| Features: antioxidant, energy production in cell mitochondria | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 → ROS ↑ (cancer cells; high dose / stressed mitochondria) ALA → ROS ↓ (normal cells; low–moderate dose) same pattern seen with: Vitamin C, Menadione, Quercetin, EGCG, Resveratrol- 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 Cancer-Relevant Pathways
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| Hypoxia-Inducible-Factor 1A (HIF1A gene, HIF1α, HIF-1α protein product) -Dominantly expressed under hypoxia(low oxygen levels) in solid tumor cells -HIF1A induces the expression of vascular endothelial growth factor (VEGF) -High HIF-1α expression is associated with Poor prognosis -Low HIF-1α expression is associated with Better prognosis -Functionally, HIF-1α is reported to regulate glycolysis, whilst HIF-2α regulates genes associated with lipoprotein metabolism. -Cancer cells produce HIF in response to hypoxia in order to generate more VEGF that promote angiogenesis Key mediators of aerobic glycolysis regulated by HIF-1α. -GLUT-1 → regulation of the flux of glucose into cells. -HK2 → catalysis of the first step of glucose metabolism. -PKM2 → regulation of rate-limiting step of glycolysis. -Phosphorylation of PDH complex by PDK → blockage of OXPHOS and promotion of aerobic glycolysis. -LDH (LDHA): Rapid ATP production, conversion of pyruvate to lactate; HIF-1α Inhibitors: -Curcumin: disruption of signaling pathways that stabilize HIF-1α (ie downregulate). -Resveratrol: downregulate HIF-1α protein accumulation under hypoxic conditions. -EGCG: modulation of upstream signaling pathways, leading to decreased HIF-1α activity. -Emodin: reduce HIF-1α expression. (under hypoxia). -Apigenin: inhibit HIF-1α accumulation. |
| 3442- | ALA, | α‑lipoic acid modulates prostate cancer cell growth and bone cell differentiation |
| - | in-vitro, | Pca, | 22Rv1 | - | in-vitro, | Pca, | C4-2B | - | in-vitro, | Nor, | 3T3 |
| 3441- | ALA, | α-Lipoic Acid Maintains Brain Glucose Metabolism via BDNF/TrkB/HIF-1α Signaling Pathway in P301S Mice |
| - | in-vivo, | AD, | NA |
| 3433- | ALA, | Alpha lipoic acid promotes development of hematopoietic progenitors derived from human embryonic stem cells by antagonizing ROS signals |
| 3271- | ALA, | Decrypting the potential role of α-lipoic acid in Alzheimer's disease |
| - | Review, | AD, | NA |
| 278- | ALA, | The Multifaceted Role of Alpha-Lipoic Acid in Cancer Prevention, Occurrence, and Treatment |
| - | Review, | NA, | NA |
| 277- | ALA, | α-lipoic acid modulates prostate cancer cell growth and bone cell differentiation |
| - | in-vitro, | Pca, | 22Rv1 | - | in-vitro, | Pca, | C4-2B |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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