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Abstract: Guggulsterone is a plant sterol that is used to treat hyperlipidemia, arthritis, and obesity. Although its anti-inflammatory and anti-hyperlipidemic effects have been well documented, the effect of guggulsterone on fibroblast-like synoviocytes (FLS) has not yet been reported. Therefore, in this study, the effect of guggulsterone on interleukin (IL)-1β-induced inflammatory responses in the FLS of rheumatic patients was investigated. Treatment of FLS with IL-1β induced production of chemokines such as RANTES and ENA-78. In addition, Western blot analysis and gelatin zymography revealed that IL-1β activated matrix metalloproteinase (MMP)-1 and -3 in FLS. However, pre-incubation with guggulsterone completely inhibited the ability of IL-1β to induce the production of chemokines and to activate MMPs. Although the NF-κB binding activity and nuclear p50 and p65 subunit levels, as well as IκBα degradation in the cytoplasm was greater in cells stimulated with IL-1β than in unstimulated cells, treatment with guggulsterone abolished all of these increases. Collectively, these results suggest that guggulsterone would be useful as an inhibitor of joint destruction in patients with rheumatoid arthritis. [Copyright &y& Elsevier]

Abstract: Scopoletin (6-methoxy-7-hydroxycoumarin) is a phenolic coumarin and a member of the phytoalexins. In this study we investigated whether scopoletin caused apoptosis in HL-60 promyelocytic cells and, if so, by what mechanisms. We found that scopoletin induced apoptosis as confirmed by a characteristic ladder pattern of discontinuous DNA fragments in a dose-dependent manner. The signal cascade activated by scopoletin included the heterodimeric redox-sensitive transcription factor NF-κB, which exhibited an upregulation of nuclear factor-kappa B (NF-κB) translocation to the nucleus by increase of IκBα degradation. In addition, scopoletin activated caspase-3 as was evidenced by both the proteolytic cleavage of the proenzyme and increased protease activity. Activation of caspase-3 resulted in the cleavage of 116 kDa poly(ADP-ribose) polymerase (PARP) to 85 kDa cleavage product in time-and dose-dependent fashions. Prior treatment of the cells with pyrrolidine dithiocarbamate, a potent inhibitor of NF-κB activation, or Ac-DEVD-CHO, a specific caspase-3 inhibitor, prevented scopoletin-induced caspase-3 activation, PARP cleavage, and finally DNA fragmentation. Taken together, these results suggest that scopoletin induces NF-κB activation, which, in turn, causes activation of caspase-3, degradation of PARP, and eventually leads to apoptotic cell death in HL-60 cells. [Copyright &y& Elsevier]