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Tomatidine decreases inducible NO synthase and COX-2 expression through suppression of I-κBα phosphorylation, NF-κB nuclear translocation and JNK activation, which in turn inhibits c-jun phosphorylation and Oct-2 expression. Tomatidine, solasodine and diosgenin (40 μM) show 66%, 22% and 41% inhibition of nitrite production, respectively. The iNOS protein is barely detectable in unstimulated cells but markedly increases after LPS treatment, and Tomatidine causes dose-dependent inhibition of LPS-induced iNOS expression. p65 is the major component of NF-κB in LPS-stimulated macrophages, the effect of Tomatidine on p65 DNA-binding activity is determined. In the presence of Tomatidine at 10-40 μM, the binding activity of NF-κB is suppressed in a dose-dependent manner. Tomatidine inhibits the phosphorylation of I-κB, blocks the I-κB production, and furthermore suppresses p65 NF-κB translocation to the nucleus and modulated binding activity.