The effect of sphingosine-1-phosphate on colonic smooth muscle contractility: Modulation by TNBS-induced colitis

Al-Jarallah, Aishah; Oriowo, Mabayoje A.

doi:10.1371/journal.pone.0170792

Cited by 4 publications

(4 citation statements)

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“…S1PR2 is ubiquitously expressed and plays a critical role in exacerbation of inflammation and colon length shortening in response to TNBS challenge in mice. 9 S1PR2 gene expression was highly upregulated in moderate/severe IBD relative to control and IBD patients in remission (Fig. 4, panel B).…”

Section: Resultsmentioning

confidence: 91%

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Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study

Suh

Degagné

Gleghorn

et al. 2018

Inflammatory Bowel Diseases

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Goal The aim of this study was to investigate gene expression levels of proteins involved in sphingosine-1-phosphate (S1P) metabolism and signaling in a pediatric inflammatory bowel disease (IBD) patient population. Background IBD is a debilitating disease affecting 0.4% of the US population. The incidence of IBD in childhood is rising. Identifying effective targeted therapies that can be used safely in young patients and developing tools for selecting specific candidates for targeted therapies are important goals. Clinical IBD trials now underway target S1PR1, a receptor for the pro-inflammatory sphingolipid S1P. However, circulating and tissue sphingolipid levels and S1P-related gene expression have not been characterized in pediatric IBD. Methods Pediatric IBD patients and controls were recruited in a four-site study. Patients received a clinical score using PUCAI or PCDAI evaluation. Colon biopsies were collected during endoscopy. Gene expression was measured by qRT-PCR. Plasma and gut tissue sphingolipids were measured by LC-MS/MS. Results Genes of S1P synthesis (SPHK1, SPHK2), degradation (SGPL1), and signaling (S1PR1, S1PR2, and S1PR4) were significantly upregulated in colon biopsies of IBD patients with moderate/severe symptoms compared with controls or patients in remission. Tissue ceramide, dihydroceramide, and ceramide-1-phosphate (C1P) levels were significantly elevated in IBD patients compared with controls. Conclusions A signature of elevated S1P-related gene expression in colon tissues of pediatric IBD patients correlates with active disease and normalizes in remission. Biopsied gut tissue from symptomatic IBD patients contains high levels of pro-apoptotic and pro-inflammatory sphingolipids. A combined analysis of gut tissue sphingolipid profiles with this S1P-related gene signature may be useful for monitoring response to conventional therapy.

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Section: Resultsmentioning

confidence: 91%

“…The dataset GSE10616 was originally published by Kugathasan et al 28 The GSE10616 dataset was analyzed using the GEO2R tool to identify differentially expressed mRNA between Controls and CD or Controls and UC. 9, 26, 27 …”

Section: Methodsmentioning

confidence: 99%

Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study

Suh

Degagné

Gleghorn

et al. 2018

Inflammatory Bowel Diseases

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“…5C,D), strongly suggests that PLP might activate some metabolic pathways in colon smooth muscles, independently of vDAO. One relevant pathway might be the transsulfuration pathway for which the by-product of cysteine degradation H 2 S is a smooth muscle relaxant 58,59 , while another one might be the degradation pathway of the pro-contractile sphingosine-1-phosphate 60,61 . We cannot also exclude the possibility that PLP might have another beneficial effect through formation of an inactive cyclic compound with histamine 62,63 .…”

Section: Discussionmentioning

confidence: 99%

Vegetal diamine oxidase alleviates histamine-induced contraction of colonic muscles

Nerée

Soret

Marcocci

et al. 2020

Sci Rep

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Excess of histamine in gut lumen generates a pronounced gastrointestinal discomfort, which may include diarrhea and peristalsis dysfunctions. Deleterious effects of histamine can be alleviated with antihistamine drugs targeting histamine receptors. However, many antihistamine agents come with various undesirable side effects. Vegetal diamine oxidase (vDAO) might be a relevant alternative owing to its histaminase activity. Mammalian intestinal mucosa contains an endogenous DAO, yet possessing lower activity compared to that of vDAO preparation. Moreover, in several pathological conditions such as inflammatory bowel disease and irritable bowel syndrome, this endogenous DAO enzyme can be lost or inactivated. Here, we tested the therapeutic potential of vDAO by focusing on the well-known effect of histamine on gut motility. Using ex vivo and in vitro assays, we found that vDAO is more potent than commercial anti-histamine drugs at inhibiting histamine-induced contraction of murine distal colon muscles. We also identified pyridoxal 5′-phosphate (the biologically active form of vitamin B6) as an effective enhancer of vDAO antispasmodic activity. Furthermore, we discovered that rectally administered vDAO can be retained on gut mucosa and remain active. These observations make administration of vDAO in the gut lumen a valid alternative treatment for histamine-induced intestinal dysfunctions.

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“…S1P comprises several types of sphingolipids (S1P1-5) that act by binding to 5 G protein-coupled receptors (S1PR1-5) and by affecting key intracellular molecules that regulate gene transcription, including activation of the pro-inflammatory transcription factor NF-κB and inhibition of histone deacetylases (HDACs), which are epigenetic regulators of gene expression. Abnormal S1P signaling has been demonstrated in preclinical colitis models, suggesting that targeting S1P production or interaction with S1PRs may alleviate colitis and reduce disease severity[ 37 - 39 ]. Metabolomic analysis of colon biopsies from IBD patients has revealed transcriptional and metabolic changes in sphingolipid metabolism that are thought to influence inflammation and intestinal mucosal integrity[ 40 ].…”

Section: Biology Of S1p Metabolism and Signaling In Ibdmentioning

confidence: 99%

Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases

Tourkochristou¹,

Mouzaki²,

Triantos³

2023

World J Gastroenterol

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Inflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract that has a high epidemiological prevalence worldwide. The increasing disease burden worldwide, lack of response to current biologic therapeutics, and treatment-related immunogenicity have led to major concerns regarding the clinical management of IBD patients and treatment efficacy. Understanding disease pathogenesis and disease-related molecular mechanisms is the most important goal in developing new and effective therapeutics. Sphingosine-1-phosphate (S1P) receptor (S1PR) modulators form a class of oral small molecule drugs currently in clinical development for IBD have shown promising effects on disease improvement. S1P is a sphingosine-derived phospholipid that acts by binding to its receptor S1PR and is involved in the regulation of several biological processes including cell survival, differentiation, migration, proliferation, immune response, and lymphocyte trafficking. T lymphocytes play an important role in regulating inflammatory responses. In inflamed IBD tissue, an imbalance between T helper (Th) and regulatory T lymphocytes and Th cytokine levels was found. The S1P/S1PR signaling axis and metabolism have been linked to inflammatory responses in IBD. S1P modulators targeting S1PRs and S1P metabolism have been developed and shown to regulate inflammatory responses by affecting lymphocyte trafficking, lymphocyte number, lymphocyte activity, cytokine production, and contributing to gut barrier function.

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The effect of sphingosine-1-phosphate on colonic smooth muscle contractility: Modulation by TNBS-induced colitis

Cited by 4 publications

References 59 publications

Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study

Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study

Vegetal diamine oxidase alleviates histamine-induced contraction of colonic muscles

Unveiling the biological role of sphingosine-1-phosphate receptor modulators in inflammatory bowel diseases

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