ascorbic-acid and Colitis

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Agranulocytosis; Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Ascorbic Acid; Autoantibodies; Autoimmune Diseases; Blood Transfusion; Chloroquine; Colitis; Colitis, Ulcerative; Drug Hypersensitivity; Drug Therapy; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Humans; Internal Medicine; Leukopenia; Lupus Erythematosus, Systemic; Neutrophils; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Splenectomy; Thrombocytopenia; Thyroiditis; Toxicology; Vitamins

Reactive oxygen species (ROS), which are exceptionally high in IBD lesions, are known to cause abnormal immune responses to inflammatory reactions in inflammatory bowel diseases (IBD) through damage to the intestinal mucosal linings. Moreover, they are theorized to be an agent of IBD development. Vitamin C is widely known to be an effective antioxidant for its ability to regulate inflammatory responses through its ROS scavenging effect. Therefore, we examined vitamin C's influence on the development and progression of IBD in Gulo(-/-) mice, which cannot synthesize vitamin C like humans due to a defect in the expression of L-gulono-γ-lactone oxidase, an essential enzyme for vitamin C production. First, we found extensive oxidative stress and an inflammation increase in the colon of vitamin C-insufficient Gulo(-/-) mice. We also found decreased IL-22 production and NKp46(+) cell recruitment and the impaired activation of the p38MAPK pathway. Additionally, comparing vitamin C-insufficient Gulo(-/-) mice to vitamin C-sufficient Gulo(-/-) mice and wild-type mice, the insufficient group faced a decrease in mucin-1 expression, accompanied by an increase in IL-6 production, followed by the activation of the STAT3 and Akt pathways. The results suggest that vitamin C insufficiency induces severe colitis, meaning vitamin C could also take on a preventative role by regulating the production of cytokines and the induction of inflammation.

Topics: Animals; Antioxidants; Ascorbic Acid; Colitis; Cytokines; Dextran Sulfate; Humans; Inflammation; Inflammatory Bowel Diseases; Interleukin-22; Interleukin-6; Interleukins; L-Gulonolactone Oxidase; Mice; Mice, Inbred C57BL; Mucin-1; Mustelidae; Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Vitamins

The current main treatment for ulcerative colitis (UC) is induction therapy by long-term administration of 5-aminosalicylic acid (5-ASA), but various side effects have been reported. Therefore, a radical cure for UC is desired. A vitamin C (VC) has anti-inflammatory effects. Therefore, this study investigated whether a VC solution enema shortens induction of remission in colitis model rats. Wistar rats (6 wk old/male) were allowed to freely ingest a 1% dextran sulfate sodium (DSS) solution for 10 d and then switched to tap water for normal breeding for 10 d (UC group). At the time of switching to tap water, an enema was performed with a 5-ASA solution (40 mg/kg/d) or VC solution (460 mg/kg/d) for 10 d. The neutrophil number, COX-2, which is an index of inflammation, and type III collagen, which is an early healing marker, were significantly increased in the UC group. However, the VC group showed decreases compared with UC groups. Furthermore, compared with UC and 5-ASA groups, the VC group showed increased expression of type I collagen, which is expressed late in healing, and significant epithelial regeneration was observed in colon tissue. The VC solution enema shortened the induction of remission by directly suppressing inflammation of damaged large intestinal tissues and promoting mucosal healing.

Topics: Animals; Ascorbic Acid; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Enema; Intestinal Mucosa; Male; Rats; Rats, Wistar; Remission Induction; Sulfates

In this study, the effects of 2-

Topics: Animals; Ascorbic Acid; Bacteria; Colitis; Cytokines; Dextran Sulfate; Disease Models, Animal; Fruit; Gastrointestinal Microbiome; Humans; Lycium; Male; Mice; Mice, Inbred C57BL; Plant Extracts

Since induced regulatory T cells (iTregs) can be produced in a large quantity in vitro, these cells are expected to be clinically useful to induce immunological tolerance in various immunological diseases. Foxp3 (Forkhead box P3) expression in iTregs is, however, unstable due to the lack of demethylation of the CpG island in the conserved non-coding sequence 2 (CNS2) of the Foxp3 locus. To facilitate the demethylation of CNS2, we over-expressed the catalytic domain (CD) of the ten-eleven translocation (TET) protein, which catalyzes the steps of the iterative demethylation of 5-methylcytosine. TET-CD over-expression in iTregs resulted in partial demethylation of CNS2 and stable Foxp3 expression. We also discovered that TET expression was enhanced under low oxygen (5%) culture conditions, which facilitated CNS2 DNA demethylation and stabilization of Foxp3 expression in a TET2- and TET3-dependent manner. In combination with vitamin C treatment, which has been reported to enhance TET catalytic activity, iTregs generated under low oxygen conditions retained more stable Foxp3 expression in vitro and in vivo and exhibited stronger suppression activity in a colitis model compared with untreated iTregs. Our data indicate that the induction and activation of TET enzymes in iTregs would be an effective method for Treg-mediated adoptive immunotherapy.

Topics: Animals; Ascorbic Acid; Colitis; Conserved Sequence; CpG Islands; Demethylation; Dioxygenases; DNA-Binding Proteins; Enzyme Induction; Forkhead Transcription Factors; Gene Expression Regulation; Humans; Hypoxia; Immunotherapy, Adoptive; Mice; Proto-Oncogene Proteins; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic relapsing disorders of the intestines. They cause severe problems, such as abdominal cramping, bloody diarrhea, and weight loss, in affected individuals. Unfortunately, there is no cure yet, and treatments only aim to alleviate symptoms. Current treatments include anti-inflammatory and immunosuppressive drugs that may cause severe side effects. This warrants the search for alternative treatment options, such as nutritional supplements, that do not cause side effects. Before their application in clinical studies, such compounds must be rigorously tested for effectiveness and security in animal models. A reliable experimental model is the dextran sulfate sodium (DSS) colitis model in mice, which reproduces many of the clinical signs of ulcerative colitis in humans. We recently applied this model to test the beneficial effects of a nutritional supplement containing vitamins C and E, L-arginine, and ω3-polyunsaturated fatty acids (PUFA). We analyzed various disease parameters and found that this supplement was able to ameliorate edema formation, tissue damage, leukocyte infiltration, oxidative stress, and the production of pro-inflammatory cytokines, leading to an overall improvement in the disease activity index. In this article, we explain in detail the correct application of nutritional supplements using the DSS colitis model in C57Bl/6 mice, as well as how disease parameters such as histology, oxidative stress, and inflammation are assessed. Analyzing the beneficial effects of different diet supplements may then eventually open new avenues for the development of alternative treatment strategies that alleviate IBD symptoms and/or that prolong the phases of remission without causing severe side effects.

Topics: Animals; Arginine; Ascorbic Acid; Colitis; Cytokines; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Intestines; Leukocytes; Mice; Mice, Inbred C57BL; Oxidative Stress; Reactive Oxygen Species; Tight Junctions

Inhibition of hypoxia inducible factor-prolyl hydroxylase-2 (HPH), leading to activation of hypoxia inducible factor (HIF)-1 is a potential therapeutic strategy for the treatment of colitis. Rosmarinic acid (RA), an ester of caffeic acid and 3,4-dihydroxyphenyllactic acid is a naturally occurring polyphenolic compound with two catechols, a or inhibition of HPH. To improve accessibility of highly hydrophilic RA to HPH, an intracellular target, RA was chemically modified to decrease hydrophilicity. Of the less-hydrophilic derivatives, rosmarinic acid methyl ester (RAME) most potently inhibited HPH. Accordingly, RAME prevented hydroxylation of HIF-1α and consequently stabilized HIF-1α protein in cells. RAME inhibition of HPH and induction of HIF-1α were diminished by elevated doses of the required factors of HPH, 2-ketoglutarate and ascorbate. RAME induction of HIF-1α led to activation of an ulcer healing pathway, HIF-1-vascular endothelial growth factor (VEGF), in human colon carcinoma cells. RAME administered rectally ameliorated TNBS-induced rat colitis and substantially decreased the levels of pro-inflammatory mediators in the inflamed colonic tissue. In parallel with the cellular effects of RAME, RAME up-regulated HIF-1α and VEGF in the inflamed colonic tissue. Thus, lipophilic modification of RA improves its ability to inhibit HPH, leading to activation of the HIF-1-VEGF pathway. RAME, a lipophilic RA derivative, may exert anti-colitic effects via activation of the ulcer healing pathway.

Topics: Animals; Ascorbic Acid; Carboxylic Acids; Cell Line, Tumor; Cinnamates; Coenzymes; Colitis; Depsides; Enzyme Inhibitors; Esters; Humans; Hydrophobic and Hydrophilic Interactions; Hydroxylation; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Ketoglutaric Acids; Protein Stability; Rats; Rosmarinic Acid; Signal Transduction; Structure-Activity Relationship; Trinitrobenzenesulfonic Acid; Vascular Endothelial Growth Factor A

We investigated anti-colitic effects of N-(2-mercaptopropionyl)-glycine (NMPG), a diffusible antioxidant, in TNBS-induced rat colitis model and a potential molecular mechanism underlying the pharmacologic effect of the antioxidant. NMPG alleviated colonic injury and effectively lowered myeloperoxidase activity. Moreover, NMPG substantially attenuated expression of pro-inflammatory mediators in the inflamed colon. NMPG induced hypoxia-inducible factor-1α (HIF-1α) in human colon carcinoma cells, leading to elevated secretion of vascular endothelial growth factor (VEGF), a target gene product of HIF-1 involved in ulcer healing of gastrointestinal mucosa. NMPG induction of HIF-1α occurred by inhibiting HIF prolyl hydroxylase-2 (HPH-2), an enzyme that plays a major role in negatively regulating HIF-1α protein stability. In in vitro Von Hippel-Lindau protein binding assay, the inhibitory effect of NMPG on HPH-2 was attenuated by escalating dose of ascorbate but not 2-ketoglutarate, cofactors of the enzyme. Consistent with this, cell-permeable ascorbate significantly attenuated NMPG induction of HIF-1α in cells. Our data suggest that NMPG is an anti-colitic antioxidant that exerts its pharmacologic effects at least partly through activation of an ulcer healing pathway, HIF-1-VEGF.

Topics: Animals; Antioxidants; Ascorbic Acid; Basic Helix-Loop-Helix Transcription Factors; Colitis; Diffusion; Enzyme Activation; HCT116 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Prolyl Hydroxylases; Rats; Rats, Sprague-Dawley; Tiopronin; Trinitrobenzenesulfonic Acid; Vascular Endothelial Growth Factor A

To investigate the mechanisms underlying the biological activity of piceatannol (PCT), a hydroxystilbene natural product that has anti-colitic properties, we examined whether PCT could modulate hypoxia-inducible factor (HIF)-1 activity in human colon carcinoma cells. PCT induced HIF-1α protein, leading to induction of its target gene products, vascular endothelial growth factor and heme oxygenase-1, which are involved in amelioration of colitis. PCT induction of HIF-1α resulted from HIF-1α protein stabilization, which occurred through inhibition of HIF-prolyl hydroxylase-2 (HPH-2). PCT inhibition of HPH-2 was reversed by addition of ascorbate, a cofactor of HPH-2, but not the cosubstrate, 2-ketoglutarate, to the reaction mixture of an in vitro von Hippel-Lindau (VHL) capture assay, and pretreatment with ascorbate abrogated PCT induction of cellular HIF-1α. Moreover, PCT prevented hydroxylation of cellular HIF-1α and attenuated coimmunoprecipitation of Flag-VHL protein and HA-HIF-1α over-expressed in human embryonic kidney 293 cells. Structural analysis using derivatives of PCT revealed that the catechol moiety in PCT was required for the stabilization of HIF-1α protein. Taken together, PCT activation of HIF-1 resulting from inhibition of HPH-2 may be a molecular mechanism for an anti-colitic effect of the natural product.

Topics: Ascorbic Acid; Cell Line, Tumor; Colitis; Colonic Neoplasms; HEK293 Cells; Heme Oxygenase-1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Inducible Factor-Proline Dioxygenases; Procollagen-Proline Dioxygenase; Stilbenes; Vascular Endothelial Growth Factor A

Previous experiments in rats with chemically induced colitis have shown that the antioxidant N-acetylcysteine plus mesalamine (5-ASA) exerted a significantly greater therapeutic effect in promoting mucosal healing when compared to either agent alone. The aims of the present study were to compare the effects of three antioxidants plus mesalamine vs. 5-ASA alone in treatment of colitis induced by trinitrobenzene sulfonic acid (TNBS) in rats.. Three days following induction of TNBS colitis, rats received 8 days of rectal therapy with 5-ASA, or 5-ASA plus vitamin C (ascorbic acid), 5-ASA plus phenyl butylnitrone (PBN) and 5-ASA plus vitamin E (alpha-tocopherol). Distal colonic tissues were examined for microscopic colitis and myeloperoxidase (MPO) activity.. Global assessments of microscopic colitis induced by TNBS indicated that 5-ASA alone significantly changed colonic injury by -31%. Combination therapy with ascorbic acid plus 5-ASA or alpha-tocopherol plus 5-ASA caused further significant change in TNBS colitis by -65 and -82%, respectively. Each of these values was significantly below scores observed with 5-ASA as monotherapy. Reduction in colitis with PBN plus 5-ASA was not different from 5-ASA alone. MPO activity was decreased significantly in response to monotherapy with 5-ASA and each of the antioxidants plus 5-ASA when compared to TNBS. alpha-Tocopherol plus 5-ASA, however, was the only treatment strategy that reduced significantly MPO activity below that recorded for 5-ASA alone. In conclusion, our results indicate that antioxidants other than N-acetylcysteine significantly enhance the therapeutic effectiveness of 5-ASA in the treatment of TNBS colitis. alpha-Tocopherol plus 5-ASA exerted profound anti-inflammatory and reparative effects upon colitis induced by TNBS.

Topics: Animals; Antioxidants; Ascorbic Acid; Colitis; Cyclic N-Oxides; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Intestinal Mucosa; Male; Mesalamine; Rats; Rats, Sprague-Dawley; Trinitrobenzenesulfonic Acid; Vitamin E

The mechanisms underlying the frequent development of carcinomas associated with ulcerative colitis (UC) are not understood. Cellular antioxidants play a crucial role in protection against neoplastic disease. The purpose of this study is to investigate a critical balance between free radical activity and the antioxidant defense system in carcinogenesis associated with UC, using a model of experimental colitis induced in mice by dextran sulfate sodium (DSS) treatment.. Chronic colitis was induced by feeding the mice for 7 days with 4% DSS, followed by drinking water alone for the subsequent 14 days. Animals were sacrificed after one, two, three, or four cycles of DSS administration. Development of dysplastic epithelium and invasive carcinoma was histologically examined. Lipid peroxide level was estimated by measuring malondialdehyde (MDA) content. Alterations in MDA content and superoxide dismutase (SOD) activity in colonic tissues together with production of serum tumor necrosis factor (TNF)-alpha were determined.. Colonic neoplasms including dysplastic epithelium and invasive carcinoma developed in 28.6 and 25.0% of the animals at the end of the third and fourth cycles, respectively. In accordance with elevation of serum TNF-alpha level, there was a substantial increase in MDA in the colonic mucosa, while tissue SOD activity tended to be suppressed during the DSS treatment periods. Dysplastic epithelium and invasive carcinoma revealed significantly lower SOD levels compared with colonic colitis, although MDA levels were not statistically different among these colonic diseases.. The results obtained in this experimental model suggest that an impaired antioxidant defense system might be critical for cancer development associated with UC.

Topics: Animals; Anticoagulants; Antioxidants; Ascorbic Acid; Chronic Disease; Colitis; Colonic Neoplasms; Dextran Sulfate; Female; Free Radicals; Intestinal Mucosa; Lipid Peroxides; Malondialdehyde; Mice; Mice, Inbred Strains; Superoxide Dismutase; Tumor Necrosis Factor-alpha

Iron supplementation may increase disease activity in ulcerative colitis, possibly through the production of reactive oxygen species from the Fenton reaction.. To assess the effects of two doses of oral iron on intestinal inflammation and oxidative stress in experimental colitis.. Colitis was induced in rats by giving 5% dextran sulphate sodium in drinking water for 7 days. First, using a 2 x 2 factorial design, rats with or without dextran sulphate sodium received the regular diet or a diet containing iron 3%/kg diet. Second, rats with dextran sulphate sodium-induced colitis were supplemented with iron 0.3%/kg diet and compared with rats on dextran sulphate sodium and regular diet. The body weight change, histological scores, colon length, rectal bleeding, plasma and colonic lipid peroxides, colonic glutathione peroxidase and plasma vitamin E and C were measured. Faecal analysis for haem and total, free and ethylenediaminetetra-acetic acid-chelatable iron was also performed.. Iron 3% and iron 0.3% increased the activity of dextran sulphate sodium-induced colitis, as demonstrated by higher histological scores, heavier rectal bleeding and further shortening of the colon. This was associated with increased lipid peroxidation and decreased antioxidant vitamins. Faecal iron available to the Fenton reaction was increased in a dose-dependent manner.. Iron supplementation taken orally enhanced the activity of dextran sulphate sodium-induced colitis and is associated with an increase in oxidative stress.

Topics: Administration, Oral; Animals; Antioxidants; Ascorbic Acid; Colitis; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Drug Interactions; Glutathione Peroxidase; In Vitro Techniques; Inflammation; Intestines; Iron; Lipid Peroxidation; Male; Mucous Membrane; Oxidative Stress; Rats; Rats, Wistar; Reactive Oxygen Species; Vitamin E

Topics: Adult; Ascorbic Acid; Colitis; Female; Folic Acid; Hot Temperature; Humans; Male; Mud Therapy; Nicotinic Acids; Riboflavin; Vitamins

Topics: Adolescent; Adult; Ascorbic Acid; Child; Colitis; Female; Humans; Male; Middle Aged; Neurologic Manifestations; Niacinamide; Pantothenic Acid; Pyridoxine; Skin Manifestations; Tetracycline; Vitamin B 12

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Anti-Bacterial Agents; Antibiotics, Antitubercular; Ascorbic Acid; Blood Transfusion; Colitis; Colitis, Ulcerative; Diet; Diet Therapy; Ergocalciferols; Humans; Isoniazid; Surgical Procedures, Operative