Genetically Engineered Resveratrol‐Enriched Rice Inhibits Neuroinflammation in Lipopolysaccharide‐Activated BV2 Microglia Via Downregulating Mitogen‐Activated Protein Kinase‐Nuclear Factor Kappa B Signaling Pathway

Abstract

Resveratrol, a natural stilbenoid, is produced by several plants, especially grape vines. Its strong potency against obesity, metabolic disorders, vascular disease, inflammation, and various cancers has already been reported. Large amounts of wine or grapes need to be consumed to obtain the amount of resveratrol required for biological activity. Pure resveratrol at concentrations as low as 10 μM induces cytotoxicity to normal cells. To overcome these limitations, we prepared genetically modified resveratrol-enriched rice (RR). We previously reported the strong antiaging potential of RR against ultraviolet B/reactive oxygen species-induced toxicity in normal human dermal fibroblasts (NHDF). As aging is characterized by neuroinflammation and neurodegeneration, we further evaluated the role of RR against LPS-induced neuroinflammation. RR inhibited nitric oxide production and the expression of inflammatory proteins such as iNOS and COX-2. RR significantly modulated mitogen-activated protein kinase signaling, activator protein AP-1 signaling, and nuclear factor kappa B (NF-κB) mediated transcription of inflammatory proteins via inhibition of NF-κB translocation, IkB phosphorylation, and proinflammatory cytokine productions such as interleukin IL-6, IL-1β, tumor necrosis factor alpha (TNF-α), and prostaglandin E2 (PGE2). These findings show that the strong antineuroinflammatory effects of RR can be beneficial for aging-mediated neurodegenerative conditions as well as disorders of the central nervous system caused by neuroinflammation.

Sulforaphane Inhibits MGO-AGE-Mediated Neuroinflammation by Suppressing NF-κB, MAPK, and AGE–RAGE Signaling Pathways in Microglial Cells

“…AGEs and LPS can activate RAGE and toll like receptor 4 (TLR4) receptors, respectively, to exert their inflammatory effects through downstream signaling. The activation of RAGE and TLR4 in microglia or macrophage share common inflammatory pathways, indicating their role in neuroinflammation [ 27 , 34 , 44 , 45 , 46 ]. SFN showed a strong potency to inhibit microglial activation to the inflammatory phenotype and to increase the levels of anti-inflammatory phenotypic markers in LPS-activated microglia [ 22 , 23 ].…”

“…BV2 cells (4 × 10 4 cells per well) were seeded onto a 96-well plate and incubated overnight. Cells were treated with either vehicle (control) or different doses of SFN (dissolved in DMSO with a final concentration of 0.05%) 30 min prior to MGO-AGEs stimulation and incubated for an additional 24 h. Nitrite production was measured by Griess reagent assay, as described previously [ 27 ]. Conditioned medium from treated cells was mixed with an equal volume of Griess reagent in a new 96-well plate for the measurement of nitrite production, as described previously [ 28 , 29 ].…”

Resveratrol alleviates nuclear factor‐κB‐mediated neuroinflammation in vasculitic peripheral neuropathy induced by ischaemia–reperfusion via suppressing endoplasmic reticulum stress

“…It should be noted that the protective effect of resveratrol against neuropathic pain associated with VPN exhibits a dose‐dependent effect. Resveratrol has been reported to modulate NF‐κB‐mediated transcription of inflammatory proteins in lipopolysaccharide‐induced neuroinflammation via inhibition of NF‐κB translocation, IκB phosphorylation, and pro‐inflammatory cytokine production . Resveratrol has also been shown to inhibit pro‐inflammatory cytokines, including TNF‐α and IL‐1β, in the peripheral nerve system and relieves animals suffering from neuropathic pain .…”

“…Resveratrol has been reported to modulate NF-κB-mediated transcription of inflammatory proteins in lipopolysaccharide-induced neuroinflammation via inhibition of NF-κB translocation, IκB phosphorylation, and pro-inflammatory cytokine production. 41 Resveratrol has also been shown to inhibit pro-inflammatory cytokines, including TNF-α and IL-1β, in the peripheral nerve system and relieves animals suffering from neuropathic pain. 18,19 Data from the molecular study support the concept that resveratrol modulates NF-κB-medicated neuroinflammation in VPN induced by IR through inhibiting the IκB phosphorylation and NF-κB translocation.…”

The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases

“…Another study showed that resveratrol suppresses the inflammatory cytokines IL-1 β and TNF- α in hypoxia-induced cytotoxicity in BV2 microglial cells by inhibition of the MAPK and NF- κ B signaling pathways [ 127 ]. Similarly, resveratrol-enriched rice attenuates several inflammatory cytokines in LPS-activated BV2 microglial cells by suppression of MAPK signaling pathways and NF- κ B translocation [ 128 ]. There is a study on the neuron cells that found that resveratrol decreases the inflammatory cytokine TNF- α and neuron damage in the hippocampus of an alcohol-induced neurodegeneration rat through the p38 MAPK pathway [ 129 ].…”