Nobiletin attenuates lipopolysaccharide/D-galactosamine-induced liver injury in mice by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated cytokine production

Abstract

Inflammation and oxidative stress serve an important role in the development of lipopolysaccharide/D-galactosamine (LPS/GalN)‑induced acute liver injury. Nobiletin, which is found in high quantities in the peel of citrus fruits, is able to modulate immune responses, including inflammatory response and oxidative stress. The present study aimed to evaluate the protective effects of nobiletin on LPS/GalN‑induced acute liver injury. Male C57BL/6 mice were intraperitoneally treated with nobiletin (50, 100 and 200 mg/kg) 2 h prior to LPS/GalN injection. Liver injury was observed in the LPS/GalN group, as demonstrated by increased levels of serum hepatic enzymes and hepatic inflammatory mediators, as well as by histopathological alterations. Treatment with nobiletin reduced serum alanine aminotransferase and aspartate aminotransferase levels, improved hepatic structure, and suppressed hepatic interleukin (IL)‑1β, IL‑6 and tumor necrosis factor‑α production 24 h after LPS/GalN exposure. Western blot analysis revealed that nobiletin treatment inhibited inducible nitric oxide synthase and cyclooxygenase‑2 liver expression. In addition, nobiletin suppressed LPS/GalN‑induced phosphorylation and degradation of inhibitor of nuclear factor (NF)‑κB (IκB)α, as well as NF‑κB p65 translocation into the nucleus. Nobiletin also upregulated the expression of nuclear NF‑E2‑related factor 2 (Nrf2) and cytoplasmic heme oxygenase‑1. In conclusion, these results indicate that nobiletin serves a protective role in LPS/GalN‑induced acute liver injury via activation of the Nrf2 antioxidant pathway and subsequent inhibition of NF‑κB‑mediated cytokine production. These findings support the potential for nobiletin as a therapeutic agent for the treatment of acute liver injury.

Nobiletin alleviates palmitic acid‑induced NLRP3 inflammasome activation in a sirtuin 1‑dependent manner in AML‑12 cells

“…Nob, a polymethoxylated flavonoid, was previously reported to attenuate cardiac dysfunction, oxidative stress and inflammation in streptozotocin-induced diabetic cardiomyopathy (33). He et al (34) reported that Nob reduced lipopolysaccharide-induced liver injury in mice by inhibiting nuclear factor-κB-mediated cytokine production. In the present study, the effect of Nob on NLRP3 inflammasome activation was investigated.…”

Anti-inflammatory effects of polymethoxyflavones from citrus peels: a review

“…After entering nuclear regions, the free NF-κB subunits will specifically bind to promoter DNA sequences and enable the transcription of a series of proinflammatory genes, including inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), cyclooxygenase 2 (COX-2) and interleukin-6 (IL-6) (Shin et al, 2012). Among all these downstream targets, TNF-α may be regarded as the most fundamental one for its inducing capacity on activation and accumulation of leukocytes (Li et al, 2018), as well as further initiation of inflammatory cascade by stimulating IL-6 and IL-1β generation (He et al, 2016). The resulting IL-6 has proven to be crucial in mediating the release of neutrophils and vascular active substances, which may cause serious tissue impairment (Shin et al, 2015;Lee et al, 2010).…”

Natural Products for Prevention and Treatment of Chemical‐Induced Liver Injuries

“…Animal products, such as Chinese traditional fermented yogurt and an extract of abalone ( Haliotis discus hannai Ino), can protect the liver against LPS toxicity with similar mechanisms as mentioned above (Peng & Jiang, ; Debnath et al., ). In addition, in mice or rats treated with LPS plus D‐galactosamine (D‐GaIN), the protective mechanisms of the natural products such as nobiletin from Citrus fruits and echinacoside from Cistanche salsa mainly lie in the activation of Nrf2 and the inhibition of NF‐κB‐mediated cytokine production to ameliorate inflammation and apoptosis (He et al., ; Li et al., ). Also, soy genistein was demonstrated to prevent D‐GalN‐driven chronic liver damage and liver fibrosis through the inhibition of TGF‐β/Smad signaling pathway (Ganai & Husain, ).…”