• Archives of Pharmacal Research
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• v.22 no.4
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• pp.354-360
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• 1999

Inflammatory bowel disease (IBD) is a multifactorial disorder with unknown etiology and pathogenesis. DA-6034,$ 7-carboxymethyloxy-3^{l}, 4^{l},$ 5-trimethoxy flavone, is a synthetic flavonoid known to possess anti-inflammatory activity. This study was performed to evaluate the oral therapeutic effect of DA-6034 in three experimental animal models of IBD : two chemical-induced IBD models of rats and the human leukocyte antigen (HLA)-B27 transgenic rat model known to develop spontaneous colitis without the use of exogenous agents. Acute chemical colitis was induced by intracolonic instillation of 1.2 ml of 4% acetic acid solution. Prednisolone (1 mg/kg), sulfasalazine (100 mg/kg) and DA-6034 (0.3~3 mg/kg) were orally administered twice daily for 6 days in these rats. In addition, chronic chemical colitis was induced by intracolonic administration of trinitrobenzene sulfonic acid (TNBS) 30 mg in 50% ethanol and agents were orally administered for 6 or 20 days. In chemical-induced IBD models, all of these agents reduced the severity of colitis and specially, DA-6034 (3 mg/kg) showed more potent effect than other drugs in macroscopic lesion score. In HLA-B27 transgenic rats, DA-6034 (3 mg/kg) and prednisolone (0.5 gm/kg) were treated orally twice daily for 6 weeks. The HLA-B27 transgenic rats showed only mild colitis, compared with the chemical-induced colitis models. DA-6034 ameliorated the loose stool and decreased microscopic damage, which is the important indicator of this model. In conclusion, oral therapy of DA-6034 attenuated the macroscopic and histologic damages of the colon in all three experimental models of IBD, which suggest that DA-6034 could be a promising drug in the treatment of IBD.

• Journal of Applied Biological Chemistry
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• v.54 no.1
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• pp.51-55
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• 2011

To develop a health-aid preparation of Dioscorea batatas (DB), lactic acid fermentation was attempted using a mixed starter comprising of Lactobacillus acidophilus, Lactobacillus plantarum, Bifidobacterium longum. The anaerobic fermentation of a 10% DB flour suspension gave a uniform suspension of pH 3.65, containing $8{\times}10^6$ CFU/mL lactic acid bacteria. During the administration of the lactic acid fermented DB (FDB) and DB to trinitrobenzene sulfonic acid (TNBS)-induced colitis mouse model, histological lesions, morphological damage, and myeloperoxidase acitivity were significantly reduced at a dosage of 200 and 400 mg/kg/day. Dose-response (200 and 400 mg/kg/day) studies revealed that FDB pre-treatment of mice significantly ameliorated the appearance of diarrhoea and the disruption of colonic architecture. In FDB-pretreated mice, there was a significant reduction in the degree of both neutrophil infiltration (measured as decrease in myeloperoxidase activity) and weight loss rates. Theses findings suggest that FDB exerts beneficial effects in experimental colitis and may be useful in the treatment of inflammatory bowel disease.

• Korean Journal of Acupuncture
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• v.24 no.4
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• pp.131-149
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• 2007

Objectives : The purpose of the present study is to evaluate the effects of herbal acupuncture (HA) with Moxi-tar for the treatment to intestinal disease in mice with 2, 4, 6 - trinitrobenzenesulfonic acid (TNBS) induced colitis. Methods : Mice were administered with 5% TNBS at day 1 and day 7. To investigate effects of HA with Moxi-tar at LI11, treatments were carried out at day -1, day 1, day 3, day 5, and day 7. It was checked on the weight and width of colon, diarrhea, edema, survival rate, changes of body weight, and myeloperoxygenase (MPO) activity. Furthermore, we carried out immunohistochemical staining and Western blot and analyzed mRNA expression by RT-PCR. Results : HA of Moxi-tar at LI11 in preventive mode suppressed macroscopic damages and damages of intestinal epithelial cells and infiltration of immune cells in the colon by TNBS. HA in early and preventive mode ameliorated various symptoms by TNBS. TNBS injection increased MPO activity in colon while HA in preventive mode suppressed increase of MPO activity. HA down-regulated NF-kB activity and reduced expression of TNF-a, IL-1b, and ICAM-1 in colon of TNBS treated mice. Similar to experiment at colon, HA down-regulated NF-kB activity and reduced expression of TNF-a, IL-1b, and ICAM-1 by TNBS in mesenteric lymph node. HA in therapeutic mode suppressed errosion and shortening of colon and MPO activity by TNBS and suppressed mRNA expression of TNF-a, IL-1b, and ICAM-1 in the colon. Conclusions : This study demonstrates that HA with Moxi-tar at LI11 represents a potential therapeutic method of inflammatory bowel diseases.

• Biomolecules & Therapeutics
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• v.24 no.6
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• pp.638-649
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• 2016

In the previous study, the rhizome mixture of Anemarrhena asphodeloides and Coptis chinensis (DW2007), improved TNBS-, oxazolone-, or DSS-induced colitis in mice by regulating macrophage activation. Therefore, to understand the effect of DW2007 on the T cell differentiation involved in the adaptive immunity, we measured its effect on both Th17 and Treg cell differentiation in splenocytes, in the lamina propria of mice with DSS-induced colitis (DIC), and in the spleens of mice with collagen-induced arthritis (CIA). Results showed that DW2007 potently inhibited the differentiation of splenocytes into Th17 cells, but increased Treg cell differentiation in vitro. In the colon of wild type and $TLR4^{-/-}$ mice with DIC, DW2007 potently suppressed DSS-induced colon shortening and myeloperoxidase activity. DW2007 also suppressed collagen-induced paw thickening, clinical index, and myeloperoxidase activity in CIA mice. Overall, DW2007 potently suppressed Th17 cell differentiation in mice with CIA and DIC, but increased Treg cell differentiation. Moreover, DW2007 strongly inhibited the expression of TNF-${\alpha}$ and IL-$1{\beta}$, as well as the activation of NF-${\kappa}B$. Based on these findings, DW2007 may ameliorate inflammatory diseases by regulating the innate immunity via the inhibition of macrophage activation and the adaptive immunity via the correction of disturbed Th17/Treg cells.

• The Korean Journal of Physiology and Pharmacology
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• v.19 no.1
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• pp.43-50
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• 2015

It has been shown that the extracts including eupatilin and quercetin-3-${\beta}$-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-${\beta}$-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-${\alpha}$ expression, total glutathione levels, and malondialdehyde concentrations in the colon. The results indicated that extracts including eupatilin and extracts including quercetin-3-${\beta}$-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-${\beta}$-D-glucuronopyranoside showed significantly decreased levels of mucosal myeloperoxidase activity, nitric oxide production, tumor necrosis factor-${\alpha}$ expression, and malondialdehyde levels, and increased total glutathione levels. Extracts including eupatilin and extracts including quercetin-3-${\beta}$-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-${\beta}$-D-glucuronopyranoside may inhibit acute colitis.

• Biomolecules & Therapeutics
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• v.21 no.5
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• pp.398-404
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• 2013

During a screening program to search the anticolitic herbal medicines, 80% ethanol extract of the rhizome of Anemarrhena asphodeloides (AA) was found to potently inhibit the expression of proinflammatory cytokines TNF-${\alpha}$ and IL-1${\beta}$, as well as the activation of NF-${\kappa}B$ in LPS-stimulated colonic macrophages, followed by that of the rhizome of C. chinensis (CC). AA also potently inhibited TNBS-induced colitic markers, shortening of the colon and increase of macroscopic score, myeloperoxidase activity, TNF-${\alpha}$, IL-1${\beta}$, and IL-6, in mice. The synergistic effect of CC against the anticolitic effect of AA was investigated. CC synergistically inhibited the anticolitic effect of AA. AC-mix (AA+CC, 1:1) potently inhibited them. AC-mix also inhibited the activation of NF-${\kappa}B$, as well as the expression of TNF-${\alpha}$, IL-1${\beta}$, IL-6, iNOS and COX-2. The effects of AC-mix against oxazolone-induced colitis were investigated in mice. AC-mix also potently inhibited oxazolone-induced inflammatory markers, colon shortening, macroscopic score, myeloperoxidase activity, NF-${\kappa}B$ activation and proinflammatory cytokines. Overall, the anti-colitic effect of AC-mix was superior to that of mesalazine. Based on these findings, AC-mix may improve colitis by inhibiting NF-${\kappa}B$ activation.

• Food Science of Animal Resources
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• v.32 no.2
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• pp.149-154
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• 2012

It is known that lactic-acid bacteria (LAB) helps keeping the intestine healthy and to enhance its immunologic competence. In addition, it is known to control the composition of the enterobacteria and the intestinal inflammatory reaction by inducing immunological enhancement. This study was performed, in a mouse model, to test the treatment and preventive effects of LAB of inflammatory bowel disease (IBD), which was induced by a blend of LAB-administering trinitrobenzene sulfonic acid (TNBS). To obtain the animal model of IBD, 2% TNBS was rectally administered once to a five-week-old male Balbc/J mouse. A probiotic combination was administered to the prevention group five times a week for eight weeks before the inducement of enteritis, and the mixture was administered to the treatment group five times a week, after the administration of TNBS. The changes in the levels of the cytokines of the lymph nodes and the tissue of the large intestine were observed, both with the naked eye and with a microscope. The observation showed that the levels of inflammatory cells, infiltration, and necrosis were much lower in the LAB-administered groups than in that of the control group. In addition, the inflammatory cytokines (e.g., TNF-${\alpha}$, IL-17A) decreased in the lymph nodes and the tissues of the large intestine. The results indicated that the administration of the combination to the animal model suppressed the inflammatory cytokines in the large intestine and in the lymph nodes, which in turn suppressed the progression of colitis.

• 한국유가공학회:학술대회논문집
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• 2007.09a
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• pp.49-58
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• 2007

Inflammatory process leads to the well-known mucosal damage and therefore a further disturbance of the epithelial barrier function, resulting abnormal intestinal wall function, even further accelerating the inflammatory process[1]. Despite of the records, etiology and pathogenesis of IBD remain rather unclear. There are many studies over the past couple of years have led to great advanced in understanding the inflammatory bowel disease(IBD) and their underlying pathophysiologic mechanisms. From the current understanding, it is likely that chronic inflammation in IBD is due to aggressive cellular immune responses including increased serum concentrations of different cytokines. Therefore, targeted molecules can be specifically eliminated in their expression directly on the transcriptional level. Interesting therapeutic trials are expected against adhesion molecules and pro-inflammatory cytokines such as TNF-${\alpha}$. The future development of immune therapies in IBD therefore holds great promises for better treatment modalities of IBD but will also open important new insights into a further understanding of inflammation pathophysiology. Treatment of cytokine inhibitors such as Immunex(Enbrel) and J&J/Centocor(Remicade) which are mouse-derived monoclonal antibodies have been shown in several studies to modulate the symptoms of patients, however, theses TNF inhibitors also have an adverse effect immune-related problems and also are costly and must be administered by injection. Because of the eventual development of unwanted side effects, these two products are used in only a select patient population. The present study was performed to elucidate the ability of TNF-${\alpha}$ antibodies produced in sheep colostrums to neutralize TNF-${\alpha}$ action in a cell-based bioassay and in a small animal model of intestinal inflammation. In vitro study, inhibitory effect of anti-TNF-${\alpha}$ antibody from the sheep was determined by cell bioassay. The antibody from the sheep at 1 in 10,000 dilution was able to completely inhibit TNF-${\alpha}$ activity in the cell bioassay. The antibodies from the same sheep, but different milkings, exhibited some variability in inhibition of TNF-${\alpha}$ activity, but were all greater than the control sample. In vivo study, the degree of inflammation was severe to experiment, despite of the initial pilot trial, main trial 1 was unable to figure out of any effect of antibody to reduce the impact of PAF and LPS. Main rat trial 2 resulted no significant symptoms like characteristic acute diarrhea and weight loss of colitis. This study suggested that colostrums from sheep immunized against TNF-${\alpha}$ significantly inhibited TNF-${\alpha}$ bioactivity in the cell based assay. And the higher than anticipated variability in the two animal models precluded assessment of the ability of antibody to prevent TNF-${\alpha}$ induced intestinal damage in the intact animal. Further study will require to find out an alternative animal model, which is more acceptable to test anti-TNF-${\alpha}$ IgA therapy for reducing the impact of inflammation on gut dysfunction. And subsequent pre-clinical and clinical testing also need generation of more antibody as current supplies are low.