Abstract
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.
Highlights
Inflammation is characterized as a protective biological response with complicated mechanisms and implicates immune cells and molecular mediators secreted from the cells that act against pathogens, damaged cells, or other irritants
We first determined the subtoxic dosage of Flavokawain A (FKA) (Figure 1(a)) on primary splenocytes derived from the BALB/c mice
The data showed that compared with control cells, splenocytes exposed to FKA did not enhance the proliferative state of splenocytes and did not induce any significant toxicity as well [24]
Summary
Inflammation is characterized as a protective biological response with complicated mechanisms and implicates immune cells and molecular mediators secreted from the cells that act against pathogens, damaged cells, or other irritants. The inflammation process rules out the initial causes of cell injury, cleans away necrotic cells, and begins tissue. There is a dynamic and ever-shifting balance exits between pro- and anti-inflammatory components of the immune system [2]. An uncontrolled shift of this balance towards excessive production of proinflammatory cytokines causes several major cellular events that lead to the pathogenesis and progression of inflammatory responses. Splenocytes are a type of white blood cells from the splenic origin that consists of a variety of T and B lymphocytes, dendritic cells, and macrophages which have different immune functions and release various factors in response to inflammatory and anti-inflammatory agents [3]. Various transcription factors and cellular signaling pathways are involved in the expression of proinflammatory genes in macrophages [4]
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