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

Abstract

We already showed that the plant sterol guggulsterone has been reported to inhibit nuclear factor-kappaB (NF-kappaB) 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-kappaB 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 IkappaB kinase (IKK) and IkappaBalpha 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-kappaB 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.

• Authors: Jung Mogg Kim, Hyoun Woo Kang, Mi Yeon Cha, Doyoung Yoo, Nayoung Kim, In-Kyoung Kim, Jeounghun Ku, Sunil Kim, Sang-Ho Ma, Hyun Chae Jung, In Sung Song, Joo Sung Kim
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 90 Issue 7 Pg. 1004-15 (Jul 2010) ISSN: 1530-0307 [Electronic] United States
• PMID: 20195240 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• CCL2 protein, human
• Chemokine CCL2
• GG-50B compound
• GG-52 compound
• Interleukin-8
• NF-kappa B
• Pregnenediones
• Pregnenes
• Tumor Necrosis Factor-alpha
• Sulfasalazine
• Trinitrobenzenesulfonic Acid
• Dextran Sulfate
• Prednisolone
• pregna-4,17-diene-3,16-dione
• I-kappa B Kinase

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Cell Line, Tumor
• Chemokine CCL2 (metabolism)
• Colitis (chemically induced, drug therapy, prevention & control)
• Dextran Sulfate
• Epithelial Cells (drug effects, metabolism)
• Humans
• I-kappa B Kinase (antagonists & inhibitors)
• Interleukin-8 (metabolism)
• Intestinal Mucosa (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• NF-kappa B (antagonists & inhibitors, metabolism)
• Prednisolone (therapeutic use)
• Pregnenediones (chemistry, pharmacology)
• Pregnenes (pharmacology, therapeutic use)
• Sulfasalazine (therapeutic use)
• Trinitrobenzenesulfonic Acid
• Tumor Necrosis Factor-alpha (metabolism)