Biochemical and immunohistochemical analysis of glycosaminoglycans in inflamed and non-inflamed intestinal mucosa of patients with Crohn’s disease

Belmiro, Celso R.; Souza, Heitor; Elia, Celeste C.; Castelo-Branco, Morgana T.; Silva, Flávia Rodrigues da; Machado, Raphael C. S.; Pavão, Mauro S. G.

doi:10.1007/s00384-004-0677-2

Cited by 33 publications

(28 citation statements)

References 30 publications

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“…Tissue-We have previously shown that in inflamed areas of the colon of patients with active Crohn disease there is an increase in the total amount of GAGs and a disorganized distribution of these molecules throughout the inflamed tissue (40). To investigate whether TNBS administration would produce a similar effect, total GAGs were isolated from rat normal or inflamed colonic tissues, quantified and subjected to biochemical analysis by agarose gel electrophoresis before and after degradation with specific GAG lyases.…”

Section: Gags Content In the Colonicmentioning

confidence: 99%

Unfractionated Heparin and New Heparin Analogues from Ascidians (Chordate-Tunicate) Ameliorate Colitis in Rats

Belmiro

Castelo-Branco²,

Melim

et al. 2009

Journal of Biological Chemistry

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The anti-inflammatory effect of mammalian heparin analogues, named dermatan sulfate and heparin, isolated from the ascidian Styela plicata was accessed in a TNBS-induced colitis model in rats. Subcutaneous administration of the invertebrate compounds during a 7-day period drastically reduced inflammation as observed by the normalization of the macroscopic and histological characteristics of the colon. At the molecular level, a decrease in the production of TNF-␣, TGF-␤, and VEGF was observed, as well as a reduction of NF-B and MAPK kinase activation. At the cellular level, the heparin analogues attenuated lymphocyte and macrophage recruitment and epithelial cell apoptosis. A drastic reduction in collagen-mediated fibrosis was also observed. No hemorrhagic events were observed after glycan treatment. These results strongly indicate the potential therapeutic use of these compounds for the treatment of colonic inflammation with a lower risk of hemorrhage when compared with mammalian heparin.

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Section: Gags Content In the Colonicmentioning

confidence: 99%

Unfractionated Heparin and New Heparin Analogues from Ascidians (Chordate-Tunicate) Ameliorate Colitis in Rats

Belmiro

Castelo-Branco²,

Melim

et al. 2009

Journal of Biological Chemistry

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“…At the same time, CS proteoglycan was shown to inhibit proteolytic degradation of collagen and Aβ (19,20). CS-E binds type V collagen, which is increased in submucosa of CD patients (21)(22)(23)(24), suggesting that matrix CS-E strengthens CS-E-collagen interaction thereby solid fibrotic formation which is an obstacle of tissue repair.…”

Section: Mechanism Of Chst15/cs-e-mediated Fibrosismentioning

confidence: 99%

New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

Suzuki

Yoneyama

2017

Ann. Transl. Med.

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Fibrosis continues to be paid a great attention in not only basic research but also clinical practice, especially for the development of novel therapeutics in various fibrotic diseases. However, there remain several obstacles to translation in developing anti-fibrosis therapy. The present review documents our translational practice from target discovery to first-in-patient studies in the development of anti-fibrosis therapy for inflammatory bowel disease (IBD). First topic is a target selection. We have focused on the target that has an ability to regulate multifactorial cascades of fibrosis. Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling during injury. Small interfering RNA (siRNA) targeting CHST15 inhibited activation of fibroblasts in vitro and reduced fibrosis in vivo. Second topic is a clinically feasible application. We established a safe and novel pancolonic delivery of siRNA, which is achieved by direct injection to extracellular matrix (ECM) through endoscope. Third topic is an endpoint for both nonclinical and clinical studies. We have focused on tissue-specific findings for co-existence of fibrosis in ulcerative lesions in IBD and investigated whether the balance of mucosal healing (MH) and fibrosis, which is evaluated by endoscopy and histology respectively, can be used for study endpoints. Phase 1 clinical trial of STNM01, a synthesized CHST15 siRNA, by a single dose endoscopic submucosal injection for non-healer patients with Crohn's disease showed high rates of MH. Analyses of biopsy specimens revealed that STNM01 reduced CHST15 expression at local lesions, repressed pre-existing fibrosis and repaired the damaged crypts. Thus, blockade of multifactorial modulator CHST15 in ECM showed a potential to treat tissue remodeling and skew fibrosis toward mucosal repair. Our practice suggests that target-and tissue-specific findings-based strategy would be a key to translation in developing anti-fibrosis therapy.

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“…In the normal intestinal tract, HS represents a key polysaccharide of the ECM and is extensively found in the basal lamina of the intestinal mucosa [115,116], where it provides a structural framework for gut tissue organization and functions as an electrostatic/mechanical barrier involved in the regulation of vascular and ECM permeability [117][118][119][120]. HS moieties were also detected at basolateral location on intestine epithelial cell surfaces [121].…”

Section: Heparan Sulfate and Heparanase In Ibdmentioning

confidence: 99%

“…HS moieties were also detected at basolateral location on intestine epithelial cell surfaces [121]. Due to its specific interaction with other ECM components, HS is important for maintaining the structural integrity of the gut wall [117,120]. Alterations in HS may significantly affect both the permeability of the colon and immune/inflammatory reactions.…”

Section: Heparan Sulfate and Heparanase In Ibdmentioning

confidence: 99%

“…Moreover, disruption of HS was found even in the noninflamed areas of intestinal samples obtained from IBD patients [117]. Given the key importance of HS in maintaining BM supramolecular architecture and perm-selective characteristics, it is plausible that disintegration of basal lamina HS represent an important determinant in IBD pathogenesis and contributes to increased vascular permeability, immunocyte/protein extravasation, and tissue remodeling.…”

Section: Heparan Sulfate and Heparanase In Ibdmentioning

confidence: 99%

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Heparanase enzyme in chronic inflammatory bowel disease and colon cancer

Hermano

Lerner

Elkin

2012

Cell. Mol. Life Sci.

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Heparanase is the sole mammalian endoglycosidase that cleaves heparan sulfate, the key polysaccharide of the extracellular matrix and basement membranes. Enzymatic cleavage of heparan sulfate profoundly affects a variety of physiological and pathological processes, including morphogenesis, neovascularization, inflammation, and tumorigenesis. Critical involvement of heparanase in colorectal tumor progression and metastatic spread is widely documented; however, until recently a role for heparanase in the initiation of colon carcinoma remained underappreciated. Interestingly, the emerging data that link heparanase to chronic inflammatory bowel conditions, also suggest contribution of the enzyme to colonic tumor initiation, at least in the setting of colitis-associated cancer. Highly coordinated interplay between intestinal heparanase and immune cells (i.e., macrophages) preserves chronic inflammatory conditions and creates a tumor-promoting microenvironment. Here we review the action of heparanase in colon tumorigenesis and discuss recent findings, pointing to a role for heparanase in sustaining immune cell-epithelial crosstalk that underlies intestinal inflammation and the associated cancer.

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Biochemical and immunohistochemical analysis of glycosaminoglycans in inflamed and non-inflamed intestinal mucosa of patients with Crohn’s disease

Abstract: We observed a marked reduction in GAGs with altered patterns of distribution in the non-inflamed colon of patients with CD. The increase in the synthesis of GAGs observed in the inflamed colon may be a compensatory mechanism for the restoration of the integrity of the intestinal mucosa.

Cited by 33 publications

References 30 publications

Unfractionated Heparin and New Heparin Analogues from Ascidians (Chordate-Tunicate) Ameliorate Colitis in Rats

Unfractionated Heparin and New Heparin Analogues from Ascidians (Chordate-Tunicate) Ameliorate Colitis in Rats

New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

Heparanase enzyme in chronic inflammatory bowel disease and colon cancer

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