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| Type: enzyme |
| PKM2 (Pyruvate Kinase, Muscle 2) is an enzyme that plays a crucial role in glycolysis, the process by which cells convert glucose into energy. PKM2 is a key regulatory enzyme in the glycolytic pathway, and it is primarily expressed in various tissues, including muscle, brain, and cancer cells. -C-myc is a common oncogene that enhances aerobic glycolysis in the cancer cells by transcriptionally activating GLUT1, HK2, PKM2 and LDH-A -PKM2 has been shown to be overexpressed in many types of tumors, including breast, lung, and colon cancer. This overexpression may contribute to the development and progression of cancer by promoting glycolysis and energy production in cancer cells. -inhibition of PKM2 may cause ATP depletion and inhibiting glycolysis. -PK exists in four isoforms: PKM1, PKM2, PKR, and PKL -PKM2 plays a role in the regulation of glucose metabolism in diabetes. -PKM2 is involved in the regulation of cell proliferation, apoptosis, and autophagy. – Pyruvate kinase catalyzes the final, rate-limiting step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate with the production of ATP. – The PKM2 isoform is uniquely regulated and can exist in both highly active tetrameric and less active dimeric forms. – Cancer cells often favor the dimeric form of PKM2 to slow pyruvate production, thereby accumulating upstream glycolytic intermediates that can be diverted into anabolic pathways to support cell growth and proliferation. – Under low oxygen conditions, cancer cells rely on altered metabolic pathways in which PKM2 is a key player. – The shift to aerobic glycolysis (Warburg effect) orchestrated in part by PKM2 helps tumor cells survive and grow in hypoxic conditions. – Elevated expression of PKM2 is frequently observed in many cancer types, including lung, breast, colorectal, and pancreatic cancers. – High levels of PKM2 are often correlated with enhanced tumor aggressiveness, poor differentiation, and advanced clinical stage. PKM2 in carcinogenesis and oncotherapy Inhibitors of PKM2: -Shikonin, Resveratrol, Baicalein, EGCG, Apigenin, Curcumin, Ursolic Acid, Citrate (best known as an allosteric inhibitor of phosphofructokinase-1 (PFK-1), a key rate-limiting enzyme in glycolysis) potential to directly inhibit or modulate PKM2 is less well established Full List of PKM2 inhibitors from Database -key connected observations: Glycolysis↓, lactateProd↓, ROS↑ in cancer cell, while some result for opposite effect on normal cells. Tumor pyruvate kinase M2 modulators Flavonoids effect on PKM2 Compounds name IC50/AC50uM Effect Flavonols 1. Fisetin 0.90uM Inhibition 2. Rutin 7.80uM Inhibition 3. Galangin 8.27uM Inhibition 4. Quercetin 9.24uM Inhibition 5. Kaempferol 9.88uM Inhibition 6. Morin hydrate 37.20uM Inhibition 7. Myricetin 0.51uM Activation 8. Quercetin 3-b- D-glucoside 1.34uM Activation 9. Quercetin 3-D -galactoside 27-107uM Ineffective Flavanons 10. Neoeriocitrin 0.65uM Inhibition 11. Neohesperidin 14.20uM Inhibition 12. Naringin 16.60uM Inhibition 13. Hesperidin 17.30uM Inhibition 14. Hesperitin 29.10uM Inhibition 15. Naringenin 70.80uM Activation Flavanonols 16. (-)-Catechin gallateuM 0.85 Inhibition 17. (±)-Taxifolin 1.16uM Inhibition 18. (-)-Epicatechin 1.33uM Inhibition 19. (+)-Gallocatechin 4-16uM Ineffective Phenolic acids 20. Ferulic 11.4uM Inhibition 21. Syringic and 13.8uM Inhibition 22. Caffeic acid 36.3uM Inhibition 23. 3,4-Dihydroxybenzoic acid 78.7uM Inhibition 24. Gallic acid 332.6uM Inhibition 25. Shikimic acid 990uM Inhibition 26. p-Coumaric acid 22.2uM Activation 27. Sinapinic acids 26.2uM Activation 28. Vanillic 607.9uM Activation |
| In Alzheimer's disease (AD), cholinergic dysfunction (often with reduced acetylcholine tone and impaired choline metabolism) is linked with cortical dysfunction, memory deficit, abnormal cerebral blood flow, task learning difficulty, sleep-cycle disruption, and neurodevelopmental effects (context-dependent). CORE HALLMARKS / HIGH-CONFIDENCE AXES: - tau and Aβ, their accumulation in AD brains is known to be a major hallmark. In AD, PP2A↓ activity is decreased (reported), contributing to hyperphosphorylated tau accumulation. SIRT-1↓ levels in AD brains are associated with accumulation of Aβ and tau (reported). - glucose metabolism↓ (brain glucose hypometabolism) occurs in AD long before significant clinical signs in many cohorts/models (reported). - Neuroinflammation / lipid mediator tone (reported): 5-LOX↑ and PGE2↑ (model-/region-dependent). - Synaptic vulnerability (reported): PSD95↓ in hippocampus and cortex; restoring PSD95 shows cognitive benefits in models. - Clearance/transport imbalance (reported): IDE↓, NEP↓, LRP1↓, and AEP↑ protein levels in AD brains (reported). COMMONLY REPORTED DIRECTIONAL CHANGES (model/region/compartment dependent): - Monoamines (reported): concentrations of 5-HTP↓, 5-HT(seratonin)↓, and 5-HIAA↓ are lower in Alzheimer's patients (varies by region/study). - Cholinergic system (clinical target): reduction in ACh↓ production; ChAT↓ activity reduced (synthesizes ACh). - Four key enzymes frequently targeted in AD symptom/adjunct strategies: AChE, BChE, MAOA, MAOB (objective inhibit). - Neurotrophic tone (reported): BDNF↓ in key regions. - Stress can decrease expression of brain-derived neurotrophic factor (BDNF). - Kinase/protease stress (reported): CDK5↑ hyperactivation; calpain↑ overactivated by increased intracellular Ca²⁺ → p-tau and aggregation. - Aβ-linked synaptic regulator (reported): STEP↑ upregulated largely due to Aβ oligomer accumulation. - α-secretase axis (reported): ADAM10↓ downregulated in AD brains. - Metabolic cofactors (reported): ALC↓ (ALCAR); Homocarnosine↓ (CSF declines with age); possible low Taurine↓ (age-related + dementia reports). - Ion/glutamate handling (reported): impaired glutamate clearance + depressed Na+/K+ ATPase → cellular ion imbalance risk. - Aging reduces NAD⁺↓ (in AD depletion may be more severe). - Mitochondrial capacity axis (reported): PGC-1↓ decreased in Alzheimer’s brains. - Innate immune DNA-sensing axis (animal): cGAS–STING↑ elevation observed in AD mice and normalized by NR treatment. - Vascular/structure (reported): a profound change in BBB permeability; progressive brain shrinkage (atrophy). - Glycation axis (reported): AGEs↑ and RAGE↑ expression. - cerebrospinal fluid (CSF) TMAO is higher in individuals with MCI and AD dementia compared to cognitively-unimpaired individuals. (gut microbes enzymatically generate trimethylamine (TMA) from choline or l-carnitine). HOMOCYSTEINE / B-VITAMIN AXIS: - Raised plasma total homocysteine (tHcy)↑ associated with cognitive impairment, AD, or vascular dementia (epidemiology). - Homocysteine can build up if vitamin B6, B12, or folate levels are low. - Homocysteine and B-vitamin in Cognitive Impairment (VITACOG) study. - Vit B6 might be an important B vitamin (often discussed along with B12 and folate). - Thiamine↓ deficiency produces a cholinergic deficit (well-aligned with AD features). - Decreased thiamine (B1) in AD may exacerbate Aβ deposition, tau hyperphosphorylation, and oxidative stress (reported). MICRONUTRIENTS / CAROTENOIDS (reported; compartment-dependent): - vitamin A↓ and β-carotene↓ lower in some AD cohorts; excess retinol may contribute to osteoporosis risk. - Diminished circulating vitamin E↓ reported in AD. - Vitamin B5↓ in multiple brain regions (reported). - Trace elements: patients with AD reported lower serum Se, Cu, and Zn↓ (serum findings vary by study). - Brain metals: some studies report higher brain copper↑ and iron↑ in specific regions/structures; compartment and region matter. Rosmarinic acid reported to reduce copper-induced neurotoxicity in vitro/in vivo and may interfere with amyloid–copper interactions (preclinical). - SAMe↓ concentrations in CSF reported in AD. - MPOD often reduced in AD patients. - AD brains reported lower levels of lutein↓, zeaxanthin↓, anhydrolutein↓, (VitA)retinol↓, lycopene↓, alpha-tocopherol↓. RISK CONTEXT: - Apolipoprotein E4 (ApoE4) genotype is the strongest known genetic risk factor for late-onset AD. - One copy of ApoE4: ~3–4× increased risk (range varies by cohort). - Two copies: ~8–12× increased risk (range varies). - VitK lower in circulating blood of APOE4 carriers (reported). - Type 2 diabetes, traumatic brain injury, stroke, diet, and above all, aging is the number ONE risk factor. Treatments / Strategy Targets (high-level): - Early intervention tends to have a greater positive effect than interventions during middle or late stages. - BOLD fMRI imaging can be used to observe brain activity via blood oxygen/flow changes. - Reduce ROS and inflammation in the brain (context-dependent; avoid over-suppressing adaptive signaling). - Inhibiting acetylcholinesterase (AChE) (which breaks down ACh), e.g., donepezil, rivastigmine. - Natural AChE inhibitors include: Berberine, Luteolin, Crocetin(saffron), Querctin, TQ - Natural AChE inhibitors in database (check BBB pass potential). - MAOB inhibitors, APP inhibitors, PGE2 inhibitors, NLRP3 inhibitors, BACE inhibitors - BDNF activators, PSD95 activator - STEP, ADAM10 - Diets with an adequate ratio (5:1) of omega-6:3 (Mediterranean diet). - Vitamins B1, B6, B12, B9 (folic acid) and D, choline, iron and iodine exert neuroprotective effects (general nutrition framing). - Antioxidants (vitamins C, E, A, zinc, selenium, lutein and zeaxanthin). - Fiber may promote gut microbiome diversity influencing brain health. - Supplementing with NAD⁺ precursors (NR or NMN) improves cognition and reduces amyloid/tau pathologies in AD mice (animal evidence). - "It is advisable to consume diets with an adequate ratio (5:1) of omega-6:3 fatty acids (Mediterranean diet) ... antioxidants ... role in oxidative stress ... cognition." Nutrition Strategies - Reduction of cognitive decline may be achieved by following a healthy dietary pattern limiting added sugars while maximizing fish, fruits, vegetables, nuts, seeds. SeNPs may also be useful as a Drug Delivery System. Related Pathways to research in this database (products that modulate them): - neuroprotective, cognitive, memory - Aβ aggregation, Tau↓, AChE↓, ACh↑, ChAT↑, acetyl-CoA↑, BDNF↑, BACE↓, NLRP3↓, PSD95↑, PGE2↓, homoC↓ - Increasing AntiOxidants: Catalase↑, GSH↑, SOD↑, HO-1↑, to decrease ROS↓ - Lower Inflammation: TNF-α↓, IL1β↓, IL6↓ Natural Products that may benefit AD. -Some key pathways are highlighted in RED in the following links Acetyl-L-carnitine, ALA, Apigenin, Anthocyanins Blueberrys, Aromatherapy, Artemisinin, Ashwagandha, β-carotene(vitamin A), Bacopa monnieri, Baicalein, Baicalin, Berberine, Betulinic acid, Boron, Boswellia (frankincense), Caffeic acid, Caffeine, Capsaicin, Carnosine, Carnosic acid, Chlorogenic acid, Choline (note U shaped dose curve-target 350mg/day), Chrysin, Cinnamon, CoQ10, Crocetin, Curcumin, dietMed, dietMet, dietSTF, EGCG, Ellagic acid, Exercise, Ferulic Acid, Fisetin, Flav, FLS, Folic Acid (5-MTHF, L-methylfolate)-reduce homocysteine, Galantamine, Ginger, Ginkgo biloba, Ginseng, Honokiol, Huperzine A, hydrogen gas, Lecithin, Lutein, Luteolin, Lycopene, M-Blu, Moringa oleifera, Mushroom Lion’s Mane, MSM, MCToil, NAD, Naringenin, PEMF, Piperine, Phenylbutyrate, Phosphatidylserine, Piperlongumine, Potassium, probiotics, Propolis, Pterostilbene, Quercetin, Resveratrol, Rivastigmine, Rosmaric Acid(reduce copper-induced neurotoxicity), Rutin, Safflower yellow, Sage, SAMe, selenium, Serotonin, Shankhpushpi, Shikonin, Shilajit/Fulvic Acid, silicon(reduce Alum bioavialability), Silymarin (Milk Thistle) silibinin, Sulforaphane, Taurine, TQ, Ursolic Acid Vitamin B1, Vitamin B2, Vitamin B3, Vitamin B5, Vitamin B6, Vitamin B12, Vitamin E, Vitamin D, Vitamin K2 Zeaxanthin, zinc, Aluminium has a negative impact on cognition but silicon can decrease Alumunium bioavailability, and Vitamin K2 may provide some protection. Example So does RMF Brain Energy Systems Matrix (AD)Tier 1–2 as “core metabolic cofactors / redox pools”Tier 4 as “alternative fuels / bypass strategies” Tier 5–6 as “capacity + delivery constraints” (often explains why supplements don’t translate)
TSF (Time-Scale Flag): P = 0–30 min, R = 30 min–3 hr, G = >3 hr (adaptation/phenotype). Evidence: "Strong (human)" = consistent clinical/epidemiologic support; "Moderate" = mixed but plausible human signals; "Emerging" = early-stage human; "Mechanistic" = preclinical/biochemical rationale. |
| 2349- | CAP, | The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer’s disease |
| - | in-vivo, | AD, | NA |
| 2345- | EMD, | Emodin ameliorates antioxidant capacity and exerts neuroprotective effect via PKM2-mediated Nrf2 transactivation |
| - | in-vitro, | AD, | PC12 |
| 2385- | MET, | Metformin activates chaperone-mediated autophagy and improves disease pathologies in an Alzheimer disease mouse model |
| - | in-vitro, | AD, | H4 | - | in-vitro, | NA, | HEK293 | - | in-vivo, | NA, | NA | - | in-vitro, | NA, | SH-SY5Y |
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
Filter Conditions: Pro/AntiFlg:% IllCat:% CanType:38 Cells:% prod#:% Target#:772 State#:% Dir#:1
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