From:  Neuroprotective insights into epigallocatechin gallate (EGCG) for neurodegenerative disorders

Therapeutic mechanisms and associated molecular pathways in disease treatment

MechanismDescriptionMolecular target/pathwayReferences
Nrf2 pathway activationUpregulates antioxidant response elements (ARE) leading to increased expression of detoxifying enzymesNrf2/ARE pathway[5]
Direct ROS neutralizationEGCG’s hydroxyl groups directly donate electrons to neutralize reactive oxygen species like superoxide and hydroxyl radicalsO2, OH, H2O2[47]
COX-2 suppressionDirectly inhibits cyclooxygenase-2 enzyme activity and expressionCOX-2 enzyme[48]
iNOS downregulationReduces inducible nitric oxide synthase expression, decreasing nitric oxide productionEnzyme[5]
Leukotriene reductionInhibits 5-lipoxygenase activity, decreasing pro-inflammatory leukotrienes5-LOX enzyme[49]
AP-1 modulationSuppresses activator protein 1 transcription factor activityAP-1 complex[50]
Adhesion molecule suppressionDecreases expression of VCAM-1, ICAM-1, reducing inflammatory cell recruitmentVCAM-1, ICAM-1[51]
Metal ion chelationForms complexes with transition metals (Fe2+, Cu2+) preventing their participation in Fenton reactions that generate free radicalsFe2+, Cu2+ ions[52]
SOD enhancementIncreases expression and activity of superoxide dismutase, improving cellular antioxidant defenseSOD1, SOD2[53]
Glutathione system supportEnhances glutathione synthesis and recycling, maintaining cellular redox balanceGSH/GSSG ratio[54]
NF-κB inhibitionSuppresses nuclear factor kappa B activation, reducing pro-inflammatory gene expressionNF-κB signaling pathway[55]
Pro-inflammatory cytokine reductionDecreases production of TNF-α, IL-1β, and IL-6 through multiple pathwaysTNF-α, IL-1β, IL-6[56]
Mitochondrial protectionPreserves mitochondrial function and reduces oxidative damageElectron transport chain[57]
MAPK pathway modulationInhibits stress-activated protein kinases involved in inflammatory signalingp38 MAPK, JNK, ERK[58]
Lipid peroxidation preventionProtects cellular membranes from oxidative damage through radical scavengingMembrane lipids[59]
NADPH oxidase inhibitionReduces cellular superoxide production by inhibiting NOX enzymesNOX family enzymes[60]
Myeloperoxidase suppressionDecreases production of hypochlorous acid and other oxidizing speciesMPO enzyme[61]
Prostaglandin synthesis inhibitionReduces inflammatory mediator production through multiple mechanismsPGE2, PGD2[62]
Heat shock responseInduces heat shock proteins that protect against oxidative stressHSP70, HSP90[63]
STAT3 pathway inhibitionReduces inflammatory signaling through STAT3 suppressionSTAT3 pathway[64]
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5-LOX: 5-lipoxygenase; AP-1: activator protein 1; COX-2: cyclooxygenase-2; EGCG: epigallocatechin gallate; ERK: extracellular signal-regulated kinase; GSH: glutathione; GSSG: glutathione disulfide; HSP: heat shock proteins; ICAM-1: intercellular adhesion molecule-1; IL-1β: interleukin-1β; iNOS: inducible nitric oxide synthase; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; MPO: myeloperoxidase; NADPH: nicotinamide adenine dinucleotide phosphate; NOX: NADPH oxidase; Nrf2: nuclear factor erythroid 2-related factor 2; PGD2: prostaglandin D2; PGE2: prostaglandin E2; ROS: reactive oxygen species; SOD: superoxide dismutase; STAT3: transducer and activator of transcription 3; TNF-α: tumor necrosis factor-alpha; VCAM-1: vascular cell adhesion molecule-1