determined in a dye transfer assay. In contrast to ufC, fC did not significantly alter GJIC. Changes in subcellular localization of the major gap junction protein in RLE cells, connexin-43 (Cx43), and of β-catenin were observed in cells exposed to ufC, fS or ufS. The loss of GJIC was counteracted by N-acetyl cysteine and was largely prevented by specific inhibitors of epidermal growth factor receptor-dependent signaling, pointing to the crucial role of two known major mediators of nanoparticle action, namely reactive oxygen species and membrane-receptor signaling, in particle-induced modulation of GJIC. © 2010 by Walter de Gruyter Berlin New York. Source

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