Description: <b>Lignan</b> found in bark of some magnolia species.<br>
Magnolol (MAG) — a bioactive biphenolic compound from Magnolia officinalis<br>
derived from the bark (roots and branches) of Magnolia species such as M. officinalis, M. obovata, and M. grandiflora<br>
The two main bioactive compounds isolated from these plants are MAG (5,5ʹ-diallyl-2,2ʹ-dihydroxybiphenyl) and <b>Honokiol</b> (3,5ʹ-diallyl-4,2ʹ-dihydroxybiphenyl) (Fig. 1) which are phenolic regioisomers. <br>
In the bark extracts of Magnolia plants, the composition of MAG ranges from 1 to 10%, while Honokiol comprises 1 to 5%<br>
Magnolol is a biphenolic neolignan isolated from the bark of Magnolia officinalis. It is structurally related to honokiol and is studied for anti-inflammatory, antioxidant, antimicrobial, and neuroactive effects. In preclinical oncology models, magnolol is reported to modulate NF-κB, STAT3, PI3K/AKT, MAPK, Wnt/β-catenin, and redox pathways, with downstream effects on cell-cycle arrest, apoptosis, invasion/EMT, and angiogenesis. Oral bioavailability is limited and many cytotoxic concentrations reported in vitro are in the tens of µM range, often above typical systemic levels from standard supplementation.<br>
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major pathways and molecular targets involved in magnolol’s anticancer actions:<br>
-Apoptosis: ↑ Bax, ↓ Bcl-2, ↑ cytochrome c, ↑ caspase-9, ↑ caspase-3 <br>
-Arrests cell cycle at G0/G1 or G2/M phase:↓ Cyclin D1, CDK4, CDK6, Cyclin B1, CDK1<br>
-Inhibits NF-κB activation: ↓ IκBα, COX-2, TNF-α<br>
-Inhibits PI3K, Akt, and mTOR phosphorylation<br>
-Suppresses angiogenesis: ↓ Bcl-XL, Mcl-1, VEGF, cyclin D1<br>
-Inhibits β-catenin nuclear translocation<br>
-increase ROS production in tumor cells → triggers mitochondrial apoptosis<br>
-Magnolol activates Nrf2 in normal cells → upregulates HO-1, NQO1: Protects normal tissue from oxidative stress during chemotherapy or inflammation.<br>
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Most in-vitro IC50 values fall in the 10–100 µM range, often above typical systemic exposure.<br>
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<!-- Magnolol (MAG) — Time-Scale Flagged Pathway Table -->
<table border="1" cellpadding="4" cellspacing="0">
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Cancer / Tumor Context</th>
<th>Normal Tissue Context</th>
<th>TSF</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
<tr>
<td>1</td>
<td>NF-κB inflammatory / survival transcription</td>
<td>NF-κB ↓; COX-2, cytokines, Bcl-2 family ↓ (reported)</td>
<td>Inflammation tone ↓</td>
<td>R, G</td>
<td>Anti-inflammatory + anti-survival transcription</td>
<td>One of the most consistently reported mechanisms in both inflammatory and tumor models.</td>
</tr>
<tr>
<td>2</td>
<td>STAT3 signaling</td>
<td>STAT3 phosphorylation ↓ (reported)</td>
<td>↔</td>
<td>R, G</td>
<td>Oncogenic transcription suppression</td>
<td>Reported in several cancer cell systems; contributes to reduced proliferation and survival signaling.</td>
</tr>
<tr>
<td>3</td>
<td>PI3K → AKT → mTOR pathway</td>
<td>PI3K/AKT signaling ↓ (model-dependent)</td>
<td>↔</td>
<td>R, G</td>
<td>Growth/survival modulation</td>
<td>Frequently described as downstream of inflammatory pathway suppression; context-dependent strength.</td>
</tr>
<tr>
<td>4</td>
<td>Nrf2 / ARE antioxidant response</td>
<td>Modulation context-dependent; may decrease oxidative stress or alter redox tone</td>
<td>Nrf2 ↑; HO-1 ↑; GSH ↑ (cytoprotective)</td>
<td>R, G</td>
<td>Redox regulation</td>
<td>Magnolol activates Nrf2 in non-malignant oxidative stress models; tumor direction varies and may influence therapy sensitivity.</td>
</tr>
<tr>
<td>5</td>
<td>MAPK pathways (ERK / JNK / p38)</td>
<td>MAPK modulation (stress activation or ERK suppression; context-dependent)</td>
<td>↔</td>
<td>P, R, G</td>
<td>Signal reprogramming</td>
<td>JNK/p38 activation and ERK modulation reported variably depending on cell type and dose.</td>
</tr>
<tr>
<td>6</td>
<td>Cell-cycle arrest (G0/G1 or G2/M)</td>
<td>Cell-cycle arrest ↑ (reported)</td>
<td>↔</td>
<td>G</td>
<td>Cytostasis</td>
<td>Associated with Cyclin D1/CDK modulation and checkpoint protein regulation.</td>
</tr>
<tr>
<td>7</td>
<td>Intrinsic apoptosis (mitochondrial pathway)</td>
<td>Apoptosis ↑; caspases ↑; Bax/Bcl-2 ratio ↑ (reported)</td>
<td>↔ (generally less activation)</td>
<td>G</td>
<td>Cell death execution</td>
<td>Often downstream of survival pathway inhibition and ROS signaling shifts.</td>
</tr>
<tr>
<td>8</td>
<td>ROS / redox modulation</td>
<td>ROS ↑ in some tumor models; antioxidant effects in non-tumor systems</td>
<td>Oxidative stress ↓ in inflammatory models</td>
<td>P, R, G</td>
<td>Context-dependent redox modulation</td>
<td>Biphasic redox behavior similar to other polyphenols; not a universally tumor-selective pro-oxidant.</td>
</tr>
<tr>
<td>9</td>
<td>Wnt/β-catenin signaling</td>
<td>β-catenin signaling ↓ (reported)</td>
<td>↔</td>
<td>G</td>
<td>Proliferation/invasion modulation</td>
<td>Reported particularly in colorectal and hepatocellular carcinoma models; keep model-qualified.</td>
</tr>
<tr>
<td>10</td>
<td>Invasion / metastasis (MMPs / EMT)</td>
<td>MMP2/MMP9 ↓; EMT markers ↓; migration ↓ (reported)</td>
<td>↔</td>
<td>G</td>
<td>Anti-invasive phenotype</td>
<td>Often secondary to NF-κB/STAT3 pathway suppression.</td>
</tr>
<tr>
<td>11</td>
<td>Bioavailability constraint</td>
<td>Limited oral bioavailability; rapid metabolism</td>
<td>—</td>
<td>—</td>
<td>Translation constraint</td>
<td>Plasma levels after oral dosing are typically lower than many in-vitro cytotoxic concentrations.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (rapid signaling/redox interactions)</li>
<li><b>R</b>: 30 min–3 hr (acute transcription and stress-response signaling shifts)</li>
<li><b>G</b>: >3 hr (gene-regulatory adaptation and phenotype outcomes)</li>
</ul>