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

Belmiro, Celso R.; Castelo-Branco, Morgana T.; Melim, Leandra Marques Chaves; Schanaider, Alberto; Elia, Celeste C.; Madi, Kalil; Pavão, Mauro S.G.; Souza, Heitor Siffert Pereira de

doi:10.1074/jbc.m807211200

Cited by 49 publications

(45 citation statements)

References 65 publications

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“…Different work groups were able to reproduce the positive effect of heparan sulfate glycosaminoglycans, especially heparins and heparin derivatives in colitis models, eg, in trinitrobenzene sulfonic acid or oxazolone induced colitis. 14,45 However, since soluble heparin can act as a mimic of both cis-(cell surface) and trans-(shed) conformations of Sdc1, we cannot fully differentiate between possible differential roles of soluble and membrane-bound forms of Sdc1 in the DSS colitis model. In addition, it has to be considered that heparin may also mimic the effects of other HSPGs.…”

Section: Enoxaparin As a Substitute For Sdc1 Functionmentioning

confidence: 99%

Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

Floer

Götte

Wild

et al. 2010

The American Journal of Pathology

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Syndecan-1 (Sdc1) plays a major role in wound healing and modulates inflammatory responses. Sdc1 expression is reduced in lesions of patients with ulcerative colitis. The aim of this study was to investigate the role of Sdc1 in murine dextran sodium sulfate (DSS)-induced colitis. DSS colitis was induced in Sdc1-deficient (knockout (KO)) and wild-type mice by oral administration of 3% DSS. KO mice exhibited a significantly increased lethality as compared with wild-type controls (61 versus 5% , P < 0.05). Impaired mucosal healing and prolonged recruitment of inflammatory cells in KO mice were accompanied by significant up-regulation of tumor necrosis factor-␣, CC chemokine ligand 3/macrophage inflammatory protein-1␣, and vascular cell adhesion molecule-1 , as determined by histological correlation between 0 and 15 days after colitis induction , TaqMan low-density array analysis , and quantitative real-time PCR. Treatment from days 7 through 14 with enoxaparin , a functional analogue of the Sdc1 heparan sulfate chains , significantly reduced lethality of KO mice due to DSS-induced colitis , which was correlated with improved mucosal healing. In vitro, Sdc1-deficient polymorphonuclear cells displayed increased adhesion to endothelial cells and intercellular adhesion molecule-1, and enoxaparin reverted adhesion to wild-type levels. Small interfering RNA-mediated knockdown of Sdc1 expression resulted in reduced basic fibroblast growth factor-mediated mitogen-activated protein kinase signaling and reduced Caco-2 cell proliferation. We conclude that Sdc1 has a protective effect during experimental colitis. The modification of missing Sdc1 function by heparin analogues may emerge as a promising anti-inflammatory approach. (Am J Pathol

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Section: Enoxaparin As a Substitute For Sdc1 Functionmentioning

confidence: 99%

Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

Floer

Götte

Wild

et al. 2010

The American Journal of Pathology

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“…For example, a fucosylated chondroitin sulfate isolated from sea cucumbers (25,26) attenuates thrombosis, by inhibiting thrombin in a serpin-mediated mechanism (18,19), and tumor metastasis, possibly by a P-and/or Lselectin-dependent mechanism (5), respectively. In addition, we have recently shown that an oversulfated dermatan sulfate from tunicate attenuates colitis in rats by reducing macrophage and lymphocyte recruitment, tumor necrosis factor (TNF) and transforming growth factor (TGF)-␤ production, and collagen deposition in inflamed colon (2). We speculated that the anti-selectin activity is a prevalent factor, which accounts for the anti-inflammatory effect of the invertebrate glycans, reducing the recruitment of inflammatory cells to the site of inflammation.…”

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confidence: 99%

Fucosylated chondroitin sulfate attenuates renal fibrosis in animals submitted to unilateral ureteral obstruction: a P-selectin-mediated event?

Melo-Filho

Belmiro

Gonçalves

et al. 2010

American Journal of Physiology-Renal Physiology

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Melo-Filho NM, Belmiro CL, Gonçalves RG, Takiya CM, Leite M Jr, Pavão MS, Mourão PA. Fucosylated chondroitin sulfate attenuates renal fibrosis in animals submitted to unilateral ureteral obstruction: a P-selectin-mediated event? Am J Physiol Renal Physiol 299: F1299 -F1307, 2010. First published September 22, 2010 doi:10.1152/ajprenal.00217.2010.-Fibrosis is the end point of most renal diseases, and several glycosaminoglycans have been shown to attenuate this process. Marine invertebrate glycosaminoglycans with unique structures have opened the possibility to test these new compounds on renal fibrosis. The effect of a fucosylated chondroitin sulfate from an echinoderm marine species is reported with the use of a model of renal fibrosis in rats, termed unilateral ureteral obstruction. Animals were given 4 mg/kg body wt of fucosylated chondroitin sulfate intraperitoneally, once a day. After 14 days, their kidneys were examined by histological, immunohistochemical, and biochemical methods. Compared with control mice, collagen deposition decreased in the course of renal fibrosis in the animals receiving fucosylated chondroitin sulfate, as revealed by Sirius red staining and hydroxyproline content. The cellularity related to myofibroblasts and macrophages was also reduced, as was the production of transforming growth factor (TGF)-␤. The glycosaminoglycan content increased in the renal interstitium of animals submitted to unilateral ureteral obstruction compared with the control contralateral kidney, mostly due to an increase of chondroitin sulfate content. Interestingly, no change in the pattern of glycosaminoglycan deposition was observed after administration of fucosylated chondroitin sulfate. Fibrosis induced by unilateral ureteral obstruction is attenuated in P-selectin-deficient mice, which also do not respond to the invertebrate glycosaminoglycan. In conclusion, fucosylated chondroitin sulfate attenuates renal fibrosis on a ureteral obstruction model in mice preponderantly through a P-selectinmediated mechanism.glycosaminoglycans; inflammatory cells; anti-selectin activity; cytokine expression; collagen accumulation THE PROGRESSION OF RENAL DISEASES has increasingly challenged investigators to test new therapeutic approaches to halt the progression of renal interstitial fibrosis. The initial aspect of the progressive renal disease may differ. Glomerular diseases may progress to glomerular sclerosis and scarring, whereas tubular diseases may develop to tubulointerstitial fibrosis. However, as the disease progresses in both circumstances, renal interstitial fibrosis is the predominant pathological outcome (15).The use of glycosaminoglycans as anti-inflammatory agents has been tested in different models of renal disease. In subtotal nephrectomized rats, heparin ameliorates glomerular sclerosis and interstitial fibrosis (1). Low-molecular-weight heparin decreases proteinuria in adriamycin-induced renal disease (3) and attenuates fibrosis in the unilateral ureteral obstruction model in rats (21).Sulfated polysaccha...

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“…Long-term administration of TNBS (>2 enemas) has been reported to result in chronic colitis that resembles human CD [18,19]. Specifically, after 1 week, TNBS administration incites a Th1 immune response with increased production of IL-12 and IFN-γ [19], while longer treatment results in a switch towards a Th2 predominant immune phenotype more closely resembling chronic inflammation, inducing increased IL-13 and TGF-β levels, with subsequent collagen deposition and fibrosis [18,19,20,21,22]. Although the acute TNBS model shows a response more akin to CD in terms of cytokine expression, the resulting damage is limited to the epithelium and mucosa, whereas a transmural inflammatory process leading to activation of cells towards a myofibroblast phenotype is required for fibrosis associated with CD.…”

Section: Chemically Induced Modelsmentioning

confidence: 99%

Mechanisms and Models for Intestinal Fibrosis in IBD

Salvo

Ray

Pizarro³

2014

Dig Dis

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Intestinal fibrosis is a common outcome in IBD leading to significant morbidity that, to date, has no effective medical treatment. Current knowledge regarding potential mechanism(s) of intestinal fibrogenesis and stricture formation is limited, due in large part to the lack of relevant animal models. Although conventional models possess aspects that are advantageous to study specific mechanisms involved in gut fibrosis, most lack the features of a spontaneously occurring process leading to the formation of intestinal fibrotic lesions following mucosal inflammatory events and the ability to investigate the natural course of disease over time. This review aims to discuss established and novel animal models of gut fibrosis, particularly focusing on the advantages and disadvantages of each model system and the insights they bring to our understanding of the mechanisms of fibrogenesis. In fact, recent enhancements to existing models and the expansion of novel animal models of gut fibrosis is opening up multiple avenues for investigation which should stimulate progress in our mechanistic understanding of intestinal fibrogenesis and facilitate the development of effective pharmacotherapy in an area of significant unmet need.

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

Cited by 49 publications

References 65 publications

Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

Enoxaparin Improves the Course of Dextran Sodium Sulfate-Induced Colitis in Syndecan-1-Deficient Mice

Fucosylated chondroitin sulfate attenuates renal fibrosis in animals submitted to unilateral ureteral obstruction: a P-selectin-mediated event?

Mechanisms and Models for Intestinal Fibrosis in IBD

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