Platycodon grandiflorus polysaccharide (PGP) is one of the main components of P. grandiflorus, but the mechanism of its anti-inflammatory effect has not been fully elucidated. The aim of this study was to evaluate the therapeutic effect of PGP on mice with dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) and explore the underlying mechanisms. The results showed that PGP treatment inhibited the weight loss of DSS-induced UC mice, increased colon length, and reduced DAI, spleen index, and pathological damage within the colon. PGP also reduced the levels of pro-inflammatory cytokines and inhibited the enhancement of oxidative stress and MPO activity. Meanwhile, PGP restored the levels of Th1, Th2, Th17, and Treg cell-related cytokines and transcription factors in the colon to regulate colonic immunity. Further studies revealed that PGP regulated the balance of colonic immune cells through mesenteric lymphatic circulation. Taken together, PGP exerts anti-inflammatory and anti-oxidant effect and regulates colonic immunity to attenuate DSS-induced UC through mesenteric lymphatic circulation.
Animals ; Mice ; Colitis, Ulcerative/drug therapy* ; Platycodon ; Colon/pathology* ; Cytokines ; Anti-Inflammatory Agents/therapeutic use* ; Polysaccharides/therapeutic use* ; Dextran Sulfate ; Disease Models, Animal ; Colitis/chemically induced* ; Mice, Inbred C57BL

This study deciphered the mechanism of Shenling Baizhu Powder in treatment of mouse model of ulcerative colitis(UC) via NOD-like receptor thermoprotein domain 3(NLRP3) signaling pathway. After three days of adaptive feeding, 70 SPF-grade BALB/c mice were randomized into 7 groups: normal group, model group(dextran sodium sulfate, DSS), mesalazine group(DSS + 5-aminosalicylic acid, 5-ASA), NLRP3 inhibitor group(DSS + MCC950), and high-, medium-, and low-dose Shenling Baizhu Powder groups(DSS + high-, medium-, and low-dose Shenling Baizhu Powder), with 10 mice per group. The normal group had free access to double distilled water, and the remaining groups had free access to DSS-containing water to establish the acute UC model. Intragastric administration was started at the same time as modeling for one week. During the experiment, the general mental state and disease activity of each group of mice were recorded and scored. After the experiment, colon and serum samples were collected. The pathological changes in colon tissue were observed through hematoxylin-eosin(HE) staining. Enzyme-linked immunosorbent assay(ELISA) was employed to determine the levels of interleukin-18(IL-18) and myeloperoxidase(MPO) in colon tissue and interleukin-1β(IL-1β) in serum. Immunofluorescence(IF) and immunohistochemistry(IHC) methods were employed to examine the expression of NLRP3 and IL-18 in colon tissue. Western blot was employed to measure the protein levels of NLRP3, apoptosis-associated speck-like protein(ASC), cystein-aspartate protease 1(caspase-1), and downstream inflammatory cytokines in colon tissue. Compared with the normal group, the modeling of UC increased the disease activity index(DAI), colon pathological injury score, IL-1β level in serum, and IL-18 and MPO levels in colon tissue(P<0.05, P<0.01). Furthermore, the modeling caused obvious pathological changes and up-regulated the expression of NLRP3, caspase-1, ASC, pro-IL-1β, cleaved-IL-1β, pro-IL-18, and cleaved-IL-18 in the colon(P<0.01). Compared with the model group, the administration of corresponding drugs decreased the DAI, pathological injury score, IL-1β level in serum, and IL-18 and MPO levels in colon tissue, and down-regulated the protein levels of NLRP3, caspase-1, ASC, pro-IL-1β, cleaved-IL-1β, pro-IL-18, and cleaved-IL-18 in the colon(P<0.05, P<0.01). According to the results of previous study and this study, we concluded that Shenling Baizhu Powder can alleviate the inflammatory response and intestinal damage of DSS-induced UC by regulating the expression of the proteins and inflammatory cytokines associated with NLRP3 signaling pathway.
Mice ; Animals ; Colitis, Ulcerative/drug therapy* ; Dextran Sulfate/adverse effects* ; NLR Family, Pyrin Domain-Containing 3 Protein/genetics* ; Interleukin-18/genetics* ; Powders ; Colon/metabolism* ; Caspase 1 ; Mesalamine/adverse effects* ; Mice, Inbred BALB C ; Disease Models, Animal ; Cytokines/metabolism* ; Water ; Colitis/pathology*

Ulcerative colitis (UC), a chronic inflammatory disease affecting the colon, has a rising incidence worldwide. The known pathogenesis is multifactorial and involves genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Nowadays, the drugs for UC include 5-aminosalicylic acid, steroids, and immunosuppressants. Long-term use of these drugs, however, may cause several side effects, such as hepatic and renal toxicity, drug resistance and allergic reactions. Moreover, the use of traditional Chinese medicine (TCM) in the treatment of UC shows significantly positive effects, low recurrence rate, few side effects and other obvious advantages. This paper summarizes several kinds of active compounds used in the experimental research of anti-UC effects extracted from TCM, mainly including flavonoids, acids, terpenoids, phenols, alkaloids, quinones, and bile acids from some animal medicines. It is found that the anti-UC activities are mainly focused on targeting inflammation or oxidative stress, which is associated with increasing the levels of anti-inflammatory cytokine (IL-4, IL-10, SOD), suppressing the levels of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-23, NF-κB, NO), reducing the activity of MPO, MDA, IFN-γ, and iNOS. This review may offer valuable reference for UC-related studies on the compounds from natural medicines.
Animals ; Colitis, Ulcerative ; drug therapy ; pathology ; Cytokines ; metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal ; chemistry ; pharmacology ; therapeutic use ; Humans ; Inflammation ; drug therapy ; metabolism ; Medicine, Chinese Traditional ; Oxidative Stress ; drug effects ; Phytochemicals ; pharmacology

BACKGROUND/AIMS: To evaluate the efficacy and safety of adalimumab (ADA) in moderately to severely active ulcerative colitis (UC) patients who are unresponsive to traditional therapy. METHODS: Electronic databases, including the PubMed, Embase, and Cochrane databases, were searched to April 20, 2014. UC-related randomized controlled trials (RCTs) that compared ADA with placebo were eligible. Review Manager 5.1 was used for data analysis. RESULTS: This meta-analysis included three RCTs. ADA was considerably more effective compared with a placebo, and it increased the ratio of patients with clinical remission, clinical responses, mucosal healing and inflammatory bowel disease questionnaire responses in the induction and maintenance phases (p<0.05), as well as patients with steroid-free remission (p<0.05) during the maintenance phase. Clinical remission was achieved in a greater number of UC cases in the ADA 160/80/40 mg groups (0/2/4 week, every other week) compared with the placebo group at week 8 (p=0.006) and week 52 (p=0.0002), whereas the week 8 clinical remission rate was equivalent between the ADA 80/40 mg groups and the placebo group. Among the patients who received immunomodulators (IMM) at baseline, ADA was superior to the placebo in terms of inducing clinical remission (p=0.01). Between-group differences were not observed in terms of serious adverse events (p=0.61). CONCLUSIONS: ADA, particularly at doses of 160/80/40 mg (0/2/4 week, every other week), is effective and safe in patients with moderate-to-severe UC who are unresponsive to traditional treatment. Concomitant IMM therapy may improve the short-term therapeutic efficacy of ADA.
Adalimumab/*therapeutic use ; Adult ; Anti-Inflammatory Agents/*therapeutic use ; Colitis, Ulcerative/*drug therapy/pathology ; Female ; Humans ; Male ; Middle Aged ; Randomized Controlled Trials as Topic ; Remission Induction/methods ; Severity of Illness Index

Inflammatory bowel disease (IBD) is a chronic progressive idiopathic inflammatory disorder that involves the digestive tract from the mouth to the anus. Over the past decades, many therapeutic strategies have been developed to manage IBD, but therapeutic strategies based only on relief of clinical symptoms have not changed the natural history of this disease entity. This underlines the importance of understanding the natural history of IBD itself. When we look at the natural history of Crohn's disease (CD), it first begins with inflammation of the intestinal mucosa and this inflammatory reaction proceeds to stenosing or penetrating reaction if not adequately controlled. However, it takes a considerable amount of time before mucosal inflammation proceeds to stenosis of the intestinal lumen or penetration into the adjacent bowel. Therefore, it can be expected that if proper care is given during that period, progression of CD to such a complicated disease could be prevented. Even though the concept of mucosal healing was introduced in the early 1990s, no correlation could be observed between healing of mucosal lesions and relief of clinical symptoms. However, the introduction of biologic agents targeting tumor necrosis factor has changed the way to treat IBD that is refractory to standard medications and has allowed us to aim for a new therapeutic goal, 'deep remission'. Further advances in biologic agents have provided highly effective treatments for IBD, making deep remission a realistic goal. Whether IBD patients may benefit by experiencing a 'deep' remission beyond the control of clinical symptoms need to be evaluated in further investigation. Nevertheless, it can be anticipated that attaining deep remission might ultimately have an impact on important outcomes such as the need for surgery and the quality of life.
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Antibodies, Monoclonal/therapeutic use ; Colitis, Ulcerative/drug therapy/metabolism/pathology ; Crohn Disease/drug therapy/metabolism/pathology ; Humans ; Inflammatory Bowel Diseases/drug therapy/metabolism/*pathology ; Intestinal Mucosa/metabolism/pathology ; Mesalamine/therapeutic use ; Tumor Necrosis Factor-alpha/immunology/metabolism

BACKGROUND/AIMS: Infliximab was approved for the treatment of ulcerative colitis (UC) in 2006 and has recently been used as rescue therapy in steroid-refractory UC. The aim of this study was to investigate the differences of medication use and prognosis in UC patients according to the periods of diagnosis. METHODS: From 1987 to 2012, a total of 1,422 patients with UC were retrospectively reviewed in 12 hospitals. The study population was divided into two groups according to the periods of diagnosis as follows; group A: 1987-2005, group B: 2006-2012. Analyzed variables were compared by using chi-square test and logistic regression analysis. RESULTS: Mean age of the subjects was 42.2 years, and the mean follow-up period was 4.7 years. In univariate analysis, the use of infliximab in group B was significantly higher than group A (4.5% vs. 7.6%, p=0.016), and UC-related hospitalization (45.8% vs. 40.1%, p=0.031) and UC-related surgery (6.4% vs. 3.5%, p=0.010) in group B was significantly lower than that of group A. The use of oral steroid in surgery group was significantly higher than non-surgery group in multivariate analysis (OR 1.85, 95% CI 1.03-3.30, p=0.039). CONCLUSIONS: Infliximab might play an important role for the treatment of steroid-refractory UC. Well-designed prospective trials based on the efficacy and safety of infliximab are required in the future.
Adult ; Anti-Inflammatory Agents, Non-Steroidal/therapeutic use ; Colitis, Ulcerative/*diagnosis/drug therapy/pathology ; Female ; Follow-Up Studies ; Hospitalization ; Humans ; Infliximab/therapeutic use ; Logistic Models ; Male ; Mesalamine/therapeutic use ; Middle Aged ; Odds Ratio ; Prognosis ; Retrospective Studies ; Time Factors

5-aminosalicylic acid (5-ASA) is drug of choice for the treatment of ulcerative colitis (UC). In this study, the efficacy of topical versus oral 5-ASA for the treatment of UC was examined as well as the action mechanism of this medication. A flexible tube was inserted into the rat cecum to establish a topical administration model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced UC. A total of 60 rats were divided into sham operation group (receiving an enema of 0.9% saline solution instead of the TNBS solution via the tube), model group, topical 5-ASA group, oral Etiasa group (a release agent of mesalazine used as positive control) and oral 5-ASA group (n=12 each). Different treatments were administered 1 day after UC induction. The normal saline (2 mL) was instilled twice a day through the tube in the sham operation group and model group. 5-ASA was given via the tube in the topical 5-ASA group (7.5 g/L, twice per day, 100 mg/kg), and rats in the oral Etiasa group and oral 5-ASA group intragastrically received Etiasa (7.5 g/L, twice per day, 100 mg/kg) and 5-ASA (7.5 g/L, twice per day, 100 mg/kg), respectively. The body weight was recorded every day. After 7 days of treatment, blood samples were drawn from the heart to harvest the sera. Colonic tissues were separated and prepared for pathological and related molecular biological examinations. The concentrations of 5-ASA were detected at different time points in the colonic tissues, feces and sera in different groups by using the high pressure liquid chromatography (HPLC). The results showed that the symptoms of acute UC, including bloody diarrhea and weight loss, were significantly improved in topical 5-ASA-treated rats. The colonic mucosal damage, both macroscopical and histological, was significantly relieved and the myeloperoxidase activity was markedly decreased in rats topically treated with 5-ASA compared with those treated with oral 5-ASA or Etiasa. The mRNA and protein expression of IL-1β, IL-6, and TNF-α was down-regulated in the colonic tissue of rats topically treated with 5-ASA, significantly lower than those from rats treated with oral 5-ASA or Etiasa. The concentrations of 5-ASA in the colonic tissue were significantly higher in the topical 5-ASA group than in the oral 5-ASA and oral Etiasa groups. It was concluded that the topical administration of 5-ASA can effectively increase the concentration of 5-ASA in the colonic tissue, decrease the expression of proinflammatory cytokines, alleviate the colonic pathological damage and improve the symptoms of TNBS-induced acute UC in rats.
Administration, Oral ; Administration, Topical ; Animals ; Anti-Inflammatory Agents, Non-Steroidal ; administration & dosage ; pharmacology ; Colitis, Ulcerative ; chemically induced ; drug therapy ; Colon ; drug effects ; metabolism ; pathology ; Down-Regulation ; drug effects ; Drug Administration Schedule ; Gene Expression ; drug effects ; Immunohistochemistry ; Interleukin-1beta ; genetics ; metabolism ; Interleukin-6 ; genetics ; metabolism ; Intestinal Mucosa ; drug effects ; metabolism ; pathology ; Male ; Mesalamine ; administration & dosage ; pharmacology ; Peroxidase ; metabolism ; Rats ; Rats, Wistar ; Reverse Transcriptase Polymerase Chain Reaction ; Time Factors ; Treatment Outcome ; Trinitrobenzenesulfonic Acid ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

In this study, we examined the therapeutic effects of an immune-stimulating peptide, WKYMVm, in ulcerative colitis. The administration of WKYMVm to dextran sodium sulfate (DSS)-treated mice reversed decreases in body weight, bleeding score and stool score in addition to reversing DSS-induced mucosa destruction and shortened colon. The WKYMVm-induced therapeutic effect against ulcerative colitis was strongly inhibited by a formyl peptide receptor (FPR) 2 antagonist, WRWWWW, indicating the crucial role of FPR2 in this effect. Mechanistically, WKYMVm effectively decreases intestinal permeability by stimulating colon epithelial cell proliferation. WKYMVm also strongly decreases interleukin-23 and transforming growth factor-beta production in the colon of DSS-treated mice. We suggest that the potent immune-modulating peptide WKYMVm and its receptor FPR2 may be useful in the development of efficient therapeutic agents against chronic intestinal inflammatory diseases.
Adjuvants, Immunologic/pharmacology/*therapeutic use ; Animals ; Caco-2 Cells ; Cell Proliferation ; Colitis, Ulcerative/*drug therapy/metabolism ; Colon/pathology ; Humans ; Interleukin-23/genetics/metabolism ; Intestinal Mucosa/drug effects/metabolism/pathology ; Mice ; Mice, Inbred C57BL ; Oligopeptides/pharmacology/*therapeutic use ; Permeability ; Receptors, Formyl Peptide/antagonists & inhibitors ; Transforming Growth Factor beta/genetics/metabolism

OBJECTIVETo explore the clinical efficacy of ulcerative colitis with spleen and kidney yang deficiency by kuijiening plaster and the impacts on IFN-gamma and IL-4 contents, as well as make the comparison with oral medication of sulfasalzine (SASP).

METHODSSixty patients of ulcerative colitis with spleen and kidney yang deficiency were randomized into a Kuijiening plaster group, a SASP group and a combined therapy group, 20 cases in each one. In the Kuijiening plaster group, Kuijiening plaster and oral administration of placebo SASP were applied. The plaster was used at Shangjuxu (ST 37), Tianshu (ST 25), Zusanli (ST 36), Mingmen (GV 4) and Guanyuan (CV 4). In the SASP group, was applied Kuijiening plaster placebo at the points and SASP oral administration was adopted. In the combined therapy group, Kuijiening plaster and SASP oral administration were given. The duration of treatment was 60 days. The follow-up visit was 2 months after treatment. The comprehensive efficacy, the efficacy on TCM syndrome and the changes in serum IFN-gamma and IL-4 before and after treatment were compared among the three groups.

RESULTSThe efficacy on TCM syndrome in the Kuijiening plaster was similar to the SASP group [85.0% (17/20) vs 75.0% (15/20), P > 0.05]. The efficacy on TCM syndrome in the Kuijiening plaster group was superior to the western medicine group [80.0% (16/20) vs 60.0% (12/20), P < 0.05]. The total effective rate of the comprehensive efficacy in the combined therapy group was 95.0% (19/20) and that of TCM syndrome efficacy was 90.0% (18/20), which were all superior to the other two groups (all P < 0.05). The differences in serum IFN-gamma and IL-4 were statistically significant before and after treatment in all of the three groups (all P < 0.05). The treatments in the three groups reduced serum IFN-gamma content and increased serum IL-4 content. The results in the Kuijiening plaster group were superior to the SASP group (P < 0.05) and the results in the combined therapy group were superior to the other two groups (all P < 0.05).

CONCLUSIONKuijiening plaster is effective in the treatment of ulcerative colitis of spleen and kidney yang deficiency, which is not inferior to that of SASP. The efficacy of kuijiening plaster on relieving TCM syndrome and improving body immunity is much superior to SASP. The effect is much better with SASP combined in the treatment.

Administration, Oral ; Adolescent ; Adult ; Aged ; Colitis, Ulcerative ; blood ; drug therapy ; pathology ; physiopathology ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Humans ; Interferon-gamma ; blood ; Interleukin-4 ; blood ; Kidney ; drug effects ; physiopathology ; Male ; Middle Aged ; Spleen ; drug effects ; physiopathology ; Yang Deficiency ; blood ; drug therapy ; pathology ; physiopathology ; Young Adult

OBJECTIVETo investigate the β2-adrenoceptor (β2AR)-β-arrestin2-nuclear factor-κB (NF-κB) signal transduction pathway and the intervention effects of oxymatrine in a rat model of ulcerative colitis.

METHODSForty SD rats were randomly divided into four groups, which included the normal control group, the model group, the mesalazine group and the oxymatrine treatment group, with 10 rats per group. Experimental colitis induced with trinitrobenzene sulfonic acid (TNBS) was established in each group except the normal control group. The rats in the oxymatrine treatment group were treated with intramuscular injection of oxymatrine 63 mg/(kg·d) for 15 days and the rats in the mesalazine group were treated with mesalazine solution 0.5 g/(kg·d) by gastric lavage for 15 days. The rats in the normal control group and model group were treated with 3 mL water by gastric lavage for 15 days. Diarrhea and bloody stool were carefully observed. Histological changes in colonic tissue were examined on day 7 in 2 rats per group that were randomly selected. The expression of β2AR, β-arrestin2 and NF-κB p65 in colon tissue and spleen lymphocytes were detected with immunohistochemistry and Western immunoblotting techniques on day 16 after fasting for 24 h. Six rats died of lavage with 2 each in the normal control, the model group and the mesalazine group; and were not included in the analysis.

RESULTSThe rats in the model group suffered from looser stool and bloody purulent stool after modeling. But in the oxymatrine and mesalazine groups, looser stool and bloody purulent stool reduced after treatment. And the colonic wall in the model group was thickened and the colon length shortened. The colon mucosa was congested in multiple areas with edema, erosion, superficial or linear ulcer and scar formation, while the intestinal mucosa injury reduced in the mesalazine and oxymatrine groups (P<0.01). In colonic mucosa and in spleen lymphocytes, compared with the normal control group, the expression of NF-κBp65 were significantly increased (P<0.01) in the model group while the expressions of β 2AR and β-arrestin2 were significantly decreased (P<0.01). Compared with the model group, the expression of NF-κ Bp65 was significantly decreased in the mesalazine group (P<0.01) and oxymatrine treatment group (P<0.01) while the expressions of β2AR and β-arrestin2 were significantly increased (P<0.01). There were no statistically significant differences in the expression of β2AR, β-arrestin2 and NF-κBp65 between the mesalazine group and oxymatrine group (P>0.05).

CONCLUSIONSThe β2AR-β-arrestin2-NF-κB signal transduction pathway participated in the pathologic course of ulcerative colitis. Oxymatrine attenuated ulcerative colitis through regulating the β2AR-β-arrestin2-NF-κB signal transduction pathway.

Alkaloids ; pharmacology ; Animals ; Arrestins ; metabolism ; Colitis, Ulcerative ; drug therapy ; metabolism ; Colon ; drug effects ; pathology ; Intestinal Mucosa ; drug effects ; metabolism ; pathology ; Lymphocytes ; metabolism ; pathology ; Male ; NF-kappa B ; metabolism ; Quinolizines ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Adrenergic, beta-2 ; metabolism ; Signal Transduction ; drug effects ; Spleen ; pathology ; beta-Arrestins