The Mediterranean diet, renowned for its health benefits, especially in reducing cardiovascular risks and protecting against diseases like diabetes and cancer, emphasizes virgin olive oil as a key contributor to these advantages. Despite being a minor fraction, the phenolic compounds in olive oil significantly contribute to its bioactive effects. This review examines the bioactive properties of hydroxytyrosol and related molecules, including naturally occurring compounds (-)-oleocanthal and (-)–oleacein, as well as semisynthetic derivatives like hydroxytyrosyl esters and alkyl ethers. (-)-Oleocanthal and (-)–oleacein show promising anti-tumor and anti-inflammatory properties, which are particularly underexplored in the case of (-)–oleacein. Additionally, hydroxytyrosyl esters exhibit similar effectiveness to hydroxytyrosol, while certain alkyl ethers surpass their precursor’s properties. Remarkably, the emerging research field of the effects of phenolic molecules related to virgin olive oil on cell autophagy presents significant opportunities for underscoring the anti-cancer and neuroprotective properties of these molecules. Furthermore, promising clinical data from studies on hydroxytyrosol, (-)–oleacein, and (-)–oleocanthal urge further investigation and support the initiation of clinical trials with semisynthetic hydroxytyrosol derivatives. This review provides valuable insights into the potential applications of olive oil-derived phenolics in preventing and managing diseases associated with cancer, angiogenesis, and atherosclerosis.

Graviola (Annona muricata) is a tropical plant with many traditional ethnobotanic uses and pharmacologic applications. A metabolomic study of both aqueous and DMSO extracts from Annona muricata leaves recently allowed us to identify dozens of bioactive compounds. In the present study, we use a proteomic approach to detect altered patterns in proteins on both conditioned media and extracts of HT-1080 fibrosarcoma cells under treatment conditions, revealing new potential bioactivities of Annona muricata extracts. Our results reveal the complete sets of deregulated proteins after treatment with aqueous and DMSO extracts from Annona muricata leaves. Functional enrichment analysis of proteomic data suggests deregulation of cell cycle and iron metabolism, which are experimentally validated in vitro. Additional experimental data reveal that DMSO extracts protect HT-1080 fibrosarcoma cells and HMEC-1 endothelial cells from ferroptosis. Data from our proteomic study are available via ProteomeXchange with identifier PXD042354.

(+)-Aeroplysinin-1 (Apl-1) is a brominated compound isolated from the marine sponge Aplysina aerophoba that exhibits pleiotropic bioactive effects, impairing cell growth in cancer cells, inhibiting angiogenesis in vitro and in vivo and modulating the redox status of different cell types, among other reported activities. In addition to the aforementioned effects, the anti-inflammatory potential of this natural compound was explored in previous work of our laboratory, but the mechanism of action underlying this effect was not described. In this work, we delve into the anti-inflammatory effect of Apl-1 in the context of vascular endothelial cells in vitro, providing new data regarding the molecular mechanism underlying this activity. The characterization of the mechanism of action points to an inhibitory effect of Apl-1 on the NF-κB pathway, one of the main axes involved in endothelial response during inflammatory events. Our results show that Apl-1 can inhibit the expression of pro-inflammatory genes in tumor necrosis factor alpha (TNF-α)- and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), targeting the nuclear factor kappa B subunit (NF-κB) pathway through a mechanism of action involving the inhibition of I kappa B kinase (IKK) complex phosphorylation and RelA/p65 nuclear import. In addition, Apl-1 prevented the phosphorylation of Akt induced by TNF-α in HUVECs, probably supporting the inhibitory effect of this compound in the NF-κB pathway. Experimental evidence reported in this work opens the door to the potential pharmacological use of this compound as an anti-inflammatory agent in diseases that course with a pathological endothelial response to inflammation, such as atherosclerosis.

Hydroxytyrosol (HT) is a bioactive phenolic compound naturally present in olives and extra virgin olive oil (EVOO) which is described as an antioxidant, antitumoral and antiangiogenic molecule. Previous studies of semi-synthetic HT-derivatives presented the hydroxytyrosyl alkyl ether HT-C6 as one of the most potent derivatives studied in the context of antioxidant, anti-platelet and antiangiogenic assays, but its direct effect on inflammation was not reported. In this work, we use RT-qPCR measure of gene expression, protein analysis by Western-blot and immunofluorescence techniques, adhesion and migration functional assays and single-cell monitoring of reactive oxygen species (ROS) in order to explore in vitro the ability of HT-C6 to interfere in the inflammatory response of endothelial cells (ECs). Our results showed that HT-C6 strongly reduces the TNF-α-induced expression of vascular cell adhesion molecule 1 (VCAM1), intercellular cell adhesion molecule 1 (ICAM1), E-selectin (SELE), C-C motif chemokine ligand 2 and 5 (CCL2 and CCL5) in HUVECs, impairing the chemotactic and adhesion potential of these cells towards THP-1 monocytes in vitro. In this work, we define a mechanism of action underlying the anti-inflammatory effect of HT-C6, which involves the abrogation of nuclear factor kappa B (NF-κB) pathway activation in ECs. These results, together with the ability of HT-C6 to reduce ROS formation in ECs, point to this compound as a promising HT-derivative to be tested in the treatment of atherosclerosis.

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.

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.