Protective role of quercetin against lead-induced inflammatory response in rat kidney through the ROS-mediated MAPKs and NF-κB pathway.

Lead (Pb) exposure is considered as a risk factor for the development of renal dysfunction. The flavonoid quercetin (QE) in diets exerts the nephroprotective effects. This study investigated the effects of quercetin on renal oxidative stress and inflammation in rats exposed to Pb. Wistar rats were divided into normal, lead exposure groups, lead plus quercetin groups and quercetin groups. Rats were exposed to lead acetate in the drinking water (500mgPb/L) with or without quercetin co-administration (25 and 50mgQU/kg intragastrically once daily). After 75days, serum uric acid, urea, creatinine, renal reactive oxygen species (ROS) production, thiobarbituric acid reactive substances (TBARS) and histopathological analysis were performed. Pb content in kidney was also assayed. The levels of tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), the extracellular-receptor kinases (ERK1/2), the c-Jun N-terminal kinases (JNK1/2), p38 MAPK and nuclear factor-κB (NF-κB) were measured. Quercetin significantly prevented Pb-induced nephrotoxicity in a dose-dependent manner, indicated by both diagnostic indicators and histopathological analysis. Quercetin significantly decreased Pb content in kidney. Pb-induced profound elevations of oxidative stress in kidney were suppressed by quercetin. Furthermore, quercetin significantly inhibited Pb-induced inflammation in rat kidney. These results suggest that quercetin has the nephroprotective actions. The inhibition of Pb-induced kidney inflammation by quercetin is due at least in part to its anti-oxidant activity and its ability to modulate the MAPK and NF-κB signaling pathway. Quercetin might be a potent nephroprotective drug to protect Pb-induced kidney injury.

Liu CM ，Sun YZ ，Sun JM ，Ma JQ ，Cheng C ... -  《-》

Protective effect of quercetin on lead-induced oxidative stress and endoplasmic reticulum stress in rat liver via the IRE1/JNK and PI3K/Akt pathway.

Liu CM ，Zheng GH ，Ming QL ，Sun JM ，Cheng C ... -  《-》

Quercetin disrupts tyrosine-phosphorylated phosphatidylinositol 3-kinase and myeloid differentiation factor-88 association, and inhibits MAPK/AP-1 and IKK/NF-κB-induced inflammatory mediators production in RAW 264.7 cells.

Quercetin is a major bioflavonoid widely present in fruits and vegetables. It exhibits anti-inflammatory, anti-tumor, antioxidant properties and reduces cardiovascular disease risks. However, the molecular mechanism of action against inflammation in RAW 264.7 cells is only partially explored. Quercetin effect on LPS-induced gene and protein expressions of inflammatory mediators and cytokines were determined. Moreover, involvement of heme-oxygenase-1, protein kinases, adaptor proteins and transcription factors in molecular mechanism of quercetin action against inflammation were examined. Quercetin inhibited LPS-induced NO, PGE₂, iNOS, COX-2, TNF-α, IL-1β, IL-6 and GM-CSF mRNA and protein expressions while it promoted HO-1 induction in a dose- and time-dependent manner. It also suppressed I-κB-phosphorylation, NF-κB translocation, AP-1 and NF-κB-DNA-binding and reporter gene transcription. Quercetin attenuated p38(MAPK) and JNK1/2 but not ERK1/2 activations and this effect was further confirmed by SB203580 and SP600125-mediated suppressions of HO-1, iNOS, and COX-2 protein expressions. Moreover, quercetin arrested Src, PI3K, PDK1 and Akt activation in a time- and dose-dependent manner, which was comparable to PP2 and LY294002 inhibition of Src, PI3K/Akt and iNOS expressions. Quercetin further arrested Src and Syk tyrosine phosphorylations and their kinase activities followed by inhibition of PI3K tyrosine phosphorylation. Moreover, quercetin disrupted LPS-induced p85 association to TLR4/MyD88 complex and it then limited activation of IRAK1, TRAF6 and TAK1 with a subsequent reduction in p38 and JNK activations, and suppression in IKKα/β-mediated I-κB phosphorylation. Quercetin limits LPS-induced inflammation via inhibition of Src- and Syk-mediated PI3K-(p85) tyrosine phosphorylation and subsequent TLR4/MyD88/PI3K complex formation that limits activation of downstream signaling pathways.

Endale M ，Park SC ，Kim S ，Kim SH ，Yang Y ，Cho JY ，Rhee MH ... -  《-》

Puerarin protects rat kidney from lead-induced apoptosis by modulating the PI3K/Akt/eNOS pathway.

Puerarin (PU), a natural flavonoid, has been reported to have many benefits and medicinal properties. However, its protective effects against lead (Pb) induced injury in kidney have not been clarified. The aim of the present study was to investigate the effects of puerarin on renal oxidative stress and apoptosis in rats exposed to Pb. Wistar rats were exposed to lead acetate in the drinking water (500mg Pb/l) with or without puerarin co-administration (100, 200, 300 and 400mg PU/kg intragastrically once daily) for 75days. Our data showed that puerarin significantly prevented Pb-induced nephrotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of kidney damage (serum urea, uric acid and creatinine) and histopathological analysis. Moreover, Pb-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of intracellular reduced glutathione (GSH) level in kidney, were suppressed by treatment with puerarin. Furthermore, TUNEL assay showed that Pb-induced apoptosis in rat kidney was significantly inhibited by puerarin. In exploring the underlying mechanisms of puerarin action, we found that activities of caspase-3 were markedly inhibited by the treatment of puerarin in the kidney of Pb-treated rats. Puerarin increased phosphorylated Akt, phosphorylated eNOS and NO levels in kidney, which in turn inactivated pro-apoptotic signaling events including inhibition of mitochondria cytochrome c release and restoration of the balance between pro- and anti-apoptotic Bcl-2 proteins in kidney of Pb-treated rats. In conclusion, these results suggested that the inhibition of Pb-induced apoptosis by puerarin is due at least in part to its antioxidant activity and its ability to modulate the PI3K/Akt/eNOS signaling pathway.

Liu CM ，Ma JQ ，Sun YZ 《-》

Ursolic acid protects mouse liver against CCl4-induced oxidative stress and inflammation by the MAPK/NF-κB pathway.

Ursolic acid (UA), a natural pentacyclic triterpenoid, has been reported to have many benefits and medicinal properties. However, its protective effects against carbon tetrachloride (CCl(4)) induced hepatotoxicity have not been clarified. The aim of the present study was to investigate the effects of UA on oxidative stress and inflammation in liver of CCl(4) treated mice. Male ICR mice were injected with CCl(4) with or without UA co-administration (25 and 50 mg/kg intragastrically once daily) for one week. Our data showed that UA significantly prevented CCl(4)-induced hepatotoxicity in a dose-dependent manner, indicated by both diagnostic indicators of liver damage (serum aminotransferase activities) and histopathological analysis. Moreover, CCl(4)-induced profound elevation of reactive oxygen species (ROS) production and oxidative stress, as evidenced by increasing of lipid peroxidation level and depleting of the total antioxidant capacity (TAC) level in liver, were suppressed by treatment with UA. Furthermore, western blot analysis showed that UA significantly decreased CYP2E1 expression levels and production of pro-inflammatory markers including TNF-α, IL-1β and COX-2 in CCl(4)-treated mouse liver. In exploring the underlying mechanisms of UA action, we found that UA decreased the activation of mitogen-activated protein kinases (JNK, p38 MAPK, ERK), which in turn inactivated the immunoregulatory transcription factor nuclear factor kappa B (NF-κB) in liver of CCl(4) treated mice. In conclusion, these results suggested that the inhibition of CCl(4)-induced inflammation by UA is due at least in part to its anti-oxidant activity and its ability to modulate the MAPK and NF-κB signaling pathway.

Ma JQ ，Ding J ，Zhang L ，Liu CM ... -  《-》