Katsuya Endo

Structures of antifungal diarylheptenones, gingerenones A, B, C and isogingerenone B, isolated from the rhizomes of Zingiber officinale

Abstract Four new diarylheptenones, 1,7-bis(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (gingerenone A), 7-(3,5-dimethoxy-4-hydroxyphenyl)-1-(4-hydroxy-3-methoxyphenyl) hept-4-en-3-one(gingerenone B), 1-(3,5-dimethoxy-4-hydroxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)hept-4-en-3-one (isogingerenone B) and 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hept-4-en-3-one (gingerenone C) have been isolated from the rhizomes of Zingiber officinale , and their structures established by spectral methods and some chemical transformations. The results indicate the similarity in the metabolic fates of the curcuminoid constituents to those of the arylalkanoids (dehydrogingerdione → gingerol → shogaol) of zingiberaceous plants. Gingerenone A exhibited a moderate anticoccidium activity in vitro and a strong antifungal effect to Pyricularia oryzae .

TNFSF15 transcripts from risk haplotype for Crohn's disease are overexpressed in stimulated T cells

TNFSF15 is a susceptibility gene for Crohns disease (CD). It remains to be elucidated how the associated single nucleotide polymorphisms (SNPs) in TNFSF15 affect the susceptibility to CD. Because there are no non-synonymous SNPs in TNFSF15, we speculated that one or more of the SNPs associated with CD may act as cis-regulatory SNPs. To reveal the effects of the SNPs on the transcriptional activity of TNFSF15, we first examined the allelic expression imbalance of TNFSF15 in peripheral blood mononuclear cells (PBMCs). When PBMCs stimulated by phytohemagglutinin (PHA) were examined, the allelic ratio of mRNA transcribed from the risk haplotype to the non-risk haplotype increased, compared with the ratio without stimulation. When peripheral blood T cells and Jurkat cells stimulated by phorbol 12-myristate 13-acetate + ionomycin were examined, an allelic expression imbalance similar to that observed in PBMCs stimulated by PHA was confirmed. The promoter assay in stimulated Jurkat cells showed that the luciferase activity of the promoter region (-979 to +35) of the risk haplotype was significantly higher than that of the non-risk haplotype, and deletion and mutagenesis analysis demonstrated that this difference resulted from the -358T/C SNP. The promoter activity of -358C (risk allele) was higher than that of -358T (non-risk allele) in stimulated T cells. This effect of -358T/C on the transcriptional activity in stimulated T cells may confer susceptibility to CD.

Changes of faecal microbiota in patients with Crohn's disease treated with an elemental diet and total parenteral nutrition.

BACKGROUND Intestinal microbiota contributes to the pathogenesis of Crohns disease. Elemental diet and total parenteral nutrition are effective therapies for Crohns disease; however, changes of microbiota as a result of both treatments have not been fully elucidated. AIM To elucidate changes of faecal microbiota in Crohns disease patients treated with elemental diet and total parenteral nutrition. METHODS Stool samples were collected from 33 active Crohns disease patients and 17 healthy subjects, and recollected after elemental diet (8 patients) and total parenteral nutrition (9 patients). Terminal restriction fragment length polymorphism analysis of bacterial 16srDNA was performed to evaluate the whole microbiota. Specific quantitative PCR was then used to determine populations of predominant bacterial groups. RESULTS In Crohns disease patients, the number of terminal restriction fragments, which reflects bacterial species, was significantly lower. Populations of total bacteria and Bifidobacterium were significantly lower and the ratio of Enterococcus was higher. The number of terminal restriction fragments was significantly decreased after total parenteral nutrition, but not after elemental diet. Population of Bacteroides fragilis significantly decreased after elemental diet, while population of Enterococcus significantly increased after total parenteral nutrition. CONCLUSION Faecal microbiota in Crohns disease patients was markedly different from healthy subjects. Species diversity was reduced by total parenteral nutrition, but not by elemental diet.

Structure of ephedradine A, a hypotensive principle of Ephedra roots

Abstract A novel flavano-flavonol ephedramin A showing the hypotensive activity has been isolated from the crude drug “ma o -kon”, the roots of Ephedra plants. The stereostructure of ephedrannin A has been elucidated as that represented by formula I on the basis of chemical and physical evidence.

Short and long-term outcomes of endoscopic balloon dilatation for Crohn’s disease strictures

AIM To investigate the short and long-term outcomes of endoscopic balloon dilatation (EBD) for Crohns disease (CD) strictures. METHODS Between January 1995 and December 2011, 47 EBD procedures were performed in 30 patients (8 females and 22 males) with CD. All patients had strictures through which an endoscope could not pass, and symptoms of these strictures included abdominal pain, abdominal fullness, nausea, and/or vomiting. The 47 strictures included 17 anastomotic and 30 de novo strictures. Endoscopy and dilatation were performed under conscious sedation with intravenous diazepam or flunitrazepam. The dilatations were all performed using through-the-scope balloons with diameters from 8 mm to 20 mm on inflation and lengths of 30-80 mm. Each dilatation session consisted of two to four, 3-min multistep inflations of the balloon, repeated at intervals of 1 wk until adequate dilatation (up to 15-20 mm in diameter) was achieved. The follow-up data were collected from medical records and analyzed retrospectively. Primary success was defined as passage of the scope through the stricture after EBD. Long-term outcomes were analyzed focusing on intervention-free survival and surgery-free survival demonstrated by the Kaplan-Meier method. (Intervention-free meant cases in which neither endoscopic balloon re-dilatation nor surgery was needed after the first dilatation during the observation period). The log rank test was used to evaluate the difference in long-term outcomes between anastomotic and de novo stricture cases. RESULTS Primary success was achieved in 44 of the 47 strictures (93.6%). Balloon dilatations failed in 3 cases (6.4%). In 1 case, EBD was a technical failure because the guide-wire could not be passed through the stricture which showed severe adhesion and was a flexural lesion of the intestine. In 2 cases, unexpected perforations occurred immediately after balloon dilatation. Of the 47 treatments, complications occurred in 5 (10.6%). All 5 patients had de novo strictures. One suffered bleeding, two high fever and there were colorectal perforations. One of the patients with a colorectal perforation was treated surgically, the other was managed conservatively. These 2 cases correspond to the two aforementioned EBD failures. Long-term outcomes were evaluated for the 44 successfully-treated strictures after a median follow-up of 26 mo (range, 2-172 mo). During the observation period, re-strictures after EBDs occurred in 26 cases (60.5%). Fourteen of these 26 re-stricture cases underwent EBD again, but in two EBD failed and surgery was ultimately performed in both cases. Twelve of the 26 re-stricture cases were initially treated surgically when the re-strictures occurred. Finally, 30 of the 47 strictures (63.8%) were successfully managed with EBD, allowing surgery to be avoided. Intervention-free survival evaluated by the Kaplan-Meier method was 75% at 12 mo, 58% at 24 mo, and 43% at 36 mo. There was no significant difference between the anastomotic strictures (n = 16) and de novo strictures (n = 28) in the intervention-free survival as evaluated by the log-rank test. Surgery-free survival evaluated by the Kaplan-Meier method was 90% at 12 mo, 75% at 24 mo, and 53% at 36 mo. The 16 anastomotic strictures were associated with significantly better surgery-free survivals than the 28 de novo strictures (log-rank test: P < 0.05). CONCLUSION Anastomotic strictures were associated with better long-term outcomes than de novo strictures, indicating that stricture type might be useful for predicting the long-term outcomes of EBD.

Biogenesis-like transformation of salidroside to rengyol and its related cyclohexyletanoids of forsythia suspensa

Abstract Photooxygenation of salidroside (8) in methanol in presence of Rose Bengal afforded cornoside (9) , which, on high pressure hydrogenation with 5 % palladium on activated carbon, yielded rengyoside B (6) Reduction of 6 with sodium borohydride gave rengyoside A (5) stereoselectively. By enzymatic hydrolysis, 9 , 6 and 5 furnished rengyolone (4) , rengyoxide (3) and rengyol (1) , respectively. Similarly, p -hydroxyphenylethanol (10) , the aglycone part of salidroside (8) , was oxygenated photochemically to a dienone alcohol, which cyclized spontaneously to rengyolone (4) . Hallerone (17) was obtained by the photooxygenation of p -hydroxyphenylethyl acetate (10b) . Thus the plausible biosynthetic routes from salidroside (8) to rengyol (1) and the related natural cyclohexylethanoids were simulated chemically.

NMR studies and structural assignment of paederoside

Detailed and extensive nmr analyses of paederoside have been carried out resulting to allow complete assignment of all of the 1 H and 13 C signals. The results provided unambiguous bases to support methyl thiocarbonate structure (3) for paederoside, a novel natural sulfur-containing iridoid glucoside of Paederia scandens

Erratum to: FCGR3A-158 polymorphism influences the biological response to infliximab in Crohn’s disease through affecting the ADCC activity

An association between FCGR3A-158 V/F polymorphism and biological responses to infliximab has been reported in Crohn’s disease (CD) in Western countries. However, little is known about the mechanism by which gene polymorphism affects the responses to infliximab. The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab. Japanese CD patients were examined retrospectively at weeks 8 and 30. Clinical and biological responses were assessed by the Crohn’s disease activity index and C-reactive protein levels, respectively. The infliximab-binding affinity of natural killer (NK) cells from FCGR3A-158 V/V, V/F and F/F donors was examined. Infliximab-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) activities were also determined using transmembrane TNF-α-expressing Jurkat T cells as target cells and peripheral blood mononuclear cells (PBMCs) from V/V, V/F and F/F donors as effector cells. Biological responses at week 8 were statistically higher in V/V patients, whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes. NK cells and PBMCs from V/V patients also showed higher infliximab-binding affinity and infliximab-mediated ADCC activity, respectively. Our results suggest that FCGR3A-158 polymorphism is a predicting factor of biological responses to infliximab in the early phases. FCGR3A-158 polymorphism was also found to affect the infliximab-binding affinity of NK cells and infliximab-mediated ADCC activity in vitro, suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients.

Structures of rengyosides A, B and C, three glucosides of Forsythia suspensa fruits

Abstract Three new glucosides, rengyosides A, B and C, having as aglycones the reduced forms of phenylethanol were isolated from Forsythia suspensa fruits. Chemical and spectroscopic studies established the structures of these natural products to be 2-(1,4-dihydroxycyclohexyl)ethyl β- d -glucopyranoside, 2-(1-hydroxy-4-ketocyclohexyl)ethyl β- d -glucopyranoside and 2-(1,4-dihydroxycyclohexyl)ethyl β- d -6-O-[2-(4-hydroxyphenyl)acetyl]glucopyranoside, respectively. Salidroside, a possible biogenetic precursor of these glucosides, was also isolated.

Modulation of endoplasmic reticulum (ER) stress-induced autophagy by C/EBP homologous protein (CHOP) and inositol-requiring enzyme 1α (IRE1α) in human colon cancer cells.

To explore the relationship between UPR and autophagy in intestinal epithelial cells, we investigated whether autophagy was induced by endoplasmic reticulum (ER) stress in colon cancer cell lines. We demonstrated that autophagy was induced by ER stress in HT29, SW480, and Caco-2 cells. In these cells, inositol-requiring enzyme1α (IRE1α) and C/EBP homologous protein (CHOP) were involved in the ER stress-autophagy pathway, and CHOP was a regulator of IRE1α protein expression. Our findings suggest that CHOP promotes IRE1α and autophagy especially in ER stress conditions. This study will provide important insights into the disclosure of the ER stress-autophagy pathway.