Synthesis and anti-inflammatory activity of paeonol analogues in the murine model of complete Freund's adjuvant induced arthritis.

A new series of paeonol alkyl ether analogues were synthesized and confirmed with IR, 1H NMR, 13C NMR and HRMS spectra. They have shown anti-inflammatory activities by scavenging mediator of free radicals and inhibiting lipid mediator of inflammation on complete Freund's adjuvant (CFA) induced arthritis in mice. The in vitro and in vivo scavenging ability of free radicals was determined by using chemical analysis and commercial assay kits, respectively. The in vivo inhibiting lipid mediator of inflammation was examined by ELISA. Our results indicated that the substitution of the hydrogen in hydroxyl group at C2 position of paeonol 1 by short carbon chain, in the presence or absence of bromo atom at C5 position, decreased its scavenging ability on radicals (3a or 4a vs 1), while the long alkyl substitution (Cn>14) increased the activity. Compared with 3a or 4a, scavenging abilities of 3a-h or 4a-h gradually increased following the length elongation of alkyl carbon chain. Compounds 3h and 4h showed great scavenging ability on OH, O2-, DPPH, ATBS+ and MDA, and good promotion on T-AOC and SOD. The results of the in vivo inhibiting lipid mediator of inflammation also demonstrated that 3h, 4h exhibited substantial inhibition on enzyme activity of COX-2, PGE2. Therefore, 3h and 4h have great potential to be the novel anti-inflammatory drug candidates for the therapy of arthritis.

Hepatoprotective effect of quercetin against LPS/d-GalN induced acute liver injury in mice by inhibiting the IKK/NF-κB and MAPK signal pathways.

Quercetin is regarded as a potential hepatoprotective agent in the treatment of acute liver injury. However, the underlying mechanism of how quercetin to protect against lipopolysaccharides/d-galactosamine (LPS/d-GalN) induced acute liver injury remains unclear. To investigate the mechanism, the antioxidative, anti-inflammatory and antiapoptotic responses were performed. The results showed that quercetin pretreatment improved the survival rate and substantially reduced the liver histopathological changes in mice. It also alleviated the hepatic damage and reduced the productions of oxidative markers induced by LPS/d-GalN. In addition, quercetin pretreatment significantly diminished the production of inflammatory cytokines, including TNF-α, IL-6 and IL-1ß, and inhibited the activation of the NF-κB and MAPK signaling pathways as well as the expression of apoptotic-related proteins induced by LPS/d-GalN. We found that the potential mechanism of this quercetin-induced protection is mainly mediated through its powerful antioxidative capacity, inhibition of hepatocyte apoptosis and suppression of inflammatory cytokines through the IKK/NF-κB and MAPK signaling pathways. Thus, quercetin shows a promising therapeutic effect on acute liver injury in mice.

Antioxidation, anti-inflammation and anti-apoptosis by paeonol in LPS/d-GalN-induced acute liver failure in mice.

To evaluate the hepatoprotective effects and potential mechanisms of paeonol (Pae) against acute liver failure (ALF) induced by lipopolysaccharide (LPS)/d-galactosamine (d-GalN) in mice, we examined anti-oxidative, anti-inflammatory and anti-apoptotic activities of Pae. We found that Pae pretreatment markedly reduced the activities of alanine transaminase and aspartate transaminase as well as the histopathological changes induced by LPS/d-GalN. Catalase, glutathione and superoxide dismutase activities increased and reactive oxygen species activity decreased after Pae treatment compared with LPS/d-GalN treatment. Pretreatment with Pae also significantly inhibited the expression levels of iNOS, nitric oxide (NO), COX-2 and prostaglandin E2 (PGE2). In addition, Pae administration prevented the phosphorylated expression of IκB kinase, inhibitor kappa B in the nuclear factor-kappa B (NF-κB) signaling pathway, and suppressed the phosphorylated expression of extracellular signal-regulated kinase (ERK), c-jun-N-terminal kinase and p38 in the MAPK signaling pathway. Pretreatment with Pae also inhibited hepatocyte apoptosis by reducing the expression of caspases 3, 8, 9, and Bax, and increasing Bcl-2. In total, protective effects of Pae against LPS/d-GalN-induced ALF in mice are attributed to its antioxidative effect, inflammatory suppression in NF-κB and MARK signaling pathways, and inhibition of hepatocyte apoptosis inhibition. Therefore, Pae can be a potential therapeutic agent in attenuating LPS/d-GalN-induced ALF in the future.

Diosmetin exerts anti-oxidative, anti-inflammatory and anti-apoptotic effects to protect against endotoxin-induced acute hepatic failure in mice.

To investigate the effects and mechanism of diosmetin on acute hepatic failure (AHF), an AHF murine model was established through administration of lipopolysaccharides/D-galactosamine (LPS/D-GalN). In vitro, diosmetin scavenged free radicals. In vivo, diosmetin decreased mortality among mice, blocked the development of histopathological changes and hepatic damage, and suppressed levels of inflammatory mediators and cytokines. In addition, diosmetin prevented the expression of phosphorylated IKK, IκBα, and NF-κB p65 in the NF-κB signaling pathway, and JNK and p38 in the MAPK signaling pathway. Diosmetin also inhibited hepatocyte apoptosis. Thus, diosmetin exerts protective effects against endotoxin-induced acute hepatic failure in mice. The underlying mechanisms are antioxidation, NF-κB signaling inhibition, inflammatory mediator/cytokine attenuation, and hepatocyte apoptosis suppression. Diosmetin is thus a potential drug candidate for use in the treatment of acute hepatic failure.