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Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains.

ABSTRACT: Epigallocatechin gallate (EGCG) is the principal bioactive ingredient in green tea and has been reported to have many health benefits. EGCG influences multiple signal transduction pathways related to human diseases, including redox, inflammation, cell cycle, and cell adhesion pathways. However, the molecular mechanisms of these varying effects are unclear, limiting further development and utilization of EGCG as a pharmaceutical compound. Here, we examined the effect of EGCG on two representative transmembrane signaling receptors, integrin?IIb?3 and epidermal growth factor receptor (EGFR). We report that EGCG inhibits talin-induced integrin ?IIb?3 activation, but it activates ?IIb?3 in the absence of talin both in a purified system and in cells. This apparent paradox was explained by the fact that the activation state of ?IIb?3 is tightly regulated by the topology of ?3 transmembrane domain (TMD); increases or decreases in TMD embedding can activate integrins. Talin increases the embedding of integrin ?3 TMD, resulting in integrin activation, whereas we observed here that EGCG decreases the embedding, thus opposing talin-induced integrin activation. In the absence of talin, EGCG decreases the TMD embedding, which can also disrupt the integrin ?-? TMD interaction, leading to integrin activation. EGCG exhibited similar paradoxical behavior in EGFR signaling. EGCG alters the topology of EGFR TMD and activates the receptor in the absence of EGF, but inhibits EGF-induced EGFR activation. Thus, this widely ingested polyphenol exhibits pleiotropic effects on transmembrane signaling by modifying the topology of TMDs.

SUBMITTER: Ye F

PROVIDER: S-EPMC5473239 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains.

Ye Feng F Yang Chansik C Kim Jiyoon J MacNevin Christopher J CJ Hahn Klaus M KM Park Dongeun D Ginsberg Mark H MH Kim Chungho C

The Journal of biological chemistry 20170509 24

Epigallocatechin gallate (EGCG) is the principal bioactive ingredient in green tea and has been reported to have many health benefits. EGCG influences multiple signal transduction pathways related to human diseases, including redox, inflammation, cell cycle, and cell adhesion pathways. However, the molecular mechanisms of these varying effects are unclear, limiting further development and utilization of EGCG as a pharmaceutical compound. Here, we examined the effect of EGCG on two representative ...[more]

PMID: 28487468

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Project description:Intimal macrophages play a critical role in atherosclerotic lesion initiation and progression by taking up oxidized low-density lipoprotein (oxLDL) and promoting inflammatory process. 1-(Palmitoyl)-2-(5-keto-6-octene-dioyl) phosphatidylcholine (KOdiA-PC), a major type of oxidized phosphatidylcholines (PC) found on oxLDL, has a high binding affinity to the macrophage scavenger receptor CD36 and participates in CD36-mediated recognition and uptake of oxLDL by intimal macrophages. We successfully synthesized epigallocatechin gallate (EGCG)-loaded nanoparticles (Enano), which were composed of EGCG, PC, (+) alpha-tocopherol acetate, and surfactant. We also incorporated KOdiA-PC on the surface of Enano to make ligand-coated Enano (L-Enano) to target intimal macrophages. The objectives of this study were to determine the anti-atherogenic effects of Enano and L-Enano in LDL receptor null (LDLr-/-) mice. Our in vitro data demonstrated that L-Enano had a higher binding affinity to mouse peritoneal macrophages than Enano. This high binding affinity was diminished by CD36 antibodies or knockdown of the CD36 receptor in mouse peritoneal macrophages, confirming the specific binding of L-Enano to the macrophage CD36 receptor. LDLr-/- mice were randomly divided to six groups and received weekly tail vein injection with PBS, EGCG, void nanoparticles (Vnano), Enano, ligand-coated Vnano (L-Vnano), or L-Enano once per week for 22?weeks. The dose of EGCG was 25?mg per kg body weight. L-Enano at 20??g/mL significantly decreased production of monocyte chemoattractant protein-1, tumor necrosis factor alpha, and interleukin-6 from mouse macrophages, while having no effect on their plasma levels compared to the PBS control. There were no significant differences in blood lipid profiles among six treatment groups. Mice treated with L-Enano also had significantly smaller lesion surface areas on aortic arches compared to the PBS control. Liver EGCG content was decreased by treatments in the order of EGCG>Enano>L-Enano. Native EGCG had inhibitory effects on liver and body fat accumulation. This molecular target approach signals an important step towards inhibiting atherosclerosis development via targeted delivery of bioactive compounds to intimal macrophages.

Project description:OBJECTIVE:Epigallocatechin-3-gallate (EGCG) is a major ingredient of catechin polyphenols and is considered one of the most promising bioactive compounds in green tea because of its strong antioxidant properties. However, the protective role of EGCG in bovine oocyte in vitro maturation (IVM) has not been investigated. Therefore, we aimed to study the effects of EGCG on IVM of bovine oocytes. METHODS:Bovine oocytes were treated with different concentrations of EGCG (0, 25, 50, 100, and 200 μM), and the nuclear and cytoplasmic maturation, cumulus cell expansion, intracellular reactive oxygen species (ROS) levels, total antioxidant capacity, the early apoptosis and the developmental competence of in vitro fertilized embryos were measured. The mRNA abundances of antioxidant genes (nuclear factor erythriod-2 related factor 2 [NRF2], superoxide dismutase 1 [SOD1], catalase [CAT], and glutathione peroxidase 4 [GPX4]) in matured bovine oocytes were also quantified. RESULTS:Nuclear maturation which is characterized by first polar body extrusion, and cytoplasmic maturation characterized by peripheral and cortical distribution of cortical granules and homogeneous mitochondrial distribution were significantly improved in the 50 μM EGCG-treated group compared with the control group. Adding 50 μM EGCG to the maturation medium significantly increased the cumulus cell expansion index and upregulated the mRNA levels of cumulus cell expansion-related genes (hyaluronan synthase 2, tumor necrosis factor alpha induced protein 6, pentraxin 3, and prostaglandin 2). Both the intracellular ROS level and the early apoptotic rate of matured oocytes were significantly decreased in the 50 μM EGCG group, and the total antioxidant ability was markedly enhanced. Additionally, both the cleavage and blastocyst rates were significantly higher in the 50 μM EGCG-treated oocytes after in vitro fertilization than in the control oocytes. The mRNA abundance of NRF2, SOD1, CAT, and GPX4 were significantly increased in the 50 μM EGCG-treated oocytes. CONCLUSION:In conclusion, 50 μM EGCG can improve the bovine oocyte maturation, and the protective role of EGCG may be correlated with its antioxidative property.

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Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains.

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Epigallocatechin gallate has pleiotropic effects on transmembrane signaling by altering the embedding of transmembrane domains.

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