Tetramethylpyrazine reduces inflammation in liver fibrosis and inhibits inflammatory cytokine expression in hepatic stellate cells by modulating NLRP3 inflammasome pathway

Abstract

Hepatic fibrosis is concomitant with liver inflammation, which has been highlighted as significant treatment of chronic liver disease. We previously demonstrated that tetramethylpyrazine (TMP), the effective component of Ligusticum chuanxiong Hort, can inhibit the activation of HSCs and consequential anti-hepatic fibrosis. In this study, our work demonstrated that TMP improved liver histological architecture, decreased hepatic enzyme levels and attenuated collagen deposition in the rat fibrotic liver. In addition, TMP significantly protected the liver from CCl4-caused injury and fibrogenesis by suppressing inflammation with reducing levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α), NLRP3, nuclear factor-kappa B (NF-κB) and interleukin-1β (IL-1β). Experiments in vitro showed that TMP inhibited inflammatory cytokine expression in HSCs associated with disrupting platelet-derived growth factor-b receptor (PDGF-βR)/NLRP3/caspase1 pathway. These data collectively indicate that TMP can attenuate liver inflammation in liver fibrosis and possibly by targeting HSCs via PDGF-βR/NLRP3/caspase1 pathway. It provides novel mechanistic insights into TMP as a potential therapeutic remedy for hepatic fibrosis.

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“…In China, the Chinese herb Chuanxiong and its main active component TMP have been used for treatment of inflammatory diseases for many years [12,13]. The precise mechanisms of TMP in anti-inflammatory effect have not been completely understood.…”

“…Tetramethylpyrazine (TMP) is a bioactive constituent found in the root of the Chinese herb Chuanxiong, which is widely used in the treatment of a series of disease for its anti-viral, anti-bacterial, anti-inflammatory, and antioxidant effects [10][11][12][13]. Recent studies have shown that TMP has the protective effect on the kidney injury in diabetic animal model, indicating that TMP may be beneficial for the clinical treatment of DN [14,15].…”

Tetramethylpyrazine Attenuates Transdifferentiation of TGF-β2–Treated Human Tenon's Fibroblasts

“…[14][15][16][17][18]29 Clinical studies also suggest that TMP shows promise as complementary therapy for various Images were captured by a confocal laser scanning microscope (Zeiss LSM 510). F-actin content was quantified using Zeiss LSM 510 Examiner software and normalized by cell number to evaluate stress fiber formation.…”

“…Several studies demonstrated that TMP has multiple pharmacologic activities, including suppressing tumor growth, inhibiting neovascularization, and attenuating pathologic fibrosis. [14][15][16][17] In vivo and in vitro studies indicate that TMP protects the liver from CCl4-induced fibrogenesis by modulating the NLRP3 inflammasome pathway 18 ; and our previous studies in rats demonstrated that TMP protects against pulmonary bleomycininduced fibrosis by modulating the SDF-1/CXCR4 axis. 16 Studies in the liver suggest that TMP likely exerts antifibrotic effects by inhibiting Smad2/3 expression; and in hypoxic myocardial cells, protective doses of TMP downregulated the p38 MAPK pathway.…”

The Influence of Hyperlipidemia on Endothelial Function of FPN1 Tek-Cre Mice and the Intervention Effect of Tetramethylpyrazine

“…Monocytes release a large number of inflammatory cytokines, such as IL-1, IL-6 and TNF-α, which contribute to vascular endothelium injury and induce the formation of plaque [42-44]. It has been reported that TMP can reduce inflammation and inhibit inflammatory cytokine expression [45]. Our results suggested that Fpn1 knockout can induce and aggravate the inflammatory response, which can be inhibited by TMP.…”