recoflavone and Disease-Models--Animal

DA-6034 has anti-inflammatory activities and exhibits cytoprotective effects in acute gastric injury models. However, explanations for the protective effects of DA-6034 on intestinal permeability are limited. This study sought to investigate the effect of DA-6034 on intestinal permeability in an indomethacin-induced small intestinal injury model and its protective effect against small intestinal injury.. Rats in the treatment group received DA-6034 from days 0 to 2 and indomethacin from days 1 to 2. Rats in the control group received indomethacin from days 1 to 2. On the fourth day, the small intestines were examined to compare the severity of inflammation. Intestinal permeability was evaluated by using fluorescein isothiocyanate-labeled dextran. Western blotting was performed to confirm the association between DA-6034 and the extracellular signal-regulated kinase (ERK) pathway.. The inflammation scores in the treatment group were lower than those in the control group, but the difference was statistically insignificant. Hemorrhagic lesions in the treatment group were broader than those in the control group, but the difference was statistically insignificant. Intestinal permeability was lower in the treatment group than in the control group. DA-6034 enhanced extracellular signal-regulated kinase expression, and intestinal permeability was negatively correlated with ERK expression.. DA-6034 may decrease intestinal permeability in an indomethacin-induced intestinal injury model via the ERK pathway.

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Dose-Response Relationship, Drug; Enteritis; Flavonoids; Indomethacin; Intestine, Small; MAP Kinase Signaling System; Permeability; Phosphorylation; Random Allocation; Rats, Sprague-Dawley

To investigate the effect of DA-6034, 7-carboxymethyloxy-3',4',5-trimethoxy flavone, in experimentally-induced inflammatory dry eye in rabbit. In addition, to elucidate the mechanism of DA-6034, we evaluated the mitogen-activated protein kinase (MAPK) signaling pathway and transcriptional factor-kappa B (NF-kB) in corneal epithelial cells.. Rabbit lacrimal glands were injected with the T-cell mitogen concanavalin A (Con A). DA-6034 was then administered topically four times a day for six days starting 24 hr after Con A injection. Tear volume, tear function, MMP-9 and inflammatory cytokine levels in the lacrimal glands, and histological evaluation were subsequently assessed. In in vitro study, phosphorylated MAPKs (c-Jun NH2-terminal kinase (JNK) and p38 MAPK) and NF-kB were detected by enzyme-linked immunosorbent assay (ELISA) using human corneal epithelial cells.. A single injection of Con A into the lacrimal glands induced a pronounced inflammatory response, caused elevated levels of MMP-9 and cytokines IL-8 and TGF-beta(1), and induced a decrease in tear volume and shortening of tear breakup time (TBUT). In this inflammation model of dry eye, DA-6034 clearly showed therapeutic efficacy by restoring tear function and inhibiting inflammatory responses after topical ocular application. Furthermore, DA-6034 attenuated the phosphorylation of JNK and p38 MAPK and inhibited NF-kB activation in a concentration-dependent manner in corneal epithelial cells.. These results suggest that DA-6034 has the therapeutic effect in rabbit lacrimal gland inflammation model of dry eye and might be a potential treatment option for acute dry eye syndrome.

Topics: Administration, Topical; Animals; Blotting, Western; Cell Culture Techniques; Cytokines; Dacryocystitis; Disease Models, Animal; Dry Eye Syndromes; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Epithelium, Corneal; Flavonoids; MAP Kinase Signaling System; Matrix Metalloproteinase 9; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Rabbits; Tears

This study was conducted to evaluate the effect of DA-6034, a potent secretagogue, on aqueous tear fluid secretion and its quality in normal rabbit. We also evaluated, in animal models of experimentally induced dry eye disease, its effectiveness over time to stimulate aqueous tear production by ocular ferning test and goblet cell proliferation.. Aqueous tear production, total protein levels, and glycoprotein levels in normal rabbits were evaluated after topical application of DA-6034 (0.3, 1, and 3%). Moreover, time course aqueous tear volume measurement and ocular ferning test in tear fluid were performed in dry eyes of rabbits that had been given 1% atropine sulfate, topically. Altogether, tear fluid production and conjunctival goblet cell numbers were measured in dry eyes of mice that had been given topical scopolamine.. Topical application of DA-6034 (0.3, 1, and 3%) significantly increased (P < 0.05) aqueous tear production in a concentration-dependent manner in normal rabbits. There was no change in total protein levels while glycoprotein levels were significantly increased (P < 0.05) at 3% DA-6034. The increase in aqueous tear fluid was significant (P < 0.05) and lasted for 2 h post-instillation in dry eyes of rabbits that had been given 1% atropine sulfate; 10-day repeated instillation of the drug in this model resulted in large and homogeneous fern-like tear patterns. In a mouse model, DA-6034 given as a 3% eyedrop solution significantly increased (P < 0.05) tear fluid production and conjunctival goblet cell number.. These results suggest that DA-6034 accelerates not only tear secretion but also mucin production and may be a potential therapeutic agent for the treatment of dry eye disease.

Topics: Administration, Topical; Animals; Atropine; Cell Proliferation; Conjunctiva; Disease Models, Animal; Dry Eye Syndromes; Eye Proteins; Female; Flavonoids; Goblet Cells; Male; Mice; Mice, Inbred C57BL; Mucins; Ophthalmic Solutions; Rabbits; Scopolamine; Tears

Previously, we have shown that DA-6034, a synthetic derivative of flavonoid eupatilin, inhibited NF-kappaB activation in colon epithelial cells and prevented trinitrobenzene sulfonic acid-induced rat colitis. The aim of this study was to investigate the preventive and therapeutic effect of DA-6034 on dextran sulfate sodium (DSS)-induced colitis and on inflammation-related cancer. C57BL/6 mice were given 4% DSS for 5 days with and without DA-6034 in the acute preventive model. In the acute therapeutic model, mice were given 4% DSS for 5 days followed by rectal administration of DA-6034. Colitis was quantified by body weight, disease activity index (DAI), colon length, and histology. In the inflammation-related cancer model, mice were given a single intraperitoneal injection of azoxymethane, then three cycles of 2% DSS for 5 days, then 2 weeks of free water consumption. Apoptosis was determined by in situ terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assay, and the expression of Ki-67, phospho-kappaB kinase alpha (IKKalpha), and COX-2 were evaluated by immunohistochemistry. In both the acute preventive and acute therapeutic models, DA-6034 significantly attenuated DSS-induced weight loss, an increase in DAI, and a shortening of colon length. DA-6034-treated mice maintained crypt architecture and revealed a scanty infiltration of inflammatory cells in both the preventive and therapeutic models. In the inflammation-related cancer model, DA-6034 reduced the number of colon tumors and ameliorated weight loss and shortening of colon length. DA-6034 strongly enhanced apoptosis and inhibited the expression of COX-2 and phospho-IKKalpha in inflammation-related colon cancer models. Our results suggest that DA-6034 prevents acute murine colitis and inhibits inflammation-related colon carcinogenesis. DA-6034 could be a potential therapeutic agent for inflammatory bowel disease.

Topics: Acute Disease; Animals; Apoptosis; Body Weight; Cell Transformation, Neoplastic; Colitis; Colonic Neoplasms; Cyclooxygenase 2; Dextran Sulfate; Disease Models, Animal; Flavonoids; I-kappa B Kinase; Ki-67 Antigen; Male; Mice; Mice, Inbred C57BL; Phosphorylation

This study evaluated the gastroprotective activity of DA-6034 against various ulcerogens including ethanol, aspirin, indomethacin, stress, and acetic acid. The basic mechanisms of DA-6034 as a defensive factor such as mucus secretion and endogenous prostaglandin E(2) synthesis were determined. Rats with gastric lesions induced by ethanol-HCl, aspirin, indomethacin, and stress that had been pretreated with DA-6034 orally showed a statistically significant decrease or decreasing tendency of the gastric lesion. In acetic acid-induced gastric lesions, repeated oral administration of DA-6034 exhibited a U-shape activity in ulcer healing, with the maximum and minimum inhibition being observed at 30 and 10 mg/kg/day, respectively. DA-6034 also increased the mucus content in the gel layer as well as endogenous prostaglandin E(2) synthesis. These results suggest that DA-6034 prevents gastric mucosal injury, and these gastroprotective activities appear to be due to the increase in the gastric defensive systems.

Topics: Acetic Acid; Administration, Oral; Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Central Nervous System Depressants; Dinoprostone; Disease Models, Animal; Ethanol; Flavonoids; Gastric Mucosa; Immersion; Indicators and Reagents; Indomethacin; Male; Mucus; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Stomach Ulcer; Stress, Psychological; Treatment Outcome