Altered levels of biochemical indices of bone turnover and bone-related vitamins in patients with Crohn's disease and ulcerative colitis

Background The pathogenesis of inflammatory bowel disease‐associated osteopenia may be related to pathological rates of bone turnover; however, the literature shows mixed results. Aim To compare bone biomarkers in inflammatory bowel disease patients (Crohn's disease: n = 68, and ulcerative colitis: n = 32, separately) with age‐ and sex‐matched healthy controls. Subjects Patients and controls were recruited from Cork University Hospital and Cork City area, respectively. Results Relative to that in their respective controls, Crohn's disease (n = 47) and ulcerative colitis (n = 26) patients (i.e. excluding supplement users) had significantly (P < 0.05–0.001) higher serum undercarboxylated osteocalcin (by 27% and 63%, respectively) and bone‐specific alkaline phosphatase (by 15% and 21%, respectively) and urinary Type I collagen cross‐linked N‐telopeptides concentrations (by 87% and 112%, respectively). Relative to that in their respective controls, Crohn's disease and ulcerative colitis patients had significantly (P < 0.01) lower serum total osteocalcin (by 20% and 42%, respectively) and 25‐hydroxyvitamin D (by 37% and 42%, respectively), while serum parathyroid hormone levels were similar. In the combined patient group (n = 100), undercarboxylated osteocalcin was positively associated with bone markers. Conclusions Both Crohn's disease and ulcerative colitis patients have altered bone turnover relative to that in healthy controls.     

Anti-inflammatory action of a novel orally available peptide 317 in mouse models of inflammatory bowel diseases

BackgroundThe endogenous opioid system constitutes an attractive target in the treatment of GI disorders, including inflammatory bowel diseases (IBD). The aim of our study was to characterize the anti-inflammatory and antinociceptive effect of P-317, a novel cyclic analog of opioid peptide morphiceptin, in animal models of IBD.MethodsThe anti-inflammatory effect of P-317 after intraperitoneal (ip) and oral (po) administration was assessed in two mouse models of IBD – Crohn's disease, induced by intracolonic instillation of trinitrobenzenesulfonic acid (TNBS) and ulcerative colitis, induced by addition of dextran sodium sulfate (DSS) into drinking water. The antinociceptive action of P-317 was characterized in mice with acute colitis using mustard oil-induced pain test. Real time RT PCR was used to assess semiquantitatively the expression of IL-1β and TNF-α mRNA in mouse colonic samples. To translate our results to clinical conditions, MOP and KOP mRNA were quantified in human colonic biopsies from IBD patients.ResultsP-317 (0.1 mg/kg, ip and 1 mg/kg, po) alleviated colonic inflammation in TNBS- and DSS-treated mice in the opioid receptor-dependent manner. The anti-inflammatory effect of P-317 was associated with the decrease in mRNA expression of proinflammatory cytokines. The antinociceptive effect of P-317 was observed after ip and po administration in mice with acute colitis.ConclusionOur results show a potent anti-inflammatory and antinociceptive effect of P-317 in mouse models of colitis upon activation of opioid receptors. The unique bioavailability of P-317 after oral administration suggests that it is a promising drug candidate for future treatment of IBD.     

Kolaviron,a Natural Antioxidant and Anti‐Inflammatory Phytochemical Prevents Dextran Sulphate Sodium‐Induced Colitis in Rats

The beneficial effects of kolaviron, a natural biflavonoid from the seeds of Garcinia kola, have been attributed mainly to its antioxidant and anti‐inflammatory effects. This study investigated these effects on dextran sulphate sodium (DSS)‐induced ulcerative colitis in rats. Sulfasalazine served as standard reference in this study. Kolaviron and sulfasalazine were separately co‐administered orally at 200 mg/kg and 500 mg/kg, respectively, to dextran sulphate sodium‐exposed rats for 5 days. The result indicated that kolaviron or sulfasalazine significantly prevented DSS‐induced body weight loss as well as the incidence of diarrhoea and bleeding in DSS‐exposed rats. Kolaviron suppressed the DSS‐mediated increase in colonic nitric oxide concentration and myeloperoxidase activity and significantly prevented the increase in inflammatory mediators, interleukin‐1β and tumour necrosis factor alpha, in the colon of DSS‐treated rats. The significant depletion in colonic antioxidant status in rats exposed to DSS alone was evident by marked reduction in colonic catalase and glutathione S‐transferase activities as well as glutathione content, leading to elevated hydrogen peroxide and lipid peroxidation levels. Histopathologically, DSS alone resulted in severe epithelial erosion, total absence of goblet cells, destruction of the crypts, necrotic and distorted glands, accompanied by marked cellular mononuclear cells infiltration. However, administration of kolaviron and sulfasalazine ameliorated DSS‐induced colitis by increasing the antioxidant status decreased hydrogen peroxide and lipid peroxidation levels and attenuated the adverse effect of DSS on colon architecture. In conclusion, the anti‐colitis effect of kolaviron is related to its intrinsic anti‐inflammatory and anti‐oxidative properties.     

Protective effect of curcumin,a Curcuma longa constituent,in early colonic inflammation in rats

Curcumin, a polyphenol derived from the plant, Curcuma longa, has a variety of pharmacological effects, including chemotherapeutic, anti‐inflammatory, antiangiogenic, and antioxidant activities. To gain a better understanding of the effects and mechanisms of action of curcumin on the acute injury caused by intra‐colonic administration of acetic acid (AA) in rats, inflammation was assessed by histology and myeloperoxidase activity (MPO; an index of neutrophil infiltration in the mucosa); Th1 and Th2 cytokine production; histological and histochemical analysis of the lesions; nitrite production in colon mucosa; and the expression of iNOS, COX‐1 and ‐2 using Western blotting and inmmunohistochemistry. We also studied the involvement of the p38 MAPK/JNK signalling pathway in the protective effect of curcumin in acute colonic inflammation. Curcumin (50–100 mg/kg/day) reduced the degree of colonic injury, the index of neutrophil infiltration and Th1 cytokine secretion, and increased IL‐10 production, reduced colonic levels of nitrites, and reduced COX‐2 and iNOS overexpression. A reduction in the activation of p38 and JNK MAPKs was also observed. Thus, we show that the widely used food additive, curcumin reduced the development of AA‐induced colitis and alleviated the inflammatory response. Inhibition of MAPK signalling by curcumin could explain the changes on the cytokine Th1/Th2 profile, the reduction of COX‐2 and iNOS signaling, as well as the decreased nitrite production in colonic mucosa, suggesting that curcumin may be useful in the treatment of ulcerative colitis. Drug Dev Res, 2009. © 2009 Wiley‐Liss, Inc.     

Ameliorative effects of riboflavin on acetic acid‐induced colonic injury in rats

Riboflavin (RF) has been found to be a promising antioxidant and/or anti‐inflammatory agent in several studies. However, the effect of RF against acetic acid (AA)‐induced colonic injury is currently unknown. This study aimed to investigate the potential antioxidant and protective effects of RF in a rat model of ulcerative colitis. Starting immediately after the colitis induction (AA+RF group) or 1 week before the colitis induction (RF+AA+RF group), the rats were treated with RF (25 mg/kg per day; p.o.) for 3 days. The control and AA groups received saline (1 mL; p.o.) whereas AA+SS group (positive control) received sulfasalazine (100 mg/kg per day; p.o.) for 3 days. Colonic samples were taken for the biochemical and histological assessments on the third day. High damage scores, elevated tissue wet weight index (WI), tissue myeloperoxidase (MPO) activity, 8‐hydroxy‐2′‐deoxyguanosine levels and chemiluminescence values, and a pronounced decrease in antioxidant glutathione (GSH) levels of the AA group were all reversed by RF pretreatment (RF+AA+RF group) and SS treatment (AA+SS group) (P < .05‐.001). Tissue WI, MPO activity and GSH levels were not statistically changed in the AA+RF group. Western blot analysis revealed that the decreased protein expressions of tissue collagen (COL) 1A1, COL3A1 and transforming growth factor‐β1 in the AA group were elevated in all the treatment groups (P < .05‐.001). In conclusion, RF exerts both the antioxidant and anti‐inflammatory effects against AA‐induced colonic inflammation by suppressing neutrophil accumulation, inhibiting reactive oxidant generation, preserving endogenous glutathione, improving oxidative DNA damage and regulating inflammatory mediators, suggesting a future potential role in the treatment and prevention of ulcerative colitis.     

糖皮质激素连接物在大鼠胃肠道的转运及其对溃疡性结肠炎的治疗

目的:研究地塞米松(DX)-右旋糖酐(500000)连接物(DXD50)在大鼠胃肠道的转运及其对大鼠溃疡性结肠炎的疗效。方法:将DXD50给大鼠ig,监测该DXD50在大鼠胃肠道不同部位释放DX的动力学过程及血药浓度变化。用三硝基苯磺酸诱导大鼠溃疡性结肠炎,以结肠溃疡面积、结肠重量、结肠组织髓过氧化物酶、大鼠外周血淋巴细胞数、胸腺及脾脏重量为指标,观察连接物的疗效。结果:口服连接物后,DX主要分布在盲肠和结肠中。DXD50及DX0.25μmol·kg~(-1)·d~(-1)可分别使大鼠溃疡面积缩小55.6％和33.3％,同时结肠重量下降17.9％和2.6％。DXD50 0.25μmol·kg~(-1)·d~(-1)对大鼠外周血淋巴细胞数、胸腺及脾脏重量无影响,而同等剂量的DX可引起大鼠外周血淋巴细胞数、胸腺及脾脏重量明显下降(P<0.05 vs control)。结论:DXD50可将DX特异地转运到结肠,它是一种有潜力的治疗炎症性肠病药物。     

Investigational treatment options in microscopic colitis

Collagenous and lymphocytic colitis are the two recognized major presentations of microscopic colitis. Both diseases present with chronic watery diarrhea and a chronic inflammatory infiltrate in the colonic mucosa without specific endoscopic abnormalities, and hence diagnosis is established by histology. Recent epidemiological studies suggest that microscopic colitis may affect as many patients as Crohn's disease or ulcerative colitis. The cause of these diseases is unknown; however, several lines of evidence support the hypothesis of mucosal injury from an unknown agent in the fecal stream. Due to the lack of disease causality, therapeutic management of microscopic colitis is now directed primarily at symptoms' resolution or improvement. Based on current evidence, oral budesonide represents an effective treatment option for patients with microscopic colitis to achieve and maintain remission. Other anti-inflammatory drugs such as mesalazine or bismuth subsalicylate are now under evaluation. The optimal long-term management strategy of microscopic colitis, however, remains an unsolved issue.     

A Review on Chemical-Induced Inflammatory Bowel Disease Models in Rodents

Ulcerative colitis and Crohn''s disease are a set of chronic, idiopathic, immunological and relapsing inflammatory disorders of the gastrointestinal tract referred to as inflammatory bowel disorder (IBD). Although the etiological factors involved in the perpetuation of IBD remain uncertain, development of various animal models provides new insights to unveil the onset and the progression of IBD. Various chemical-induced colitis models are widely used on laboratory scale. Furthermore, these models closely mimic morphological, histopathological and symptomatical features of human IBD. Among the chemical-induced colitis models, trinitrobenzene sulfonic acid (TNBS)-induced colitis, oxazolone induced-colitis and dextran sulphate sodium (DSS)-induced colitis models are most widely used. TNBS elicits Th-1 driven immune response, whereas oxazolone predominantly exhibits immune response of Th-2 phenotype. DSS-induced colitis model also induces changes in Th-1/Th-2 cytokine profile. The present review discusses the methodology and rationale of using various chemical-induced colitis models for evaluating the pathogenesis of IBD.     

Novel formulation of solid lipid microparticles of curcumin for anti‐angiogenic and anti‐inflammatory activity for optimization of therapy of inflammatory bowel disease

Objectives This project was undertaken with a view to optimize the treatment of inflammatory bowel disease through a novel drug delivery approach for localized treatment in the colon. Curcumin has poor aqueous solubility, poor stability in the gastrointestinal tract and poor bioavailability. The purpose of the study was to prepare and evaluate the anti‐inflammatory activity of solid lipid microparticles (SLMs) of curcumin for the treatment of inflammatory bowel disease in a colitis‐induced rat model by a colon‐specific delivery approach. Methods We have developed a novel formulation approach for treating experimental colitis in the rat model. SLMs of curcumin were prepared with various lipids, such as palmitic acid, stearic acid and soya lecithin, with an optimized percentage of poloxamer 188. The SLMs of curcumin were characterized for particle size, drug content, drug entrapment, in‐vitro release, surface morphology and infrared, differential scanning calorimetry and X‐ray studies. The colonic delivery system of SLM formulations of curcumin were further investigated for their anti‐angiogenic and anti‐inflammatory activity using chick embryo and rat colitis models. Key findings Particle size, drug content, drug entrapment and in‐vitro release studies showed that formulation F4 containing one part stearic acid and 0.5% surfactant had the smallest diameter of 108 μm, 79.24% entrapment and exhibited excellent in‐vitro release characteristics when compared with other formulations and pure curcumin. SLMs of curcumin (F4) proved to be a potent angio‐inhibitory compound, as demonstrated by inhibition of angiogenesis in the chorioallantoic membrane assay. Rats treated with curcumin and its SLM complex showed a faster weight gain compared with dextran sulfate solution (DSS) control rats. The increase in whole colon length appeared to be significantly greater in SLM‐treated rats when compared with pure curcumin and DSS control rats. An additional finding in the DSS‐treated rats was chronic cell infiltration with predominance of eosinophils. Decreased mast cell numbers in the mucosa of the colon of SLMs of curcumin and pure curcumin‐treated rats was observed. Conclusions The degree of colitis caused by administration of DSS was significantly attenuated by colonic delivery of SLMs of curcumin. Being a nontoxic natural dietary product, curcumin could be useful in the therapeutic strategy for inflammatory bowel disease patients.     

Ameliorative effect of pyrrolidinedithiocarbamate on acetic acid-induced colitis in rats

Ulcerative colitis is a chronically recurrent inflammatory bowel disease of unknown origin. The present study examined the effect of NF-kappaB inhibitor and antioxidant, pyrrolidinedithiocarbamate (PDTC) on experimental ulcerative colitis in rats. Animals were randomly divided into 4 groups, each consisting of 6 animals; normal control group, acetic acid group, PDTC-treated group and sulfasalazine-treated group as a positive control group. Induction of colitis by intracolonic administration of 3% acetic acid produced severe macroscopic inflammation in the colon 24 h after acetic acid administration as assessed by the colonic damage score. Microscopically, colonic tissues showed ulceration, oedema and inflammatory cells infiltration. Biochemical studies revealed increased serum levels of lactate dehydrogenase (LDH), and nitrite/nitrate and colonic concentrations of tumor necrosis factor-alpha (TNF-alpha) and the neutrophil infiltration index, myeloperoxidase (MPO). Oxidative stress was indicated by elevated lipid peroxides formation and depleted reduced glutathione concentrations (GSH) in colonic tissues. Immunohistochemical studies of colonic sections revealed upregulation of inducible nitric oxide synthase (iNOS). Pretreatment with PDTC at a dose of (200 mg/kg/day, i.p.), three days before induction of colitis decreased serum LDH, nitrite/nitrate and TNF-alpha levels, colonic concentrations of MPO and lipid peroxides while increased colonic GSH concentration. Moreover, PDTC pretreatment attenuated colonic iNOS expression. Finally, histopathological changes were nearly restored by PDTC pretreatment. The findings of the present study provide evidence that PDTC may be beneficial in patients with inflammatory bowel disease.     

Early detection of renal injury using urinary vanin‐1 in rats with experimental colitis

Renal complications are often detected in patients with inflammatory bowel disease (IBD). Because conventional markers such as serum creatinine and β2‐microglobulin are not sensitive and/or specific, a new renal biomarker is needed. We have recently identified urinary vanin‐1 as an early biomarker for the detection of nephrotoxicant‐induced renal injury. In this study, we compared the usefulness of urinary vanin‐1 with other newly developed biomarkers [urinary monocyte chemoattractant protein‐1 (MCP‐1), kidney injury molecule‐1 (Kim‐1) and N‐acetyl‐beta‐D‐glucosaminidase (NAG)] for the detection of renal complications in rats with experimental colitis. On day 2 after intracolonic injection of 2,4,6‐trinitrobenzene sulfonic acid (TNBS), male Wistar rats developed not only colitis, but histologically evident renal injury. Urinary vanin‐1 started to elevate on day 1, whereas serum creatinine and urinary excretions of glucose, total protein, albumin, Kim‐1, MCP‐1 and NAG significantly increased only on day 2. The mRNA expressions of vanin‐1 and Kim‐1 significantly increased in the kidney, but not in the colon. In addition, vanin‐1 did not appear in the blood. On the other hand, colonic mRNA expression and the serum concentration of MCP‐1 were significantly higher in the TNBS‐treated rats than in the control animals. These results suggest that, in contrast to MCP‐1, urinary vanin‐1 and Kim‐1 mainly originated from the kidney rather than the colon in this model. Compared with Kim‐1 and MCP‐1, vanin‐1 might be an earlier biomarker for the detection of renal injury in rats with experimental colitis. Copyright © 2013 John Wiley & Sons, Ltd.     

Heparin and low-molecular-weight heparin (enoxaparin) significantly ameliorate experimental colitis in rats

Background and aims:

The anticoagulants, unfractionated heparin and low‐molecular‐weight heparin, demonstrated anti‐inflammatory effects in animal models and in humans. Because of its dual effects, high‐dose heparin was proposed as a therapeutic modality for ulcerative colitis. We investigated whether a low dose of low‐molecular‐weight heparin—enoxaparin (Clexane, Rhône‐Poulenc Rorer, France)—ameliorates the inflammatory response in two models of experimental colitis.

Methods:

Colitis was induced in rats by intrarectal administration of dinitrobenzene sulphonic acid. Enoxaparin (40, 80 and 200 μg/kg) or unfractionated heparin (100, 200 and 400 U/kg) were administered subcutaneously immediately after the induction of damage. Enoxaparin, 80 μg/kg, was also administered after induction of colitis by intrarectal administration of iodoacetamide. Rats were sacrificed 1, 3 or 7 days after induction of injury. Colonic damage was assessed macroscopically and histologically. Mucosal prostaglandin E₂ generation, myeloperoxidase and nitric oxide synthase activities and tumour necrosis factor‐α levels in blood were determined.

Results:

Enoxaparin and heparin significantly ameliorated the severity of dinitrobenzene sulphonic acid‐ and iodoacetamide‐induced colitis as demonstrated by a decrease in mucosal lesion area, colonic weight and mucosal myeloperoxidase and nitric oxide synthase activities. The dose–response curve had a bell‐shaped configuration: enoxaparin, 80 μg/kg, and unfractionated heparin, 200 U/kg, were the optimal doses.

Conclusions:

Low‐dose enoxaparin and unfractionated heparin ameliorate the severity of experimental colitis. This effect is related to their anti‐inflammatory rather than anticoagulant properties.

     

Lipocortin-1 autoantibody concentration in children with inflammatory bowel disease

Background: Corticosteroids are widely used to treat children with inflammatory bowel disease although the response is variable, side-effects are common, and many patients develop a partial or complete steroid resistance. The mechanism underlying these phenomena are unclear. Corticosteroids mediate some of their actions through lipocortin-l, and the inductic of autoantibodies to lipocortin has been proposed as a possible mechanism by which steroid efficacy is suboptimal in vivo. Patients and methods: We have measured serum lipocortin-1 antibody concentration by ELISA in 38 children with Crohn's disease, 12 with ulcerative colitis and in 15 controls. Results: IgG and IgA anti-lipocortin-1 antibody levels were higher in the Crohn's group than in the ulcerative colitis or control groups. Elevated concentrations did not relate to disease activity, history of steroid therapy or steroid-responsiveness. Lipocortin IgM antibody status was similar in all three groups. Conclusion: It is therefore unlikely that serum antibodies to lipocortin-1 have a role in the development of steroid-resistance in children with inflammatory bowel disease.     

Anti-inflammatory Effects of Flavonoids on TNBS-induced Colitis of Rats

It has been shown that the extracts including eupatilin and quercetin-3-β-D-glucuronopyranoside had mucoprotective effects on the esophagus and stomach through their antioxidant activities. This study was designed to investigate the anti-inflammatory effect of these flavonoid compounds in an animal model of inflammatory bowel disease induced by 2,4,6-trinitrobenzene sulfonic acid. Experimental colitis was induced by intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid. Extracts including eupatilin or quercetin-3-β-D-glucuronopyranoside were orally administered to animals 48, 24, and 1 h prior to the induction of colitis and then again 24 h later. The animals were sacrificed 48 h after by 2,4,6-trinitrobenzene sulfonic acid treatment and the macroscopic appearance of the colonic lesions was scored in a blinded manner on a scale of 1 to 10. The inflammatory response to colitis induction was assessed by measuring myeloperoxidase activity, nitric oxide production, tumor necrosis factor-α expression, total glutathione levels, and malondialdehyde concentrations in the colon. The results indicated that extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside dose-dependently improved the morphology of the lesions induced by 2,4,6-trinitrobenzene sulfonic acid and reduced the ulcer index accordingly. In addition, rats receiving extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside showed significantly decreased levels of mucosal myeloperoxidase activity, nitric oxide production, tumor necrosis factor-α expression, and malondialdehyde levels, and increased total glutathione levels. Extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside ameliorated the inflammatory response and colonic injury in acute colitis by decreasing oxidative stress and neutrophil activation. Extracts including eupatilin and extracts including quercetin-3-β-D-glucuronopyranoside may inhibit acute colitis.     

Prediction of clinical effects of infliximab administered for inflammatory bowel disease based on pharmacokinetic and pharmacodynamic modeling

Infliximab (IFX) is used as a therapeutic agent for ulcerative colitis (UC) and Crohn's disease (CD). Although the dosage regimen has been established through clinical trial experience, it has yet to be assessed with a pharmacokinetic and pharmacodynamic model. The present study analysed sequential changes of clinical response in patients with ulcerative colitis and Crohn's disease following repeated administrations of infliximab using the pharmacokinetic/pharmacodynamic model. In addition, the dosage regimen presently used for patients with ulcerative colitis was evaluated, as well as the potential efficacy gained by increasing the dose and/or reducing the interval of administration for patients with Crohn's disease. Furthermore, the possibility of evaluating the difference between both diseases with regard to the efficacy of infliximab was investigated. Sequential changes in the clinical response values obtained with our model were in good agreement with the observed values following administration of infliximab in patients with ulcerative colitis and Crohn's disease. The results showed the importance of a loading dose for patients with ulcerative colitis, as well as the efficacy of increasing the dose and reducing the interval for patients with Crohn's disease. Also, the efficacy of infliximab for both diseases is suggested to be similar. In conclusion, our results show a possible modeling scenario that can accommodate the clinical response to infliximab administered for ulcerative colitis and Crohn's disease. Furthermore, it provides confirmation for the present dosage regimens given for these diseases.     

The cyclo-oxygenase-2 inhibitor, rofecoxib, attenuates mucosal damage due to colitis induced by trinitrobenzene sulphonic acid in rats

Cyclo-oxygenase-2 overexpression has been described in experimental colitis. However, there are controversial findings suggesting that its inhibition by selective cyclo-oxygenase-2 inhibitors not only may have a beneficial effect on experimental colitis, but also exacerbate the inflammation-associated colonic injury. Thus, the role of cyclo-oxygenase-2 inhibitors in the possible modulation of colon inflammation is controversial and remains uncertain. In this study, we evaluated the effects of the selective cyclo-oxygenase-2 inhibitor, rofecoxib, on the extent and severity of ulcerative colitis caused by intracolonic administration of 2,4,6-trinitrobenzene sulphonic acid (TNBS) in rats. The lesions and the inflammatory response were assessed by histology and measurement of myeloperoxidase activity. Interleukin-1 beta, prostaglandin E(2) and D(2) levels in colon mucosa and the immunohistochemical expression of the cyclo-oxygenases-1 and -2 were also studied. Finally, we investigated the effects of rofecoxib on apoptosis of colonocytes by the appearance of DNA fragmentation. Inflammation following TNBS was characterized by increased colonic wall thickness, oedema, diffuse inflammatory cell infiltration in the mucosa, and necrosis. Increased myeloperoxidase activity, as an index of neutrophil infiltration in the mucosa, and interleukin-1 beta levels were also measured in the colon. Administration of rofecoxib significantly (P<0.05) reduced the colonic damage, the degree of neutrophil infiltration, and interleukin-1 beta levels. In addition, apoptosis was significantly increased in TNBS-treated rats, but not in rofecoxib plus TNBS-treated rats. We concluded that rofecoxib seems to have beneficial effects in TNBS-induced colitis by diminishing the initial stage of inflammation, probably by a mechanism related to inhibition of prostaglandin E(2) by the cyclo-oxygenase-2 pathway. The data suggest that cyclo-oxygenase-2-selective inhibitors may have a therapeutic role in ulcerative colitis.     

Anti-inflammatory effects of sinapic acid on 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice

This study was conducted to evaluate the effect of sinapic acid, a cinnamic acid derivative, on inflammatory changes in a mouse model of colitis. Colitis was induced by intracolonic instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Sinapic acid (10, 30, and 100 mg/kg) and dexamethasone (2 mg/kg) were orally administered to Balb/c female mice after TNBS instillation. The anti-inflammatory effect of sinapic acid on colonic injury or damage was assessed by clinical, macroscopic, microscopic, and biochemical analyses. Compared with TNBS control, treatment with sinapic acid significantly improved colonic weight and length and decreased the macroscopic and microscopic changes in TNBS-induced colitis. Furthermore, myeloperoxidase activity and the colonic tissue levels of malondialdehyde and tumor necrosis factor alpha were decreased by administration of sinapic acid. The findings of this study suggest that sinapic acid exerts anti-inflammatory effects on intestinal inflammation and can be selected as a novel therapeutic candidate in the treatment of inflammatory bowel disease.     

Mucosal gene expression changes induced by anti-TNF treatment in inflammatory bowel disease patients

In the last two decades anti-tumor necrosis factor (anti-TNF) therapy for inflammatory bowel disease (IBD) has been widely used to induce and maintain clinical and endoscopical remission, completely changing management of the disease. In this study, we aimed to identify gene expression changes in inflamed mucosa from Crohn's disease and ulcerative colitis patients treated with 5-aminosalicylic acid (5-ASA) (N = 25) or anti-TNF agents (N = 12) compared to drug-free IBD patients (N = 12) and non-IBD control subjects (N = 18). The mucosal expression of 84 genes previously associated with IBD was evaluated by qPCR. We found that both therapeutic regimens induce a decrease in LCN2, NOS2, and TFF1, the levels of which are overexpressed in drug-free patients compared to non-IBD control subjects. Interestingly, a stronger effect of anti-TNF drugs was observed on LCN2 and TFF1 levels. However, 5-ASA seems to induce a more robust reduction of NOS2 expression. Moreover, we found that anti-TNF treatment significantly increased ABCB1, leading to levels similar to those found in non-IBD control subjects.     

Dose-dependent antiinflammatory effect of ursodeoxycholic acid in experimental colitis

The denomination of inflammatory bowel disease comprises a group of chronic inflammatory diseases of the digestive tract, ulcerative colitis and Crohn's disease being the most important conditions. Bile acids may play a role both in etiology and pharmacology of this disease. Thus, although deoxycholic acid is regarded as a proinflammatory agent ursodeoxycholic acid, which is currently being used to treat certain types of cholestasis and primary biliary cirrhosis, because of their choleretic, cytoprotective and immunomodulatory effects, it has been reported to exert an anti-inflammatory activity. We aim to confirm and characterize the intestinal antiinflammatory activity of ursodeoxycholic acid. The experimental model trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats has been used. Animal status was characterized by a number of macroscopic and biochemical parameters. Oral administration of ursodeoxycholic acid was able to ameliorate experimental colonic inflammation. This occurred only at a relatively high dose (50 mg/kg day), whereas ursodeoxycholic acid was without significant effect at doses of 10 and 25 mg/kg day. The therapeutic effect was evidenced, among others, by a higher body weight recovery, a diminished affected to total mucosal area and lower alkaline phosphatase activity in treated vs. control (TNBS treated) animals. These results indicate that, at the appropriate dose, ursodeoxycholic acid is a potentially useful drug to reduce intestinal inflammation and could be envisaged to be incorporated in the treatment of inflammatory bowel diseases.