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.

Apigenin induces ROS‐dependent apoptosis and ER stress in human endometriosis cells

“…Similar to previous studies, apigenin-induced apoptosis was also mediated by inactivation of ERK1/2 and JNK proteins and regulation of AKT protein in human endometriosis cells. In addition, the previous reports support the apigenin-regulated signal transduction, including PI3K/AKT and MAPK, in cell cycle arrest leading to cell death (Shin et al, 2009;Shukla & Gupta, 2007;Wu et al, 2015).…”

“…Apigenin induction of ER stress indicated its anti‐cancer activity in human colon cancer cells due to abundant increases in intracellular ROS generation and release of calcium ions (Wang & Zhao, ). Apigenin‐controlled ER stress is regulated in response to MAPK and NRF2 signaling with activation of ROS scavenger and UPR genes (Nisha, Anusree, Priyanka, & Raghu, ; Wu, Yen, Kou, & Wu, ). Similar to previous studies, apigenin‐induced apoptosis was also mediated by inactivation of ERK1/2 and JNK proteins and regulation of AKT protein in human endometriosis cells.…”

Pathophysiological Alterations of Redox Signaling and Endocannabinoid System in Granulocytes and Plasma of Psoriatic Patients

“…Increased Keap1 levels observed in psoriasis, should mean stronger Nrf2 degradation. However, Keap1 has several critical cysteine residues that may be modified by ROS and by the lipid peroxidation product 4-HNE [56,57]. Levels of 4-HNE were revealed as increased in psoriatic patients, which might prevent Nrf2 and Keap1 binding [58].…”

Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

“…In healthy cells exposed to internal or external stressors, apigenin plays a cell-specific cytoprotective role by reducing oxidative stress through its direct free radical scavenging action, upregulation of intracellular anti-oxidant defenses, inhibition of endoplasmic reticulum stress response and activation of MAPK, Nrf2 and UPR (unfolded protein response) signaling cascades (41)(42)(43). In 19 cancer cells, apigenin shows anti-proliferative and pro-oxidative stress properties (44)(45)(46)(47).…”