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Alzheimer°¶s                                         

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   2007/7-11/24              

Neurobiol Aging. 2007 Jun 21; [Epub ahead of print]Click here to read Links

Epigallocatechin gallate (EGCG) suppresses beta-amyloid-induced neurotoxicity through inhibiting c-Abl/FE65 nuclear translocation and GSK3beta activation.

Lin CL, Chen TF, Chiu MJ, Way TD, Lin JK.

Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is caused by an accumulation of Abeta plaque deposits in the brains. Evidence is increasing that green tea flavonoids can protect cells from Abeta-mediated neurotoxicity. However, the underlying mechanism remains unclear. Here, we used a human neuronal cell line MC65 conditional expression of an amyloid precursor protein fragment (APP-C99) to investigate the protection mechanism of epigallocatechin gallate (EGCG), the main constituent of green tea. We demonstrated that treatment with EGCG reduced the Abeta levels by enhancing endogenous APP nonamyloidogenic proteolytic processing. Furthermore, EGCG also decreased nuclear translocation of c-Abl and blocked APP-C99-dependent GSK3beta activation, and these inhibitory effects occurred through the interruption of c-Abl/Fe65 interaction. Our results indicated that the neuroprotective action of EGCG may take place through some mechanisms other than the promotion of APP nonamyloidogenic proteolysis, as was reported previously.

PMID: 17590240 [PubMed - as supplied by publisher]

Exp Dermatol. 2007 Aug;16(8):678-84.

Green tea polyphenol induces caspase 14 in epidermal keratinocytes via MAPK pathways and reduces psoriasiform lesions in the flaky skin mouse model.

Hsu S, Dickinson D, Borke J, Walsh DS, Wood J, Qin H, Winger J, Pearl H, Schuster G, Bollag WB.

Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, Medical College of Georgia, Augusta, GA, USA.

Psoriasiform lesions are characterized by hyperproliferation and aberrant differentiation of epidermal keratinocytes, accompanied by inflammation, leading to a disrupted skin barrier with an abnormal stratum corneum. The expression and proteolytic processing of caspase 14, a member of the caspase family which is associated with epithelial cell differentiation, planned cell death, and barrier formation, is altered in psoriatic epidermis. We recently reported that human psoriatic tissues lack normal expression of caspase 14 [J Dermatol Sci37 (2005) 61], and caspase 14 is induced by EGCG, a green tea polyphenol (GTP), in exponentially growing normal human epidermal keratinocytes (NHEK) [J Pharmacol Exp Ther315 (2005) 805]. This suggests that GTPs may have beneficial effects on psoriasiform lesions. The current study aimed to determine whether MAPK pathways are required for GTP-induced caspase 14 expression in NHEK and if GTPs can modulate the expression of pathological markers in the psoriasiform lesions that develop in the flaky skin mouse. The results indicate that the p38 and JNK MAPK pathways are required for EGCG-induced expression of caspase 14 in NHEK. Importantly, topical application of 0.5% GTPs significantly reduced the symptoms of epidermal pathology in the flaky skin mice, associated with efficient caspase 14 processing and reduction in proliferating cell nuclear antigen levels. This suggests that GTP-activated pathways may be potential targets for novel therapeutic approaches to the treatment of some psoriasiform skin disorders.

PMID: 17620095 [PubMed - in process]

Cancer Res. 2007 Jul 1;67(13):6493-501.Click here to read

The inhibitory effect of (-)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells.

Adachi S, Nagao T, Ingolfsson HI, Maxfield FR, Andersen OS, Kopelovich L, Weinstein IB.

Herbert Irving Comprehensive Cancer Center and Department of Medicine, Columbia University Medical Center, New Yourk, NY 10032-2704, USA.

(-)-Epigallocatechin gallate (EGCG), a major biologically active constituent of green tea, inhibits activation of the epidermal growth factor (EGF) receptor (EGFR) and downstream signaling pathways in several types of human cancer cells, but the precise mechanism is not known. Because several plasma membrane-associated receptor tyrosine kinases (RTK) including EGFR are localized in detergent-insoluble ordered membrane domains, so-called "lipid rafts," we examined whether the inhibitory effect of EGCG on activation of the EGFR is associated with changes in membrane lipid order in HT29 colon cancer cells. First, we did cold Triton X-100 solubility assays. Phosphorylated (activated) EGFR was found only in the Triton X-100-insoluble (lipid raft) fraction, whereas total cellular EGFR was present in the Triton X-100-soluble fraction. Pretreatment with EGCG inhibited the binding of Alexa Fluor 488-labeled EGF to the cells and also inhibited EGF-induced dimerization of the EGFR. To examine possible effects of EGCG on membrane lipid organization, we labeled the cells with the fluorescent lipid analogue 1, 1'-dihexadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate, which preferentially incorporates into ordered membrane domains in cells and found that subsequent treatment with EGCG caused a marked reduction in the Triton X-100-resistant membrane fraction. Polyphenon E, a mixture of green tea catechins, had a similar effect but (-)-epicatechin (EC), the biologically inactive compound, did not significantly alter the Triton X-100 solubility properties of the membrane. Furthermore, we found that EGCG but not EC caused dramatic changes in the function of bilayer-incorporated gramicidin channels. Taken together, these findings suggest that EGCG inhibits the binding of EGF to the EGFR and the subsequent dimerization and activation of the EGFR by altering membrane organization. These effects may also explain the ability of EGCG to inhibit activation of other membrane-associated RTKs, and they may play a critical role in the anticancer effects of this and related compounds.

PMID: 17616711 [PubMed - in process]