Anti-inflammatory Activity of 8-Hydroxydaidzein in LPS-Stimulated BV2 Microglial Cells via Activation of Nrf2-Antioxidant and Attenuation of Akt/NF-κB-Inflammatory Signaling Pathways, as Well As Inhibition of COX-2 Activity

Abstract

It was demonstrated that isoflavones can cross the blood-brain barrier, making them desirable candidate agents for the prevention of neurological symptoms. 8-Hydroxydaidzein (8-OHD, 4',7,8-trihydoxyisoflavone) is an isoflavone found only in fermented soy food. Current results showed that 8-OHD inhibited LPS-stimulated production of nitric oxide (NO) and proinflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-6, by inhibiting gene expression in BV2 microglial cells. Moreover, 8-OHD markedly quenched reactive oxygen species (ROS) and activated NF-E2-related factor 2 (Nrf2) so as to upregulate expression of Phase II enzymes, including heme oxygenase (HO)-1, NAD(P)H quinone dehydrogenase 1 (NQO1), and the modifier subunit of glutamate cysteine ligase (GCLM). 8-OHD also suppressed LPS-stimulated phosphorylation of Akt and NF-κB-p65. The anti-inflammatory activity of 8-OHD was attenuated by the HO-1 inhibitor zinc protoporphyrin (Znpp) but augmented by the PI3K/Akt inhibitor LY294002. 8-OHD also diminished LPS-induced prostaglandin E (PGE) production without affecting cyclooxygenase (COX)-2 expression. In vitro assay shows that 8-OHD displayed mixed-type inhibition of COX-2 with an IC of 8.9 ± 1.2 μM. These data suggest that the anti-inflammatory activity of 8-OHD may be associated with the activation of Nrf2/HO-1 and attenuation of Akt/NF-κB signaling pathways as well as inhibition of COX-2 enzyme activity. In conclusion, 8-OHD, a potent Nrf2 activator, Akt/NF-κB activation suppressor, and COX-2 enzyme inhibitor, may have health-promoting effects for mitigating microglia activation and preventing neuroinflammation.

Regulation of 8-Hydroxydaidzein in IRF3-Mediated Gene Expression in LPS-Stimulated Murine Macrophages

“…Analysis of upstream enzymes of IRF-3 demonstrated that 8-HD was able to decrease the phosphorylation level of AKT. This result is in agreement with a previous report that 8-HD can inhibit AKT phosphorylation [15]. Furthermore, we also found that 8-HD treatment decreased the phosphorylation level of IKKε but had no effect on phosphorylation of TBK1.…”

“…Increasing evidence has highlighted the potential pharmacological benefits of 8-HD, including anti-inflammatory activities [13,15,16]. Although a few of these reports have described some inhibitory mechanisms by which this compound exhibits its anti-inflammatory activities, the exact mechanism remains to be determined.…”

“…Several bioactivities of 8-HD have been reported with regard to anti-cancer-related activity such as anti-proliferative and anti-mutagenic activity, anti-melanogenic activities such as an irreversible tyrosinase inhibitor, and other bioactivities such as aldose reductase inhibitor and depigmenting activities [13,14]. In regard to inflammation, 8-HD has been recently reported to exert anti-inflammatory activities via activation of Nrf2-antioxidant, inhibition of AKT phosphorylation in NF-κB-signaling pathways, and suppression of TAK1 activation followed by decreasing phosphorylation levels of downstream signaling molecules in AP-1 activation pathways, which are mostly triggered by bacterial and fungal infections [15,16]. Although the anti-inflammatory activities of this compound have been described, there have been no reports regarding the regulatory activities of 8-HD with respect to the IRF-3 signaling pathway which is important in virus-or virus/bacterium-induced inflammatory responses [17].…”

Dexmedetomidine Attenuates Neuroinflammatory–Induced Apoptosis after Traumatic Brain Injury via Nrf2 signaling pathway

“…Nrf2 is an important protective protein and plays a key role in cells adapting to oxidative stress by elevating phase α enzymes, such as NQO1 and HO‐1, which are activated after TBI . Noxious stimulation can increase Nrf2 expression and its translocation into the nucleus to bind with antioxidant response‐element sequences . To confirm that the Nrf2 signaling pathway is involved in the neuroprotection by DEX, Nrf2 protein expression in the brain tissue of rats with TBI was assessed after administering DEX.…”

“…Nuclear factor erythroid 2‐related factor 2 (Nrf2) is an important transcription factor that regulates cellular antioxidant activity and has been shown to protect organs in several animal models . Nrf2–mediated antioxidant gene expression can reduce the macrophage M1 phenotype and ROS production; therefore, activating the Nrf2 pathway may inhibit the progression of inflammation and may be a potential therapeutic strategy for many disorders such as cardiovascular diseases, neurodegenerative diseases and multiple sclerosis . Moreover, Nrf2 has been reported to be an important regulator in protecting against TBI–induced secondary brain injury.…”