@phdthesis{Henning2024, author = {Henning, Thorsten}, title = {Cross-sectional associations of dietary biomarker patterns with health and nutritional status}, school = {Universit{\"a}t Potsdam}, pages = {111}, year = {2024}, language = {en} } @phdthesis{Koelman2023, author = {Koelman, Liselot A.}, title = {The role of diet in immune health and ageing}, school = {Universit{\"a}t Potsdam}, year = {2023}, language = {en} } @phdthesis{LopesFernando2023, author = {Lopes Fernando, Raquel Sofia}, title = {The impact of aging on proteolytic systems, transcriptome and metabolome of slow and fast muscle fiber types}, doi = {10.25932/publishup-60579}, school = {Universit{\"a}t Potsdam}, pages = {XI, 125}, year = {2023}, abstract = {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.}, language = {en} } @phdthesis{Geisendoerfer2022, author = {Geisend{\"o}rfer, Birte}, title = {Autologer Ansatz zur Entwicklung von 2D- und 3D-Kokultivierungsmethoden f{\"u}r die Bestimmung des sensibilisierenden Potenzials von Xenobiotika}, school = {Universit{\"a}t Potsdam}, pages = {166}, year = {2022}, abstract = {Die allergische Kontaktdermatitis ist eine immunologisch bedingte Hauterkrankung mit insbesondere in den westlichen Industrienationen hoher und weiter ansteigender Pr{\"a}valenz. Es handelt sich hierbei um eine Hypersensitivit{\"a}tsreaktion vom Typ IV, die sich nach Allergenkontakt durch Juckreiz, R{\"o}tung, Bl{\"a}schenbildung und Absch{\"a}lung der Haut {\"a}ußert. Zahlreiche Xenobiotika besitzen das Potenzial, Kontaktallergien auszul{\"o}sen, darunter Konservierungsstoffe, Medikamente, Duftstoffe und Chemikalien. Die wirksamste Maßnahme zur Eind{\"a}mmung der Erkrankung ist die Expositionsprophylaxe, also die Vermeidung des Kontakts mit den entsprechenden Substanzen. Dies wiederum setzt die Kenntnis des jeweiligen sensibilisierenden Potenzials einer Substanz voraus, dessen Bestimmung aus diesem Grund eine hohe toxikologische Relevanz besitzt. Zu diesem Zweck existieren von der OECD ver{\"o}ffentlichte Testleitlinien, welche auf entsprechend validierten Testmethoden basieren. Goldstandard bei der Pr{\"u}fung auf hautsensibilisierendes Potenzial war {\"u}ber lange Zeit der murine Lokale Lymphknotentest. Seit der 7. {\"A}nderung der EU-Kosmetikrichtlinie, welche Tierversuche f{\"u}r Kosmetika und deren Inhaltsstoffe untersagt, wurden vermehrt Alternativmethoden in die OECD-Testleitlinien implementiert.. Die bestehenden in vitro Methoden sind jedoch alleinstehend nur begrenzt aussagekr{\"a}ftig, da sie lediglich singul{\"a}re Mechanismen bei der Entstehung einer Kontaktallergie abbilden. Die Entwicklung von Testmethoden, welche mehrere dieser Schl{\"u}sselereignisse ber{\"u}cksichtigen, erscheint daher richtungsweisend. Einen vielversprechenden Ansatz liefert hierbei der Loose-fit coculture-based sensitisation assay (LCSA), welcher eine Kokultur aus prim{\"a}ren Keratinozyten und PBMC darstellt. Bei der Kokultivierung von Immunzellen mit anderen Zelltypen stellt sich allerdings die Frage, inwiefern die Nutzung von Zellen derselben Spender*innen (autologe Kokultur) bzw. verschiedener Spender*innen (allogene Kokultur) einen Einfluss nimmt. Zu diesem Zweck wurden im Rahmen dieser Arbeit Hautzellen spenderspezifisch aus gezupften Haarfollikeln isoliert und der LCSA mit den generierten HFDK in autologen und allogenen Ans{\"a}tzen verglichen. Zus{\"a}tzlich wurde auch ein Vergleich zwischen der Nutzung von HFDK und NHK, welche aus humaner Vorhaut isoliert wurden, im LCSA durchgef{\"u}hrt. Dabei ergaben sich keine signifikanten Unterschiede zwischen autologen und allogenen Kokulturen bzw. zwischen der Verwendung von HFDK und NHK. Die Verwendung allogener Zellen aus anonymem Spendermaterial sowie die Nutzung von Keratinozyten aus unterschiedlichen Quellen scheint im Rahmen des LCSA problemlos m{\"o}glich. Einige der getesteten Kontaktallergene, darunter DNCB und NiCl2, erwiesen sich im LCSA jedoch als problematisch und konnten nicht zufriedenstellend als sensibilisierend detektiert werden. Daher wurde eine Optimierung der Kokultur durch Verwendung ex vivo differenzierter Langerhans Zellen (MoLC) angestrebt, welche ein besseres Modell prim{\"a}rer epidermaler Langerhans Zellen darstellen als die dendritischen Zellen aus dem LCSA. Zus{\"a}tzlich wurden weitere, den Erfolg der Kokultur beeinflussende Faktoren, wie die Art und Zusammensetzung des Mediums und die Kokultivierungsdauer, untersucht und angepasst. Das schlussendlich etablierte Kokultivierungsprotokoll f{\"u}hrte zu einer maßgeblich verst{\"a}rkten Expression von CD207 (Langerin) auf den MoLC, was auf eine wirkungsvolle Interaktion zwischen Haut- und Immunzellen in der Kokultur hindeutete. Des Weiteren konnten DNCB und NiCl2 im Gegensatz zum LCSA durch Verwendung des kostimulatorischen Molek{\"u}ls CD86 sowie des Reifungsmarkers CD83 als Ausleseparameter eindeutig als Kontaktallergene identifiziert werden. Die Untersuchungen zur Kokultur von MoLC und HFDK wurden jeweils vergleichend in autologen und allogenen Ans{\"a}tzen durchgef{\"u}hrt. {\"A}hnlich wie beim LCSA kam es aber auch hier zu keinen signifikanten Unterschieden, weder hinsichtlich der Expression von Charakterisierungs- und Aktivierungsmarkern auf MoLC noch hinsichtlich der Zytokinsekretion in den Zellkultur{\"u}berstand. Die Hinweise aus zahlreichen Studien im Mausmodell, dass Zellen des angeborenen Immunsystems zur Erkennung von und Aktivierung durch allogene Zellen bzw. Gewebe in der Lage sind, best{\"a}tigten sich im Rahmen dieser Arbeit dementsprechend nicht. Aus diesem Grund wurden abschließend CD4+ T-Lymphozyten, die Effektorzellen des adaptiven Immunsystems, in die Kokultur aus MoLC und autologen bzw. allogenen HFDK integriert. {\"U}berraschenderweise traten auch hier keine verst{\"a}rkten Aktivierungen in allogener Kokultur im Vergleich zur autologen Kokultur auf. Die Nutzung autologer Prim{\"a}rzellen scheint im Rahmen der hier getesteten Methoden nicht notwendig zu sein, was die Validierung von Kokulturen und deren Implementierung in die OECD-Testleitlinien erleichtern d{\"u}rfte. Zuletzt wurde eine Kokultivierung prim{\"a}rer Haut- und Immunzellen auch im 3D-Vollhautmodell durchgef{\"u}hrt, wobei autologe MoLC in die Epidermis{\"a}quivalente entsprechender Modelle integriert werden sollten. Obwohl die erstellten Hautmodelle unter Verwendung autologer Haarfollikel-generierter Keratinozyten und Fibroblasten eine zufriedenstellende Differenzierung und Stratifizierung aufwiesen, gestaltete sich die Inkorporation der MoLC als problematisch und konnte im Rahmen dieser Arbeit nicht erreicht werden.}, language = {de} } @phdthesis{Wetzel2022, author = {Wetzel, Alexandra}, title = {Epigenetische Regulation des Epstein-Barr Virus-induzierten Gens 3 (EBI3) und dessen Bedeutung bei Colitis ulcerosa}, school = {Universit{\"a}t Potsdam}, pages = {164}, year = {2022}, abstract = {Epigenetische Mechanismen spielen eine entscheidende Rolle bei der Pathogenese von Colitis ulcerosa (CU). Ihr Einfluss auf das beobachtete Ungleichgewicht zwischen pro- und anti-inflammatorischen Cytokinen ist hingegen weitgehend unerforscht. Einige der wichtigsten immunmodulatorischen Cytokine sind die Mitglieder der heterodimeren Interleukin- (IL-) 12-Familie, die durch das Kombinieren einer der drei α-Ketten (IL-12p35, IL-27p28, IL-23p19) mit den ß-Untereinheiten IL-12p40 oder EBI3 (Epstein-Barr Virus-induziertes Gen 3) charakterisiert sind. IL-35 (IL-12p35/EBI3) spielt eine bedeutende anti-inflammatorische Rolle bei verschiedenen Erkrankungen, wohingegen seine Level bei chronischen Entz{\"u}ndungen erniedrigt sind. Eine m{\"o}gliche Ursache k{\"o}nnte eine transkriptionelle Stilllegung {\"u}ber epigenetische Modifikationen sein. Tats{\"a}chlich konnte durch die Stimulation mit dem DNA-Methyltransferase-Inhibitor (DNMTi) Decitabin (DAC; Dacogen®) eine Induktion von EBI3 in humanen Epithelzellen aus gesundem Colon (HCEC) erreicht werden, die als Modell f{\"u}r ein lokales Entz{\"u}ndungsgeschehen dienten. Diese Regulation {\"u}ber DNA-Methylierung konnte in weiteren humanen Zellen unterschiedlichen Ursprungs sowie durch Stimulation von HCEC-Zellen mit zwei weiteren DNMTi, dem Cytosin-Analogon Azacytidin (AZA; Vidaza®) und dem nat{\"u}rlich vorkommenden, epigenetisch wirksamen Polyphenol Epigallocatechingallat (EGCG), verifiziert werden. Die kombinierte Inkubation mit Tumor-Nekrose-Faktor α (TNFα) resultierte jeweils in einer {\"u}ber-additiven Induktion von EBI3. Weiterf{\"u}hrende Untersuchungen zeigten, dass TNFα trotz Beeinflussung der epigenetischen DNMT- und Ten-eleven Translocation- (TET-) Enzyme keinen Einfluss auf die globalen Methylierungs- oder Hydroxymethylierungslevel hatte, jedoch eine genspezifische DNA-Hypomethylierung im EBI3-Promotor induzierte. Durch Nutzung verschiedener Inhibitoren konnte dar{\"u}ber hinaus nachgewiesen werden, dass der beobachtete synergistische Effekt der gemeinsamen DAC und TNFα-Stimulation haupts{\"a}chlich {\"u}ber NFκB (Nuclear factor "kappa-light-chain-enhancer" of activated B-cells) vermittelt wird. Ein Teil verl{\"a}uft dabei {\"u}ber p38 MAPK (mitogen-activated protein kinases), w{\"a}hrend die JNK- (c-Jun N-terminale Kinasen-) und ERK- (extracellular-signal-regulated kinases) Signalwege keine Rolle spielen. In der vorliegenden Arbeit wurde zudem gezeigt, dass die DNA-Hypomethylierung w{\"a}hrend eines entz{\"u}ndlichen Zustandes auch in einer erh{\"o}hten EBI3-Proteinexpression resultiert. Die H{\"o}he der immunologisch detektierten Banden wies auf eine Dimerbildung sowohl im Zelllysat als auch im {\"U}berstand hin. Humane Colonepithelzellen sind demnach in der Lage, Cytokine zu bilden und zu sezernieren, was die Bedeutung von Nicht-Immunzellen bei der lokalen Immunantwort unterstreicht. Mittels Genexpressionsanalysen wurden IL-12p35 und IL-23p19 als m{\"o}gliche Bindungspartner identifiziert. Aufgrund kreuzreaktiver Antik{\"o}rper ist ein direkter Nachweis der EBI3-Dimere derzeit nicht m{\"o}glich. Die stattdessen genutzte Kombination verschiedener Methoden dient als geeigneter Ersatz f{\"u}r die problematischen Antik{\"o}rper-basierten Analysen wie Immunpr{\"a}zipitation oder ELISA. Durch molekularbiologische, immunologische und massenspektrometrische Methoden konnte IL-35 identifiziert werden, w{\"a}hrend IL-39 (IL-23p19/EBI3) nicht detektiert wurde. Dies ist in Einklang mit den Erkenntnissen mehrerer Forschungsgruppen, die eine Bildung des nativen humanen Dimers aus IL-23p19 und EBI3 bezweifeln. Des Weiteren wurde die biologische Aktivit{\"a}t des behandlungsinduzierten IL 35-Proteins durch einen Funktionsassay nachgewiesen. Neben einer DNMTi-bedingten transkriptionellen Aktivierung konnte eine Regulation von EBI3 {\"u}ber Histonacetylierungen gezeigt werden. Der EBI3-induzierende Effekt des Histondeacetylasen-Inhibitors (HDACi) Trichostatin A (TSA) wurde durch SAHA (suberoylanilide hydroxamic acid (Vorinostat; Zolinza®)) verifiziert. {\"A}hnlich zu der Stimulation mit den hypomethylierenden Substanzen wurde ein synergistischer Effekt bei paralleler Inkubation mit TNFα beobachtet, der in einer gesteigerten Bildung des EBI3-Proteins resultierte. Um die Befunde in einem komplexeren in vivo-Modell zu untersuchen, wurde eine chronische Colitis in Ebi3-defizienten M{\"a}usen und dem dazugeh{\"o}rigen Wildtypstamm C57BL/6 durch zyklische Applikation von Natriumdextransulfat (Dextran sodium sulfate (DSS)) induziert. Der Vergleich klinischer Parameter wie Mortalit{\"a}tsrate und K{\"o}rper- sowie Milzgewicht wies bei Abwesenheit von Ebi3 signifikant st{\"a}rkere colitische Symptome auf. Dies best{\"a}tigte die zentrale Rolle von Ebi3 in der Colitisentwicklung und deutete auf eine bevorzugte Bildung des anti-inflammatorisch wirkenden IL-35 statt des pro-inflammatorischen IL-39 in den Wildtyptieren hin. Durch zus{\"a}tzliche therapeutische Behandlung der C57BL/6-M{\"a}use nach der DSS-Gabe konnte die in der Literatur beschriebene positive Wirkung von SAHA auf die Colitismanifestation best{\"a}tigt werden. Im Gegensatz dazu war der HDACi in den Ebi3-defizienten Tieren nicht in der Lage, die colitischen Parameter zu verbessern beziehungsweise verschlimmerte den Krankheitsph{\"a}notyp. Expressionsanalysen von Up- und Downstream-Target-Genen lieferten weitere Hinweise darauf, dass bei Anwesenheit von Ebi3 IL-35 statt IL-39 gebildet wird, was in Einklang mit den in vitro-Untersuchungen steht. Die vorliegende Arbeit konnte durch den Vergleich der C57BL/6-M{\"a}use mit den Ebi3-defizienten Tieren neue Erkenntnisse {\"u}ber die Wirkungsweise von SAHA erbringen. Histonacetylierende Bedingungen verbessern colitische Symptome {\"u}ber einen Mechanismus, der die epigenetische Induktion von Ebi3 mit nachfolgender IL-35-Bildung involviert. Durch Kooperation der epigenetischen Mechanismen Hypomethylierung und Histonacetylierung wurde der st{\"a}rkste Effekt auf die EBI3-Induktion bewirkt. Insgesamt konnte in der vorliegenden Arbeit durch in vitro- und in vivo-Analysen die epigenetische und NFκB-vermittelte Induktion von EBI3 {\"u}ber DNA-Demethylierung und Histonacetylierung mit nachfolgender IL-35-Bildung und -Sezernierung nachgewiesen werden. Da IL-35 in der Lage ist, colitische Symptome zu mildern, stellt die epigenetische Reaktivierbarkeit von EBI3 durch DNMTi und HDACi eine vielversprechende Alternative f{\"u}r die derzeit genutzten, oft nicht oder nur kurzfristig wirksamen Therapien bei der Behandlung einer CU dar. Einer {\"u}berm{\"a}ßigen Immunantwort w{\"a}hrend schubweiser entz{\"u}ndlicher Phasen k{\"o}nnte entgegengewirkt und Komplikationen wie die Bildung Colitis-assoziierter Karzinome verhindert werden.}, language = {de} } @phdthesis{Knoche2022, author = {Knoche, Lisa}, title = {Untersuchung von Transformationsprodukten ausgew{\"a}hlter Tierarzneimittel generiert durch Elektrochemie, Mikrosomal Assay, Hydrolyse und Photolyse}, pages = {163, III}, year = {2022}, abstract = {The knowledge of transformation pathways and transformation products of veterinary drugs is important for health, food and environmental matters. Residues, consisting of original veterinary drug and transformation products, are found in food products of animal origin as well as the environment (e.g., soil or surface water). Several transformation processes can alter the original veterinary drug, ranging from biotransformation in living organism to environmental degradation processes like photolysis, hydrolysis, or microbial processes. In this thesis, four veterinary drugs were investigated, three ionophore antibiotics Monensin, Salinomycin and Lasalocid and the macrocyclic lactone Moxidectin. Ionophore antibiotics are mainly used to cure and prevent coccidiosis in poultry especially prophylactic in broiler farming. Moxidectin is an antiparasitic drug that is used for the treatment of internal and external parasites in food-producing and companion animals. The main objective of this work is to employ different laboratory approaches to generate and identify transformation products. The identification was conducted using high-resolution mass spectrometry (HRMS). A major focus was placed on the application of electrochemistry for simulation of transformation processes. The electrochemical reactor - equipped with a three-electrode flow-through cell - enabled the oxidation or reduction by applying a potential. The transformation products derived were analyzed by online coupling of the electrochemical reactor and a HRMS and offline by liquid chromatography (LC) combined with HRMS. The main modification reaction of the identified transformation products differed for each investigated veterinary drug. Monensin showed decarboxylation and demethylation as the main modification reactions, for Salinomycin mostly decarbonylation occurred and for Lasalocid methylation was prevalent. For Moxidectin, I observed an oxidation (hydroxylation) reaction and adduct formation with solvent. In general, for Salinomycin and Lasalocid, more transient transformation products (online measurement) than stable transformation products (offline measurements) were detected. By contrast, the number of transformation products using online and offline measurements were identical for Monensin and Moxidectin. As a complementary approach, metabolism tests with rat or human liver microsomes were conducted for the ionophore antibiotics. Monensin was investigated by using rat liver microsomes and the transformation products identified were based on decarboxylation and demethylation. Salinomycin and Lasalocid were converted by human and rat liver microsomes. For both substances, more transformation products were found by using human liver microsomes. The transformation products of the rat liver microsome conversion were redundant, and the transformation products were also found at the human liver microsome assay. Oxidation (hydroxylation) was found to be the main modification reaction for both. In addition, a frequent ion exchange between sodium and potassium was identified. The final two experiments were performed for one substance each, whereby the hydrolysis of Monensin and the photolysis of Moxidectin was investigated. The transformation products of the pH-dependent hydrolysis were based on ring-opening and dehydration. Moxidectin formed several transformation products by irradiation with UV-C light and the main modification reactions were isomeric changes, (de-)hydration and changes of the methoxime moiety. In summary, transformation products of the four investigated veterinary drugs were generated by the different laboratory approaches. Most of the transformation products were identified for the first time. The resulting findings provide an improved understanding of clarifying the transformation behavior.}, language = {en} } @phdthesis{Schell2022, author = {Schell, Mareike}, title = {Investigating the effect of Lactobacillus rhamnosus GG on emotional behavior in diet-induced obese C57BL/6N mice}, school = {Universit{\"a}t Potsdam}, pages = {XVI, 117}, year = {2022}, abstract = {The prevalence of depression and anxiety is increased in obese patients compared to healthy humans, which is partially due to a shared pathogenesis, including insulin resistance and inflammation. These factors are also linked to intestinal dysbiosis. Additionally, the chronic consumption of diets rich in saturated fats results in body weight gain, hormonal resistances and unfavorable changes in the microbiome composition. The intake of Lactobacilli has already been shown to improve dysbiosis along with metabolism and mood. Yet, the beneficial role and the underlying mechanism of Lactobacillus rhamnosus GG (LGG) to improve emotional behavior in established diet-induced obese conditions are, so far, unknown. To characterize the role of LGG in diet-induced obesity, female and male C57BL/6N mice were fed a semi-synthetic low-fat diet (LFD, 10 \% kcal from fat) or a conventional high-fat diet (HFD, 45 \% kcal from fat) for initial 6 weeks, which was followed by daily oral gavage of vehicle or 1x10^8 CFU of LGG until the end of the experiment. Mice were subjected to basic metabolic and extensive behavioral phenotyping, with a focus on emotional behavior. Moreover, composition of cecal gut microbiome, metabolomic profile in plasma and cerebrospinal fluid was investigated and followed by molecular analyses. Both HFD-feeding and LGG application resulted in sex-specific differences. While LGG prevented the increase of plasma insulin, adrenal gland weight and hyperactivity in diet-induced obese female mice, there was no regulation of anxiodepressive-like behavior. In contrast, metabolism of male mice did not benefit from LGG application, but strikingly, LGG decreased specifically depressive-like behavior in the Mousetail Suspension Test which was confirmed by the Splash Test characterizing motivation for 'self-care'. The microbiome analysis in male mice revealed that HFD-feeding, but not LGG application, altered cecal microbiome composition, indicating a direct effect of LGG on behavioral regulation. However, in female mice, both HFD-feeding and LGG application resulted in changes of microbiome composition, which presumably affected metabolism. Moreover, as diet-induced obese female mice unexpectedly did not exhibit anxiodepressive-like behavior, follow-up analyses were conducted in male mice. Here, HFD-feeding significantly altered abundance of plasma lipids whereas LGG decreased branched chain amino acids which associated with improved emotional behavior. In nucleus accumbens (NAcc) and VTA/SN, which belong to the dopaminergic system, LGG restored HFD-induced decrease of tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, on gene expression level. Lastly, transcriptome analysis in the NAcc identified gene expression of cholecystokinin as a potential mediator of the effect of LGG on HFD-induced emotional alterations. In summary, this thesis revealed the beneficial effects of LGG application on emotional alterations in established diet-induced obesity. Furthermore, both HFD-feeding and LGG treatment exhibited sex-specific effects, resulting in metabolic improvements in female mice while LGG application mitigated depressive-like behavior in obese male mice along with a molecular signature of restored dopamine synthesis and neuropeptide signaling.}, language = {en} } @phdthesis{Herpich2021, author = {Herpich, Catrin}, title = {Fibroblast growth factor 21 and its association with nutritional stimuli in older age}, school = {Universit{\"a}t Potsdam}, pages = {75}, year = {2021}, abstract = {Fibroblast growth differentiation factor 21 (FGF21) is known as a pivotal regulator of the glucose and lipid metabolism. As such, it is considered beneficial and has even been labelled a longevity hormone. Nevertheless, recent observational studies have shown that FGF21 is increased in higher age with possible negative effects such as loss of lean and bone mass as well as decreased survival. Hepatic FGF21 secretion can be induced by various nutritional stimuli such as starvation, high carbohydrate and fat intake as well as protein deficiency.. So far it is still unclear whether the FGF21 response to different macronutrients is altered in older age. An altered response would potentially contribute to explain the higher FGF21 concentrations found in older age. In this publication-based doctoral dissertation, a cross-sectional study as well as a dietary challenge were conducted to investigate the influence of nutrition on FGF21 concentrations and response in older age. In a cross-sectional study, FGF21 concentrations were assessed in older patients with and without cachexia anorexia syndrome anorexia syndrome compared to an older community-dwelling control group. Cachexia anorexia syndrome is a multifactorial syndrome frequently occurring in old age or in the context of an underlying disease. It is characterized by a severe involuntary weight loss, loss of appetite (anorexia) and reduced food intake, therefore representing a state of severe nutrient deficiency, in some aspects similar to starvation. The highest FGF21 concentrations were found in patients with cachexia anorexia syndrome. Moreover, FGF21 was positively correlated with weight loss and loss of appetite. In addition, cachexia anorexia syndrome itself was associated with FGF21 independent of sex, age and body mass index. As cachectic patients presumably exhibit protein malnutrition and FGF21 has been proposed a marker for protein insufficiency, the higher levels of FGF21 in patients with cachexia anorexia syndrome might be partly explained by insufficient protein intake. In order to investigate the acute response of FGF21 to different nutritional stimuli, a dietary challenge with a parallel group design was conducted. Here, healthy older (65-85 years) and younger (18-35 years) adults were randomized to one of four test meals: a dextrose drink, a high carbohydrate, high fat or high protein meal. Over the course of four hours, postprandial FGF21 concentrations (dynamics) were assessed and the FGF21 response (incremental area under the curve) to each test meal was examined.. In a sub-group of older and younger women, also the adiponectin response was investigated, as adiponectin is a known mediator of FGF21 effects on glucose and lipid metabolism. The dietary meal challenge revealed that dextrose and high carbohydrate intake result in higher FGF21 concentrations after four hours in older adults. This was partly explained by higher postprandial glucose concentrations in the old. For high fat ingestion no age differences were found. For the first time, acute FGF21 response to high protein intake was shown. Here, protein ingestion resulted in lower FGF21 concentrations in younger compared to older adults. Furthermore, sufficient protein intake, according to age-dependent recommendations, of the previous day, was associated with lower FGF21 concentrations in both age groups. The higher FGF21 response to dextrose ingestion resulted in a higher adiponectin response in older women, independent of fat mass, insulin resistance, triglyceride concentrations, inflammation and oxidative stress. Following the high fat meal, adiponectin concentrations declined in older women. Adiponectin response was not affected by meal composition in younger women. In summary, this thesis showed a positive association of FGF21 and cachexia anorexia syndrome with concomitant anorexia in older patients. Regarding the acute FGF21 response, a higher response following dextrose and carbohydrate ingestion was found in older compared with younger subjects. This might be attributed to a higher glucose response in older age. Furthermore, it was shown that the higher FGF21 response after dextrose ingestion possibly contributes to a higher adiponectin response in older women, independent of potential metabolic and inflammatory confounders. Acute protein ingestion resulted in a significant decrease in FGF21 concentrations. Moreover, protein intake of the previous day was inversely associated with fasting FGF21 concentrations. This might explain why FGF21 concentrations are higher in cachexia anorexia syndrome. These results therefore support the role of FGF21 as a sensor of protein restriction.}, language = {en} } @phdthesis{Grimmer2022, author = {Grimmer, Benjamin}, title = {Pannexin 1}, school = {Universit{\"a}t Potsdam}, pages = {66, XXIX}, year = {2022}, abstract = {Hypoxic pulmonary vasoconstriction is an active alveolar hypoxia-caused physiological response redirecting pulmonary blood flow from poorly ventilated areas to better oxygenated lung regions in order to optimize oxygen supply. However, the signaling pathways underlying this pulmonary vascular response remain an area under investigation. In the present study I investigated the functional relevance of Pannexin 1 (Panx1)-mediated ATP release in hypoxic pulmonary vasoconstriction and chronic hypoxic pulmonary hypertension using murine isolated perfused lungs, chronic hypoxic mice, and pulmonary artery smooth muscle cell culture. In isolated mouse lungs, switch to hypoxic gas induced a marked increase in pulmonary artery pressure. Pharmacological inhibition of Panx1 using probenecid, Panx1 specific inhibitory peptide (10Panx1) or spironolactone as well as genetic deletion of Panx1 in smooth muscle cells diminished hypoxic pulmonary vasoconstriction in isolated perfused mouse lungs. Fura-2 imaging revealed a reduced Ca2+ response to hypoxia in pulmonary artery smooth muscle cells treated with spironolactone or 10Panx1. Although these findings suggested an important role of Panx1 in HPV, neither smooth muscle cell nor endothelial cell specific genetic deletion of Panx1 prevented the development of pulmonary hypertension in chronic hypoxic mice. Surprisingly, hypoxia did not induce ATP release and inhibition of purinergic receptors or ATP degradation by ATPase failed to decrease the pulmonary vasoconstriction response to hypoxia in isolated perfused mouse lungs. However, Panx1 antagonism as well as TRPV4 inhibition prevented the hypoxia-induced increase in intracellular Ca2+ concentration in pulmonary artery smooth muscle cells in an additive manner suggesting that Panx1 might modulate intracellular Ca2+ signaling independently of the ATP-P2-TRPV4 signaling axis. In line with this assumption, overexpression of Panx1 in HeLa cells increased intracellular Ca2+ concentrations in response to acute hypoxia. Conclusion: In this study I identifiy Panx1 as novel regulator of HPV.. Yet, the role of Panx1 was not attributable to the release of ATP and downstream P2 signaling pathways or activation of TRPV4 but rathter relates to a role of Panx1 as indirect or direct modulator of the Ca2+ response to hypoxia in PASMCs. Genetic deletion of Panx1 did not influence the development of chronic hypoxic pulmonary hypertension in mice.}, language = {en} } @phdthesis{Engel2021, author = {Engel, Anika}, title = {Endocrine effects of plasticizers and the development of a breast cell-based toxicity screening system}, doi = {10.25932/publishup-53117}, school = {Universit{\"a}t Potsdam}, pages = {VIII, 89}, year = {2021}, abstract = {Humans are frequently exposed to a variety of endocrine disrupting chemicals (EDCs), which can cause harmful effects, e.g. disturbance of growth, development and reproduction, and cancer (UBA, 2016). EDCs are often components of synthetically manufactured products. Materials made of plastics, building materials, electronic items, textiles or cosmetic products can be particularly contaminated (Ain et al., 2021). One group of EDCs that has gained increased interest in recent years is phthalates. They are used as plasticizers in plastic materials to which people are daily exposed to. Phthalate plasticizers exert their harmful effects among others via activation of the estrogen receptor α (ERα), the estrogen receptor β (ERβ) and via inhibition of the androgen receptor (AR). Some phthalates have already been classified by the EU as Cancerogenic-, Mutagenic-, Reprotoxic- (CMR) substances and their use in industry has been restricted. After oral ingestion, phthalates are metabolized and are finally excreted with the urine. Numerous toxicological studies exist on phthalates, but mainly with the parent substances, not with their primary and secondary metabolites. In the course of the restriction of phthalates by the EU, the phthalate-free plasticizer di-isononylcyclohexane-1,2-dicarboxylate (DINCH®), was introduced to the market. So far, almost no toxicologically relevant properties have been identified for DINCH®. However, the effects of DINCH® have only been studied in animal experiments and, as with phthalates, almost exclusively with the parent substance. However, toxic effects of a particular compound may be induced by its metabolites and not by the parent compound itself. Therefore, potential endocrine effects of 15 phthalates, 19 phthalate metabolites, DINCH®, and five of its metabolites were investigated using reporter gene assays on the ERα, ERβ, and the AR. In addition, studies of the influence of some selected plasticizers on peroxisome proliferator-activated receptor α (PPARα) and peroxisome proliferator-activated receptor γ (PPARγ) activity were performed. Furthermore, a H295R steroidogenesis assay was performed to determine the influence of DINCH® and its metabolites on estradiol or testosterone synthesis. Analysis of the experiments shows that the phthalates either stimulated or inhibited ERα and ERβ activity and inhibited AR activity, whereas the phthalate metabolites did not affect the activity of these human hormone receptors. In contrast, metabolites of di-(2-ethylhexyl) phthalate (DEHP) stimulated transactivation of the human PPARα and PPARγ in analogous reporter gene assays, although DEHP itself did not activate these nuclear receptors. Therefore, primary and secondary phthalate metabolites appear to exert different effects at the molecular level compared to the parent compounds. Similarly, the results showed that the phthalate-free plasticizer DINCH® itself did not affect the activity of ERα, ERβ, AR, PPARα and PPARγ, while the DINCH® metabolites were shown to activate all these receptors. In the case of AR, DINCH® metabolites mainly enhanced AR activity stimulated by dihydrotestosterone (DHT). In the H295R steroidogenesis assay, neither DINCH® nor any of its metabolites affected estradiol or testosterone synthesis. Primary and secondary metabolites of DINCH® thus exert different effects at the molecular level than DINCH® itself. However, all these in vitro effects of DINCH® metabolites were observed only at high concentrations, which were about three orders of magnitude higher than the reported DINCH® metabolite concentrations in human urine. Therefore, the in vitro data does not support the assumption that DINCH® or any of the metabolites studied could have significant endocrine effects in vivo at relevant exposure levels in humans. Following the demonstration of direct and indirect endocrine effects of the studied plasticizers, a new effect-based in vitro 3D screening tool for toxicity assays of non-genotoxic carcinogens was developed using estrogen receptor-negative (ER-) MCF10-A cells and estrogen receptor-positive (ER+) MCF-12A cells. This arose from the background that breast cancer is the most common cancer occurring in women and estrogenic substances, such as phthalates, can probably influence the disease. The human mammary epithelial cell lines MCF-10A and MCF-12A form well-differentiated acini-like structures when cultured in three-dimensional Matrigel culture for a period of 20 days. The model should make it possible to detect substance effects on cell differentiation and growth, on mammary cell acini, and to differentiate between estrogenic and non-estrogenic effects at the same time. In the present study, both cell lines were tested for their suitability as an effect-based in vitro assay system for non-genotoxic carcinogens. An Automated Acinus Detection And Morphological Evaluation (ADAME) software solution has been developed for automatic acquisition of acinus images and determination of morphological parameters such as acinus size, lumen size, and acinus roundness. Several test substances were tested for their ability to affect acinus formation and cellular differentiation. Human epithelial growth factor (EGF) stimulated acinus growth for both cell lines, while all trans retinoic acid (RA) inhibited acinar growth. The potent estrogen 17β-estradiol had no effect on acinus formation of MCF-10A cells but resulted in larger MCF-12A acini. Thus, the parallel use of both cell lines together with the developed high content screening and evaluation tool allows the rapid identification of the estrogenic and cancerogenic properties of a given test compound. The morphogenesis of the acini was only slightly affected by the test substances. On the one hand, this suggests a robust test system, on the other hand, it probably cannot detect low-potent estrogenic compounds such as phthalates or DINCH®. The advantage of the robustness of the system, however, may be that vast numbers of "positive" results with questionable biological relevance could be avoided, such as those observed in sensitive reporter gene assays.}, language = {en} } @phdthesis{Wandt2021, author = {Wandt, Viktoria Klara Veronika}, title = {Trace elements, ageing, and sex}, school = {Universit{\"a}t Potsdam}, pages = {iii, 204}, year = {2021}, language = {en} } @phdthesis{Reichmann2021, author = {Reichmann, Robin}, title = {Novel applications of machine learning techniques in epidemiology of age-related diseases}, school = {Universit{\"a}t Potsdam}, pages = {164, xlv}, year = {2021}, language = {en} } @phdthesis{Saussenthaler2021, author = {Saussenthaler, Sophie}, title = {The impact of DNA methylation on susceptibility to typ 2 diabetes in NZO mice}, school = {Universit{\"a}t Potsdam}, pages = {XIX, 150}, year = {2021}, abstract = {The development of type 2 diabetes (T2D) is driven by genetic as well as life style factors. However, even genetically identical female NZO mice on a high-fat diet show a broad variation in T2D onset. The main objective of this study was to elucidate and investigate early epigenetic determinants of type 2 diabetes. Prior to other experiments, early fat content of the liver (<55.2 HU) in combination with blood glucose concentrations (>8.8 mM) were evaluated as best predictors of diabetes in NZO females. Then, DNA methylome and transcriptome were profiled to identify molecular pathophysiological changes in the liver before diabetes onset. The major finding of this thesis is that alterations in the hepatic DNA methylome precede diabetes onset. Of particular interest were 702 differentially methylated regions (DMRs), of which 506 DMRs had genic localization. These inter-individual DMRs were enriched by fivefold in the KEGG pathway type 2 diabetes mellitus, independent of the level of gene expression, demonstrating an epigenetic predisposition toward diabetes. Interestingly, among the list of hepatic DMRs, eleven DMRs were associated with known imprinted genes in the mouse genome. Thereby, six DMRs (Nap1l5, Mest, Plagl1, Gnas, Grb10 and Slc38a4) localized to imprinting control regions, including five iDMRs that exhibited hypermethylation in livers of diabetes-prone mice. This suggests that gain of DNA methylation in multiple loci of the paternal alleles has unfavourable metabolic consequences for the offspring. Further, the comparative liver transcriptome analysis demonstrated differences in expression levels of 1492 genes related to metabolically relevant pathways, such as citrate cycle and fatty acid metabolism. The integration of hepatic transcriptome and DNA methylome indicated that 449 differentially expressed genes were potentially regulated by DNA methylation, including genes implicated in insulin signaling. In addition, liver transcriptomic profiling of diabetes-resistant and diabetes-prone mice revealed a potential transcriptional dysregulation of 17 hepatokines, in particular Hamp. The hepatic expression of Hamp was decreased by 52\% in diabetes-prone mice, on account of an increase in DNA methylation of promoter CpG-118. Hence, HAMP protein levels were lower in mice prone to develop diabetes, which correlated to higher liver triglyceride levels.. In sum, the identified DNA methylation changes appear to collectively favor the initiation and progression of diabetes in female NZO mice. In near future, epigenetic biomarkers are likely to contribute to improved diagnosis for T2D.}, language = {en} } @phdthesis{Baeseler2021, author = {Baeseler, Jessica}, title = {Trace element effects on longevity and neurodegeneration with focus on C. elegans}, school = {Universit{\"a}t Potsdam}, pages = {X,114,VIII}, year = {2021}, abstract = {The trace elements zinc and manganese are essential for human health, especially due to their enzymatic and protein stabilizing functions. If these elements are ingested in amounts exceeding the requirements, regulatory processes for maintaining their physiological concentrations (homeostasis) can be disturbed. Those homeostatic dysregulations can cause severe health effects including the emergence of neurodegenerative disorders such as Parkinson's disease (PD). The concentrations of essential trace elements also change during the aging process. However, the relations of cause and consequence between increased manganese and zinc uptake and its influence on the aging process and the emergence of the aging-associated PD are still rarely understood. This doctoral thesis therefore aimed to investigate the influence of a nutritive zinc and/or manganese oversupply on the metal homeostasis during the aging process. For that, the model organism Caenorhabditis elegans (C. elegans) was applied. This nematode suits well as an aging and PD model due to properties such as its short life cycle and its completely sequenced, genetically amenable genome. Different protocols for the propagation of zinc- and/or manganese-supplemented young, middle-aged and aged C. elegans were established. Therefore, wildtypes, as well as genetically modified worm strains modeling inheritable forms of parkinsonism were applied. To identify homeostatic and neurological alterations, the nematodes were investigated with different methods including the analysis of total metal contents via inductively-coupled plasma tandem mass spectrometry, a specific probe-based method for quantifying labile zinc, survival assays, gene expression analysis as well as fluorescence microscopy for the identification and quantification of dopaminergic neurodegeneration.. During aging, the levels of iron, as well as zinc and manganese increased.. Furthermore, the simultaneous oversupply with zinc and manganese increased the total zinc and manganese contents to a higher extend than the single metal supplementation. In this relation the C. elegans metallothionein 1 (MTL-1) was identified as an important regulator of metal homeostasis. The total zinc content and the concentration of labile zinc were age-dependently, but differently regulated. This elucidates the importance of distinguishing these parameters as two independent biomarkers for the zinc status. Not the metal oversupply, but aging increased the levels of dopaminergic neurodegeneration. Additionally, nearly all these results yielded differences in the aging-dependent regulation of trace element homeostasis between wildtypes and PD models. This confirms that an increased zinc and manganese intake can influence the aging process as well as parkinsonism by altering homeostasis although the underlying mechanisms need to be clarified in further studies.}, language = {en} } @phdthesis{Mancini2021, author = {Mancini, Carola}, title = {Analysis of the effects of age-related changes of metabolic flux on brown adipocyte formation and function}, doi = {10.25932/publishup-51266}, school = {Universit{\"a}t Potsdam}, pages = {xvii, 134}, year = {2021}, abstract = {Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis, thereby allowing mammals to maintain a constant body temperature in a cold environment. Thermogenic capacity of this tissue is due to a high mitochondrial density and expression of uncoupling protein 1 (UCP1), a unique brown adipocyte marker which dissipates the mitochondrial proton gradient to produce heat instead of ATP. BAT is actively involved in whole-body metabolic homeostasis and during aging there is a loss of classical brown adipose tissue with concomitantly reduced browning capacity of white adipose tissue. Therefore, an age-dependent decrease of BAT-related energy expenditure capacity may exacerbate the development of metabolic diseases, including obesity and type 2 diabetes mellitus. Given that direct effects of age-related changes of BAT-metabolic flux have yet to be unraveled, the aim of the current thesis is to investigate potential metabolic mechanisms involved in BAT-dysfunction during aging and to identify suitable metabolic candidates as functional biomarkers of BAT-aging. To this aim, integration of transcriptomic, metabolomic and proteomic data analyses of BAT from young and aged mice was performed, and a group of candidates with age-related changes was revealed. Metabolomic analysis showed age-dependent alterations of metabolic intermediates involved in energy, nucleotide and vitamin metabolism, with major alterations regarding the purine nucleotide pool. These data suggest a potential role of nucleotide intermediates in age-related BAT defects. In addition, the screening of transcriptomic and proteomic data sets from BAT of young and aged mice allowed identification of a 60-kDa lysophospholipase, also known as L-asparaginase (Aspg), whose expression declines during BAT-aging. Involvement of Aspg in brown adipocyte thermogenic function was subsequently analyzed at the molecular level using in vitro approaches and animal models. The findings revealed sensitivity of Aspg expression to β3-adrenergic activation via different metabolic cues, including cold exposure and treatment with β3-adrenergic agonist CL. To further examine ASPG function in BAT, an over-expression model of Aspg in a brown adipocyte cell line was established and showed that these cells were metabolically more active compared to controls, revealing increased expression of the main brown-adipocyte specific marker UCP1, as well as higher lipolysis rates. An in vitro loss-of-function model of Aspg was also functionally analyzed, revealing reduced brown adipogenic characteristics and an impaired lipolysis, thus confirming physiological relevance of Aspg in brown adipocyte function. Characterization of a transgenic mouse model with whole-body inactivation of the Aspg gene (Aspg-KO) allowed investigation of the role of ASPG under in vivo conditions, indicating a mild obesogenic phenotype, hypertrophic white adipocytes, impairment of the early thermogenic response upon cold-stimulation and dysfunctional insulin sensitivity. Taken together, these data show that ASPG may represent a new functional biomarker of BAT-aging that regulates thermogenesis and therefore a potential target for the treatment of age-related metabolic disease.}, language = {en} } @phdthesis{Rausch2021, author = {Rausch, Ann-Kristin}, title = {Development of LC-MS/MS Multi-Methods for the Analysis of Contaminants and Residues}, school = {Universit{\"a}t Potsdam}, pages = {IX, 234, v}, year = {2021}, abstract = {Mycotoxins are secondary metabolites produced by several filamentous fungal species, thus occurring ubiquitously in the environment and food. While the heterogeneous group shows differences in their bioavailability and toxicity, the low-molecular-weight xenobiotics are capable of impacting human and animal health acutely and chronically. Therefore, maximum levels for the major mycotoxins in food and feed are regulated in the current European legislation. Besides free mycotoxins, naturally occurring modified mycotoxins are gaining more attention in recent years. Modified mycotoxins constitute toxins altered by plants, microorganisms, and living organisms in different metabolic pathways or food processing steps. The toxicological relevant compounds often co-occur with their free forms in infested food and feed. Thus, the toxins may contribute to the overall toxicity of mycotoxins, wherefore their presence and toxicity should be considered in risk assessment. Until now, however, there are no regulated limits for modified mycotoxins within the European Union. In this thesis, rapid, sensitive, and robust methods for the analysis of mycotoxins and their modified forms were developed and validated using state-of-the-art high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) systems. Firstly, two analytical methods for determining 38 mycotoxins in cereals and 41 mycotoxins in beer were established since agricultural products count as the primary source of mycotoxin contamination. For the analysis of cereal samples, a QuEChERS- based extraction approach was pursued, while analytes from beer samples were extracted using an acetonitrile precipitation scheme. Validation in cereals, namely wheat, corn, rice, and barley, as well as in beer, demonstrated satisfactory results. To obtain information regarding the natural occurrence of mycotoxins in food products, the developed methods were applied to the analysis of several commercial samples partly produced worldwide. The Fusarium toxins deoxynivalenol and its conjugated metabolite deoxynivalenol-3-glucoside turned out to be the most abundant toxins. None of the other modified mycotoxins were quantified in the samples. However, one cereal sample showed traces of zearalenone- 14-sulfate below the limit of quantification. Moreover, pesticides, plant growth regulators, and tropane alkaloids were investigated in this thesis. Pesticides present biologically highly effective compounds applied in the environment to protect humans from the hazardous effects of pests. While plant growth regulators show similar functions, mainly improving agricultural production, tropane alkaloids are naturally occurring secondary metabolites mainly in the species of Solanaceae that may pose unintended poisoning of humans. The third part of the present thesis aimed to analyze cereal-relevant compounds simultaneously, wherefore a multi-method for the analysis of (modified) mycotoxins, pesticides, plant growth regulators, and tropane alkaloids was established. After processing the samples, this should be done in a single extraction step with subsequent one-time measurements. Various sample preparation procedures were compared, whereby an approach based on an acidified acetonitrile/water extraction, followed by an online clean-up, was finally chosen. The simultaneous determination of more than 350 analytes required an analytical tool that offered an increased resolving power, represented as an enhanced peak capacity, and the possibility of analyzing a broad polarity range. Thus, a two-dimensional LC-MS/MS system based on two different separation mechanisms that performed orthogonal to one another was used for the analysis. Validation of the developed method revealed good performance characteristics for most analytes, while subsequent application showed that 86\% of the samples were contaminated with at least one compound. In summary, this thesis provides novel insights into the analysis of food-relevant (modified) mycotoxins. Different sample preparation and LC-MS/MS approaches were introduced, resulting in the development of three new analytical methods. For the first time, such a high number of modified mycotoxins was included in multi-mycotoxin methods and a multi-method ranging both contaminants and residues. Although first steps towards the analysis of modified mycotoxins have been made, further research is needed to elucidate their (co-) occurrence and toxicological behavior in order to understand their relevance to human health in the future.}, language = {en} } @phdthesis{RodriguezSillke2021, author = {Rodriguez-Sillke, Yasmina}, title = {Der Einfluss von Nahrungsmittelantigenen auf die mukosale sowie periphere Hom{\"o}ostase und Entz{\"u}ndung bei chronisch entz{\"u}ndlichen Darmerkrankungen}, school = {Universit{\"a}t Potsdam}, pages = {134}, year = {2021}, language = {de} } @phdthesis{Nieschalke2021, author = {Nieschalke, Kai}, title = {Proteinaddukte und Urinmetaboliten des Nagetierkanzerogens Methyleugenol als Biomarker der Exposition}, school = {Universit{\"a}t Potsdam}, pages = {142, XLIV}, year = {2021}, language = {de} } @phdthesis{HaferkornStarke2021, author = {Haferkorn-Starke, Robert Christian}, title = {Entwicklung eines Lebensmitteluntersuchungssystems f{\"u}r mikrobielle Erreger mit Hilfe molekularbiologischer Methoden}, school = {Universit{\"a}t Potsdam}, pages = {XVII, 239, vi}, year = {2021}, language = {de} } @phdthesis{LenihanGeels2020, author = {Lenihan-Geels, Georgia Ngawai}, title = {The regulation of metabolic flexibility by p53 in skeletal muscle and brown adipose tissue}, school = {Universit{\"a}t Potsdam}, year = {2020}, language = {en} } @phdthesis{Alfine2021, author = {Alfine, Eugenia}, title = {Investigation of Sirtuin 3 overexpression as a genetic model of fasting in hypothalamic neurons}, school = {Universit{\"a}t Potsdam}, pages = {134}, year = {2021}, language = {en} } @phdthesis{AgaBarfknecht2021, author = {Aga-Barfknecht, Heja}, title = {Investigation of the phenotype and genetic variant(s) of the diabetes locus Nidd/DBA}, school = {Universit{\"a}t Potsdam}, year = {2021}, abstract = {Diabetes is a major public health problem with increasing global prevalence. Type 2 diabetes (T2D), which accounts for 90\% of all diagnosed cases, is a complex polygenic disease also modulated by epigenetics and lifestyle factors. For the identification of T2D-associated genes, linkage analyses combined with mouse breeding strategies and bioinformatic tools were useful in the past. In a previous study in which a backcross population of the lean and diabetes-prone dilute brown non-agouti (DBA) mouse and the obese and diabetes-susceptible New Zealand obese (NZO) mouse was characterized, a major diabetes quantitative trait locus (QTL) was identified on chromosome 4. The locus was designated non-insulin dependent diabetes from DBA (Nidd/DBA). The aim of this thesis was (i) to perform a detailed phenotypic characterization of the Nidd/DBA mice, (ii) to further narrow the critical region and (iii) to identify the responsible genetic variant(s) of the Nidd/DBA locus. The phenotypic characterization of recombinant congenic mice carrying a 13.6 Mbp Nidd/DBA fragment with 284 genes presented a gradually worsening metabolic phenotype. Nidd/DBA allele carriers exhibited severe hyperglycemia (~19.9 mM) and impaired glucose clearance at 12 weeks of age. Ex vivo perifusion experiments with islets of 13-week-old congenic mice revealed a tendency towards reduced insulin secretion in homozygous DBA mice. In addition, 16-week-old mice showed a severe loss of β-cells and reduced pancreatic insulin content. Pathway analysis of transcriptome data from islets of congenic mice pointed towards a downregulation of cell survival genes. Morphological analysis of pancreatic sections displayed a reduced number of bi-hormonal cells co-expressing glucagon and insulin in homozygous DBA mice, which could indicate a reduced plasticity of endocrine cells in response to hyperglycemic stress. Further generation and phenotyping of recombinant congenic mice enabled the isolation of a 3.3 Mbp fragment that was still able to induce hyperglycemia and contained 61 genes. Bioinformatic analyses including haplotype mapping, sequence and transcriptome analysis were integrated in order to further reduce the number of candidate genes and to identify the presumable causative gene variant. Four putative candidate genes (Ttc39a, Kti12, Osbpl9, Calr4) were defined, which were either differentially expressed or carried a sequence variant. In addition, in silico ChIP-Seq analyses of the 3.3 Mbp region indicated a high number of SNPs located in active regions of binding sites of β-cell transcription factors. This points towards potentially altered cis-regulatory elements that could be responsible for the phenotype conferred by the Nidd/DBA locus. In summary, the Nidd/DBA locus mediates impaired glucose homeostasis and reduced insulin secretion capacity which finally leads to β-cell death. The downregulation of cell survival genes and reduced plasticity of endocrine cells could further contribute to the β-cell loss. The critical region was narrowed down to a 3.3 Mbp fragment containing 61 genes, of which four might be involved in the development of the diabetogenic Nidd/DBA phenotype.}, language = {en} } @phdthesis{Martinez2020, author = {Martinez, Maria Teresa Casta{\~n}o}, title = {Effects of Dietary Methionine and Protein Restriction on the Prevention and Treatment of Type 2 Diabetes}, pages = {100}, year = {2020}, language = {en} } @phdthesis{Winkelbeiner2020, author = {Winkelbeiner, Nicola Lisa}, title = {Impact of element species on DNA repair processes}, pages = {XV, 182, iii}, year = {2020}, language = {en} } @phdthesis{Schiborn2020, author = {Schiborn, Catarina}, title = {Extension of the German Diabetes Risk Score with regard to risk communication and cardiovascular outcomes}, school = {Universit{\"a}t Potsdam}, pages = {218}, year = {2020}, language = {en} } @phdthesis{Finke2020, author = {Finke, Hannah}, title = {Toxicological Characterization of Arsenolipids in vitro and Analysis of Global DNA (Hydroxy)methylation in the Context of Aging, Trace Element Status, and Genomic Stability}, school = {Universit{\"a}t Potsdam}, pages = {t, 222, XXVII}, year = {2020}, language = {de} } @phdthesis{ColemanMacGregorofInneregny, author = {Coleman Mac Gregor of Inneregny, Charles Dominic}, title = {Rolle von mPGES1-abh{\"a}ngig gebildetem Prostaglandin E2 bei der Ausbildung von Insulinresistenz und nicht-alkoholischer Fettlebererkrankung durch die Modulation der Funktion von Lebermakrophagen}, school = {Universit{\"a}t Potsdam}, pages = {183}, abstract = {Eine St{\"o}rung des Leberstoffwechsels durch die Ausbildung einer Insulinresistenz kann zu Folgeerkrankungen wie der nicht alkoholischen Fettlebererkrankung (NAFLD) bis hin zur Steatohepatitis (NASH) und zur Entwicklung eines Diabetes Typ II f{\"u}hren. Am Krankheitsverlauf sind residente (Kupfferzellen) sowie infiltrierende Makrophagen beteiligt, die durch inflammatorische Stimuli aktiviert werden und zur Progression von Lebererkrankungen f{\"u}hren k{\"o}nnen. Im Rahmen dieser Arbeit wurde die Rolle von mPGES1-abh{\"a}ngig gebildetem Prostaglandin E2 (PGE2) an der Modulation von aktivierten Lebermakrophagen untersucht. Dazu wurden Kupfferzellen und Peritonealmakrophagen (als Modell f{\"u}r infiltrierende Makrophagen) aus Wildtyp und mPGES1-defizienten M{\"a}usen isoliert. Beide Makrophagen­populationen wurden in Zellkulturversuchen mit Lipopolysacchariden (LPS) aktiviert und auf ihre PGE2-Synthese, Genexpression und Sekretion von verschiedenen Cytokinen hin untersucht. Die beiden Makrophagenpopulationen unterschieden sich hinsichtlich der PGE2-Synthese bei mPGSE1-Defizienz. W{\"a}hrend bei Peritonealmakrophagen die LPS-abh{\"a}ngige PGE2-Synthese bei Abwesenheit der mPGES1 fast vollst{\"a}ndig reprimiert war, war bei Kupfferzellen nur eine 25\%ige Abnahme zu verzeichnen. Die postulierte selbstverst{\"a}rkende R{\"u}ckkopplungsschleife von PGE2 im Hinblick auf seine eigene Synthese konnte in isolierten Peritonealmakrophagen, nicht jedoch in Kupfferzellen, best{\"a}tigt werden. In Kupfferzellen f{\"u}hrte exogenes PGE2 ferner zu einer Repression von den pro-inflammatorischen Cytokinen TNFα und IL-1β und f{\"u}r endogenes PGE2 konnte in diesem Zelltyp kein Effekt festgestellt werden. In Peritonealmakrophagen konnte hingegen auch f{\"u}r endogenes PGE2 eine reprimierende Wirkung auf die Expression von TNFα beobachtet werden. Das ist eventuell auf eine h{\"o}here Sensitivit{\"a}t gegen{\"u}ber PGE2 von Peritonealmakrophagen im Vergleich zu Kupfferzellen zur{\"u}ckzuf{\"u}hren. PGE2 wirkte unter den gew{\"a}hlten Versuchsbedingungen in vitro somit eher anti-inflammatorisch. Cholesterolkristalle induzierten in Kupfferzellen die Expression der PGE2-synthetisierenden Enzyme und verschiedener pro-inflammatorische Cytokine. Sie k{\"o}nnten somit zu einer Progression von NAFL zu NASH beitragen. Die Daten aus dieser Arbeit deuten darauf hin, dass PGE2 im Rahmen von entz{\"u}ndlichen Leberver{\"a}nderungen eine eher protektive Wirkung im Hinblick auf die Progression von NAFLD und Insulinresistenz haben k{\"o}nnte.}, language = {de} } @phdthesis{Ziemann2020, author = {Ziemann, Vanessa}, title = {Toxische Effekte von Arsenolipiden in humanen Kulturzellen und Caenorhabditis elegans}, school = {Universit{\"a}t Potsdam}, pages = {112}, year = {2020}, language = {de} } @phdthesis{Schwerbel2019, author = {Schwerbel, Kristin}, title = {Der Einfluss zweier immun-assoziierter GTPasen auf die Entstehung einer Hepatosteatose}, school = {Universit{\"a}t Potsdam}, pages = {133}, year = {2019}, language = {de} } @phdthesis{Gaballa2019, author = {Gaballa, Mohamed Mahmoud Salem Ahmed}, title = {New pharmacological approaches targeting vascular calcification in chronic kidney disease}, address = {Potsdam}, school = {Universit{\"a}t Potsdam}, pages = {X, 110}, year = {2019}, language = {en} } @phdthesis{Eichelmann2019, author = {Eichelmann, Fabian}, title = {Novel adipokines as inflammatory biomarkers of chronic disease risk}, school = {Universit{\"a}t Potsdam}, pages = {133}, year = {2019}, language = {en} } @phdthesis{Gottmann2019, author = {Gottmann, Pascal}, title = {In silico Analyse zur Kl{\"a}rung der Beteiligung von micro-RNAs, die in QTL lokalisiert sind, an den metabolischen Erkrankungen Adipositas und Typ-2-Diabetes mit Hilfe von Mausmodellen}, school = {Universit{\"a}t Potsdam}, pages = {XIII, 106}, year = {2019}, language = {de} } @phdthesis{Rohn, author = {Rohn, Isabelle}, title = {Food-relevant selenium species}, school = {Universit{\"a}t Potsdam}, pages = {132,VIII}, language = {en} } @phdthesis{ColemanMacGregorofInneregny, author = {Coleman Mac Gregor of Inneregny, Verena}, title = {Cell-autonomous and cell-non-autonomous adaptation to skeletal muscle mitochondrial stress}, school = {Universit{\"a}t Potsdam}, pages = {86}, language = {en} } @phdthesis{Ring2018, author = {Ring, Christiane}, title = {The role of the commensal gut bacterium Akkermansia muciniphila in acute and chronic intestinal inflammation}, year = {2018}, abstract = {Microbiota analyses of patients suffering from various diseases suggest a beneficial role of Akkermansia muciniphila in the maintenance of health, whereas several studies in animal models of intestinal inflammation report that this organism may aggravate inflammation. Therefore, it is important to clarify under which circumstances A. muciniphila exerts negative effects in the intestine of its host. The previously reported observation that A. muciniphila aggravates acute intestinal inflammation in the Salmonella enterica serovar Typhimurium infection mouse model colonized with a simplified human intestinal microbiota was investigated in this study. To unravel the underlying mechanism that led to the observed phenomenon, the time course of events following the infection was analyzed. In mice colonized with a simplified human intestinal microbiota, Salmonella infection induced clear signs of intestinal inflammation three days post infection. The inflammatory response was similar in mice colonized with A. muciniphila before Salmonella infection. These observations were independent of the time when colonization with the simplified human intestinal microbiota occurred, right after birth or only after weaning, and contradict the previous report. To find out whether A. muciniphila influences the development of chronic intestinal inflammation in a genetically predisposed host, mono-associated interleukin-10-deficient (Il10-/-) mice, Il10-/- mice dual-associated with A. muciniphila and colitogenic Escherichia coli NC101, as well as Il10-/- mice associated with A. muciniphila and a simplified human intestinal microbiota were compared to the respective mice without A. muciniphila. The data clearly show that in these gnotobiotic Il10-/- mice, A. muciniphila neither induces intestinal inflammation itself nor modulates it after induction by a colitogenic bacterium or by a simplified human intestinal microbiota. The experiments lead to the conclusion that the promotion of intestinal inflammation is not an intrinsic feature of this bacterium. The results of this study encourage the proposed use of A. muciniphila for the prevention or treatment of metabolic disorders.}, language = {en} } @phdthesis{Radloff2018, author = {Radloff, Katrin}, title = {The role of the fatty acid profile and its modulation by cytokines in the systemic inflammation in cancer cachexia}, school = {Universit{\"a}t Potsdam}, pages = {156}, year = {2018}, abstract = {Systemic inflammation is a hallmark of cancer cachexia. Among tumor-host interactions, the white adipose tissue (WAT) is an important contributor to inflammation as it suffers morphological reorganization and lipolysis, releasing free fatty acids (FA), bioactive lipid mediators (LM) and pro-inflammatory cytokines, which accentuate the activation of pro-inflammatory signaling pathways and the recruitment of immune cells to the tissue. This project aimed to investigate which inflammatory factors are involved in the local adipose tissue inflammation and what is the influence of such factors upon enzymes involved in FA or LM metabolism in healthy individuals (Control), weight stable gastro-intestinal cancer patients (WSC) and cachectic cancer patients (CC). The results demonstrated that the inflammatory signature of systemic inflammation is different from local adipose tissue inflammation. The systemic inflammation of the cachectic cancer patients was characterized by higher levels of circulating saturated fatty acids (SFA), tumor-necrosis-factor-α (TNF-α), interleukins IL-6, IL-8 and CRP while levels of polyunsaturated fatty acids (PUFAs), especially n3-PUFAs, were lower in CC than in the other groups. In vitro and in adipose tissue explants, pro-inflammatory cytokines and SFAs were shown to increase the chemokines IL-8 and CXCL10 that were found to be augmented in adipose tissue inflammation in CC which was more profound in the visceral adipose tissue (VAT) than in subcutaneous adipose tissue (SAT). Systemic inflammation was negatively associated with the expression of PUFA synthesizing enzymes, though gene and protein expression did hardly differ between groups. The effects of inflammatory factors on enzymes in the whole tissue could have been masked by differentiated modulation of the diverse cell types in the same tissue. In vitro experiments showed that the expression of FA-modifying enzymes such as desaturases and elongases in adipocytes and macrophages was regulated into opposing directions by TNF-α, IL-6, LPS or palmitate. The higher plasma concentration of the pro-resolving LM resolvin D1 in CC cannot compensate the overall inflammatory status and the results indicate that inflammatory cytokines interfere with synthesis pathways of pro-resolving LM. In summary, the data revealed a complex inter-tissue and inter-cellular crosstalk mediated by pro-inflammatory cytokines and lipid compounds enhancing inflammation in cancer cachexia by feed-forward mechanisms.}, language = {en} } @phdthesis{Dambeck2018, author = {Dambeck, Ulrike}, title = {Kohlenhydratarme, n-6-reiche Di{\"a}t versus fettarme Di{\"a}t}, school = {Universit{\"a}t Potsdam}, pages = {187}, year = {2018}, language = {de} } @phdthesis{Hasan2018, author = {Hasan, Ahmed Abdallah Abdalrahman Mohamed}, title = {GLP-1 receptor-independent mechanisms of DPP-4 inhibition on renal disease progression}, school = {Universit{\"a}t Potsdam}, pages = {113}, year = {2018}, language = {en} } @phdthesis{Kammel2018, author = {Kammel, Anne}, title = {Identifizierung fr{\"u}her epigenetischer Ver{\"a}nderungen, die zur Ausbildung einer Fettleber beitragen}, school = {Universit{\"a}t Potsdam}, pages = {130}, year = {2018}, language = {de} } @phdthesis{Waizenegger2018, author = {Waizenegger, Julia}, title = {Untersuchung der molekularen Toxizit{\"a}t von Pyrrolizidinalkaloiden in der humanen Hepatomzelllinie HepaRG}, school = {Universit{\"a}t Potsdam}, pages = {129, XLI}, year = {2018}, language = {de} } @phdthesis{Eckel2017, author = {Eckel, Nathalie}, title = {Metabolically healthy obesity and metabolically unhealthy normal weight - identification and associated risks}, school = {Universit{\"a}t Potsdam}, pages = {177}, year = {2017}, language = {en} } @phdthesis{Edlich2018, author = {Edlich, Alexander}, title = {Interaktionen zwischen Nanotransportern und antigenpr{\"a}sentierenden Zellen der Haut}, school = {Universit{\"a}t Potsdam}, pages = {181}, year = {2018}, language = {de} } @phdthesis{Weiss2018, author = {Weiß, Stefanie}, title = {Contribution of bacterially synthesized folate vitamers to folate status and impact on crohn's Disease}, school = {Universit{\"a}t Potsdam}, pages = {148}, year = {2018}, language = {en} } @phdthesis{Mueller2018, author = {M{\"u}ller, Sandra Marie}, title = {Food-relevant arsenic species}, school = {Universit{\"a}t Potsdam}, pages = {163, Viii}, year = {2018}, language = {en} } @phdthesis{Jank2017, author = {Jank, Anne-Marie}, title = {Effects of senescence on microenvironment-progenitor cell interaction}, school = {Universit{\"a}t Potsdam}, pages = {156}, year = {2017}, language = {en} } @phdthesis{Schraplau2017, author = {Schraplau, Anne}, title = {Regulation der Expression von Xenobiotika-metabolisierenden Enzymen und Deiodasen durch die Xenobiotika-abh{\"a}ngige wechselseitige Induktion von Xenosensor-Transkriptionsfaktoren und Prostaglandin E2}, school = {Universit{\"a}t Potsdam}, pages = {x, 241}, year = {2017}, language = {de} } @phdthesis{Jannasch2017, author = {Jannasch, Franziska}, title = {Methodological aspects of the derivation of dietary patterns and their association with type 2 diabetes}, school = {Universit{\"a}t Potsdam}, pages = {X, 205}, year = {2017}, abstract = {Hintergrund: Die Untersuchung von Ern{\"a}hrungsmustern als komplement{\"a}rer Ansatz zu der Untersuchung einzelner Lebensmittel nimmt stetig zu. Generell k{\"o}nnen drei verschiedene Ans{\"a}tze unterschieden werden um Ern{\"a}hrungsmuster herzuleiten: A priori Indizes, welche das Wissen {\"u}ber gesundheitsf{\"o}rderliche und -sch{\"a}dliche Eigenschaften eines Lebensmittels f{\"u}r einen gewissen Endpunkt nutzen; A posteriori (exploratorische) Ern{\"a}hrungsmuster, welche die populationsspezifischen vorliegenden Daten ohne eine vorangegangene Hypothese nutzen; gemischte Methoden, die das Wissen {\"u}ber bestimmte N{\"a}hrstoffe oder Biomarker, welche in der Krankheitsentstehung eine Rolle spielen, nutzen und mit einer exploratorischen Methode kombinieren um krankheitsrelevante Ern{\"a}hrungsmuster zu generieren. Vorangegangene systematische {\"U}bersichtsarbeiten, welche die Evidenz der Assoziation zwischen Ern{\"a}hrungsmustern und Diabetes mellitus Typ 2 zusammenfassten, waren entweder beschr{\"a}nkt auf eine Mustermethode oder kombinierten die Muster verschiedener Methoden, ohne die Zusammensetzung der Ern{\"a}hrungsmuster zu ber{\"u}cksichtigen. Ziel: Das Ziel dieser Dissertation war eine umfassende Untersuchung der Assoziation von Ern{\"a}hrungsmustern mit Diabetes mellitus Typ 2. Das erste Teilprojekt zielte auf die Erstellung einer systematischen {\"U}bersichtsarbeit von prospektiven Studien ab, unter der Ber{\"u}cksichtigung der verschiedenen Methoden zur Herleitung von Ern{\"a}hrungsmustern in der meta-analytischen Zusammenfassung, was in vorangegangen {\"U}bersichtsarbeiten eine Limitation darstellte. Das zweite Teilprojekt hatte die Untersuchung der Assoziation mit Diabetes mellitus Typ 2 von exploratorischen Ern{\"a}hrungsmustern, welche mit der Hauptkomponentenanalyse in einer multi-zentrischen europ{\"a}ischen Fall-Kohorten Studie hergeleitet wurden, zum Ziel. Des Weiteren wurde der eingeschr{\"a}nkten Anwendbarkeit von exploratorischen Mustern in anderen Studienpopulationen mit Methoden der Replikation dieser Ern{\"a}hrungsmuster begegnet. Methoden: Im ersten Teilprojekt wurde eine systematische Literatursuche in den Datenbanken MEDLINE und Web of Science vorgenommen, sowie ein dreistufiger Screeningprozess. Die identifizierten Studien wurden nach den jeweiligen Methoden zur Erstellung von Ern{\"a}hrungsmustern zusammengefasst und Meta-Analysen nur f{\"u}r diejenigen Ern{\"a}hrungsmuster mit vergleichbarer Zusammensetzung vorgenommen. Im zweiten Teilprojekt wurden l{\"a}nderspezifische Ern{\"a}hrungsmuster mittels Hauptkomponentenanalyse aus 36 standardisierten Lebensmittelgruppen hergeleitet. Die Assoziation mit Diabetes mellitus Typ 2 Risiko wurde mit verschieden adjustierten Cox Regressionsmodellen zur Berechnung von Hazardratenverh{\"a}ltnissen untersucht. Die Ern{\"a}hrungsmuster, welche eine signifikante Assoziation mit dem Diabetesrisiko aufzeigten, wurden anschließend {\"u}ber alle L{\"a}nder in der EPIC-InterAct Studie repliziert: Entweder wurden Summenscores ungewichteter standardisierter Lebensmittelgruppen berechnet (wenn die Korrelation mit dem originalen Ern{\"a}hrungsmuster r ≥ 0.90 war) oder Summenscores der Produkte von standardisierten Scoringkoeffizienten mit standardisierten Lebensmittelgruppen (wenn die Korrelation mit dem originalen Ern{\"a}hrungsmuster r < 0.90). Die resultierenden Scores wurden standardisiert nach der Verteilung der gesamten EPIC-InterAct Subkohorte, dann in jedem Land angewendet und die Assoziation mit Diabetes mellitus Typ 2 anhand der Cox Regressionsmodelle berechnet. Anschließend wurden Meta-Analysen zur Berechnung der gepoolten Sch{\"a}tzer durchgef{\"u}hrt. Ergebnisse: Im ersten Teilprojekt ergab die Literatursuche 48 Artikel, welche 16 Kohorten umfassten. Die Einhaltung der Mediterranen Di{\"a}t (relatives Risiko (RR) f{\"u}r den Vergleich der extremen Quantile: 0,87; 95\%-Konfidenzintervall (KI): 0,82, 0,93), der DASH Di{\"a}t (RR: 0,81; 95\%-KI: 0,72, 0,92) und des Alternative Healthy Eating Index (AHEI) (RR: 0,79; 95\%-KI: 0,69, 0,90) war mit einer signifikanten Reduzierung des Diabetesrisikos assoziiert. Exploratorische Ern{\"a}hrungsmuster, charakterisiert durch rotes und verarbeitetes Fleisch, prozessiertes Getreide, hochfette Milchprodukte, Eier und frittierte Produkte, waren positiv mit dem Diabetesrisiko assoziiert (RR: 1,44; 95\%-KI: 1,27, 1,62), w{\"a}hrend Ern{\"a}hrungs-muster, charakterisiert durch Gem{\"u}se, H{\"u}lsenfr{\"u}chte, Obst, Gefl{\"u}gel und Fisch, invers mit dem Diabetesrisiko assoziiert waren (RR: 0,84; 95\%-KI: 0,77, 0,91). Ern{\"a}hrungsmuster, welche mit reduzierter Rangregression hergeleitet wurden und charakterisiert waren durch eine hohe Aufnahme von prozessiertem Getreide, zuckerges{\"u}ßten Getr{\"a}nken und verarbeitetem Fleisch und einen niedrigen Weinkonsum, waren alle signifikant mit dem Diabetesrisiko assoziiert. Im zweiten Teilprojekt konnten zwei wesentliche Ern{\"a}hrungsmuster in jedem Land mit der Hauptkomponentenanalyse hergeleitet werden. Ein Ern{\"a}hrungsmuster, welches in Frankreich hergeleitet wurde und charakterisiert war durch N{\"u}sse, andere Fr{\"u}chte, verarbeitetes Fleisch, Fisch, Eier, Kuchen und Kekse, Kaffee und andere alkoholische Getr{\"a}nke, war signifikant assoziiert mit einem erniedrigten Diabetesrisiko. Drei andere Ern{\"a}hrungsmuster, hergeleitet in Spanien, Norfolk und Oxford, welche sich erheblich in ihrer Zusammensetzung unterschieden, waren mit einem erh{\"o}hten Diabetesrisiko assoziiert. Keine der Replikationen dieser vier Ern{\"a}hrungsmuster konnte die signifikante Assoziation mit Diabetes mellitus Typ 2 {\"u}ber andere L{\"a}nder best{\"a}tigen. Schlussfolgerung: Aus der systematischen {\"U}bersichtsarbeit ließ sich schlussfolgern, dass Ern{\"a}hrungsweisen gem{\"a}ß der Mediterranen Di{\"a}t, DASH und AHEI ein starkes Potenzial zur Pr{\"a}vention von Diabetes mellitus Typ 2 zu haben, obwohl sie sich in einigen Komponenten unterscheiden. Exploratorische Ern{\"a}hrungsmuster wurden basierend auf konkordanten Lebensmitteln gruppiert und waren signifikant mit dem Diabetesrisiko assoziiert, auch wenn die Untersuchungen einzelner Lebensmittel eher begrenzte Evidenz f{\"u}r einen Zusammenhang aufwiesen. Trotzdem bleiben sie populationsspezifische Beobachtungen. Das wurde auch in dem zweiten Teilprojekt unterstrichen, als l{\"a}nderspezifische Ern{\"a}hrungsmuster generiert wurden und keines der Ern{\"a}hrungsmuster, welches signifikant mit dem Diabetesrisiko assoziiert war, durch Simplifizierung oder Replikation der Musterstruktur des Originalmusters {\"u}ber alle L{\"a}nder best{\"a}tigt werden konnte. F{\"u}r drei RRR-Muster konnten konsistente positive Assoziationen mit dem Diabetesrisiko {\"u}ber verschiedene Studienpopulationen beobachtet werden.}, language = {en} } @phdthesis{Graja2017, author = {Graja, Antonia}, title = {Aging-related changes of progenitor cell function and microenvironment impair brown adipose tissue regeneration}, school = {Universit{\"a}t Potsdam}, pages = {152}, year = {2017}, language = {en} } @phdthesis{Weitkunat2017, author = {Weitkunat, Karolin}, title = {Dietary fibers and short-chain fatty acids in the development of diet-induced obesity}, school = {Universit{\"a}t Potsdam}, pages = {121}, year = {2017}, language = {en} } @phdthesis{Stadion2017, author = {Stadion, Mandy}, title = {Validation and Characterization of lfi202b and Zfp69, two Novel Disease Genes in Obesity-Associated Insulin Resistance}, school = {Universit{\"a}t Potsdam}, pages = {158}, year = {2017}, language = {en} } @phdthesis{Koenig2017, author = {K{\"o}nig, Jeannette}, title = {Lipofuscin - Entstehung und Rolle in der Zellalterung}, school = {Universit{\"a}t Potsdam}, pages = {115}, year = {2017}, language = {de} } @phdthesis{Neuber2017, author = {Neuber, Corinna}, title = {Analytik zur Biotransformation des Sphingosin 1-phosphat-abbauproduktes (2E)-Hexadecenal}, school = {Universit{\"a}t Potsdam}, pages = {161}, year = {2017}, language = {de} } @phdthesis{Roediger2017, author = {R{\"o}diger, Maria}, title = {The Impact of the ARFRP1 Action at the Golgi Apparatus on Adipocyte Function}, school = {Universit{\"a}t Potsdam}, pages = {116}, year = {2017}, language = {en} } @phdthesis{Ott2016, author = {Ott, Christiane}, title = {Untersuchung der intrazellul{\"a}ren Proteolyse w{\"a}hrend der Zellalterung}, school = {Universit{\"a}t Potsdam}, pages = {100}, year = {2016}, language = {de} } @phdthesis{Nowotny2016, author = {Nowotny, Kerstin}, title = {The impact of collagen modifications by methylglyoxal on fibroblast function and the role in aging}, school = {Universit{\"a}t Potsdam}, pages = {107}, year = {2016}, language = {de} } @phdthesis{Trenkmann2017, author = {Trenkmann, Tom}, title = {Bedeutung von Sphingosin-1-Phosphat in der Pathogenese des Morbus Crohn und Entwicklung und Charakterisierung eines murinen Colitis-Modells}, school = {Universit{\"a}t Potsdam}, pages = {165}, year = {2017}, language = {de} } @phdthesis{Marschall2017, author = {Marschall, Talke Anu}, title = {Zytotoxizit{\"a}t, Bioverf{\"u}gbarkeit und Metabolismus kleiner Selenspezies in humanen Zellen und Entwicklung von ICP-QQQ-MS-basierten Methoden f{\"u}r deren Nachweis}, school = {Universit{\"a}t Potsdam}, pages = {115, VI}, year = {2017}, language = {de} } @phdthesis{Reeg2016, author = {Reeg, Sandra}, title = {Degradation of oxidized proteins by the proteasome - Involvement of chaperones and the ubiquitin-system}, school = {Universit{\"a}t Potsdam}, pages = {117}, year = {2016}, language = {en} } @phdthesis{Meyer2015, author = {Meyer, S{\"o}ren}, title = {Toxicity and toxicokinetics of arsenolipids and their metabolites}, school = {Universit{\"a}t Potsdam}, pages = {152, VIII}, year = {2015}, language = {en} } @phdthesis{Reinke2016, author = {Reinke, Julia}, title = {The Role of Kallistatin in Energy Metabolism and Glucose Homeostasis in Mice}, school = {Universit{\"a}t Potsdam}, pages = {77}, year = {2016}, language = {en} } @phdthesis{Luckert2016, author = {Luckert, Claudia}, title = {Molekulare Mechanismen von hepatotoxischen Pyrrolizidinalkaloiden}, school = {Universit{\"a}t Potsdam}, pages = {127, LXXVII}, year = {2016}, language = {de} } @phdthesis{Jaeger2016, author = {J{\"a}ger, Susanne}, title = {Genetic variants and metabolic pathways of type 2 diabetes within the EPIC-Potsdam study}, school = {Universit{\"a}t Potsdam}, pages = {139, XXVII}, year = {2016}, language = {en} } @phdthesis{Hallahan2016, author = {Hallahan, Nicole}, title = {Identification and characterization of a T2D QTL arising from an NZO.DBA mouse cross}, school = {Universit{\"a}t Potsdam}, pages = {133}, year = {2016}, language = {en} } @phdthesis{Ambrosi2016, author = {Ambrosi, Thomas H.}, title = {The Role of Bone-residing Adipocyte Progenitors in Age-related Stem Cell Dysfunction and Regenerative Processes}, school = {Universit{\"a}t Potsdam}, pages = {132}, year = {2016}, language = {en} } @phdthesis{Huettl2014, author = {H{\"u}ttl, Christine}, title = {Synthese und Charakterisierung von multivalenten peptidbasierten Liganden als biomolekulare Erkennunngseinheit f{\"u}r Influenzaviren}, address = {Potsdam}, pages = {139 S.}, year = {2014}, language = {de} } @phdthesis{Benz2014, author = {Benz, Verena}, title = {Sex-specific differences in the regulation of body weight dynamics and adipose tissue metabolism}, address = {Potsdam}, pages = {119 S.}, year = {2014}, language = {en} } @phdthesis{Doecke2013, author = {D{\"o}cke, Stephanie}, title = {Untersuchung von ausgew{\"a}hlten pathogenetischen Signalwegen der humanen nicht-alkoholischen Fettlebererkrankung}, address = {Potsdam}, pages = {113 S.}, year = {2013}, language = {de} } @phdthesis{Seltmann2013, author = {Seltmann, Anne-Cathrin}, title = {Nutrigenetik der metabolischen Adaptation an eine isokalorische Hochfettdi{\"a}t bei gesunden Zwillingen}, address = {Potsdam}, pages = {157 S.}, year = {2013}, language = {de} } @phdthesis{Gerecke2013, author = {Gerecke, Christian}, title = {Entwicklung eines hochsensitiven Verfahrens zur Detektion von Mutationen im Tumorsuppressor APC und Analyse des Methylierungsstatus der Genpromotoren von ITGA4, TFPI2 und Vimentin in humanen Kolongeweben und F{\"a}zes}, address = {Potsdam}, pages = {147 S.}, year = {2013}, language = {de} } @phdthesis{Muehlenbruch2013, author = {M{\"u}hlenbruch, Kristin}, title = {Updating the german diabetes risk score - model extensions, validation and reclassification}, address = {Potsdam}, pages = {131 S.}, year = {2013}, language = {en} } @phdthesis{Barknowitz2013, author = {Barknowitz, Gitte}, title = {Serumalbumin- und H{\"a}moglobin-Addukte als Biomarker der Exposition gegen{\"u}ber Mutagenen Metaboliten von 1-Methoxy-Indolylmethyl-Glucosinolat-Untersuchungen in Maus und Menschen}, address = {Potsdam}, pages = {118 S.}, year = {2013}, language = {de} } @phdthesis{Lehmann2013, author = {Lehmann, Carsten}, title = {Glucosinolate in der entz{\"u}ndungsgetriebenen Kolonkanzerogenese - Induktion von Phase I und Phase II Enzymen sowie der Einfluss der intestinalen Mikrobiota}, address = {Potsdam}, pages = {117 S.}, year = {2013}, language = {de} } @phdthesis{Lippmann2013, author = {Lippmann, Doris}, title = {Der Einfluss glucosinolatreicher Brassica Gem{\"u}se auf das endogene Schutzsystem und die entz{\"u}ndungsassoziierte Colonkanzerogenese in der Maus}, address = {Potsdam}, pages = {105 S.}, year = {2013}, language = {de} } @phdthesis{Khalil2013, author = {Khalil, Mahmoud Abd Elhamid}, title = {Improvement of stability and bioavailability of lutein and lutein ester in emulsion-based delivery systems}, address = {Potsdam}, pages = {145 S.}, year = {2013}, language = {en} } @phdthesis{Monien2012, author = {Monien, Bernhard}, title = {LC-MS/MS-Methoden zur Untersuchung von Bildung, Transport und Gentoxizit{\"a}t reaktiver Sulfatester einiger Lebensmittelkanzerogene}, address = {Potsdam}, pages = {119 S.}, year = {2012}, language = {de} } @phdthesis{Ott2013, author = {Ott, Ina Mirijam}, title = {Alternative Therapieans{\"a}tze im murinen Modell der diabetischen Nephropathie : Stimulation der l{\"o}slichen Guanylatzyklase und Inhabition der Dipeptidylpeptidase-4}, address = {Potsdam}, pages = {116 S.}, year = {2013}, language = {de} } @phdthesis{Behrens2011, author = {Behrens, Maik}, title = {Molekularbiologie menschlicher Bittergeschmacksrezeptoren}, address = {Potsdam}, year = {2011}, language = {de} } @phdthesis{Matthies2012, author = {Matthies, Anastasia}, title = {Die Rolle der Darmbakterien bei der Bioaktivierung von Isoflavonen}, address = {Potsdam}, pages = {121 S.}, year = {2012}, language = {de} } @phdthesis{Herbst2012, author = {Herbst, Uta}, title = {Untersuchungen zur In-vitro-Zelltransformation in Dickdarmepithelzellen des Menschen und D{\"u}nndarmephithelzellen der Ratte durch Benzo(c)phenanthren-3,4-dihydrodiol-1,2-epoxide}, address = {Potsdam}, pages = {105 S.}, year = {2012}, language = {de} } @phdthesis{Dokas2012, author = {Dokas, Janine}, title = {Untersuchung zur Rolle von Tbc1d1 im Stoffwechsel anhand von Mausmodellen}, address = {Potsdam}, pages = {127 S.}, year = {2012}, language = {de} } @phdthesis{Freudenberg2011, author = {Freudenberg, Anne}, title = {Effects of high-protein diets and leucine supplementation on the metabolic syndrome in mice}, address = {Potsdam}, pages = {80 S.}, year = {2011}, language = {en} } @phdthesis{Schulz2011, author = {Schulz, Nadja}, title = {Die Rolle der 3-L-Hydroxyacyl-Coenzym-A-Dehydrogenase in der Regulation des {\"o}rpergewichts, der Thermogenese sowie der Glucosehom{\"o}ostase}, address = {Potsdam}, pages = {92 S.}, year = {2011}, language = {de} } @phdthesis{Mirhashemi2011, author = {Mirhashemi, Farshad}, title = {Einfluss von Fetten und Kohlenhydraten auf die Entwicklung der Insulinresistenz und des Typ-2-Diabetes in verschiedenen Mausmodellen}, address = {Potsdam}, pages = {122 S.}, year = {2011}, language = {de} } @phdthesis{Keipert2011, author = {Keipert, Susanne}, title = {The effects of mitochondrial uncoupling in skeletal muscle on lifespan, substrate and energy metabolism in mice}, address = {Potsdam}, pages = {75 S.}, year = {2011}, language = {en} } @phdthesis{Flehmig2011, author = {Flehmig, Karin Gesine}, title = {Evaluation des BCM-Programms der PreCon GmbH \& Co. nach MIRA-Konzept}, address = {Potsdam}, pages = {118, XXVII S.}, year = {2011}, language = {de} } @phdthesis{Schueler2011, author = {Sch{\"u}ler, Rita}, title = {Identifizierung und Charakterisierung neuer nat{\"u}rlicher Liganden des Peroxisomen-Proliferator aktivierten Rezeptors y (PPARy)}, address = {Potsdam}, pages = {165 S.}, year = {2011}, language = {de} } @phdthesis{Kutschera2010, author = {Kutschera, Maren}, title = {Interaktionen von Flavanolen mit der humanen intestinalen Mikrobiota}, address = {Potsdam}, pages = {X, 113 S.}, year = {2010}, language = {de} } @phdthesis{Gerber2010, author = {Gerber, Chimgee Baasanjav}, title = {Detection and identification of genotoxicant from brassica plants}, address = {Potsdam}, pages = {191 S.}, year = {2010}, language = {en} } @phdthesis{Fleissner2011, author = {Fleißner, Christine}, title = {Einfluss der gastrointestinalen Mikrobiota auf den Energiestoffwechsel und die Entstehung von Adipositas im Mausmodell}, address = {Potsdam}, pages = {117 S.}, year = {2011}, language = {de} } @phdthesis{Becker2011, author = {Becker, Natalie}, title = {Etablierung des Modells einer simplifizierten humanen Darmmikrobiota in gnotobiotischen Ratten und Anwendung der definierten Mikrobiota im chemischen induzierten Kolonkanzerogenesemodell}, address = {Potsdam}, pages = {92 S.}, year = {2011}, language = {de} } @phdthesis{Henkel2010, author = {Henkel, Janin}, title = {Modulation der Insulin-abh{\"a}ngigen Regulation des hepatischen Glucose- und Lipidmetabolismus durch Prostaglandin E2}, address = {Potsdam}, pages = {213 S.}, year = {2010}, language = {de} } @phdthesis{Hesse2010, author = {Hesse, Deike}, title = {Die Rolle des trans-Goli-Proteins ARFRP1 f{\"u}r den Glucose- und Lipidmetabolismus in der Leber und im Fettgewebe der Maus}, address = {Potsdam}, pages = {113 S.}, year = {2010}, language = {de} } @phdthesis{Blum2010, author = {Blum, Claudia}, title = {Biosynthese und Zielsteuerung von TAS2R-Bitterrezeptoren}, address = {Potsdam}, pages = {106 S.}, year = {2010}, language = {de} } @phdthesis{Wiese2010, author = {Wiese, Stefanie}, title = {Biokinetik und biologische Aktivit{\"a}t von Flavan-3-olen}, pages = {IX, 190, XXI S. : graph. Darst.}, year = {2010}, language = {de} } @phdthesis{John2010, author = {John, Andrea}, title = {Biomarker lebensmittel- und umweltrelevanter Xenobiotika : Analytik von Glutathionkonjugaten und Mercapturs{\"a}uren}, publisher = {Cuvillier}, address = {G{\"o}ttingen}, pages = {VI, 163 S. : graph. Darst.}, year = {2010}, language = {de} } @phdthesis{Wohlgemuth2010, author = {Wohlgemuth, Steffen}, title = {Microbial and host factors associated with chronic intestinal inflammation of the Interleukin-10 deficient mouse}, address = {Potsdam}, pages = {IX, 125 Bl. : Ill., graph. Darst.}, year = {2010}, language = {en} } @phdthesis{Kucia2009, author = {Kucia, Marzena}, title = {Impact of a high protein diet on maternal health status, milk composition and rearing success during pregnancy and lactation of two mouse genotypes}, address = {Potsdam}, pages = {X, 109 Bl. : graph. Darst.}, year = {2009}, language = {en} } @phdthesis{Mueller2009, author = {M{\"u}ller, Carsten}, title = {Nachweis antioxidativer und chemopr{\"a}ventiver Eigenschaften von Naturstoffen zur Verwendung als potenzielle Nahrungserg{\"a}nzungsmittel}, address = {Potsdam}, pages = {139 Bl. : graph. Darst.}, year = {2009}, language = {de} } @phdthesis{Hessel2009, author = {Hessel, Stefanie}, title = {Mechanismen zur Detoxifizierung von Benzo[a]pyren-Metaboliten in der gastrointestinalen Barriere}, address = {Potsdam}, pages = {VI, 124, XXXI S. : zahlr. graph. Darst.}, year = {2009}, language = {de} } @phdthesis{Hanisch2009, author = {Hanisch, Christiana}, title = {Die Wirkung eines Symbiotikums auf die Zusammensetzung der intestinalen Mikrobiota, die f{\"a}kale Exkretion von kurzkettigen Fetts{\"a}uren sowie ausgew{\"a}hlte Parameter der Darmfunktion bei {\"u}ber 65-j{\"a}hrigen Frauen und M{\"a}nnern}, pages = {VI, 160 S. : graph. Darst.}, year = {2009}, language = {de} }