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Mucosal atrophy and enlarged folds of stomach by double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) are two major features of Helicobacter pylori-induced chronic gastritis. These were previously shown to be risk indicators of gastric cancer, but their predictability for clinicopathological characters of developed gastric cancer is unelucidated. In addition, evidence for decreasing the mortality of gastric cancer by appropriate follow-up of UGI screening is needed. The 5134 generally healthy UGI-XR examinees, who underwent follow-up UGI-XR or upper gastrointestinal endoscopy (UGI-ES) more than once, were prospectively observed for 10 years. At the beginning of follow-up, 1515 (29.5%) had mucosal atrophy and 990 (19.5%) had enlarged folds. For the serum anti-H. pylori IgG, 1301 (25.3%) were positive, 177 (3.4%) were possibly positive, and 3656 (71.2%) were negative. During the 10-year observation period, gastric cancer developed in 15 subjects, among which 13 had mucosal atrophy and 10 had enlarged folds. These two features were expectedly useful indicators for gastric cancer incidence, but they showed no significant association with tumor stage or histological type of developed cancer. Only one of the 5134 subjects died of gastric cancer during 10 years, which was significantly lower than the predicted number of gastric cancer death (6.78 for 10 years) according to the mortality rate in Japan. Neither mucosal atrophy nor enlarged folds of stomach showed a significant association with clinicopathological features of developed gastric tumors. Appropriate follow-up of cancer screening by UGI-XR or UGI-ES can reduce the risk of gastric cancer-related death.

The red maple and sugar maple (Acer rubrum and A. saccharum, respectively) contain acertannins (ginnalins and maplexins), galloylated derivatives of 1,5-anhydro- d -glucitol (1,5-AG, 1). These compounds have a variety of potential medicinal properties and we have shown that some of them promote the expression of ceramide synthase 3. We now report on the beneficial effects of ginnalin B, (6-O-galloyl-1,5-AG, 5), leading to acceleration of skin metabolism and reduction of the turnover time. Ginnalin B dose-dependently increased the relative amount of keratin 10, keratin 1, and filaggrin gene, with maximal increase of 1.7-, 2.9, and 5.2-fold at 100 μM, respectively. The validation study showed that it had superior capacity to induce multiple stages of keratinocyte differentiation and significantly elevated the immunostaining site of keratin 10 and filaggrin in a 3-dimensional cultured human skin model, by 1.2 and 2.8-fold, respectively. Furthermore, ginnalin B caused the arrest of proliferation at the G0/G1 phase but it did not induce apoptotic cell death in normal human keratinocytes. Molecular studies revealed that ginnalin B up-regulated the levels of NOTCH1 and a concomitant increase p21 expression. Ginnalin B, therefore, represents a new class of promising functional and medical cosmetic compound and it could contribute to the maintenance of homeostasis of the epidermis.

Intestinal metaplasia induced by ectopic expression of caudal-type homeobox (CDX)2 and/or CDX1 (CDX) is frequently observed around gastric cancer (GC). Abnormal expression of CDX is also observed in GC and suggests that inappropriate gastrointestinal differentiation plays essential roles in gastric tumorigenesis, but their roles on tumorigenesis remain unelucidated. Publicly available databases show that GC patients with higher CDX expression have significantly better clinical outcomes. We introduced CDX2 and CDX1 genes separately into GC-originated MKN7 and TMK1 cells deficient in CDX. Marked suppression of cell growth and dramatic morphological change into spindle-shaped flat form were observed along with induction of intestinal marker genes. G0-G1 growth arrest was accompanied by changed expression of cell cycle-related genes but not with apoptosis or senescence. Microarray analyses additionally showed decreased expression of gastric marker genes and increased expression of stemness-associated genes. Hierarchical clustering of 111 GC tissues and 21 non-cancerous gastric tissues by selected 18 signature genes based on our transcriptome analyses clearly categorized the 132 tissues into non-cancer, "CDX signature"-positive GC, and "CDX signature"-negative GC. Gene set enrichment analysis indicated that "CDX signature"-positive GC has lower malignant features. Immunohistochemistry of 89 GC specimens showed that 50.6% were CDX2-deficient, 66.3% were CDX1-deficient, and 44.9% were concomitant CDX2/CDX1-deficient, suggesting that potentially targetable GC cases by induced intestinal differentiation are quite common. In conclusion, exogenous expression of CDX2/CDX1 can lead to efficient growth inhibition of CDX-deficient GC cells. It is based on rapidly induced intestinal differentiation, which may be a future therapeutic strategy.

Gastric cancer (GC) is rich in many different histological types, but how the histological pattern is defined remains to be proved. The relation between GC histological types and the expression of nectin1, which is one of the cell adhesion molecules that composes adherens junction, has not been reported. According to a publicly available database of 406 GC patients, the median overall survival of Nectin1 high expression patients was 55.4 months and that of low expression patients was 25.6 months (P = 0.0246). Using surgically or endoscopically resected GC samples, nectin1 expression was analyzed by immunohistochemistry. Nectin1 expressed at adherens junction in all the normal epithelial cells. However, nectin1 expressed not at adherens junction but at apical membrane in epithelial cells in intestinal metaplasia. The expression pattern of nectin1 in intestinal type GC resembled to intestinal metaplasia. In order to analyze the difference in nectin1 expression between GC histological types, a total of 116 intestinal type GC and 33 diffuse type GC. The expression of necitin1 in diffuse type GC (3.0%) was remarkably decreased compared to that in intestinal type GC (65.5%) (P < 0.0001). In conclusion, this is the first report showing an association between nectin1 expression and histological subtypes of GC.

The mechanism behind the pathogenesis and carcinogenesis of these neoplasms is not fully understood. The objective of this study was to identify genetic markers and pathways specific to precancerous duodenal adenomas and early stage adenocarcinomas through gene expression analysis. Gene expression profiling was performed in 4 pairs of duodenal adenoma/adenocarcinomas and corresponding matched normal tissue. Genes with consistent expression differences were identified and confirmed in 7 independent pairs. Gene set enrichment analysis (GSEA) was performed to characterize gene expression profiles of duodenal adenoma/adenocarcinomas, together with immunohistochemical staining of candidate oncogenic genes. 626 probes consistently demonstrated over a twofold expression difference between tumor–normal pairs. Reverse transcriptase polymerase chain reaction of genes with the most prominent difference in expression between tumors and normal mucosa (KLK7, KLK6, CEMIP, MMP7, KRT17, LGR5, G6PC, S100G, APOA1) validated the results of gene expression analysis. GSEA demonstrated a strong association between duodenal adenoma/adenocarcinomas with colorectal adenomas (p

BackgroundSeveral previous studies have suggested that Helicobacter pylori (H. pylori) infection affects the serum lipid profile. However, it remains controversial and the mechanism has not been elucidated. The purpose of this study is to use an epidemiological perspective to evaluate the association between H. pylori infection and the serum lipid profile.MethodsMultivariate analysis was performed using the data of serum lipid profile, infection status of H. pylori, fitness/lifestyle habits, and various subjects' characteristics which were derived from the 15,679 generally healthy individuals in Japan. The average treatment effects (ATEs) of H. pylori infection on the serum lipid profile were estimated using augmented inverse probability weighting (AIPW). A meta-analysis was also performed using the 27 studies worldwide in which the status of H. pylori infection and at least one serum examination value (high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), or triglyceride (TG)) were described.ResultsThe ATEs determined with AIPW showed that H. pylori infection has significant positive effects on LDL-C and TC (ATE (95% confidence interval [95%CI]) = 3.4 (2.36-4.49) and 1.7 (0.58-2.88), respectively) but has significant negative effects on HDL-C and TG (ATE (95%CI) = -1.2 (-1.74 to -0.72) and -3.5 (-5.92 to -1.06), respectively). The meta-analysis to estimate the association between H. pylori infection and the serum lipid profile revealed that H. pylori infection is positively associated with LDL-C, TC, and TG (standardized mean difference [SMD] (95%CI) = 0.11 (0.09-0.12), 0.09 (0.07-0.10) and 0.06 (0.05-0.08), respectively) and negatively associated with HDL-C (SMD = -0.13 (-0.14 to -0.12)).ConclusionBoth our multivariate analyses and meta-analysis showed that H. pylori infection significantly affects the serum lipid profile, which might lead to various dyslipidemia-induced severe diseases like coronary thrombosis or cerebral infarction.

The restoration capability of charophyte Chara braunii was studied in arsenic-polluted water in the context of biogenic calcium and manganese depositions on the plant. In addition to calcite encrustation, formation of craterlike shape deposits of manganese oxides (MnOx) with diameters of 5–10 μm was detected on the cell walls of the plants grown in Mn-rich media. Relative proportions of arsenic taken up by the plant biomass to those incorporated into the calcium and manganese biominerals were determined using a modified sequential chemical extraction method. The mean total arsenic recovery from water reached its highest value at 375 mg kg−1 in treatment with HCO3− and high concentrations of Ca and Mn (40 and 2 mg L−1, respectively). The percentage of arsenic associated with the manganese deposits in the plants exposed to 0.5 mg L−1 As(III) increased from 16.3% to 51.7% of the total arsenic accumulation at low and high Mn levels (

Double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) is the standard gastric cancer screening method in Japan. Atrophic gastritis and enlarged gastric folds are considered the two major features of Helicobacter pylori-induced chronic gastritis, but the clinical meaning of evaluating them by UGI-XR has not been elucidated. We analyzed healthy UGI-XR examinees without a history of gastrectomy, previous Helicobacter pylori eradication and usage of gastric acid suppressants. Of the 6433 subjects, 1936 (30.1 %) had atrophic gastritis and 1253 (19.5 %) had enlarged gastric folds. During the 3-year prospective observational follow-up, gastric cancer developed in seven subjects, six of whom (85.7 %) had atrophic gastritis with H. pylori infection and five of whom (71.4 %) had enlarged gastric folds with H. pylori infection. The Kaplan-Meier method with log-rank testing revealed that both UGI-XR-based atrophic gastritis (p = 0.0011) and enlarged gastric folds (p = 0.0003) are significant predictors for future gastric cancer incidence.

MUC5AC is a well-known gastric differentiation marker, which has been frequently used for the classification of stomach cancer. However, the molecular mechanism of regulation of MUC5AC expression remains to be elucidated. In previous studies, we have shown that Gli regulated MUC5AC transcription through the Gli-binding motif in the 5′ region of MUC5AC. Gli played important roles, but independently was not sufficient for MUC5AC expression. In this study, we analyzed a 4010 bp fragment of the 5′-flanking promoter region of the human MUC5AC gene by luciferase assay, and found a novel distal enhancer region located between −1434 bp to −3000 bp upstream from the first ATG initiation codon. This region is composed of repetitive DNA sequences 5′-TCACTCAC-3′. The strength of enhancer activities depended on the length of the repetitive region. The tandem repeats are conserved among primates, but not in other mammals. The tandem repeat regions enhanced promoter activities not only of MUC5AC but also of other genes. The enhancer effect of the tandem repeat regions was maintained even when inverted. ChIP analysis revealed that H3K9me3 binds to the tandem repeat regions. Together, our results suggest that the tandem repeat region in the MUC5AC promoter has the potential to act as a strong enhancer, and H3K9me3 may contribute to histone modifications of this region. Keywords: MUC5AC, Tandem repeat, Enhancer, H3K9me3

Double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) is a method broadly used for gastric cancer screening in Japan. Gastric polyp is one of the most frequent findings detected by UGI-XR, but how to handle it remains controversial. Gastric polyps of the 17,264 generally healthy subjects in Japan who underwent UGI-XR or upper gastrointestinal endoscopy (UGI-ES) in 2010 were analyzed. Of the 6,433 UGI-XR examinees (3,405 men and 3,028 women, 47.4 ± 9.0 years old), gastric polyps were detected in 464 men (13.6 %) and 733 women (24.2 %) and were predominantly developed on the non-atrophic gastric mucosa (p

Cordyceps sinensis, a parasitic fungus on the larvae of Lepidoptera, has been used as a traditional Chinese medicine. We previously reported that the growth of B16-BL6 mouse melanoma (B16-BL6) cells was inhibited by cordycepin (3'-deoxyadenosine), an active ingredient of C. sinensis, and its effect was antagonized by MRS1191, a selective adenosine A3 receptor antagonist. In this study, the radioligand binding assay using [125I]-AB-MECA (a selective adenosine A3 receptor agonist) has shown that B16-BL6 cells express adenosine A3 receptors and that cordycepin binds to these receptors. We also confirmed the involvement of adenosine A3 receptors in the action of cordycepin using MRS1523 and MRS1220, specific adenosine A3 receptor antagonists. Next, indirubin, a glycogen synthase kinase-3beta (GSK-3beta) inhibitor, antagonized the growth suppression induced by cordycepin. Furthermore, the level of cyclin D1 protein in B16-BL6 cells was decreased by cordycepin using Western blot analysis. In conclusion, this study demonstrated that cordycepin inhibits the proliferation of B16-BL6 cells by stimulating adenosine A3 receptors followed by the Wnt signaling pathway, including GSK-3beta activation and cyclin D1 inhibition.

Upper gastrointestinal endoscopy (UGI-ES) and double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) are two major image-based methods to diagnose atrophic gastritis, which is mostly induced by Helicobacter pylori infection. However, there have been few studies directly comparing them.Atrophic gastritis was evaluated using the data of 962 healthy subjects who underwent UGI-ES and UGI-XR within 1 year.Based on UGI-ES and UGI-XR, 602 subjects did not have atrophic gastritis and 254 subjects did have it. Considering UGI-ES-based atrophic gastritis as the standard, sensitivity and specificity of UGI-XR-based atrophic gastritis were 92.0 % (254/276) and 92.8 % (602/649), respectively. The seven-grade Kimura-Takemoto classification of UGI-ES-based atrophic gastritis showed a strong and significant association with the four-grade UGI-XR-based atrophic gastritis. Sensitivity and specificity of serum anti-Helicobacter pylori IgG to detect UGI-ES/UGI-XR-based atrophic gastritis were 89.4 % (227/254) and 99.8 % (601/602), indicating that atrophic gastritis can be overlooked according to serum anti-Helicobacter pylori IgG alone.

Background There have been very few reports assessing the relationship between various upper gastrointestinal (GI) symptoms or evaluating each individual upper GI symptom separately. Methods Based on the answers to Frequency Scale for the Symptoms of GERD from a large-scale population of healthy adults in Japan, a hierarchical cluster analysis was performed to categorize the typical 12 upper GI symptoms. The associations between the 12 symptoms and 13 background factors were systematically analyzed among the 18,097 digestive drug-free subjects, 364 proton-pump inhibitor (PPI) users, and 528 histamine H2-receptor antagonist (H2RA) users. Results The derived relationship between the 12 upper GI symptoms suggests the five symptom categories: heartburn (2), dyspepsia (4), acid regurgitation (3), pharyngo-upper esophageal discomfort (2), and fullness while eating (1). Among the digestive drug-free subjects, inadequate sleep, weight gain in adulthood, NSAID use, meals immediately prior to sleep, and frequent skipping of breakfast showed significant positive association with most upper GI symptoms. Compared to the digestive drug-free subjects, significantly associated factors for PPI and H2RA users are respectively different in “4 of 5” and “5 of 5” symptoms in heartburn and acid regurgitation categories, “1 of 2” and “1 of 2” symptoms in pharyngo-upper esophageal discomfort category, and “0 of 5” and “3 of 5” symptoms in dyspepsia and fullness while eating categories. These differences between digestive drug-free subjects and gastric acid suppressant users seem to correlate with our experiences in clinical situations: heartburn and acid regurgitation category symptoms are effectively controlled with PPI and H2RA whereas other category symptoms are not. Conclusions The 12 upper GI symptoms can be classified into five categories, which are statistically associated with various background factors. The differences of associated factors between digestive drug-free subjects and digestive drug users may be useful in studying the drug effects upon diverse upper GI symptoms.

Our aim is to elucidate causative factors for gallstones, especially focusing on Helicobacter pylori (HP) infection.We analyzed 15,551 Japanese adults who had no history of gastrectomy, cholecystectomy, HP eradication, and didn't use proton pump inhibitors, anti-diabetic drugs, or anti-cholesterol drugs. 1,057 subjects who previously had HP eradication were analyzed separately.Gallstones were detected in 409 of 8,625 men (4.74%) and 285 of 6,926 women (4.11%) by ultrasonography. Among the 25 factors univariately analyzed, age, HP infection, alcohol intake, weight, body mass index (BMI), and 14 blood test values (AST, ALT, ALP, γ-GTP, T-Chol, HDL-Chol, LDL-Chol, TG, TP, Hb, HbA1c, pepsinogen I, pepsinogen II, and pepsinogen I/II ratio) displayed significant association with gallstones (p0.05), whereas gender, smoking, height, and three blood test values (Alb, T-Bil, MCV) did not. Multivariate analysis showed that age, gender, alcohol intake, BMI, γ-GTP, LDL-Chol, TP, and HP infection had significant association (p0.05). Successive multiple logistic regression analysis calculating odds ratio (OR) and standardized coefficients (β) showed that age (OR/β = 1.57/0.450), BMI (OR/β = 1.30/0.264), HP infection (OR/β = 1.51/0.206), lower alcohol intake (OR/β = 1.33/0.144), γ-GTP (OR/β = 1.15/0.139), and pepsinogen I/II ratio (OR/β = 1.08/0.038) have significant positive association with gallstones, whereas gender does not. The gallstone prevalence among HP-negative, HP-eradicated, and HP-positive subjects was 3.81, 4.73 and 6.08%, respectively. The matched analysis controlling age, BMI, γ-GTP, alcohol intake, pepsinogen I/II ratio and gender also demonstrated that gallstone prevalence among HP-eradicated subjects was significantly lower compared with HP-positive subjects (p0.05).HP infection is positively associated with gallstones. HP eradication may lead to prevention of gallstones.

The higher order structure of Mucor miehei lipase and micelle size in a cationic cetyltrimethylammonium bromide (CTAB) reverse micellar system was investigated. Circular dichroic (CD) measurement revealed that the lipase far-UV CD spectra changed markedly, going from buffer solution to the reverse micellar solution, and were very similar for any organic solvent used. The ellipticity of the solubilized lipase in the far-UV region markedly decreased with increasing water content ( W 0 : molar ratio of water to CTAB), indicating that the secondary structure of lipase changed with the water content. The linear correlation between the W 0 and the micelle size was obtained by measuring dynamic light scattering. From the linear correlation between the micelle size and W 0 , the higher order structure of the solubilized lipase appears to be affected directly by the micellar interface. The species and concentration of alcohol as a cosurfactant had an inferior effect on lipase structure. Especially, at ratios of 1-pentanol to CTAB of less than 8, the secondary and tertiary structures of lipase were preserved in the reverse micelles. The CTAB concentration had little effect on the lipase structure in the micelles. The catalytic activity of the lipase solubilized in the CTAB reverse micelles increased with increasing the W 0 .

Background Double-contrast upper gastrointestinal barium X-ray radiography (UGI-XR) is one of the most widely conducted gastric cancer screening methods. It has been executed to find gastric cancer, but has not been usually executed to detect premalignant atrophic mucosa of stomach. To understand the meaning of UGI-XR-based atrophic gastritis, we analyzed its association with several causative factors including Helicobacter pylori (HP) infection. Methods We evaluated 6,901 healthy adults in Japan. UGI-XR-based atrophic gastritis was diagnosed based on the irregular shape of areae gastricae and its expansion in the stomach. Results Of the 6,433 subjects with no history of HP eradication and free from gastric acid suppressants, 1,936 were diagnosed as UGI-XR-based atrophic gastritis (mild: 234, moderate: 822, severe: 880). These were univariately associated with serum HP IgG and serum pepsinogen I/II ratio with statistical significance. The multiple logistic analysis calculating standardized coefficients (β) and odds ratio (OR) demonstrated that serum HP IgG (β = 1.499, OR = 4.48), current smoking (β = 0.526, OR = 1.69), age (β = 0.401, OR = 1.49), low serum pepsinogen I/II ratio (β = 0.339, OR = 1.40), and male gender (β = 0.306, OR = 1.36) showed significant positive association with UGI-XR-based atrophic gastritis whereas drinking and body mass index did not. Among the age/sex/smoking/drinking-matched 227 pairs derived from chronically HP-infected and successfully HP-eradicated subjects, UGI-XR-based atrophic gastritis was detected in 99.1% of the former but in only 59.5% of the latter subjects (p