Atherosclerotic cardiovascular disease is a metabolic and inflammatory disorder. In vitro studies have suggested that protein arginine methyltransferase 4 (PRMT4) may act as a transcriptional... Show moreAtherosclerotic cardiovascular disease is a metabolic and inflammatory disorder. In vitro studies have suggested that protein arginine methyltransferase 4 (PRMT4) may act as a transcriptional coactivator to modulate inflammatory and metabolic processes. Here we investigated the potential anti-atherogenic effect of PRMT4 inhibitor TP-064 in vivo.\nMale apolipoprotein E knockout mice fed a high cholesterol/high fat Western-type diet were intraperitoneally injected three times a week with 2.5 mg/kg (low dose) or 10 mg/kg (high dose) TP-064 or with DMSO control.\nTP-064 induced a dose-dependent decrease in lipopolysaccharide-induced ex vivo blood monocyte Tnfα secretion (p < 0.05 for trend) in the context of unchanged blood monocyte concentrations and neutrophilia induction (p < 0.01 for trend). A dose-dependent decrease in gonadal white adipose tissue expression levels of PPARγ target genes was detected, which translated into a reduced body weight gain after high dose TP-064 treatment (p < 0.05). TP-064 treatment also dose-dependently downregulated gene expression of the glycogen metabolism related protein G6pc in the liver (p < 0.001 for trend). In addition, a trend towards lower plasma insulin and higher blood glucose levels was observed, which was paralleled by a reduction in hepatic mRNA expression levels of the insulin-responsive genes Fasn (-55%; p < 0.001) and Gck (-47%; p < 0.001) in high dose-treated mice. Plasma triglyceride levels were reduced by high dose TP-064 treatment (-30%; p < 0.05). However, no change was observed in the size or composition of aortic root atherosclerotic lesions.\nThe PRMT4 inhibitor TP-064 impacts both inflammatory and metabolic processes without changing atherosclerosis susceptibility of male apolipoprotein E knockout mice. Show less
The research described in this thesis combines the latest insights in lysosomal function with lysosome centred cell signalling. Novel imaging and labelling techniques are applied to provide in... Show moreThe research described in this thesis combines the latest insights in lysosomal function with lysosome centred cell signalling. Novel imaging and labelling techniques are applied to provide in depth characterization of lysosome function in health and disease. An integrative approach was used to study the physiological role of the lysosome, characterizing the function of lysosomal hydrolases and signalling on a cellular level as well as within the context of tissue. Show less
Hoekstra, M.; Ouweneel, A.B.; Price, J.; Geest, R. van der; Sluis, R.J. van der; Geerling, J.J.; ... ; Eck, M. van 2020
Scavenger receptor BI (SR-BI) has been suggested to modulate adipocyte function. To uncover the potential relevance of SR-BI for the development of obesity and associated metabolic complications,... Show moreScavenger receptor BI (SR-BI) has been suggested to modulate adipocyte function. To uncover the potential relevance of SR-BI for the development of obesity and associated metabolic complications, we compared the metabolic phenotype of wild-type and SR-BI deficient mice fed an obesogenic diet enriched in fat. Both male and female SR-BI knockout mice gained significantly more weight as compared to their wild-type counterparts in response to 12 weeks high fat diet feeding (1.5-fold; P < .01 for genotype). Plasma free cholesterol levels were ~2-fold higher (P < .001) in SR-BI knockout mice of both genders, whilst plasma cholesteryl ester and triglyceride concentrations were only significantly elevated in males. Strikingly, the exacerbated obesity in SR-BI knockout mice was paralleled by a better glucose handling. In contrast, only SR-BI knockout mice developed atherosclerotic lesions in the aortic root, with a higher predisposition in females. Biochemical and histological studies in male mice revealed that SR-BI deficiency was associated with a reduced hepatic steatosis degree as evident from the 29% lower (P < .05) liver triglyceride levels. Relative mRNA expression levels of the glucose uptake transporter GLUT4 were increased (+47%; P < .05), whilst expression levels of the metabolic PPARgamma target genes CD36, HSL, ADIPOQ and ATGL were reduced 39%-58% (P < .01) in the context of unchanged PPARgamma expression levels in SR-BI knockout gonadal white adipose tissue. In conclusion, we have shown that SR-BI deficiency is associated with a decrease in adipocyte PPARgamma activity and a concomitant uncoupling of obesity development from hepatic steatosis and glucose intolerance development in high fat diet-fed mice. Show less
Hoekstra, M.; Sluis, R.J. van der; Hildebrand, R.B.; Lammers, B.; Zhao, Y.; Praticò, D.; ... ; Eck, M. van 2020
C]cholesteryl oleate after intravenous VLDL-like particle injection.\nWe have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in... Show moreC]cholesteryl oleate after intravenous VLDL-like particle injection.\nWe have shown that disruption of PLTP-mediated HDL maturation reduces SR-BI deficiency-driven atherosclerosis susceptibility in mice despite the induction of proatherogenic metabolic complications in the double knockout mice.\nOBJECTIVE\nCONCLUSIONS Show less
Childhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In... Show moreChildhood obesity is an increasing health issue. In the first part of this thesis comorbidities in children with obesity were studied, concerning the diagnostic process and dosing regimens. In children with obesity and respiratory symptoms the diagnosis of asthma was studied and in children with ADHD dosing regimens. Overtreatment as a consequence of overdiagnosis was frequently observed in children with obesity and asthma and undertreatment due to relative underdosing in the ADHD population with obesity. This highlights the necessity for accurate diagnostic processes alongside dosing regimens based on pharmacokinetic changes caused by obesity. The focus in the second part of this thesis was on screening for complications of obesity namely insulin resistance and cardiovascular diseases. Given the high prevalence of insulin resistance and the observed changes of cardiovascular parameters, screening on cardiometabolic complications is warranted in all children with obesity. Pharmacological treatment with metformin in addition to lifestyle intervention was studied in the last part of this thesis. Given the favorable effect on BMI in children and adults and the maintenance of weight loss and reduction in progression towards T2DM in adults, metformin can be considered in children with obesity and insulin resistance in addition to lifestyle intervention. Show less
Hassing, G.J.; Wall, H.E.C. van der; Westen, G.J.P. van; Kemme, M.J.B.; Adiyaman, A.; Elvan, A.; ... ; Gal, P. 2019
IntroductionAn increased body mass index (BMI) (>25 kg/m2) is associated with a wide range of electrocardiographic changes. However, the association between electrocardiographic changes and BMI in... Show moreIntroductionAn increased body mass index (BMI) (>25 kg/m2) is associated with a wide range of electrocardiographic changes. However, the association between electrocardiographic changes and BMI in healthy young individuals with a normal BMI (18.5–25 kg/m2) is unknown. The aim of this study was to evaluate the association between BMI and electrocardiographic parameters.MethodsData from 1,290 volunteers aged 18 to 30 years collected at our centre were analysed. Only subjects considered healthy by a physician after review of collected data with a normal BMI and in sinus rhythm were included in the analysis. Subjects with a normal BMI (18.5–25 kg/m2) were divided into BMI quartiles analysis and a backward multivariate regression analysis with a normal BMI as a continuous variable was performed.ResultsMean age was 22.7 ± 3.0 years, mean BMI was 22.0, and 73.4% were male. There were significant differences between the BMI quartiles in terms of maximum P-wave duration, P-wave balance, total P-wave area in lead V1, PR-interval duration, and heart axis. In the multivariate model maximum P-wave duration (standardised coefficient (SC) = +0.112, P < 0.001), P-wave balance in lead V1 (SC = +0.072, P < 0.001), heart axis (SC = −0.164, P < 0.001), and Sokolow-Lyon voltage (SC = −0.097, P < 0.001) were independently associated with BMI.ConclusionIncreased BMI was related with discrete electrocardiographic alterations including an increased P-wave duration, increased P-wave balance, a leftward shift of the heart axis, and decreased Sokolow-Lyon voltage on a standard twelve lead electrocardiogram in healthy young individuals with a normal BMI. Show less
Smit, C.; Hoogd, S. de; Bruggemann, R.J.M.; Knibbe, C.A.J. 2018
Cardiovascular disease is the number one cause of death worldwide. The most important risk factor for developing this disease is high cholesterol levels in the blood. Other risk factors... Show moreCardiovascular disease is the number one cause of death worldwide. The most important risk factor for developing this disease is high cholesterol levels in the blood. Other risk factors contributing to cardiovascular disease can develop in individuals which are overweight. The clinical consequences of being overweight are clustered in the medical term: metabolic syndrome. Included in the metabolic syndrome are high blood pressure, dyslipidemia and glucose intolerance. At present, most cardiovascular disease patients are treated with statins which lower blood cholesterol levels. However, this treatment is not as effective in all patients and can cause some adverse drug reactions. Therefore, it is essential that novel therapeutic targets for the treatment of cardiovascular disease are identified. In this thesis, potential novel therapeutic targets in cardiovascular disease and metabolic syndrome are validated. In total, three potential targets were investigated: proteoglycan 4, protein arginine methyltransferase 3 and stabilin 1. Our studies showed the involvement of two of these targets in the development of cardiovascular disease and metabolic syndrome. Moreover, our results stress (1) that cardiovascular disease and metabolic syndrome are complex, multifactorial diseases with overlapping mechanisms and (2) that integration of research into both diseases can benefit therapeutic target identification and validation. Show less
This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several... Show more This Thesis reports on the discovery and optimization of potent inhibitors for the serine hydrolases sn-1 diacylglycerol lipase α (DAGLα) and α/β hydrolase domain 16A (ABHD16A). Several structure- and ligand-based drug discovery methodologies were employed, such as in silico screening and high throughput screening, in combination with activity-based protein profiling (ABPP). The glycine sulfonamides reported in this Thesis, such as LEI106, are important peripherally restricted inhibitors that can be used to evaluate the contribution of perturbing DAGL activity in the potential treatment of metabolic syndrome, diabetes and pheriphiral obesity. The α-keto heterocycles in this Thesis, such as LEI107, could be important inhibitors to evaluate if a therapeutic window can be established for (central) DAGL inhibitors in the potential treatment of addiction, obesity and neuroinflammation. Lastly, 1,2,4-triazole urea sulfonamides that are reported in this Thesis can be used as novel tool compounds to evaluate DAGL and ABHD16A function in both health and disease. Show less
Despite the rich diversity in molecular structures and biological functionality, the complex matrix of the compounds with a broad dynamic range has limited the use of plants as an important source... Show moreDespite the rich diversity in molecular structures and biological functionality, the complex matrix of the compounds with a broad dynamic range has limited the use of plants as an important source for drug development. Adressing this issue, several papers have described the use of the more holistic approach targeting on a wide range of metabolite present in plant extract, i.e. metabolomics. This new approach involves the use of various analytical methods followed by appropriate multivariate data analysis. The aim is to shorten the bioassay guided isolation route, particularly in the identification and dereplication step This thesis describes a new strategy to improve dereplication and identification steps in drug discovery process from plants. The integration of comprehensive extraction coupled to NMR metabolomics and multivariate data analysis is found to be a potential new approach to uncovering bioactive compounds from crude plant extracts. Show less