Identification and Evaluation of Olive Phenolics in the Context of Amine Oxidase Enzyme Inhibition and Depression: In Silico Modelling and In Vitro Validation.

The Mediterranean diet well known for its beneficial health effects, including mood enhancement, is characterised by the relatively high consumption of extra virgin olive oil (EVOO), which is rich in bioactive phenolic compounds. Over 200 phenolic compounds have been associated with Olea europaea, and of these, only a relatively small fraction have been characterised. Utilising the OliveNetTM library, phenolic compounds were investigated as potential inhibitors of the epigenetic modifier lysine-specific demethylase 1 (LSD1). Furthermore, the compounds were screened for inhibition of the structurally similar monoamine oxidases (MAOs) which are directly implicated in the pathophysiology of depression. Molecular docking highlighted that olive phenolics interact with the active site of LSD1 and MAOs. Protein-peptide docking was also performed to evaluate the interaction of the histone H3 peptide with LSD1, in the presence of ligands bound to the substrate-binding cavity. To validate the in silico studies, the inhibitory activity of phenolic compounds was compared to the clinically approved inhibitor tranylcypromine. Our findings indicate that olive phenolics inhibit LSD1 and the MAOs in vitro. Using a cell culture model system with corticosteroid-stimulated human BJ fibroblast cells, the results demonstrate the attenuation of dexamethasone- and hydrocortisone-induced MAO activity by phenolic compounds. The findings were further corroborated using human embryonic stem cell (hESC)-derived neurons stimulated with all-trans retinoic acid. Overall, the results indicate the inhibition of flavin adenine dinucleotide (FAD)-dependent amine oxidases by olive phenolics. More generally, our findings further support at least a partial mechanism accounting for the antidepressant effects associated with EVOO and the Mediterranean diet.

The cellular and molecular basis of major depressive disorder: towards a unified model for understanding clinical depression.

Major depressive disorder (MDD) is considered a serious public health issue that adversely impacts an individual's quality of life and contributes significantly to the global burden of disease. The clinical heterogeneity that exists among patients limits the ability of MDD to be accurately diagnosed and currently, a symptom-based approach is utilized in many cases. Due to the complex nature of this disorder, and lack of precise knowledge regarding the pathophysiology, effective management is challenging. The aetiology and pathophysiology of MDD remain largely unknown given the complex genetic and environmental interactions that are involved. Nonetheless, the aetiology and pathophysiology of MDD have been the subject of extensive research, and there is a vast body of literature that exists. Here we overview the key hypotheses that have been proposed for the neurobiology of MDD and highlight the need for a unified model, as many of these pathways are integrated. Key pathways discussed include neurotransmission, neuroinflammation, clock gene machinery pathways, oxidative stress, role of neurotrophins, stress response pathways, the endocannabinoid and endovanilloid systems, and the endogenous opioid system. We also describe the current management of MDD, and emerging novel therapies, with particular focus on patients with treatment-resistant depression (TRD).

Utilisation of the OliveNet™ Library to investigate phenolic compounds using molecular modelling studies in the context of Alzheimer's disease.

Alzheimer's disease (AD) is a debilitating neurodegenerative disease that affects over 47 million people worldwide, and is the most common form of dementia. There is a vast body of literature demonstrating that the disease is caused by an accumulation of toxic extracellular amyloid-ß (Aß) peptides and intracellular neurofibrillary tangles that consist of hyperphosphorylated tau. Adherence to the Mediterranean diet has been shown to reduce the incidence of AD and the phenolic compounds in extra virgin olive oil, including oleocanthal, have gained a significant amount of attention. A large number of these ligands have been described in the pre-existing literature and 222 of these compounds have been characterised in the OliveNet™ database. In this study, molecular docking was used to screen the 222 phenolic compounds from the OliveNet™ database and assess their ability to bind to various forms of the Aß and tau proteins. The phenolic ligands were found to be binding strongly to the hairpin-turn of the Aß1-40 and Aß1-42 monomers, and binding sites were also identified in the tau fibril protein structures. Luteolin-4'-O-rutinoside, oleuricine A, isorhoifolin, luteolin-7-O-rutinoside, cyanidin-3-O-rutinoside and luteolin-7,4-O-diglucoside were predicted to be novel lead compounds. Molecular dynamics (MD) simulations performed using well-known olive ligands bound to Aß1-42 oligomers highlighted that future work may examine potential anti-aggregating properties of novel compounds in the OliveNet™ database. This may lead to the development and evaluation of new compounds that may have efficacy against Alzheimer's disease.