4.3 Article

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

Journal

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
Volume 2020, Issue -, Pages -

Publisher

HINDAWI LTD
DOI: 10.1155/2020/3476212

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Funding

  1. Ministry of Science and Technology [MOST-106-2320-B-039-054-MY3, MOST-107-2320-B-039-013-MY3]
  2. Asia University
  3. China Medical University, Taiwan [CMU 107-ASIA-15]
  4. Chinese Medicine Research Center, China Medical University from The Featured Areas Research Center Program within Ministry of Education (MOE), Taiwan [CMRC-CHM-8]

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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 mu M) significantly suppressed the proinflammatory cytokine (TNF-alpha, IL-1 beta, and IL-6) release but induced the secretion of interleuldn-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 NF kappa B (p65) pathway leading to the significant suppression of iNOS, COX-2, TNF-alpha, and IL-1 beta protein expressions. Notably, FKA favored the nuclear translocation of Nrf2 leading to the downstream expression of antioxidant proteins HO-1, NQO-1, and gamma-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-alpha, IL-1 beta, 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-alpha/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.

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