Description: <p><b>Flavonoids</b> — a large class of plant polyphenols (natural products) including flavonols (quercetin, kaempferol), flavones (apigenin, luteolin), flavanones (naringenin), isoflavones (genistein), flavan-3-ols (EGCG/catechins), and anthocyanins. Sources: fruits/berries, tea/cocoa, legumes, herbs, and standardized extracts.</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) Redox signaling modulation (often hormetic: low-dose NRF2 ↑; high-dose ROS ↑ in cancer)<br>
2) Anti-inflammatory transcription suppression (NF-κB ↓; cytokines ↓)<br>
3) Kinase signaling modulation (PI3K/AKT/mTOR ↓; MAPK context-dependent)<br>
4) Mitochondrial stress → apoptosis (cancer; often high concentration only)<br>
5) Iron/copper chelation + lipid-peroxidation effects (ferroptosis overlap in select contexts)</p>
<p><b>Bioavailability / PK relevance:</b> Many flavonoids have low oral bioavailability (rapid phase II conjugation: glucuronidation/sulfation; microbiome-derived metabolites). Plasma free aglycone levels are typically low; tissue effects often reflect metabolites and chronic exposure.</p>
<p><b>In-vitro vs oral exposure:</b> Many “anti-cancer” cytotoxic effects occur at micromolar aglycone concentrations exceeding typical systemic exposure from diet/supplements (high concentration only), unless specialized formulations or local GI exposure is the intent.</p>
<p><b>Clinical evidence status:</b> Broad epidemiology + small human trials for cardiometabolic/inflammatory endpoints; oncology evidence mostly preclinical/adjunct-hypothesis; no class-wide RCT oncology approval.</p>
<br>
Flavonoids are classified into seven structural classes: <br>
1.flavanones<br>
-Nargenin, Naringin, Hesperetin, Isosakuranetin, Eriodictyol, Taxifolin<br>
2.flavonols<br>
-Quercetin, Myrcetin, Fisetin, Rutin Morin, Kaempferol <br>
3.chalcones<br>
-Butein, Xanthohumol, Isoliquintigenin, Cardamonin, Bavachalone, Xanthohumol, Phloretin<br>
4.flavanols<br>
-Catechin, Gallocatechin, Epicatechin, Epigallocatechin-3-galate<br>
5.anthocyanidins<br>
-Cyanidin<br>
6.flavones<br>
-Chrysin, Apigenin, Luteolin, Vitexin, Orientin, Bacalein, Wogonin, Oroxylin A, Saponarin<br>
7.isoflavonoids<br>
-Daidzein, Genistein, Glycitein<br>
<br>
<h3>Flavonoids — Cancer vs Normal Cell Pathway Map (Class-Level)</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-dependent)</td>
<td>↓ (physiologic / adaptive)</td>
<td>P/R</td>
<td>Redox reprogramming</td>
<td>Class hallmark: hormesis. Low–moderate exposure often antioxidant/mitochondrial-protective; high exposure can be pro-oxidant/cytotoxic in cancer models.</td>
</tr>
<tr>
<td>2</td>
<td>NRF2 (stress-defense; resistance role)</td>
<td>↑ (context-dependent)</td>
<td>↑</td>
<td>R/G</td>
<td>Antioxidant gene induction</td>
<td>Normal: cytoprotection. Cancer: NRF2 ↑ can reduce therapy sensitivity in some contexts (double-edged).</td>
</tr>
<tr>
<td>3</td>
<td>NF-κB / inflammatory cytokine programs</td>
<td>↓</td>
<td>↓</td>
<td>R/G</td>
<td>Anti-inflammatory transcription suppression</td>
<td>One of the most consistent class-level effects across models.</td>
</tr>
<tr>
<td>4</td>
<td>PI3K/AKT/mTOR</td>
<td>↓ (model-dependent)</td>
<td>↔ / ↓ (metabolic/inflammatory improvement)</td>
<td>R/G</td>
<td>Reduced anabolic survival signaling</td>
<td>Frequently reported but not uniform; often secondary to redox/inflammation changes.</td>
</tr>
<tr>
<td>5</td>
<td>MAPK (ERK/JNK/p38)</td>
<td>↑ stress MAPKs; ↓ ERK (context-dependent)</td>
<td>↔</td>
<td>P/R</td>
<td>Stress-response tuning</td>
<td>JNK/p38 often ↑ with pro-apoptotic stress; ERK effects vary by compound/model.</td>
</tr>
<tr>
<td>6</td>
<td>Intrinsic apoptosis (mitochondrial; caspases)</td>
<td>↑ (high concentration only)</td>
<td>↔</td>
<td>R/G</td>
<td>Experimental tumor cytotoxicity</td>
<td>Common in vitro endpoint; translation limited by PK and achievable free aglycone levels.</td>
</tr>
<tr>
<td>7</td>
<td>Cell-cycle checkpoints</td>
<td>↓ proliferation (model-dependent)</td>
<td>↔</td>
<td>G</td>
<td>Checkpoint enforcement</td>
<td>Often downstream of kinase/redox modulation.</td>
</tr>
<tr>
<td>8</td>
<td>Ferroptosis (iron/lipid peroxidation contexts)</td>
<td>↑ or ↓ (compound-dependent)</td>
<td>↔</td>
<td>R/G</td>
<td>Lipid-ROS vulnerability shift</td>
<td>Some flavonoids chelate iron (anti-ferroptotic) while others promote lipid peroxidation under stress (pro-ferroptotic); not class-uniform.</td>
</tr>
<tr>
<td>9</td>
<td>HIF-1α / Warburg coupling</td>
<td>↓ (model-dependent; high concentration only)</td>
<td>↔</td>
<td>G</td>
<td>Reduced hypoxia-adaptation signaling</td>
<td>Reported in some models (often via PI3K/mTOR or ROS), but not a universal class mechanism at dietary exposure.</td>
</tr>
<tr>
<td>10</td>
<td>Ca²⁺ / ER stress coupling</td>
<td>↑ or ↔ (stress-dependent)</td>
<td>↔</td>
<td>P/R</td>
<td>UPR/excitability modulation</td>
<td>Relevant mainly when apoptosis/UPR/excitotoxicity endpoints are measured; not a core class axis.</td>
</tr>
<tr>
<td>11</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>↓ (constraint)</td>
<td>—</td>
<td>PK + heterogeneity</td>
<td>Major constraints: low bioavailability, metabolite-dominant exposure, large heterogeneity across subclasses, and frequent in-vitro concentration gaps.</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>Flavonoids — AD relevance:</b> Flavonoid-rich diets and select supplements are studied for neuroprotection via antioxidant/anti-inflammatory effects, cerebrovascular support, and synaptic plasticity signaling. Effects are generally supportive and exposure/metabolite dependent.</p>
<p><b>Primary mechanisms (conceptual rank):</b><br>
1) ↓ Oxidative stress (ROS ↓; lipid peroxidation ↓)<br>
2) ↓ Neuroinflammation (NF-κB/cytokines ↓; microglial tone ↓)<br>
3) ↑ Synaptic plasticity signaling (BDNF/CREB ↑; network efficiency; chronic adaptation)<br>
4) Vascular/endothelial support (NO signaling; perfusion coupling)<br>
5) Secondary Aβ/tau pathway modulation (preclinical; not class-uniform)</p>
<p><b>Bioavailability / PK relevance:</b> Brain effects likely mediated by metabolites and chronic intake; large variability by subclass and microbiome.</p>
<p><b>Clinical evidence status:</b> Signals in small human trials (often with specific subclasses like cocoa flavanols/anthocyanins); AD disease-modification not established.</p>
<h3>Flavonoids — AD / Neurodegeneration Pathway Map (Class-Level)</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>Core neuroprotection rationale; effect depends on subclass/metabolites and baseline oxidative stress.</td>
</tr>
<tr>
<td>2</td>
<td>Neuroinflammation (NF-κB, cytokines)</td>
<td>↓</td>
<td>R/G</td>
<td>Lower inflammatory stress</td>
<td>Common class-level effect; relevant to microglial activation tone.</td>
</tr>
<tr>
<td>3</td>
<td>NRF2 axis</td>
<td>↑ (adaptive; context-dependent)</td>
<td>R/G</td>
<td>Stress-defense upshift</td>
<td>Often supports antioxidant enzymes; magnitude varies widely by compound and exposure.</td>
</tr>
<tr>
<td>4</td>
<td>BDNF / CREB / synaptic plasticity</td>
<td>↑ (supportive)</td>
<td>G</td>
<td>Plasticity and learning support</td>
<td>Frequently invoked across flavonoid cognition studies; typically requires weeks–months intake.</td>
</tr>
<tr>
<td>5</td>
<td>Vascular/endothelial function (NO coupling)</td>
<td>↑ (supportive)</td>
<td>R/G</td>
<td>Perfusion and neurovascular support</td>
<td>Often attributed to flavanols/anthocyanins; supports “vascular cognitive impairment” framing.</td>
</tr>
<tr>
<td>6</td>
<td>Aβ / tau-associated pathology</td>
<td>↔ / ↓ (preclinical; compound-dependent)</td>
<td>G</td>
<td>Pathology modulation (hypothesis)</td>
<td>Not class-uniform; strongest evidence is preclinical, with limited biomarker-confirmed human replication.</td>
</tr>
<tr>
<td>7</td>
<td>Ca²⁺ homeostasis / excitotoxic vulnerability</td>
<td>↔ / stabilized (indirect)</td>
<td>P/R</td>
<td>Excitotoxic buffering</td>
<td>Secondary to antioxidant/mitochondrial support; include as primary only with explicit Ca²⁺ endpoints.</td>
</tr>
<tr>
<td>8</td>
<td>Clinical Translation Constraint</td>
<td>↓ (constraint)</td>
<td>—</td>
<td>Heterogeneity + metabolite dependence</td>
<td>Large differences across subclasses, dosing, and microbiome; effects generally supportive, not disease-modifying.</td>
</tr>
</table>
<p><b>TSF legend:</b> P: 0–30 min; R: 30 min–3 hr; G: >3 hr</p>