The BCR-ABL1 Inhibitors Imatinib and Ponatinib Decrease Plasma Cholesterol and Atherosclerosis, and Nilotinib and Ponatinib Activate Coagulation in a Translational Mouse Model

Treatment with the second and third generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) increases cardiovascular risk in chronic myeloid leukemia (CML) patients. We investigated the vascular adverse effects of three generations of TKIs in a translational model for atherosclerosis, the APOE*3Leiden.CETP mouse. Mice were treated for sixteen...

Prolonged high-fat diet induces gradual and fat depot-specific DNA methylation changes in adult mice

High-fat diets (HFD) are thought to contribute to the development of metabolism-related diseases. The long-term impact of HFD may be mediated by epigenetic mechanisms, and indeed, HFD has been reported to induce DNA methylation changes in white adipose tissue (WAT) near metabolism related genes. However, previous studies were limited to a single...

Uncovering a Predictive Molecular Signature for the Onset of NASH-Related Fibrosis in a Translational NASH Mouse Model

Background & Aims: The incidence of nonalcoholic steatohepatitis (NASH) is increasing. The pathophysiological mechanisms of NASH and the sequence of events leading to hepatic fibrosis are incompletely understood. The aim of this study was to gain insight into the dynamics of key molecular processes involved in NASH and to rank early markers for...

Anacetrapib reduces (V)LDL-cholesterol by inhibition of CETP activity and reduction of plasma PCSK9

Recently, we showed in APOE*3-Leiden.CETP mice that anacetrapib attenuated atherosclerosis development by reducing (V)LDL-C rather than by raising HDL-C. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP. APOE*3-Leiden.CETP mice were fed a Western type diet...

Novel combination of collagen dynamics analysis and transcriptional profiling reveals fibrosis-relevant genes and pathways

Collagen deposition is a key process during idiopathic pulmonary fibrosis; however, little is known about the dynamics of collagen formation during disease development. Tissue samples of early stages of human disease are not readily available and it is difficult to identify changes in collagen content, since standard collagen analyses do not...

Metabolic profiling reveals differences in concentrations of oxylipins and fatty acids secreted by the infrapatellar fat pad of donors with end-stage osteoarthritis and normal donors

Objective The infrapatellar fat pad (IPFP) in the knee joint is hypothesized to contribute to osteoarthritis (OA) development by the IFPF possibly by influencing inflammatory processes. Oxylipins are essential mediators in the inflammatory process. We undertook this study to investigate secretion by the IFPF of fatty acids and oxylipins derived...

Gene expression profiling identifies mechanisms of protection to recurrent trinitrobenzene sulfonic acid colitis mediated by probiotics

Background: Host-microbiota interactions in the intestinal mucosa play a major role in intestinal immune homeostasis and control the threshold of local inflammation. The aim of this study was to evaluate the efficacy of probiotics in the recurrent trinitrobenzene sulfonic acid (TNBS)-induced colitis model and gain more insight into protective...

Lipidomics reveals multiple pathway effects of a multi-components preparation on lipid biochemistry in ApoE*3Leiden.CETP mice

Background: Causes and consequences of the complex changes in lipids occurring in the metabolic syndrome are only partly understood. Several interconnected processes are deteriorating, which implies that multi-target approaches might be more successful than strategies based on a limited number of surrogate markers. Preparations from Chinese...

Exploring pathway interactions in insulin resistant mouse liver

Background: Complex phenotypes such as insulin resistance involve different biological pathways that may interact and influence each other. Interpretation of related experimental data would be facilitated by identifying relevant pathway interactions in the context of the dataset.Results: We developed an analysis approach to study interactions...

26th Hohenheim Consensus Conference, September 11, 2010 Scientific substantiation of health claims: Evidence-based nutrition

Objective: The objective was to define the term evidence based nutrition on the basis of expert discussions and scientific evidence. Methods and procedures: The method used is the established Hohenheim Consensus Conference. The term "Hohenheim Consensus Conference" defines conferences dealing with nutrition-related topics. The major aim of the...

Alterations in hepatic one-carbon metabolism and related pathways following a high-fat dietary intervention

Obesity frequently leads to insulin resistance and the development of hepatic steatosis. to characterize the molecular changes that promote hepatic steatosis, transcriptomics, proteomics, and metabolomics technologies were applied to liver samples from c57bl/6j mice obtained from two independent intervention trials. after 12 wk of high-fat...

Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models

Objective: Polyphenols such as quercetin may exert several beneficial effects, including those resulting from anti-inflammatory activities, but their impact on cardiovascular health is debated. We investigated the effect of quercetin on cardiovascular risk markers including human C-reactive protein (CRP) and on atherosclerosis using transgenic...

Plasma and liver lipidomics response to an intervention of rimonabant in ApoE*3Leiden.CETP transgenic mice

Background: Lipids are known to play crucial roles in the development of life-style related risk factors such as obesity, dyslipoproteinemia, hypertension and diabetes. The first selective cannabinoid-1 receptor blocker rimonabant, an anorectic anti-obesity drug, was frequently used in conjunction with diet and exercise for patients with a body...

Time-resolved and tissue-specific systems analysis of the pathogenesis of insulin resistance

BACKGROUND: The sequence of events leading to the development of insulin resistance (IR) as well as the underlying pathophysiological mechanisms are incompletely understood. As reductionist approaches have been largely unsuccessful in providing an understanding of the pathogenesis of IR, there is a need for an integrative, time-resolved approach...