Schisandrin B induces an Nrf2‐mediated thioredoxin expression and suppresses the activation of inflammasome in vitro and in vivo

Abstract

Reactive oxygen species (ROS)-mediated activation of inflammasome is involved in the development of a wide spectrum of diseases. We aimed to investigate whether (-)schisandrin B [(-)Sch B], a phytochemical that can induce cellular antioxidant response, can suppress the inflammasome activation. Results showed that (-)Sch B can induce an nuclear factor erythroid 2-related factor 2-driven thioredoxin expression in primary peritoneal macrophages and cultured RAW264.7 macrophages. A 4-h priming of peritoneal macrophages with LPS followed by a 30-min incubation with ATP caused the activation of caspase 1 and the release of IL-1β, indicative of inflammasome activation. Although LPS/ATP did not activate inflammasome in RAW264.7 macrophages, it caused the ROS-dependent c-Jun N-terminal kinase1/2 (JNK1/2) activation and an associated lactate dehydrogenase (LDH) release in RAW264.7 macrophages, an indication of cytotoxicity. (-)Sch B suppressed the LPS/ATP-induced activation of caspase 1 and release of IL-1β in peritoneal macrophages. (-)Sch B also attenuated the LPS/ATP-induced ROS production, JNK1/2 activation and LDH release in RAW264.7 macrophages. The ability of (-)Sch B to suppress LPS/ATP-mediated inflammation in vitro was further confirmed by an animal study, in which schisandrin B treatment (2 mmol/kg p.o.) ameliorated the Imject Alum-induced peritonitis, as indicated by suppressions of caspase1 activation and plasma IL-1β level. The ensemble of results suggests that (-)Sch B may offer a promising prospect for preventing the inflammasome-mediated disorders.

Differential Action between Schisandrin A and Schisandrin B in Eliciting an Anti-Inflammatory Action: The Depletion of Reduced Glutathione and the Induction of an Antioxidant Response

“…This was corroborated by the observation that co-incubation with a CYP inhibitor (or NAC) as well as Nrf2 knockdown could attenuate the anti-inflammatory action elicited by Sch B. A recent finding in our laboratory has shown that the Sch B-induced expression of TRX can inhibit the activation of NLRP3 inflammasome in cultured mouse macrophages [ 30 ]. Taken together, the anti-inflammatory action of Sch B may, at least in part, be secondary to the induction of an antioxidant response.…”

Schisandrin B attenuates CCl<span style="font-size: 8.33333px">4</span>-induced liver fibrosis in rats by regulation of Nrf2-ARE and TGF-&beta;/Smad signaling pathways

“… 46 – 49 Interestingly, several studies have revealed that Sch B exhibited anti-inflammatory and antioxidant activities by activating Nrf2 pathways. 50 , 51 In addition, recent reports also showed that S. chinensis extract and Sch B could activate Nrf2 reporter gene and induce the expression of HO-1 and NQO1. 52 However, whether Sch B activates Nrf2-ARE signaling against liver fibrosis has not been studied.…”

Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming

“…More recently, Pei-Yi Tsai demonstrated that epigallocatechin-3-gallate had prophylactic effects on lupus nephritis by increasing the Nrf2 antioxidant signaling pathway and inhibiting renal NLRP3 inflammasome activation (11), which could also be applied to the treatment of glomerulonephritis (50). In addition, schisandrin B was reported to induce Nrf2 expression and attenuate ROSdependent peritonitis (26). Although studies have revealed that enhancing Nrf2 and suppressing NLRP3 can be used to treat inflammation, it is still unknown whether there is a crosslink between the Nrf2-ARE pathway and NLRP3 inflammasome and whether Nrf2 inducers could be adopted to protect against NLRP3-associated diseases.…”