1,118 research outputs found
Indoleamine-2,3-dioxygenase (IDO) metabolic activity is detrimental for cervical cancer patient survival
No full textThe expression of the immunomodulating enzyme indoleamine-2,3-dioxygenase (IDO) suppresses T-lymphocyte function, thus correlating with poor survival in a variety of cancer patients. IDO degrades the essential amino acid tryptophan leading to immunosuppressive kynurenines production. In the present study, concentrations of tryptophan, 3-hydroxykynurenine, and kynurenine were measured in pre-treatment serum samples of 251 cervical cancer patients by a mass-spectrometric method (XLC-MS/MS) and IDO activity determined by the kynurenine/tryptophan (Kyn/Trp) ratio. A low concentration of tryptophan was found to be significantly associated with tumors greater than 4 cm and lymph node metastatic spread. Furthermore, significant positive correlations were found between high concentrations of the tryptophan metabolites kynurenine and 3-hydroxykynurenine and advanced disease stage (FIGO > IIA) and lymph node metastases. High levels of kynurenine were further associated with parametrial invasion and tumor size. A high Kyn/Trp ratio was related to lymph node metastasis, FIGO stage, tumor size, parametrial invasion and poor disease-specific survival. These results suggest that IDO activation is linked to poor clinicopathological parameters and worse survival in cervical cancer, warranting the use of IDO inhibitors in future clinical trials
Tryptophan metabolism in aging and disease: Insights from Caenorhabditis elegans
Get PDFVeroudering van de wereldpopulatie over de laatste jaren correleert met een toenemend aantal mensen met ouderdomsziekten. Tryptofaan metabolisme is betrokken bij meerdere ouderdomsaandoeningen zoals neurodegeneratie, kanker en diabetes type 2, wat het een kandidaat maakt voor therapeutische interventies. In model organismen voor kanker en neurodegeneratie zorgt de remming van het tryptofaan afbrekende enzym, tryptofaan- 2,3 dioxygenase (TDO), voor een verbeterde gezondheid en levensduur. Tryptofaan metabolieten spelen hierbij een rol, maar kunnen niet alle beschermende effecten verklaren. Dit proefschrift is gericht op het inzicht krijgen in hoe tryptofaan en zijn metabolisme het verouderingsproces beïnvloeden en hoe het werkt op de ontwikkeling van neurodegeneratieve aandoeningen. Bevindingen in dit proefschrift zijn gedaan met behulp van Caenorhabditis elegans, een model organisme die makkelijk genetisch is te manipuleren en waarin de levensduur snel te meten is. We identificeerden een nieuwe, niet tryptofaan metabolieten afhankelijke, functie van TDO: de regulatie van de energie metabolisme in de mitochondriën. Ook andere aminozuur deoxygenases lijken mitochondriële functies, gezondheid en levensduur, op een soortgelijke manier, te reguleren. De mitochondriën spelen een centrale rol in het verouderingsproces en hun ontregeling is vaak karakteristiek voor ouderdomsaandoeningen. Ook hebben we een evolutionair geconserveerde regio in het TDO eiwit ontdekt, die essentieel is voor zijn enzymfunctie en wat gebruikt zou kunnen worden als doel voor het ontwikkelen van nieuwe TDO remmers. Onze resultaten laten zien dat de remming van TDO of andere aminozuur deoxygenases verder onderzocht zou kunnen worden als therapeutische strategie om mitochondrieel metabolisme te beheersen, veroudering te vertragen en ouderdomsaandoeningen te verbeteren
Improving quantification and identification in metabolomics
Get PDFChapter 1 introduces and discusses metabolomics and related analytical techniques such as NMR, direct infusion-MS, GC-MS, and LC-MS. Next LC-MS-based untargeted metabolomics, including metabolite sample collection and preparation and untargeted LC-MS analysis platforms, are discussed. Chapter 2 apply the dynamic mass error theory to improve the quantification of metabolites. The aim of this project is the implementation of the dynamic binning algorithm, which considers the exact width broadening of a peak in mass spectra to construct extracted ion chromatograms (EICs), and which provides more accurate quantification than using EIC constructed with linear or constant thresholds implemented in the most widely used metabolomics software, XCMS. Chapter 3 describes applying dynamic thresholds to improve untargeted metabolite identification and includes the PEP score and q-value calculation to provide an estimated ensemble and individual error for untargeted metabolomics identification. Chapter 4 includes lipid identification and quantification. The transcriptomic data show that Vitamin B12, cofactor biosynthesis pathways, and ribosomal proteins are activated upon CP treatment. Especially the genes related to phospholipid biosynthesis and fatty acid are differentially expressed. These changes upon CP were further affirmed by the cell membrane’s composition change of fatty acids and phospholipids, as shown by both phospholipid composition and the membrane fluidity measurements. The growth inhibition of F. prausnitzii upon CP exposure can be explained by the cell membrane lipid composition and fluidity changes. Chapter 5 describes an R package with a graphic user interface, which enables untargeted metabolomics data pre-processing and analysis without programming skills
Towards personalized cardiovascular risk management in renal transplant recipients
Get PDFHart- en vaatziekten (HVZ) vormen de nummer één doodsoorzaak bij niertransplantatiepatiënten. Het risico op overlijden aan HVZ in niertransplantatiepatiënten is derhalve vele malen groter dan in de algemene populatie. Dit komt door een optelsom van algemene risicofactoren voor HVZ die ook in de algemene populatie voorkomen (zoals hoge bloeddruk, overgewicht en suikerziekte) én transplantatie-specifieke risicofactoren (zoals slechtere nierfunctie en gebruik van medicijnen tegen afstoting zoals prednisolon). In dit proefschrift onderzochten we mogelijke manieren om het risico op HVZ bij niertransplantatiepatiënten te verlagen en de behandeling aan te passen aan de individuele patiënt. Hoge bloeddruk is de meest voorkomende risicofactor op HVZ bij niertransplantatiepatiënten. We vonden (met een gerandomiseerde cross-over studie) dat een zoutbeperkt dieet de bloeddruk bij niertransplantatiepatiënten aanzienlijk doet dalen, zonder dat het nadelige effecten heeft op de nierfunctie. Daarnaast keken we naar de behandeling met prednisolon. Langdurige behandeling met prednisolon kent vele bijwerkingen (zoals hoge bloeddruk, suikerziekte en botontkalking). Prednisolon lijkt erg op ons lichaamseigen stress-hormoon cortisol en beïnvloedt daarom de aanmaak en omzetting van dit hormoon. We vonden dat de mate waarin prednisolon de aanmaak en omzetting van cortisol beïnvloedt, gerelateerd is aan het aantal bijwerkingen van prednisolon, het optreden van het metabool syndroom en op overlijden aan HVZ op de lange termijn. Behandeling met een zoutbeperkt dieet en het monitoren van de behandeling met prednisolon (door middel van het meten van lichaamseigen cortisol) zouden in de toekomst dus manieren kunnen zijn om het risico op HVZ bij niertransplantatiepatiënten te verlagen
Clinical chemistry of serotonin and catecholamines. Contributions to carcinoid tumours, phaeochromocytoma and Parkinson's disease
Get PDFThe scope of the thesis was to further develop assays of serotonin, catecholamines and their metabolites, and to investigate their usefulness in diagnosis and follow-up of patients with carcinoid tumours, further elucidation of catecholamine metabolism, and experimental therapies of Parkinson's disease. ...
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Diet-sensitive prognostic markers for cardiovascular and renal disease
Get PDFDiet plays a relevant role in the development and progression of lifestyle-related diseases like hypertension and type 2 diabetes and the subsequent risk of cardiovascular and renal disease. Riphagen used several diet-sensitive biomarkers to further explore the effects of diet on cardiovascular and renal health. Lifestyle measures including dietary sodium restriction and increased potassium intake are recognized to lower blood pressure. Increased potassium intake during sodium restriction, however, was found to have little effect on blood pressure. Riphagen investigated the effects of potassium supplementation on blood pressure and fluid balance in 35 (pre)hypertensive subjects during a fully controlled sodium-restricted diet using a panel of biomarkers. Potassium supplementation was found to have a relatively small blood pressure-lowering effect during sodium restriction. The blood pressure-lowering effects seemed mitigated by activation of several counter regulatory mechanisms involved in regulation of fluid balance and blood pressure (i.e., vasopressin, the renin-angiotensin-aldosterone system [RAAS], and heart rate). Vascular calcification is also an important risk factor for cardiovascular disease. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification. During vitamin K insufficiency, MGP is inactive. Riphagen investigated the prevalence of vitamin K insufficiency and its health consequences through measurement of inactive MGP in a general population-based cohort. Vitamin K insufficiency was found to be a common phenomenon especially among elderly and subjects with chronic diseases and was associated with an increased (cardiovascular) mortality risk. Diet-sensitive biomarkers are a useful tool to further explore the effects of diet on cardiovascular and renal health
Correlations between IDO enzymatic activity and levels of inflammatory soluble factors implicated in IDO induction.
No full text<p>Associations between IDO activity (Kyn/Trp ratio) and plasmatic levels of (<b>A</b>) IL-1β (<b>B</b>) IFNγ (<b>C</b>) sCD40L (<b>D</b>) TNF-α and (<b>E</b>) IL-6 in ST: ART-successfully treated, ART-naïve, EC: elite controllers, and HS: healthy subjects. n=14 per study group. Pearson rank correlation was used for statistical analysis.</p
The protective effect of 1-methyltryptophan isomers in renal ischemia-reperfusion injury is not exclusively dependent on indolamine 2,3-dioxygenase inhibition
Get PDFBACKGROUND AND PURPOSE: Indolamine 2,3-dioxygenase (IDO), an enzyme that catalyses the metabolism of tryptophan, may play a detrimental role in ischemia-reperfusion injury (IRI). IDO can be inhibited by 1-methyl-tryptophan, which exists in a D (D-MT) or L (L-MT) isomer. These forms show different pharmacological effects besides IDO inhibition. Therefore, we sought to investigate whether these isomers can play a protective role in renal IRI, either IDO-dependent or independent.EXPERIMENTAL APPROACH: We studied the effect of both isomers in a rat renal IRI model with a focus on IDO-dependent and independent effects.KEY RESULTS: Both MT isomers reduced creatinine and BUN levels, with D-MT having a faster onset of action but shorter duration and L-MT a slower onset but longer duration (24 h and 48 h vs 48 h and 96 h reperfusion time). Interestingly, this effect was not exclusively dependent on IDO inhibition, but rather from decreased TLR4 signalling, mimicking changes in renal function. Additionally, L-MT increased the overall survival of rats. Moreover, both MT isomers interfered with TGF-β signalling and epithelial-mesenchymal transition. In order to study the effect of isomers in all mechanisms involved in IRI, a series of in vitro experiments was performed. The isomers affected signalling pathways in NK cells and tubular epithelial cells, as well as in dendritic cells and T cells.CONCLUSION AND IMPLICATIONS: This study shows that both MT isomers have a renoprotective effect after ischemia-reperfusion injury, mostly independent of IDO inhibition, involving mutually different mechanisms. We bring novel findings in the pharmacological properties and mechanism of action of MT isomers, which could become a novel therapeutic target of renal IRI.</p
Exercise Enhances Whole-Body Cholesterol Turnover in Mice
No full textMEISSNER, M., R. HAVINGA, R. BOVERHOF, I. KEMA, A. K. GROEN, and F. KUIPERS. Exercise Enhances Whole-Body Cholesterol Turnover in Mice. Med. Sci. Sports Exerc., Vol. 42, No. 8, pp. 1460-1468, 2010. Purpose: Regular exercise reduces cardiovascular risk in humans by reducing cholesterol levels, but the underlying mechanisms have not been fully explored. Exercise might provoke changes in cholesterol and bile acid metabolism and thereby reduce cardiovascular risk. We examined whether voluntary wheel running in mice modulates cholesterol and bile acid metabolism. Methods: Male mice (10 wk old) were randomly assigned to have access to a voluntary running wheel for 2 wk (RUN group) or remained sedentary (SED group). Running wheel activity was recorded daily. In a first experiment, fecal sterol outputs, fecal bile acid profiles, plasma parameters, and expression levels of genes involved in cholesterol and bile acid metabolism were determined. In a second experiment, bile flow, biliary bile acid profile, and biliary secretion rates of cholesterol, phospholipids, and bile acids were determined. Results: The RUN group ran an average of 10 km.d(-1) and displayed lower plasma cholesterol compared with SED (P = 0.030). Fecal bile acid loss was induced by similar to 30% in running mice compared with SED (P = 0.0012). A similar to 30% increase in fecal cholesterol output in RUN (P = 0.014) was consistent with changes in parameters of cholesterol absorption, such as reduced plasma plant sterol-cholesterol ratio (P = 0.044) and decreased jejunal expression of Npc1l1 (P = 0.013). Supportive of an increased cholesterol synthesis to compensate for fecal sterol loss were increased hepatic mRNA levels of HMGCoA reductase (P = 0.006) and an increased plasma lathosterol-cholesterol ratio (P = 0.0011) in RUN. Conclusions: Voluntary wheel running increased cholesterol turnover in healthy mice owing to an increased fecal bile acid excretion and a decreased intestinal cholesterol absorption. Enhanced cholesterol turnover may contribute to the established reduction of cardiovascular risk induced by regular exercise
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