# A Narrative Review of Metabolomic Insights into Olive Oil's Nutritional Value
## 2 Olive Oil Metabolomics
### Hydroxytyrosine  
As previously mentioned, OLE is a precursor of HT which has several beneficial effects on health. In oxidative stress situations, HT is able to not only stimulate the activity of protective enzymes but also act in mitochondrial biogenesis. Furthermore, it improves endoplasmatic reticulum (ER) homeostasis and activates a pathway that follows ER stress, thereby preventing ROS accumulation. HT exhibits the capability of inhibiting copper sulphate-induced oxidation of LDL, decreasing the plasma levels of LDL and total cholesterol, and increasing the levels of HDL, thereby contributing to overall cardiovascular health [37]. Further health benefits of HT have been described, including its involvement in protection against metabolic disorders [48; 49], neuroprotective effects [50; 51], and impressive potential for cancer prevention and therapeutics [51]. The numerous health benefits of olives and their bioproducts can be attributed to the anti-inflammatory properties of polyphenols [52], like HT and OLE, whose such properties have been extensively studied and treated [53]. The administration of olive oil containing 5 mg/kg HT affected serum TNF-\(\alpha\) levels and iNOS and COX-2 expression [54]. Similarly, treatment with HT-20, a preparation containing 20% HT, reduced the TNF-\(\alpha\) and IL-1\(\beta\) mRNA levels in a mouse model of acute inflammation and hyperalgesia but did not influence the IL-10 levels [54]. Furthermore, THP-1 macrophages cultured with increasing doses of HT (25, 50, and 100 uM) before LPS stimulation showed a dose-dependent reduction in TNF-\(\alpha\), iNOS, and COX-2 protein and gene expression levels, underlying the connection between the modulation of inflammatory and oxidative processes [55]. Similar results were obtained in a model of inflammation in LPS-stimulated [774] murine macrophages, in which downregulation of iNOS and COX-2 gene expression was observed by preventing NF-\(\kappa\)B, STAT-1\(\alpha\), and IRF-1 activation mediated by LPS-induced ROS generation [56]. Treatment with HT and the derivatives of LPS-stimulated human monocytes induced a reduction in the mRNA levels of COX-2 and prostaglandin 2 and increased TNF-\(\alpha\) production, in contrast to what we have observed thus far [57]. HT also reduces the expression of IL-1\(\beta\) and chemokines such as macrophage migration inhibitory factor and RANTES, as well as ROS production [58]. The cells considered in these in vitro studies, such as monocytes and macrophages, are important players in atherosclerotic plaque formation and in the pathological process underlying the development of CVDs. The addition of olive oil extracts enriched in OLE to THP-1 cell cultures modulated the levels of MMP-9 and TNF-\(\alpha\) expression, influencing the function of monocytes in the onset of vascular diseases such as atherosclerosis, in which the inflammatory component is prevalent [58]. An effort in this study was made by the administration of OLE to a myocardial infarction group of people, which reduced the TNF-\(\alpha\) and IL-1\(\beta\) levels [59]. Interestingly, the phenolic compound oleocanthal has anti-inflammatory effects comparable to those of ibuprofen through the inhibition of COX-1 and COX-2, which are involved in prostaglandin synthesis. This mechanism of action may contribute to the prevention of CVDs and cancer [52; 60]. The neuroprotective action of oleocanthal as well as its ability to enhance neuronal energy metabolism and diminish the harmful effects of protein glycation have been reported [61]. Furthermore, this compound can enhance the removal of amyloid beta protein from neurons, a key component in the pathogenesis of Alzheimer's disease, and mitigate astrocyte inflammation [62]. Hydroxy-isocoromanans have also been found to exhibit anti-inflammatory activities [59]. Generally, flavonoids appear to have anti-inflammatory and antioxidant activities as well as antidiabetic, anticancer, and cardiovascular protective properties [63].