5
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Evaluation of glycine-bearing celecoxib derivatives as a colon-specific mutual prodrug acting on nuclear factor-κB, an anti-inflammatory target

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          In an inflammatory state where HOCl is generated, glycine readily reacts with HOCl to produce glycine chloramine, an anti-inflammatory oxidant. Colonic delivery of celecoxib elicits anticolitic effects in a trinitrobenzene sulfonic acid-induced rat colitis model. Glycine-bearing celecoxib derivatives were prepared and evaluated as a colon-specific mutual prodrug acting on nuclear factor-κB (NFκB), an anticolitic target. Glycylcelecoxib (GC), N-glycylaspart-1-ylcelecoxib (N-GA1C), and C-glycylaspart-1-ylcelecoxib (C-GA1C) were synthesized and their structures identified using infrared and proton nuclear magnetic resonance spectrometer. The celecoxib derivatives were chemically stable in pH 6.8 and 1.2 buffers. GC and C-GA1C were resistant to degradation in the small intestinal contents, while N-GA1C was substantially cleaved to release celecoxib. In contrast, all the celecoxib derivatives were degraded to liberate celecoxib in the cecal content. These results suggest that GC and C-GA1C could be delivered to and liberate celecoxib and glycine in the large intestine. In human colon carcinoma HCT116 and murine macrophage RAW264.7 cells, combined celecoxib–glycine chloramine treatment additively suppressed the production of proinflammatory NFκB target gene products. Collectively, our data suggest that C-GA1C is a potential colon-specific mutual prodrug acting against NFκB.

          Related collections

          Most cited references 19

          • Record: found
          • Abstract: found
          • Article: not found

          NF-kappaB in inflammatory bowel disease.

          Apart from genetic and environmental factors, the mucosal immune system of the gut plays a central role in the pathogenesis of inflammatory bowel disease (IBD). In the healthy gut, the mucosal immune system ensures the balance between pro- and anti-inflammatory mediators and thereby allows an effective defence against luminal pathogens but at the same time prevents an overwhelming immune reaction directed against the huge amount of harmless luminal antigens (for example, components of food or nonpathological bacteria). In both entities of IBD (Crohn's disease and ulcerative colitis) this immunological balance is severely impaired and shifted towards the pro-inflammatory side. The chronic mucosal inflammation in IBD is caused by hyperactivation of effector immune cells, which produce high levels of pro-inflammatory cytokines like tumour necrosis factor-alpha, interleukin-6 and interferon-gamma, resulting in colonic tissue damage. The nuclear transcription factor kappaB (NF-kappaB) was identified as one of the key regulators in this immunological setting. Its activation is markedly induced in IBD patients and through its ability to promote the expression of various pro-inflammatory genes, NF-kappaB strongly influences the course of mucosal inflammation. Considering the different cell-type specific effects which are mediated by NF-kappaB, this review aims at describing the complex role of NF-kappaB in IBD and discusses existing pharmacological attempts to block the activation of NF-kappaB to develop new therapeutic strategies in IBD.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Safety of celecoxib in patients with ulcerative colitis in remission: a randomized, placebo-controlled, pilot study.

            The safety of selective cyclooxygenase-2 inhibitors in patients with ulcerative colitis in remission is unknown. We performed a placebo-controlled pilot trial to evaluate the safety of celecoxib in patients with ulcerative colitis in remission who had a present or past history of nonspecific arthritis, arthralgia, or other condition amenable to nonsteroidal anti-inflammatory drug therapy. A total of 222 patients with ulcerative colitis in remission were randomized to receive oral celecoxib 200 mg or placebo twice daily for 14 days. Remission was defined as a total Mayo Clinic score of 2 points or less and an endoscopic score of 1 point or less. Disease exacerbation was defined as a total Mayo Clinic score of 5 points or more and an increase in the endoscopic score of 1 point or more. The primary analysis was disease exacerbation through day 14 among patients who underwent randomization, had at least 1 dose of study drug, and had both endoscopy and Mayo Clinic disease activity index scores at the baseline and final assessments. Three percent of patients in the celecoxib group experienced disease exacerbation through day 14, as compared with 4% in the placebo group (P = .719). Eleven percent of patients in each group experienced a bowel-related adverse event (P > .20). Therapy with celecoxib for up to 14 days did not have a greater relapse rate than placebo in patients with ulcerative colitis in remission who had a present or past history of nonspecific arthritis, arthralgia, or other condition amenable to nonsteroidal anti-inflammatory drug therapy.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Metabolic and pharmacological properties of rutin, a dietary quercetin glycoside, for treatment of inflammatory bowel disease.

              Orally administered rutin reportedly ameliorates 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis of rats. We investigated the metabolic and pharmacological properties of rutin underlying the rutin-mediated amelioration of the rat colitis. Apparent partition coefficients of rutin and its aglycone quercetin were compared. The biochemical/chemical stability of rutin was examined in the contents of various segments of gastrointestinal tracts of rats. Inflammatory indices were determined in the colitis rats after oral administration of rutin or rectal administration of quercetin. In human colon epithelial cells, the effect of quercetin on tumor necrosis factor-alpha (TNF-alpha)-induced nuclear factor kappa B (NFkappaB) activation was examined. The sugar residue in rutin greatly lowered the apparent partition coefficient and was rapidly deglycosylated to liberate quercetin in the cecal contents, whereas it was stable in the contents of the upper intestine. Not only oral administration of rutin but also rectal administration of quercetin remarkably ameliorated TNBS-induced colitis rats, indicating that quercetin liberated from rutin is therapeutically active. Furthermore, quercetin dose-dependently inhibited an inflammatory signal TNF-alpha-dependent NFkappaB activation. Our data suggest that rutin acted as a quercetin deliverer to the large intestine and its anti-inflammatory action in TNBS-induced colitis rats may be through quercetin-mediated inhibition of TNF-alpha-induced NFkappaB activation.
                Bookmark

                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                07 August 2015
                : 9
                : 4227-4237
                Affiliations
                [1 ]College of Pharmacy, Pusan National University, Busan, South Korea
                [2 ]Bio-Nanomedicine Lab, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
                Author notes
                Correspondence: Yunjin Jung, College of Pharmacy, Pusan National University, 2 Busandaehak-ro 63 Beon-gil, Geumjeong-gu, Busan 609-735, South Korea, Tel +82 51 510 2527, Fax +82 51 513 6754, Email jungy@ 123456pusan.ac.kr
                [*]

                These authors contributed equally to this work

                Article
                dddt-9-4227
                10.2147/DDDT.S88543
                4535551
                © 2015 Lee et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Comments

                Comment on this article