The challenge of developing green tea polyphenols as therapeutic agents

Huo, Congde; Wan, Shengbiao; Lam, Wai Har; Li, L.; Wang, Z.; Landis-Piwowar, Kristin R.; Chen, D.; Dou, Q. Ping; Chan, Tak Hang

doi:10.1007/s10787-008-8031-x

Cited by 83 publications

(66 citation statements)

References 32 publications

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“…EGCG, similarly to other naturally occurring flavonoids with known beneficial effects on human health, 45 has a wide range of pharmacological effects. 46,47 EGCG reportedly inhibits several kinases, 48 among which protein kinase CSNK2 (casein kinase 2 or protein kinase CK2). 49 The inhibition of CSNK2 has been reported to prevent the degradation of CFTR protein, particularly in the case of F508del-CFTR mutant.…”

Section: Resultsmentioning

confidence: 99%

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

et al. 2014

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These authors equally contributed to this work.Keywords: cystic fibrosis, CFTR, autophagy, cysteamine, epigallocatechin gallate, sweat chloride Abbreviations: BECN1/Beclin 1, autophagy-related; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CHX, cycloheximide; CSNK2, casein kinase 2; CXCL2, chemokine (C-X-C motif) ligand 2; CXCL8, chemokine (C-X-C motif) ligand 8; EGCG, epigallocatechin gallate; FEV, forced expiratory volume; PM, plasma membrane; RPD, rectal potential difference; SQSTM1, sequestosome 1; TGM2, transglutaminase 2; TNF, tumor necrosis factor.Restoration of BECN1/Beclin 1-dependent autophagy and depletion of SQSTM1/p62 by genetic manipulation or autophagy-stimulatory proteostasis regulators, such as cystamine, have positive effects on mouse models of human cystic fibrosis (CF). These measures rescue the functional expression of the most frequent pathogenic CFTR mutant, F508del, at the respiratory epithelial surface and reduce lung inflammation in Cftr F508del homozygous mice. Cysteamine, the reduced form of cystamine, is an FDA-approved drug. Here, we report that oral treatment with cysteamine greatly reduces the mortality rate and improves the phenotype of newborn mice bearing the F508del-CFTR mutation. Cysteamine was also able to increase the plasma membrane expression of the F508del-CFTR protein in nasal epithelial cells from F508del homozygous CF patients, and these effects persisted for 24 h after cysteamine withdrawal. Importantly, this cysteamine effect after washout was further sustained by the sequential administration of epigallocatechin gallate (EGCG), a green tea flavonoid, both in vivo, in mice, and in vitro, in primary epithelial cells from CF patients. In a pilot clinical trial involving 10 F508del-CFTR homozygous CF patients, the combination of cysteamine and EGCG restored BECN1, reduced SQSTM1 levels and improved CFTR function from nasal epithelial cells in vivo, correlating with a decrease of chloride concentrations in sweat, as well as with a reduction of the abundance of TNF/ TNF-alpha (tumor necrosis factor) and CXCL8 (chemokine [C-X-C motif] ligand 8) transcripts in nasal brushing and TNF and CXCL8 protein levels in the sputum. Altogether, these results suggest that optimal schedules of cysteamine plus EGCG might be used for the treatment of CF caused by the F508del-CFTR mutation.

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Section: Resultsmentioning

confidence: 99%

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

et al. 2014

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“…The EGCG-protein association is also sufficiently strong to survive the reducing and denaturing conditions of SDS-PAGE. Moreover, in view of the common hydrophobicity of BSA, RCMκ-CN and EGCG, 37,40,[44][45][46][47][48] and since the hydrophobic regions of proteins are readily exposed under SDS-PAGE conditions, 49 these results suggest that a non-specific non-covalent hydrophobic interaction mediates EGCG binding to these proteins.…”

Section: Egcg Binds Strongly To Rcmκ-cn Via Intermolecular Hydrophobimentioning

confidence: 89%

“…8,13,14,34 Moreover, analogues may be the solution to the challenges of stability, bioavailability and metabolic transformation that face the development of green tea polyphenols as therapeutic agents. 46 Although EGCG was unable to act as a β-sheet breaker (data not shown), the ability of future anti-aggregates to disrupt and destroy preformed amyloid fibrils, and thus reverse the fibrillation pathway, is an important goal. Overall, this work confirms that small-molecule anti-aggregates are an exciting therapeutic strategy for the treatment of amyloidosis and that EGCG, in particular, presents a promising way forward in this endeavour.…”

Section: Discussionmentioning

confidence: 99%

(−)-Epigallocatechin-3-Gallate (EGCG) Maintains κ-Casein in Its Pre-Fibrillar State without Redirecting Its Aggregation Pathway

Hudson

Ecroyd

Dehle

et al. 2009

Journal of Molecular Biology

133

120

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The polyphenol (-)-epigallocatechin-3-gallate (EGCG) has recently attracted much research interest in the field of protein-misfolding diseases because of its potent anti-amyloid activity against amyloid-beta, alphasynuclein and huntingtin, the amyloid-fibril-forming proteins involved in Alzheimer's, Parkinson's and Huntington's diseases, respectively. EGCG redirects the aggregation of these polypeptides to a disordered offfolding pathway that results in the formation of non-toxic amorphous aggregates. whether this anti-fibril activity is specific to these disease-related target proteins or ismore generic remains to be established. In addition, the mechanism by which EGCG exerts its effects, as with all anti-amyloidogenic polyphenols, remains unclear. To address these aspects, we have investigated the ability of EGCG to inhibit amyloidogenesis of the generic model fibril-forming protein RCMkappa-CN (reduced and carboxymethylated kappa-casein) and thereby protect pheochromocytoma-12 cells from RCMkappa-CN amyloid-induced toxicity. We found that EGCG potently inhibits in vitro fibril formation byRCMkappa-CN [the IC50 for 50 uM RCMkappa-CN is 1 uM]. Biophysical studies reveal that EGCG prevents RCMkappa-CN fibril formation by stabilising RCMkappa-CN in its nativelike state rather than by redirecting its aggregation to the disordered, amorphous aggregation pathway. Thus, while it appears that EGCG is a generic inhibitor of amyloid-fibril formation, the mechanism by which it achieves this inhibition is specific to the target fibril-forming polypeptide. It is proposed that EGCG is directed to the amyloidogenic sheet-turn-sheet motif of monomeric RCMkappa-CN with high affinity by strong non-specific hydrophobic associations. Additional non-covalent pi-pi stacking interactions between the polyphenolic and aromatic residues common to the amyloidogenic sequence are also implicated. The polyphenol (−)-epigallocatechin-3-gallate (EGCG) has recently attracted much research interest in the field of protein-misfolding diseases because of its potent anti-amyloid activity against amyloid-β, α-synuclein and huntingtin, the amyloid-fibril-forming proteins involved in Alzheimer's, Parkinson's and Huntington's diseases, respectively. EGCG redirects the aggregation of these polypeptides to a disordered off-folding pathway that results in the formation of non-toxic amorphous aggregates. Whether this anti-fibril activity is specific to these disease-related target proteins or is more generic remains to be established. In addition, the mechanism by which EGCG exerts its effects, as with all anti-amyloidogenic polyphenols, remains unclear. To address these aspects, we have investigated the ability of EGCG to inhibit amyloidogenesis of the generic model fibril-forming protein RCMκ-CN (reduced and carboxymethylated κ-casein) and thereby protect pheochromocytoma-12 cells from RCMκ-CN amyloid-induced toxicity. We found that EGCG potently inhibits in vitro fibril formation by RCMκ-CN [the IC 50 for 50 μM RCMκ-CN is 13 ± 1 μM]. Biophys...

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“…[10]. The poor oral bioavailability of catechins, mainly EGC and EGCG, is attributed to their poor stability, as shown in studies of in vitro digestive simulated gastro-intestinal tract (GIT) conditions [11], and to poor intestinal permeability [12,13].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Gelatin-γ-Polyglutamic Acid-Based Hydrogel for the In Vitro Controlled Release of Epigallocatechin Gallate (EGCG) from Camellia sinensis

et al. 2013

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Abstract:The antioxidant property and other health benefits of the most abundant catechin, epigallocatechin gallate (EGCG), are limited because of poor stability and permeability across intestine. Protecting the EGCG from the harsh gastrointestinal tract (GIT) environment can help to increase its bioavailability following oral administration. In this study, EGCG was loaded to hydrogel prepared from ionic interaction between an optimized concentration of gelatin and γ-polyglutamic acid (γ-PGA), with ethylcarbodiimide (EDC) as the crosslinker. Physicochemical characterization of hydrogel was done using Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The dependence of the swelling degree (SD) of the hydrogel to the amount of gelatin, γ-PGA, EDC, swelling time and pH was determined. A high SD of the crosslinked hydrogel was noted at pH 4.5, 6.8 OPEN ACCESSPolymers 2014, 6 40 and 9.0 compared to pH 7.4, which describes pH-responsiveness. Approximately 67% of the EGCG from the prepared solution was loaded to the hydrogel after 12 h post-loading, in which loading efficiency was related to the amount of EDC. The in vitro release profile of EGCG at pH 1.2, 6.8 and 7.4, simulating GIT conditions, resulted in different sustained release curves. Wherein, the released EGCG was not degraded instantly compared to free-EGCG at controlled temperature of 37 °C at different pH monitored against time. Therefore, this study proves the potential of pH-responsive gelatin-γ-PGA-based hydrogel as a biopolymer vehicle to deliver EGCG.

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The challenge of developing green tea polyphenols as therapeutic agents

Cited by 83 publications

References 32 publications

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

Restoration of CFTR function in patients with cystic fibrosis carrying the F508del-CFTR mutation

(−)-Epigallocatechin-3-Gallate (EGCG) Maintains κ-Casein in Its Pre-Fibrillar State without Redirecting Its Aggregation Pathway

Synthesis of Gelatin-γ-Polyglutamic Acid-Based Hydrogel for the In Vitro Controlled Release of Epigallocatechin Gallate (EGCG) from Camellia sinensis

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