UNASSIGNED: Type 2 diabetes mellitus (T2DM) is associated with cardiometabolic changes, and menopause exacerbates these conditions, leading to a greater risk of cardiovascular diseases (CVDs). The G protein-coupled estrogen receptor (GPER), which mediates the rapid effects of estrogen, has beneficial cardiac effects in both T2DM and menopause, but its mechanism of action is not well understood.
UNASSIGNED: This study aimed to determine whether G1 as a selective GPER-agonist has beneficial effects on cardiac lipid metabolism in ovariectomized rats with T2DM.
UNASSIGNED: Female Wistar rats were divided into 5 groups (n = 7 in each group): Sham-control (Sh-Ctl), T2DM, ovariectomized-T2DM (OVX-T2DM), OVX-T2DM-G1 (GPER-agonist), and OVX-T2DM-vehicle (OVX-T2DM-Veh). After stabilization of T2DM, G1 (200 μg/Kg) was administrated for 6 weeks. Then, the levels of free fatty acids (FFAs), CD36, peroxisome proliferator-activated receptor α (PPARα), and lipid accumulation in the cardiac tissue were determined.
UNASSIGNED: Compared with the Sh-Ctl group, cardiac FFAs (P < 0.001), CD36 (P < 0.05), and lipid accumulation (P < 0.001) increased, and cardiac PPARα (P < 0.01) decreased in T2DM animals; ovariectomy intensified these changes. Also, cardiac FFAs, PPARα, and lipid accumulation (P < 0.05) significantly decreased in the OVX-T2DM-G1 group compared to the OVX-T2DM-Veh group. However, cardiac CD36 levels did not change.
UNASSIGNED: G1 as a selective GPER-agonist affects lipid metabolism in T2DM animals. It also plays a vital role in improving cardiac metabolism during postmenopausal diabetic conditions.

OBJECTIVE: Gestational diabetes mellitus (GDM) and hypertensive disorder complicating pregnancy (HDCP) are common complications during pregnancy. This study estimated the correlation of serum miR-518 and inflammatory factors in GDM complicated with HDCP patients (GDM&HDCP).
METHODS: Total 240 pregnant women were enrolled, including 118 cases with GDM alone, 57 cases with GDM&HDCP, and 65 healthy pregnant women. The expressions of serum miR-518 and PPARα were detected by RT-qPCR. The clinical diagnostic efficacy of miR-518 for GDM and GDM&HDCP was analyzed via ROC curve. Pearson coefficient was used to analyze the correlation between miR-518 and serum inflammatory factors (hs-CRP, IL-6, and TNF-α), and the relevance between peroxisome proliferator-activated receptor α (PPARα) and serum inflammatory factors. The targeted binding of miR-518 and PPARα was verified using dual-luciferase assay.
RESULTS: Serum miR-518 was highly-expressed in GDM and GDM&HDCP patients, but far higher in GDM&HDCP patients. Serum miR-518 level > 1.815 could assist the diagnosis of GDM (81.53% sensitivity and 100% specificity). Serum miR-518 expression was positively-correlated with serum inflammatory factors. miR-518 targeted PPARα and PPARα was lowly-expressed in the serum of GDM and GDM&HDCP patients. PPARα was negatively-linked with serum inflammatory factors.
CONCLUSIONS: High expression of miR-518 assists the diagnosis of GDM and GDM&HDCP, and miR-518 regulates the serum inflammatory factors by inhibiting PPARα.

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.

Fatty liver is one of the most common metabolic syndrome affecting the global population. Presently, limited treatment modalities with symptomatic approach are available for alleviating fatty liver. Traditional and herbal treatment modalities have shown evidence to improve the disease pathology. In the present research work, evaluation of a selected medicinal plant Lysimachia candida Lindl. was carried out to investigate its beneficial effects on fatty liver disease in rats. Male Sprague Dawley (SD) rats were fed with high-fat high-fructose diet to induce fatty liver phenotypes. After induction for 15 weeks, methanolic extract of Lysimachia candida Lindl. (250 mg/kg b. w. p. o.) was administrated to the rats daily for the next 17 weeks. Blood samples were collected at different time points to analyze fasting blood glucose levels and relevant biochemical parameters important for the assessment of metabolic disease phenotypes. Liquid chromatography-mass spectrometry (LC-MS) based metabolomics was done to study the dynamics of metabolic changes in the serum during disease progression and how the medicinally important plant extract treatment reversed the metabolic diseases. Multivariate data analysis approaches have been employed to understand the metabolome changes and disease pathology. This study has identified the interplay of some metabolic pathways that alter the disease progression and their reversal after administration of the plant extract. Different group of metabolites mainly bile acids, fatty acids, carnitines, and their derivatives were found to be altered in the diseased rats. However, all the metabolites identified between control and disease groups are mainly related to lipid metabolism. The results depict that the treatment with the above-mentioned plant extract improves the regulation of aberrant lipid metabolism, and reverses the metabolic syndrome phenotype. Therefore, the present study reveals the potential mechanism of the herbal extract to prevent metabolic syndrome in rats.

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.

Parabens are widely used as preservatives in personal care products, medicines and foods, resulting in substantial human exposures, even though some harmful effects, such as endocrine-disrupting activity, have been reported. Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor α (PPARα), which are members of the nuclear receptor superfamily, regulate the metabolism of endogenous substrates including hormones. Therefore, we hypothesized that parabens may alter hormone-metabolizing activities by acting on these receptors, and such changes could contribute to the endocrine-disrupting activity. To test this idea, we systematically examined the effects of 17 parabens on these receptors using reporter gene assays. Nine parabens significantly activated human and rat PXR. Parabens with C2-C5 (linear and branched) side chains were most active. Butylparaben and isobutylparaben also significantly activated rat CAR. We found that long-side-chain (C7-C12) parabens showed up to 2-fold activation of PPARα at 10 μM. Furthermore, pentylparaben and hexylparaben showed rat PXR antagonistic activity and rat CAR inverse agonistic activity. The activity of butylparaben towards PXR and CAR was lost after carboxylesterase-mediated metabolism. These findings confirm that parabens influence the activities of PXR, CAR and PPARα, and thus have the potential to contribute to endocrine disruption by altering hormone metabolism.

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.

This investigation is aimed to improve the knowledge on the physiological alterations occurring at morphological and molecular level in European sea bass naturally infected by A. ocellatum and reared at different salinities. European sea bass juveniles (Dicentrarchus labrax) weighing 20 ± 0.5 g were divided in three aquaponics systems: CTRL, reared at 20 ppt salinity; AFI, reared in freshwater (0 ppt) and infected with the dinoflagellate Amyloodinium ocellatum; ASI, reared at 20 ppt salinity and infected with A. ocellatum. Beta vulgaris plants were introduced in each of the aquaponic systems. Temperature was increased 1 °C every second day from 18 to 25 °C during the experiment. At the end of the trial, liver, brain, intestine and gills were sampled for molecular and histological analyses. A. ocellatum affected D. labrax growth (insulin-like growth factor I, IGF-I) and appetite (Neuropeptide Y, NPY) signals in ASI. Immune system was activated in ASI by the presence of parasites by producing higher levels of Interleukin-1 (IL-1) and Tumor Necrosis Factor α (TNFα). Peroxisome proliferator-activated receptor α (PPAR α), codifying for a protein involved in lipid metabolism, was upregulated in ASI because of the necessity to produce energy to maintain homeostasis. On the contrary, A. ocellatum did not cause signs of infection in AFI as confirmed by gene expression and histological analysis, that were similar to CTRL. However, in freshwater reared fish, a modification of lipid metabolism was observed through a reduction in PPARα gene expression and hepatic lipid content.

Peroxisome proliferator (PP)-activated receptor-α (PPARα) agonists exhibit species-specific effects on livers of the rodent and human (h), which has been considered to reside in the difference of PPARα gene structures. However, the contribution of h-hepatocytes (heps) to the species-specificity remains to be clarified. In this study, the effects of fenofibrate were investigated using a hepatocyte-humanized chimeric mouse (m) model whose livers were replaced with h-heps at >70%. Fenofibrate induced hepatocellular hypertrophy, cell proliferation, and peroxisome proliferation in livers of severe combined immunodeficiency (SCID) mice, but not in the h-hep of chimeric mouse livers. Fenofibrate increased the expression of the enzymes of β- and ω-hydroxylation and deoxygenation of lipids at both gene and protein levels in SCID mouse livers, but not in the h-heps of chimeric mouse livers, supporting the studies with h-PPARα-transgenic mice, a hitherto reliable model for studying the regulation of h-PPARα in the h-liver in most respects, except the induction of the peroxisome proliferation. This study indicates the importance of not only h-PPARα gene but also h-heps themselves to correctly predict effects of fibrates on h-livers, and, therefore, suggests that the chimeric mouse is a currently available, consistent, and reliable model to obtain pharmaceutical data concerning the effects of fibrates on h-livers.