Description: <b>Alpha-Lipoic-Acid:</b> also known as lipoic acid or thioctic acid (reduced form is dihydrolipoic acid).<br>
"Universal antioxidant" because it is both water- and fat-soluble and can neutralize free radicals.<br>
-Treatment sometimes as ALA/N (alpha-lipoic acid/low-dose naltresone)<br>
-Also done in IV<br>
-Decreases ROS production, but also has pro-oxidant role.<br>
Normal adult can take 300 milligrams twice a day with food, but they should always take a B-complex vitamin with it. Because B complex vitamins, especially thiamine, and biotin, and riboflavin, are depleted during this metabolic process.<br>
α-Lipoic acid acts as a chelating agent for metal ions, a quenching agent for reactive oxygen species, and a reducing agent for the oxidized form of glutathione and vitamins C and E.<br>
-It seems a paradox that LA functions as both antioxidant and prooxidant. LA functions the pro-oxidant only in special cancer cells, such as A549 and PC9 cells which should show high-level NRF2 expression and high glycolytic level. Through inhibiting PDK1 to further prohibit NRF2; LA functions as anticancer prooxidant.<br>
<br>
α-lipoic acid possesses excellent silver chelating properties.<br>
<br>
<pre>
ALA → ROS ↑ (cancer cells; high dose / stressed mitochondria)
ALA → ROS ↓ (normal cells; low–moderate dose)
same pattern seen with: Vitamin C, Menadione, Quercetin, EGCG, Resveratrol
</pre>
- ALA acts as pro-Oxidant only in <a href="tbResEdit.php?rid=278">cancer cells:#278</a>
- Pro-Oxidant Dose <a href="tbResEdit.php?rid=304">margin >100uM:#304 </a><br>
<br>
- Bioavailability: 80-90%, but conversion to EPA/DHA is 5-10% (and takes longer time).<br>
- AI (Adequate Intake): 1.1-1.6g/day. <br>
- human studies have shown that ALA levels decline significantly with age <br>
- 1g of ALA might achieve 500uM in the blood. <br>
- ALA is poorly soluble, lecithin has been used as an amphiphilic matrix to enhance its bioavailability. <br>
- Pilot studies or observational interventions have used flaxseed supplementation (rich in ALA) in doses providing roughly 3–4 g of ALA daily.<br>
- Flaxseed oil is even more concentrated in ALA – typical 50–60% ALA by weight.<br>
- single walnut may contain 300mg of ALA<br>
- chia oil contains 55-65% ALA.<br>
- α-LA can also be obtained from the diet through the consumption of dark green leafy vegetables and meats<br>
- ALA is more stable in chia seeds, (2grams of ALA per tablespoon)<br>
- ALA degrades when exposed to heat, light, and air. (prone to oxidation)<br>
<br>
-Note <a href="tbResList.php?qv=29&tsv=1109&wNotes=on&exSp=open">half-life</a> 1-2 hrs.<br>
<a href="tbResList.php?qv=29&tsv=792&wNotes=on&exSp=open">BioAv</a> 30-40% from walnuts, 60-80% from supplements. Co-ingestion with fat improves absorption. Both fat and water soluble
<br>
Pathways:<br>
<!-- ROS : MMP↓, ER Stress↑, Ca+2↑, Cyt‑c↑, Casp3↑, Casp9↑, DNAdam↑, UPR↑, cl-PARP↑-->
- induce
<a href="tbResList.php?qv=29&tsv=275&wNotes=on">ROS</a> production<br>
- ROS↑ related:
<a href="tbResList.php?qv=29&tsv=197&wNotes=on&word=MMP↓">MMP↓</a>(ΔΨm),
<a href="tbResList.php?qv=29&tsv=103&wNotes=on">ER Stress↑</a>,
<a href="tbResList.php?qv=29&tsv=459&wNotes=on">UPR↑</a>,
<a href="tbResList.php?qv=29&tsv=356&wNotes=on">GRP78↑</a>,
<!-- <a href="tbResList.php?qv=29&tsv=38&wNotes=on&word=Ca+2↑">Ca+2↑</a>, -->
<a href="tbResList.php?qv=29&tsv=77&wNotes=on">Cyt‑c↑</a>,
<a href="tbResList.php?qv=29&wNotes=on&word=Casp">Caspases↑</a>,
<a href="tbResList.php?qv=29&tsv=82&wNotes=on&word=DNAdam↑">DNA damage↑</a>,
<!-- <a href="tbResList.php?qv=29&tsv=239&wNotes=on">cl-PARP↑</a>, -->
<!-- <a href="tbResList.php?qv=29&wNotes=on&word=HSP">HSP↓</a>, -->
<!-- <a href="tbResList.php?qv=29&wNotes=on&word=Prx">Prx</a>, --><!-- mitochondrial antioxidant enzyme-->
<br>
<!-- ANTIOXIDANT : NRF2, SOD, GSH, CAT, HO-1, GPx, GPX4, -->
- Lowers AntiOxidant defense in Cancer Cells:
<a href="tbResList.php?qv=29&tsv=226&wNotes=on&word=NRF2↓">NRF2↓</a>,
<!-- <a href="tbResList.php?qv=29&word=Trx&wNotes=on">TrxR↓**</a>, --><!-- major antioxidant system -->
<a href="tbResList.php?qv=29&tsv=298&wNotes=on&word=SOD↓">SOD↓</a>,
<a href="tbResList.php?qv=29&tsv=137&wNotes=on&word=GSH↓">GSH↓</a>
<a href="tbResList.php?qv=29&tsv=46&wNotes=on">Catalase↓</a>
<a href="tbResList.php?qv=29&tsv=597&wNotes=on">HO1↓</a>
<a href="tbResList.php?qv=29&wNotes=on&word=GPx">GPx↓</a>
<br>
- Raises
<a href="tbResList.php?qv=29&tsv=1103&wNotes=on&word=antiOx↑">AntiOxidant</a>
defense in Normal Cells:
<a href="tbResList.php?qv=29&tsv=275&wNotes=on&word=ROS↓">ROS↓</a>,
<a href="tbResList.php?qv=29&tsv=226&wNotes=on&word=NRF2↑">NRF2↑</a>,
<a href="tbResList.php?qv=29&tsv=298&wNotes=on&word=SOD↑">SOD↑</a>,
<a href="tbResList.php?qv=29&tsv=137&wNotes=on&word=GSH↑">GSH↑</a>,
<a href="tbResList.php?qv=29&tsv=46&wNotes=on&word=Catalase↑">Catalase↑</a>,
<!-- genes involved in the oxidative stress-antioxidant defense system PRNP, NQO1, and GCLM -->
<br>
<!-- INFLAMMATION : NF-kB↓, COX2↓, COX2↓ PRO-INFL CYTOKINES: IL-1β↓, TNF-α↓, IL-6↓, IL-8↓, -->
- lowers
<a href="tbResList.php?qv=29&tsv=953&wNotes=on&word=Inflam">Inflammation</a> :
<a href="tbResList.php?qv=29&tsv=214&wNotes=on&word=NF-kB↓">NF-kB↓</a>,
<a href="tbResList.php?qv=29&tsv=66&wNotes=on&word=COX2↓">COX2↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=235&wNotes=on&word=p38↓">p38↓</a>, --> Pro-Inflammatory Cytokines :
<!-- <a href="tbResList.php?qv=29&tsv=908&wNotes=on&word=NLRP3↓">NLRP3↓</a>, -->
<a href="tbResList.php?qv=29&tsv=978&wNotes=on&word=IL1β↓">IL-1β↓</a>,
<a href="tbResList.php?qv=29&tsv=309&wNotes=on&word=TNF-α↓">TNF-α↓</a>,
<a href="tbResList.php?qv=29&tsv=158&wNotes=on&word=IL6↓">IL-6↓</a>,
<a href="tbResList.php?qv=29&tsv=368&wNotes=on&word=IL8↓">IL-8↓</a>
<br>
<!-- GROWTH/METASTASES : EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1, uPA↓, VEGF↓, ERK↓
inhibiting metastasis-associated proteins such as ROCK1, FAK, (RhoA), NF-κB and u-PA, MMP-1 and MMP-13.-->
- inhibit Growth/Metastases :
<a href="tbResList.php?qv=29&tsv=604&wNotes=on">TumMeta↓</a>,
<a href="tbResList.php?qv=29&tsv=323&wNotes=on">TumCG↓</a>,
<a href="tbResList.php?qv=29&tsv=96&wNotes=on">EMT↓</a>,
<a href="tbResList.php?qv=29&tsv=204&wNotes=on">MMPs↓</a>,
<a href="tbResList.php?qv=29&tsv=201&wNotes=on">MMP2↓</a>,
<a href="tbResList.php?qv=29&tsv=203&wNotes=on">MMP9↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=308&wNotes=on">TIMP2</a>, -->
<a href="tbResList.php?qv=29&wNotes=on&word=IGF">IGF-1↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=428&wNotes=on">uPA↓</a>, -->
<a href="tbResList.php?qv=29&tsv=334&wNotes=on">VEGF↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=1284&wNotes=on">ROCK1↓</a>, -->
<a href="tbResList.php?qv=29&tsv=110&wNotes=on">FAK↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=273&wNotes=on">RhoA↓</a>, -->
<a href="tbResList.php?qv=29&tsv=214&wNotes=on">NF-κB↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=79&wNotes=on">CXCR4↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=1247&wNotes=on">SDF1↓</a>, -->
<a href="tbResList.php?qv=29&tsv=304&wNotes=on">TGF-β↓</a>,
<a href="tbResList.php?qv=29&tsv=719&wNotes=on">α-SMA↓</a>,
<a href="tbResList.php?qv=29&tsv=105&wNotes=on">ERK↓</a>
<!-- <a href="tbResList.php?qv=29&tsv=1178&wNotes=on">MARK4↓</a> --> <!-- contributing to tumor growth, invasion, and metastasis-->
<br>
<!-- REACTIVATE GENES : HDAC↓, DNMT1↓, DNMT3A↓, EZH2↓, P53↑, -->
<!--
- reactivate genes thereby inhibiting cancer cell growth :
<a href="tbResList.php?qv=29&tsv=140&wNotes=on">HDAC↓</a>,
<a href="tbResList.php?qv=29&wNotes=on&word=DNMT">DNMTs↓</a>,
<a href="tbResList.php?qv=29&tsv=108&wNotes=on">EZH2↓</a>,
<a href="tbResList.php?qv=29&tsv=236&wNotes=on">P53↑</a>,
<a href="tbResList.php?qv=29&wNotes=on&word=HSP">HSP↓</a>,
<a href="tbResList.php?qv=29&tsv=506&wNotes=on">Sp proteins↓</a>,
<a href="tbResList.php?qv=29&wNotes=on&word=TET">TET↑</a>
<br> -->
<!-- CELL CYCLE ARREST : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓ -->
- cause Cell cycle arrest :
<a href="tbResList.php?qv=29&tsv=322&wNotes=on">TumCCA↑</a>,
<a href="tbResList.php?qv=29&tsv=73&wNotes=on">cyclin D1↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=378&wNotes=on">cyclin E↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=467&wNotes=on">CDK2↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=894&wNotes=on">CDK4↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=895&wNotes=on">CDK6↓</a>, -->
<br>
<!-- MIGRATION/INVASION : TumCMig↓, TumCI↓, FAK↓, ERK↓, -->
- inhibits Migration/Invasion :
<a href="tbResList.php?qv=29&tsv=326&wNotes=on">TumCMig↓</a>,
<a href="tbResList.php?qv=29&tsv=324&wNotes=on">TumCI↓</a>,
<a href="tbResList.php?qv=29&tsv=309&wNotes=on&word=TNF-α↓">TNF-α↓</a>, <!-- encourages invasion, proliferation, EMT, and angiogenesis -->
<a href="tbResList.php?qv=29&tsv=110&wNotes=on">FAK↓</a>,
<a href="tbResList.php?qv=29&tsv=105&wNotes=on">ERK↓</a>,
<a href="tbResList.php?qv=29&tsv=96&wNotes=on">EMT↓</a>,
<!-- <a href="tbResList.php?qv=29&wNotes=on&word=TOP">TOP1↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=657&wNotes=on">TET1</a>, -->
<br>
<!-- GLYCOLYSIS : ATP↓, HIF-1α↓, PKM2↓, cMyc↓, PDK1↓, GLUT1↓, LDHA↓, HK2↓, Glucose↓, GlucoseCon↓, lactateProd, OXPHOS -->
- inhibits
<a href="tbResList.php?qv=29&tsv=129&wNotes=on">glycolysis</a>
<!-- /<a href="tbResList.php?qv=29&tsv=947&wNotes=on">Warburg Effect</a> --> and
<a href="tbResList.php?qv=29&tsv=21&wNotes=on&word=ATP↓">ATP depletion</a> :
<a href="tbResList.php?qv=29&tsv=143&wNotes=on">HIF-1α↓</a>,
<a href="tbResList.php?qv=29&tsv=772&wNotes=on">PKM2↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=35&wNotes=on">cMyc↓</a>, -->
<a href="tbResList.php?qv=29&tsv=566&wNotes=on&word=GLUT">GLUT1↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=906&wNotes=on">LDH↓</a>, -->
<a href="tbResList.php?qv=29&tsv=175&wNotes=on&word=LDH">LDHA↓</a>,
<a href="tbResList.php?qv=29&tsv=773&wNotes=on">HK2↓</a>,
<a href="tbResList.php?qv=29&wNotes=on&word=PFK">PFKs↓</a>,
<a href="tbResList.php?qv=29&wNotes=on&word=PDK">PDKs↓</a>,
<a href="tbResList.php?qv=29&tsv=847&wNotes=on">ECAR↓</a>,
<a href="tbResList.php?qv=29&tsv=230&wNotes=on">OXPHOS↓</a>,
<a href="tbResList.php?qv=29&tsv=356&wNotes=on">GRP78↑</a>,
<a href="tbResList.php?qv=29&tsv=1278&wNotes=on">Glucose↓</a>,
<a href="tbResList.php?qv=29&tsv=623&wNotes=on">GlucoseCon↓</a>
<br>
<!-- ANGIOGENESIS : VEGF↓, VEGFR2↓, HIF-1α↓, NOTCH↓, FGF↓, PDGF↓, EGFR↓ ITG(Integrins↓)-->
- inhibits
<a href="tbResList.php?qv=29&tsv=447&wNotes=on">angiogenesis↓</a> :
<a href="tbResList.php?qv=29&tsv=334&wNotes=on">VEGF↓</a>,
<a href="tbResList.php?qv=29&tsv=143&wNotes=on">HIF-1α↓</a>,
<!-- <a href="tbResList.php?qv=29&wNotes=on&word=NOTCH">Notch↓</a>, -->
<!-- <a href="tbResList.php?qv=29&wNotes=on&word=FGF">FGF↓</a>, -->
<!-- <a href="tbResList.php?qv=29&wNotes=on&word=PDGF">PDGF↓</a>, -->
<a href="tbResList.php?qv=29&tsv=94&wNotes=on&word=EGFR↓">EGFR↓</a>,
<a href="tbResList.php?qv=29&&wNotes=on&word=ITG">Integrins↓</a>,
<br>
<!-- CSCs : CSC↓, CK2↓, Hh↓, GLi↓, GLi1↓, -->
- small indication of inhibiting Cancer Stem Cells :
<a href="tbResList.php?qv=29&tsv=795&wNotes=on">CSC↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=524&wNotes=on">CK2↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=141&wNotes=on">Hh↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=434&wNotes=on">GLi↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=124&wNotes=on">GLi1↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=677&wNotes=on">CD133↓</a>, -->
<a href="tbResList.php?qv=29&tsv=655&wNotes=on">CD24↓</a>,
<a href="tbResList.php?qv=29&tsv=342&wNotes=on">β-catenin↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=357&wNotes=on">n-myc↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=656&wNotes=on">sox2↓</a>, -->
<!-- <a href="tbResList.php?qv=29&wNotes=on&word=NOTCH">Notch2↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=1024&wNotes=on">nestin↓</a>, -->
<!-- <a href="tbResList.php?qv=29&tsv=508&wNotes=on">OCT4↓</a>, -->
<br>
<!-- OTHERS : -->
- Others: <a href="tbResList.php?qv=29&tsv=252&wNotes=on">PI3K↓</a>,
<a href="tbResList.php?qv=29&tsv=4&wNotes=on">AKT↓</a>,
<a href="tbResList.php?qv=29&wNotes=on&word=JAK">JAK↓</a>,
<a href="tbResList.php?qv=29&wNotes=on&word=STAT">STAT↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=377&wNotes=on">Wnt↓</a>, -->
<a href="tbResList.php?qv=29&tsv=342&wNotes=on">β-catenin↓</a>,
<a href="tbResList.php?qv=29&tsv=9&wNotes=on">AMPK</a>,
<!-- <a href="tbResList.php?qv=29&tsv=475&wNotes=on">α↓</a>, -->
<a href="tbResList.php?qv=29&tsv=105&wNotes=on">ERK↓</a>,
<!-- <a href="tbResList.php?qv=29&tsv=1014&wNotes=on">5↓</a>, -->
<a href="tbResList.php?qv=29&tsv=168&wNotes=on">JNK</a>,
<!-- - <a href="tbResList.php?qv=29&wNotes=on&word=SREBP">SREBP</a> (related to cholesterol). --><br>
<!-- SYNERGIES : -->
- Synergies:
<a href="tbResList.php?qv=29&tsv=1106&wNotes=on">chemo-sensitization</a>,
<a href="tbResList.php?qv=29&tsv=1171&wNotes=on">chemoProtective</a>,
<a href="tbResList.php?qv=29&tsv=1107&wNotes=on">RadioSensitizer</a>,
<a href="tbResList.php?qv=29&tsv=1185&wNotes=on">RadioProtective</a>,
<a href="tbResList.php?qv=29&tsv=961&esv=2&wNotes=on&exSp=open">Others(review target notes)</a>,
<a href="tbResList.php?qv=29&tsv=1105&wNotes=on">Neuroprotective</a>,
<a href="tbResList.php?qv=29&tsv=557&wNotes=on">Cognitive</a>,
<a href="tbResList.php?qv=29&tsv=1175&wNotes=on">Renoprotection</a>,
<a href="tbResList.php?qv=29&tsv=1179&wNotes=on">Hepatoprotective</a>,
<a href="tbResList.php?&qv=29&tsv=1188&wNotes=on">CardioProtective</a>,
<br>
<br>
<!-- SELECTIVE: -->
- Selectivity:
<a href="tbResList.php?qv=29&tsv=1110&wNotes=on">Cancer Cells vs Normal Cells</a><br>
<br>
<h3>Lipoic Acid Cancer Mechanisms</h3>
<table>
<thead>
<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>
</thead>
<tbody>
<tr>
<td>1</td>
<td>Mitochondrial redox and ROS</td>
<td>↑ mitochondrial ROS; ↔/↓ total ROS (context-dependent)</td>
<td>↓ ROS</td>
<td>P/R</td>
<td>Apoptosis and redox disruption</td>
<td>Central but bidirectional mechanism. HT-29 and A549 models show pro-oxidant ROS-mediated death, whereas MCF-7 and some prostate models show ROS lowering with growth inhibition.</td>
</tr>
<tr>
<td>2</td>
<td>PI3K Akt survival signaling</td>
<td>↓ Akt; ↑ p27; ↓ proliferation</td>
<td>↔/↑ Akt (context-dependent)</td>
<td>R/G</td>
<td>Cell-cycle arrest and apoptosis</td>
<td>Breast cancer studies demonstrate suppression of Akt with G1 arrest, Bax/Bcl-2 shift and apoptotic signaling.</td>
</tr>
<tr>
<td>3</td>
<td>Mitochondria and MPTP</td>
<td>↑ permeability transition; ↓ membrane potential; ↑ cytochrome c</td>
<td>Generally protected from oxidative mitochondrial injury</td>
<td>R</td>
<td>Intrinsic apoptosis</td>
<td>Provides a mechanistic bridge between altered mitochondrial metabolism, ROS production and caspase activation.</td>
</tr>
<tr>
<td>4</td>
<td>ER stress CHOP XBP1</td>
<td>↑ GRP78; ↑ CHOP; ↑ XBP1; ↑ caspases</td>
<td>Not established as a therapeutic effect</td>
<td>R/G</td>
<td>ER-stress-mediated apoptosis</td>
<td>Demonstrated prominently in A549 lung cancer cells and substantially dependent on ROS.</td>
</tr>
<tr>
<td>5</td>
<td>Ca²⁺ and TRPV1 signaling</td>
<td>↑ Ca²⁺; ↑ TRPV1-dependent mitochondrial apoptosis</td>
<td>Context-dependent</td>
<td>P/R</td>
<td>Apoptotic amplification</td>
<td>Particularly evident with cisplatin; Ca²⁺ has also been implicated in ALA-induced lung-cancer apoptosis.</td>
</tr>
<tr>
<td>6</td>
<td>Bax Bcl-2 caspase axis</td>
<td>↑ Bax; ↓ Bcl-2/Bcl-XL; ↑ caspase-3/9; ↑ PARP cleavage</td>
<td>Often ↓ inappropriate apoptosis during oxidative injury</td>
<td>R/G</td>
<td>Apoptosis</td>
<td>Downstream convergence point for multiple ALA-responsive pathways.</td>
</tr>
<tr>
<td>7</td>
<td>KEAP1 NRF2 p62</td>
<td>↓ NRF2/p62 in selected prostate models</td>
<td>↑ NRF2; ↑ HO-1/SOD antioxidant defense</td>
<td>R/G</td>
<td>Context-dependent redox regulation</td>
<td>NRF2 should not be classified simply as increased or decreased. ALA activates protective NRF2 signaling in normal cells but can suppress NRF2 in some malignant cells.</td>
</tr>
<tr>
<td>8</td>
<td>Glutathione redox system</td>
<td>↑ GSH in some models; ↓ functional antioxidant defense during pro-oxidant killing (context-dependent)</td>
<td>↑ GSH; ↑ GSH/GSSG ratio; ↑ antioxidant protection</td>
<td>R/G</td>
<td>Redox buffering and context-dependent modulation of apoptosis</td>
<td>ALA/DHLA can increase intracellular GSH and stimulate GSH synthesis, particularly in normal or oxidatively stressed cells. In cancer cells, however, increased GSH can oppose ROS-dependent ALA cytotoxicity; several anticancer models instead show ROS accumulation or suppression of antioxidant enzymes. Therefore GSH is mechanistically important but not uniformly anticancer.</td>
</tr>
<tr>
<td>9</td>
<td>Autophagy mTOR Beclin-1 LC3</td>
<td>↓ Beclin-1; ↓ LC3; ↓ autophagy in prostate models</td>
<td>Context-dependent</td>
<td>G</td>
<td>Reduced cancer-cell survival</td>
<td>ALA-associated ↑ mTOR and inhibition of autophagy have been reported in LNCaP and DU-145 cells; not established as universal.</td>
</tr>
<tr>
<td>10</td>
<td>NF-κB IKK inflammatory signaling</td>
<td>↓ NF-κB (model-dependent)</td>
<td>↓ inflammatory NF-κB activation</td>
<td>R/G</td>
<td>Reduced survival and inflammatory signaling</td>
<td>ALA can inhibit IKK/NF-κB independently of its antioxidant activity, but much of the evidence is from non-malignant experimental systems.</td>
</tr>
<tr>
<td>11</td>
<td>Integrin FAK EMT invasion</td>
<td>↓ β1-integrin/FAK; ↓ MMP-2/MMP-9; ↓ EMT</td>
<td>Not established</td>
<td>G</td>
<td>Reduced migration and invasion</td>
<td>Preclinical evidence supports antimetastatic effects, but systemic clinical relevance has not been established.</td>
</tr>
<tr>
<td>12</td>
<td>Chemosensitization</td>
<td>↑ cisplatin-associated ROS, Ca²⁺ and apoptosis (model-dependent)</td>
<td>↓ chemotherapy-associated oxidative injury in several normal tissues</td>
<td>R/G</td>
<td>Potential selective treatment modulation</td>
<td>ALA can enhance cisplatin cytotoxicity in cultured cancer cells while protecting normal tissue in other models. Clinical net effect on antitumor efficacy is unresolved.</td>
</tr>
<tr>
<td>13</td>
<td>Radiosensitivity and radioprotection</td>
<td>↔ antitumor radiosensitization not established</td>
<td>↓ radiation-induced ROS and tissue injury</td>
<td>R/G</td>
<td>Predominantly radioprotection</td>
<td>Human and preclinical literature is oriented toward mitigation of normal-tissue radiation toxicity rather than tumor radiosensitization.</td>
</tr>
<tr>
<td>14</td>
<td>Clinical Translation Constraint</td>
<td>Common experimental concentrations exceed oral systemic exposure</td>
<td>Systemic antioxidant effects occur at clinically used doses</td>
<td>G</td>
<td>Limits direct anticancer translation</td>
<td>Oral bioavailability is approximately 30%, elimination is rapid, and many cancer experiments use 250–1000 µM compared with transient human plasma concentrations typically in the low tens of micromolar.</td>
</tr>
</tbody>
</table>
<p>P: 0–30 min R: 30 min–3 hr G: >3 hr</p>
<p><b>Lipoic acid and Alzheimer’s disease</b> — ALA has sufficient AD-specific mechanistic and human evidence to justify a separate database section, although efficacy remains unproven. Its rationale includes mitochondrial cofactor activity, reduction of oxidative stress, regeneration of endogenous antioxidants, modulation of inflammatory signaling and potential improvement of neuronal glucose/energy metabolism. Small open-label studies using 600 mg/day reported slower cognitive decline, while a small randomized trial of omega-3 plus 600 mg/day ALA found less decline in selected MMSE and instrumental-ADL outcomes but no benefit in its primary oxidative-stress endpoint or ADAS-cog. Another randomized antioxidant combination containing 900 mg/day ALA produced an unexpected greater MMSE decline, making the clinical evidence mixed and insufficient for therapeutic conclusions.</p>
<p><b>Clinical evidence status:</b> Small human / pilot RCT / adjunct use. No adequately powered confirmatory trial establishes ALA as a disease-modifying treatment for Alzheimer’s disease.</p>
<h3>Lipoic Acid in Alzheimer’s Disease</h3>
<table>
<thead>
<tr>
<th>Rank</th>
<th>Pathway / Axis</th>
<th>Modulation</th>
<th>Primary Effect</th>
<th>Notes / Interpretation</th>
</tr>
</thead>
<tbody>
<tr>
<td>1</td>
<td>Oxidative stress and glutathione redox cycling</td>
<td>↓ ROS; ↑ antioxidant capacity</td>
<td>Neuroprotection</td>
<td>ALA/DHLA can scavenge oxidants and regenerate endogenous antioxidant systems; biologically plausible but clinical disease modification is unproven.</td>
</tr>
<tr>
<td>2</td>
<td>Mitochondrial energy metabolism</td>
<td>↑ mitochondrial cofactor function</td>
<td>Support of neuronal bioenergetics</td>
<td>Lipoyl groups are essential cofactors for pyruvate and α-ketoglutarate dehydrogenase complexes.</td>
</tr>
<tr>
<td>3</td>
<td>NRF2 antioxidant response</td>
<td>↑ NRF2-associated antioxidant defense</td>
<td>Reduced oxidative injury</td>
<td>Well supported mechanistically in non-cancer tissues but direct AD clinical validation is limited.</td>
</tr>
<tr>
<td>4</td>
<td>NF-κB inflammatory signaling</td>
<td>↓ NF-κB</td>
<td>Reduced neuroinflammatory signaling</td>
<td>Mechanistically plausible; much supporting evidence is indirect rather than from human AD brain studies.</td>
</tr>
<tr>
<td>5</td>
<td>Cognitive and functional decline</td>
<td>↔/↓ decline (study-dependent)</td>
<td>Possible clinical neuroprotection</td>
<td>Small open-label and omega-3 plus ALA studies produced signals of benefit, but larger confirmatory evidence is lacking and antioxidant-combination data include a possible adverse cognitive signal.</td>
</tr>
</tbody>
</table>