Saffron Pre-Treatment Promotes Reduction in Tissue Inflammatory Profiles and Alters Microbiome Composition in Experimental Colitis Mice

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract with an incompletely understood pathogenesis. Long-standing colitis is associated with increased risk of colon cancer. Despite the availability of various anti-inflammatory and immunomodulatory drugs, many patients fail to respond to pharmacologic therapy and some experience drug-induced adverse events. Dietary supplements, particularly saffron (Crocus sativus), have recently gained an appreciable attention in alleviating some symptoms of digestive diseases. In our study, we investigated whether saffron may have a prophylactic effect in a murine colitis model. Saffron pre-treatment improved the gross and histopathological characteristics of the colonic mucosa in murine experimental colitis. Treatment with saffron showed a significant amelioration of colitis when compared to the vehicle-treated mice group. Saffron treatment significantly decreased secretion of serotonin and pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, in the colon tissues by suppressing the nuclear translocation of NF-κB. The gut microbiome analysis revealed distinct clusters in the saffron-treated and untreated mice in dextran sulfate sodium (DSS)-induced colitis by visualization of the Bray–Curtis diversity by principal coordinates analysis (PCoA). Furthermore, we observed that, at the operational taxonomic unit (OTU) level, Cyanobacteria were depleted, while short-chain fatty acids (SCFAs), such as isobutyric acid, acetic acid, and propionic acid, were increased in saffron-treated mice. Our data suggest that pre-treatment with saffron inhibits DSS-induced pro-inflammatory cytokine secretion, modulates gut microbiota composition, prevents the depletion of SCFAs, and reduces the susceptibility to colitis.     

Alleviation of Ulcerative Colitis Potentially through th1/th2 Cytokine Balance by a Mixture of Rg3-enriched Korean Red Ginseng Extract and Persicaria tinctoria

Ginseng is a vastly used herbal supplement in Southeast Asian countries. Red ginseng extract enriched with Rg3 (Rg3-RGE) is a formula that has been extensively studied owing to its various biological properties. Persicaria tinctoria (PT), belonging to the Polygonaceae family, has also been reported for its anti-inflammatory properties. Ulcerative colitis (UC) is inflammation of the large intestine, particularly in the colon. This disease is increasingly common and has high probability of relapse. We investigated, separately and in combination, the effects of Rg3-RGE and PT using murine exemplary of UC induced by DSS (Dextran Sulfate Sodium). For in vitro and in vivo experiments, nitric oxide assay, qRT-Polymerase Chain Reaction (PCR), Western blot, ulcerative colitis introduced by DSS, Enzyme Linked Immunosorbent Assay (ELISA), and flow cytometry analysis were performed. The results obtained demonstrate that treatment with Rg3-RGE + PT showed synergism to suppress inflammation (in vitro) in RAW 264.7 cells via mitogen-activated protein kinase and nuclear factor κB pathways. Moreover, in C57BL/6 mice, this mixture exhibits strong anti-inflammatory effects in restoring colon length, histopathological damage, pro-inflammatory mediators, and cytokines amount, and decreasing levels of NLRP3 inflammasome (in vivo). Our results recommend that this mixture can be used for the prevention of UC as a prophylactic/therapeutic supplement.     

The immune-stimulating peptide WKYMVm has therapeutic effects against ulcerative colitis

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-β 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.     

Sensitivity and significance of disease outcome measures in inflammatory bowel disease

In inflammatory bowel disease (IBD), proxy measures of clinical outcome are often collected into summary indices of qualitative self-rated disease markers, clinical observations, and quantitative biochemical analyses. In Crohn's disease (CD), a frequently used index is the Crohn's disease activity index (DCAI). This index consists of six qualitative variables and two quantitative variables. The aim of this presentation is to illustrate the use of this index to calculate its range, to estimate errors in the index, its sensitivity, and the number of significant steps in the index. The measure of sensitivity of the summary index was analyzed for the signal-to-noise ratio (SNR), the reference change value (RCV) and the confidence interval (CI). If identical errors were assumed in patient self-rated health and clinically judged disease manifestations, such as tumours and fistulas, the majority of the variance of the index was caused by the self-rated experience of health, the number of days over which the individual variable was rated, and the prognostic multiplier of each variable.The range of the index has no upper limit, but can be estimated to 403 units, of which patient self-rating of well-being account for up to one-third of the summary index maximal score range. The median signal noise measure of index sensitivity was 18 SDs. The two disease classification limits of 150 units for moderate disease and 450 for severe disease on average cover an interval of limit ±41.5 units vs. ±60.5 units. In judgments on change in clinical outcome the RCV interval of steps of 121 units are valid. Conclusion: Both variance and range of the CDAI summary score are primarily decided by the self-rated experience of well-being. Variables on disease signs have a minor impact on the index. Rating of the two important outcome parameters: Self-experienced health and medical outcome would favourably be given in two individual scores.Presented at the 10th Conference Quality in the Spotlight, March 2005, Antwerp, Belgium.     

Establishment of fingerprint of Gegen Qinlian decoction and its formula compatibility groups using UHPLC–MS/MS and its study to spectrum–effect relationship

Based on the establishment of analytical method of ultra-high performance liquid chromatography-tandem mass spectrometry fingerprint and obtaining pharmacodynamic information of the effects on IL-4, IL-10, TNF-α, and IFN-γ of serum and interstitial fluid of the damp-type ulcerative colitis mice of Gegen Qinlian decoction and its formula compatibility groups, the spectrum–effect relationship study was performed by using the method of principal component analysis. The study built the common pattern of UHPLC–MS/MS fingerprint of Gegen Qinlian decoction and formula compatibility groups and identified eight components which were rooted in monarch and subject drugs and represented the whole pharmacodynamic information of Gegen Qinlian decoction. The research on formula compatibility and spectrum–effect relationship can provide scientific basis for revealing pharmacodynamic material basis and compatibility regularity of Gegen Qinlian decoction.     

Agent-Based Network Modeling Study of Immune Responses in Progression of Ulcerative Colitis

Ulcerative colitis, an inflammatory bowel disease, is a chronic inflammatory disorder that results in ulcers of the colon and rectum without known etiology.Ulcerative colitis causes a huge public health care burden particularly in developed countries.Many studies suggest that ulcerative colitis results from an abnormal immune response against components of commensal microbiota in genetically susceptible individuals.However, understanding of the disease mechanisms at cellular and molecular levels remains largely elusive.In this paper, a network model is developed based on our previous study and computer simulations are performed using an agent-based network modeling to elucidate the dynamics of immune response in ulcerative colitis progression.Our modeling study identifies several important positive feedback loops as a driving force for ulcerative colitis initiation and progression.The results demonstrate that although immune response in ulcerative colitis patients is dominated by anti-inflammatory/regulatory cells such as alternatively activated macrophages and type Ⅱ natural killer T cells, proinflammatory cells including classically activated macrophages, T helper 1 and T helper 17 cells, and their secreted cytokines tumor necrosis factor-α, interleukin-12, interleukin-23, interleukin-17 and interferon-γ remain at certain levels (lower than those in Crohn's disease, another inflammatory bowel disease).Long-term exposure to these proinflammatory components, causes mucosal tissue damage persistently, leading to ulcerative colitis.Our simulation results are qualitatively in agreement with clinical and laboratory measurements, offering novel insight into the disease mechanisms.     

Rectal administration of nanosystems: from drug delivery to diagnostics

The rectal administration of drugs has been an enduring medical practice for either the management of local or systemic conditions. Although mostly regarded as an alternative to other delivery routes, the colorectal mucosa offers an effective pathway for enhanced systemic bioavailability of many active molecules. The fairly stable physicochemical and enzymatic environment of the mucosa and the possibility of partially avoiding the hepatic first-pass effect are some of the potential advantages of rectal drug delivery. At the same time, higher drug levels of drugs can be achieved at colorectal fluids and tissues, which can aid management of local conditions. However, problems with patient acceptability as well as poor and erratic drug absorption may impair efficient use of the rectal drug delivery route. The valuable features of nanotechnology-based systems for mucosal use are well recognized, and their potential as carriers for drug delivery has already been proven for different medical applications/delivery routes. Although still limited, the development of rectal nanomedicines with therapeutic, diagnostic, and prophylactic purposes is steadily emerging and may circumvent some of the problems associated with the more standard delivery approaches. This review discusses the rationale behind the use of nanotechnology-based strategies for rectal drug delivery and provides a critical overview on the various types of nanosystems proposed so far.     

微量元素锌和铁与溃疡性结肠炎关系的探讨

测定了溃疡性结肠炎患者血清、头发中锌和铁含量，结果表明，其含量均明显低于正常对照组，并有显著性差异，提示锌和铁的测定可作为误差溃疡性结肠炎的参考指标之一，还提出适当补充锌与铁制剂是治疗溃疡性结肠炎的辅助手段。     

治疗溃疡性结肠炎中药制剂金属元素含量分析

采用火焰原子吸收法检测了两种溃疡性结肠炎中药制剂中Ｍｎ、Ｃｒ、Ｋ、Ｎａ、Ｃａ、Ｍｇ等金属元素的含量。结果显示,肠炎宁灌肠散中Ｍｎ、Ｃｒ、Ｎａ、Ｍｇ元素含量均明显高于肠炎宁口服胶囊中含量,而Ｋ元素则明显低于口服胶囊中含量。结果提示,中药肠炎宁疗效与金属元素含量有一定关系。     

The Regulatory Effects of Licochalcone A on the Intestinal Epithelium and Gut Microbiota in Murine Colitis

The gut epithelium is a mechanical barrier that protects the host from the luminal microenvironment and interacts with the gut microflora, which influences the development and progression of ulcerative colitis (UC). Licochalcone A (LA) exerts anti-inflammatory effects against UC; however, whether it also regulates both the gut barrier and microbiota during colitis is unknown. The current study was conducted to reveal the regulatory effects of LA on the intestinal epithelium and gut microflora in C57BL/6 mice subjected to dextran sodium sulfate (DSS). Sulfasalazine (SASP) was used as the positive control. Results of clinical symptoms evaluation, hematoxylin, and eosin (H&E) staining, and enzyme-linked immunosorbent (ELISA) assays showed that LA significantly inhibited DSS-induced weight loss, disease activity index (DAI) increase, histological damage, and gut inflammation. Additionally, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and immunohistochemical (IHC) analysis showed that LA maintained the integrity of the intestinal barrier by suppressing cell apoptosis and preserving the expression of tight junction (TJ) proteins. Notably, the optimal dose of LA for gut barrier preservation was low, while that for anti-inflammatory effects was high, indicating that LA might preserve gut barrier integrity via direct effects on the epithelial cells (ECs) and TJ proteins. Furthermore, 16S rRNA analysis suggested that the regulatory effect of LA on the gut microbiota differed distinctly according to dose. Correlation analysis indicated that a low dose of LA significantly modulated the intestinal barrier-associated bacteria as compared with a moderate or high dose of LA. Western blot (WB) analysis indicated that LA exhibited anti-UC activity partly by blocking the mitogen-activated protein kinase (MAPK) pathway. Our results further elucidate the pharmacological activity of LA against UC and will provide valuable information for future studies regarding on the regulatory effects of LA on enteric diseases.