Anti-ulcer activity of newly synthesized acylquinoline derivatives was investigated. For the in vitro screening, the effects of compounds on gastric $H^{+}/K^{+}$ ATPase isolated from hog and rabbit were examined. Among them, AU-090, AU-091, AU-254, AU-413 and AU-466 exhibited good in vitro activity on both enzymes. To correlate the in vitro activity with in vivo action, the effects of the compounds on the basal gastric acid secretion were studied. Some derivatives showed considerable anti-secretory activities, and AU-413 was selected for further studies. AU-413 protected gastric damage induced by either ethanol or NaOH dose dependently when given orally. $ED_{50}$ values of 12 mg/kg, p.o. (ethanol) and 41 mg/kg, p.o. (NaOH) were obtained. In addition, histamine-stimulated gastric secretion was reduced upon AU-413 administration. Taken together, newly synthesized acylquinoline derivatives, especially AU-413, is worthy of further investigation to be developed as an anti-ulcer agent.
We conducted a hospital case-control study by genotyping four potential functional single nucleotide polymorphisms (SNPs) to assess the association of Xeroderma pigmentosum complementation group F (XPF) with gastric cancer susceptibility, and role of XPF polymorphisms in combination with H.pylori infection in risk definition. A total of 331 patients with gastric cancer and 355 controls were collected. Four SNPs of XPF, rs180067, rs1799801, rs2276466 and rs744154, were genotyped by Taqman real-time PCR method with a 7900 HT sequence detector system. The gastric cancer patients were more likely to have smoking habit, a family history of cancer and H.pylori infection. We did not find any significant difference in the genotype distributions of XPF rs180067, rs1799801, rs2276466 and rs744154 between cases and controls. However, multivariate logistic analysis showed a non-significant decreased risk in patients carrying rs180067 G allele, rs1799801 T allele or rs2276466 T allele genotypes. A non-significant increased risk of gastric cancer was found in individuals carrying the rs744154 GG genotype. Stratification by H.pylori infection and smoking was not significantly different in polymorphisms of XPF rs180067, rs1799801, rs2276466 and rs744154. The four XPF SNPs did not show significant interaction with H.pylori infection and smoking status (P for interaction was 0.35 and 0.18, respectively). Our study indicated that polymorphisms in rs180067, rs1799801, rs2276466 and rs744154 may affect the risk of gastric cancer but further large sample size studies are needed to validate any association.
Background: An aberrant function of the mismatch repair system has been reported to underlie carcinogenesis in several tumors, including colorectal and gastric carcinomas, and to induce the typical genotype of microsatellite instability (MSI). Purpose: We aimed to determine the frequency of MSI in early-onset sporadic gastric carcinoma and elucidate the role of promoter methylation in hMLH1 as the mechanism of MSI. Materials and Methods: Thirty-six early-onset sporadic gastric carcinomas were analyzed to determine the status of MSI and the frequency of methylation of the promoter region in hMLH1. MSI was determined using five markers recommended by NCI: MSI-H (high), MSI-L (low), and MSS (Microsatellite stable). Methylation specific PCR (MSP) and direct automated genomic sequencing analysis with DNA modified by sodium bisulfite have been performed to confirm promoter region methylation. All the data were analyzed regarding characteristics of molecular changes, and clinicopathologic variables. Results: The microsatellite status was determined as MSI-H in five cases ($13.8\%$), MSI-L in 13 cases ($36.1\%$), and MSS in 18 cases ($50.0\%$). hMLH1 was methylated in seven cases ($19.4\%$). In all cases of MSI-H, promoter of hMLH1 was methylated, and in two of the 13 cases of MSI-L, hMLH1 promoter methylation was identified. Methylation was not found in any cases of MSS. Promoter methylation in hMLH1 was significantly correlated with MSI status (P<0.001). We could not find any relationship between MSI and clinicopathologic parameters. Conclusion: These results suggest that an abnormal function of the mismatch repair system may be associated with gastric carcinogenesis in more than $10\%$ of early-onset gastric carcinomas and MSI appeared to be closely related to the promoter methylation in hMLH1.
Jung, Da Hyun;Kim, Jie-Hyun;Lee, Yong Chan;Lee, Sang Kil;Shin, Sung Kwan;Park, Jun Chul;Chung, Hyun Soo;Kim, Hyunki;Kim, Hoguen;Kim, Yong Hoon;Park, Jae Jun;Youn, Young Hoon;Park, Hyojin
Journal of Gastric Cancer
/
제15권4호
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pp.246-255
/
2015
Purpose: The importance of Helicobacter pylori eradication after endoscopic resection (ER) of gastric neoplasms remains controversial. In this study, we clarified the importance of H. pylori eradication for metachronous lesions after ER. Materials and Methods: This study included 3,882 patients with gastric neoplasms who underwent ER. We included patients infected with H. pylori who received eradication therapy. Among them, 34 patients with metachronous lesions after ER and 102 age- and sex-matched patients (nonmetachronous group) were enrolled. Background mucosal pathologies such as atrophy and intestinal metaplasia (IM) were evaluated endoscopically. The expression levels of CDX1, CDX2, Sonic hedgehog (SHH), and SOX2 were evaluated based on H. pylori eradication and the development of metachronous lesions. Results: The eradication failure rate was higher in the metachronous group than in the nonmetachronous group (P=0.036). Open-type atrophy (P=0.003) and moderate-to-severe IM (P=0.001) occurred more frequently in the metachronous group. In patients with an initial diagnosis of dysplasia, the eradication failure rate was higher in the metachronous group than in the nonmetachronous group (P=0.002). In addition, open-type atrophy was more frequent in the metachronous group (P=0.047). In patients with an initial diagnosis of carcinoma, moderate-to-severe IM occurred more frequently in the metachronous group (P=0.003); however, the eradication failure rate was not significantly different between the two groups. SHH and SOX2 expression was increased, and CDX2 expression was decreased in the nonmetachronous group after eradication (P<0.05). Conclusions: Open-type atrophy, moderate-to-severe IM, and H. pylori eradication failure were significantly associated with metachronous lesions. However, eradication failure was significantly associated with dysplasia, but not carcinoma, in the metachronous group. Thus, H. pylori eradication may play an important role in preventing metachronous lesions after ER for precancerous lesions before carcinomatous transformation.
Gastroesophageal reflux is thought to be an important etiology of the various upper aerodigestive tract disease. To investigate the role of gastric acid and pepsin as an etiologic factor of laryngotracheal stenosis, and the difference of injury by synthetic gastric juice between in ciliated respiratory epithelium and in squamous epithelium, experimental study was carried out using rabbits. Mucociliary transport affected by synthetic gastric juice was also studied in dogs. Synthetic gastric juice of low pH caused serious damage and Impairment of mucociliary transport in the epithelium of the larynx and trachea. Gastric acid played major role in the mucosal damage. Squamous epithelium of vocal folds and pharynx was more resistant to synthetic gastric juice than respiratory epitheium. In conclusion, gastroesophageal reflux may be an etiologic factor in the developement of laryngotracheal stenosis, so the adequate management is necessory In patients of laryngotracheal stenosis.
Ascorbic acid is one of the most well-known nutritional supplement and antioxidant found in fruits and vegetables. Calcium ascorbate has been developed to mitigate the gastric irritation caused by the acidity of ascorbic acid. The aim of this study was to compare calcium ascorbate and ascorbic acid, focusing on their antioxidant activity and effects on gastric juice pH, total acid output, and pepsin secretion in an in vivo rat model, as well as pharmacokinetic parameters. Calcium ascorbate and ascorbic acid had similar antioxidant activity. However, the gastric fluid pH was increased by calcium ascorbate, whereas total acid output was increased by ascorbic acid. In the rat pylorus ligation-induced ulcer model, calcium ascorbate increased the gastric fluid pH without changing the total acid output. Administration of calcium ascorbate to rats given a single oral dose of 100 mg/kg as ascorbic acid resulted in higher plasma concentrations than that from ascorbic acid alone. The area under the curve (AUC) values of calcium ascorbate were 1.5-fold higher than those of ascorbic acid, and the $C_{max}$ value of calcium ascorbate (91.0 ng/ml) was higher than that of ascorbic acid (74.8 ng/ml). However, their $T_{max}$ values were similar. Thus, although calcium ascorbate showed equivalent antioxidant activity to ascorbic acid, it could attenuate the gastric high acidity caused by ascorbic acid, making it suitable for consideration of use to improve the side effects of ascorbic acid. Furthermore, calcium ascorbate could be an appropriate antioxidant substrate, with increased oral bioavailability, for patients with gastrointestinal disorders.
Melatonin (MT) is an indole amide pineal hormone. It has not only very short half-life but also pH-sensitive property. The sustained release dosage form which delivers MT in a circadian fashion over 8 h is clinical value. The purpose of this study is to prepare sugar beads using multiple coating methods and enteric-coated in a sustained release to evaluate in vitro release characteristics in simulated gastric and intestinal fluids. The $Eudragit^{\circledR}$ as a polymer, sustained release membrane, and triethylcitrate (TEC) as a plasticzer were used. Multi-coated melatonin delivery system was composed of sugar, various excipients, $Eudragit^{\circledR}$ and enteric materials (e.g. hydroxy propyl methyl cellulose phthalate, HPMCP), and prepared by fluid bed coater. The dissolution test was carried out using the basket method at a stirring speed of 100 rpm at $37^{\circ}C$ in simulated gastric (pH 1.2) and intestinal fluid (pH 7.4). The released amount of MT was determined by High performance liquid chromatography method. The morhologies of surface and cross section of multi-coated beads were observed by scanning electron microscope. Size of multi-coated sugar beads was ranged over $1000{\sim}1300\;{\mu}m$. The release rate of MT from coated beads was limited in simulated gastric fluid (pH 1.2), but it was sustained in intestinal fluid (pH 7.4) during $3{\sim}8$ hours. The MT beads may provide small-intestine-targeted device for oral delivery. Studies on animal and relative experiment are in process.
Park, Hee-Seon;Jeong, Hye-Yun;Kim, Young-Suk;Seo, Chang-Seob;Ha, Hyekyung;Kwon, Hyo-Jung
Journal of Veterinary Science
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제21권3호
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pp.39.1-39.15
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2020
Background: There are various Helicobacter species colonizing the stomachs of animals. Although Helicobacter species usually cause asymptomatic infection in the hosts, clinical signs can occur due to gastritis associated with Helicobacter in animals. Among them, Helicobacter pylori is strongly associated with chronic gastritis, gastric ulcers, and gastric cancers. As the standard therapies used to treat H. pylori have proven insufficient, alternative options are needed to prevent and eradicate the diseases associated with this bacterium. Cheonwangbosim-dan (CBD), a traditional herbal formula that is popular in East Asia, has been commonly used for arterial or auricular flutter, neurosis, insomnia, and cardiac malfunction-induced disease. Objectives: The present study investigated the antimicrobial effect of CBD on H. pylori-infected human gastric carcinoma AGS cells and model mice. Methods: AGS cells were infected with H. pylori and treated with a variety of concentrations of CBD or antibiotics. Mice were given 3 oral inoculations with H. pylori and then dosed with CBD (100 or 500 mg/kg) for 4 weeks or with standard antibiotics for 1 week. One week after the last treatment, gastric samples were collected and examined by histopathological analysis, real-time quantitative polymerase chain reaction, and immunoblotting. Results: Our results showed that CBD treatment of AGS cells significantly reduced the H. pylori-induced elevations of interleukin-8, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In the animal model, CBD treatment inhibited the colonization of H. pylori and the levels of malondialdehyde, inflammation, proinflammatory cytokines, iNOS, and COX-2 in gastric tissues. CBD also decreased the phosphorylation levels of p38 mitogen-activated protein kinase family. Conclusions: This study suggests that CBD might be a prospective candidate for treating H. pylori-induced gastric injury.
This study was conducted to assess the relationship between occurrence of gastric cancer and peptic ulcer, and the presence of H. pylori cagA gene and anti-CagA IgG, and to estimate the value of these antibodies in detecting infection by cagA gene-positive H. pylori strains in Saudi patients. The study included 180 patients who were subjected to upper gastrointestinal endoscopy in Taif province and Western region of Saudi Arabia (60 gastric cancer, 60 peptic ulcer, and 60 with non-ulcer dyspepsia). Gastric biopsy specimens were obtained and tested for H. pylori infection by rapid urease test and culture. PCR was performed on the isolated strains and biopsy specimens for detection of the cagA gene. Blood samples were collected and tested for CagA IgG by ELISA. H. pylori infection was detected among 72.8% of patients. The cagA gene and anti-CagA IgG were found in 63.4% and 61.8% of H. pylori-infected patients, respectively. They were significantly (p < 0.01) higher in patients with gastric cancer and peptic ulcer compared with those with non-ulcer dyspepsia. Detection of the CagA IgG was 91.6% sensitive, 89.6% specific, and 90.8% accurate compared with detection of the cagA gene. Its positive and negative predictive values were 93.8% and 86%, respectively. The study showed a significant association between the presence of the cagA gene and gastric cancer and peptic ulcer disease, and between anti-CagA IgG and the cagA gene in Saudi patients. However, a further larger study is required to confirm this finding.
Tongtawee, Taweesak;Dechsukhum, Chavaboon;Leeanansaksiri, Wilairat;Kaewpitoon, Soraya;Kaewpitoon, Natthawut;Loyd, Ryan A;Matrakool, Likit;Panpimanmas, Sukij
Asian Pacific Journal of Cancer Prevention
/
제16권18호
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pp.8487-8490
/
2016
Background: Helicobacter pylori infection and premalignant gastric mucosa can be reliably identified using conventional narrow band imaging (C-NBI) gastroscopy. The aim of our study was to compare standard biopsy with site specific biopsy for diagnosis of H. pylori infection and premalignant gastric mucosa in daily clinical practice. Materials and Methods: Of a total of 500 patients who underwent gastroscopy for investigation of dyspeptic symptoms, 250 patients underwent site specific biopsy using C-NBI (Group 1) and 250 standard biopsy (Group 2). Sensitivity, specificity, and positive and negative predictive values were assessed. The efficacy of detecting H. pylori associated gastritis and premalignant gastric mucosa according to the updated Sydney classification was also compared. Results: In group 1 the sensitivity, specificity, positive and negative predictive values for predicting H. pylori positivity were 95.4%, 97.3%, 98.8% and 90.0% respectively, compared to 92.9%, 88.6%, 83.2% and 76.1% in group 2. Site specific biopsy was more effective than standard biopsy in terms of both H. pylori infection status and premalignant gastric mucosa detection (P<0.01). Conclusions: Site specific biopsy using C-NBI can improve detection of H. pylori infection and premalignant gastric mucosa in daily clinical practice.
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