SummaryReactive oxygen species (ROS) are produced mainly during oxidative phosphorylation and by activated phagocytic cells during oxidative burst. The excessive production of ROS can damage lipids, protein, membrane and nucleic acids. They also serve as important intracellular signalling that enhances the inflammatory response. Many studies have demonstrated a role of ROS in the pathogenesis of inflammatory chronic arthropathies, such as rheumatoid arthritis. It is known that ROS can function as a second messenger to activate nuclear factor kappa-B, which orchestrates the expression of a spectrum of genes involved in the inflammatory response. Therefore, an understanding of the complex interactions between these pathways might be useful for the development of novel therapeutic strategies for rheumatoid arthritis.

Increasing evidence in both experimental and clinical studies suggests that oxidative stress is involved in the pathogenesis and progression of diabetic tissue damage. This study investigated the protective effects of quercetin treatment on oxidative stress, nuclear factor (NF)-kappaB activation and expression of inducible nitric oxide synthase (iNOS) in streptozotocin-induced diabetic rats. Male Wistar rats were divided into 4 groups: control rats, control rats treated daily with quercetin (150 micromol/kg, i.p.), untreated diabetic rats, and diabetic rats treated with quercetin. Diabetes was induced by a single i.p. injection of streptozotocin (70 mg/kg). Eight weeks later we measured TBARS and hydroperoxide-initiated chemiluminescence (QL) in liver as markers of oxidative stress, and activities of the antioxidant enzymes catalase, superoxide dismutase (SOD), and glutathione peroxidase, NF-kappaB activation by an electrophoretic mobility shift assay and expression of IkappaB kinases (IKKalpha and IKKbeta), the inhibitor IkappaB (IkappaBalpha and IkappaBbeta), and iNOS by Western blot. The plasma glucose concentration was significantly increased in diabetic rats and was not changed by quercetin. Streptozotocin administration induced significant increases in hepatic TBARS concentration, QL, and SOD and catalase activities that were prevented by quercetin. Activation of NF-kappaB, induction of IKKalpha and iNOS protein levels, and increased degradation of IkappaBalpha were also observed in streptozotocin-treated rats. All of those effects were abolished by quercetin. These findings suggest that quercetin treatment, by abolishing the IKK/NF-kappaB signal transduction pathway, may block the production of noxious mediators involved in the development of early diabetes tissue injury and in the evolution of late complications.

We investigated whether quercetin protects from steatosis and limits the expression of proinflammatory and fibrogenic genes in C57BL/6J mice with nonalcoholic steatohepatitis (NASH) induced by feeding a methionine-choline-deficient (MCD) diet. Quercetin (50 mg/kg) was given by oral route daily. Mice were randomly divided into 4 groups that received for 2 or 4 wk: the control diet plus vehicle, control diet plus quercetin, MCD diet plus vehicle, and MCD diet plus quercetin. At both 2 and 4 wk, feeding the MCD diet resulted in liver steatosis, inflammatory cell accumulation, oxidative stress evaluated by the concentration of TBARS, and fibrosis evidenced by the staining of α-smooth muscle actin-positive cells in the liver. At both 2 and 4 wk, the MCD diet induced an increase in the mRNA levels of Il6, Tnf, Ptgs2, and Hmgb1 and increased the protein concentrations of Toll-like receptor-4, c-Jun terminal kinase, and p65 NFκB subunit compared with control rats. Feeding the mice the MCD diet also triggered an increase of Col1a1, Col3a1, Plod3, Tgfb1, Smad3, Smad7, Pdgfb, Ctgf, Areg, Mmp9, and Timp1 mRNA levels. These effects were totally or partially prevented by treatment with quercetin. The data obtained suggest that attenuation of multiple profibrotic and proinflammatory gene pathways contributes to the beneficial effects of quercetin in mice with MCD diet-induced steatohepatitis.