Simvastatin inhibits NF-κB signaling in intestinal epithelial cells and ameliorates acute murine colitis

Lee, Nam Young; Kim, Sang Woo; Kim, Jung Mogg; Kim, Nayoung; Jung, Hyun Chae; Song, In Sung

doi:10.1016/j.intimp.2006.10.013

Cited by 86 publications

(68 citation statements)

References 49 publications

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“…Simvastatin inhibits proinflammatory gene expression by blocking nuclear factor kappa B (NFkB) signaling in intestinal epithelial cells, and attenuates dextran sodium sulfate-induced acute murine colitis (36). It has also been reported that pitavastatin inhibits NFkB activation and decreases IL-6 in human mammary carcinoma cells (37).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor

Teraoka

Mutoh

Takasu

et al. 2011

Cancer Prevention Research

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It has been suggested that hyperlipidemia is positively associated with colon carcinogenesis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, reduce serum lipid levels. In this study, we clarified the effects of a novel chemically synthesized statin, pitavastatin, on intestinal polyp formation in Min mice, and further examined serum lipid and adipocytokine levels, and proinflammatory and adipocytokine gene levels in intestinal mucosa of Min mice. Treatment with pitavastatin at doses of 20 and 40 ppm decreased the total number of polyps dose-dependently to 85.2% and 65.8% (P < 0.05) of the untreated value, respectively. Serum levels of total cholesterol and triglyceride were slightly reduced and those of IL-6, leptin, and MCP-1 were decreased by 40-ppm pitavastatin treatment. mRNA expression levels of cyclooxygenase-2, IL-6, inducible nitric oxide (iNOS), MCP-1, and Pai-1 were significantly reduced in intestinal nonpolyp parts by pitavastatin treatment. Among them, iNOS mRNA levels were also reduced in the intestinal polyps. Moreover, oxidative stress represented by 8-nitroguanosine in the small intestinal epithelial cells was reduced by pitavastatin treatment. Related to these proinflammatory genes, PPARg activity was activated in the intestinal nonpolyp parts and in the liver of Min mice with pitavastatin treatment. These results indicated that pitavastatin has potential benefit for the suppression of intestinal polyp development. Cancer Prev Res; 4(3); 445-53. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor

Teraoka

Mutoh

Takasu

et al. 2011

Cancer Prevention Research

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“…The human colon cancer cell line COLO 205 [KCLB 10222, Korean Cell Line Bank (KCLB), Seoul, Korea] was used between passages 20 and 40. 16 Cells were grown in DMEM (Sigma, St Louis, MO, USA) supplemented with 10% fetal bovine serum, 2 mM glutamine and antibiotics (100 unit/ml of penicillin and 100 mg/ml of streptomycin). Cells were seeded at 0.5-2 Â 10 6 cells per well onto six-well plates and allowed to attach overnight.…”

Section: Biosynthesis Of Guggulsterone Derivatives and Cell Culturementioning

confidence: 99%

“…10 Therefore, NF-kB activation in IECs seems to be strongly associated with IBD, suggesting that modulation of NF-kB signaling could be a potential target for the treatment of IBD. 9,11,12 Recently, we showed that guggulsterone [4,17(20)-pregnadiene-3, 16-dione] blocks NF-kB signaling pathway and attenuates acute murine colitis. 13 Guggulsterone is an active compound extracted from the gum resin of the tree Commiphora mukul that has been used for thousands of years to treat arthritis, obesity, lipid metabolism disorders, hypothyroidism, and inflammation in the traditional Indian medicinal system.…”

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confidence: 99%

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

Kim

Kang

Yeon

et al. 2010

Laboratory Investigation

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We already showed that the plant sterol guggulsterone has been reported to inhibit nuclear factor-kB (NF-kB) 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-kB signals and the upregulated expression of interleukin-8 (IL-8) in COLO 205 cells stimulated with tumor necrosis factor-a (TNF-a). Pretreatment with GG-50B and GG-52 attenuated the increased IkB kinase (IKK) and IkBa phsophorylation induced by TNF-a. 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-kB 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.

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“…This and other findings have spurred research into what other effects statins can effectuate on the body. Since the mevalonate pathway is ubiquitous in nature and involved in so many crucial cellular reactions, it perhaps to no surprise that effects have been demonstrated in models ranging from angiogenesis, inflammatory reactions, neural glial cell development and neoplastic cell cultures to osteoporosis (Davignon andLeiter 2005, Ahmed et al 2006;Campbell et al 2006, Crisby 2006, de Souza Neto et al 2006, Dirks and Jones 2006, Iwata et al 2006, Poli and Pujia 2006, Ray et al 2006, Steffens and Mach 2006, Weber et al 2006, Acheampong et al 2007, Akdim et al 2007, Alegret and Silvestre 2007, Beaudry et al 2007, Campese and Park 2007, Cimino et al 2007, Devaraj et al 2007, Ghittoni et al 2007, Lee et al 2007, Okuyama et al 2007, Shirai et al 2007, Tousoulis et al 2007, von Tresckow et al 2007). It is also well known that statins, although usually well tolerated, do carry with them the risk for the potentially lethal side effect of rhabdomyalysis, a breakdown of muscular tissue, especially when combined with other cholesterol lowering drugs, as demonstrated by the recent withdrawal of the newer and more potent drug cerivastatin from the market.…”

Section: Statinsmentioning

confidence: 99%

Following the mevalonate pathway to bone heal alley

Skoglund¹

2007

Acta Orthopaedica

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Simvastatin inhibits NF-κB signaling in intestinal epithelial cells and ameliorates acute murine colitis

Cited by 86 publications

References 49 publications

Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor

Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor

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

Following the mevalonate pathway to bone heal alley

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