(-)-Oleacein and (-)-oleocanthal, two phenolic compounds present in Extra Virgin Olive Oil, inhibit angiogenesis

Phenolic compounds in the Mediterranean diet contribute to many of the health-related benefits accounted in this dietary choice. (-)-Oleocanthal and the less studied (-)-oleacein, are two phenolic compounds present in the Extra Virgin Olive Oil that have shown anti-tumoural effects both in vitro and in vivo. Among their effects on cancer, they could inhibit tumour cell migration and invasion, key processes also in angiogenesis, the process by which de novo blood vessels are formed. Herein, we explored the anti-angiogenic potential of (-)-oleocanthal and (-)-oleacein in a comparative study in in vitro experiments on endothelial cells, and in two in vivo models. (-)-Oleocanthal and (-)-oleacein affected endothelial viability in the micromolar range, as well as the formation of tubule-like structures by these cells, and their migration. Interestingly, only oleacein inhibited cell migration and induced apoptosis significantly. Regarding cellular signalling, both compounds were able to reduce the activation of the AKT and ERK1/2 pathways, which are related to survival and proliferation, respectively. Finally, both compounds showed anti-angiogenic activity in a zebrafish model of regeneration and in the chicken chorioallantoic membrane. Altogether, these results support the anti-angiogenic potential of (-)-oleocanthal and (-)-oleacein, and suggest that (-)-oleacein exerts more potent effects on endothelial cell migration and induction of apoptosis. Thus, we propose these two phenolic compounds, with a special focus on (-)-oleacein, as new candidates for clinical use as anti-cancer and anti-angiogenic agents. [Grants: PID2019-105010RB-I00 and RTI2018-098560-BC22 (Spanish Government), UMA18-FEDERJA-220, and PY20_00257 (Andalusian Government and FEDER). Funds from BIO 267 (Andalusian Government). CIBERER, CIBERCV].Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The immunomodulator dimethyl taconite inhibits several key steps of angiogenesis in cultured endothelial cells

Dimethyl itaconate (DMI) is a cell-permeable derivative of itaconate, a known immunomodulator metabolite synthesized from the Krebs cycle intermediate cis-aconitate by the enzyme aconitate dehydrogenase. Although DMI is not metabolized into itaconate intracellularly, immunomodulatory, anti-inflammatory and anti-oxidative effects has been described for this compound. Some of these processes affected by DMI are directly related to angiogenesis; however, nothing has been published yet in this field. The aim of this work is to evaluate the potential effect of DMI in different key steps of the angiogenic process.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

A comparative study of the antiangiogenic activity of hydroxytyrosyl alkyl ethers

Versión preprint del manuscrito de los autores, publicado finalmente en: Food Chemistry 333 (2020) 127476 con DOI: 10.1016/j.foodchem.2020.127476The phenolic compound hydroxytyrosol and its derivatives are responsible for some of the health benefits of the intake of virgin olive oil, having shown antiangiogenic properties. In this study, we explored the antiangiogenic potential of six synthetic hydroxytyrosyl alkyl ethers (HT C1, C2, C4, C6, C8 and C12). Our results showed that all compounds affected endothelial cell viability in vitro at low micromolar doses. In addition, compounds HT C1, C2, C4 and C6 inhibited endothelial cell migration and formation of tubular-like structures. In these assays, hydroxytyrosyl hexyl ether (HT C6) exhibited the most potent inhibitory activity in vitro, activating as well apoptosis in endothelial cells. Furthermore, the antiangiogenic activity of HT C6 was confirmed in vivo in the chick chorioallantoic membrane assay. Hence, we present hydroxytyrosol synthetic derivative HT C6 as a new antiangiogenic compound and as a good candidate for an antiangiogenic drug in the treatment of angiogenesisdependent diseases.This work was supported by the Spanish Ministry of Science, Innovation and Universities (grants AGL2007-66373 and PID2019- 105010RB-I00), Andalusian Government and FEDER (P12-CTS-1507, UMA18-FEDERJA-220 and funds from group BIO 267), as well as funds from the University of Málaga (“Plan Propio de Investigación y Transferencia”). The “CIBER de Enfermedades Raras” and “CIBER de Enfermedades Cardiovasculares” are initiatives from the ISCIII (Spain). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript

Antiangiogenic Phytochemicals Constituent of Diet as Promising Candidates for Chemoprevention of Cancer.

Despite the extensive knowledge on cancer nature acquired over the last years, the high incidence of this disease evidences a need for new approaches that complement the clinical intervention of tumors. Interestingly, many types of cancer are closely related to dietary habits associated with the Western lifestyle, such as low fruit and vegetable intake. Recent advances around the old-conceived term of chemoprevention highlight the important role of phytochemicals as good candidates for the prevention or treatment of cancer. The potential to inhibit angiogenesis exhibited by many natural compounds constituent of plant foods makes them especially interesting for their use as chemopreventive agents. Here, we review the antitumoral potential, with a focus on the antiangiogenic effects, of phenolic and polyphenolic compounds, such as quercetin or myricetin; terpenoids, such as ursolic acid or kahweol; and anthraquinones from Aloe vera, in different in vitro and in vivo assays, and the available clinical data. Although clinical trials have failed to assess the preventive role of many of these compounds, encouraging preclinical data support the efficacy of phytochemicals constituent of diet in the prevention and treatment of cancer, but a deeper understanding of their mechanisms of action and better designed clinical trials are urgently needed

Pyroptosis Modulators: New Insights of Gasdermins in Health and Disease

Pyroptosis is an inflammation-dependent type of cell death that has been in the spotlight for the scientific community in the last few years. Crucial players in the process of pyroptosis are the members of the gasdermin family of proteins, which have been parallelly studied. Upon induction of pyroptosis, gasdermins suffer from structural changes leading to the formation of pores in the membrane that subsequently cause the release of pro-inflammatory contents. Recently, it has been discovered that oxidation plays a key role in the activation of certain gasdermins. Here, we review the current knowledge on pyroptosis and human gasdermins, focusing on the description of the different members of the family, their molecular structures, and their influence on health and disease directly or non-directly related to inflammation. Noteworthy, we have focused on the existing understanding of the role of this family of proteins in cancer, which could translate into novel promising strategies aimed at benefiting human health. In conclusion, the modulation of pyroptosis and gasdermins by natural and synthetic compounds through different mechanisms, including modification of the redox state of cells, has been proven effective and sets precedents for future therapeutic strategies

Conformation-dependent QSAR approach for the prediction of inhibitory activity of bromodomain modulators

<p>Epigenetic drug discovery is a promising research field with growing interest in the scientific community, as evidenced by the number of publications and the large amount of structure-epigenetic activity information currently available in the public domain. Computational methods are valuable tools to analyse and understand the activity of large compound collections from their structural information. In this manuscript, QSAR models to predict the inhibitory activity of a diverse and heterogeneous set of 88 organic molecules against the bromodomains BRD2, BRD3 and BRD4 are presented. A conformation-dependent representation of the chemical structures was established using the RDKit software and a training and test set division was performed. Several two-linear and three-linear QuBiLS-MIDAS molecular descriptors (<a href="http://www.tomocomd.com" target="_blank">www.tomocomd.com</a>) were computed to extract the geometric structural features of the compounds studied. QuBiLS-MIDAS-based features sets, to be used in the modelling, were selected using dimensionality reduction strategies. The multiple linear regression procedure coupled with a genetic algorithm were employed to build the predictive models. Regression models containing between 6 to 9 variables were developed and assessed according to several internal and external validation methods. Analyses of outlier compounds and the applicability domain for each model were performed. As a result, the models against BRD2 and BRD3 with 8 variables and the model with 9 variables against BRD4 were those with the best overall performance according to the criteria accounted for. The results obtained suggest that the models proposed will be a good tool for studying the inhibitory activities of drug candidates against the bromodomains considered during epigenetic drug discovery.</p

The Immunomodulator Dimethyl Itaconate Inhibits Several Key Steps of Angiogenesis in Cultured Endothelial Cells

The dimethyl derivative of the immunomodulator itaconate has been previously shown to have anti-inflammatory, anti-oxidative, and immunomodulatory effects. In the present work, we evaluate the potential of dimethyl itaconate as an anti-angiogenic compound by using cultured endothelial cells and several in vitro assays that simulate key steps of the angiogenic process, including endothelial cell proliferation, migration, invasion, and tube formation. Our results show that dimethyl itaconate interferes with all the previously mentioned steps of the angiogenic process, suggesting that dimethyl itaconate behaves as an anti-angiogenic compound