Alpha-Lipoic-Acid: also known as lipoic acid or thioctic acid (reduced form is dihydrolipoic acid).
"Universal antioxidant" because it is both water- and fat-soluble and can neutralize free radicals.
-Treatment sometimes as ALA/N (alpha-lipoic acid/low-dose naltresone)
-Also done in IV
-Decreases ROS production, but also has pro-oxidant role.
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.
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.
-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.
α-lipoic acid possesses excellent silver chelating properties.
- ALA acts as pro-Oxidant only in cancer cells:#278
- Pro-Oxidant Dose margin >100uM:#304
- Bioavailability: 80-90%, but conversion to EPA/DHA is 5-10% (and takes longer time).
- AI (Adequate Intake): 1.1-1.6g/day.
- human studies have shown that ALA levels decline significantly with age
- 1g of ALA might achieve 500uM in the blood.
- ALA is poorly soluble, lecithin has been used as an amphiphilic matrix to enhance its bioavailability.
- Pilot studies or observational interventions have used flaxseed supplementation (rich in ALA) in doses providing roughly 3–4 g of ALA daily.
- Flaxseed oil is even more concentrated in ALA – typical 50–60% ALA by weight.
- single walnut may contain 300mg of ALA
- chia oil contains 55-65% ALA.
- α-LA can also be obtained from the diet through the consumption of dark green leafy vegetables and meats
- ALA is more stable in chia seeds, (2grams of ALA per tablespoon)
- ALA degrades when exposed to heat, light, and air. (prone to oxidation)
-Note half-life 1-2 hrs.
BioAv 30-40% from walnuts, 60-80% from supplements. Co-ingestion with fat improves absorption. Both fat and water soluble
Pathways:
- induce
ROS production
- ROS↑ related:
MMP↓(ΔΨm),
ER Stress↑,
UPR↑,
GRP78↑,
Cyt‑c↑,
Caspases↑,
DNA damage↑,
- Lowers AntiOxidant defense in Cancer Cells:
NRF2↓,
SOD↓,
GSH↓
Catalase↓
HO1↓
GPx↓
- Raises
AntiOxidant
defense in Normal Cells:
ROS↓,
NRF2↑,
SOD↑,
GSH↑,
Catalase↑,
- lowers
Inflammation :
NF-kB↓,
COX2↓,
Pro-Inflammatory Cytokines :
IL-1β↓,
TNF-α↓,
IL-6↓,
IL-8↓
- inhibit Growth/Metastases :
TumMeta↓,
TumCG↓,
EMT↓,
MMPs↓,
MMP2↓,
MMP9↓,
IGF-1↓,
VEGF↓,
FAK↓,
NF-κB↓,
TGF-β↓,
α-SMA↓,
ERK↓
- cause Cell cycle arrest :
TumCCA↑,
cyclin D1↓,
- inhibits Migration/Invasion :
TumCMig↓,
TumCI↓,
TNF-α↓,
FAK↓,
ERK↓,
EMT↓,
- inhibits
glycolysis
and
ATP depletion :
HIF-1α↓,
PKM2↓,
GLUT1↓,
LDHA↓,
HK2↓,
PFKs↓,
PDKs↓,
ECAR↓,
OXPHOS↓,
GRP78↑,
Glucose↓,
GlucoseCon↓
- inhibits
angiogenesis↓ :
VEGF↓,
HIF-1α↓,
EGFR↓,
Integrins↓,
- small indication of inhibiting Cancer Stem Cells :
CSC↓,
CD24↓,
β-catenin↓,
- Others: PI3K↓,
AKT↓,
JAK↓,
STAT↓,
β-catenin↓,
AMPK,
ERK↓,
JNK,
- Synergies:
chemo-sensitization,
chemoProtective,
RadioSensitizer,
RadioProtective,
Others(review target notes),
Neuroprotective,
Cognitive,
Renoprotection,
Hepatoprotective,
CardioProtective,
- Selectivity:
Cancer Cells vs Normal Cells
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