Cordycepin inhibits IL-1beta-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts.

OBJECTIVE: MMP is a key enzyme in the degradation of extracellular matrices, and its expression plays important roles in inflammatory diseases. Cordycepin (3'-deoxyadenosine), a bioactive compound of Cordyceps militaris, has been shown to exhibit many pharmacological activities, such as anti-cancer, anti-inflammatory and anti-infection activities. In this study, we aimed at the inhibitory effect of cordycepin on IL-1beta-induced MMP-1 and MMP-3 expression as well as the molecular basis using RA synovial fibroblasts (RASFs). METHODS: RASFs were isolated from synovial tissue obtained from 12 patients with RA and cultured in monolayer. Expression of MMP-1 and MMP-3 was evaluated using western blotting and real-time PCR. Chemokines were analysed by ELISA. The phosphorylation of mitogen-activated protein kinase was measured by western blotting. Electrophoretic mobility shift assay was performed to evaluate binding activities of DNA to nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1). RESULTS: Cordycepin inhibited IL-1beta-induced MMP-1 and MMP-3 expressions in RASFs in a dose-dependent manner. Among various chemokines [such as monocyte chemoattractant protein-1 (MCP-1), GRO-alpha, regulated upon activation, normal T-cell expressed and presumably secreted (RANTES) and epithelial neutrophil activating peptide 78 (ENA-78)], cordycepin specifically blocked IL-1beta-induced ENA-78 production in RASF. Moreover, cordycepin significantly inhibited IL-1beta-induced p38/JNK and AP-1 activation, but not extracellular signal-regulated kinase (ERK) and NF-kappaB activation. CONCLUSIONS: Cordycepin is a potent inhibitor of IL-1beta-induced chemokine production and MMP expression and strongly blocks the p38/JNK/AP-1 signalling pathway in RASFs.

Solanum nigrum produces nitric oxide via nuclear factor-kappaB activation in mouse peritoneal macrophages.

Nitric oxide (NO) is an antitumour molecule produced in activated macrophages and Solanum nigrum is a plant used in oriental medicine to treat tumours. In this study using mouse peritoneal macrophages, we have examined the mechanism by which Solanum nigrum regulates NO production. When Solanum nigrum was used in combination with 20 U/ml of recombinant interferon-gamma (rIFN-gamma), there was a marked cooperative induction of NO production. The increase in NO synthesis was reflected as an increased amount of inducible NO synthase (iNOS) protein. The production of NO from rIFN-gamma plus Solanum nigrum-stimulated peritoneal macrophages was decreased by treatment with N-monomethyl-L-arginine or N-tosyl-Phe chloromethyl ketone, an iNOS inhibitor. Additionally, the increased production of NO from rIFN-gamma plus Solanum nigrum-stimulated cells was almost completely inhibited by pretreatment with 100 micromol/l of pyrrolidine dithiocarbamate, an inhibitor of nuclear factor kappaB (NF-kappaB). Furthermore, Solanum nigrum increased activation of NF-kappaB. These findings suggest that Solanum nigrum increases the production of NO by rIFN-gamma-primed macrophages and NF-kappaB plays a critical role in mediating these effects.

Effect of an extract of the root of Scutellaria baicalensis and its flavonoids on aflatoxin B1 oxidizing cytochrome P450 enzymes.

The inhibition of aflatoxin B1 (AFB1) metabolism by a water extract of the root of Scutellaria baicalensis and its flavonoids was examined in liver microsomes. AFB1 is known to be metabolized to aflatoxin M1 (AFM1), aflatoxin Q1 (AFQ1), and AFB1-8,9-epoxide (AFBO). The water extract potently inhibited the production of AFM1 by cytochrome P450 (CYP)1A1/2 and slightly reduced AFBO formation by CYP1A1/2, CYP2B1, CYP2C11 and CYP3A1/2 in TCDD-treated rat liver microsomes. IC50 values for AFM1 and AFBO formation were 6.8 and 122.4 microg/ml, respectively. Wogonin showed the highest inhibitory activity towards AFM1 formation among the flavonoids isolated from the extract. On the other hand, the extract had no effects on the formation of AFBO and AFQ1 in human liver microsomes, and on the activities of CYP2B1, CYP2C11 and CYP3A1/2 which were detected by hydroxylation patterns of testosterone. These results demonstrated that the extract of the root of Scutellaria baicalensis has a specific inhibitory effect on CYP1A1/2 among CYP enzymes involved in AFB1 metabolism by rat and human microsomes.