Two New Cyototoxic Cardenolides from the Whole Plants of Adonis multiflora Nishikawa & Koki Ito.

A phytochemical investigation of the whole plants of Adonis multiflora Nishikawa & Koki Ito. resulted in the isolation and identification of two new cardenolides--adonioside A (1) and adonioside B (6)--as well as four known cardenolides: tupichinolide (2) oleandrine (3), cryptostigmin II (4), and cymarin (5). Their structures were elucidated on the basis of NMR, MS, and IR spectroscopic analyses. Compounds 1, 2, 5, and 6 showed significant cytotoxicity against six human cancer cell lines (HCT-116, HepG2, HeLa, SK-OV-3, and SK-MEL-5, and SK-BR-3).

Neolignans from the fruits of Magnolia obovata and their inhibition effect on NO production in LPS-induced RAW 264.7 cells.

Three new neolignans, named 9-methoxyobovatol (6), magnobovatol (7), and 2-hydroxyobovaaldehyde (9), along with six known ones, magnolol (1), honokiol (2), isomagnolol (3), obovatol (4), obovatal (5), and obovaaldehyde (8), were isolated from the fruits of Magnolia obovata using silica gel and ODS column chromatography. From the results of spectroscopic data including EIMS, IR, 1H- and 13C-NMR, DEPT, and 2D-NMR (gCOSY, gHSQC, gHMBC), the chemical structures were determined. All isolated compounds were evaluated for inhibition activity on nitric oxide production in LPS-induced RAW 264.7 cells, and compounds 1-4, 6, 7, and 9 showed significant activity with IC50 values of 15.8 ± 0.3, 3.3 ± 1.2, 14.1 ± 0.9, 6.2 ± 1.2, 14.8 ± 2.3, 14.2 ± 1.2, and 14.8 ± 3.2 µM, respectively, without any visible toxic effect.

Increased incidence of gastric cancer in renal transplant recipients.

OBJECTIVE: The risk of malignancy after transplantation is regarded to be higher than in the general population. The aim of this study was to evaluate the frequency of gastric cancer in renal transplant recipients. METHODS: A total of 820 renal transplantation recipients were invited for gastric cancer screening. Frequencies of gastric cancer in this cohort and in 10,080 asymptomatic subjects were compared. Cancer specimens were examined for Epstein-Barr virus by in situ hybridization. RESULTS: A total of 509 recipients (mean age, 48.1 ± 10.7 y; men, 56.8%) participated. Fifteen (2.9%) and 10 (0.1%) cases of adenocarcinoma were identified among recipients and controls, respectively (P<0.001; odds ratio, 30.58). Early gastric cancer was detected in 9 of the 15 recipients, and 4 of the 9 were treated by endoscopic resection. Recipient age was found to be a significant factor of gastric cancer development. In cancer tissues, Epstein-Barr virus was detected in 5 (33.3%) renal recipients and in 1 (10%) of the controls, respectively. CONCLUSIONS: The frequency of gastric cancer was found to be higher in renal recipients than in controls. Gastric cancer screening should be considered after transplantation, because it would provide cure by minimally invasive treatment.

Bioactive 3,4-seco-Triterpenoids from the Fruits of Acanthopanax sessiliflorus.

Eight new 3,4-seco-lupane triterpenes and glycosides, acanthosessiligenins I and II (1, 3) and acanthosessiliosides A-F (2, 4-8), as well as six known 3,4-seco-lupane triterpenes (9-14) were isolated from an ethanolic extract of Acanthopanax sessiliflorus fruits. The chemical structures of 1-8 were determined by spectroscopic data interpretation. All isolated compounds were tested for their cytotoxicity against six human cancer cell lines and their ability to inhibit LPS-induced nitric oxide production in RAW 264.7 macrophages.

The effect of exenatide and erythromycin on postprandial symptoms and their relation to gastric functions.

BACKGROUND: The relationship between abnormal gastric motor function and postprandial abdominal symptoms has not been fully clarified. The aim of the study was to investigate this relationship in response to mediators that affect gastric function. METHODS: Ten healthy volunteers participated in a 3-way cross-over study of treatment with placebo, exenatide and erythromycin. The studies were performed at 1-week intervals. Each subject underwent 3-dimensional single photon emission computed tomography to measure fasting and postprandial gastric volumes. A combined nutrient drink test and cutaneous electrogastrography (EGG) were performed on the next day. RESULTS: Erythromycin reduced postprandial symptoms compared with placebo. The postprandial gastric volume after exenatide was greater than after placebo and erythromycin treatment. Exenatide did not aggravate postprandial symptoms compared with placebo. The ratio of postprandial over fasting gastric volume was inversely correlated with the total postprandial symptom score after placebo, exenatide and erythromycin treatment. The postprandial symptom score of the normal EGG group was significantly lower than that of the abnormal group, considering overall treatments. CONCLUSIONS: Erythromycin reduced postprandial symptoms, whereas exenatide did not aggravate postprandial symptoms, possibly due to its enhancement of gastric accommodation. An abnormal EGG rhythm was associated with postprandial symptoms.

Endoscopic submucosal dissection of gastric neoplasia involving the pyloric channel by retroflexion in the duodenum.

BACKGROUND: Tumors involving the pyloric channel have been considered as difficult lesions for successful endoscopic resection. We studied the feasibility of endoscopic submucosal dissection (ESD) using retroflexion in the duodenum to resect the gastric neoplasia involving the pyloric channel. AIM: To compare the treatment outcomes of a new ESD technique using retroflexion to those without retroflexion in the duodenum. METHODS: Twenty-four cases of gastric neoplasia involving the pyloric channel were resected by ESD. In 14 cases, ESDs were performed from both the antrum and duodenal bulb using retroflexion (retroflexion group). In ten cases, ESDs were performed conventionally only from the side of the antrum (conventional group). We compared the outcomes between the two methods. RESULTS: There was no complication regarding retroflexion in the duodenum. In the retroflexion group, the en bloc and complete resection rate was 100%, respectively. The rate of complete resection was significantly higher in the retroflexion group than in the conventional group (P = 0.01). In the conventional group, three patients with early gastric cancer underwent additional subtotal gastrectomy for positive lateral margin, and one patient with perforation was treated additionally by surgical repair. In the retroflexion group, microperforation and pyloric channel stenosis occurred in one patient, which resolved with conservative treatment. CONCLUSIONS: Tumors involving the pyloric channel could be successfully resected by ESD using retroflexion in the duodenum without severe complication. This technique appears to be a feasible and effective method for the treatment of tumors involving the pyloric channel.

Prospective assessment of risk of bacteremia following colorectal stent placement.

BACKGROUND: Colorectal stent insertion is an invasive endoscopic procedure. However, there are no reports regarding the incidence of bacteremia with colorectal stent. OBJECTIVE: This study was to evaluate the risk of bacteremia and infectious complications after stent insertion for colorectal obstruction. METHODS: Patients who underwent colorectal stent insertion were enrolled consecutively. Blood cultures were obtained before colorectal stent insertion and at 30 min after the procedure. Patients were monitored for 48 h after colorectal stent insertion to detect the development of infectious complications. Procedural data collected included location of obstruction, degree of bowel preparation, obstructive symptoms, and the time required for the procedure. RESULTS: Of 64 patients undergoing colorectal stent, four (6.3%) had a positive post-stent blood culture. All patients, including those with positive cultures, remained asymptomatic during the 48 h after the procedure. Site of obstruction, degree of bowel preparation, age, and underlying disease were not different between the two groups. Development of bacteremia was associated with long procedure time (p < 0.05). CONCLUSIONS: Colorectal stent insertion does not induce significant bacteremia in patients with colorectal obstruction. These findings suggest that the routine use of prophylactic antibiotics may not be necessary in colorectal stent insertion.

Maximizing field-effect mobility and solid-state luminescence in organic semiconductors.

Conductive and emissive: organic transistors made from a simple styrylanthracene derivative have high charge mobility and high luminescence quantum yields. These properties are attributed to the lack of singlet fission, and challenge the idea that the efficient π interactions required for high mobility always lead to quenching of emission. The transistors emit blue electroluminescence and are stable during operation and storage.

Antiproliferative mechanism of a cannabinoid agonist by cell cycle arrest in human gastric cancer cells.

For gastric cancers, the antineoplastic activity of cannabinoids has been investigated in only a few reports and knowledge regarding the mechanisms involved is limited. We have reported previously that treatment of gastric cancer cells with a cannabinoid agonist significantly decreased cell proliferation and induced apoptosis. Here, we evaluated the effects of cannabinoids on various cellular mediators involved in cell cycle arrest in gastric cancer cells. AGS and MKN-1 cell lines were used as human gastric cancer cells and WIN 55,212-2 as a cannabinoid agonist. Cell cycles were analyzed by flow cytometry and western blotting. Treatment with WIN 55,212-2 arrested the cell cycle in the G0/G1 phase. WIN 55,212-2 also upregulated phospho-ERK1/2, induced Kip1/p27 and Cip1/WAF1/p21 expression, decreased cyclin D1 and cyclin E expression, decreased Cdk 2, Cdk 4, and Cdk 6 expression levels, and decreased phospho-Rb and E2F-1 expression. ERK inhibitor decreased the proportion of G0/G1 phase which was induced by WIN 55,212-2. Inhibition of pAKT led to cell cycle arrest in gastric cancer cells. Cell cycle arrest preceded apoptotic response. Thus, this cannabinoid agonist can reduce gastric cancer cell proliferation via G1 phase cell cycle arrest, which is mediated via activation of the MAPK pathway and inhibition of pAKT.

Polymorphisms in the intermediate region of VacA impact Helicobacter pylori-induced disease development.

Helicobacter pylori is the etiological agent of diseases such as gastritis, gastric and duodenal ulcers, and two types of gastric cancers. While some insight has been gained into the etiology of these diverse manifestations, by and large, the reason that some individuals develop more severe disease remains elusive. Recent studies have focused on the roles of H. pylori toxins CagA and VacA on the disease process and have suggested that both toxins are intimately involved. Moreover, CagA and VacA are polymorphic within different H. pylori strains, and particular polymorphisms seem to show a correlation with the development of particular disease states. Among VacA polymorphisms, the intermediate region has recently been proposed to play a major role in disease outcome. In this article, we describe a detailed sequence analysis of the polymorphic intermediate region of vacA from strains obtained from a large South Korean population. We show that polymorphisms found at amino acid position 196 are associated with more severe disease manifestations. Additionally, polymorphisms found at amino acid position 231 are linked to disease in strains that carry the non-EPIYA-ABD allele of CagA. Collectively, these data help explain the impact of the VacA intermediate region on disease and lead to the hypothesis that there are allele-driven interactions between VacA and CagA.

Cannabinoid receptor 1 gene polymorphism and irritable bowel syndrome in the Korean population: a hypothesis-generating study.

OBJECTIVE: The cannabinoids affect gastrointestinal function and are thought to be involved in the pathogenesis of irritable bowel syndrome (IBS). We hypothesized that genetic variants of the cannabinoid receptor 1 gene (CNR1) might be associated with IBS. METHODS: One hundred sixty-two IBS patients, who met the Rome II criteria, and 423 healthy controls were subjected to genotyping of polymorphic triplet AAT repeats located in the 3-flanking region of the CNR1 gene. RESULTS: Allele frequencies of AAT triplet repeats in the CNR1 gene differed markedly between the controls and IBS patients (P<0.01). Controls had a lower frequency of distribution of 10 alleles or more. We divided the alleles into 2 groups (≤ 10 and >10), and 3 genotypes ≤ 10/≤ 10, heterozygote, and >10/>10. The CNR1 having>10/>10 AAT triplet repeats occurred with greater frequency in IBS patients than in the controls (P<0.01). A strong genotype association was observed between the CNR1 >10/>10 genotype and all IBS subtypes compared with controls (P<0.01 for each). The allele frequencies and the CNR1 genotypes did not differ between the 3 IBS subtypes. Symptom scores for abdominal discomfort or pain were higher in patients with the CNR1 >10/>10 genotype than in patients with the other genotypes (P<0.05). CONCLUSIONS: We found a different distribution of allelic frequency of AAT repeats in the CNR1 gene in healthy controls and IBS patients, and a significant association between the CNR1 >10/>10 genotype and IBS. These results suggest that the CNR1 gene is a potential candidate gene involved in IBS in Korea.

Successful control of peristomal infection by introducer-type percutaneous endoscopic gastrostomy: a retrospective historical control study.

BACKGROUND: The techniques of percutaneous endoscopic gastrostomy are classified as the pull and introducer methods. Peristomal infection is the most common procedure-related complication in the pull method. OBJECTIVES: The objective of this study was to compare procedure-related complications between the two methods and to assess the outcome of long-term use of the introducer method. METHODS: Between January 1999 and November 2009, 116 patients received percutaneous endoscopic gastrostomy at Seoul St. Mary's Hospital in Korea. Before June 2006, the pull method was used for all patients; since then, every patient had been treated using the introducer method. We compared outcomes and complications within 180 days of gastrostomy placement for the two methods. RESULTS: The pull method was performed on 63 patients and the introducer method on 53 patients. The occurrence of peristomal infection within 30 days was significantly lower in the introducer method group than in the pull method group (1.9% vs. 36.5%, P = 0.001). Methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the major organisms isolated from the peristomal infection. The requirement for catheter reinsertion because of displacement, obstruction, or damage to the catheter between 30 and 180 days was significantly higher in the introducer method group than in the pull method group (40.5% vs. 0%, P = 0.001). CONCLUSIONS: Our results suggest the superiority of the introducer method in terms of infection control. However, the balloon-type catheter is associated with problems such as balloon insufficiency in long-term use.

Effect of a synthetic cannabinoid agonist on the proliferation and invasion of gastric cancer cells.

Although cannabinoids are associated with antineoplastic activity in a number of cancer cell types, the effect in gastric cancer cells has not been clarified. In the present study, we investigated the effects of a cannabinoid agonist on gastric cancer cell proliferation and invasion. The cannabinoid agonist WIN 55,212-2 inhibited the proliferation of human gastric cancer cells in a dose-dependent manner and that this effect was mediated partially by the CB(1) receptor. We also found that WIN 55,212-2 induced apoptosis and down-regulation of the phospho-AKT expression in human gastric cancer cells. Furthermore, WIN 55,212-2 treatment inhibited the invasion of gastric cancer cells, and down-regulated the expression of MMP-2 and VEGF-A through the cannabinoid receptors. Our results open the possibilities in using cannabinoids as a new gastric cancer therapy.

Epidemiological link between gastric disease and polymorphisms in VacA and CagA.

Gastritis, peptic ulcer disease, and gastric cancer are a few of the diverse disease manifestations that have been shown to be associated with infection by Helicobacter pylori. Why some individuals develop more severe forms of disease remains largely unknown. In this study, 225 South Korean strains were genotyped for vacA and then analyzed to determine if particular genotypes varied across disease state, sex, or cagA allele. Of these strains, 206 strains carried an s1/i1/m1 allele, 11 strains carried an s1/i1/m2 allele, and 8 strains carried an s1/i2/m2 allele. By using Fisher's exact test, a statistical association between variations in the cagA and vacA alleles was identified (P = 0.0007), and by using log linear modeling, this variation was shown to affect the severity of disease outcome (P = 0.027). Additionally, we present evidence that variation within the middle region of VacA contributes significantly to the distribution of vacA alleles across gender (P = 0.008) as well as the association with disease outcome (P = 0.011). In this South Korean population, the majority of H. pylori strains carry the vacA s1/i1/m1 allele and the CagA EPIYA-ABD allele. These facts may contribute to the high incidence of gastric maladies, including gastric cancer.

The prevalence and patterns of pharyngoesophageal dysmotility in patients with early stage Parkinson's disease.

Dysphagia occurs in the majority of patients with Parkinson's disease (PD) and is known to correlate with abnormalities of oropharyngeal function. The aim of this study was to evaluate pharyngoesophageal activity in patients with early-stage PD. Newly diagnosed PD patients with a symptom duration not exceeding 3 years were included. All PD patients were questioned about symptoms of dysphagia and underwent combined multichannel intraluminal impedance manometry and multiple rapid swallow tests. Fifty-four patients (22 men and 32 women, 67.1 ± 10.3 years) were enrolled. The duration of Parkinsonian motor symptoms was 11.5 ± 8.8 months, the Hoehn and Yahr stage was 1.6 ± 0.4, and the total Unified Parkinson's Disease Rating Scale was 25.1 ± 18.6. Esophageal manometry in the liquid swallow and viscous swallow tests was abnormal in 22 (40.7%) and 31 (67.4%) patients, respectively. Although manometric abnormalities were more common in patients with more severe dysphagia symptoms, many patients with no or minimal symptoms also had manometric abnormalities. Repetitive deglutition significantly correlated with failed peristalsis and incomplete bolus transit. Abnormal responses to multiple rapid swallow tests were found in 33 out of 54 patients; 29 with incomplete inhibition (repetitive contraction) and 4 with failed peristalsis. These results suggest that the majority of patients with early-stage PD showed pharyngeal and esophageal dysfunction even before clinical manifestations of dysphagia, which may reflect selective involvement of either the brain stem or the esophageal myenteric plexus in early-stage PD.

Diagnostic value of the PPI test for detection of GERD in Korean patients and factors associated with PPI responsiveness.

OBJECTIVES: Data supporting the use of the proton pump inhibitor (PPI) test as a diagnostic test of gastroesophageal reflux disease (GERD) in Asia are lacking. The aims of this study were to evaluate the diagnostic characteristics of the PPI test and factors associated with responsiveness to PPIs. METHODS: The PPI test was evaluated using lansoprazole (30 mg bid) for two weeks. All patients underwent endoscopy after symptom assessment. Patients without erosive esophagitis (ERD) underwent 48 h esophageal Bravo pH monitoring. Subjects were considered to be responsive to PPIs if they reported a > 50% reduction in reflux symptom score. RESULTS: Seventy-three patients (M:F = 40:37, 47 +/- 13 years) were enrolled. We identified 46 patients with ERD, 18 patients with nonerosive reflux disease (NERD) and 9 patients without GERD. The PPI response rate was higher in patients with GERD than in patients without GERD (49/64, 77% vs. 4/9, 44%; p < 0.05). The sensitivity, specificity, and positive and negative predictive values were 77%, 56%, 92% and 25%, respectively. The PPI responsiveness was 80% (37/46) in the ERD group and 67% (12/18) in the NERD group. PPI response was not affected by age, sex, Helicobacter pylori, the psychological characteristics or cytochrome P2C genotypes. ERD and symptom-reflux association were the factors affecting PPI responsiveness. CONCLUSIONS: The PPI test was modestly sensitive and specific for diagnosing GERD. However, it would be useful for discriminating patients with ERD. In the NERD group, patients with positive symptom-reflux association would be most benefit from PPI treatment.

Risk factors in malignant transformation of gastric epithelial neoplasia categorized by the revised Vienna classification: endoscopic, pathological, and immunophenotypic features.

BACKGROUND: According to the revised Vienna classification, the surgical removal of gastric epithelial neoplasia category 3 (low-grade dysplasia) lesions is not necessary, whereas the removal of category 4 lesions (high-grade dysplasia and intramucosal cancer) is obligatory. However, approximately 15%-30% of low-grade adenomas/dysplasia progress to high-grade lesions or adenocarcinoma, and it is difficult to determine which lesions will advance to true malignancy. The aim of this study was to evaluate the endoscopic, pathological, and immunophenotypic differences between category 3 and 4 lesions according to the revised Vienna classification. METHODS: All tissue samples were excised by endoscopic mucosal resection. Fifty-two category 3 tissue samples and 54 category 4 samples were evaluated by endoscopic findings; by pathology examination of the surrounding mucosa; and by CD10, MUC2, MUC5AC, MUC6, and RUNX3 immunohistochemical staining. RESULTS: Univariate analysis showed that the size of the lesion, color change, ulceration, gastritis score of the surrounding mucosa, and positive expression of MUC6 were associated with category 4 lesions. Multivariate analysis showed that the size of the lesion, ulceration, and positive expression of MUC6 were strongly associated with category 4 lesions. CONCLUSION: Lesions more than 17 mm in diameter or lesions that are associated with ulceration have the potential for malignant transformation. Positive immunoreactivity for MUC6 appears to be a complementary marker for malignant transformation of gastric epithelial neoplasia.

Clinical trial: inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects.

BACKGROUND AND AIM: Revaprazan is a novel acid pump antagonist. The aim of this study was to investigate the inhibitory effect of revaprazan on gastric acid secretion in healthy male subjects. METHODS: In a double-blind, three-way cross-over study, 30 healthy male volunteers were randomized to 100, 150 or 200 mg of oral revaprazan daily for 7 days. Serum gastrin concentration was measured, and 24-h intragastric pH was recorded at baseline and on days 1 and 7 of each administration period. Serial blood samples were processed for pharmacokinetics. RESULTS: Median intragastric pH over 24 h and mean percentage time that pH was > 4 increased in a dose-dependent manner and were significantly higher on days 1 and 7 compared with baseline in all groups (P < 0.05). The antisecretory effect of revaprazan was rapid and nearly maximal on day 1 in all groups. Serum gastrin levels were rapidly normalized by 100 and 150 mg/day of revaprazan on days 1 and 7, but were significantly higher in the 200 mg/day revaprazan group. The pharmacokinetic effect was rapidly absorbed and eliminated on days 1 and 7 in all groups. CONCLUSIONS: Revaprazan rapidly and effectively inhibits gastric acid secretion in healthy male subjects. Therefore, revaprazan can be used as an effective drug for acid-related disease.

Effectiveness of stent placement for palliative treatment in malignant colorectal obstruction and predictive factors for stent occlusion.

BACKGROUND: Self-expandable metallic stent (SEMS) for malignant colorectal obstruction is widely used in palliative treatment and as an alternative to surgery. The aims of this study are to evaluate the effectiveness of stent placement for palliative treatment and to identify the predictive factors associated with stent occlusion. METHODS: A retrospective analysis was performed in 55 patients who had undergone placement of an uncovered SEMS from February 2004 to April 2007 for palliative treatment of malignant colorectal obstruction with metastatic or locally advanced cancer that was surgically unresectable. We analyzed the technical and clinical outcomes of stent placement, complications related to the procedure, stent patency rate, and predictive factors associated with stent occlusion. RESULTS: The causes of colorectal obstruction before stent placement were primary colorectal cancer in 42 patients and noncolorectal extrinsic cancer in 13 patients. The initial technical success rate was 98.2%, and the clinical success rate was 94.4%. Complications occurred in 17 patients (30.9%). These included stent occlusion (n = 8), migration (n = 6), bowel perforation (n = 1), stent distortion (n = 1), and fistula formation (n = 1). The mean and median stent patency periods were 184 days [95% confidence interval (CI), 137-230 days] and 141 days (95% CI, 69-213 days), respectively. The degree of expansion 48 h after stent placement was significantly better in the nonocclusion group than in the stent occlusion group. In the multivariate Cox proportional hazard model, insufficient stent expansion (<70%) 48 h after stent placement was significantly associated with an increase in stent occlusion during the follow-up period (odds ratio, 12.55; p = 0.002). CONCLUSIONS: Uncovered SEMS placement is an effective palliative treatment for malignant colorectal obstruction. The degree of stent expansion 48 h after stent placement is significantly associated with the maintenance of stent patency and is a predictive factor for stent occlusion.

Clinical outcomes of self-expandable metal stent and prognostic factors for stent patency in gastric outlet obstruction caused by gastric cancer.

The aim of this study was to assess clinical outcomes of endoscopic stenting for a gastric outlet obstruction caused by gastric cancer and the prognostic factors for stent patency by reviewing medical records. Eighty-one stents were inserted into 75 patients (48 men, average age 66 years). The technical and clinical success rates were 98 and 87%, respectively. The median stent patency was 55 days (95% CI 40-70 days). The median survival was 79 days (95% CI 58-123 days). Stent reobstruction caused by tumor ingrowth or overgrowth occurred in 25 cases (31%). Cox multivariate regression analysis showed that covered stents (odds ratio 0.29, 95% CI 0.11-0.76; P = 0.01) and chemotherapy after stent placement (odds ratio 0.34, 95% CI 0.13-0.91; P = 0.03) were significant prognostic factors for stent patency. This study found that endoscopic stenting is a safe and effective palliation treatment for malignant gastric outlet obstruction and a covered stent and chemotherapy are significant prognostic factors for stent patency.