Here, the case of a 92-year-old female patient, who was diagnosed with atrial fibrillation and treated with phenprocoumon (Marcumar®), is reported. Pre-existing comorbidities were arterial hypertension, coronary heart disease, diabetes mellitus type 2, mild senile dementia and renal insufficiency. Despite treatment with phenprocoumon (Marcumar®), the patient experienced an ischaemic stroke. Her measured international normalized ratio (INR)-values during the months before the stroke were within the therapeutic range of 2-3, then suddenly decreased to 1.25. A retrospective inquiry failed to identify any significant changes in behaviour or therapy adherence, other than the consumption of 1.5 kg (3.3 lb) of hard-boiled candy liquorice in the days leading up to the stroke. The sudden decrease in INR-values may be explained by the influence of liquorice and its compounds on the pharmacokinetics of phenprocoumon (Marcumar®). In this context, the most important factors are the susceptibility of vitamin K antagonists to nutrition or metabolic irregularities, the influence of liquorice on the function of isoenzymes of the cytochrome P450 family that may lead to reduced bioavailability of phenprocoumon, and the influence of liquorice on peroxisome proliferator-activated receptor alpha transactivation.

Athletic ability is influenced by several exogenous and endogenous factors including genetic component. Hundreds of gene variants have been proposed as potential genetic markers associated with fitness-related phenotypes as well as elite-level athletic performance. Among others, variants within the PPARA gene that code for the peroxisome proliferator activated receptor α are of potential interest. The main goal of the present study was to determine PPARA (G/C, rs4253778) genotype distribution among a group of Polish, Lithuanian and Italian international level male gymnasts and to compare our findings with those of previous research on the frequency of the PPARA intron 7 C allele/CC genotype in power/strength-oriented athletes. A total of 464 male subjects (147 gymnasts and 317 controls) from Poland (n = 203), Italy (n = 146) and Lithuania (n = 107) participated in the study. No statistically significant differences were found in any of the analyzed cohorts. However, a significantly higher frequency of the CC genotype of the PPARA rs4253778 polymorphism was observed when all gymnasts were pooled and compared with pooled control using a recessive model of inheritance (OR = 3.33, 95% CI = 1.18-10, p = 0.022). It is important to know that we investigated a relatively small sample of male European gymnasts and our results are limited only to male participants. Thus, it is necessary to validate our results in larger cohorts of athletes of different ethnicities and also in female gymnasts to find out whether there is a gender effect.

Our studies in primary human adipocytes show that naringenin, a citrus flavonoid, increases oxygen consumption rate and gene expression of uncoupling protein 1 (UCP1), glucose transporter type 4, and carnitine palmitoyltransferase 1β (CPT1β). We investigated the safety of naringenin, its effects on metabolic rate, and blood glucose and insulin responses in a single female subject with diabetes. The subject ingested 150 mg naringenin from an extract of whole oranges standardized to 28% naringenin three times/day for 8 weeks, and maintained her usual food intake. Body weight, resting metabolic rate, respiratory quotient, and blood chemistry panel including glucose, insulin, and safety markers were measured at baseline and after 8 weeks. Adverse events were evaluated every 2 weeks. We also examined the involvement of peroxisome proliferator-activated receptor α (PPARα), peroxisome proliferator-activated receptor γ (PPARγ), protein kinase A (PKA), and protein kinase G (PKG) in the response of human adipocytes to naringenin treatment. Compared to baseline, the body weight decreased by 2.3 kg. The metabolic rate peaked at 3.5% above baseline at 1 h, but there was no change in the respiratory quotient. Compared to baseline, insulin decreased by 18%, but the change in glucose was not clinically significant. Other blood safety markers were within their reference ranges, and there were no adverse events. UCP1 and CPT1β mRNA expression was reduced by inhibitors of PPARα and PPARγ, but there was no effect of PKA or PKG inhibition. We conclude that naringenin supplementation is safe in humans, reduces body weight and insulin resistance, and increases metabolic rate by PPARα and PPARγ activation. The effects of naringenin on energy expenditure and insulin sensitivity warrant investigation in a randomized controlled clinical trial.

Peroxisome proliferator activated receptor α (PPARα) has the most relevant biological functions among PPARs. Activation by drugs and dietary components lead to major metabolic changes, from reduced triglyceridemia to improvement in the metabolic syndrome. Polymorphisms of PPARα are of interest in order to improve our understanding of metabolic disorders associated with a raised or reduced risk of diseases. PPARα polymorphisms are mainly characterized by two sequence changes, L162V and V227A, with the latter occurring only in Eastern nations, and by numerous SNPs (Single nucleotide polymorphisms) with a less clear biological role. The minor allele of L162V associates with raised total cholesterol, LDL-C (low-density lipoprotein cholesterol), and triglycerides, reduced HDL-C (high-density lipoprotein metabolism), and elevated lipoprotein (a). An increased cardiovascular risk is not clear, whereas a raised risk of diabetes or of liver steatosis are not well supported. The minor allele of the V227A polymorphism is instead linked to a reduction of steatosis and raised γ-glutamyltranspeptidase levels in non-drinking Orientals, the latter being reduced in drinkers. Lastly, the minor allele of rs4353747 is associated with a raised high-altitude appetite loss. These and other associations indicate the predictive potential of PPARα polymorphisms for an improved understanding of human disease, which also explain variability in the clinical response to specific drug treatments or dietary approaches.

Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein\'s active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand-protein interactions within the complexes. The study was carried out on peroxisome proliferator-activated receptor α (PPARα). Findings derived from the dynamic analysis of interactions were then used as features for pharmacophore generation and constraints for generating the docking grid for use in virtual screening. We found that information derived from short multiple MD simulations using different molecules within the binding pocket of the target can improve the early enrichment of active ligands in the virtual screening process for this receptor. In the end we adopted a consensus scoring based on docking score and pharmacophore alignment to rank our dataset. Our results showed an improvement in virtual screening performance in early recognition when screening was performed with the Molecular dYnamics SHAred PharmacophorE (MYSHAPE) approach.