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Goek O.-N.,Albert Ludwigs University of Freiburg | Doring A.,Helmholtz Center for Environmental Research | Gieger C.,Helmholtz Center for Environmental Research | Heier M.,Helmholtz Center for Environmental Research | And 15 more authors.
American Journal of Kidney Diseases | Year: 2012

Background: Metabolites such as creatinine and urea are established kidney function markers. High-throughput metabolomic studies have not been reported in large general population samples spanning normal kidney function and chronic kidney disease (CKD). Study Design: Cross-sectional observational studies of the general population. Setting & Participants: 2 independent samples: KORA F4 (discovery sample, n = 3,011) and TwinsUK (validation sample, n = 984). Exposure Factors: 151 serum metabolites, quantified by targeted mass spectrometry. Outcomes & Measurements: Metabolites and their 22,650 ratios were analyzed by multivariable-adjusted linear regression for their association with glomerular filtration rate (eGFR), estimated separately from creatinine and cystatin C levels by CKD-EPI (CKD Epidemiology Collaboration) equations. After correction for multiple testing, significant metabolites (P < 3.3 × 10 -4 for single metabolites; P < 2.2 × 10 -6 for ratios) were meta-analyzed with independent data from the TwinsUK Study. Results: Replicated associations with eGFR were observed for 22 metabolites and 516 metabolite ratios. Pooled P values ranged from 7.1 × 10 -7 to 1.8 × 10 -69 for the replicated single metabolites. Acylcarnitines such as glutarylcarnitine were associated inversely with eGFR (-3.73 mL/min/1.73 m 2 per standard deviation [SD] increase, pooled P = 1.8 × 10 -69). The replicated ratio with the strongest association was the ratio of serine to glutarylcarnitine (P = 3.6 × 10 -81). Almost all replicated phenotypes associated with decreased eGFR (<60 mL/min/1.73 m 2; n = 172 cases) in KORA F4: per 1-SD increment, ORs ranged from 0.29-2.06. Across categories of a metabolic score consisting of 3 uncorrelated metabolites, the prevalence of decreased eGFR increased from 3% to 53%. Limitations: Cross-sectional study design, GFR was estimated, limited number of metabolites. Conclusions: Distinct metabolic phenotypes were reproducibly associated with eGFR in 2 separate population studies. They may provide novel insights into renal metabolite handling, improve understanding of pathophysiology, or aid in the diagnosis of kidney disease. Longitudinal studies are needed to clarify whether changes in metabolic phenotypes precede or result from kidney function impairment. © 2012 National Kidney Foundation, Inc.


News Article | November 15, 2016
Site: www.eurekalert.org

Ferroptosis is a recently discovered form of cell death, which is still only partially understood. Scientists at the Helmholtz Zentrum München have now identified an enzyme that plays a key role in generating the signal that initiates cell death. Their findings, published in two articles in the journal Nature Chemical Biology, could now give new impetus to research into the fields of cancer, neurodegeneration and other degenerative diseases. The term ferroptosis was first coined in 2012. It is derived from the Greek word ptosis, meaning "a fall", and ferrum, the Latin word for iron, and describes a form of regulated necrotic cell death in which iron appears to play an important role. "The individual mechanisms involved in this type of cell death remain only partly understood, and our findings make an important contribution towards a better understanding of ferroptotic cell death," says study leader Dr. Marcus Conrad, who is heading a research group at the Institute of Developmental Genetics at the Helmholtz Zentrum München. Along with his team and colleagues from the University of Pittsburgh, he was able to show that ACSL4*, an enzyme involved in the metabolism of fatty acids, plays a central role in ferroptosis. In order for the lethal mechanism to be triggered, a certain amount of specific oxidized lipid molecules must be present in membranes. "Acsl4 is critically involved in shaping the cellular lipid composition by storing more poly-unsaturated long-chain fatty acids in cellular membranes, thereby providing the starting materials for the generation of the lethal lipid signals driving ferroptosis" explains PhD student Sebastian Doll, first author of one of the two studies. "Previously it was assumed that iron-dependent lipid oxidation occurs randomly; however, our data now demonstrate that ACSL4 centrally contributes to the formation of oxidized lipid death signals in ferroptosis." Potential applications for the treatment of cancer and neurodegenerative diseases Although the term 'cell death' is generally viewed as an adverse event and thus has a rather negative image, it has been shown - particularly in the context of cancer - that the selective destruction of aberrant cells is vital for the human body. The scientists therefore examined the role of ACSL4 in this context. They showed that a subset of breast cancer cells (i.e. triple negative breast cancer cells) that do not produce ACSL4 are extremely resistant to ferroptosis, while those that express the enzyme respond very sensitively to ferroptosis induction. "This is a highly interesting finding given the fact that the presence of ACSL4 determines whether or not cells can embark on the ferroptosis pathway" explains Dr. José Pedro Friedmann Angeli, who was centrally involved in both studies. It is thus well conceivable, he says, that the molecule could be used as a biomarker in cancer patient stratification. The researchers also provided the first molecular approach for targeting ACSL4 in the signalling pathway. In a model experiment using thiazolidinediones, a class of active compounds commonly used in the treatment of diabetes, they succeeded in slowing down the process of ferroptosis. "Our intriguing insights that the ACSL4 enzyme plays a substantial role in the process of cell death provide novel cues for yet-unrecognized therapeutic approaches towards inhibiting ferroptosis in degenerative diseases or inducing ferroptosis in certain tumor diseases," says study leader Dr. Conrad. In particular, tumors that are otherwise very difficult to treat with standard chemotherapy might be amenable for ferroptosis therapy, the researchers say. * Acyl-CoA is a group of coenzymes involved in the metabolism of fatty acids. ACSL4 stands for Acyl-CoA synthetase long-chain family member 4. Background: Up until now ferroptosis is only partially understood. However, the importance of cellular suicide has already been impressively documented by research concerning apoptosis, the first identified cell death pathway, which has been explored by far more comprehensively throughout the last decades than ferroptosis. Moreover, ferroptosis appears to play a key role in cancer and in cell demise in response to oxidative stress (e.g. in neurons). Previously, only a few essential molecules, such as glutathione peroxidase 4 (GPX4), have been implicated in the ferroptotic process. Kagan, VE. et al. (2016): Oxidized Arachidonic and Adrenic PEs Navigate Cells to Ferroptosis. Nature Chemical Biology, doi: 10.1038/nchembio.2238 http://www. The Helmholtz Zentrum München, the German Research Center for Environmental Health, pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München is headquartered in Neuherberg in the north of Munich and has about 2,300 staff members. It is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members. http://www. Rising life expectancy is causing an increase in age-related, but also sociological and environmental, influences on the genes. The Institute of Developmental Genetics (IDG) examines these changes in genetic material. In the Mouse Genetics group, genetic animal models are developed to investigate various diseases. These models are analyzed in the Disease Modelling research group in order to identify gene functions and cell processes and evaluate the influence of the environment and aging processes. The group focuses on the examination of neurological and psychiatric diseases. http://www. The Institute of Human Genetics (IHG) at the Helmholtz Zentrum München and the Technical University of Munich: The Institute is concerned with identifying genes associated with disease and characterizing their functions. The main aim of the research projects is to develop disease-related genetic variation in humans and mice as well as to develop chromosome analysis techniques and new methods for dealing with specific issues in the sphere of pre- and post-natal diagnostics and tumor cytogenetics. http://www. The research objective of the Institute of Experimental Genetics (IEG) is to elucidate the causes and pathogenesis of human diseases. Due to its prominent role in interdisciplinary and international consortia, the IEG is a global leader in the systemic study of mouse models for human diseases and the elucidation of involved genes. The main focus is on metabolic diseases such as diabetes. The IEG is part of the Helmholtz Diabetes Center (HDC). http://www. The Institute of Pathology (PATH) contributes to the identification and characterization of molecular mechanisms and pathways, which are relevant for disease development and progression. We endeavor to understand the interplay between environment and genetic, and to identify novel targets for therapeutic intervention. http://www. Contact for the media: Department of Communication, Helmholtz Zentrum München - German Research Center for Environmental Health, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 2238 - Fax: +49 89 3187 3324 - E-mail: presse@helmholtz-muenchen.de Scientific Contact at Helmholtz Zentrum München: Dr. Marcus Conrad, Helmholtz Zentrum München - German Research Center for Environmental Health, Institute of Developmental Genetics, Ingolstädter Landstr. 1, 85764 Neuherberg - Tel. +49 89 3187 4608, E-mail: marcus.conrad@helmholtz-muenchen.de


Wittenbecher C.,German Institute of Human Nutrition | Wittenbecher C.,German Center for Diabetes Research | Muhlenbruch K.,German Institute of Human Nutrition | Muhlenbruch K.,German Center for Diabetes Research | And 18 more authors.
American Journal of Clinical Nutrition | Year: 2015

Background: Habitual red meat consumption was consistently related to a higher risk of type 2 diabetes in observational studies. Potentially underlying mechanisms are unclear. Objective: This study aimed to identify blood metabolites that possibly relate red meat consumption to the occurrence of type 2 diabetes. Design: Analyses were conducted in the prospective European Prospective Investigation into Cancer and Nutrition-Potsdam cohort (n = 27,548), applying a nested case-cohort design (n = 2681, including 688 incident diabetes cases). Habitual diet was assessed with validated semiquantitative food-frequency questionnaires. Total red meat consumption was defined as energy-standardized summed intake of unprocessed and processed red meats. Concentrations of 14 amino acids, 17 acylcarnitines, 81 glycerophospholipids, 14 sphingomyelins, and ferritin were determined in serum samples from baseline. These biomarkers were considered potential mediators of the relation between total red meat consumption and diabetes risk in Cox models. The proportion of diabetes risk explainable by biomarker adjustment was estimated in a bootstrapping procedure with 1000 replicates. Results: After adjustment for age, sex, lifestyle, diet, and body mass index, total red meat consumption was directly related to diabetes risk [HR for 2 SD (11 g/MJ): 1.26; 95% CI: 1.01, 1.57]. Six biomarkers (ferritin, glycine, diacyl phosphatidylcholines 36:4 and 38:4, lysophosphatidylcholine 17:0, and hydroxy-sphingomyelin 14:1) were associated with red meat consumption and diabetes risk. The red meat-associated diabetes risk was significantly (P < 0.001) attenuated after simultaneous adjustment for these biomarkers [biomarker-adjusted HR for 2 SD (11 g/MJ): 1.09; 95% CI: 0.86, 1.38]. The proportion of diabetes risk explainable by respective biomarkers was 69% (IQR: 49%, 106%). Conclusion: In our study, high ferritin, low glycine, and altered hepatic-derived lipid concentrations in the circulation were associated with total red meat consumption and, independent of red meat, with diabetes risk. The red meat-associated diabetes risk was largely attenuated after adjustment for selected biomarkers, which is consistent with the presumed mediation hypothesis. © 2015 American Society for Nutrition.


Yan X.,Helmholtz Center Munich | Yan X.,University of Jinan | Sabrautzki S.,Institute of Experimental Genetics | Horsch M.,Institute of Experimental Genetics | And 9 more authors.
Human Molecular Genetics | Year: 2014

Mutations in Peroxidasin (PXDN) cause severe inherited eye disorders in humans, such as congenital cataract, corneal opacity and developmental glaucoma. The role of peroxidasin during eye development is poorly understood. Here,wedescribethe firstPxdnmousemutant whichwasinducedbyENU(N-ethyl-N-nitrosourea)andled to a recessive phenotype. Sequence analysis of cDNArevealed a T3816Amutation resulting in a premature stop codon (Cys1272X) in the peroxidase domain. This mutation causes severe anterior segment dysgenesis and microphthalmia resembling the manifestations in patients with PXDN mutations. The proliferation and differentiation of the lens is disrupted in association with aberrant expression of transcription factor genes (Pax6 and Foxe3) in mutant eyes. Additionally, Pxdn is involved in the consolidation of the basement membrane and lens epithelium adhesion in the ocular lens. Lens material including g-crystallin is extruded into the anterior and posterior chamber due to local loss of structural integrity of the lens capsule as a secondary damage to the anteriorsegmentdevelopmentleadingtocongenital ocularinflammation. Moreover,Pxdnmutantsexhibited an early-onset glaucoma and progressive retinal dysgenesis. Transcriptome profiling revealed that peroxidasin affects the transcription of developmental and eye disease-related genes at early eye development. These findings suggest that peroxidasin is necessary for cell proliferation and differentiation and for basement membrane consolidation during eye development. Our studies provide pathogenic mechanisms of PXDN mutationinduced congenital eye diseases. © The Author 2014. Published by Oxford University Press.


Goncalves I.,Lund University | Goncalves I.,Skåne University Hospital | Edsfeldt A.,Lund University | Ko N.Y.,Lund University | And 13 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

Objectives-To determine whether the level of lysophosphatidylcholine (lysoPC) generated by lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with severity of inflammation in human atherosclerotic plaques. Elevated plasma Lp-PLA2 is associated with increased cardiovascular risk. Lp-PLA2 inhibition reduces atherosclerosis. Lp-PLA2 hydrolyzes low-density lipoprotein-oxidized phospholipids generating lysoPCs. According to in vitro studies, lysoPCs are proinflammatory but the association between their generation and plaque inflammation remains unknown. Methods and Results-Inflammatory activity in carotid plaques (162 patients) was determined immunohistochemically and by analyzing cytokines in homogenates (multiplex immunoassay). LysoPCs were quantified using mass spectrometry and Lp-PLA2 and the lysoPC metabolite lysophosphatidic acid (LPA) by ELISA. There was a strong correlation among lysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 in plaques. LysoPC 16:0, 18:0, 18:1, LPA, and Lp-PLA2 correlated with interleukin-1β, interleukin-6, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, regulated on activation normal T-cell expressed and secreted, and tumor necrosis factor-α in plaques. High lysoPC and Lp-PLA2 correlated with increased plaque macrophages and lipids and with low content of smooth muscle cells, whereas LPA only correlated with plaque macrophages. Lp-PLA2, lysoPC 16:0, 18:0, and 18:1, but not LPA were higher in symptomatic than in asymptomatic plaques. Conclusions-The associations among Lp-PLA2, lysoPCs, LPA, and proinflammatory cytokines in human plaques suggest that lysoPCs play a key role in plaque inflammation and vulnerability. Our findings support Lp-PLA2 inhibition as a possible strategy for the prevention of cardiovascular disease. © 2012 American Heart Association, Inc.


Lattka E.,Helmholtz Center for Environmental Research | Eggers S.,Helmholtz Center for Environmental Research | Moeller G.,Institute of Experimental Genetics | Heim K.,Helmholtz Center for Environmental Research | And 7 more authors.
Journal of Lipid Research | Year: 2010

Fatty acid desaturases (FADS) play an important role in the formation of omega-6 and omega-3 highly unsaturated fatty acids (HUFAs). The composition of HUFAs in the human metabolome is important for membrane fluidity and for the modulation of essential physiological functions such as inflammation processes and brain development. Several recent studies reported significant associations of single nucleotide polymorphisms (SNPs) in the human FADS gene cluster with HUFA levels and composition. The presence of the minor allele correlated with a decrease of desaturase reaction products and an accumulation of substrates. We performed functional studies with two of the associated polymorphisms (rs3834458 and rs968567) and showed an influence of polymorphism rs968567 on FADS2 promoter activity by luciferase reporter gene assays. Electrophoretic mobility shift assays proved allele-dependent DNA-binding ability of at least two protein complexes to the region containing SNP rs968567. One of the proteins binding to this region in an allele-specific manner was shown to be the transcription factor ELK1 (a member of ETS domain transcription factor family). These results indicate that rs968567 influences FADS2 transcription and offer first insights into the modulation of complex regulation mechanisms of FADS2 gene transcription by SNPs. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.


Suhre K.,Helmholtz Center for Environmental Research | Suhre K.,Ludwig Maximilians University of Munich | Romisch-Margl W.,Helmholtz Center for Environmental Research | De Angelis M.H.,Institute of Experimental Genetics | And 5 more authors.
Journal of Biomolecular Screening | Year: 2011

The fatty acid binding protein 4 (FABP4) belongs to the family of lipid chaperones that control intracellular fluxes and compartmentalization of their respective ligands (e.g., fatty acids). FABP4, which is almost exclusively expressed in adipocytes and macrophages, contributes to the development of insulin resistance and atherosclerosis in mice. Lack of FABP4 protects against the development of insulin resistance associated with genetic or diet-induced obesity in mice. Furthermore, total or macrophage-specific FABP4 deficiency is protective against atherosclerosis in apolipoprotein E-deficient mice. The FABP4 small-molecule inhibitor BMS309403 has demonstrated efficacy in mouse models for type 2 diabetes mellitus and atherosclerosis, resembling phenotypes of mice with FABP4 deficiency. However, despite the therapeutically attractive long-term effects of FABP4 inhibition, an acute biomarker for drug action is lacking. The authors applied mass spectrometry lipidomics analysis to in vitro and in vivo (plasma and adipose tissue) samples upon inhibitor treatment. They report the identification of a potential biomarker for acute in vivo FABP4 inhibition that is applicable for further investigations and can be implemented in simple and fast-flow injection mass spectrometry assays. In addition, this approach can be considered a proof-of-principle study that can be applied to other lipid-pathway targeting mechanisms. © 2011 Society for Laboratory Automation and Screening.


Moller G.,Helmholtz Center Munich | Husen B.,Solvay Group | Kowalik D.,Helmholtz Center Munich | Hirvela L.,Hormos Medical | And 7 more authors.
PLoS ONE | Year: 2010

Steroid-related cancers can be treated by inhibitors of steroid metabolism. In searching for new inhibitors of human 17betahydroxysteroid dehydrogenase type 1 (17β-HSD 1) for the treatment of breast cancer or endometriosis, novel substances based on 15-substituted estrone were validated. We checked the specificity for different 17β-HSD types and species. Compounds were tested for specificity in vitro not only towards recombinant human 17β-HSD types 1, 2, 4, 5 and 7 but also against 17β-HSD 1 of several other species including marmoset, pig, mouse, and rat. The latter are used in the processes of pharmacophore screening. We present the quantification of inhibitor preferences between human and animal models. Profound differences in the susceptibility to inhibition of steroid conversion among all 17β-HSDs analyzed were observed. Especially, the rodent 17β-HSDs 1 were significantly less sensitive to inhibition compared to the human ortholog, while the most similar inhibition pattern to the human 17β-HSD 1 was obtained with the marmoset enzyme. Molecular docking experiments predicted estrone as the most potent inhibitor. The best performing compound in enzymatic assays was also highly ranked by docking scoring for the human enzyme. However, species-specific prediction of inhibitor performance by molecular docking was not possible. We show that experiments with good candidate compounds would out-select them in the rodent model during preclinical optimization steps. Potentially active human-relevant drugs, therefore, would no longer be further developed. Activity and efficacy screens in heterologous species systems must be evaluated with caution. © 2010 Möller et al.


Breier M.,Helmholtz Center for Environmental Research | Breier M.,German Center for Diabetes Research | Breier M.,Ludwig Maximilians University of Munich | Wahl S.,Helmholtz Center for Environmental Research | And 19 more authors.
PLoS ONE | Year: 2014

Background: Information regarding the variability of metabolite levels over time in an individual is required to estimate the reproducibility of metabolite measurements. In intervention studies, it is critical to appropriately judge changes that are elicited by any kind of intervention. The pre-analytic phase (collection, transport and sample processing) is a particularly important component of data quality in multi-center studies. Methods: Reliability of metabolites (within-and between-person variance, intraclass correlation coefficient) and stability (shipment simulation at different temperatures, use of gel-barrier collection tubes, freeze-thaw cycles) were analyzed in fasting serum and plasma samples of 22 healthy human subjects using a targeted LC-MS approach. Results: Reliability of metabolite measurements was higher in serum compared to plasma samples and was good in most saturated short-and medium-chain acylcarnitines, amino acids, biogenic amines, glycerophospholipids, sphingolipids and hexose. The majority of metabolites were stable for 24 h on cool packs and at room temperature in non-centrifuged tubes. Plasma and serum metabolite stability showed good coherence. Serum metabolite concentrations were mostly unaffected by tube type and one or two freeze-thaw cycles. Conclusion: A single time point measurement is assumed to be sufficient for a targeted metabolomics analysis of most metabolites. For shipment, samples should ideally be separated and frozen immediately after collection, as some amino acids and biogenic amines become unstable within 3 h on cool packs. Serum gel-barrier tubes can be used safely for this process as they have no effect on concentration in most metabolites. Shipment of non-centrifuged samples on cool packs is a cost-efficient alternative for most metabolites. © 2014 Breier et al.


Tokarz J.,Institute of Experimental Genetics | Moller G.,Institute of Experimental Genetics | Hrabe De Angelis M.,Institute of Experimental Genetics | Hrabe De Angelis M.,TU Munich | And 4 more authors.
Journal of Steroid Biochemistry and Molecular Biology | Year: 2013

Zebrafish, Danio rerio, has long been used as a model organism in developmental biology. Nowadays, due to their advantages compared to other model animals, the fish gain popularity and are also increasingly used in endocrinology. This review focuses on an important aspect of endocrinology in zebrafish by summarizing the progress in steroid hormone related research. We present the state of the art of research on steroidogenesis, the action of steroid hormones, and steroid catabolism and cover the incremental usage of zebrafish as a test animal in endocrine disruption research. By this approach, we demonstrate that some aspects of steroid hormone research are well characterized (e.g., expression patterns of the genes involved), while other aspects such as functional analyses of enzymes, steroid hormone elimination, or the impact of steroid hormones on embryonic development or sex differentiation have not been extensively studied and are poorly understood. This article is part of a Special Issue entitled 'CSR 2013'. © 2013 Elsevier Ltd. All rights reserved.

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