Description: <p><b>Proanthocyanidins (PACs; condensed tannins)</b> = oligomeric/polymeric flavan-3-ols (e.g., catechin/epicatechin units); abundant in grape seed, cocoa, cranberry, apple skin, pine bark. Degree of polymerization (DP) influences bioactivity and absorption.<br>
<b>Primary mechanisms (conceptual rank):</b><br>
1) Redox modulation → direct ROS scavenging + metal chelation (Fe²⁺/Cu²⁺).<br>
2) NRF2 activation → endogenous antioxidant enzymes (HO-1, NQO1, GCLC).<br>
3) Anti-inflammatory signaling → ↓ NF-κB / ↓ COX-2 / ↓ cytokines.<br>
4) Anti-proliferative / pro-apoptotic signaling in cancer (MAPK, PI3K/Akt modulation; dose-dependent).<br>
5) Anti-angiogenic / anti-metastatic effects (VEGF, MMPs; model-dependent).<br>
<b>PK / bioavailability:</b> monomers/low-DP oligomers absorbed; higher-DP polymers poorly absorbed but metabolized by gut microbiota to phenolic acids; plasma parent PAC levels modest vs many in-vitro studies.<br>
<b>In-vitro vs systemic exposure:</b> many cancer studies use ≥10–100 µM equivalents; achievable circulating levels typically lower and largely conjugated/metabolite-driven.<br>
<b>Clinical evidence status:</b> strongest human data in vascular/cardiometabolic endpoints; oncology evidence largely preclinical/adjunct.</p>
<b>Polyphenols</b> found in cranberry, blueberry, and grape seeds.<br>
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Proanthocyanidin B2 (PB2) is a type of dimer flavonoid that is found in grape seed, pine bark, wine, and tea leaves [17]. PB2 has been shown to possess various bioactivities, including anti-oxidant, anti-inflammation, and anti-obesity activities, and it has also shown efficacy in the treatment of cancer, cardiovascular disease, type 2 diabetes, ulcerative colitis, as well as acute liver injury.
<a href="https://pmc.ncbi.nlm.nih.gov/articles/PMC6525465/"> PKM2 is the target of proanthocyanidin B2 </a><br>
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PB2 also suppressed glucose uptake and lactate levels via the direct inhibition of the key glycolytic enzyme, PKM2.<br>
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<h3>Proanthocyanidins (PACs) — Cancer-Relevant Pathways</h3>
<table>
<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 tone / redox balance</td>
<td>↓ (low–mod dose); ↑ (high concentration only)</td>
<td>↓</td>
<td>P→R</td>
<td>Antioxidant; metal chelation</td>
<td>Catechol-rich structure scavenges radicals; pro-oxidant shift reported at high doses in tumors (model-dependent).</td>
</tr>
<tr>
<td>2</td>
<td>NRF2 axis</td>
<td>↑ (context-dependent)</td>
<td>↑</td>
<td>R→G</td>
<td>Endogenous antioxidant induction</td>
<td>↑ HO-1/NQO1; protective in normal tissue; may support tumor stress resistance (context-dependent).</td>
</tr>
<tr>
<td>3</td>
<td>NF-κB / inflammatory signaling</td>
<td>↓</td>
<td>↓</td>
<td>R→G</td>
<td>Anti-inflammatory</td>
<td>Reduces cytokines, COX-2; anti-tumor microenvironment effect plausible.</td>
</tr>
<tr>
<td>4</td>
<td>PI3K/Akt / MAPK pathways</td>
<td>↓ proliferation (model-dependent)</td>
<td>↔</td>
<td>R→G</td>
<td>Growth signaling attenuation</td>
<td>Observed in breast, colon, prostate models; dose and DP dependent.</td>
</tr>
<tr>
<td>5</td>
<td>Apoptosis (caspase activation)</td>
<td>↑ (dose-dependent)</td>
<td>↔ / ↓</td>
<td>R→G</td>
<td>Pro-apoptotic signaling</td>
<td>Mitochondrial depolarization reported; often supra-physiologic exposure.</td>
</tr>
<tr>
<td>6</td>
<td>Angiogenesis (VEGF)</td>
<td>↓ (preclinical)</td>
<td>↔</td>
<td>G</td>
<td>Anti-angiogenic</td>
<td>↓ VEGF expression in models; human oncologic data limited.</td>
</tr>
<tr>
<td>7</td>
<td>Ferroptosis axis</td>
<td>↓ (anti-lipid-ROS bias)</td>
<td>↓</td>
<td>P→R</td>
<td>Lipid peroxidation inhibition</td>
<td>Strong antioxidant property may counter ferroptotic strategies (context-dependent).</td>
</tr>
<tr>
<td>8</td>
<td>Clinical Translation Constraint</td>
<td>—</td>
<td>—</td>
<td>—</td>
<td>Bioavailability & dose gap</td>
<td>High-DP PACs poorly absorbed; many in-vitro doses exceed realistic plasma exposure; adjunct role most plausible.</td>
</tr>
</table>
<p><b>TSF Legend:</b> P: 0–30 min | R: 30 min–3 hr | G: >3 hr</p>
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<h3>Proanthocyanidins (PACs) — Alzheimer’s Disease–Relevant Axes</h3>
<table>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cells (neurons/glia)</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>Lipid peroxidation / neuronal ROS</td>
<td>↓</td>
<td>P</td>
<td>Neuroprotective antioxidant</td>
<td>Reduces oxidative damage markers in models; aligns with AD oxidative stress hypothesis.</td>
</tr>
<tr>
<td>2</td>
<td>NRF2 activation</td>
<td>↑</td>
<td>R→G</td>
<td>Endogenous antioxidant upregulation</td>
<td>Supports neuronal resilience; mostly preclinical evidence.</td>
</tr>
<tr>
<td>3</td>
<td>Neuroinflammation (NF-κB)</td>
<td>↓</td>
<td>R→G</td>
<td>Microglial modulation</td>
<td>Reduced cytokine production in animal models.</td>
</tr>
<tr>
<td>4</td>
<td>Aβ aggregation / toxicity</td>
<td>↓ (preclinical)</td>
<td>G</td>
<td>Interference with amyloid aggregation</td>
<td>Reported inhibition of Aβ fibrillization in vitro; human data limited.</td>
</tr>
<tr>
<td>5</td>
<td>BDNF / synaptic plasticity</td>
<td>↑ (model-dependent)</td>
<td>G</td>
<td>Neurotrophic signaling</td>
<td>Observed in flavanol-rich cocoa/grape extract studies; translation to PAC isolates unclear.</td>
</tr>
<tr>
<td>6</td>
<td>Clinical Translation Constraint</td>
<td>—</td>
<td>—</td>
<td>Dietary-level evidence</td>
<td>Human trials mostly use flavanol-rich extracts; cognitive effects modest and stage-dependent.</td>
</tr>
</table>
<p><b>TSF Legend:</b> P: 0–30 min | R: 30 min–3 hr | G: >3 hr</p>