Quercetin Prevents Pyrrolizidine Alkaloid Clivorine-Induced Liver Injury in Mice by Elevating Body Defense Capacity

Abstract

Quercetin is a plant-derived flavonoid that is widely distributed in nature. The present study is designed to analyze the underlying mechanism in the protection of quercetin against pyrrolizidine alkaloid clivorine-induced acute liver injury in vivo. Serum transaminases, total bilirubin analysis, and liver histological evaluation demonstrated the protection of quercetin against clivorine-induced liver injury. Terminal dUTP nick end-labeling assay demonstrated that quercetin reduced the increased amount of liver apoptotic cells induced by clivorine. Western-blot analysis of caspase-3 showed that quercetin inhibited the cleaved activation of caspase-3 induced by clivorine. Results also showed that quercetin reduced the increase in liver glutathione and lipid peroxidative product malondialdehyde induced by clivorine. Quercetin reduced the enhanced liver immunohistochemical staining for 4-hydroxynonenal induced by clivorine. Results of the Mouse Stress and Toxicity PathwayFinder RT2 Profiler PCR Array demonstrated that the expression of genes related with oxidative or metabolic stress and heat shock was obviously altered after quercetin treatment. Some of the alterations were confirmed by real-time PCR. Our results demonstrated that quercetin prevents clivorine-induced acute liver injury in vivo by inhibiting apoptotic cell death and ameliorating oxidative stress injury. This protection may be caused by the elevation of the body defense capacity induced by quercetin.

Quercetin protects mouse liver against CCl4-induced inflammation by the TLR2/4 and MAPK/NF-κB pathway

“…Several evidences have also revealed that acute CCl 4 intoxication increased circulating levels of inflammatory cytokines/chemokines, including interleukins, cytokines and nuclear factor-κB (NF-κB) [2,11,12,27]. Under normal physiological conditions, IκBα is an intracellular functional protein that acts on inhibiting the NF-κB transcription in the nucleus.…”

“…Under normal physiological conditions, IκBα is an intracellular functional protein that acts on inhibiting the NF-κB transcription in the nucleus. When IκBα phosphorylation occurs, NF-κB transcription factors will bind to DNA sites to facilitate the transcription of many downstream genes encoding inflammation associated enzymes such as inducible nitric oxide synthase (iNOS), interleukin-1beta (IL-1β) and cyclooxygenase-2 (COX-2) [2,[11][12][13]. Excessive ROS induced by CCl 4 intermediates can also function as signaling messengers to NF-κB and ultimately lead to increased inflammatory cytokine production [2,3].…”

“…Ninety mice were randomly divided into four groups (10-15 mice/group). Mice in Group 1 were given twice weekly injections of olive oil (vehicle control); mice in Group 2 were injected with CCl 4 and received water containing 0.1% Tween 80 by oral gavage; mice in Group 3 and Group 4 were injected with CCl 4 , as in Group 2, and received QE in distilled water containing 0.1% Tween 80 at a dose of 40 and 80 mg/(kg day) by oral gavage, respectively [11]; mice in Groups 5-7 were injected with CCl 4 , as in Group 2, and PD98059 (PD), SB203580 (SB), SP600125 (SP) (5 mg/kg) were intraperitoneally injected 1 h prior to CCl 4 shot every day [25].…”

“…Among them, TLR2 and TLR4 are crucial players in initiating innate immune responses and influence subsequent adaptive immune responses [9]. The nuclear factor kappa B (NF-κB) is one of the most ubiquitous transcription factors and functions as a central player in the inflammatory processes [10][11][12]. Activation of NF-κB is initiated by the signal-induced degradation of IκB proteins.…”

“…The newly synthesized IκB then reinhibits NF-κB and, thus, forms an auto feedback loop, which results in oscillations of NF-κB activity [13]. Activated TLR4 and TLR2 can initiate a complex signaling pathway, including the activation of mitogen-activated protein kinases (MAPKs) and inhibitory κB (IκB), which in turn inactivated NF-κB and the inflammatory cytokines [10,11]. In the murine model, elements of the innate immune system such as TLR2 and TLR4 play important protection roles in the liver damage of CCl 4 -treated animals [12,14].…”