Tae-Young Oh

Oxidative damages are critical in pathogenesis of reflux esophagitis: implication of antioxidants in its treatment

Abstract Background: The facts that the severity of reflux esophagitis cannot be accurately predicted on the basis of acid exposure and acid suppression treatment is not enough for the complete healing, suggested that other damaging factors might be involved in pathogenesis of reflux esophagitis. Aims: The present study was designed to evaluate the oxidative stress as the major pathogenic factor of reflux esophagitis and the importance of antioxidant in treatment of reflux esophagitis. Materials and Methods: Reflux esophagitis was induced by the insertion of small caliber ring (3 mm in diameter) into the duodenum 1 cm distal to the ligament of Treitz in rats. Results: DA-9601, a novel antioxidant substance, attenuated the gross esophagitis significantly compared to that treated with ranitidine, histamine-2 receptor antagonist (H2-RA), in a dose-dependent manner. Severe, hemorrhagic, and longitudinal ulcerations were developed in H2-RA pretreated group, whereas mildly scattered erosions were observed in antioxidant-pretreated group. Significantly increased amounts of malondialdehyde (MDA), increased NF-κB activation, and the mucosal depletion of reduced glutathione (GSH) were observed in the esophagus of reflux esophagitis. H2-RA treatment didn’t affect the levels of GSH and MDA, whereas DA-9601 attenuated the decrement of the GSH levels and significantly decreased lipid peroxides in the esophagus. Antioxidants treatment showed significant reductions in the activation of NF-κB, inflammation-associated transcription factor, especially p50 component in accordance with significant higher levels of NF-κB repressor, IκBα expression. Conclusion: Oxygen-derived free radicals seem to be one of the important mediators in generation of reflux esophagitis, which suggests that the combination of antioxidant and anti-secretory medications will be ideal and more beneficial in the prevention and treatment of reflux esophagitis than currently prescribed antisecretory treatment alone.

Preventive effect of the flavonoid, wogonin, against ethanol-induced gastric mucosal damage in rats

Whether wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of Scutellaria baicalensis Georgi, which has been shown to have antiinflammatory and antitumor activities in various cell types, possesses a gastric cytoprotective effect was investigated in an ethanol-induced gastric damage model in rats. Ethanol administration alone induced evident gastric damage including gastric hemorrhages and edema, while this gastric damage was significantly attenuated by wogonin pretreatment (30 mg/kg B.W.) 1 hr before ethanol administration. As major protective mechanisms of wogonin on ethanol-induced gastric damage, we found that wogonin showed either antiinflammatory effects through dual actions on arachidonic acid metabolism, i.e., induction of prostaglandin D2 and suppression of 5S-hydroxyeicosatetraenoic acid (5S-HETE), or preventive induction of profuse apoptosis in the stomach. Conclusively, the flavonoid wogonin could be used as a preventive agent of alcohol-induced gastropathy, whose actions were proven to be strong antiinflammation and apoptosis induction.

Novel antioxidant ameliorates the fibrosis and inflammation of cerulein-induced chronic pancreatitis in a mouse model.

Background/Aim: Oxygen free radicals (OFRs) mediate an important step in the initiation of experimental acute pancreatitis and several clinical findings suggested the possible contribution of OFRs to the pathogenesis of pancreatic fibrosis. So far, there are no studies which reporting potential role of OFRs in development of chronic pancreatitis with the prevention with antioxidants. This study was aimed to establish the mice model of chronic fibrosing pancreatitis and to prove the involvement of OFRs in chronic pancreatitis with fibrosis. Methods: Repeated intraperitoneal cerulein injection was performed to induce chronic pancreatitis in mice. Histological changes in the pancreas were examined, and markers for oxidative stress were measured in the pancreatic tissue and serum of the mice. DA-9601, a phytochemical possessing anti-inflammatory and antioxidative action, was given together with cerulein to the mice. Results: Repeated intraperitoneal injection of cerulein provoked significant severity of chronic fibrosing pancreatitis after 5 weeks. After treatment of DA-9601, the extents of pancreatic fibrosis were statistically significantly decreased in accordance with lessened pancreatic inflammations. The NF-ĸB binding activities were increased in chronic pancreatitis, which were significantly attenuated after DA-9601 treatment. The levels of myeloperoxidase and iNOS activities were also significantly decreased in DA-9601-treated group compared to the pancreatitis only group. Cytoprotective proteins such as heat shock protein-70 (HSP) and metallothionein were significantly increased in the DA-9601-treated group. DA-9601 decreased the expressions of α-SMA and type I collagen in cultured pancreatic stellate cells. Conclusions: Oxidative stress was principally involved in the pathogenesis of chronic pancreatitis with fibrosis.

Chemopreventive Effects of the Standardized Extract (DA-9601) of Artemisia asiatica on Azoxymethane-Initiated and Dextran Sulfate Sodium-Promoted Mouse Colon Carcinogenesis

Dextran sulfate sodium (DSS) administration has been reported to cause inflammation in mouse colonic mucosa, which promotes colon carcinogenesis. When male ICR mice were treated with a single intraperitoneal dose (10 mg/kg body weight) of azoxymethane (AOM) followed by 2.5% DSS in drinking water for 7 consecutive days, all developed tumors at the 16th wk, mostly in the distal colon. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) were markedly upregulated in the AOM-initiated and DSS-promoted colon tumors. The DNA binding activity of nuclear factor-kappaB (NF-κ B) was also elevated in the colon tumors. In this study, we examined the chemopreventive effects of the standardized extract (DA-9601) of Artemisia asiatica that has been used in the traditional herbal medicine for the treatment of inflammatory disorders. Mice fed the chow diet containing 10% DA-9601 for 15 wk following DSS treatment displayed the significantly lower multiplicity of colon tumors. DA-9601 treatment suppressed the expression of COX-2 and iNOS as well as NF-κ B DNA binding in the colonic tissues. It also downregulated the phosphorylation of extracellular, signal-regulated protein kinase and p38 mitogen-activated protein kinase that are upstream of NF-κ B. Furthermore, DA-9601 reduced expression of β-catenin in colonic mucosa of mice challenged with AOM plus DSS.

Sa1389 The Safety, Tolerability, and Pharmacokinetics of DA-6886, a Novel Serotonin 5-Hydroxytryptamine4 Receptor Agonist, in Healthy Subjects

descending (D) and sigmoid colon (S)] and the rectum (R) were measured. The stool and/ or gas distribution was evaluated using the following parameters: 1) Constipation index (CI)summing up the transverse diameter of each of the 5 segments according to the following formula [A+T+D+S+R / 5]; 2) Left/Right ratio (L/R)calculated from the following formula [(D+S) / (A+T)]. Colon transit time (CTT) was also assessed using radio opaque markers according to the established method by Metcalf, et al. First, patients were treated by either fiber or osmotic laxatives for 2 weeks. When constipation had not improved despite 2 weeks of treatment, stimulant laxatives were prescribed and followed for additional 2 weeks. Results: There was a significantly correlation between CI and CTT (r=0.75, p<0.01) (Fig). CI was significantly higher in CC patients than those with healthy subjects (p<0.05). According to their clinical courses, patients were divided into 3 groups: responder to either fiber or osmotic laxatives (group A), responder to stimulant laxatives (group B), and nonresponder (group C). CI was significantly lower in group A compared with both group B and C (p<0.05), and ROC curve analysis gave a cutoff value for CI of 19.7 for prediction of unfavorable outcomes of either fiber or osmotic laxatives (p<0.05), while L/R was significantly lower in group C compared with group B (p<0.05), and ROC curve analysis gave a cutoff value for L/R of 0.5 for prediction of non-responder of stimulant laxatives (p<0.05). Conclusions: Our data show that the stool and/or gas distribution evaluated by the US becomes an indirect indicator for CTT, and parameters evaluated by the US are associated with responsiveness to medical therapy for CC patients. These findings may assist physicians in predicting the unfavorable outcomes to medical therapies without side effects for this patient population.