Description: <b>Oleocanthal</b> is essentially found ONLY in: Fresh, unrefined extra-virgin olive oil (EVOO)<br>
It is part of the pungent, throat-stinging phenolic fraction that disappears in refined oils.<br>
<p><b>Oleuropein</b> (OLEU) — a secoiridoid polyphenol from <b>olive leaf</b> and <b>olive fruit/extra-virgin olive oil</b>; major in-vivo related phenolic is <b>hydroxytyrosol</b> (via hydrolysis/metabolism). Sources: olive leaf extract (standardized to oleuropein), EVOO phenolics.</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) Redox modulation (ROS ↓ in normal tissue; stress/hormesis; NRF2 ↑ context-dependent)<br>
2) Anti-inflammatory transcription suppression (NF-κB ↓)<br>
3) Anti-proliferative signaling in cancer models (PI3K/AKT/mTOR ↓; MAPK modulation; apoptosis ↑; model-dependent)<br>
4) Anti-angiogenic / hypoxia coupling (HIF-1α/VEGF ↓; model-dependent)</p>
<p><b>Bioavailability / PK relevance:</b> Human data show absorption/metabolism after oral olive leaf extract; circulating forms are largely metabolites (and hydroxytyrosol-related), with limited free parent compound exposure. :contentReference[oaicite:0]{index=0}</p>
<p><b>In-vitro vs oral exposure:</b> Many direct “anticancer” cytotoxic effects occur at micromolar concentrations that may exceed typical systemic exposure from supplements/foods (high concentration only for direct tumor cytotoxicity in many models). :contentReference[oaicite:1]{index=1}</p>
<p><b>Clinical evidence status:</b> Nutraceutical/food bioactive with human data mainly for cardiometabolic/inflammation endpoints; oncology evidence largely preclinical/adjunct-hypothesis (no oncology approval). </p>
Also available as a supplement usually labeled as Olive Leaf Extract. (20-50% concentrations)<br>
- commonly used in CSC (Cancer Stem Cell) research.<br>
Main CSC mechanisms:<br>
-Inhibits Wnt/β-catenin — a core CSC survival pathway<br>
-↓ALDH (Reduces ALDH-high CSC subpopulations)<br>
-downregulates stemness geens: SOX2/OCT4/Nanog → reduced sphere formation/self-renewal.<br>
<h3>Oleuropein — Cancer vs Normal Cell Pathway Map</h3>
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th><th>Pathway / Axis</th><th>Cancer Cells</th><th>Normal Cells</th><th>TSF</th><th>Primary Effect</th><th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td><td>ROS</td>
<td>↑ or ↓ (dose-/model-dependent)</td><td>↓ (primary)</td><td>P/R</td>
<td>Redox reprogramming</td>
<td>Normal tissue: antioxidant/lipid-peroxidation reduction common. Cancer: higher exposures can induce stress/apoptosis; direction varies by model and co-stressors.</td>
</tr>
<tr>
<td>2</td><td>NF-κB / cytokine programs</td>
<td>↓</td><td>↓</td><td>R/G</td>
<td>Anti-inflammatory / anti-survival transcription</td>
<td>Commonly reported mechanism for oleuropein/olive phenolics. :contentReference[oaicite:3]{index=3}</td>
</tr>
<tr>
<td>3</td><td>NRF2 (protective vs resistance role)</td>
<td>↔ / ↑ (context-dependent)</td><td>↑</td><td>R/G</td>
<td>Antioxidant gene induction</td>
<td>NRF2 modulation is frequently discussed for olive polyphenols; in cancer contexts can be double-edged (cytoprotection/resistance). :contentReference[oaicite:4]{index=4}</td>
</tr>
<tr>
<td>4</td><td>PI3K/AKT/mTOR</td>
<td>↓ (model-dependent; high concentration only)</td><td>↔</td><td>R/G</td>
<td>Reduced anabolic survival signaling</td>
<td>Reported across cancer models and olive phenolic literature; translation depends on exposure. :contentReference[oaicite:5]{index=5}</td>
</tr>
<tr>
<td>5</td><td>Intrinsic apoptosis (Bax↑/Bcl-2↓; caspases)</td>
<td>↑ (model-dependent; high concentration only)</td><td>↔</td><td>R/G</td>
<td>Mitochondrial apoptosis</td>
<td>Common downstream endpoint in preclinical cancer work; often coupled to redox and PI3K/AKT shifts. :contentReference[oaicite:6]{index=6}</td>
</tr>
<tr>
<td>6</td><td>HIF-1α / VEGF (angiogenesis)</td>
<td>↓ (model-dependent)</td><td>↔</td><td>G</td>
<td>Reduced hypoxia-adaptation / vascular support</td>
<td>Typically secondary; varies strongly by model and readout.</td>
</tr>
<tr>
<td>7</td><td>Cell cycle checkpoints</td>
<td>↓ proliferation (model-dependent)</td><td>↔</td><td>G</td>
<td>Cytostatic growth restraint</td>
<td>Often reported as G0/G1 or G2/M arrest in vitro; exposure gap is common. :contentReference[oaicite:7]{index=7}</td>
</tr>
<tr>
<td>8</td><td>Ferroptosis</td>
<td>↔ (limited / context-dependent)</td><td>↔</td><td>R/G</td>
<td>Not canonical</td>
<td>Olive phenolics can influence lipid peroxidation, but a consistent oleuropein-driven ferroptosis program is not a core claim in the main reviews.</td>
</tr>
<tr>
<td>9</td><td>Ca²⁺ signaling</td>
<td>↔</td><td>↔</td><td>P/R</td>
<td>No primary role</td>
<td>Include only if a specific ER/mitochondrial stress model measures Ca²⁺ endpoints.</td>
</tr>
<tr>
<td>10</td><td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td><td>↓ (constraint)</td><td>—</td>
<td>Metabolite-dominant exposure</td>
<td>Human absorption/metabolism exists, but many tumor-directed effects rely on higher in-vitro exposures; extract standardization and formulation matter. :contentReference[oaicite:8]{index=8}</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min; R: 30 min–3 hr; G: >3 hr</p>
<br>
<br>
<p><b>Oleuropein — AD relevance:</b> Oleuropein/olive leaf phenolics show neuroprotection in models via oxidative- and heat-shock/proteostasis stress responses, with reported reduction of <b>Aβ</b> and <b>tau</b> proteotoxicity in preclinical systems; human AD disease-modifying evidence is not established.</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) ↓ Oxidative stress (ROS ↓; lipid peroxidation ↓; NRF2-linked defense ↑)<br>
2) ↓ Neuroinflammation (NF-κB tone ↓)<br>
3) Proteostasis support (heat-shock/stress-response pathways; context-dependent)<br>
4) Aβ/tau proteotoxicity ↓ (preclinical)</p>
<p><b>Bioavailability / PK relevance:</b> Human absorption/metabolism supports systemic exposure mainly as metabolites; brain relevance likely chronic/adaptive. :contentReference[oaicite:9]{index=9}</p>
<p><b>Clinical evidence status:</b> Predominantly preclinical for AD mechanisms; limited AD-specific clinical endpoint evidence. </p>
<h3>Oleuropein — AD / Neurodegeneration Pathway Map</h3>
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th><th>Pathway / Axis</th><th>Cells</th><th>TSF</th><th>Primary Effect</th><th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td><td>ROS / lipid peroxidation</td>
<td>↓</td><td>P/R</td>
<td>Reduced oxidative burden</td>
<td>Central neuroprotection rationale for olive polyphenols (includes oleuropein/hydroxytyrosol pathways). :contentReference[oaicite:11]{index=11}</td>
</tr>
<tr>
<td>2</td><td>NRF2 axis</td>
<td>↑ (context-dependent)</td><td>R/G</td>
<td>Stress-defense upshift</td>
<td>NRF2 modulation is repeatedly discussed for olive polyphenols in cognition-related health framing. :contentReference[oaicite:12]{index=12}</td>
</tr>
<tr>
<td>3</td><td>Neuroinflammation (NF-κB / cytokines)</td>
<td>↓</td><td>R/G</td>
<td>Lower inflammatory stress</td>
<td>Often paired with antioxidant effects; model-dependent magnitude.</td>
</tr>
<tr>
<td>4</td><td>Proteostasis / heat-shock stress responses</td>
<td>↑ (supportive)</td><td>R/G</td>
<td>Improved handling of misfolded proteins</td>
<td>Oleuropein-rich olive leaf extract reduced Aβ and tau proteotoxicity via oxidative/heat-shock stress regulation in a C. elegans model. :contentReference[oaicite:13]{index=13}</td>
</tr>
<tr>
<td>5</td><td>Aβ / tau proteotoxicity</td>
<td>↓ (preclinical)</td><td>G</td>
<td>Reduced pathology-linked toxicity</td>
<td>Evidence is stronger in models than in biomarker-confirmed human AD studies. :contentReference[oaicite:14]{index=14}</td>
</tr>
<tr>
<td>6</td><td>Ca²⁺ homeostasis / excitotoxic vulnerability</td>
<td>↔ / stabilized (indirect)</td><td>P/R</td>
<td>Supportive (secondary)</td>
<td>Typically secondary to mitochondrial/redox support unless a study explicitly measures Ca²⁺ endpoints.</td>
</tr>
<tr>
<td>7</td><td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td><td>—</td>
<td>Preclinical-dominant AD evidence</td>
<td>Most AD-relevant mechanisms are model-based; human AD efficacy endpoints remain limited. :contentReference[oaicite:15]{index=15}</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min; R: 30 min–3 hr; G: >3 hr</p>