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Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation.

ABSTRACT: Celastrol is an anti-inflammatory natural triterpenoid, isolated from the herb Tripterygium wilfordii or thunder god vine. Here, we define mechanisms mediating anti-inflammatory activity of celastrol and demonstrate efficacy of a dietary celastrol supplement for chemoprevention of inflammation-driven carcinogenesis in mice. Dietary celastrol (31.25 ppm in rodent diet from 8 weeks to 25 weeks of age) is well tolerated and protects against LPS-induced acute inflammation in C57BL/6 mice, potently suppressing LPS-induction of inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, Interleukin (IL)-6 and IL-1?. To test whether dietary celastrol suppresses inflammation-driven colorectal cancer (CRC), we employed a unique model of spontaneous, inflammation-driven CRC in mice harboring a germ line deletion of the p27Kip1 gene and a T cell-specific deletion of Smad4 gene (Smad4co/co;Lck-crep27Kip1-/-or DKO), which develop severe intestinal inflammation and carcinogenesis as early as 3 months of age. Exposure of DKO mice to daily dietary celastrol (12.5 ppm in diet) from 6 weeks of age significantly suppressed development of colitis-associated CRC (CAC). Celastrol chemoprevention of CAC in this new model of intestinal neoplasia was associated with significant suppression of iNOS at 4 months of age, and iNOS, COX-2 and NF?B at 6 months of age, with significant reduction in inflammatory cytokines, IL-6 and IL-1?. Chemoprevetion of CAC by dietary celastrol was further confirmed in the model of azoxymethane (AOM) plus dextran sodium sulfate (DSS)-induced carcinogenesis in C57BL/6 mice. These data suggest the potential for celastrol as a safe and effective dietary supplement in the chemoprevention of CAC in humans.

SUBMITTER: Barker EC

PROVIDER: S-EPMC5862246 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation.

Barker Emily C EC Kim Byung-Gyu BG Yoon Ji Hee JH Tochtrop Gregory P GP Letterio John J JJ Choi Sung Hee SH

Carcinogenesis 20180101 1

Celastrol is an anti-inflammatory natural triterpenoid, isolated from the herb Tripterygium wilfordii or thunder god vine. Here, we define mechanisms mediating anti-inflammatory activity of celastrol and demonstrate efficacy of a dietary celastrol supplement for chemoprevention of inflammation-driven carcinogenesis in mice. Dietary celastrol (31.25 ppm in rodent diet from 8 weeks to 25 weeks of age) is well tolerated and protects against LPS-induced acute inflammation in C57BL/6 mice, potently s ...[more]

PMID: 29069290

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Project description:Celastrol is well known for its anti-inflammatory and anti-cancer effects. In this study, the efficacy of celastrol against dextran sulfate sodium (DSS)-induced inflammatory bowel disease (IBD) in mice was established and the mechanism was investigated using lipidomics. Celastrol treatment significantly alleviated DSS-induced colitis in mice, as revealed by the body weight, colon length, scores of rectal bleeding and diarrhea, serum TNF-? level, and histological analysis results. Lipidomics analysis based on UPLC/MS revealed characteristic changes in the metabolic profiles of the colitis mice, with altered levels of lipid markers associated with IBD, including LPC18?:?0, LPC18?:?1, LPC18?:?2, sphingomyelin (SM), and increased LPC18?:?0/LPC18?:?1 and LPC18?:?0/LPC18?:?2 ratios. For the celastrol-treated colitis mice, however, levels of the above lipid markers were restored, together with recovered saturated LPC/unsaturated LPC ratios. Accordingly, using GC-MS analysis, increased stearic acid (C18?:?0)/oleic acid (C18?:?1) and stearic acid (C18?:?0)/linoleic acid (C18?:?2) ratios were observed in colitis mice, which were later recovered after celastrol treatment. Quantitative real-time PCR analysis revealed that the liver expression of stearoyl-coenzyme A desaturase 1 (SCD1), the key enzyme controlling the desaturation of saturated fatty acid, was dramatically inhibited in IBD mice, and was obviously recovered after celastrol treatment. These results suggest that the increased saturated LPC/unsaturated LPC (and saturated fatty acid/unsaturated fatty acid) ratios associated with SCD1 down-regulation could be regarded as biomarkers of colitis, and celastrol alleviates DSS-induced colitis partially via up-regulation of SCD1, restoring the altered balance between stearic acid- and oleic acid-derived lipid species, which plays an important role in alleviating colitis. In all, this study provided the scientific basis for further development of celastrol in treating IBD.

Project description:Leg problems often result from the rapid weight gain and poor bone quality in modern ducks, leading to a high risk of fractures and continuous pain. We hypothesized that improving bone quality in combination with delaying weight gain via a low nutrient density (LND) diet probably reverses these skeletal abnormalities. Studies indicated that 25-hydroxycholecalciferol (25-OH-D3), a vitamin D3 metabolite, is effective in treating bone-related disorders. Therefore, Exp. 1 evaluated the effects of 25-OH-D3 on tibial mass of meat ducks. Male meat ducklings were fed a standard nutrient density diet (containing a regular vitamin regimen) without or with 25-OH-D3 at 0.069 mg/kg for 35 d. The results showed that 25-OH-D3 supplementation improved the mineral content, microarchitecture and mechanical properties of tibias, and this companied by a decreased serum bone resorption marker and a concomitant decrement in osteoclast-specific marker genes expression. Subsequently, Exp. 2 was conducted to examine the impacts of 25-OH-D3 incorporating an LND diet on tibial quality of ducks under 2 different vitamin regimens (regular and high). Ducklings were allocated to a 2 × 2 factorial arrangement with 2 kinds of vitamin premixes and without or with 25-OH-D3 at 0.069 mg/kg in LND diets. The high premix had higher levels of all vitamins except biotin than the regular premix. The results demonstrated that high vitamin diets exhibited more significant effects than regular vitamin diets on inhibiting bone turnover and increasing minerals deposition. Tibial mineral content, microarchitecture, and strength of birds under the regular vitamin regimen were increased by 25-OH-D3 supplementation; However, these positive effects were not observed in ducks under the high vitamin regimen. To conclude, 25-OH-D3 supplementation improves tibial mass by suppressing osteoclast-mediated bone resorption in meat ducks, and this positive impact only was observed in regular but not high vitamin regimen when birds fed an LND diet.

Dataset Information

Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation.

Publications

Potent suppression of both spontaneous and carcinogen-induced colitis-associated colorectal cancer in mice by dietary celastrol supplementation.

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