Resveratrol (RVT) is one of the main natural compounds studied worldwide due to its potential therapeutic use in the treatment of many diseases, including cancer, diabetes, cardiovascular diseases, neurodegenerative diseases and metabolic disorders. Nevertheless, the mechanism of action of RVT in all of these conditions is not completely understood, as it can modify not only biochemical pathways but also epigenetic mechanisms. In this paper, we analyze the biological activities exhibited by RVT with a focus on the epigenetic mechanisms, especially those related to DNA methyltransferase (DNMT), histone deacetylase (HDAC) and lysine-specific demethylase-1 (LSD1).

Resveratrol and curcumin are natural products with important therapeutic properties useful to treat several human diseases, including cancer. In the last years, the number of studies describing the effect of both polyphenols against cancer has increased; however, the mechanism of action in all of those cases is not completely comprehended. The unspecific effect and the ability to interfere in assays by both polyphenols make this challenge even more difficult. Herein, we analyzed the anticancer activity of resveratrol and curcumin reported in the literature in the last 11 years, in order to unravel the molecular mechanism of action of both compounds. Molecular targets and cellular pathways will be described. Furthermore, we also discussed the ability of these natural products act as chemopreventive and its use in association with other anticancer drugs.

The chemopreventive and anticancer effects of resveratrol (RSV) are widely reported in the literature. Specifically, mechanisms involving epigenetic regulation are promising targets to regulate tumor development. Bromodomains act as epigenetic readers by recognizing lysine acetylation on histone tails and boosting gene expression in order to regulate tissue-specific transcription. In this work, we showed that RSV is a pan-BET inhibitor. Using Differential Scanning Fluorimetry (DSF), we showed that RSV at 100 µM increased the melting temperature (∆Tm) of BET bromodomains by around 2.0 °C. The micromolar dissociation constant (K_d) range was characterized using Isothermal Titration Calorimetry (ITC). The RSV K_d value accounted to 6.6 µM in case of BRD4(1). Molecular docking proposed the binding mode of RSV against BRD4(1) mimicking the acetyl-lysine interactions. All these results suggest that RSV can also recognize epigenetic readers domains by interacting with BET bromodomains.

Histatin 5 (Hst5) is an antifungal peptide (AFP) naturally produced by parotid glands with strong activity against Candida albicans. One of its mechanisms of action is the generation of reactive oxygen species (ROS) inside the C. albicans cells. Despite being an important peptide for the human innate immune response, its activity is reduced or inactivated by proteolytic degradation caused by salivary enzymes. To overcome this barrier, we used solid phase peptide synthesis (SPPS) to modify the Hst5 amino acid sequence improving its antifungal action and minimizing its degradation. We synthesized five peptides, three of which were based on the Hst5 functional domain. We determined that the smallest peptides (8WH5, 7WH5 and 6WH5) demonstrated the greatest antifungal action against C. albicans, including one fluconazole-resistant strain. Besides that, cationic-PAGE and HPLC assays showed that the degradation in saliva was slower for the smaller peptides than for 0WHst5 and WP113. Furthermore, 8WH5, 7WH5 and 6WH5 were found in the samples even after 8 h in whole saliva, while 0WHst5 and WP113 completely disappear after 1.5 h. Finally, we found that the smaller peptides were less fragmented than the 0WHst5 and WP113, so they were the smallest fragments of Hst5 to preserve its antifungal action with reduced degradation in whole saliva. Thus, they can be considered promising molecules for the treatment of C. albicans in the oral cavity.