title: Luteolin and Apigenin Attenuate 4-Hydroxy-2-Nonenal-Mediated Cell Death through Modulation of UPR, Nrf2-ARE and MAPK Pathways in PC12 Cells.
abstract: Luteolin and apigenin are dietary flavones and exhibit a broad spectrum of biological activities including antioxidant, anti-inflammatory, anti-cancer and neuroprotective effects. The lipid peroxidation product 4-hydroxy-2-nonenal (4-HNE) has been implicated as a causative agent in the development of neurodegenerative disorders. This study investigates the cytoprotective effects of luteolin and apigenin against 4-HNE-mediated cytotoxicity in neuronal-like catecholaminergic PC12 cells. Both flavones restored cell viability and repressed caspase-3 and PARP-1 activation in 4-HNE-treated cells. Luteolin also mitigated 4-HNE-mediated LC3 conversion and reactive oxygen species (ROS) production. Luteolin and apigenin up-regulated 4-HNE-mediated unfolded protein response (UPR), leading to an increase in endoplasmic reticulum chaperone GRP78 and decrease in the expression of UPR-targeted pro-apoptotic genes. They also induced the expression of Nrf2-targeted HO-1 and xCT in the absence of 4-HNE, but counteracted their expression in the presence of 4-HNE. Moreover, we found that JNK and p38 MAPK inhibitors significantly antagonized the increase in cell viability induced by luteolin and apigenin. Consistently, enhanced phosphorylation of JNK and p38 MAPK was observed in luteolin- and apigenin-treated cells. In conclusion, this result shows that luteolin and apigenin activate MAPK and Nrf2 signaling, which elicit adaptive cellular stress response pathways, restore 4-HNE-induced ER homeostasis and inhibit cytotoxicity. Luteolin exerts a stronger cytoprotective effect than apigenin possibly due to its higher MAPK, Nrf2 and UPR activation, and ROS scavenging activity.
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, 717, Taiwan.
authors.forename: Pei-Shan
authors.initials: PS
authors.lastname: Wu
authors.affiliation: Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, 970, Taiwan.
authors.forename: Jui-Hung
authors.initials: JH
authors.lastname: Yen
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, 717, Taiwan.
authors.forename: Mei-Chun
authors.initials: MC
authors.lastname: Kou
authors.affiliation: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan, 717, Taiwan.
authors.forename: Ming-Jiuan
authors.initials: MJ
authors.lastname: Wu
mesh_terms: D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D047310:Apigenin / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects*; D000091342:Endoplasmic Reticulum Chaperone BiP; D005786:Gene Expression Regulation / Q000187:drug effects; D015227:Lipid Peroxidation; D047311:Luteolin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D047310:Apigenin; D053148:Caspase 3; C027576:4-hydroxy-2-nonenal; D047311:Luteolin