Paeonia lactiflora Pall. regulates the NF-κB-NLRP3 inflammasome pathway to alleviate cholestasis in rats.

Cholestasis is a critical risk factor for severe hepatic disease or cirrhosis. The anti-inflammatory effect of Paeonia lactiflora Pall. (PLP), named Chishao in traditional Chinese medicine (TCM), on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis model was tried to be elucidated in this research. Therapeutic effect indices on hepatic function, including ALT, AST, TBIL, DBIL, ALP, TBA and γ-GT, were measured. To further investigate the protective mechanism of PLP, the mRNA and protein expression levels of NF-κB-NLRP3 inflammasome pathway were detected. Our results showed that compared with the model group, PLP could significantly reduce the increased serum indices such as ALT, AST, TBIL, DBIL, ALP, TBA and γ-GT induced by ANIT in a dose-dependent way. Moreover, we found that PLP downregulated the mRNA expression levels including IKK, p65, NLRP3, caspase-1 and IL-1β, especially at the large dose. Furthermore, PLP also significantly inhibited NF-κB-NLRP3 inflammasome pathway by decreasing the protein levels of p65, p-p65, p-IKK, NLRP3, caspase-1 and IL-1β. The results indicated that PLP could ameliorate ANIT-induced cholestasis in rats and the anti-inflammatory effect of PLP might be related to regulating NF-κB-NLRP3 inflammasome pathway. This study will provide scientific evidence for PLP as a potential drug candidate for cholestasis.

Ma X ，Wen JX ，Gao SJ ，He X ，Li PY ，Yang YX ，Wei SZ ，Zhao YL ，Xiao XH ... -  《-》

Paeonia lactiflora Pall. protects against ANIT-induced cholestasis by activating Nrf2 via PI3K/Akt signaling pathway.

Ma X ，Zhao YL ，Zhu Y ，Chen Z ，Wang JB ，Li RY ，Chen C ，Wei SZ ，Li JY ，Liu B ，Wang RL ，Li YG ，Wang LF ，Xiao XH ... -  《Drug Design Development and Therapy》

Paeoniflorin ameliorates cholestasis via regulating hepatic transporters and suppressing inflammation in ANIT-fed rats.

Paeoniflorin has shown the obvious effect on cholestasis according to our previous research. However, its mechanism has not been absolutely explored yet. This study aims at evaluating the potential effect of paeoniflorin on alpha-naphthylisothiocyanate (ANIT) -induced cholestasis by inhibiting nuclear factor kappa-B (NF-κB) and simultaneously regulating hepatocyte transporters. Cholestasis was induced by administration of ANIT. The effect of paeoniflorin on serum indices such as total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ-glutamyltranspeptidase (γ-GT), total bile acid (TBA) and histopathology of liver were determined. Liver protein levels of NF-κB, interleukin 1β (IL-1β) and the hepatocyte transporters such as Na+/taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2) and cholesterol 7α-hydroxylase (Cyp7a1) were investigated by western blotting. The results demonstrated that paeoniflorin could decrease serum ALT, AST, ALP, γ-GT, TBIL, DBIL and TBA in ANIT-treated rats. Histological examination revealed that rats treated with paeoniflorin represented fewer neutrophils infiltration, edema and necrosis in liver tissue compared with ANIT rats. Moreover, paeoniflorin significantly reduced the over expressions of NF-κB and IL-1β induced by ANIT in liver tissue. In addition, the relative protein expressions of NTCP, BSEP, MRP2 but not Cyp7a1 were also restored by paeoniflorin. The potential mechanism of paeoniflorin in alleviating ANIT-induced cholestasis seems to be related to reduce the over expressions of NF-κB and hepatocyte transporters such as NTCP, BSEP as well as MRP2.

Zhao Y ，He X ，Ma X ，Wen J ，Li P ，Wang J ，Li R ，Zhu Y ，Wei S ，Li H ，Zhou X ，Li K ，Liu H ，Xiao X ... -  《-》

The hepatoprotective effects of Sedum sarmentosum extract and its isolated major constituent through Nrf2 activation and NF-κB inhibition.

Sedum sarmentosum, which is recorded in Chinese Pharmacopoeia, has been applied clinically to treat liver and gallbladder diseases. This study aimed to explore the hepatoprotective effect of S. sarmentosum less polar extract (SSE) against ANIT-induced liver injury in rats, and the protective activity and mechanism of one major constituent isolated from this extract on D-GalN-induced human hepatic QSG7701 cell damage. Rats were divided into groups and then administrated intragastrically with SSE at doses of 100, 200 and 400 mg/kg for 7 days. They were modeled in the experiments with ANIT (70 mg/kg) to induce liver injury after the sixth day administration. The levels of serum biochemical markers ALT, AST, ALP, GGT/γ-GT, DBiL, TBiL, ALB, TP, and bile flow rate, as well as the histopathology of the liver tissue were used as indices of liver damage and measured. The inflammatory response and oxidative stress were thought to be key contributors to ANIT-induced liver injury in rats. Therefore, the inflammatory mediators (TNF-α, IFN-γ, IL-4) and oxidative stress (ROS, SOD, GSH-PX) were measured in the serum and liver homogenates, respectively. Next, phytochemical research was performed to produce the main component, and the isolated compound was evaluated for its hepatoprotective activity against QSG7701 cell injured by D-GalN through the measurement of cell viabilities, ALT, AST, IL-1β, TNF-α, IL-6, ROS, GSH-PX and SOD productions. Furthermore, the protein expression of the Nrf2 and NF-κB pathways were analyzed by western blotting. SSE had an obvious effect on the decreases of ALT, AST, ALP, GGT/γ-GT, DBiL and TBiL levels, the increases of ALB and TP levels in serum, and the ANIT-induced deceleration in bile flow for liver injury. Meanwhile, SSE pretreatment alleviated ANIT-induced liver pathological injuries exhibited by HE stain of the liver. Moreover, SSE significantly suppressed levels of pro-inflammatory cytokines TNF-α and IFN-γ, and elevated level of anti-inflammatory cytokine IL-4 in serum. SSE also attenuated oxidative stress by reducing ROS level and by enhancing antioxidative enzymes (SOD and GSH-PX) activities after ANIT administration in liver tissue. Further, the major compound shown in HPLC was isolated from SSE. Its structure was identified by the spectroscopic data analysis and comparison with literature values. The principal constituent had potent protective effect on D-GalN-induced QSG7701 cells damage in a dose dependent manner with survival rates of 58.2% and 69.5% at 10 μM and 20 μM, respectively. Its cytoprotective effect was associated with the reduction of ALT, AST, IL-1β, TNF-α, IL-6 and ROS levels, and the elevation of GSH-PX and SOD productions in QSG7701 cells induced by D-GalN. Western blotting showed that this compound enhanced the expression of Nrf2, HO1, NQO1 and GCLC, and inhibited D-GalN-induced IκBα and NF-κB p65 phosphorylation. Current study showed that SSE treatment exerted a protective effect on ANIT-induced liver injury. The main compound δ-amyrone isolated from the extract was characterized as the effective component with hepatoprotective activity by promoting Nrf2 antioxidant defense and suppressing NF-κB inflammatory response.

Wang GW ，Zhang XL ，Wu QH ，Jin YB ，Ning CT ，Wang R ，Mao JX ，Chen M ... -  《-》

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome.

Shao A ，Wu H ，Hong Y ，Tu S ，Sun X ，Wu Q ，Zhao Q ，Zhang J ，Sheng J ... -  《-》