Description: <b>Methylene blue (MB)</b>, also known as methylthioninium chloride, is a thiazine dye that can be used as a medication, and can be administered orally, subcutaneously or intravenously.<br>
Mainly used to treat methemoglobinemia by chemically reducing the ferric iron in hemoglobin to ferrous iron<br>
Methylene blue is commonly used in medical practice, especially as a dye in microbiological staining<br>
Antidote in cyanide poisoning: an oxidation-reduction indicator: an antiseptic<br>
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Pathways:<br>
- may increases the oxygen consumption of normal tissues having aerobic glycolysis, and of tumors<br>
- generate reactive oxygen species (ROS) upon light activation<br>
-effects on mitochondrial metabolism may contribute to modulation of apoptosis and energy metabolism in cancer cells.<br>
-can affect the generation of reactive oxygen species.<br>
-Historically, it was used in patients with urinary tract infection <br>
-MB has also been used as a tracer for cancer diagnosis and as a photosensitizer for cancer treatment <br>
-shifts redox balance and can promote OXPHOS over glycolysis in some models(reverse Warburg effect)<br>
-can cross BBB and reach brain at concentrations 10 times higher than that in the circulation<br>
-causes shift from shift from glycolysis to oxidative phosphorylation.<br>
-reduces glutathione reductase GSR (an enzyme of glutathione metabolism), context- and concentration-dependent
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<!-- Methylene Blue (MB) — Cancer-Oriented Time-Scale Flagged Pathway Table -->
<!-- Methylene Blue (M-Blu) — Cancer-Oriented Time-Scale Flagged Pathway Table (Refined) -->
<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>Mitochondrial redox cycling (electron shuttle)</td>
<td>Redox modulation; NADH oxidation ↑ (context)</td>
<td>Mitochondrial efficiency ↑ at low doses (reported)</td>
<td>P, R</td>
<td>Bioenergetic modulation</td>
<td>MB can accept electrons from NADH and donate downstream in the ETC; effects are dose-dependent and context-specific.</td>
</tr>
<tr>
<td>2</td>
<td>OXPHOS vs glycolysis balance</td>
<td>Shift toward oxidative metabolism reported in some tumor models</td>
<td>Improved mitochondrial coupling (low dose)</td>
<td>R</td>
<td>Metabolic reprogramming</td>
<td>Sometimes described as “Warburg reversal,” but more accurately a redox/respiratory modulation that varies by system.</td>
</tr>
<tr>
<td>3</td>
<td>ROS modulation (biphasic)</td>
<td>ROS ↑ at higher doses; apoptosis ↑ (reported)</td>
<td>ROS ↓ or stabilized at lower doses</td>
<td>P, R</td>
<td>Redox destabilization (dose-dependent)</td>
<td>Acts antioxidant at low concentrations; can become pro-oxidant as concentration increases.</td>
</tr>
<tr>
<td>4</td>
<td>Mitochondrial membrane potential (ΔΨm)</td>
<td>ΔΨm collapse at higher doses (reported)</td>
<td>Stabilization possible at low doses</td>
<td>R</td>
<td>Mitochondrial stress</td>
<td>High-dose exposure can impair mitochondrial integrity and promote apoptosis.</td>
</tr>
<tr>
<td>5</td>
<td>Intrinsic apoptosis signaling</td>
<td>Caspases ↑; apoptosis ↑ (reported in vitro)</td>
<td>↔</td>
<td>G</td>
<td>Cell death execution</td>
<td>Generally downstream of ROS and mitochondrial perturbation.</td>
</tr>
<tr>
<td>6</td>
<td>Photodynamic ROS generation (light-activated)</td>
<td>ROS ↑↑ when photoactivated</td>
<td>Localized ROS if illuminated</td>
<td>P</td>
<td>Photoactivated cytotoxicity</td>
<td>Distinct mechanism: MB acts as a photosensitizer under light exposure.</td>
</tr>
<tr>
<td>7</td>
<td>Glutathione system modulation (GSR / redox enzymes)</td>
<td>Redox enzyme modulation reported (model-dependent)</td>
<td>Redox buffering alteration possible</td>
<td>R</td>
<td>Redox regulation</td>
<td>Some reports show interaction with glutathione metabolism; not a dominant universal pathway.</td>
</tr>
<tr>
<td>8</td>
<td>Blood–brain barrier penetration</td>
<td>—</td>
<td>CNS accumulation (high tissue levels)</td>
<td>P, R</td>
<td>Pharmacokinetic property</td>
<td>MB crosses the BBB and can accumulate in brain tissue at higher concentrations than plasma.</td>
</tr>
<tr>
<td>9</td>
<td>Monoamine oxidase (MAO) inhibition</td>
<td>—</td>
<td>MAO-A inhibition (clinically relevant)</td>
<td>R</td>
<td>Off-target pharmacology</td>
<td>Important interaction risk with SSRIs/SNRIs (serotonin syndrome).</td>
</tr>
<tr>
<td>10</td>
<td>Safety constraints (G6PD deficiency; serotonin syndrome)</td>
<td>—</td>
<td>Hemolysis risk (G6PD); serotonin toxicity risk</td>
<td>—</td>
<td>Clinical risk management</td>
<td>Well-established safety considerations in clinical use.</td>
</tr>
</table>
<p><b>Time-Scale Flag (TSF):</b> P / R / G</p>
<ul>
<li><b>P</b>: 0–30 min (rapid redox cycling; photoactivation)</li>
<li><b>R</b>: 30 min–3 hr (mitochondrial and redox signaling shifts)</li>
<li><b>G</b>: >3 hr (apoptosis/autophagy outcomes)</li>
</ul>