Nitric oxide-releasing aspirin but not conventional aspirin improves healing of experimental colitis

Zwolińska–Wcisło, Małgorzata; Brzozowski, Tomasz; Ptak‐Belowska, Agata; Targosz, Aneta; Urbańczyk, Katarzyna; Kwiecień, Sławomir; Śliwowski, Zbigniew

doi:10.3748/wjg.v17.i36.4076

Cited by 20 publications

(15 citation statements)

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“…A pro-inflammatory cytokine inhibitor such as infliximab, an anti-TNF-α antibody, is used in treatment of IBD patients [39] . iNOS and COX-2 are also involved in the process of inflammation, regulating the expression of inflammatory mediators NO and PGE2 [40,41] . The above-mentioned evidence indicates that increased expression of inflammatory mediators is found in intestinal inflammation, suggesting that down-regulation of those inflammatory mediators would be beneficial in the amelioration of intestinal inflammation.…”

Section: Discussionmentioning

confidence: 99%

Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function

et al. 2017

Acta Pharmacol Sin

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Geniposide is an iridoid glycosides purified from the fruit of Gardenia jasminoides Ellis, which is known to have antiinflammatory, antioxidative and anti-tumor activities. The present study aimed to investigate the effects of geniposide on experimental rat colitis and to reveal the related mechanisms. Experimental rat colitis was induced by rectal administration of a TNBS solution. The rats were treated with geniposide (25, 50 mg·kg, ig) or with sulfasalazine (SASP, 100 mg·kg, ig) as positive control for 14 consecutive days. A Caco-2 cell monolayer exposed to lipopolysaccharides (LPS) was used as an epithelial barrier dysfunction model. Transepithelial electrical resistance (TER) was measured to evaluate intestinal barrier function. In rats with TNBS-induced colitis, administration of geniposide or SASP significantly increased the TNBS-decreased body weight and ameliorated TNBS-induced experimental colitis and related symptoms. Geniposide or SASP suppressed inflammatory cytokine (TNF-α, IL-1β, and IL-6) release and neutrophil infiltration (myeloperoxidase activity) in the colon. In Caco-2 cells, geniposide (25-100 μg/mL) ameliorated LPS-induced endothelial barrier dysfunction via dose-dependently increasing transepithelial electrical resistance (TER). The results from both in vivo and in vitro studies revealed that geniposide down-regulated NF-κB, COX-2, iNOS and MLCK protein expression, up-regulated the expression of tight junction proteins (occludin and ZO-1), and facilitated AMPK phosphorylation. Both AMPK siRNA transfection and AMPK overexpression abrogated the geniposide-reduced MLCK protein expression, suggesting that geniposide ameliorated barrier dysfunction via AMPKmediated inhibition of the MLCK pathway. In conclusion, geniposide ameliorated TNBS-induced experimental rat colitis by both reducing inflammation and modulating the disrupted epithelial barrier function via activating the AMPK signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function

et al. 2017

Acta Pharmacol Sin

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“…After 6 weeks of exercise training, the colitis was induced in groups of trained and untrained rats fed different diets by intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid (TNBS, Sigma, Slough, UK) at a dose of 10 mg/kg, dissolved in 50% solution of ethanol as reported in our previous studies [ 22 , 23 ]. Briefly, the animals were anaesthetized with phenobarbital (60 mg/kg i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…The abdominal cavity was opened and, after separation of the colon, the CBF in the areas of the mucosa not affected by inflammatory lesions was measured. CBF was expressed as a percentage of the CBF in the vehicle-control rats without TNBS administration as reported by our group elsewhere [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

Moderate Exercise Training Attenuates the Severity of Experimental Rodent Colitis: The Importance of Crosstalk between Adipose Tissue and Skeletal Muscles

Bilski

Mazur-Biały

Brzozowski

et al. 2015

Mediators of Inflammation

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Although progress has been recently made in understanding of inflammatory bowel diseases (IBD), their etiology is unknown apart from several factors from adipose tissue and skeletal muscles such as cytokines, adipokines, and myokines were implicated in the pathogenesis of ulcerative colitis. We studied the effect high-fat diet (HFD; cholesterol up to 70%), low-fat diet (LFD; cholesterol up to 10%), and the normal diet (total fat up to 5%) in rats with TNBS colitis forced to treadmill running exercise (5 days/week) for 6 weeks. In nonexercising HFD rats, the area of colonic damage, colonic tissue weight, the plasma IL-1β, TNF-α, TWEAK, and leptin levels, and the expression of IL-1β-, TNF-α-, and Hif1α mRNAs were significantly increased and a significant fall in plasma adiponectin and irisin levels was observed as compared to LFD rats. In HFD animals, the exercise significantly accelerated the healing of colitis, raised the plasma levels of IL-6 and irisin, downregulated the expression of IL-1β, TNF-α, and Hif1α, and significantly decreased the plasma IL-1β, TNF α, TWEAK, and leptin levels. We conclude that HFD delays the healing of colitis in trained rats via decrease in CBF and plasma IL-1β, TNF-α, TWEAK, and leptin levels and the release of protective irisin.

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“…There is now ample experimental evidence from preclinical models that NO‐releasing forms of approved steroidal and NSAIDs, including COX inhibitors such as aspirin and glucocorticoids such as prednisolone and flunisolide, exhibit similar or increased efficacy and a more favourable side effect profile than the parent molecules in several preclinical disease settings (Fiorucci et al ., ; Paul‐Clark et al ., ; Turesin et al ., ; Wallace et al ., ). Such anti‐inflammatory drug NO conjugates have been experimentally shown to modulate ovarian (Bratasz et al ., ) skin (Chaudhary et al ., ) or intestinal (Williams et al ., ) solid tumour growth, exert anti‐inflammatory activity with reduced symptoms of gastric damage properties (Wallace et al ., ; Fiorucci et al ., ) and protect against or accelerate improvement of experimental colitis (Fiorucci et al ., ; Zwolinska‐Wcislo et al ., ). The increased anti‐inflammatory efficacy of at least one of them, the prednisolone derivative NCX‐1015, may in part be attributed to glucocorticoid receptor nitration resulting in more robust signalling (Paul‐Clark et al ., ).…”

Section: New Lead Molecules Targeting the No‐sgc‐cgmp Pathwaymentioning

confidence: 99%

Extending the translational potential of targeting NO/cGMP‐regulated pathways in the CVS

Papapetropoulos

Hobbs

Topouzis

2015

British J Pharmacology

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The discovery of NO as both an endogenous signalling molecule and as a mediator of the cardiovascular effects of organic nitrates was acknowledged in 1998 by the Nobel Prize in Physiology/Medicine. The characterization of its downstream signalling, mediated through stimulation of soluble GC (sGC) and cGMP generation, initiated significant translational interest, but until recently this was almost exclusively embodied by the use of PDE5 inhibitors in erectile dysfunction. Since then, research progress in two areas has contributed to an impressive expansion of the therapeutic targeting of the NO-sGC-cGMP axis: first, an increased understanding of the molecular events operating within this complex pathway and second, a better insight into its dys-regulation and uncoupling in human disease. Already-approved PDE5 inhibitors and novel, first-in-class molecules, which up-regulate the activity of sGC independently of NO and/or of the enzyme's haem prosthetic group, are undergoing clinical evaluation to treat pulmonary hypertension and myocardial failure. These molecules, as well as combinations or second-generation compounds, are also being assessed in additional experimental disease models and in patients in a wide spectrum of novel indications, such as endotoxic shock, diabetic cardiomyopathy and Becker's muscular dystrophy. There is well-founded optimism that the modulation of the NO-sGC-cGMP pathway will sustain the development of an increasing number of successful clinical candidates for years to come. LINKED ARTICLESThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx

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Nitric oxide-releasing aspirin but not conventional aspirin improves healing of experimental colitis

Abstract: NO-releasing ASA, in contrast to ASA, COX-1 inhibitors, and SC-560, accelerated the healing of colitis via a mechanism involving NO mediated improvement of microcirculation and activation of sensory nerves releasing CGRP.

Cited by 20 publications

References 35 publications

Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function

Geniposide ameliorates TNBS-induced experimental colitis in rats via reducing inflammatory cytokine release and restoring impaired intestinal barrier function

Moderate Exercise Training Attenuates the Severity of Experimental Rodent Colitis: The Importance of Crosstalk between Adipose Tissue and Skeletal Muscles

Extending the translational potential of targeting NO/cGMP‐regulated pathways in the CVS

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