Novel guggulsterone derivative GG-52 inhibits NF-kappa B signaling in intestinal epithelial cells and attenuates acute murine colitis

作者：Kim Jung Mogg; Kang Hyoun Woo; Cha Mi Yeon; Yoo Doyoung; Kim Nayoung; Kim In Kyoung; Ku Jeounghun; Kim Sunil; Ma Sang Ho; Jung Hyun Chae; Song In Sung; Kim Joo Sung^*

来源：Laboratory Investigation, 2010, 90(7): 1004-1015.

DOI：10.1038/labinvest.2010.54

• guggulsterone derivatives
• inflammatory bowel disease
• murine colitis
• NF-kappa B

We already showed that the plant sterol guggulsterone has been reported to inhibit nuclear factor-kappa B (NF-kappa B) signaling in intestinal epithelial cells (IECs) and to attenuate dextran sulfate sodium (DSS)-induced colitis. This study investigates the anti-inflammatory effects of novel guggulsterone derivatives on IEC and preventive and therapeutic murine models of DSS-induced colitis. Novel guggulsterone derivates with high lipophilicity were designed and four derivates, including GG-46, GG-50B, GG-52, and GG-53, were synthesized. Two guggulsterone derivatives, GG-50B and GG-52, significantly inhibited the activated NF-kappa B signals and the upregulated expression of interleukin-8 (IL-8) in COLO 205 cells stimulated with tumor necrosis factor-alpha (TNF-alpha). Pretreatment with GG-50B and GG-52 attenuated the increased I kappa B kinase (IKK) and I kappa B alpha phsophorylation induced by TNF-alpha. In preventive and therapeutic models of murine colitis, administration of GG-52 significantly reduced the severity of DSS-induced colitis, as assessed by disease activity index, colon length, and histology. In contrast, GG-50B did not show a significant reduction in the colitis severity. Moreover, the efficacy on attenuating colitis by GG-52 was comparable to that by sulfasalazine or prednisolone. These results indicate that the novel guggulsterone derivative GG-52 blocks NF-kappa B activation in IEC and ameliorates DSS-induced acute murine colitis, which suggests that GG-52 is a potential therapeutic agent for the treatment of inflammatory bowel diseases. Laboratory Investigation (2010) 90, 1004-1015; doi: 10.1038/labinvest.2010.54; published online 1 March 2010

• 出版日期2010-7