Wogonin alleviates liver injury in sepsis through Nrf2‐mediated NF‐κB signalling suppression

Abstract

Sepsis is a life‐threatening organ dysfunction syndrome, and liver is a susceptible target organ in sepsis, because the activation of inflammatory pathways contributes to septic liver injury. Oxidative stress has been documented to participate in septic liver injury, because it not only directly induces oxidative genotoxicity, but also exacerbates inflammatory pathways to potentiate damage of liver. Therefore, to ameliorate oxidative stress is promising for protecting liver in sepsis. Wogonin is the compound extracted from the medicinal plant Scutellaria baicalensis Geogi and was found to exert therapeutic effects in multiple inflammatory diseases via alleviation of oxidative stress. However, whether wogonin is able to mitigate septic liver injury remains unknown. Herein, we firstly proved that wogonin treatment could improve survival of mice with lipopolysaccharide (LPS)‐ or caecal ligation and puncture (CLP)‐induced sepsis, together with restoration of reduced body temperature and respiratory rate, and suppression of several pro‐inflammatory cytokines in circulation. Then, we found that wogonin effectively alleviated liver injury via potentiation of the anti‐oxidative capacity. To be specific, wogonin activated Nrf2 thereby promoting expressions of anti‐oxidative enzymes including NQO‐1, GST, HO‐1, SOD1 and SOD2 in hepatocytes. Moreover, wogonin‐induced Nrf2 activation could suppress NF‐κB‐regulated up‐regulation of pro‐inflammatory cytokines. Ultimately, we provided in vivo evidence that wogonin activated Nrf2 signalling, potentiated anti‐oxidative enzymes and inhibited NF‐κB‐regulated pro‐inflammatory signalling. Taken together, this study demonstrates that wogonin can be the potential therapeutic agent for alleviating liver injury in sepsis by simultaneously ameliorating oxidative stress and inflammatory response through the activation of Nrf2.

The liver in sepsis: molecular mechanism of liver failure and their potential for clinical translation

“…Clinical studies show that cell death mechanisms are a promising therapeutic approach for treating liver diseases. However, further research needs to elucidate the relationship between the different cell death mechanisms in hepatocytes to understand the pathological machinery of liver diseases (Dai et al 2021 ). Concluding, the diversity of the described pathway in the context of cell death yields various targets for possible targeted therapies.…”

Hepatoprotective Effect of Mitochondria-Targeted Antioxidant Mito-TEMPO against Lipopolysaccharide-Induced Liver Injury in Mouse

“…ROS can lead to host genetic mutation and inflammation, consequently causing liver injury [ 59 ]. In the progression of sepsis, the generation of ROS is closely linked to the occurrence and development of liver damage, not only via the direct damage to hepatocytes by promoting the formation of oxidative protein adducts and lipid peroxides but also through the proinflammatory response accentuated by oxidative stress [ 7 ]. In fact, as the main metabolic organ responsible for deoxygenation, lipid synthesis, and glycogen storage, the liver is more vulnerable to oxidative stress induced by a variety of factors, including sepsis-associated inflammatory responses [ 60 ].…”

“…Recent studies have demonstrated that oxidative stress is a common mechanism of sepsis-induced liver injury. It not only directly leads to genotoxic damage (DNA damage) but also exacerbates the inflammatory pathway to amplify the injury of hepatocytes [ 7 ]. Oxidative stress is regarded as an imbalance between reactive oxygen species (ROS) production and elimination by antioxidant systems [ 8 ].…”

Protective effects of β-eudesmol against septic liver injury via inhibition of NF-κB signaling

“…Oxidative stress also promoted the release of proinflammatory factors in hepatocytes and Kupffer cells, and induced infiltration of neutrophils and lymphocytes to augment the liver damage [16]. Suppression of oxidative stress and inflammation ameliorated septic liver damage [17]. βeudesmol reduced hydrogen peroxide-induced inflammation and oxidative stress in dermal fibroblasts [9].…”

“…NF-κB, essential for the secretion of proinflammatory factors, was activated in cecal ligation and puncture-induced septic rats [18]. Inhibition of NF-κB signaling attenuated cecal ligation and puncture-induced septic liver injury [17]. β-eudesmol suppressed the activation of NF-κB signaling in hydrogen peroxide-induced dermal fibroblasts in order to reduce inflammation and oxidative stress [9].…”