Dynamic changes in hepatic DNA methylation during the development of nonalcoholic fatty liver disease induced by a high-sugar diet.

DNA methylation is an important epigenetic mechanism of gene expression control. The present study aimed to evaluate the temporal effect of isocaloric high-sugar diet (HSD) intake on the development of nonalcoholic fatty liver disease (NAFLD) and the role of DNA methylation in this event. Newly weaned Wistar rats were divided into eight groups and fed a standard chow diet or an HSD ad libitum for 4 weeks, 8 weeks, 15 weeks, and 18 weeks. After the experimental periods, the animals were euthanized and their livers were removed for histological analysis, gene expression of maintenance methylase (Dnmt1), de novo methylases (Dnmt3a and Dnmt3b), demethylases (Tet2 and Tet3) of DNA, and global DNA methylation. HSD intake led to the gradual development of NAFLD. HSD intake for 18 weeks was associated with downregulation of Dnmt1 expression and global DNA hypomethylation; these results were negatively correlated with more severe steatosis scores observed in these animals. The HSD consumption for 18 weeks was also associated with a decrease in Dnmt3a and Tet2 expression. Interestingly, the expression of de novo methyltransferase Dnmt3b was reduced by HSD during all experimental periods. Together, these results indicate that the downregulation of de novo DNA methylation, Dnmt3b, induced by HSD is the primary factor in the development of NAFLD. On the other hand, disease progression is associated with downregulation of maintenance DNA methylation and global DNA hypomethylation. These results suggest a link between the dynamic changes in hepatic DNA methylation and the development of NAFLD induced by an HSD intake.

High-sugar diet intake, physical activity, and gut microbiota crosstalk: Implications for obesity in rats.

This study aims to evaluate the effect of long-term high-sugar diet (HSD) intake and regular physical activity on gut microbiota as well as its health impact. Weaned male Wistar rats were fed with standard chow diet (SSD) or HSD ad libitum and subjected or not to regular swimming training with a workload (2% of body weight) for 15 weeks. Feces samples were used on microbiome analysis using 16S rRNA amplicon sequencing. HSD increased body mass, adipose cushions, and the serum levels of triglycerides and VLDL, also changed the bacteria taxons associated with metabolic disorders (increase taxons belonging to Proteobacteria phylum and decrease Pediococcus genus); the swim training reverted these changes. SSD intake increased the abundance of bacteria associated with metabolization of dietary fiber. Training in association with SSD consumption beneficially modulated the microbiota, increasing the Bacteroidetes, Bacteroidaceae, Porphyromonadaceae, Parabacteroides, and Lactobacillaceae, and decreasing the Firmicute/Bacteroidetes ratio; training was not able to maintain this profile in animals SHD-fed. Physical training modulates the gut microbiota reversing the obesogenic response caused by SHD. However, training itself is not efficient for up-regulating the probiotic bacteria in comparison to its association with a balanced diet.

Uncovering epigenetic landscape: a new path for biomarkers identification and drug development.

Scientific advances in recent decades have revealed an incredible degree of plasticity in gene expression in response to various environmental, nutritional, physiological, pathological, and behavioral conditions. Epigenetics emerges in this sense, as the link between the internal (genetic) and external (environmental) factors underlying the expression of the phenotype. Methylation of DNA and histone post-translationa modifications are canonical epigenetic events. Additionally, noncoding RNAs molecules (microRNAs and lncRNAs) have also been proposed as another layer of epigenetic regulation. Together, these events are responsible for regulating gene expression throughout life, controlling cellular fate in both normal and pathological development. Despite being a relatively recent science, epigenetics has been arousing the interest of researchers from different segments of the life sciences and the general public. This review highlights the recent advances in the characterization of the epigenetic events and points promising use of these brands for the diagnosis, prognosis, and therapy of diseases. We also present several classes of epigenetic modifying compounds with therapeutic applications (so-call epidrugs) and their current status in clinical trials and approved by the FDA. In summary, hopefully, we provide the reader with theoretical bases for a better understanding of the epigenetic mechanisms and of the promising application of these marks and events in the medical clinic.

Cytotoxic and toxicogenomic effects of silibinin in bladder cancer cells with different TP53 status.

Silibinin is a natural phenol found in the seeds of the milk thistle plant. Recent data have shown its effectiveness for preventing/treating bladder tumours. Therefore, in this study we investigated the cytotoxic and toxicogenetic activity of silibinin in bladder cancer cells with different TP53 statuses. Two bladder urothelial carcinoma cell lines were used: RT4 (wild-type TP53 gene) and T24 (mutated TP53 gene). Cell proliferation, clonogenic survival, apoptosis rates, genotoxicity and relative expression profile of FRAP/mTOR, FGFR3, AKT2 and DNMT1 genes and of miR100 and miR203 were evaluated. Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutated cells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survival assay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 expression occurred in RT4 cells. Modulation of miR203 was observed in both cell lines. In conclusion, despite the reduction of clone formation in both cell lines, the toxicogenomic effect of silibinin on FRAP/mTOR, AKT2, FGFR3, DNMT1 and miR100 was dependent on the TP53 status. Taken together, the data confirmed the role of silibinin as an antiproliferative compound, whose mechanism of action was related to the TP53 status.

Biological Activities of Red Propolis: A Review.

BACKGROUND: The red propolis (RdProp) is a resin produced by Apis mellifera bees, which collect the reddish exudate on the surface of its botanic source, the species Dalbergia ecastophyllum, popularly known in Brazil as "rabo de bugio". Considered as the 13th type of Brazilian propolis, this resin has been gaining prominence due to its natural composition, rich in bioactive substances not found in other types of propolis. OBJECTIVE: This review aims to address the most important characteristics of RdProp, its botanical origin, the main constituents, its biological properties and the patents related to this natural product. METHOD: By means of the SciFinder, Google Patents, Patus® and Spacenet, scientific articles and patents involving the term "red propolis" were searched until August 2017. RESULTS: A number of biological properties, including antimicrobial, anti-inflammatory, antiparasitic, antitumor, antioxidant, metabolic and nutraceutical activities are attributed to RdProp, demonstrating the great potential of its use in the food, pharmaceutical and cosmetics industries. CONCLUSION: The available papers are associated to pharmacological potential of RdProp, but the molecular mechanisms or bioactive compounds responsible for each activity have not yet been fully elucidat ed. The RdProp patents currently found are directed to components for the pharmaceutical industry (EP2070543A1; WO2014186851A1; FR3006589A1; CN1775277A; CN105797149A; CN1879859A), cosmetic (JP6012138B2; JP2008247830A; JP6012138B2) and food (JP5478392B2; CN101380052A; WO2006038690A1).