Suppression of LPS-Induced Inflammation by Chalcone Flavokawain A through Activation of Nrf2/ARE-Mediated Antioxidant Genes and Inhibition of ROS/NFκB Signaling Pathways in Primary Splenocytes

• Published in: Oxidative medicine and cellular longevity Vol. 2020; no. 2020; pp. 1 - 14
• Main Authors: Hseu, You Cheng, Liao, Jiunn-Wang, Liao, Chun-Huei, Gowrisankar, Yugandhar Vudhya, Yang, Ting-Yu, Yang, Hsin-Ling, Huang, Pei-Jane
• Format: Journal Article
• Language: English
• Published: Cairo, Egypt Hindawi Publishing Corporation 2020; Hindawi; John Wiley & Sons, Inc
• Subjects: Animals; Antibodies; Antioxidant Response Elements - genetics; Antioxidants; Antioxidants - metabolism; Cells, Cultured; Chalcone - analogs & derivatives; Chalcone - chemistry; Chalcone - pharmacology; Chalcone - therapeutic use; Cytokines; Cytokines - metabolism; Enzymes; Female; Gene expression; Gene Expression Regulation - drug effects; Inflammation; Inflammation - blood; Inflammation - drug therapy; Inflammation - genetics; Laboratory animals; Lipase - blood; Lipopolysaccharides; Mice; Mice, Inbred BALB C; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Oxidative stress; Pancreatitis - blood; Pancreatitis - pathology; RAW 264.7 Cells; Reactive Oxygen Species - metabolism; Signal Transduction; Spleen - metabolism; Tumor necrosis factor-TNF; St Louis Missouri; United States > US; Germany; Taiwan
• ISSN: 1942-0900; 1942-0994; 1942-0994
• DOI: 10.1155/2020/3476212

Oxidative stress is an important contributing factor for inflammation. Piper methysticum, also known as Kava-kava, is a shrub whose root extract has been consumed as a drink by the pacific islanders for a long time. Flavokawain A (FKA) is a novel chalcone derived from the kava plant that is known to have medicinal properties. This study was aimed at demonstrating the antioxidant molecular mechanisms mediated by FKA on lipopolysaccharide- (LPS-) induced inflammation in BALB/c mouse-derived primary splenocytes. In vitro data show that the nontoxic concentrations of FKA (2-30 μM) significantly suppressed the proinflammatory cytokine (TNF-α, IL-1β, and IL-6) release but induced the secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine. It was also shown that FKA pretreatment significantly downregulated the LPS-induced ROS production and blocked the activation of the NFκB (p65) pathway leading to the significant suppression of iNOS, COX-2, TNF-α, and IL-1β protein expressions. Notably, FKA favored the nuclear translocation of Nrf2 leading to the downstream expression of antioxidant proteins HO-1, NQO-1, and γ-GCLC via the Nrf2/ARE signaling pathway signifying the FKA’s potent antioxidant mechanism in these cells. Supporting the in vitro data, the ex vivo data obtained from primary splenocytes derived from the FKA-preadministered BALB/c mice (orally) show that FKA significantly suppressed the proinflammatory cytokine (TNF-α, IL-1β, and IL-6) secretion in control-, LPS-, or Concanavalin A- (Con A-) stimulated cells. A significant decrease in the ratios of pro- and anti-inflammatory cytokines (IL-6/IL-10; TNF-α/IL-10) showed that FKA possesses strong anti-inflammatory properties. Furthermore, BALB/c mice induced with experimental pancreatitis using cholecystokinin- (CCK-) 8 showed decreased serum lipase levels due to FKA pretreatment. We conclude that with its potent antioxidant and anti-inflammatory properties, chalcone flavokawain A could be a novel therapeutic agent in the treatment of inflammation-associated diseases.