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Improving the analysis of designed studies by combining statistical modelling with study design information

TNO Kwaliteit van Leven (author), Thissen, U. (author), Wopereis, S. (author), van den Berg, S.A.A. (author), Bobeldijk, I. (author), Kleemann, R. (author), Kooistra, T. (author), van Dijk, K.W. (author), van Ommen, B. (author), Smilde, A.K. (author)

Background: In the fields of life sciences, so-called designed studies are used for studying complex biological systems. The data derived from these studies comply with a study design aimed at generating relevant information while diminishing unwanted variation (noise). Knowledge about the study design can be used to decompose the total data...

article 2009

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LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: Time course and mechanisms

TNO Kwaliteit van Leven (author), Verschuren, L. (author), van der Vries de Weij, J. (author), Zadelaar, A.S.M. (author), Kleemann, R. (author), Kooistra, T. (author)

The aim of this study was to define the anti-atherosclerotic role of liver-X-receptors (LXRs) under lesion progressive and lesion regressive conditions, to establish a temporal line of events, and to gain insights into the mechanisms underlying the anti-atherogenic potency of LXRs. We used apoE*3Leiden (E3L) mice to comprehensively and time...

article 2009

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Quantitative profiling of bile acids in biofluids and tissues based on accurate mass high resolution LC-FT-MS: Compound class targeting in a metabolomics workflow

Bobeldijk, I. (author), Hekman, M. (author), van der Vries de- Weij, J. (author), Coulier, L. (author), Ramaker, R. (author), Kleemann, R. (author), Kooistra, T. (author), Rubingh, C. (author), Freidig, A. (author), Verheij, E. (author), TNO Kwaliteit van Leven (author)

We report a sensitive, generic method for quantitative profiling of bile acids and other endogenous metabolites in small quantities of various biological fluids and tissues. The method is based on a straightforward sample preparation, separation by reversed-phase high performance liquid-chromatography mass spectrometry (HPLC-MS) and electrospray...

article 2008

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Cytokines and atherosclerosis: A comprehensive review of studies in mice

Kleemann, R. (author), Zadelaar, A.S.M. (author), Kooistra, T. (author), Gaubius Instituut TNO (author)

In the past few years, inflammation has emerged as a major driving force of atherosclerotic lesion development. It is now well-established that from early lesion to vulnerable plaque formation, numerous cellular and molecular inflammatory components participate in the disease process. The most prominent cells that invade in evolving lesions are...

article 2008

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cAMP-dependent signaling regulates the adipogenic effect of n-6 polyunsaturated fatty acids

TNO Kwaliteit van Leven (author), Madsen, L. (author), Pedersen, L.M. (author), Liaset, B. (author), Ma, T. (author), Petersen, R.K. (author), van den Berg, S. (author), Pan, J. (author), Müller-Decker, K.M. (author), Dülsner, E.D. (author), Kleemann, R. (author), Kooistra, T. (author), Døskeland, S.O. (author), Kristiansen, K. (author)

The effect of n-6 polyunsaturated fatty acids (n-6 PUFAs) on adipogenesis and obesity is controversial. Using in vitro cell culture models, we show that n-6 PUFAs was pro-adipogenic under conditions with base-line levels of cAMP, but anti-adipogenic when the levels of cAMP were elevated. The anti-adipogenic action of n-6 PUFAs was dependent on a...

article 2008

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Mouse models for atherosclerosis and pharmaceutical modifiers

Zadelaar, A.S.M. (author), Kleemann, R. (author), Verschuren, L. (author), de Vries-van der Weij, J. (author), van der Hoorn, J. (author), Princen, H.M. (author), Kooistra, T. (author), TNO Kwaliteit van Leven (author)

Atherosclerosis is a multifactorial highly-complex disease with numerous etiologies that work synergistically to promote lesion development. The ability to develop preventive and ameliorative treatments will depend on animal models that mimic the human subject metabolically and pathophysiologically and will develop lesions comparable to those in...

article 2007

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Atherosclerosis and liver inflammation induced by increased dietary cholesterol intake: A combined transcriptomics and metabolomics analysis

Kleemann, R. (author), Verschuren, L. (author), van Erk, M.J. (author), Nikolsky, Y. (author), Cnubben, N.H.P. (author), Verheij, E.R. (author), Smilde, A.K. (author), Hendriks, H.F.J. (author), Zadelaar, A.S.M. (author), Smith, G.J. (author), Kaznacheev, V. (author), Nikolskaya, T. (author), Melnikov, A. (author), Hurt-Camejo, E. (author), van der Greef, J. (author), van Ommen, B. (author), Kooistra, T. (author), TNO Kwaliteit van Leven (author)

Background: Increased dietary cholesterol intake is associated with atherosclerosis. Atherosclerosis development requires a lipid and an inflammatory component. It is unclear where and how the inflammatory component develops. To assess the role of the liver in the evolution of inflammation, we treated ApoE* 3Leiden mice with cholesterol-free ...

article 2007

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Olmesartan and pravastatin additively reduce development of atherosclerosis in APOE*3Leiden transgenic mice

TNO Kwaliteit van Leven (author), van der Hoorn, J.W.A. (author), Kleemann, R. (author), Havekes, L.M. (author), Kooistra, T. (author), Princen, H.M.G. (author), Jukema, J.W. (author)

AIM: This study was designed to investigate the effect of the angiotensin II receptor blocker olmesartan alone, or in combination with standard treatment with a statin, pravastatin, on atherosclerosis development in APOE*3Leiden transgenic mice. METHODS AND RESULTS: Four groups of 15 mice received an atherogenic diet alone (plasma cholesterol 17...

article 2007

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Apolipoprotein C-I is crucially involved in lipopolysaccharide-induced atherosclerosis development in apolipoprotein E-knockout mice

TNO Kwaliteit van Leven (author), Westerterp, M. (author), Berbée, J.F.P. (author), Pires, N.M.M. (author), van Mierlo, G.J.D. (author), Kleemann, R. (author), Romijn, J.A. (author), Havekes, L.M. (author), Rensen, P.C.N. (author)

BACKGROUND - Lipopolysaccharide (LPS), which is released from Gram-negative bacteria on multiplication or lysis, aggravates atherosclerosis in humans and rodents by inducing inflammation via toll-like receptors. Because apolipoprotein C-I (apoCI) enhances the LPS-induced inflammatory response in macrophages in vitro and in mice, we investigated...

article 2007

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Apolipoprotein CI stimulates the response to lipopolysaccharide and reduces mortality in gram-negative sepsis.

Berbée, J.F. (author), van der Hoogt, C.C. (author), Kleemann, R. (author), Schippers, E.F. (author), Kitchens, R.L. (author), van Dissel, J.T. (author), Bakker-Woudenberg, I.A. (author), Havekes, L.M. (author), Rensen, P.C. (author), TNO Kwaliteit van Leven (author)

Gram-negative sepsis is a major death cause in intensive care units. Accumulating evidence indicates the protective role of plasma lipoproteins such as high-density lipoprotein (HDL) in sepsis. It has recently been shown that septic HDL is almost depleted from apolipoprotein CI (apoCI), suggesting that apoCI may be a protective factor in sepsis....

article 2006

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Transgenic flavonoid tomato intake reduces C-reactive protein in human C-reactive protein transgenic mice more than wild-type tomato

Rein, D. (author), Schijlen, E. (author), Kooistra, T. (author), Herbers, K. (author), Verschuren, L. (author), Hall, R. (author), Sonnewald, U. (author), Bovy, A. (author), Kleemann, R. (author), TNO Kwaliteit van Leven TNO Voeding (author)

The increased consumption of fruits and vegetables is associated with reduced cardiovascular disease. The molecular basis of this health effect is not fully understood, yet dietary flavonoids are thought to play an important role. Genetic engineering has enabled us to overexpress specific flavonoids (flavones and flavonols) in tomato fruit....

article 2006

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Fenofibrate reduces atherogenesis in ApoE*3Leiden mice: Evidence for multiple antiatherogenic effects besides lowering plasma cholesterol

Kooistra, T. (author), Verschuren, L. (author), van der Vries de-Weij, J. (author), Koenig, W. (author), Toet, K. (author), Princen, H.M.G. (author), Kleemann, R. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - To demonstrate, quantify, and mechanistically dissect antiatherosclerotic effects of fenofibrate besides lowering plasma cholesterol per se. METHODS AND RESULTS - ApoE*3Leiden transgenic mice received either a high-cholesterol diet (HC) or HC containing fenofibrate (HC+FF) resulting in 52% plasma cholesterol-lowering. In a separate...

article 2006

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Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF)

Burger-Kentischer, A. (author), Göbel, H. (author), Kleemann, R. (author), Zernecke, A. (author), Bucala, R. (author), Leng, L. (author), Finkelmeier, D. (author), Geiger, G. (author), Schaefer, H.E. (author), Schober, A. (author), Weber, C. (author), Brunner, H. (author), Rütten, H. (author), Ihling, C. (author), Bernhagen, J. (author), TNO Kwaliteit van Leven (author)

Atherosclerosis is an inflammatory response of the arterial wall to "injury", which is prominently driven by cytokines. The inflammatory mediator macrophage migration inhibitory factor (MIF) is a unique cytokine that was recently associated with atherogenesis. Here, we have investigated whether MIF has a role in spontaneous atherosclerosis by...

article 2006

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Effect of low dose atorvastatin versus diet-induced cholesterol lowering on atherosclerotic lesion progression and inflammation in apolipoprotein E*3-Leiden transgenic mice

Verschuren, L. (author), Kleemann, R. (author), Offerman, E.H. (author), Szalai, A.J. (author), Emeis, S.J. (author), Princen, H.M.G. (author), Kooistra, T. (author), TNO Kwaliteit van Leven (author)

Objective - To evaluate whether low-dose atorvastatin suppresses atherosclerotic lesion progression and inflammation in apolipoprotein E*3 (apoE*3)-Leiden mice beyond its cholesterol-lowering effect. Methods and Results - ApoE*3-Leiden mice were fed a high-cholesterol (HC) diet until mild atherosclerotic lesions had formed. Subsequently, HC diet...

article 2005

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Evidence for anti-inflammatory activity of statins and PPARα activators in human C-reactive protein transgenic mice in vivo and in cultured human hepatocytes in vitro

Kleemann, R. (author), Verschuren, L. (author), de Rooij, B.J. (author), Lindeman, J. (author), de Maat, M.M. (author), Szalai, A.J. (author), Princen, H.M.G. (author), Kooistra, T. (author), Gaubius Instituut TNO (author)

Inflammatory processes, aside from cholesterol, play a central role in atherogenesis. Human C-reactive protein (huCRP) signals systemic inflammation and independently predicts future cardiovascular risk. Cholesterol-lowering statins reduce atherosclerosis and plasma huCRP levels. Evidence is sought for a direct anti-inflammatory statin effect in...

article 2004

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Global Suppression of IL-6-induced Acute Phase Response Gene Expression after Chronic in Vivo Treatment with the Peroxisome Proliferator-activated Receptor-alpha Activator Fenofibrate

TNO Preventie en Gezondheid (author), Gervois, P. (author), Kleemann, R. (author), Pilon, A. (author), Percevault, F. (author), Koenig, W. (author), Staels, B. (author), Kooistra, T. (author)

The peroxisome proliferator-activated receptor alpha (PPARalpha), which is highly expressed in liver, plays key roles in lipid metabolism and inflammation. Interleukin-6 (IL-6) is the principal inducer of acute phase response (APR) gene expression. In the present study, we demonstrate that chronic treatment with the PPARalpha agonist fenofibrate...

article 2004

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The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment

TNO Preventie en Gezondheid (author), Mandard, S. (author), Zandbergen, F. (author), Nguan, S.T. (author), Escher, P. (author), Patsouris, D. (author), Koenig, W. (author), Kleemann, R. (author), Bakker, A. (author), Veenman, F. (author), Wahli, W. (author), Müller, M. (author), Kersten, S. (author)

The fasting-induced adipose factor (FIAF, ANGPTL4, PGAR, HFARP) was previously identified as a novel adipocytokine that was up-regulated by fasting, by peroxisome proliferator-activated receptor agonists, and by hypoxia. To further characterize FIAF, we studied regulation of FIAF mRNA and protein in liver and adipose cell lines as well as in...

article 2004

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Fibrates down-regulate IL-1-stimulated C-reactive protein gene expression in hepatocytes by reducing nuclear p50-NFκB-C/EBP-β complex formation

Kleemann, R. (author), Gervois, P.P. (author), Verschuren, L. (author), Staels, B. (author), Princen, H.M.G. (author), Kooistra, T. (author), Gaubius Instituut TNO (author)

C-reactive protein (CRP) is a major acute-phase protein in humans. Elevated plasma CRP levels are a risk factor for cardiovascular disease. CRP is predominantly expressed in hepatocytes and is induced by interleukin-1 (IL-1) and IL-6 under inflammatory situations, such as the acute phase. Fibrates are hypolipidemic drugs that act through the...

article 2003

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Rosuvastatin reduces atherosclerosis development beyond and independent of its plasma cholesterol-lowering effect in APOE*3-Leiden transgenic mice: Evidence for antiinflammatory effects of rosuvastatin

Kleemann, R. (author), Princen, H.M.G. (author), Emeis, J.J. (author), Jukema, J.W. (author), Fontijn, R.D. (author), Horrevoets, A.J.G. (author), Kooistra, T. (author), Havekes, L.M. (author)

Background - Statins can exert anti-inflammatory antiatherosclerotic effects through an anti-inflammatory action, independent of lowering cholesterol. We addressed the question whether the anti-inflammatory activities of statins can reduce atherosclerosis beyond the reduction achieved by cholesterol lowering per se. Methods and Results - Two...

article 2003

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A 16-Residue Peptide Fragment of Macrophage Migration Inhibitory Factor, MIF-(50-65), Exhibits Redox Activity and Has MIF-like Biological Functions

Gaubius Instituut TNO (author), Nguyen, M.T. (author), Beck, J. (author), Lue, H. (author), Fünfzig, H. (author), Kleemann, R. (author), Koolwijk, P. (author), Kapurniotu, A. (author), Bernhagen, J. (author)

Macrophage migration inhibitory factor (MIF) is a cytokine that participates in the host inflammatory response. A Cys-Xaa-Xaa-Cys (CXXC)-based thiol-protein oxidoreductase activity of MIF is associated with certain biological functions. Peptides spanning the CXXC region of thiol-protein oxidoreductases retain some biochemical properties of the...

article 2003