Modulation of Akt, JNK, and p38 Activation Is Involved in Citrus Flavonoid-Mediated Cytoprotection of PC12 Cells Challenged by Hydrogen Peroxide

Abstract

The physiological benefits of dietary flavonoids have been attributed to their antioxidant and signaling properties. Our previous study revealed that hesperetin exhibits neuroprotection in PC12 cells by diverse mechanisms. Biological activities of flavonoids might be determined by their chemical structures. Here, we further studied the effects of hesperetin and its structural counterparts, isorhamnetin and isosakuranetin, on kinases related to survival signaling as well as other cytoprotective actions. Pretreatment with flavonoids (0.8 or 50 microM) increased cell viability and catalase activity (CA) and decreased membrane damage, reactive oxygen species (ROS) generation, intracellular calcium level ([Ca2+]i), and caspase-3 activity in H2O2-treated PC12 cells. Increased CA, [Ca2+]i, and ROS levels, but lower caspase-3 activities, were obtained upon treatment with 50 microM isorhamnetin or isosakuranetin. Based on their structural differences and the concentrations used, these flavonoids differentially activated pro-survival signaling molecules, including Akt/protein kinase B, p38 mitogen-activated protein kinase, and inhibited the activation of c-jun N-terminal kinase, which triggers apoptosis. Our results demonstrate that signaling actions of thses flavonoids are involved in their neuroprotection against oxidative stress and that they act more as signaling molecules than antioxidants.

Protective Effects of Flavonoids Against Oxidative Stress Induced by Simulated Microgravity in SH-SY5Y Cells

“…Isorhamnetin is an active anti-cancer metabolite of quercetin [25] and an antiinflammatory compound [26]. It can prevent endothelial cell dysfunction [27], inhibit adipogenesis [28] and become active in inhibiting oxidative damage [27,29,30]. Luteolin is a natural anti-oxidant with a lower pro-oxidant potential, and it displays excellent radical scavenging and cytoprotective properties, especially in complex biological systems and with respect to specific anti-inflammatory effects [31].…”

Citrus Flavonoids and Effects in Dementia and Age-Related Cognitive Decline

“…Neuroprotective mechanisms of citrus flavonoids against oxidative damage are illustrated in Figure 80.2. Nevertheless, they most likely act as signaling molecules to increase endogenous antioxidant defense capacity and trigger procellular survivalsignaling pathways in neural cells [4,33]. Importantly, both mechanisms may be involved in the control of de novo protein synthesis in neurons.…”

“…Hesperetin (Htn, 0.1-1 μM) simultaneously triggers both ER-and tyrosine receptor kinase A (TrkA)-mediated signaling pathways, leading to antioxidative stress/cell survival and suppression of oxidative stress-induced apoptosis via PI3K/Akt/ASK1 signaling [4,34,40]. Htn, isorhamnetin (Ish), and isosakuranetin (Isk) scavenge ROS, activate Akt, inactivate JNK, and differentially modulate p38 activation (low concentration of Htn, 0.8 μM, inhibits p38 signaling for apoptosis; high concentration of Ish and Isk, 50 μM, activate p38 signaling for cell survival) to rescue cells from oxidative insult [33,34]. * Nobiletin triggers non-TrkA mediated PKA/ MEK/ERK signaling pathways to induce neurite outgrowth in cultural hippocampal neurons [27].…”

Impediment of selenite-induced cataract in rats by combinatorial drug laden liposomal preparation

“…The combination of drugs chosen was lanosterol and hesperetin, since lanosterol, a tetracyclic triterpenoid compound was already proposed as a cataract impediment drug by Zhao et al [1] although refuted by Shangumam [4] for not being quick enough. Hesperetin, 4ʹmethoxy derivative of eriodictyol and a flavonoid, may perfectly synergize with lanosterol being a natural flavonoid and also is proven to be capable of inhibiting reactive oxygen species by activating the antioxidant enzymes, namely, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione (GSH) reductase [13–15]. These two drugs were encapsulated in a liposomal formulation and noted that with liposomal encapsulation there occur substantial changes in the drug functional properties like ability to invade the immune system and increased half-life.…”