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| In all eukaryotic cells, intracellular Ca2+ levels are maintained at low resting concentrations (approximately 100 nM) by the activity of the major Ca2+ extrusion system, the plasma membrane Ca2+-ATPase (PMCA), which exchanges extracellular protons (H+) for cytosolic Ca2+. Indeed, sustained elevation of [Ca2+]C in the form of overload, saturating all Ca2+-dependent effectors, prolonged decrease in [Ca2+]ER, causing ER stress response, and high [Ca2+]M, inducing mitochondrial permeability transition (MPT), are considered to be pro-death factors. In cancer the Ca2+-handling toolkit undergoes profound remodelling (figure 1) to favour activation of Ca2+-dependent transcription factors, such as the nuclear factor of activated T cells (NFAT), c-Myc, c-Jun, c-Fos that promote hypertrophic growth via induction of the expression of the G1 and G1/S phase transition cyclins (D and E) and associated cyclin-dependent kinases (CDK4 and CDK2). Thus, cancer cells may evade apoptosis through decreasing calcium influx into the cytoplasm. This can be achieved by either downregulation of the expression of plasma membrane Ca2+-permeable ion channels or by reducing the effectiveness of the signalling pathways that activate these channels. Such protective measures would largely diminish the possibility of Ca2+ overload in response to pro-apoptotic stimuli, thereby impairing the effectiveness of mitochondrial and cytoplasmic apoptotic pathways. Voltage-Gated Calcium Channels (VGCCs): Overexpression of VGCCs has been associated with increased tumor growth and metastasis in various cancers, including breast and prostate cancer. Store-Operated Calcium Entry (SOCE): SOCE mechanisms, such as STIM1 and ORAI1, are often upregulated in cancer cells, contributing to enhanced cell survival and proliferation. High intracellular calcium levels are associated with increased cell proliferation and migration, leading to a poorer prognosis. Calcium signaling can also influence hormone receptor status, affecting treatment responses. Increased Ca²⁺ signaling is associated with advanced disease and metastasis. Patients with higher CaSR expression may have a worse prognosis due to enhanced tumor growth and resistance to apoptosis. -Ca2+ is an important regulator of the electric charge distribution of bio-membranes. |
| 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. 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, 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. |
| 3887- | Api, | The flavonoid apigenin protects brain neurovascular coupling against amyloid-β₂₅₋₃₅-induced toxicity in mice |
| - | in-vivo, | AD, | NA |
| 3205- | EGCG, | The Role of Epigallocatechin-3-Gallate in Autophagy and Endoplasmic Reticulum Stress (ERS)-Induced Apoptosis of Human Diseas |
| - | Review, | Var, | NA | - | Review, | AD, | NA |
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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