Novel guggulsterone derivative GG-52 inhibits NF-kappaB signaling in intestinal epithelial cells and attenuates acute murine colitis.
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.
Kim
Jung Mogg
JM
Department of Microbiology, Hanyang University College of Medicine, Seoul, Korea.
Kang
Hyoun Woo
HW
Cha
Mi Yeon
MY
Yoo
Doyoung
D
Kim
Nayoung
N
Kim
In-Kyoung
IK
Ku
Jeounghun
J
Kim
Sunil
S
Ma
Sang-Ho
SH
Jung
Hyun Chae
HC
Song
In Sung
IS
Kim
Joo Sung
JS
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D018932:Chemokine CCL2 / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000517:prevention & control; D016264:Dextran Sulfate; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D016209:Interleukin-8 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011239:Prednisolone / Q000627:therapeutic use; D011282:Pregnenediones / Q000737:chemistry* / Q000494:pharmacology; D011283:Pregnenes / Q000494:pharmacology / Q000627:therapeutic use*; D012460:Sulfasalazine / Q000627:therapeutic use; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C550855:GG-50B compound; C550854:GG-52 compound; D016209:Interleukin-8; D016328:NF-kappa B; D011282:Pregnenediones; D011283:Pregnenes; D014409:Tumor Necrosis Factor-alpha; D012460:Sulfasalazine; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D011239:Prednisolone; C023617:pregna-4,17-diene-3,16-dione; D051550:I-kappa B Kinase