Mechanisms of action free radical scavenging, anti-inflammatory effects

EGCG is a compound with a complex molecular structure that plays a crucial role in free radical scavenging and anti-inflammatory processes. Its intricate structure allows it to neutralize ROS and modulate complex inflammatory responses with precision. EGCG’s ability to interact with free radicals at multiple sites prevents oxidative cascade reactions and supports cellular homeostasis. Its anti-inflammatory mechanisms involve modulating cellular signaling pathways, including suppressing NF-κB activation, a critical inflammatory transcription factor [5]. EGCG inhibits pro-inflammatory cytokine production, interrupting inflammatory cascade processes and promoting resolution of responses. It activates Nrf2, a regulator of antioxidant defense, triggering comprehensive cellular protection strategies. This unique approach to managing oxidative and inflammatory stress involves suppressing pro-inflammatory pathways and activating protective cellular mechanisms, supporting mitochondrial function and promoting resolution of inflammatory responses [20]. Advanced proteomics research shows that EGCG can modulate protein interactions involved in inflammatory processes, inhibiting enzyme activities like cyclooxygenase and lipoxygenase, and providing multilayered protection against chronic inflammatory conditions. Its epigenetic modulation capabilities also suggest it can influence DNA methylation patterns and histone modifications, potentially providing long-term regulatory mechanisms for inflammatory processes [44]. Immunomodulatory properties represent another critical dimension of EGCG’s action mechanisms. The compound demonstrates a remarkable capacity to regulate immune cell function, modulating macrophage and neutrophil activities. By supporting balanced immune responses and preventing excessive inflammatory reactions, EGCG offers a nuanced approach to managing complex immunological challenges. Computational biology techniques have provided unprecedented insights into EGCG’s molecular interactions [45]. Machine learning algorithms and simulation platforms are enabling researchers to study protein-ligand interactions, predicting potential inflammatory pathway modulations with accuracy. This technology is expanding scientific understanding beyond traditional experimental methods. Interdisciplinary research is integrating molecular biology, immunology, computational modeling, and biochemistry to understand EGCG’s free radical scavenging and anti-inflammatory capabilities. While evidence shows potential, rigorous investigations are needed to definitively establish its mechanisms and potential therapeutic applications Table 2 [46].

Mechanisms of EGCG in neuroprotection

EGCG, a polyphenol found in green tea, is a promising compound in neuroprotective research due to its multifaceted protective mechanisms against neurological disorders. Its complex interactions within neural systems help mitigate oxidative stress, neuroinflammation, and neurodegenerative processes. EGCG’s molecular mechanisms involve intricate signaling pathways that modulate neuroinflammatory responses and promote neuronal survival. Research indicates that EGCG can effectively suppress pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), which are typically elevated during neurological disorders. Moreover, it activates critical neuroprotective transcription factors such as Nrf2, which triggers the expression of antioxidant response elements, enhancing the cell’s endogenous defense mechanisms against oxidative stress and neuronal degradation [65]. Recent neurobiological studies suggest that EGCG is crucial in preventing neurodegenerative diseases like Alzheimer’s and Parkinson’s. It inhibits protein aggregation, particularly in the misfolding and accumulation of beta-amyloid and tau proteins, potentially interrupting neuronal damage. EGCG also enhances neuroplasticity and cognitive function by stimulating neurogenesis, promoting synaptic plasticity, and supporting brain-derived neurotrophic factor (BDNF) signaling. These mechanisms contribute to improved neural connectivity, potentially mitigating age- EGCG, a natural compound, has shown promising potential in neurological disease prevention and management. It can cross the blood-brain barrier, allowing direct interactions with neural tissues. Research also indicates EGCG’s ability to modulate neuronal calcium homeostasis and protect against excitotoxicity. However, further clinical investigations are needed to fully understand its neuroprotective mechanisms and establish standardized therapeutic protocols [66].

The communication between microglia and the gut microbiota forms a critical aspect of neuro-immune interactions, influencing brain health and disease. Microglia, the primary immune cells of the central nervous system, are deeply affected by signals originating from the gut microbiota, including microbial metabolites like short-chain fatty acids (SCFAs) and endotoxins such as lipopolysaccharides (LPS). These signals can regulate microglial activation states, shaping their roles in neuroinflammation, neuroprotection, and overall brain function. Conversely, microglial responses influence gut physiology and immune responses through bidirectional pathways, including the vagus nerve and immune mediators. This intricate crosstalk highlights the interconnectedness of the gut-brain axis, where disruptions in microbial balance (dysbiosis) or microglial dysfunction can contribute to neurodegenerative and neuroinflammatory disorders Figure 1.

Display full size

Figure 1. 

Mechanisms of EGCG in neuroprotective disorder of microglia and gut microbiota in neuro-immune communication. EGCG: epigallocatechin gallate; CNS: central nervous system

Antioxidant and anti-inflammatory pathways

EGCG is a potent bioactive compound that significantly impacts antioxidant and anti-inflammatory biological pathways. It neutralizes ROS and mitigates oxidative stress. EGCG activates the Nrf2 signaling pathway, triggering the expression of antioxidant enzymes like superoxide dismutase (SOD), catalase, and glutathione peroxidase, enhancing cellular resilience against oxidative damage [67]. EGCG has impressive anti-inflammatory capabilities, suppressing inflammatory responses through intricate molecular interactions. It effectively inhibits pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 through complex mechanisms that interrupt inflammatory cascades. EGCG’s molecular structure allows it to scavenge free radicals and modulate cellular signaling pathways, providing a comprehensive approach to cellular defense. This dual-action mechanism intercepts potential damage at multiple levels and supports overall cellular homeostasis [68]. EGCG’s potential in managing oxidative and inflammatory processes is being explored through its ability to influence epigenetic modifications. This suggests a long-term protective strategy beyond immediate inflammatory suppression. EGCG’s intricate interactions with cellular signaling pathways reveal a sophisticated mechanism of action beyond traditional antioxidants [69]. EGCG, a natural compound, offers a comprehensive approach to cellular protection by targeting multiple molecular targets simultaneously. Its ability to cross cellular membranes and interact with various molecular targets makes it potent in managing oxidative stress and inflammatory responses. However, more clinical studies are needed to fully understand its mechanisms and develop targeted therapeutic interventions. EGCG’s complex role in cellular protection makes it a critical compound for understanding and potentially mitigating oxidative and inflammatory challenges in human health Figure 2 [69].

Display full size

Figure 2. 

Anti-inflammatory pathways. NOX2: NADPH oxidases 2; MAPK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; AP-1: activator protein 1; PRR: pattern recognition receptor; CD11b: cluster of differentiation molecule 11B; TLR4: toll-like receptor 4; NLRP3: nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3; DAMPs: damage-associated molecular patterns; ONOO⁻: peroxynitrite; SOD: superoxide dismutase; GSH: glutathione; GSSG: glutathione disulfide; CAT: catalase; TFAM: mitochondrial transcription factor A; HMGB1: high mobility group box 1

Modulation of mitochondrial function and oxidative stress

Recent research on EGCG, the primary catechin found in green tea, has revealed significant insights into its effects on mitochondrial function and oxidative stress regulation. Studies have demonstrated that EGCG can directly influence mitochondrial bioenergetics by enhancing the efficiency of the electron transport chain and promoting mitochondrial biogenesis through activation of key signaling pathways, particularly peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α). The compound has been shown to upregulate antioxidant defense mechanisms by activating Nrf2, a transcription factor that controls the expression of various antioxidant enzymes. EGCG’s ability to scavenge ROS while simultaneously boosting cellular antioxidant capacity makes it particularly effective in protecting mitochondria from oxidative damage [70]. Recent investigations have highlighted EGCG’s role in maintaining mitochondrial membrane potential and reducing mitochondrial fragmentation under stress conditions. The polyphenol has also been found to modulate mitochondrial dynamics through regulation of fusion and fission proteins, contributing to improved mitochondrial network stability. Notably, research has uncovered EGCG’s capacity to enhance mitochondrial ATP production while reducing excessive ROS generation, suggesting a balanced approach to energy metabolism regulation. These effects have been particularly relevant in neurodegenerative conditions and metabolic disorders, where mitochondrial dysfunction plays a central role. The compound’s ability to cross the blood-brain barrier and accumulate in mitochondria-rich tissues has made it an interesting candidate for therapeutic applications targeting mitochondrial health Figure 3 [71].

Display full size

Figure 3. 

Oxidative stress of mitochondria and modulation in neurological disorders. ATP13A2: ATPase cation transporting 13A2; PARK7: Parkinson’s disease 7; PINK1: PTEN-induced kinase 1; SNCA: alpha-synuclein; PRKN: Parkin; LRRK: leucine-rich repeat kinase 2; VPS35: vascular protein sorting ortholog 35; CHCHD2: coiled-coil-helix-coiled-coil-helix domain containing 2

Role in reducing neurotoxic aggregates (e.g., amyloid-beta, alpha-synuclein)

EGCG is a promising drug for neurodegenerative diseases due to its ability to prevent and mitigate protein aggregation through various mechanisms. Its polyphenolic structure allows it to form non-covalent interactions with unfolded or partially folded proteins, targeting hydrophobic regions prone to aggregation. EGCG also interferes with the early stages of oligomerization in Aβ peptides, binding to monomeric and low molecular weight oligomeric species, and converting mature Aβ fibrils into non-toxic, amorphous aggregates through remodeling. It also prevents toxic oligomers and fibrils by stabilizing the protein’s native conformation [72]. EGCG, a compound with anti-aggregation properties, also plays a role in protein homeostasis by enhancing the unfolded protein response (UPR) and activating heat shock proteins. It also upregulates autophagy, facilitating the clearance of protein aggregates from neurons. Its ability to cross the blood-brain barrier can lead to significant accumulation in brain tissues [73]. EGCG, a compound with neuroprotective effects, has been found to modulate microglial activation, reduce neuroinflammation, suppress pro-inflammatory cytokines, and decrease oxidative stress. It also promotes the non-amyloidogenic processing of amyloid precursor protein, reducing Aβ peptide production. In synucleinopathies, EGCG enhances alpha-synuclein clearance and protects mitochondrial function. These findings are particularly relevant for neurodegenerative disorders, with studies showing improvements in cognitive function in Alzheimer’s and motor function in PD models. EGCG’s multiple mechanisms of action make it a promising candidate for therapeutic development [74].

Regulation of apoptosis and autophagy in neural cells

EGCG regulates cell death and survival in neural cells, modulating apoptosis and autophagy mechanisms. Its influence on apoptotic pathways is context-dependent, promoting survival in healthy neurons and preventing unnecessary cell death in stressed or damaged ones. EGCG also modulates key apoptotic regulators, such as Bcl-2 family proteins, increasing anti-apoptotic expression while regulating pro-apoptotic proteins under normal physiological conditions [71]. EGCG influences survival signaling cascades, including PI3K/Akt and extracellular signal-regulated kinases 1 and 2 (ERK1/2), for neuroprotection against stressors. It regulates autophagy through cellular recycling mechanisms, enhancing autophagic flux through adenosine monophosphate-activated protein kinase (AMPK) activation and mammalian target of rapamycin (mTOR) inhibition. It also modulates silent information regulator sirtuin 1 (SIRT1) activity, a key regulator of autophagy-related genes, thereby influencing autophagy [75]. EGCG, a polyphenol, has been found to increase the expression of key autophagy-related proteins, leading to improved clearance of cellular debris and damaged organelles. This regulation is crucial in neurodegenerative conditions. EGCG promotes selective autophagy of damaged mitochondria through the PTEN-induced kinase 1 (PINK1)/Parkin pathway, maintaining neuronal health. It also enhances protein aggregate clearance through autophagy while protecting neurons from excessive autophagy, which could lead to cell death. This balance is maintained through its effects on oxidative stress and calcium homeostasis [76]. Recent research has revealed that EGCG regulates endoplasmic reticulum (ER) stress responses in neural cells by modulating the UPR pathways. It interacts with stress sensors like PERK and IRE1α, coordinating cellular responses to stressors. EGCG also influences the crosstalk between apoptotic and autophagic pathways through p53 and NF-κB, allowing coordinated responses. This dual regulation of apoptosis and autophagy has therapeutic implications for neurodegenerative conditions and acute neural injury. The compound’s concentration-dependent ability suggests potential applications in neurological conditions [77].

Alzheimer’s disease

EGCG has shown potential in treating AD by targeting multiple pathological aspects. It directly interferes with Aβ aggregation through its polyphenolic structure, binding to unfolded Aβ monomers and oligomers, preventing their assembly into toxic fibrils. EGCG can redirect the aggregation pathway towards non-toxic oligomers by stabilizing off-pathway conformations. It also remodels toxic Aβ fibrils into benign aggregates, reducing pathogenic species in neural tissues. Additionally, EGCG modulates secretase activity to favor the non-amyloidogenic pathway in APP processing [82]. EGCG, a compound, enhances α-secretase activity and inhibits β-secretase, reducing Aβ production. This dual action addresses the source of Aβ accumulation, not just managing existing aggregates. It also increases the expression of neprilysin and insulin-degrading enzyme, contributing to reduced Aβ loads in neural tissues. EGCG also reduces tau hyperphosphorylation through multiple mechanisms, inhibiting kinases responsible for tau phosphorylation and activating protein phosphatase 2A. It can also influence tau aggregation directly, preventing toxic tau oligomers and promoting aggregate clearance through enhanced autophagy pathways [83]. EGCG, a compound, plays a crucial role in AD pathology by activating macro-autophagy and chaperone-mediated autophagy through AMPK-dependent pathways. This leads to improved protein clearance and damaged organelles. EGCG also enhances lysosomal function and promotes heat shock proteins, acting as molecular chaperones to prevent protein misfolding. Its modulation of the UPR helps maintain protein homeostasis and protect against ER stress-induced neuronal death [84]. EGCG, a compound, activates the Nrf2 pathway, promoting antioxidant enzymes and reducing oxidative damage. It also chelates metal ions, particularly copper and iron, which contribute to oxidative stress and Aβ aggregation in AD. EGCG targets inflammation and synaptic dysfunction in AD by modulating microglial activation, reducing pro-inflammatory cytokines and promoting the release of anti-inflammatory factors. It enhances synaptic plasticity by promoting BDNF expression and protecting against Aβ-induced synaptic toxicity through NMDA receptor activity and calcium homeostasis. EGCG influences DNA methylation patterns and histone modifications, affecting genes involved in AD pathogenesis. It regulates microRNA expression, particularly those involved in APP processing and tau phosphorylation, providing additional therapeutic action. However, bioavailability and stability remain important considerations for clinical applications. Recent research focuses on developing modified delivery systems and EGCG derivatives with enhanced stability and brain penetrance [85].

Parkinson’s disease

EGCG has shown potential in PD through its complex neuroprotective mechanisms. It interacts with α-synuclein, a protein involved in PD pathogenesis, preventing aggregation and redirecting it towards non-toxic conformations. EGCG’s unique molecular structure allows it to remodel toxic α-synuclein fibrils into benign forms, reducing pathogenic species in dopaminergic neurons. It also enhances the clearance of α-synuclein aggregates through multiple protein degradation pathways [5]. EGCG is a compound that significantly improves mitochondrial function, which is crucial in PD. It enhances mitochondrial biogenesis and improves electron transport chain efficiency, protecting against complex I inhibition and electron leakage. EGCG also promotes mitophagy through the PINK1/Parkin pathway, removing damaged mitochondria before cell death. It also manages oxidative stress, particularly in dopaminergic neurons, by activating the Nrf2-antioxidant response elements (ARE) pathway and increasing the expression of antioxidant enzymes. It also chelates iron, which accumulates abnormally in PD brains and contributes to oxidative damage, providing additional protection. EGCG’s influence on neuroinflammation in PD is particularly significant [86]. EGCG, a polyphenol, has been shown to modulate microglial activation towards an anti-inflammatory phenotype, reducing the production of pro-inflammatory cytokines and promoting the release of anti-inflammatory factors. It inhibits the NF-κB pathway and reduces nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation, key mediators of neuroinflammation in PD. EGCG also protects against astrogliosis and maintains blood-brain barrier integrity, reducing peripheral immune cell infiltration. It also plays a role in dopamine homeostasis and signaling, protecting dopaminergic neurons by enhancing dopamine transporter function and reducing dopamine oxidation. It also enhances macroautophagy and chaperone-mediated autophagy through AMPK-dependent pathways, improving the clearance of protein aggregates and damaged organelles [87]. Polyphenol (EGCG) is a compound that regulates heat shock proteins, preventing protein misfolding and aggregation. It also modulates the UPR, maintaining protein homeostasis under stress. EGCG’s neuroprotective effects extend to synaptic function and axonal transport, promoting the expression of neurotrophic factors like BDNF and GDNF. It enhances axonal transport by maintaining microtubule stability and regulating motor protein function, which are often impaired in PD. However, bioavailability and stability remain important considerations [88].

Huntington’s disease

HD is a genetic disorder characterized by the accumulation of toxic self-propagating, amyloidogenic mutant huntingtin (mHTT) aggregates in neurons. These aggregates disrupt essential cellular functions, especially in medium spiny neurons. mHTT interferes with transcriptional regulation, axonal transport, synaptic transmission, and mitochondrial function. EGCG, a compound, has emerged as a promising therapeutic for HD through multiple mechanisms. EGCG can modulate protein aggregation, affecting the accumulation of mHTT, by promoting proper protein folding and enhancing cellular protein quality control systems. It also activates molecular chaperones to prevent protein misfolding and aggregate formation [89]. EGCG’s interaction with cellular pathways is crucial in HD treatment, as it activates AMPK signaling, which plays a vital role in cellular energy homeostasis and autophagy regulation. Additionally, EGCG’s antioxidant properties help combat increased oxidative stress in HD neurons by directly scavenging ROS and upregulating endogenous antioxidant systems through Nrf2 pathway activation. Recent molecular studies have shown that EGCG can influence transcriptional regulation in head direction cells, potentially normalizing gene expression patterns disrupted in HD. This includes restoring BDNF expression, a crucial neurotrophic factor typically reduced in HD patients. EGCG also modulates calcium signaling and glutamate receptor function, potentially preventing excitotoxicity, a major contributor to neuronal death in HD. Its anti-inflammatory properties in HD have been shown to reduce microglial activation and decrease pro-inflammatory cytokine production in the brain. EGCG’s ability to cross the blood-brain barrier makes it an attractive therapeutic candidate. Laboratory studies have demonstrated that EGCG treatment can improve mitochondrial function in HD models, maintaining membrane potential and enhancing ATP production. Additionally, EGCG regulates the UPR, helping cells manage protein folding stress without triggering apoptotic pathways, which is particularly relevant in HD [90].

Other disorders

EGCG has shown significant therapeutic potential in treating neurodegenerative disorders like HD and ALS. It prevents mutant huntingtin protein aggregation and enhances cellular quality control systems. It interacts with polyglutamine-expanded huntingtin protein, promoting clearance through autophagy and SIRT1-mediated pathways. EGCG also enhances BDNF expression, which is typically depleted in HD, through CREB signaling pathways. Overall, EGCG has multiple protective effects [91]. EGCG is a polyphenol that reduces SOD1 and TDP-43 aggregation in ALS pathology, while enhancing protein degradation pathways. It protects motor neurons from glutamate excitotoxicity by modulating calcium signaling and NMDA receptor activity. EGCG’s anti-inflammatory properties help reduce microglial activation and pro-inflammatory cytokine production, contributing to motor neuron death in ALS. In MS, EGCG modulates T-cell responses, protects oligodendrocytes, and promotes remyelination through specific signaling pathways. It also reduces oxidative stress and inflammation in the central nervous system, preserving axonal integrity and reducing disease progression. In Prion diseases, EGCG exhibits anti-aggregation properties against pathogenic prion proteins, promoting the clearance of existing aggregates. Its ability to modulate protein folding and enhance cellular quality control mechanisms provides additional protection against prion-induced neurodegeneration [92]. EGCG has potential for treating age-related cognitive decline and mild cognitive impairment by enhancing synaptic plasticity, promoting adult neurogenesis, improving cerebral blood flow and glucose metabolism, reducing oxidative stress and inflammation, and promoting cellular repair mechanisms. It also has potential in treating rare neurodegenerative disorders, such as spinocerebellar ataxias, by reducing polyglutamine protein aggregation and improving protein quality control systems, and hereditary spastic paraplegias by improving mitochondrial function and axonal transport [93]. EGCG, a compound with common protective mechanisms, has been shown to enhance autophagy, reduce oxidative stress, modulate mitochondrial function, and regulate inflammation. Its ability to cross the blood-brain barrier makes it relevant for therapeutic applications. EGCG also has epigenetic effects, modifying DNA methylation patterns and histone modifications, influencing gene expression in neuroprotection and cellular repair. Its regulation of microRNA expression provides additional therapeutic action in neurological disorders. Recent studies have focused on optimizing EGCG delivery and bioavailability for various neurological conditions, exploring modified delivery systems like nanoparticle formulations and EGCG derivatives [94].

In clinical applications

EGCG faces challenges in clinical application due to its complex molecular interactions and systemic limitations. Despite its biological properties, EGCG’s inherent characteristics create barriers to effective systemic absorption and cellular delivery. Its pharmacokinetic profile reveals metabolic transformations, leading to reduced bioavailability and diminished therapeutic potential due to rapid metabolism and conjugation processes in the intestinal epithelium and liver [95]. Metabolomic analyses reveal EGCG undergoes glucuronidation and sulfation, reducing its concentration in circulation. Innovative delivery strategies, including nanotechnology-based formulations, lipid-based nanoparticles, polymeric micelles, and molecular carriers, are being explored to improve EGCG’s stability, extend circulation time, and facilitate targeted cellular delivery, overcoming limitations in the compound’s structure and metabolic behaviour [96]. Computational modelling and molecular simulation techniques have provided insights into EGCG’s absorption mechanisms, revealing intricate molecular behaviour and suggesting chemical modifications and innovative delivery mechanisms. Clinical trials have highlighted challenges in achieving therapeutically relevant EGCG concentrations, with conventional oral administration strategies often resulting in low systemic concentrations.

Researchers are exploring controlled-release formulations, alternative routes of administration, and combination approaches with absorption-enhancing compounds to address these limitations [97]. Metabolic variability in EGCG’s clinical applications is a challenge due to individual genetic differences in metabolic enzymes. Pharmacogenomic research is exploring these variations, suggesting personalized approaches. Advanced analytical techniques, such as high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy, provide detailed insights into complex metabolic pathways [98]. Technological advancements are improving our understanding of EGCG’s systemic behavior and potential therapeutic limitations. Interdisciplinary research collaborations are integrating perspectives from pharmaceutical sciences, molecular biology, nanotechnology, and computational modeling to develop sophisticated strategies for enhancing its clinical utility. Alternative administration strategies, such as sublingual delivery and advanced transdermal formulations, are being explored to circumvent traditional absorption limitations. Advanced chemical engineering techniques are being used to develop derivatives with enhanced stability and cellular penetration. Despite the promising evidence, researchers advocate for rigorous clinical trials and advanced technological interventions [5].

Therapeutic applications

EGCG, a compound with diverse biological activities, has shown potential in treating various diseases, including cancer, cardiovascular diseases, metabolic disorders, and neurodegenerative conditions. It modulates cell proliferation, survival, and metastasis through mechanisms like inhibiting DNA methyltransferases, regulating microRNA expression, and modulating key signaling molecules like NF-κB and MAPK. EGCG’s significant therapeutic application lies in treating metabolic disorders, enhancing insulin sensitivity and regulating glucose metabolism through activation of AMPK signaling pathways [4]. EGCG has shown promise in reducing lipid accumulation and improving metabolic parameters in obesity-related conditions through mechanisms like increased fat oxidation, reduced lipogenesis, and enhanced energy expenditure. However, its poor bioavailability when administered orally is a major challenge. Recent research focuses on developing novel delivery systems like nanoencapsulation techniques and targeted delivery systems to improve EGCG’s bioavailability. Additionally, EGCG’s stability is affected by environmental factors like pH, temperature, and oxidative conditions, posing challenges for formulation and storage [99]. EGCG’s therapeutic window varies based on target condition and patient factors, with high doses potentially leading to adverse effects like hepatotoxicity. Recent studies aim to identify biomarkers to predict individual responses and optimize dosing strategies. Drug interactions are another significant challenge, as EGCG interacts with medications through various mechanisms, including effects on drug-metabolizing enzymes and transport proteins. For example, EGCG can inhibit certain cytochrome P450 enzymes, potentially affecting drug metabolism [20]. Understanding interactions is crucial for safe and effective therapeutic use. Advances in delivery technology have led to the development of modified EGCG derivatives with improved pharmacokinetic properties, aiming to enhance stability, bioavailability, and target specificity while maintaining therapeutic efficacy. Researchers are also investigating combination therapies incorporating EGCG with other therapeutic agents to enhance treatment efficacy. EGCG’s potential in preventive medicine is promising, but determining optimal dosing strategies and duration of use remains challenging. Research is ongoing to establish evidence-based guidelines for preventive applications, considering individual genetic variations and environmental factors [100].

Advances in formulation: nanoparticles, liposomes, and prodrugs

Recent research has shown that EGCG delivery systems have been significantly improved by nanoparticle formulations using biocompatible materials like poly (lactic-co-glycolic acid) (PLGA), chitosan, and zein. These nanocarriers enhance stability and cellular uptake by controlling size distribution and surface modification capabilities. PLGA-based nanoparticles can increase EGCG’s cellular uptake by up to 10-fold compared to free EGCG, while maintaining biological activity. Surface modification with targeting ligands enhances their selective delivery to target tissues. Liposomal formulations are also promising for EGCG delivery [104]. PEGylated liposomes containing EGCG have been developed to improve circulation time and stability, achieving up to 3−4 times higher plasma concentrations than free EGCG. These liposomal formulations can also selectively release EGCG in acidic tumor environments, enhancing therapeutic efficacy while reducing systemic exposure. Prodrug development has also advanced EGCG’s pharmacokinetic properties by creating EGCG prodrugs through strategic chemical modifications. Acetylated EGCG derivatives have shown improved cellular uptake and metabolic stability and are designed to release active EGCG through enzymatic or chemical hydrolysis at target sites, providing sustained therapeutic effects. Certain EGCG prodrugs can achieve up to 5-fold higher bioavailability compared to unmodified EGCG [105]. Hybrid delivery systems, such as nanoparticle-in-liposome systems and prodrug-loaded nanocarriers, have been developed to provide both protection and controlled release properties. These systems have shown promising results in preclinical studies, improving pharmacokinetic profiles and therapeutic efficacy. Recent innovations in smart delivery systems have also incorporated stimuli-responsive materials into EGCG formulations. New materials, such as pH-sensitive polymers, thermosensitive materials, and enzyme-responsive carriers, have been developed to target specific tissues. Temperature-sensitive liposomes containing EGCG release their cargo at slightly elevated temperatures, while enzyme-responsive nanoparticles release EGCG in response to disease sites. Novel surface modification techniques have enhanced targeting capabilities, and recent studies have explored cell-penetrating peptides, aptamers, and receptor ligands to improve cellular uptake and tissue specificity. These modifications have shown promise in crossing biological barriers, including the blood-brain barrier, expanding EGCG’s therapeutic applications [106].

Potential for synergistic effects with other therapies

EGCG has shown promising synergistic effects when combined with conventional chemotherapeutic agents in cancer treatment, enhancing the efficacy of drugs like doxorubicin and cisplatin by inhibiting drug efflux pumps, particularly P-glycoprotein. This can reduce drug doses by up to 50% while maintaining therapeutic efficacy, potentially minimizing adverse effects. EGCG also shows promising synergistic effects in neurodegenerative disease therapy when combined with established treatments [107]. Studies show that EGCG can enhance neuroprotective effects in AD models by complementing memantine or cholinesterase inhibitors through its antioxidant properties and regulation of amyloid processing pathways. This combination can improve cognitive outcomes more effectively than either treatment alone. EGCG also has potential to combat antibiotic resistance by disrupting bacterial cell membranes and inhibiting efflux pumps, allowing antibiotics to accumulate more effectively within bacterial cells. This synergistic effect is particularly strong against methicillin-resistant Staphylococcus aureus (MRSA) and other resistant pathogens [108]. EGCG has shown potential in cardiovascular therapy when combined with standard treatments like statins or antihypertensive medications. It provides antioxidant and anti-inflammatory benefits, potentially reducing the dose of conventional medications. Combination therapy improves endothelial function and reduces inflammation markers. EGCG’s role in enhancing immunotherapy outcomes has also gained attention, as it can improve treatment responses in various cancer types by modulating the tumor microenvironment and enhancing T-cell responses [109]. EGCG, when used as an adjuvant therapy, has been shown to increase tumor infiltration and improve treatment outcomes. Combining EGCG with anti-inflammatory agents has shown promise in treating chronic inflammatory conditions. The synergy works through complementary anti-inflammatory pathways, with EGCG providing additional benefits through NF-κB pathway inhibition and antioxidant effects. This approach reduces inflammation and may lower the required doses of traditional anti-inflammatory medications [110].

Prevalence and impact of neurodegenerative disorders (e.g., Alzheimer’s, Parkinson’s)

Neurodegenerative disorders, like Alzheimer’s and Parkinson’s, are a global health challenge due to progressive neuronal degeneration and impaired cognitive and motor functions. Green tea’s primary polyphenol, EGCG, has shown potential in mitigating oxidative stress, neuroinflammation, and protein misfolding, which are key pathological processes in these diseases [111]. EGCG has shown promising neuroprotective effects in AD by inhibiting Aβ aggregation and reducing neuroinflammatory responses. It interacts with Aβ peptides, preventing their oligomerization and neurotoxic cascade. EGCG’s ability to cross the blood-brain barrier allows direct neuronal protection and potentially modulates neuroinflammatory pathways [3]. For PD, EGCG exhibits remarkable antioxidant and anti-apoptotic properties, particularly in protecting dopaminergic neurons. Research published in the Journal of Neurochemistry demonstrates EGCG’s capacity to counteract mitochondrial dysfunction, reduce ROS generation, and modulate key signaling pathways involved in neuronal survival. Experimental models have consistently shown that EGCG can mitigate α-synuclein aggregation, a hallmark of Parkinson’s pathogenesis [87, 112]. EGCG’s neuroprotective effects involve multiple pathways, including activation of Nrf2, inhibition of pro-inflammatory cytokines, and modulation of cellular stress response proteins. Recent meta-analyses suggest sustained, moderate EGCG consumption may contribute to long-term neurological health and slow disease progression. Advanced research is exploring advanced delivery mechanisms and synthetic derivatives to enhance EGCG’s bioavailability and neurological targeting, using nanotechnology-based approaches and targeted drug delivery systems [78]. Clinical trials are advancing to understand optimal dosage, long-term effects, and potential combinations with existing pharmacological interventions. While preliminary research is promising, more comprehensive human trials are needed to definitively establish EGCG’s therapeutic efficacy, as it represents a potential complementary strategy in comprehensive neurological management [113]. Recent review papers highlight the potential of natural compounds like EGCG in managing neurodegenerative diseases, emphasizing the need for further research into nutritional and phytochemical interventions to develop novel therapeutic strategies for these challenging neurological conditions [114].

Novel therapeutic approaches

Researchers are exploring innovative strategies for neurodegenerative disorders, with EGCG emerging as a promising compound. Advances in nanomedicine have revolutionized EGCG’s therapeutic potential, particularly in targeted drug delivery systems. Advanced nanoformulations are being developed to enhance bioavailability and neurological targeting, allowing precise delivery of EGCG to specific neural regions affected by neurodegenerative processes [115]. Innovative encapsulation techniques, such as lipid-based nanoparticles and polymeric nanocarriers, optimize EGCG’s therapeutic efficacy. Precision medicine is another frontier where EGCG shows promise. Personalized therapeutic strategies integrate genetic profiling, metabolomic analysis, and individual neurological risk assessments. Understanding genetic variations and molecular mechanisms underlying neurodegenerative disorders allows for tailored interventions using EGCG’s unique properties, allowing for personalized treatment protocols [116]. Computational biology techniques are revolutionizing EGCG research by using advanced molecular modeling and artificial intelligence-driven predictive analyses. Machine learning algorithms simulate EGCG interactions with complex neurological protein structures, predicting therapeutic interventions with unprecedented accuracy. This allows researchers to explore molecular interactions, design effective derivatives, and understand intricate neurological pathway modulations [117]. EGCG’s therapeutic application in immunomodulatory approaches is promising, as it can regulate neuroinflammatory responses, a key factor in neurodegenerative progression. By regulating microglial activation, reducing pro-inflammatory cytokine production, and enhancing neuroprotective immune responses, EGCG can manage neurological inflammation and address underlying disease mechanisms. It also has potential in supporting neurogenesis and neural stem cell proliferation in regenerative medicine [56]. EGCG, a substance that promotes neuroplasticity and supports cellular regeneration, could be used to develop therapeutic strategies that slow disease progression and potentially reverse neurological damage. Interdisciplinary collaboration between experts from neuroscience, pharmacology, nanotechnology, and computational biology is driving these approaches. Recent scientific literature highlights the transformative potential of EGCG in developing novel therapeutic paradigms [118]. Advanced technology, molecular understanding, and research methodologies offer unprecedented opportunities for developing personalized neurodegenerative interventions. However, these approaches are complex and multifaceted. Researchers are cautiously optimistic, recognizing the need for continuous refinement, clinical validation, and interdisciplinary collaboration to translate promising scientific insights into tangible clinical interventions [119].

Future directions and research gaps

The research gap lies in understanding the precise molecular mechanisms of EGCG’s action in various disease conditions. Despite numerous pathways identified, there is uncertainty about their interaction and their significance for therapeutic effects. Future research should use advanced molecular techniques like proteomics and metabolomics to map the cellular interactions, optimizing therapeutic applications and predicting drug interactions. Developing reliable biomarkers for monitoring EGCG’s efficacy is also crucial [120]. Current studies lack standardized methods for measuring EGCG’s biological effects in vivo, making it difficult to optimize dosing regimens and predict treatment outcomes. Future research should focus on identifying biomarkers that reliably indicate EGCG’s therapeutic effectiveness across different conditions, develop novel imaging techniques, and incorporate pharmacogenomic approaches to identify genetic markers that predict treatment response. This could lead to personalized therapeutic approaches and improved patient outcomes [121]. Long-term safety data for EGCG is lacking, especially in specific patient populations with compromised liver function or multiple medications. Future research should include extended follow-up periods and diverse patient populations. Optimizing delivery systems remains a challenge, despite advances in formulation technology, to overcome biological barriers while maintaining EGCG’s stability [122]. Future research should focus on developing novel delivery platforms that enhance bioavailability and precise targeting capabilities, exploring new nanocarrier materials and tissue-specific targeting strategies. Translation of promising preclinical findings into clinical applications is crucial, as many studies have failed to demonstrate efficacy in clinical trials [123]. EGCG’s potential for drug interactions and resistance development is understudied, especially in combination therapy approaches. Future research should focus on comprehensive drug interaction studies and resistance mechanisms, especially in cancer therapy. The role of EGCG in preventive medicine is emerging, but optimal timing, dosing, and duration remain unclear. Large-scale, long-term preventive trials with well-defined endpoints and consideration of various population groups are needed [124].

Large-scale, randomized clinical trials

Current research underscores the critical need for large-scale randomized clinical trials (RCTs) of EGCG for neurodegenerative disorders. While preclinical studies show promise, existing clinical evidence primarily comes from small-scale trials with methodological limitations. Recent meta-analyses highlight significant heterogeneity in study designs, dosing protocols, and outcome measures, making it difficult to draw definitive conclusions about EGCG’s therapeutic efficacy. Comprehensive RCTs are needed to establish optimal dosing regimens, evaluate long-term safety profiles, and determine EGCG’s effectiveness across different disease stages and patient populations [100]. Multi-center trials with standardized protocols would help assess biomarkers, cognitive outcomes, and disease progression markers. Additionally, studies should investigate EGCG’s interaction with standard treatments and potential synergistic effects. Key areas requiring investigation include bioavailability enhancement strategies, therapeutic window identification, and patient stratification based on genetic and environmental factors. Modern trial designs incorporating advanced imaging techniques and molecular biomarkers could provide deeper insights into EGCG’s mechanisms of action in human subjects. These large-scale studies would also help establish evidence-based guidelines for EGCG supplementation in clinical practice [125].

Exploration of EGCG derivatives for enhanced efficacy

Recent research has focused on developing EGCG derivatives with improved pharmacological properties. Structure-activity relationship studies have identified key molecular modifications that enhance stability, bioavailability, and blood-brain barrier penetration. Novel synthetic derivatives demonstrate increased half-life and reduced susceptibility to oxidation compared to natural EGCG. Promising modifications include the addition of lipophilic groups to improve membrane permeability and targeted delivery systems using nanocarriers. Studies show certain derivatives exhibit enhanced neuroprotective effects through stronger binding to therapeutic targets and improved cellular uptake [126]. Computational modeling has guided the design of derivatives with optimized interactions with amyloid proteins and key signaling molecules. Current research gaps include limited understanding of derivatives’ long-term safety profiles and metabolic fate. Future work should focus on comparative efficacy studies between natural EGCG and its derivatives, optimization of synthesis methods for large-scale production, and investigation of potential side effects. Development of site-specific derivatives targeting particular aspects of neurodegenerative pathways could lead to more effective therapeutic strategies [127].

Long-term safety and toxicity studies

Research on EGCG’s long-term safety reveals complex considerations for therapeutic applications. While generally recognized as safe, high-dose studies indicate potential hepatotoxicity risks, particularly in susceptible individuals. Recent investigations highlight dose-dependent effects on liver enzymes and the importance of monitoring hepatic function during extended EGCG supplementation. Clinical data suggests variation in individual tolerance levels, with factors like genetic polymorphisms and pre-existing conditions affecting susceptibility to adverse effects. Studies recommend establishing personalized dosing guidelines based on patient characteristics. Current research emphasizes the need for standardized safety protocols and identification of biomarkers for early detection of toxicity [128]. Key areas requiring further investigation include cumulative effects of chronic exposure, drug interactions, and impact on various organ systems. Emerging evidence points to the importance of considering circadian rhythms and timing of administration in safety profiles. Development of more sensitive toxicity screening methods and establishment of clear safety thresholds across different patient populations remain crucial research priorities. Recent findings also underscore the need to evaluate potential interactions with common medications and supplements used in treating neurodegenerative disorders. This includes understanding how EGCG’s antioxidant properties might affect other therapeutic interventions and identifying any contraindications [129].

Integrating EGCG into combination therapies for naturopathic doctors

Recent studies demonstrate promising synergistic effects when combining EGCG with established treatments for neurodegenerative disorders. Research shows EGCG enhances the efficacy of conventional medications through complementary mechanisms, particularly in targeting multiple pathological pathways simultaneously. Clinical investigations reveal positive interactions between EGCG and cholinesterase inhibitors in Alzheimer’s treatment, showing improved cognitive outcomes compared to monotherapy [130]. Studies also indicate EGCG’s potential to reduce side effects of standard treatments while enhancing their therapeutic benefits through antioxidant and anti-inflammatory mechanisms. Current research focuses on optimal combination strategies, including timing of administration and dosage ratios. Emerging evidence suggests EGCG may enhance drug delivery across the blood-brain barrier when used in combination therapies. Investigation of EGCG’s role in targeting multiple aspects of neurodegeneration, including protein aggregation and oxidative stress, shows promise for developing more effective therapeutic approaches. Future directions include determining ideal drug combinations, understanding potential interactions, and developing standardized protocols for combination therapy. This includes evaluating EGCG’s impact on drug metabolism and identifying patient populations most likely to benefit from combined treatment approaches [131].