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The 4'-hydroxyl group of resveratrol is functionally important for direct activation of PPAR?.

ABSTRACT: Long-term moderate consumption of red wine is associated with a reduced risk of developing lifestyle-related diseases such as cardiovascular disease and cancer. Therefore, resveratrol, a constituent of grapes and various other plants, has attracted substantial interest. This study focused on one molecular target of resveratrol, the peroxisome proliferator activated receptor ? (PPAR?). Our previous study in mice showed that resveratrol-mediated protection of the brain against stroke requires activation of PPAR?; however, the molecular mechanisms involved in this process remain unknown. Here, we evaluated the chemical basis of the resveratrol-mediated activation of PPAR? by performing a docking mode simulation and examining the structure-activity relationships of various polyphenols. The results of experiments using the crystal structure of the PPAR? ligand-binding domain and an analysis of the activation of PPAR? by a resveratrol analog 4-phenylazophenol (4-PAP) in vivo indicate that the 4'-hydroxyl group of resveratrol is critical for the direct activation of PPAR?. Activation of PPAR? by 5 ?M resveratrol was enhanced by rolipram, an inhibitor of phosphodiesterase (PDE) and forskolin, an activator of adenylate cyclase. We also found that resveratrol has a higher PDE inhibitory activity (IC50 = 19 ?M) than resveratrol analogs trans-4-hydroxystilbene and 4-PAP (IC50 = 27-28 ?M), both of which has only 4'-hydroxyl group, indicating that this 4'-hydroxyl group of resveratrol is not sufficient for the inhibition of PDE. This result is consistent with that 10 ?M resveratrol has a higher agonistic activity of PPAR? than these analogs, suggesting that there is a feedforward activation loop of PPAR? by resveratrol, which may be involved in the long-term effects of resveratrol in vivo.

SUBMITTER: Takizawa Y

PROVIDER: S-EPMC4370454 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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The 4'-hydroxyl group of resveratrol is functionally important for direct activation of PPARα.

Takizawa Yoshie Y Nakata Rieko R Fukuhara Kiyoshi K Yamashita Hiroshi H Kubodera Hideo H Inoue Hiroyasu H

PloS one 20150323 3

Long-term moderate consumption of red wine is associated with a reduced risk of developing lifestyle-related diseases such as cardiovascular disease and cancer. Therefore, resveratrol, a constituent of grapes and various other plants, has attracted substantial interest. This study focused on one molecular target of resveratrol, the peroxisome proliferator activated receptor α (PPARα). Our previous study in mice showed that resveratrol-mediated protection of the brain against stroke requires acti ...[more]

PMID: 25798826

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Project description:Background & aimsLong noncoding RNAs (lncRNAs) are found to have profound impacts on diverse cellular processes. Although high-throughput sequencing studies have shown the differential lncRNA expression profiles between hepatocellular carcinoma (HCC) and nontumor livers, the functional impacts of lncRNAs on HCC development await further investigation. Herein, we sought to address the functional roles of lncRNAs in HCC pathogenesis by in vivo functional screening.MethodsWe performed genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/dead CRISPR-associated protein 9 (dCas9) lncRNA activation screening in HCC xenografts. We characterized the clinical relevance of positively selected lncRNAs using transcriptomic data sets. We used CRISPR-based gene activation and knockdown approaches to show the functional roles of positively selected lncRNAs including Cancer Susceptibility 11 (CASC11) in HCC. RNA sequencing and chromatin isolation by RNA purification sequencing were used to investigate the molecular mechanisms of CASC11 in HCC progression.ResultsThe in vivo functional screening identified 1603 positively selected lncRNAs, 538 of which were overexpressed in HCC patients. Systematic transcriptomic data analysis and clinical investigation showed that patients with high expression of these lncRNA candidates correlated with aggressive tumor behaviors. Overexpression of these lncRNAs aggravated HCC cell growth. Detailed characterization of a lncRNA candidate, CASC11, showed its pivotal role in cell proliferation and tumor growth. Mechanistically, chromatin isolation by RNA purification sequencing showed that CASC11 was bound to the CASC11/MYC proto-oncogene shared promoter region on chromosome 8q24. CASC11 modulated the transcriptional activity of MYC in a cis-regulatory manner, which affected the expression of MYC downstream target genes, consequently promoting G1/S progression.ConclusionsOur study showed the power of in vivo CRISPR screening, which comprehensively investigated the functionality of lncRNAs in HCC progression, providing a rationale for targeting these lncRNAs clinically.

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The 4'-hydroxyl group of resveratrol is functionally important for direct activation of PPAR?.

Publications

The 4'-hydroxyl group of resveratrol is functionally important for direct activation of PPARα.

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