Xanthorrhizol attenuates dextran sulfate sodium-induced colitis via the modulation of the expression of inflammatory genes in mice

AimsThe aim of this study was to investigate the effects of xanthorrhizol (5-(1,5-dimethyl-4-hexenyl)-2-methylphenol, XA) in a mouse model of dextran sulfate sodium (DSS)-induced colitis.Main methodsExperimental colitis was induced by exposing male BALB/c mice to 5% DSS in drinking water for 7 days. XA (10 or 100 mg/kg) was administered orally once a day, together with the DSS. We evaluated body weight, colon length, histological changes, and myeloperoxidase (MPO) activity. A cDNA microarray was used to assess the gene expression profiles that were affected by XA and DSS treatment and a co-citation analysis was used to examine the biological relationship between XA-responsive genes and colitis.Key findingsDecreased body weight, shortened colon length, and damaged colon were observed in the group that was exposed to DSS. Oral administration of XA (10 or 100 mg/kg) rescued these symptomatic and histopathological features. The DSS-induced increase in MPO activity, which was used as an index of neutrophil infiltration, was significantly decreased after treatment with XA. Microarray analysis revealed that XA treatment regulated the expression of 34 genes that were altered by exposure to DSS, and that these XA-responsive genes were associated with colonic inflammation. Furthermore, co-citation analysis and graphing of XA-responsive genes revealed a network associated with the gene that encodes for MPO.SignificanceThese results suggest that XA attenuates acute DSS-induced colitis, possibly by modulating the expression of genes mostly associated with colonic inflammation.     

Protection against dextran sodium sulfate-induced colitis by dehydroepiandrosterone and 7alpha-hydroxy-dehydroepiandrosterone in the rat

In this study the anti-oxidant effect of DHEA and 7alpha-hydroxy-DHEA against oxidative stress induced by colitis was investigated in vivo in rats. The two steroids were intraperitoneally injected once daily (50 mg/kg body weight) for 7 days before the induction of colitis that was effected by a daily treatment of 5% (w/v) dextran sodium sulfate (DSS) in drinking water for 7 days. This was quantified by the evidence of weight loss, rectal bleeding, increased wall thickness, and colon length. The inflammatory response was assessed by neutrophil infiltration after a histological examination and myeloperoxidase (MPO) activity measurement. Two markers of oxidative damage were measured in colon homogenates after the onset of DSS treatment: protein carbonyls and thiobarbituric acid-reacting substances. The colonic metabolism of corticosterone by 11beta-hydroxysteroid dehydrogenases types 1 and 2 (11beta-HSD) was investigated in control and treated animals. Results indicated that colitis caused a decrease in body weight and colon length. Severe lesions were observed in the colon with a reduced number of goblet cells which contained less mucins. The lesions were associated with increased MPO activity and oxidative damage. Colonic inflammation down and up regulated the 11beta-HSD2 and 11beta-HSD1, respectively. Treatments by DHEA and 7alpha-hydroxy-DHEA attenuated the inflammatory response when MPO activity decreased; but this did not increase the colonic oxidation of corticosterone into 11-dehydrocorticosterone. Both DHEA and 7alpha-hydroxy-DHEA exerted a significant anti-oxidant effect against oxidative stress induced by colitis through reducing the oxidative damage to proteins and lipids. This resulted in a moderate increase in the amount of colonic mucus. Both DHEA and 7alpha-hydroxy-DHEA may prove useful in the prevention or treatment of colitis.     

Protection against dextran sulfate sodium-induced colitis by microspheres of ellagic acid in rats

Ellagic acid (EA), a naturally occurring plant phenol, has the antioxidant and anti-inflammatory activities. In the present study, we examined the effect of EA contained in microspheres on the ulcerative colitis induced experimentally in rats by dextran sulfate sodium (DSS). Experimental colitis was induced in male Fisher 344 rats by daily treatment with 3% DSS solution in drinking water for 7 days. EA of microspheres (mcEA: 1 approximately 10 mg/kg as EA contents) was administered p.o. twice daily for 6 days. In a preliminary study, we found that these microsphere capsules, when administered p.o., are effectively dissolved in the proximal to the ileo-cecal junction and distributed to the terminal ileum and the colon. The ulceration area, colon length, and mucosal myeloperoxidase (MPO) activity as well as thiobarbituric acid-reactive substances (TBARS) were measured on 7th day after the onset of DSS treatment. The DSS treatment for 7 days caused severe mucosal lesions in the colon, accompanied with the increases of MPO activity and TBARS as well as the decreases of body weight gain and colon length. Administration of mcEA reduced the severity of DSS-induced colitis in a dose-dependent manner, and a significant effect was observed at 10 mg/kg, the ED50 being 2.3 mg/kg. This mcEA treatment also significantly mitigated changes in various biochemical parameters in the colonic mucosa induced by DSS. Although plain EA (without using microspheres) was also effective in reducing the severity of DSS-induced colitis, this effect was much less potent as compared with that of mcEA; the ED50 was about 15 times higher than that of mcEA. In addition, a significant effect on DSS-induced colitis was also obtained by intra-rectal administration of superoxide dismutase, an anti-oxidative agent. These results suggest that EA prevents the ulcerative colitis induced by DSS, probably by radical scavenging and/or anti-oxidative actions. The microspheres used in this study may be useful for delivering an orally administered drug specifically to the colon.     

Anti-inflammatory effect of Euphorbia supina extract in dextran sulfate sodium-induced colitis mice

The aim of this study is to examine the anti-inflammatory effect of Euphorbia supina (ES) ethanol extract in dextran sulfate sodium (DSS)-induced experimental colitis model. ES was per orally administered at different doses of 4 or 20 mg/kg body weight with 5% DSS in drinking water for 7 days. Twenty mg/kg of ES administration regulated body weight decrease, recovered colon length shortening, and increased disease activity index score and myeloperoxidase level in DSS-induced colitis. Histological features showed that 20 mg/kg of ES administration suppressed edema, mucosal damage, and the loss of crypts induced by DSS. Furthermore, ES suppressed the expressions of COX-2, iNOS, NF-kB, IkBα, pIkBα in colon tissue. These findings demonstrated a possible effect of amelioration of ulcerative colitis and could be clinically applied.     

鼠衣原体改善DSS诱导的小鼠溃疡性结肠炎的作用研究

【目的】探讨鼠衣原体(Chlamydia muridarum)对小鼠溃疡性结肠炎的作用。【方法】取15只雌性C57BL/6J小鼠随机分为3组,每组5只动物,分别为空白对照组(Control)、肠炎模型组(DSS)、实验组(CM+DSS)。选取CM+DSS组小鼠予以2×10~5 IFU的鼠衣原体灌胃处理,并在其感染后第29天开始,给予DSS组和CM+DSS组的小鼠2%DSS饮水,持续5d,每天监测小鼠体重和肠炎疾病评分,实验结束后检测小鼠结肠长度和结肠组织炎性改变。【结果】肠炎模型组的小鼠均表现出典型的肠炎症状(包括体重减轻、肠炎疾病评分、结肠长度和组织炎性改变);而经鼠衣原体预处理的小鼠(CM+DSS组)肠炎症状显著减轻,表现在肠炎疾病评分降低,体重和结肠长度有所恢复,肠组织炎性损伤减轻。【结论】鼠衣原体对DSS诱导的小鼠溃疡性结肠炎具有改善作用。     

Anthocyanin-containing purple potatoes ameliorate DSS-induced colitis in mice

Ulcerative colitis (UC), a major form of inflammatory bowel disease (IBD), is on the rise worldwide. Approximately three million people suffer from IBD in the United States alone, but the current therapeutic options (e.g., corticosteroids) come with adverse side effects including reduced ability to fight infections. Thus, there is a critical need for developing effective, safe and evidence-based food products with anti-inflammatory activity. This study evaluated the antiinflammatory potential of purple-fleshed potato using a dextran sodium sulfate (DSS) murine model of colitis. Mice were randomly assigned to control (AIN-93G diet), P15 (15% purple-fleshed potato diet) and P25 (25% purple-fleshed potato diet) groups. Colitis was induced by 2% DSS administration in drinking water for six days. The results indicated that purple-fleshed potato supplementation suppressed the DSS-induced reduction in body weight and colon length as well as the increase in spleen and liver weights. P15 and P25 diets suppressed the elevation in the intestinal permeability, colonic MPO activity, mRNA expression and protein levels of pro-inflammatory interleukins IL-6 and IL-17, the relative abundance of specific pathogenic bacteria such as Enterobacteriaceae, Escherichia coli (E. coli) and pks⁺ E. coli, and the increased flagellin levels induced by DSS treatment. P25 alone suppressed the elevated systemic MPO levels in DSS-exposed mice, and elevated the relative abundance of Akkermansia muciniphila (A. muciniphila) as well as attenuated colonic mRNA expression level of IL-17 and the protein levels of IL-6 and IL-1β. Therefore, the purple-fleshed potato has the potential to aid in the amelioration of UC symptoms.     

5-氨基水杨酸纳米粒对TNBS诱导小鼠结肠炎的治疗作用

目的:评价超临界分散法制备的5-氨基水杨酸(5-ASA)结肠定位纳米粒对小鼠结肠炎的治疗作用。方法:将24只6周龄BABL/c小鼠随机分为空白对照组,结肠炎模型组,5-ASA治疗组,5-ASA纳米粒治疗组。三硝基苯磺酸(TNBS)造模后的第2-7 d分别给予0.9%氯化钠,5-ASA和5-ASA纳米粒灌胃,于第8 d处死所有小鼠,评估小鼠的疾病活动指数(DAI),组织病理形态以及结肠组织学损伤情况;检测结肠组织髓过氧化物酶(MPO)活性。结果:5-ASA和5-ASA纳米粒均能明显减轻结肠重量,缩小溃疡面积,降低MPO活性。超临界分散法制备的5-ASA纳米粒在DAI,减轻局部的炎症程度(MPO水平)方面,其疗效与5-ASA组(50 mg/Kg)相当。结论:超临界分散法制备的5-ASA纳米粒对TNBS诱导小鼠的结肠炎有明显的治疗作用。     

Effects of proanthocyanidins from grape seed on treatment of recurrent ulcerative colitis in rats

The aim of the present study was to investigate the therapeutic effect and mechanism of proanthocyanidins from grape seed (GSPE) in the treatment of recurrent ulcerative colitis (UC) in rats. To induce recurrent colitis, rats were instilled with 2,4,6-trinitrobenzenesulfonic acid (TNBS) (80?mg/kg) into the colon through the cannula in the first induced phase, and then the rats were instilled a second time with TNBS (30?mg/kg) into the colon on the sixteenth day after the first induction UC. Rats were intragastrically administered GSPE (200?mg/kg) per day for 7?days after twice-induced colitis by TNBS. Sulfasalazine at 500?mg/kg was used as a positive control drug. Rats were killed 7?days after GSPE treatment. The colonic injury and inflammation were assessed by macroscopic and macroscopic damage scores, colon weight/length ratio (mg/cm), and myeloperoxidase activity. Then, superoxide dismutase, glutathione peroxidase, inducible nitric oxide synthase (iNOS) activities, and the levels of malonyldialdehyde, glutathione, and nitric oxide in serum and colonic tissues were measured. Compared with the recurrent UC group, GSPE treatment facilitated recovery of pathologic changes in the colon after induction of recurrent colitis, as demonstrated by reduced colonic weight/length ratio and macroscopic and microscopic damage scores. The myeloperoxidase and iNOS activities with malonyldialdehyde and nitric oxide levels in serum and colon tissues of colitis rats were significantly decreased in the GSPE group compared with those in the recurrent UC group. In addition, GSPE treatment was associated with notably increased superoxide dismutase, glutathione peroxidase activities, and glutathione levels of colon tissues and serum of rats. GSPE exerted a protective effect on recurrent colitis in rats by modifying the inflammatory response, inhibiting inflammatory cell infiltration and antioxidation damage, promoting damaged tissue repair to improve colonic oxidative stress, and inhibiting colonic iNOS activity to reduce the production of nitric oxide.     

Dual role of endogenous nitric oxide in development of dextran sodium sulfate-induced colitis in rats.

The role of nitric oxide (NO) in the etiology of ulcerative colitis is controversial with reports of the improvement and aggravation of colonic lesions by inducible NO synthase (iNOS) inhibitors. In the present study, we compared the effect of the selective iNOS inhibitor aminoguanidine and the nonselective NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) on a dextran sulfate sodium (DSS)-induced model of colitis in rats. Experimental colitis was induced by a 3% DSS-solution added to drinking water for 7 days. Aminoguanidine (5 approximately 20 mg/kg) and L-NAME (10 mg/kg) were administered p.o. twice daily for the first 3 days, the last 3 days or all 6 days of DSS treatment. Body weight and severity of colitis (diarrhea, bloody feces) were observed over a period of 7 days. DSS treatment resulted in severe colonic lesions, accompanied by diarrhea, bloody feces, decrease of body weight and colon shortening. All of the parameters investigated improved significantly with aminoguanidine treatment at 20 mg/kg for 6 days or the last 3 days of DSS-treatment, but L-NAME did not significantly affect the colitis during these periods. When L-NAME or aminoguanidine was given in the first 3 days of DSS treatment, the colonic lesions were slightly aggravated by L-NAME but not affected by aminoguanidine. The expression of iNOS mRNA was observed from the 3(rd) day of DSS treatment. These results suggested that endogenous NO exerts a biphasic influence on DSS-induced colitis, depending on the NOS isoenzyme; a beneficial effect of NO derived from constitutive NOS and a detrimental effect of NO produced by iNOS in the development of colitis.     

Temporal and Spatial Analysis of Clinical and Molecular Parameters in Dextran Sodium Sulfate Induced Colitis

Background

Inflammatory bowel diseases (IBD), including mainly ulcerative colitis (UC) and Crohn''s disease (CD), are inflammatory disorders of the gastrointestinal tract caused by an interplay of genetic and environmental factors. Murine colitis model induced by Dextran Sulfate Sodium (DSS) is an animal model of IBD that is commonly used to address the pathogenesis of IBD as well as to test efficacy of therapies. In this study we systematically analyzed clinical parameters, histological changes, intestinal barrier properties and cytokine profile during the colitic and recovery phase.

Methods

C57BL/6 mice were administered with 3.5% of DSS in drinking water for various times. Clinical and histological features were determined using standard criteria. Myeloperoxidase (MPO) activity, transepithelial permeability and proinflammatory mediators were determined in whole colon or proximal and distal parts of colon.

Results

As expected after administration of DSS, mice manifest loss of body weight, shortening of colon length and bloody feces. Histological manifestations included shortening and loss of crypts, infiltration of lymphocytes and neutrophil, symptoms attenuated after DSS withdrawal. The MPO value, as inflammation indicator, also increases significantly at all periods of DSS treatment, and even after DSS withdrawal, it still held at very high levels. Trans-mucosal permeability increased during DSS treatment, but recovered to almost control level after DSS withdrawal. The production of proinflammatory mediators by colonic mucosa were enhanced during DSS treatment, and then recovered to pre-treated level after DSS withdrawal. Finally, enhanced expression of proinflammatory mediators also revealed a different profile feature in proximal and distal parts of the colon.

Conclusion

Experimental colitis induced by DSS is a good animal model to study the mechanisms underlying the pathogenesis and intervention against IBD, especially UC.     

Oral nitrite ameliorates dextran sulfate sodium-induced acute experimental colitis in mice

Inflammatory bowel diseases (IBDs) such as Crohn’s disease and ulcerative colitis are chronic inflammatory disorders of the intestinal tract with excessive production of cytokines, adhesion molecules, and reactive oxygen species. Although nitric oxide (NO) is reported to be involved in the onset and progression of IBDs, it remains controversial as to whether NO is toxic or protective in experimental colitis. We investigated the effects of oral nitrite as a NO donor on dextran sulfate sodium (DSS)-induced acute colitis in mice. Mice were fed DSS in their drinking water with or without nitrite for up to 7 days. The severity of colitis was assessed by disease activity index (DAI) observed over the experimental period, as well as by the other parameters, including colon lengths, hematocrit levels, and histological scores at day 7. DSS treatment induced severe colitis by day 7 with exacerbation in DAI and histological scores. We first observed a significant decrease in colonic nitrite levels and increase in colonic TNF-α expression at day 3 after DSS treatment, followed by increased colonic myeloperoxidase (MPO) activity and increased colonic expressions of both inducible NO synthase (iNOS) and heme oxygenase-1 (HO-1) at day 7. Oral nitrite supplementation to colitis mice reversed colonic nitrite levels and TNF-α expression to that of normal control mice at day 3, resulting in the reduction of MPO activity as well as iNOS and HO-1 expressions in colonic tissues with clinical and histological improvements at day 7. These results suggest that oral nitrite inhibits inflammatory process of DSS-induced experimental colitis by supplying nitrite-derived NO instead of impaired colonic NOS activity.     

Expression of HAb18G in non-small lung cancer and characterization of activation, migration, proliferation, and apoptosis in A549 cells following siRNA-induced downregulation of HAb18G

VSL#3 probiotics can be effective on induction and maintenance of the remission of clinical ulcerative colitis. However, the mechanisms are not fully understood. The aim of this study was to examine the effects of VSL#3 probiotics on dextran sulfate sodium (DSS)-induced colitis in rats. Acute colitis was induced by administration of DSS 3.5 % for 7 days in rats. Rats in two groups were treated with either 15 mg VSL#3 or placebo via gastric tube once daily after induction of colitis; rats in other two groups were treated with either the wortmannin (1 mg/kg) via intraperitoneal injection or the wortmannin + VSL#3 after induction of colitis. Anti-inflammatory activity was assessed by myeloperoxidase (MPO) activity. Expression of inflammatory related mediators (iNOS, COX-2, NF-κB, Akt, and p-Akt) and cytokines (TNF-α, IL-6, and IL-10) in colonic tissue were assessed. TNF-α, IL-6, and IL-10 serum levels were also measured. Our results demonstrated that VSL#3 and wortmannin have anti-inflammatory properties by the reduced disease activity index and MPO activity. In addition, administration of VSL#3 and wortmannin for 7 days resulted in a decrease of iNOS, COX-2, NF-κB, TNF-α, IL-6, and p-Akt and an increase of IL-10 expression in colonic tissue. At the same time, administration of VSL#3 and wortmannin resulted in a decrease of TNF-α and IL-6 and an increase of IL-10 serum levels. VSL#3 probiotics therapy exerts the anti-inflammatory activity in rat model of DSS-induced colitis by inhibiting PI3K/Akt and NF-κB pathway.     

白藜芦醇对小鼠溃疡性结肠炎的影响*

目的:研究白藜芦醇通过调节Wnt/β-catenin信号通路抗溃疡性结肠炎的作用机制。方法:①葡聚糖硫酸钠盐(DSS)诱发溃疡性结肠炎实验:28只C57BL/6小鼠随机分为4组(n=7):control组、 DSS组、DSS+白藜芦醇(DSS+Res)组和Res组。实验周期为3周,小鼠饮用DSS水诱导溃疡性结肠炎并给予白藜芦醇灌胃。实验期间每天称小鼠体重并观察小鼠活动和粪便情况。处理结束后,安乐死小鼠,取小鼠脾脏称重,取小鼠结肠测量长度。苏木精-伊红染色法(H&E)染色观察小鼠结肠组织病理改变;实时荧光定量PCR(qPCR)检测小鼠结肠组织miRNA-31的表达;Western Blot检测小鼠结肠组织β-catenin、Cyclin D1蛋白的表达。②离体实验:以10 mg/ml浓度的白藜芦醇处理HCT 116细胞,检测HCT 116细胞β-catenin、低密度脂蛋白受体相关蛋白6(LRP-6)、卷曲蛋白3(FZD3)、c-Myc蛋白的表达;HCT 116细胞转染miRNA-31 mimic和inhibitor,检测β-catenin蛋白的表达。结果:①DSS组小鼠实验期间体重下降明显,精神萎靡,活动减少,出现血便;处理结束后小鼠的结肠长度缩短,脾脏增大。而给予白藜芦醇后小鼠的以上情况得到改善。②白藜芦醇抑制了溃疡性结肠炎小鼠结肠组织miRNA-31的表达及β-catenin、Cyclin D1蛋白的表达。③白藜芦醇下调HCT 116细胞β-catenin、LRP-6、FZD3、c-Myc蛋白的表达。转染miRNA-31 inhibitor后,HCT 116细胞中β-catenin蛋白表达减少。结论:白藜芦醇能够抑制DSS诱导的小鼠溃疡性结肠炎,这种作用与下调Wnt信号通路有关,其对Wnt 信号的下调作用与miRNA-31有关。     

Investigating Intestinal Inflammation in DSS-induced Model of IBD

Inflammatory bowel disease (IBD) encompasses a range of intestinal pathologies, the most common of which are ulcerative colitis (UC) and Crohn''s Disease (CD). Both UC and CD, when present in the colon, generate a similar symptom profile which can include diarrhea, rectal bleeding, abdominal pain, and weight loss.¹ Although the pathogenesis of IBD remains unknown, it is described as a multifactorial disease that involves both genetic and environmental components.²There are numerous and variable animal models of colonic inflammation that resemble several features of IBD. Animal models of colitis range from those arising spontaneously in susceptible strains of certain species to those requiring administration of specific concentrations of colitis-inducing chemicals, such as dextran sulphate sodium (DSS). Chemical-induced models of gut inflammation are the most commonly used and best described models of IBD. Administration of DSS in drinking water produces acute or chronic colitis depending on the administration protocol.³ Animals given DSS exhibit weight loss and signs of loose stool or diarrhea, sometimes with evidence of rectal bleeding.^4,5 Here, we describe the methods by which colitis development and the resulting inflammatory response can be characterized following administration of DSS. These methods include histological analysis of hematoxylin/eosin stained colon sections, measurement of pro-inflammatory cytokines, and determination of myeloperoxidase (MPO) activity, which can be used as a surrogate marker of inflammation.⁶The extent of the inflammatory response in disease state can be assessed by the presence of clinical symptoms or by alteration in histology in mucosal tissue. Colonic histological damage is assessed by using a scoring system that considers loss of crypt architecture, inflammatory cell infiltration, muscle thickening, goblet cell depletion, and crypt abscess.⁷ Quantitatively, levels of pro-inflammatory cytokines with acute inflammatory properties, such as interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α,can be determined using conventional ELISA methods. In addition, MPO activity can be measured using a colorimetric assay and used as an index of inflammation.⁸In experimental colitis, disease severity is often correlated with an increase in MPO activity and higher levels of pro-inflammatory cytokines. Colitis severity and inflammation-associated damage can be assessed by examining stool consistency and bleeding, in addition to assessing the histopathological state of the intestine using hematoxylin/eosin stained colonic tissue sections. Colonic tissue fragments can be used to determine MPO activity and cytokine production. Taken together, these measures can be used to evaluate the intestinal inflammatory response in animal models of experimental colitis.     

Natural flavone tricin exerted anti-inflammatory activity in macrophage via NF-κB pathway and ameliorated acute colitis in mice

BackgroundUlcerative colitis is a subtype of inflammatory bowel disease, characterized by relapsing inflammation in the gastrointestinal tract with limited treatment options. Previous studies suggested that the natural compound tricin, a flavone isolated from rice bran, could suppress chemically-induced colitis in mice, while our recent study also demonstrated the anti-metastatic effect of tricin in colon tumor-bearing mice.Hypothesis/PurposeHere we further investigated the underlying mechanism of the inhibitory effects of tricin on lipopolysaccharides-activated macrophage RAW264.7 cells and explored the efficacy of tricin in acute colitis mouse model induced by 4.5% dextran sulfate sodium (DSS) for 7 days.MethodsTricin (75, 100, and 150 mg/kg) or the positive control drug sulfasalazine (200 mg/kg) were orally administered to mice for 7 days. Stool consistency scores, stool blood scores, and body weight were recorded daily. Disease activity index (DAI) was examined on day 7, and colon tissues were collected for biochemical analyses. The fecal microbiome of colitis mice after tricin treatment was characterized for the first time in this study using 16S rDNA amplicon sequencing.ResultsResults showed that tricin (50 µM) remarkably reduced nitric oxide production in lipopolysaccharides-activated RAW264.7 cells and the anti-inflammatory activity of tricin was shown to act through the NF-κB pathway. Besides, tricin treatment at 150 mg/kg significantly reversed colon length reduction, reduced myeloperoxidase activities and DAI scores, as well as restored the elevated myeloid-derived suppressive cells population in acute colitis mice. The influence from DSS on gut microbiota, such as the increased population of Proteobacteria phylum and Ruminococcaceae family, was shown to be relieved after tricin treatment.ConclusionOur present study firstly demonstrated that tricin ameliorated acute colitis by improving colonic inflammation and modulating gut microbiota profile, which supports the potential therapeutic use of tricin for colitis treatment.     

The anti-inflammatory effect of leptin on experimental colitis: involvement of endogenous glucocorticoids

The present study was designed to compare the effect of leptin on acute colonic inflammation with that of acute stress exposure, which acts via the hypothalamic-pituitary-adrenal (HPA) axis. Sprague-Dawley rats of both sexes were administered intrarectally with acetic acid. Either leptin (10 microg/kg; i.p.) or saline was injected immediately before and 6 h after the induction of colitis. A group of rats was exposed to water avoidance stress (WAS) for 30 min at the 6th h of colitis induction. RU-486 (2 mg/kg; i.p.), a glucocorticoid receptor antagonist, was injected intraperitoneally, at 12 and 1 h before the initial leptin injection, and at 1 h before the second leptin injection or exposure to WAS. Rats were decapitated at 24 h and the distal 8 cm of the colon were removed for macroscopic and microscopic scoring, determination of tissue wet weight index (WI) and tissue myeloperoxidase activity (MPO). Acetic acid-induced colitis significantly increased macroscopic and microscopic damage scores, WI and MPO, compared to control group. Exposure to acute WAS or treatment with leptin reduced the elevations in damage scores, WI and MPO induced by colitis, but no additive inhibitory effect was observed when WAS and leptin were applied together. RU-486 treatment reversed the inhibitory effects of leptin or WAS on colonic inflammation. Our results demonstrate that exogenous leptin mimics the effects of HPA axis activation on colitis-induced inflammatory process. The results also suggest that the anti-inflammatory effect of leptin involves a tissue neutrophil-dependent mechanism and is dependent on the release of glucocorticoids.     

Anti‐inflammatory effects of eriocitrin against the dextran sulfate sodium–induced experimental colitis in murine model

Inflammatory bowel disease (IBD) is a continual ailment condition which engrosses the entire alimentary canal. The IBD can be primarily distinguished into two forms, ulcerative colitis, and Crohn's disease. The major symptoms of IBD include pustules or abscesses, severe abdominal pain, diarrhea, fistula, and stenosis, which may directly affect the patient's quality of life. A variety of mediators can stimulate the circumstances of IBD, some examples include infections by microbes such as bacteria, perturbation of the immune system and the surrounding environment of the intestines. Severe colitis was stimulated in the experimental animals through administering 4% dextran sulfate sodium (DSS) which is mixed in water ad libitum for 6 days. Eriocitrin (30 mg/kg) was then administered to the experimental animals followed by the induction of severe colitis to evaluate the therapeutic prospective of eriocitrin against the colon inflammation stimulated by DSS. In this study, eriocitrin (30 mg/kg) demonstrated significant (P < .05) attenuation activity against the DSS‐stimulated severe colitis in experimental animals. Eriocitrin counteracted all of the clinical deleterious effects induced by DSS, such as body‐weight loss, colon shortening, histopathological injury, accretion of infiltrated inflammatory cells at the inflamed region and the secretion of inflammatory cytokines. The results clearly showed that eriocitrin effectively attenuated DSS‐induced acute colitis in experimental animals.     

Part II: beneficial effects of the peroxynitrite decomposition catalyst FP15 in murine models of arthritis and colitis

BACKGROUND: Peroxynitrite is a reactive oxidant species produced from nitric oxide and superoxide, which has been indirectly implicated in the pathogenesis of many inflammatory conditions including arthritis and colitis. Here, using a novel peroxynitrite decomposition catalyst, FP15, we directly investigate the role of peroxynitrite in the pathogenesis of arthritis and colitis in rodent models. METHODS: Arthritis was induced in mice by intradermal collagen injection; incidence and severity of arthritis was monitored using a macroscopic scoring system. At the end of the experiment paws were taken for determination of neutrophil infiltration (myeloperoxidase [MPO] activity), oxidative stress (malondialdehyde [MDA] level), and cytokine/chemokine levels. Colitis was induced in mice by 5% dextran sodium sulfate (DSS) in their drinking water. Colitis symptoms were assessed 10 days later, the parameters determined included body weight, rectal bleeding, colon length, colonic MPO and MDA levels, and colon histologic damage. RESULTS: Treatment with FP15 significantly reduced the inflammation and oxidative stress in arthritis and colitis. FP15 reduced both the incidence and severity of arthritis in mice and this was associated with reduced paw MPO and MDA levels. Similarly, in colitis, FP15 reduced colon damage, and this was associated with reduced colon neutrophil infiltration and oxidative stress. CONCLUSIONS:The protective effect of FP15 suggests that peroxynitrite plays a significant pathogenetic role in arthritis and colitis in the currently employed rodent models. Further work is needed to determine whether neutralization of peroxynitrite also represents a promising strategy to treat human inflammatory diseases such as arthritis and colitis.     

A protective effect of the synthetic coumarine derivative Cloricromene against DNB-colitis in the rat

Biologic therapies, namely antibodies against tumor necrosis factor-alpha (TNF- alpha) or its receptors, have been recently introduced for the treatment of patients with inflammatory bowel disease (IBD). In the present study the effects of cloricromene, an agent with known antithrombotic actions and with demonstrated anti-TNF- alpha activity were investigated in a rat model of experimental colitis induced with dinitrobenzenesulphonic acid (DNB)/ethanol. We investigated three experimental groups: (i) sham-colitis with vehicle-treatment (controls, n = 6), (ii) colitis with vehicle-treatment (saline, 0.1 ml s.c., daily) (DNB-V, n = 7), (iii) colitis with cloricromene-treatment (10 mg/kg/day s.c.; DNB-C, n = 8). After 7 days, the weight gain, colon wet weight, macroscopic damage score, coagulation parameters, colon mucosal myeloperoxidase activity (MPO), and tissue concentrations of TNF- alpha and of macrophage inhibitory peptide-2 (MIP-2) were assessed. The macroscopic damage scores, colon wet weights, and tissue MIP-2 levels were significantly increased in untreated and in cloricromene-treated rats compared with controls. Cloricromene treatment was associated with a minor body weight loss (p < 0.025) and significantly reduced tissue concentrations of MPO and TNF-alpha (p < 0.02, both). Blood coagulation parameters were not affected by treatment. In the DNB-model treatment with cloricromene effectively reduces tissue levels of TNF- alpha and of myeloperoxidase, whereas MIP-2 concentrations were not influenced. Blood coagulation parameters remained unchanged indicating safety of treatment. Since biological therapies frequently fail to improve disease course of IBD, other therapies with similar targets should be further investigated.     

Preventive effects of Goji berry on dextran-sulfate-sodium-induced colitis in mice

Goji berry (Lycium barbarum) exerts immune modulation and suppresses inflammation in vitro and in vivo. We hypothesized that Goji berry had beneficial effects on dextran sulfate sodium (DSS)-induced colitis in C57BL/6 mice through suppressing inflammation. Six-week-old male C57BL/6 mice were supplemented with a standard AIN-93G diet with or without 1% (w/w) Goji berry for 4 weeks. Then, colitis was induced by supplementing 3% DSS in drinking water for 7 days, followed by 7 days of remission period to mimic ulcerative colitis symptoms. Goji berry supplementation ameliorated DSS-induced body weight loss, diminished diarrhea and gross bleeding, and resulted in a significantly decreased disease activity index, as well as DSS-associated colon shortening. Moreover, 30% mortality rate caused by DSS-induced colitis was avoided because of Goji berry supplementation. Histologically, Goji berry ameliorated colonic edema, mucosal damage and neutrophil infiltration into colonic intestinal tissue in response to DSS challenge, which was associated with decreased expression of chemokine (C-X-C motif) ligand 1 and monocyte chemoattractant protein-1, as well as inflammatory mediators interleukin-6 and cyclooxygenase-2. In conclusion, Goji supplementation confers protective effects against DSS­induced colitis, which is associated with decreased neutrophil infiltration and suppressed inflammation. Thus, dietary Goji is likely beneficial to inflammatory bowel disease patients as a complementary therapeutic strategy.