Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo-Controlled Trial

Lewis, James D.; Lichtenstein, Gary R.; Deren, Julius J.; Sands, Bruce E.; Hanauer, Stephen B.; Katz, Jeffrey A.; Lashner, Bret A.; Present, Daniel H.; Chuai, Shaokun; Ellenberg, Jonas H.; Nessel, Lisa; Wu, Gary D.

doi:10.1053/j.gastro.2007.12.012

Cited by 199 publications

(160 citation statements)

References 34 publications

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“…Furthermore, the PPAR-agonist rosiglitazone is a potent inducer of a subset of -defensin in mouse colon. Accordingly, rosiglitazone was shown to be efficacious in mild-tomoderate UC [331]. This finding raises a new potential mechanism for the improvement of gut barrier function in CD.…”

Section: Normalization Of the Altered Composition Of Microbial Floramentioning

confidence: 83%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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Inflammatory bowel disease (IBD) is a chronic and relapsing inflammatory condition of the gastrointestinal tract. The two main forms of IBD are Crohn's disease and ulcerative colitis. According to the recent concept the disease is caused by a combination of factors, including genetics, immune dysregulation, barrier dysfunction and the change in microbial flora. Environmental factors, such as changes in diet, antibiotic use, smoking or improved domestic hygiene (e.g. eradication of intestinal helminths) probably contribute to the development and increased prevalence of IBD. Dysregulation of mucosal immunity in IBD causes an overproduction of inflammatory cytokines which resulted in uncontrolled intestinal inflammation. Based on extensive research over the last decade, besides the conventional therapy, there are several novel pathways and specific targets, on which focus new therapeutics. New therapeutics aim 1./ to correct genetic susceptibility by stimulating NOD2 expression, TLR3 signaling or inhibition of TLR4 pathway, 2./ to restore the immune dysregulation by inhibition of pro-inflammatory cytokines (TNF-, IL-6, IL-13, IL-17, IL-18, IL-21), Th1 polarisation (IL-2, IL-12, IL-23, IFN-), T-cell activation, leukocyte adhesion, as well as by immunostimulation (GM-CSF, G-CSF) and anti-inflammatory cytokines (IL-10, IL-11, IFN--1a), 3./ to restore mucosal barrier function and stimulate mucosal healing by different growth factors, such as GH, EGF, KGF, TGF-, VEGF, 4./ to restore the normal bacterial flora by antibiotics, probiotics. However, in spite of these numerous potential targets, the true value and clinical significance of most of the new biologics and molecules are not clear yet.

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Section: Normalization Of the Altered Composition Of Microbial Floramentioning

confidence: 83%

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gyires¹,

Tóth²,

Zádori

2014

CPD

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“…Genetic ablation of PPARγ was found to result in increased susceptibility to experimental colitis in rodents (5). Conversely, engagement of PPARγ-mediated signaling by its cognate agonists, such as rosiglitazone, attenuated the severity of inflammatory lesions in both experimental and spontaneous models of colitis (5) and might be effective in UC (6). Consequently, we evaluated the role of PPARγ in host defense through regulation of antimicrobial peptides in the intestinal mucosa of patients with IBD.…”

mentioning

confidence: 99%

Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon

Peyrin–Biroulet

Beisner

Wang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

178

137

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Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) is essential for intestinal homeostasis in response to both dietaryand microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARγ functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of β-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Pparγ mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARγ-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARγ-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.β-defensin 1 | Crohn's disease | microbiota | nutrition | PPAR-γ

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“…Furthermore, PPAR␥ natural and synthetic ligands were equally effective in the treat- ment of chronic and acute colitis (42), and the beneficial effects were reflected in reduced mortality and a lower intensity of lesion in experimental animals (43). An association between decreased PPAR␥ expression and ulcerative colitis has been demonstrated (43), whereas short-term therapy with rosiglitazone resulted in clinical remission for patients with active ulcerative colitis (44). Given our results that OCTN2 is a colon target of PPAR␥, it is suggested that the up-regulation of OCTN2 expression by PPAR␥ may contribute to the protective effects of TZDs in inflammatory bowel disease.…”

Section: Discussionmentioning

confidence: 99%

Colon OCTN2 Gene Expression Is Up-regulated by Peroxisome Proliferator-activated Receptor γ in Humans and Mice and Contributes to Local and Systemic Carnitine Homeostasis

D’Argenio¹,

Petillo

Margarucci

et al. 2010

Journal of Biological Chemistry

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In the large intestine organic cation transporter type-2 (OCTN2) is recognized as a transporter of compounds such as carnitine and colony sporulation factor, promoting health of the colon intestinal epithelium. Recent reports suggest that OCTN2 expression in small intestine is under control of peroxisome proliferator-activated receptor-␣ (PPAR␣). However, PPAR␣ contribution to colonic OCTN2 expression remains controversial. Here we examined the transcriptional regulation of colon OCTN2 gene by PPAR␥. To exclude any additional modulation of other PPAR to OCTN2 expression, we used both in vivo and in vitro PPAR-null models and specific PPAR inhibitors. The PPAR␥ agonists thiazolidinediones increased both OCTN2 mRNA and protein expression in colonic epithelial cell lines independently by PPAR␣ expression. The induction was blocked only by PPAR␥ antagonists or by ␥ORF4, a PPAR␥ isoform with dominant negative activity, suggesting a PPAR␥-dependent mechanism. A conserved noncanonical PPAR-responsive element was found by computational analysis in the first intron of human OCTN2 gene and validated by EMSA assay. Promoterreporter assays further confirmed transcriptional functionality of the putative PPAR response element, whereas selective mutation caused complete loss of responsiveness to PPAR␥ activation. Finally, adenovirus-mediated overexpression of constitutively active PPAR␥ mutant increased colon OCTN2 expression in PPAR␣ ؊/؊ mice. Interestingly, animals overexpressing colon PPAR␥ showed a significant increase in plasma carnitine, thus demonstrating the functional contribution of large intestine to systemic carnitine homeostasis. This study reveals a PPAR␥-dependent absorption machinery in colon that is likely involved in the health of colon epithelium, in the microbiota-host interactions and in the absorption of nutraceuticals and drugs.

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Rosiglitazone for Active Ulcerative Colitis: A Randomized Placebo-Controlled Trial

Cited by 199 publications

References 34 publications

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Gut Inflammation: Current Update on Pathophysiology, Molecular Mechanism and Pharmacological Treatment Modalities

Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon

Colon OCTN2 Gene Expression Is Up-regulated by Peroxisome Proliferator-activated Receptor γ in Humans and Mice and Contributes to Local and Systemic Carnitine Homeostasis

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