6-Shogaol alleviates CCl4-induced liver fibrosis by attenuating inflammatory response in mice through the NF-κB pathway

Abstract

Liver fibrosis is a global health problem caused by a number of diseases related to liver damage. 6-Shogaol is a biologically active substance derived from the rhizome of Zingiber officinale Roscoe with anti-tumor, anti-inflammatory, and antioxidant properties. To explore the effects of 6-Shogaol on liver fibrosis, we used a mouse model of the condition in which mice were injected intraperitoneally with carbon tetrachloride (CCl4) at a dose of 2 mL/kg three times per week for a period of 4 weeks. 6-Shogaol was administered orally at two different doses (5 mg/kg, 20 mg/kg) 30 min before CCl4 injection. CCl4 induced severe liver injury and fibrosis, as indicated by significant inflammatory cell infiltration, disordered liver structure, increased activities of aspartate aminotransferase and alanine aminotransferase (liver damage markers) in serum, elevated collagen deposition, and overexpressed alpha-smooth muscle actin (α-SMA, marker of hepatic stellate cells activation) in liver tissues, whereas 6-Shogaol administration rescued those alterations dose-dependently. We found that 6-Shogaol suppressed CCl4-induced inflammatory response by inhibiting macrophage recruitment, release of pro-inflammatory factors, and activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome in liver tissues. Additionally, we demonstrated that 6-Shogaol blocked CCl4-induced activation of the nuclear factor-kappa B (NF-κB) pathway, which is a vital transcriptional regulator of the inflammatory response. Altogether, this study demonstrates that 6-Shogaol can prevent CCl4-induced liver fibrosis by suppressing inflammatory response through the NF-κB pathway and suggests that 6-Shogaol can be used for liver fibrosis prevention.

6-Shogaol Ameliorates Liver Inflammation and Fibrosis in Mice on a Methionine- and Choline-Deficient Diet by Inhibiting Oxidative Stress, Cell Death, and Endoplasmic Reticulum Stress

“…This was evidenced by a decrease in collagen fibers as observed in Masson’s trichrome staining and a reduction in the production of extracellular matrix proteins in the liver. Consistent with our results, recent studies have also demonstrated the anti-fibrotic effects of 6-shogaol in both the liver [ 13 ] and heart [ 38 ]. Furthermore, 6-shogaol remarkably inhibited the accumulation of α-SMA-positive myofibroblasts in mice exposed to the MCD diet.…”

“…These pro-inflammatory cytokines further stimulate the recruitment and activation of additional immune cells, perpetuating a cycle of inflammation that can drive the progression of NASH [ 36 ]. In line with our results, Qiu et al showed that 6-shogaol alleviated macrophage accumulation and cytokine production in a murine model of liver fibrosis induced by carbon tetrachloride [ 13 ]. Similarly, Kim et al reported a significant reduction in both the number of macrophages and levels of cytokine expression in a mouse model of periodontitis upon treatment with 6-shogaol [ 37 ].…”

“…These protective effects were associated with the suppression of oxidative stress, cell death, and inflammation. Earlier studies have demonstrated the protective potential of 6-shogaol in various liver diseases such as acetaminophen-induced hepatotoxicity [ 11 ], sepsis-induced liver injury [ 12 ], and carbon tetrachloride-induced liver fibrosis [ 13 ] in mouse models. However, the potential effects of 6-shogaol on NASH have not been explored.…”

Gentiopicroside ameliorates CCl4-induced liver injury in mice by regulating the PPAR-γ/Nrf2 and NF-κB/IκB signaling pathways

“…26 It has been reported that NF-jB plays an important role in CCl 4induced liver injury by activating inflammatory signaling pathways. 27 The results in this study revealed that serum TNF-a and IL-1b levels were significantly increased in CCl 4 -treated mice, and p-IjB-a and p-NF-jB p65 expression was also elevated. Following Gent administration, TNF-a and IL-1b secretion and p-IjB-a and p-NF-jB p65 expression were markedly reduced.…”

Anticancer perspective of 6-shogaol: anticancer properties, mechanism of action, synergism and delivery system

“…The inhibition of NF-kB by 6-shogaol was also accompanied by down-regulation of its downstream target protein genes cyclinD1, survivin and cMyc [ 58 ]. Inhibition of 6-shogaol targeting of NF-kB signalling molecules is a key step in the treatment of several diseases caused by inflammation, such as acute kidney injury [ 98 ], CCL4-induced liver fibrosis [ 99 ] and cardioprotection [ 100 ].…”