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BACKGROUD: Trimethylamine oxide (TMAO) represents a gut metabolite and it's physiological concentration is proposed to be influenced by the abundance of precursor trimethylamine (TMA)-producing microbiota in the gut.OBJECTIVE: Lifestyle factors, such as diet and exercise, modify the microbiome, but their long-term impact on plasma TMAO and TMA production in the gut is poorly understood.METHODS: Fecal microbiome composition was analyzed and correlated with TMAO serum concentrations in female Sprague-Dawley rats that received either a healthy normal or a high-fat diet (HFD) for 10 months. Half of the animals performed regular running exercise, the other half served as sedentary controls.RESULTS: HFD consumption induced an alteration of the fecal microbiome with increased alpha diversity on ASV levels. More importantly, HFD reduced the abundance of genera containing potential TMA producers, such as certain members of Clostridiaand Lachnospiraceae. In line with this observation, serum TMAO concentrations were found to be lower with HFD and to correlate with the abundance of these genera. Regular exercise also induced changes in microbiome beta diversity but had no effect on serum TMAO in female rats.CONCLUSION: A diet containing high amounts of dietary fat reduced serum TMAO, probably through a reduced intestinal abundance of TMA-producing bacteria. In contrast, regular exercise altered beta diversity of the microbiome composition, but without significant effects on serum TMAO concentrations.

Obesity is associated with hypoadiponectemia, dyslipidemia, and increased risk of cardiovascular disease (CVD). Mechanisms linking these conditions remain to be fully understood. Cholesterol efflux capacity (CEC) is a crucial functional property of high-density lipoprotein (HDL) that strongly predicts CVD incidence.

The integration of lipoprotein-related or apolipoprotein-targeted nanoparticles as pharmaceutical carriers opens new therapeutic and diagnostic avenues in nanomedicine. The concept is to exploit the intrinsic characteristics of lipoprotein particles as being the natural transporter of apolar lipids and fat in human circulation. Discrete lipoprotein assemblies and lipoprotein-based biomimetics offer a versatile nanoparticle platform that can be manipulated and tuned for specific medical applications. This article reviews the possibilities for constructing drug loaded, reconstituted or artificial lipoprotein particles. The advantages and limitations of lipoproteinbased delivery systems are critically evaluated and potential future challenges, especially concerning targeting specificity, concepts for lipoprotein rerouting and design of innovative lipoprotein mimetic particles using apolipoprotein sequences as targeting moieties are discussed. Finally, the review highlights potential medical applications for lipoprotein-based nanoparticle systems in the fields of cardiovascular research, cancer therapy, gene delivery and brain targeting focusing on representative examples from literature.

AbstractNanomedicine, a young and innovative field, offers interesting approaches for diagnosis and treatment in personalized medicine. Myocardial infarction and stroke belong to the most important challenges in this context because an improved early diagnosis of individuals well before fatal clinical endpoints occur is urgently needed. The underlying cause of myocardial infarction and stroke is atherosclerosis, a chronic immune-mediated inflammation of the vascular wall involving monocytes, macrophages, T-lymphocytes, and arterial wall cells. Hence, an immense number of pro-inflammatory mediators have been investigated in the context of nanomedicine and atherosclerosis but, interestingly, only few anti-inflammatory biomarkers. Nevertheless, the anti-inflammatory axis is always present as a negative feedback if a critical inflammatory perpetuation destabilizes atherosclerotic lesions. Hence, we could show that the immune-modulating, anti-inflammatory molecules, adiponectin and interleukin-10, are useful for molecular imaging of AS plaques. Based on recent publications in animal models of atherosclerosis, we strongly assume that the inflammatory “brake” mechanisms may represent an interesting new tool to specifically target the scenario of culprit AS-lesions. In this review article we discuss the potential of adiponectin, interleukin-10 and other anti-inflammatory active molecules like targeted liposomes and high dense lipoproteins towards this.

Atherosclerosis (AS) causes cardiovascular disease, which leads to fatal clinical end points like myocardial infarction or stroke, the most prevalent causes of death in developed countries. An early, noninvasive method of detection and diagnosis of atherosclerotic lesions is necessary to prevent and treat these clinical end points. Working toward this goal, we examined recombinant interleukin-10 (IL-10), stealth liposomes with nanocargo potency for NMRI relevant contrast agents, and IL-10 coupled to stealth liposomes in an ApoE-deficient mouse model using confocal laser-scanning microscopy (CLSM). Through ex vivoincubation and imaging with CLSM, we showed that fluorescently labeled IL-10 is internalized by AS plaques, and a low signal is detected in both the less injured aortic surfaces and the arteries of wild-type mice. In vivoexperiments included intravenous injections of (i) fluorescent IL-10, (ii) IL-10 targeted carboxyfluorescin (CF−) labeled stealth liposomes, and (iii) untargeted CF-labeled stealth liposomes. Twenty-four hours after injection the arteries were dissected and imaged ex vivo. Compared to free IL-10, we observed a markedly stronger fluorescence intensity with IL-10 targeted liposomes at AS plaque regions. Moreover, untargeted CF-labeled liposomes showed only weak, unspecific binding. Neither free IL-10 nor IL-10 targeted liposomes showed significant immune reaction when injected into wild-type mice. Thus, the combined use of specific anti-inflammatory proteins, high payloads of contrast agents, and liposome particles should enable current imaging techniques to better recognize and visualize AS plaques for research and prospective therapeutic strategies.

Objective. Cardiovascular disease is associated with inflammation and immune activation, concentrations of immune activation markers like neopterin predict outcome in adults. Methods. Serum neopterin concentrations and early metabolic and pre-atherosclerotic symptoms were analyzed in 295 obese juveniles and 101 normal weight controls of similar age. Additionally, the influence of a 12 months weight reduction program on neopterin levels was investigated in 31 obese juveniles. Results. Intima-media thickness of common carotid arteries (IMT) and the concentrations of C-reactive protein (CRP) were increased in the obese juveniles (𝑃<.001). Also triglycerides, oxidized LDL, fasted insulin levels, HOMA-index, leptin, liver transaminases and uric acid were increased compared to the controls. However, serum neopterin was decreased in the obese versus non-obese juveniles (𝑃<.03). The intervention consisting of regular sports, nutritional devices, and a psychologic attendance led after 12 months to an increase of neopterin concentration (𝑃<.05; paired test). Conclusions. Neopterin concentrations in juvenile obesity behaved considerably different from what was demonstrated in adults, levels did not correlate with metabolic and pre-atherosclerotic symptoms found in early phases although early vascular burden and chronic low grade inflammation was indicated by increased IMT and CRP. Neopterin concentrations increased after a 12 months intervention program.

A common T/A polymorphism (rs9939609) in the fat mass and obesity associated (FTO) gene was found associated with early-onset and severe obesity in both adults and children. However, recent observations failed to find associations of FTO with obesity. To investigate the genetic background of early obesity, we analysed the single nucleotide polymorphism (SNP) rs9939609 of FTO in 371 styrian adolescents towards degree of obesity, subcutaneous adipose tissue (SAT)-distribution determined by lipometry, early metabolic and preatherosclerotic symptoms. The percentage of AA homozygotes for the rs9939609 SNP of FTO was significantly increased in the obese adolescents. Compared to the TT wildtype, AA homozygotes showed significantly elevated values of SAT thickness at the trunk-located lipometer measure points neck and frontal chest, body weight, body mass index, waist, and hip circumference. No associations were found with carotis communis intima media thickness, systolic, diastolic blood pressure, ultrasensitive C-reactive protein (US-CRP), homocystein, total cholesterol, triglycerides, HDL cholesterol, oxidized LDL, fasted glucose, insulin, HOMA-index, liver transaminases, uric acid, and adipokines like resistin, leptin, and adiponectin. Taken together, to the best of our knowledge we are the first to report that the rs9939609 FTO SNP is associated with trunk weighted obesity as early as in adolescence.