TY - JOUR A1 - Balazadeh, Salma A1 - Schildhauer, Joerg A1 - Araujo, Wagner L. A1 - Munne-Bosch, Sergi A1 - Fernie, Alisdair R. A1 - Proost, Sebastian A1 - Humbeck, Klaus A1 - Müller-Röber, Bernd T1 - Reversal of senescence by N resupply to N-starved Arabidopsis thaliana: transcriptomic and metabolomic consequences JF - Journal of experimental botany N2 - Leaf senescence is a developmentally controlled process, which is additionally modulated by a number of adverse environmental conditions. Nitrogen shortage is a well-known trigger of precocious senescence in many plant species including crops, generally limiting biomass and seed yield. However, leaf senescence induced by nitrogen starvation may be reversed when nitrogen is resupplied at the onset of senescence. Here, the transcriptomic, hormonal, and global metabolic rearrangements occurring during nitrogen resupply-induced reversal of senescence in Arabidopsis thaliana were analysed. The changes induced by senescence were essentially in keeping with those previously described; however, these could, by and large, be reversed. The data thus indicate that plants undergoing senescence retain the capacity to sense and respond to the availability of nitrogen nutrition. The combined data are discussed in the context of the reversibility of the senescence programme and the evolutionary benefit afforded thereby. Future prospects for understanding and manipulating this process in both Arabidopsis and crop plants are postulated. KW - Arabidopsis KW - gene expression KW - metabolomics KW - nitrogen limitation KW - senescence KW - transcriptome Y1 - 2014 U6 - https://doi.org/10.1093/jxb/eru119 SN - 0022-0957 SN - 1460-2431 VL - 65 IS - 14 SP - 3975 EP - 3992 PB - Oxford Univ. Press CY - Oxford ER - TY - THES A1 - Bulut, Mustafa T1 - Assessing the genetic architecture underlying systemic responses to variable environments in crops using multi-omics N2 - Plant metabolism serves as the primary mechanism for converting assimilated carbon into essential compounds crucial for plant growth and ultimately, crop yield. This renders it a focal point of research with significant implications. Despite notable strides in comprehending the genetic principles underpinning metabolism and yield, there remains a dearth of knowledge regarding the genetic factors responsible for trait variation under varying environmental conditions. Given the burgeoning global population and the advancing challenges posed by climate change, unraveling the intricacies of metabolic and yield responses to water scarcity became increasingly important in safeguarding food security. Our research group has recently started to work on the genetic resources of legume species. To this end, the study presented here investigates the metabolic diversity across five different legume species at a tissue level, identifying species-specific biosynthesis of alkaloids as well as iso-/flavonoids with diverse functional groups, namely prenylation, phenylacylation as well as methoxylation, to create a resource for follow up studies investigation the metabolic diversity in natural diverse populations of legume species. Following this, the second study investigates the genetic architecture of drought-induced changes in a global common bean population. Here, a plethora of quantitative trait loci (QTL) associated with various traits are identified by performing genome-wide association studies (GWAS), including for lipid signaling. On this site, overexpression of candidates highlighted the induction of several oxylipins reported to be pivotal in coping with harsh environmental conditions such as water scarcity. Diverging from the common bean and GWAS, the following study focuses on identifying drought-related QTL in tomato using a bi-parental breeding population. This descriptive study highlights novel multi-omic QTL, including metabolism, photosynthesis as well as fruit setting, some of which are uniquely assigned under drought. Compared to conventional approaches using the bi-parental IL population, the study presented improves the resolution by assessing further backcrossed ILs, named sub-ILs. In the final study, a photosynthetic gene, namely a PetM subunit of the cytochrome b6f complex encoding gene, involved in electron flow is characterized in an horticultural important crop. While several advances have been made in model organisms, this study highlights the transition of this fundamental knowledge to horticultural important crops, such as tomato, and investigates its function under differing light conditions. Overall, the presented thesis combines different strategies in unveiling the genetic components in multi-omic traits under drought using conventional breeding populations as well as a diverse global population. To this end, it allows a comparison of either approach and highlights their strengths and weaknesses. N2 - Der pflanzliche Stoffwechsel ist der wichtigste Mechanismus für die Umwandlung von assimiliertem Kohlenstoff in essenzielle Verbindungen, die für das Pflanzenwachstum und letztlich den Ernteertrag entscheidend sind. Dies macht ihn zu einem Schwerpunkt der Forschung mit erheblichen Auswirkungen. Trotz bemerkenswerter Fortschritte beim Verständnis der genetischen Prinzipien, die dem Stoffwechsel und den Erträgen zugrunde liegen, gibt es nach wie vor einen Mangel an Wissen über die genetischen Faktoren, die für die Variation von Merkmalen unter verschiedenen Umweltbedingungen verantwortlich sind. In Anbetracht der wachsenden Weltbevölkerung und der zunehmenden Herausforderungen durch den Klimawandel wird es immer wichtiger, die Feinheiten des Stoffwechsels und des Ertrags auf Wasserknappheit zu entschlüsseln, um die Ernährungssicherheit zu gewährleisten. Unsere Forschungsgruppe hat vor kurzem damit begonnen, sich mit den genetischen Ressourcen von Leguminosen zu befassen. Zu diesem Zweck untersucht die hier vorgestellte Studie die Stoffwechselvielfalt bei fünf verschiedenen Leguminosen auf Gewebeebene und identifiziert die artspezifische Biosynthese von Alkaloiden sowie Iso-/Flavonoiden mit verschiedenen funktionellen Gruppen, nämlich Prenylierung, Phenylacylierung sowie Methoxylierung, um eine Ressource für Folgestudien zu schaffen, die die Stoffwechselvielfalt in verschiedenen natürlichen Populationen von Leguminosen untersuchen. Im Anschluss daran wird in der zweiten Studie die genetische Architektur trockenheitsbedingter Veränderungen in einer globalen Bohnenpopulation untersucht. Hier wird eine Vielzahl von quantitativen Merkmalsloci (QTL) identifiziert, die mit verschiedenen Merkmalen assoziiert sind, darunter auch für die Lipidsignalübertragung, unter Durchführung genomweite Assoziationsstudien (GWAS). Die Überexpression von Kandidaten auf dieser Seite hat die Induktion mehrerer Oxylipine hervorgehoben, die Berichten zufolge für die Bewältigung rauer Umweltbedingungen wie Wasserknappheit von zentraler Bedeutung sind. Abweichend von der Bohne und der GWAS konzentriert sich die folgende Studie auf die Identifizierung trockenheitsbezogener QTL bei der Tomate unter Verwendung einer bi-elterlichen Zuchtpopulation. Diese deskriptive Studie hebt neuartige multi-omische QTL hervor, einschließlich für Stoffwechsel, Photosynthese und Fruchtansatz, von denen einige eindeutig dem Dürre-Stress zugeordnet werden. Im Vergleich zu herkömmlichen Ansätzen, bei denen die bi-elterliche IL-Population verwendet wird, verbessert die vorgestellte Studie die Auflösung, indem weitere rückgekreuzte ILs, so genannte sub-ILs, untersucht werden. In der letzten Studie wird ein photosynthetisches Gen, nämlich eine PetM-Untereinheit des Cytochrom b6fKomplexes, das am Elektronenfluss beteiligt ist, in einer für den Gartenbau wichtigen Pflanze charakterisiert. Während bei Modellorganismen bereits zahlreiche wissenschaftliche Fortschritte erzielt wurden, beleuchtet diese Studie den Übergang dieses grundlegenden Wissens auf wichtige Gartenbaupflanzen wie die Tomate und untersucht ihre Funktion unter verschiedenen Lichtbedingungen. Insgesamt werden in der vorliegenden Arbeit verschiedene Strategien kombiniert, um die genetischen Komponenten multi-omischer Merkmale bei Trockenheit aufzudecken, wobei sowohl konventionelle Zuchtpopulationen als auch eine vielfältige globale Population verwendet werden. Zu diesem Zweck ermöglicht sie einen Vergleich beider Ansätze und zeigt ihre Stärken und Schwächen auf. KW - genomics KW - metabolomics KW - phenomics KW - genome-wide association studies (GWAS) KW - genotype-by-Environmental interaction (GxE) KW - plasticity Y1 - 2023 ER - TY - THES A1 - Bölling, Christian T1 - Comprehensive metabolite analysis in Chlamydomonas reinhardtii : method development and application to the study of environmental and genetic perturbations T1 - Multiparallele Metabolitenanalyse in Chlamydomonas reinhardtii N2 - This study introduces a method for multiparallel analysis of small organic compounds in the unicellular green alga Chlamydomonas reinhardtii, one of the premier model organisms in cell biology. The comprehensive study of the changes of metabolite composition, or metabolomics, in response to environmental, genetic or developmental signals is an important complement of other functional genomic techniques in the effort to develop an understanding of how genes, proteins and metabolites are all integrated into a seamless and dynamic network to sustain cellular functions. The sample preparation protocol was optimized to quickly inactivate enzymatic activity, achieve maximum extraction capacity and process large sample quantities. As a result of the rapid sampling, extraction and analysis by gas chromatography coupled to time-of-flight mass spectrometry (GC-TOF) more than 800 analytes from a single sample can be measured, of which over a 100 could be positively identified. As part of the analysis of GC-TOF raw data, aliquot ratio analysis to systematically remove artifact signals and tools for the use of principal component analysis (PCA) on metabolomic datasets are proposed. Cells subjected to nitrogen (N), phosphorus (P), sulfur (S) or iron (Fe) depleted growth conditions develop highly distinctive metabolite profiles with metabolites implicated in many different processes being affected in their concentration during adaptation to nutrient deprivation. Metabolite profiling allowed characterization of both specific and general responses to nutrient deprivation at the metabolite level. Modulation of the substrates for N-assimilation and the oxidative pentose phosphate pathway indicated a priority for maintaining the capability for immediate activation of N assimilation even under conditions of decreased metabolic activity and arrested growth, while the rise in 4-hydroxyproline in S deprived cells could be related to enhanced degradation of proteins of the cell wall. The adaptation to sulfur deficiency was analyzed with greater temporal resolution and responses of wild-type cells were compared with mutant cells deficient in SAC1, an important regulator of the sulfur deficiency response. Whereas concurrent metabolite depletion and accumulation occurs during adaptation to S deprivation in wild-type cells, the sac1 mutant strain is characterized by a massive incapability to sustain many processes that normally lead to transient or permanent accumulation of the levels of certain metabolites or recovery of metabolite levels after initial down-regulation. For most of the steps in arginine biosynthesis in Chlamydomonas mutants have been isolated that are deficient in the respective enzyme activities. Three strains deficient in the activities of N-acetylglutamate-5-phosphate reductase (arg1), N2 acetylornithine-aminotransferase (arg9), and argininosuccinate lyase (arg2), respectively, were analyzed with regard to activation of endogenous arginine biosynthesis after withdrawal of externally supplied arginine. Enzymatic blocks in the arginine biosynthetic pathway could be characterized by precursor accumulation, like the amassment of argininosuccinate in arg2 cells, and depletion of intermediates occurring downstream of the enzymatic block, e.g. N2-acetylornithine, ornithine, and argininosuccinate depletion in arg9 cells. The unexpected finding of substantial levels of the arginine pathway intermediates N-acetylornithine, citrulline, and argininosuccinate downstream the enzymatic block in arg1 cells provided an explanation for the residual growth capacity of these cells in the absence of external arginine sources. The presence of these compounds, together with the unusual accumulation of N-Acetylglutamate, the first intermediate that commits the glutamate backbone to ornithine and arginine biosynthesis, in arg1 cells suggests that alternative pathways, possibly involving the activity of ornithine aminotransferase, may be active when the default reaction sequence to produce ornithine via acetylation of glutamate is disabled. N2 - Entwicklung und Anwendung von Methoden zur multiparallelen Analyse von Metaboliten in der einzelligen Grünalge Chlamydomonas reinhardtii, einem der wichtigsten Modellorganismen der Zellbiologie, sind Gegenstand dieser Arbeit. Metabolomanalyse, die umfassende Analyse von Veränderungen der Konzentrationen von Stoffwechselprodukten durch Umweltreize oder genetische und entwicklungsbedingte Signale, ist ein wichtiges Komplement anderer Genomanalysemethoden, um die Integration von Genen, Proteinen und Metaboliten in ein nahtloses und dynamisches Netzwerk zur Aufrechterhaltung der Lebensfunktionen eines Organismus zu verstehen. Die Methode wurde im Hinblick auf schnelle Inaktivierung enzymatischer Aktivität, Maximierung der Extraktionskapazität und Behandlung großer Probenmengen optimiert. Im Ergebnis der Probenaufarbeitung, Extraktion und Analyse mittels Gaschromatographie und Time-Of-Flight-Massenspektrometrie konnten mehr als 800 analytische Signale in Einzelproben dargestellt werden, von denen über 100 identifiziert werden konnten. Die Arbeit stellt methodische Innovationen zur systematischen Erkennung von Artefakten in GC-MS Chromatogrammen und Werkzeuge zur Anwendung der Hauptkomponentenanalyse auf Metabolom-Daten vor. Zellen unter Stickstoff- (N), Phosphor- (P), Schwefel- (S), oder Eisen- (Fe) Mangel zeigen deutliche Unterschiede in ihrer Metabolitenausstattung. Die Anpassung an die einzelnen Nährstoffmangelsituationen ist durch spezifische Änderungen einer Reihe von Metaboliten zentraler Prozesse des Primärstoffwechsels gekennzeichnet. Die Konzentrationsänderungen von Substraten für die Stickstoffassimilation und den oxidativen Pentosephosphatweg deuten darauf hin, dass die Fähigkeit zur schnellen Aktivierung der N-Assimilation auch unter Bedingungen herabgesetzter Stoffwechsel- und Wachstumsaktivität aufrechterhalten wird. Die Akkumulation von 4-Hydroxyprolin unter Schwefelmangel könnte im Zusammenhang stehen mit der Degradation von Proteinen der Chlamydomonas-Zellwand, deren wesentlicher Bestandteil hydroxyprolinreiche Glykoproteine sind und die unter Schwefelmangel aktiv umgebaut wird. Die Anpassung an Schwefelmangel wurde mit größerer zeitlicher Auflösung in Wildtyp-Zellen und Zellen des sac1-Stammes untersucht. SAC1 ist ein zentraler Regulator der Schwefelmangelantwort in Chlamydomonas. Zeitgleiche Ab- und Zunahme von Metaboliten ist ein charakteristisches Element der Anpassung an Schwefelmangel in Wildtypzellen. Die Reaktion von SAC1-Mutanten auf Schwefelmangel ist durch weit reichenden Verlust zur Steuerung von Prozessen gekennzeichnet, die normalerweise zur vorübergehenden oder dauerhaften Anreicherung bestimmter Metabolite führen. Die Verfügbarkeit von Chlamydomonas-Stämmen mit fehlender Enzymaktivität für fast jeden der Schritte der Argininbiosynthese eröffnet die Möglichkeit, das Potential der Metabolitenanalyse zur Untersuchung der Regulation der Aminosäurebiosynthese in photosynthetischen Eukaryoten zur Anwendung zu bringen. Drei Stämme, mit fehlender Aktivität für N-Acetylglutamat-5-phosphat Reduktase (arg1), N2 Acetylornithin-Aminotransferase (arg9) beziehungsweise Argininosuccinat Lyase (arg2) wurden in Bezug auf die Aktivierung ihrer endogenen Argininbiosynthese nach Entzug externer Argininquellen analysiert. Die einzelnen enzymatischen Blocks konnten durch Precursor-Anreicherung, wie die Anhäufung von Argininosuccinat in arg2-Zellen, und Erschöpfung von Intermediaten nachgelagerter Reaktionen, beispielsweise die deutliche Abnahme von N2-Acetylornithin, Ornithin und Argininosuccinat in arg9-Zellen charakterisiert werden. Das unerwartete Vorhandensein von zum Teil das Wildtyp-Niveau überschreitender Mengen von N2-Acetylornithin, Citrullin und Argininosuccinat, die Produkte bzw. Substrate dem enzymatischen Block nachgelagerter Reaktionen in arg1-Zellen sind, bot eine Erklärung für eine noch vorhandene Restkapazität zum Wachstum des arg1-Stamms auch ohne äußere Arginingabe. Der Nachweis dieser Verbindungen sowie die ungewöhnliche Anreicherung von N-Acetylglutamat, der ersten Verbindung, die das Glutamat-Gerüst für die Ornithin- und Argininsynthese bindet, in arg1-Zellen könnte auf alternative Reaktionen, möglicherweise unter Beteiligung von Ornithin-Aminotransferase, zur Synthese von Ornithin hindeuten, die in Erscheinung treten, wenn die Synthesekette nach Acetylierung von Glutamat blockiert ist. KW - Chlamydomonas KW - Metabolite KW - Schwefel KW - Argininbiosynthese KW - Stoffwechsel KW - Chlamydomonas KW - metabolite profiling KW - metabolomics KW - sulfur KW - arginine biosynthesis Y1 - 2006 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus-11329 ER - TY - JOUR A1 - Catchpole, Gareth A1 - Platzer, Alexander A1 - Weikert, Cornelia A1 - Kempkensteffen, Carsten A1 - Johannsen, Manfred A1 - Krause, Hans A1 - Jung, Klaus A1 - Miller, Kurt A1 - Willmitzer, Lothar A1 - Selbig, Joachim A1 - Weikert, Steffen T1 - Metabolic profiling reveals key metabolic features of renal cell carcinoma JF - Journal of cellular and molecular medicine : a journal of translational medicine N2 - Recent evidence suggests that metabolic changes play a pivotal role in the biology of cancer and in particular renal cell carcinoma (RCC). Here, a global metabolite profiling approach was applied to characterize the metabolite pool of RCC and normal renal tissue. Advanced decision tree models were applied to characterize the metabolic signature of RCC and to explore features of metastasized tumours. The findings were validated in a second independent dataset. Vitamin E derivates and metabolites of glucose, fatty acid, and inositol phosphate metabolism determined the metabolic profile of RCC. alpha-tocopherol, hippuric acid, myoinositol, fructose-1-phosphate and glucose-1-phosphate contributed most to the tumour/normal discrimination and all showed pronounced concentration changes in RCC. The identified metabolic profile was characterized by a low recognition error of only 5% for tumour versus normal samples. Data on metastasized tumours suggested a key role for metabolic pathways involving arachidonic acid, free fatty acids, proline, uracil and the tricarboxylic acid cycle. These results illustrate the potential of mass spectroscopy based metabolomics in conjunction with sophisticated data analysis methods to uncover the metabolic phenotype of cancer. Differentially regulated metabolites, such as vitamin E compounds, hippuric acid and myoinositol, provide leads for the characterization of novel pathways in RCC. KW - kidney cancer KW - metabolism KW - metabolomics KW - metastasis Y1 - 2011 U6 - https://doi.org/10.1111/j.1582-4934.2009.00939.x SN - 1582-1838 VL - 15 IS - 1 SP - 109 EP - 118 PB - Wiley-Blackwell CY - Malden ER - TY - GEN A1 - Hische, Manuela A1 - Larhlimi, Abdelhalim A1 - Schwarz, Franziska A1 - Fischer-Rosinský, Antje A1 - Bobbert, Thomas A1 - Assmann, Anke A1 - Catchpole, Gareth S. A1 - Pfeiffer, Andreas F. H. A1 - Willmitzer, Lothar A1 - Selbig, Joachim A1 - Spranger, Joachim T1 - A distinct metabolic signature predictsdevelopment of fasting plasma glucose T2 - Postprints der Universität Potsdam : Mathematisch Naturwissenschaftliche Reihe N2 - Background High blood glucose and diabetes are amongst the conditions causing the greatest losses in years of healthy life worldwide. Therefore, numerous studies aim to identify reliable risk markers for development of impaired glucose metabolism and type 2 diabetes. However, the molecular basis of impaired glucose metabolism is so far insufficiently understood. The development of so called 'omics' approaches in the recent years promises to identify molecular markers and to further understand the molecular basis of impaired glucose metabolism and type 2 diabetes. Although univariate statistical approaches are often applied, we demonstrate here that the application of multivariate statistical approaches is highly recommended to fully capture the complexity of data gained using high-throughput methods. Methods We took blood plasma samples from 172 subjects who participated in the prospective Metabolic Syndrome Berlin Potsdam follow-up study (MESY-BEPO Follow-up). We analysed these samples using Gas Chromatography coupled with Mass Spectrometry (GC-MS), and measured 286 metabolites. Furthermore, fasting glucose levels were measured using standard methods at baseline, and after an average of six years. We did correlation analysis and built linear regression models as well as Random Forest regression models to identify metabolites that predict the development of fasting glucose in our cohort. Results We found a metabolic pattern consisting of nine metabolites that predicted fasting glucose development with an accuracy of 0.47 in tenfold cross-validation using Random Forest regression. We also showed that adding established risk markers did not improve the model accuracy. However, external validation is eventually desirable. Although not all metabolites belonging to the final pattern are identified yet, the pattern directs attention to amino acid metabolism, energy metabolism and redox homeostasis. Conclusions We demonstrate that metabolites identified using a high-throughput method (GC-MS) perform well in predicting the development of fasting plasma glucose over several years. Notably, not single, but a complex pattern of metabolites propels the prediction and therefore reflects the complexity of the underlying molecular mechanisms. This result could only be captured by application of multivariate statistical approaches. Therefore, we highly recommend the usage of statistical methods that seize the complexity of the information given by high-throughput methods. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 850 KW - prediction KW - fasting glucose KW - type 2 diabetes KW - metabolomics KW - plasma KW - random forest KW - metabolite KW - regression KW - biomarker Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-427400 SN - 1866-8372 IS - 850 ER - TY - JOUR A1 - Jüppner, Jessica A1 - Mubeen, Umarah A1 - Leisse, Andrea A1 - Caldana, Camila A1 - Brust, Henrike A1 - Steup, Martin A1 - Herrmann, Marion A1 - Steinhauser, Dirk A1 - Giavalisco, Patrick T1 - Dynamics of lipids and metabolites during the cell cycle of Chlamydomonas reinhardtii JF - The plant journal N2 - Metabolites and lipids are the final products of enzymatic processes, distinguishing the different cellular functions and activities of single cells or whole tissues. Understanding these cellular functions within a well-established model system requires a systemic collection of molecular and physiological information. In the current report, the green alga Chlamydomonas reinhardtii was selected to establish a comprehensive workflow for the detailed multi-omics analysis of a synchronously growing cell culture system. After implementation and benchmarking of the synchronous cell culture, a two-phase extraction method was adopted for the analysis of proteins, lipids, metabolites and starch from a single sample aliquot of as little as 10-15million Chlamydomonas cells. In a proof of concept study, primary metabolites and lipids were sampled throughout the diurnal cell cycle. The results of these time-resolved measurements showed that single compounds were not only coordinated with each other in different pathways, but that these complex metabolic signatures have the potential to be used as biomarkers of various cellular processes. Taken together, the developed workflow, including the synchronized growth of the photoautotrophic cell culture, in combination with comprehensive extraction methods and detailed metabolic phenotyping has the potential for use in in-depth analysis of complex cellular processes, providing essential information for the understanding of complex biological systems. KW - Chlamydomonas reinhardtii KW - synchronized cell cultures KW - photoautotrophic growth KW - cell cycle KW - metabolomics KW - lipidomics KW - systems biology KW - two-phase extraction KW - diurnal cycle KW - technical advance Y1 - 2017 U6 - https://doi.org/10.1111/tpj.13642 SN - 0960-7412 SN - 1365-313X VL - 92 SP - 331 EP - 343 PB - Wiley CY - Hoboken ER - TY - GEN A1 - Kühn, Tilman A1 - Floegel, Anna A1 - Sookthai, Disorn A1 - Johnson, Theron A1 - Rolle-Kampczyk, Ulrike A1 - Otto, Wolfgang A1 - von Bergen, Martin A1 - Boeing, Heiner A1 - Kaaks, Rudolf T1 - Higher plasma levels of lysophosphatidylcholine 18:0 are related to a lower risk of common cancers in a prospective metabolomics study T2 - BMC medicine N2 - Background: First metabolomics studies have indicated that metabolic fingerprints from accessible tissues might be useful to better understand the etiological links between metabolism and cancer. However, there is still a lack of prospective metabolomics studies on pre-diagnostic metabolic alterations and cancer risk. Methods: Associations between pre-diagnostic levels of 120 circulating metabolites (acylcarnitines, amino acids, biogenic amines, phosphatidylcholines, sphingolipids, and hexoses) and the risks of breast, prostate, and colorectal cancer were evaluated by Cox regression analyses using data of a prospective case-cohort study including 835 incident cancer cases. Results: The median follow-up duration was 8.3 years among non-cases and 6.5 years among incident cases of cancer. Higher levels of lysophosphatidylcholines (lysoPCs), and especially lysoPC a C18:0, were consistently related to lower risks of breast, prostate, and colorectal cancer, independent of background factors. In contrast, higher levels of phosphatidylcholine PC ae C30:0 were associated with increased cancer risk. There was no heterogeneity in the observed associations by lag time between blood draw and cancer diagnosis. Conclusion: Changes in blood lipid composition precede the diagnosis of common malignancies by several years. Considering the consistency of the present results across three cancer types the observed alterations point to a global metabolic shift in phosphatidylcholine metabolism that may drive tumorigenesis. T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 437 KW - metabolomics KW - epidemiology KW - breast cancer KW - prostate cancer KW - colorectal cancer Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-407258 ER - TY - JOUR A1 - Lisec, Jan A1 - Römisch-Margl, Lilla A1 - Nikoloski, Zoran A1 - Piepho, Hans-Peter A1 - Giavalisco, Patrick A1 - Selbig, Joachim A1 - Gierl, Alfons A1 - Willmitzer, Lothar T1 - Corn hybrids display lower metabolite variability and complex metabolite inheritance patterns JF - The plant journal N2 - We conducted a comparative analysis of the root metabolome of six parental maize inbred lines and their 14 corresponding hybrids showing fresh weight heterosis. We demonstrated that the metabolic profiles not only exhibit distinct features for each hybrid line compared with its parental lines, but also separate reciprocal hybrids. Reconstructed metabolic networks, based on robust correlations between metabolic profiles, display a higher network density in most hybrids as compared with the corresponding inbred lines. With respect to metabolite level inheritance, additive, dominant and overdominant patterns are observed with no specific overrepresentation. Despite the observed complexity of the inheritance pattern, for the majority of metabolites the variance observed in all 14 hybrids is lower compared with inbred lines. Deviations of metabolite levels from the average levels of the hybrids correlate negatively with biomass, which could be applied for developing predictors of hybrid performance based on characteristics of metabolite patterns. KW - heterosis KW - Zea mays KW - metabolomics Y1 - 2011 U6 - https://doi.org/10.1111/j.1365-313X.2011.04689.x SN - 0960-7412 VL - 68 IS - 2 SP - 326 EP - 336 PB - Wiley-Blackwell CY - Malden ER - TY - THES A1 - Lopes Fernando, Raquel Sofia T1 - The impact of aging on proteolytic systems, transcriptome and metabolome of slow and fast muscle fiber types N2 - Aging is a complex process characterized by several factors, including loss of genetic and epigenetic information, accumulation of chronic oxidative stress, protein damage and aggregates and it is becoming an emergent drug target. Therefore, it is the utmost importance to study aging and agerelated diseases, to provide treatments to develop a healthy aging process. Skeletal muscle is one of the earliest tissues affected by age-related changes with progressive loss of muscle mass and function from 30 years old, effect known as sarcopenia. Several studies have shown the accumulation of protein aggregates in different animal models, as well as in humans, suggesting impaired proteostasis, a hallmark of aging, especially regarding degradation systems. Thus, different publications have explored the role of the main proteolytic systems in skeletal muscle from rodents and humans, like ubiquitin proteasomal system (UPS) and autophagy lysosomal system (ALS), however with contradictory results. Yet, most of the published studies are performed in muscles that comprise more than one fiber type, that means, muscles composed by slow and fast fibers. These fiber types, exhibit different metabolism and contraction speed; the slow fibers or type I display an oxidative metabolism, while fast fibers function towards a glycolytic metabolism ranging from fast oxidative to fast glycolytic fibers. To this extent, the aim of this thesis sought to understand on how aging impacts both fiber types not only regarding proteostasis but also at a metabolome and transcriptome network levels. Therefore, the first part of this thesis, presents the differences between slow oxidative (from Soleus muscle) and fast glycolytic fibers (Extensor digitorum longus, EDL) in terms of degradation systems and how they cope with oxidative stress during aging, while the second part explores the differences between young and old EDL muscle transcriptome and metabolome, unraveling molecular features. More specifically, the results from the present work show that slow oxidative muscle performs better at maintaining the function of UPS and ALS during aging than EDL muscle, which is clearly affected, accounting for the decline in the catalytic activity rates and accumulation of autophagy-related proteins. Strinkingly, transcriptome and metabolome analyses reveal that fast glycolytic muscle evidences significant downregulation of mitochondrial related processes and damaged mitochondria morphology during aging, despite of having a lower oxidative metabolism compared to oxidative fibers. Moreover, predictive analyses reveal a negative association between aged EDL gene signature and lifespan extending interventions such as caloric restriction (CR). Although, CR intervention does not alter the levels of mitochondrial markers in aged EDL muscle, it can reverse the higher mRNA levels of muscle damage markers. Together, the results from this thesis give new insights about how different metabolic muscle fibers cope with age-related changes and why fast glycolytic fibers are more susceptible to aging than slow oxidative fibers. N2 - Altern ist ein komplexer Prozess, der durch mehrere Faktoren gekennzeichnet ist, darunter der Verlust genetischer und epigenetischer Informationen, oxidativer Stress, sowie die Anhäufung von Proteinschäden und Aggregaten. Daher ist es von größter Bedeutung, das Altern und altersbedingte Krankheiten zu erforschen, um Arzneimittel und andere Behandlungen für einen gesunden Alterungsprozess zu entwickeln. Die Skelettmuskulatur ist eines der ersten Gewebe, das von altersbedingten Veränderungen betroffen ist. Ab einem Alter von 30 Jahren kommt es zu einem fortschreitenden Verlust der Muskelmasse und -funktion, der auch als Sarkopenie bezeichnet wird. Mehrere Studien haben die Anhäufung von Proteinaggregaten beim Altern in verschiedenen Tiermodellen und auch beim Menschen gezeigt, was auf eine gestörte Proteostase, insbesondere hinsichtlich der Abbauprozesse schließen lässt. Demnach wurde weiterführend die Rolle der wichtigsten proteolytischen Systeme, das Ubiquitin Proteasom System (UPS) und AutophagieLysosomale System (ALS), im alternden Skelettmuskel von Nagetieren und Menschen untersucht. Die Ergebnisse waren widersprüchlich, jedoch wurden die meisten der veröffentlichten Studien an Muskeln durchgeführt, die aus mehr als einem Muskelfasertyp bestehen, d.h. Muskeln, die aus langsamen und schnellen Muskelfasern zusammengesetzt sind. Diese Muskelfasertypen unterscheiden sich hinsichtlich des Stoffwechsels und der Kontraktionsgeschwindigkeit. Die langsamen Fasern oder der Typ I haben einen oxidativen Stoffwechsel, während die schnellen Fasern einen glykolytischen Stoffwechsel aufweisen und aus schnellen oxidativen bis zu schnellen glykolytischen Fasern bestehen können. Insofern war es das Ziel dieser Arbeit zu verstehen, wie sich das Altern auf beide Fasertypen auswirkt, und zwar nicht nur im Hinblick auf die Proteostase, sondern auch auf das Metabolom und Transkriptom. Im ersten Teil dieser Arbeit werden die Unterschiede zwischen langsamen oxidativen (Soleus-Muskel) und schnellen glykolytischen Fasern (Extensor digitorum longus-Muskel; EDL) in Bezug auf die Proteinabbausysteme und die Art und Weise, wie sie mit oxidativem Stress während des Alterns umgehen, dargestellt. Im zweiten Teil werden die Unterschiede zwischen dem Transkriptom und dem Metabolom des jungen und alten EDL-Muskels untersucht, um die molekularen Merkmale zu entschlüsseln. Im Einzelnen zeigen die Ergebnisse der vorliegenden Arbeit, dass der langsam oxidierende Muskel im Vergleich zum EDL-Muskel besser in der Lage ist, die Funktion von UPS und ALS während des Alterns aufrechtzuerhalten. Die Funktionalität des UPS und ALS ist im alternden EDL-Muskels vermindert, was durch den Rückgang der katalytischen Aktivitätsraten und die Anhäufung von mit Autophagie-assoziierten Proteinen gezeigt wurde. Transkriptom- und Metabolomanalysen zeigen, dass schnelle glykolytische Muskeln eine signifikante Herabregulierung mitochondrialer Prozesse und eine geschädigte Mitochondrienmorphologie während des Alterns aufweisen, obwohl sie im Vergleich zu oxidativen Fasern durch einen geringeren oxidativen Stoffwechsel charakterisiert sind. Darüber hinaus ergeben prädiktive Analysen einen negativen Zusammenhang zwischen der Gensignatur des gealterten EDL-Muskels und lebensverlängernden Maßnahmen wie der kalorischenRestriktion. Obwohl die kalorischen Restriktion Intervention die Werte der mitochondrialen Marker im gealterten EDL-Muskel nicht verändert, kann sie die höheren mRNA-Werte der Muskelschädigungsmarker umkehren. Zusammenfassend liefern die Ergebnisse dieser Arbeit neue Erkenntnisse darüber, wie verschiedene metabolische Muskelfasern mit altersbedingten. Veränderungen umgehen und warum schnelle glykolytische Fasern anfälliger für die Alterung als langsame oxidative Fasern sind. KW - skeletal muscle aging KW - proteostasis KW - slow and fast fiber types KW - transcriptomics KW - metabolomics KW - sarcopenia KW - Skelettmuskelalterung KW - Proteostase KW - langsame und schnelle Fasertypen KW - Transkriptom KW - Metabolom KW - ubiquitin proteasomal system KW - autophagy lysosomal system KW - Ubiquitin Proteasom System KW - Autophagie Lysosomale System Y1 - 2023 U6 - https://doi.org/10.25932/publishup-60579 ER - TY - GEN A1 - Lu, Yong-Ping A1 - Reichetzeder, Christoph A1 - Prehn, Cornelia A1 - von Websky, Karoline A1 - Slowinski, Torsten A1 - Chen, You-Peng A1 - Yin, Liang-Hong A1 - Kleuser, Burkhard A1 - Yang, Xue-Song A1 - Adamski, Jerzy A1 - Hocher, Berthold T1 - Fetal serum metabolites are independently associated with Gestational diabetes mellitus T2 - Postprints der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe N2 - Background/Aims: Gestational diabetes (GDM) might be associated with alterations in the metabolomic profile of affected mothers and their offspring. Until now, there is a paucity of studies that investigated both, the maternal and the fetal serum metabolome in the setting of GDM. Mounting evidence suggests that the fetus is not just passively affected by gestational disease but might play an active role in it. Metabolomic studies performed in maternal blood and fetal cord blood could help to better discern distinct fetal from maternal disease interactions. Methods: At the time of birth, serum samples from mothers and newborns (cord blood samples) were collected and screened for 163 metabolites utilizing tandem mass spectrometry. The cohort consisted of 412 mother/child pairs, including 31 cases of maternal GDM. Results: An initial non-adjusted analysis showed that eight metabolites in the maternal blood and 54 metabolites in the cord blood were associated with GDM. After Benjamini-Hochberg (BH) procedure and adjustment for confounding factors for GDM, fetal phosphatidylcholine acyl-alkyl C 32:1 and proline still showed an independent association with GDM. Conclusions: This study found metabolites in cord blood which were associated with GDM, even after adjustment for established risk factors of GDM. To the best of our knowledge, this is the first study demonstrating an independent association between fetal serum metabolites and maternal GDM. Our findings might suggest a potential effect of the fetal metabolome on maternal GDM. (c) 2018 The Author(s) Published by S. Karger AG, Basel T3 - Zweitveröffentlichungen der Universität Potsdam : Mathematisch-Naturwissenschaftliche Reihe - 637 KW - Gestational diabetes KW - metabolomics KW - phosphatidylcholine acyl-alkyl C 32:1 KW - proline Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-424585 SN - 1866-8372 IS - 637 ER -