chondroitin-sulfates and Colitis

Ulcerative colitis (UC) is a high incidence disease worldwide and clinically presents as relapsing and incurable inflammation of the colon. Bilirubin (BR), a natural antioxidant with significant anti-colitic effects, is utilized in preclinical studies as an intestinal disease therapy. Due to their water-insolubility, the design of BR-based agents usually involves complicated chemosynthetic processes, introducing various uncertainties in BR development. After screening numerous materials, it is identified that chondroitin sulfate can efficiently mediate the construction of BR self-assembled nanomedicine (BSNM) via intermolecular hydrogen bonds between dense sulfate and carboxyl of chondroitin sulfate and imino groups of BR. BSNM exhibits pH sensitivity and reactive oxygen species responsiveness, enabling targeted delivery to the colon. After oral administration, BSNM significantly inhibits colonic fibrosis and apoptosis of colon and goblet cells; it also reduces the expression of inflammatory cytokines. Moreover, BSNM maintains the normal level of zonula occludens-1 and occludin to sustain the integrity of intestinal barrier, regulates the macrophage polarization from M1 to M2 type, and promotes the ecological recovery of intestinal flora. Collectively, the work provides a colon-targeted and transformable BSNM that is simple to prepare and is useful as an efficient targeted UC therapy.

Topics: Animals; Bilirubin; Chondroitin Sulfates; Colitis; Colitis, Ulcerative; Colon; Disease Models, Animal; Mice; Mice, Inbred C57BL

Sea cucumber body wall contains several naturally occurring bioactive components that possess health-promoting properties.

Topics: Animals; Anti-Inflammatory Agents; Chondroitin Sulfates; Colitis; Dextran Sulfate; Disease Models, Animal; Glycosaminoglycans; HaCaT Cells; Humans; In Vitro Techniques; Mexico; Mice; Otitis; Sea Cucumbers; Tetradecanoylphorbol Acetate; Tissue Extracts

The common food additive kappa-carrageenan (κ-CGN) is a sulfated polysaccharide that resembles chondroitin-4-sulfate (C4S) and dermatan sulfate (DS). All have a sulfate group on C4 of a glycoside (galactose for CGN and N-acetylgalactosamine for C4S), and the sulfate-bearing glycoside is linked in a β-1,4-configuration to an unsulfated, six-carbon sugar (galactose for CGN, glucuronate for C4S and iduronate for DS). The enzyme arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfate) is the highly selective enzyme that removes the four-sulfate group from the nonreducing terminus of C4S and DS, thereby regulating subsequent degradation. In this report, κ-CGN is shown to be a substrate for recombinant human ARSB (rhARSB). Sulfate was generated from both C4S and κ-CGN following incubation with rhARSB. Exposure of human colonic epithelial cells to κ-CGN, but not to C4S, produced reactive oxygen species (ROS) and increased interleukin (IL)-8 secretion. The ROS production from κ-CGN was reduced by exposure to rhARSB, but increased by competition from C4S or DS, but not from chondroitin-6-sulfate. Prior treatment of either lambda- or iota-CGN with rhARSB had no impact on ROS, IL-8 or inorganic sulfate production, demonstrating a specific effect of the molecular configuration of κ-CGN. By mimicry of C4S and DS and by interaction with ARSB, κ-CGN can directly interfere with the normal cellular functions of C4S, DS and ARSB. Since C4S and DS are present in high concentration in tissues, the impact of κ-CGN exposure may be due to some extent to interference with the normal biological functions of ARSB, C4S and DS.

Topics: Adaptor Proteins, Signal Transducing; B-Cell CLL-Lymphoma 10 Protein; Carbohydrate Conformation; Carrageenan; Cell Line; Chondroitin Sulfates; Colitis; Colon; Competitive Bidding; Dermatan Sulfate; Food Additives; Food Technology; Humans; Hydrolysis; Interleukin-8; Intestinal Mucosa; Molecular Mimicry; N-Acetylgalactosamine-4-Sulfatase; Reactive Oxygen Species; Recombinant Proteins; Substrate Specificity

The biosynthesis and modification of mucopolysaccharides and glycosaminoglycans (GAGs), secreted from gastrointestinal mucosal cells, are increased in colitis and influence the viability of the defense barrier. Therefore, to evaluate the role of GAG-degrading intestinal microflora during the progression of colitis, we investigated the degradation activity of intestinal bacterial GAG, cytotoxicity of GAGs and their metabolites, such as iduronic acid, D: -uronic acid or D: -glucuronic acid and D: -galactosamine or D: -glucosamine, against intestinal cells. We also tested their deteriorative effects against colitis. Colitis was induced using 2,4,6-trinitrobenzene sulfonic acid (TNBS) with and without antibiotics in mice. The TNBS treatment caused colon shortening, increased myeloperoxidase activity, induced IL-1beta, TNF-alpha, and IL-6 expression in the colon, activated NF-kappaB, and potentiated the GAG-degrading activities of intestinal microflora. The antibiotic treatment inhibited colon shortening, decreased myeloperoxidase activity, and reduced proinflammatory cytokine expression, NF-kappaB activation, and GAG degradation, induced by TNBS. Among the GAG metabolites, d-glucosamine and d-galactosamine showed cytotoxicity against intestinal cells, Caco-2 and IEC-18 cells, synergistically deteriorated the cytotoxicity of TNBS as well as the TNBS-induced colitis in mice. Based on these findings, intestinal microflora may degrade GAGs in colitis, their metabolites deteriorate the progress of colitis and antibiotics ameliorate the colitis by the inhibition of GAG-degrading bacterial growth.

Topics: Animals; Anti-Bacterial Agents; Chondroitin Sulfates; Colitis; Galactosamine; Glucosamine; Glucuronic Acid; Glycosaminoglycans; Hyaluronic Acid; Iduronic Acid; Intestinal Mucosa; Male; Mice; Mice, Inbred ICR; Uronic Acids

Chondroitin sulfate (CS) is currently marketed as a therapeutic drug for neurodynia, lumbago and arthrodynia. Recently, many clinical studies have demonstrated the therapeutic effects of orally administered CS against diseases with inflammation. Furthermore, these reports suggest CS plays an important role in the protection of the base of ulcers and has anti-inflammatory activity. We investigated the effects of CS against dextran sulfate sodium (DSS)-induced rat colitis. Rats were given 3% DSS solution for 10 days ad libitum. CS and 5-aminosalicylic acid (5-ASA) were orally administered daily. The doses of the CS groups were 20 or 100 mg/kg and that for the 5-ASA group was 100 mg/kg. Evaluations were made of bloody stools, areas of erosion and hematological data. CS improved the symptoms of bloody stools, erosion and increase of white blood cells. Especially, CS (100 mg/kg) group showed markedly more improvement than the 5-ASA group. We think that the major mechanism of the therapeutic effects of CS are the prevention of tissue damage by the protection of digestive mucosa and anti-inflammatory effects. Therefore, CS may have therapeutic value for alimentary tract diseases such as inflammatory bowel disease or ulcer.

Topics: Animals; Blood; Chondroitin Sulfates; Colitis; Dextran Sulfate; Feces; Male; Rats; Rats, Wistar

The glycosaminoglycans from normal colonic mucosa and colons with a variety of inflammatory diseases, as well as benign and malignant neoplasms were analyzed. Normal colonic mucosa contains predominantly chondroitin sulfates and dermatan sulfate. Increases in the levels of hyaluronic acid and heparan sulfate, as well as substantial increases in the amount of total glycosaminoglycans were characteristic of invasive colonic adenocarcinoma. Lesser elevations in the amount of total glycosaminoglycans and hyaluronic acid and heparan sulfate were present in neonatal colonic mucosa, villous adenoma, ulcerative colitis, and mucosa adjacent to carcinoma. The degree of elevation was proportional to the dysplastic potential. Since dysplastic lesions have scant connective tissue, the epithelial component of colonic neoplasms may contribute to these neoplasm-related alterations in glycosaminoglycan composition.

Topics: Adenocarcinoma; Adult; Aged; Chondroitin Sulfates; Colitis; Colon; Colonic Neoplasms; Dermatan Sulfate; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Intestinal Mucosa; Male; Middle Aged