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An 80-year-old man presented to our hospital with general fatigue on exertion that had gradually worsened over 6 months. His blood test revealed severe anemia, and gastroscopy revealed findings consistent with gastric antral vascular ectasia (GAVE) and autoimmune gastritis. We diagnosed the patient with severe anemia caused by GAVE and autoimmune gastritis. The present case suggested that GAVE is triggered by autoimmune gastritis, and the mechanism is likely related to hypergastrinemia. The reporting of this rare case may help elucidate the cause of GAVE, which is currently unknown.

A 77-year-old man complained of postmeal vomiting and sustained general fatigue. An abdominal computed tomography scan showed massive gastric expansion and fluid storage. Gastroscopy revealed four gastric bezoars that were considered to have caused pyloric ring obstruction. The patient was asked to drink 500 mL per day of Coca-Cola® for 4 days. On the fourth day, we performed endoscopic crushing and removal by injecting Coca-Cola®, cutting the softened bezoar with endoscopic snares, and collecting the pieces with endoscopic nets. We herein report (with a video presentation) a rare case of tannin-phytobezoars endoscopically removed with the administration and injection of Coca-Cola®.

This paper describes the syntheses of four types of nitrile N-oxides (NOs) and studies on the thermal isomerization of NOs to isocyanates (Isocs). It is found that a bulky electron-withdrawing subs...

A 74-year-old woman with recurrent gastric cancer underwent laparotomy for peritoneal dissemination, and the damaged jejunum formed a jejunocutaneous fistula. Because conservative treatment alone could not cure the fistula, we performed an endoscopic placement of a partially covered self-expandable metallic stent (SEMS) to cover the fistula. After the procedure, the contrast medium no longer leaked from the intestinal lumen. One month after stent placement, the cutaneous opening had closed. This case report demonstrates the potential for using partially covered SEMS to treat intractable jejunocutaneous fistula in patients with terminal-stage malignant tumors.

The procyanidin B series is a family of dimeric flavonoids composed of catechin(s) and/or epicatechin(s) with a C4-C8′ interflavan bond. We previously reported four TMSOTf-promoted couplings for C4...

Lignin acylated with acetate and/or p-coumarate is common in many herbaceous plants. Herein, the biomimetic oxidation of γ-acylated monolignols with Ag2O was studied to understand the effect of γ-acyl groups on monolignol polymerization. The oxidation of sinapyl acetate gave γ-acylated and α-acylated β-O-4 dimers in 71 and 9.5% yields, respectively. The oxidation of sinapyl p-coumarate produced γ-acylated β-O-4 and γ-acylated tetralin β-β dimers in 53 and 16% yields, respectively. Only the sinapyl alcohol moiety in sinapyl p-coumarate reacted, and the p-coumarate moiety remained unchanged, suggesting that p-coumaric acid is not incorporated into the lignin backbone in the acylated lignins. All of the γ-acylated monolignols used in this study produced the γ-acylated β-O-4 dimers, which suggests that the γ-acylated monolignols act as lignin monomers. The relatively high yields of the β-O-4 dimers indicate that Ag2O oxidation of the monolignols can be used as an easy method for synthesizing the β-O-4 dimer model compounds.

Background: The association between obstructive sleep apnea syndrome (OSAS) and gastroesophageal reflux disease has been reported in multiple studies and meta-analyses. Although obesity has been cited as a common risk factor for both conditions, in Far East Asia, sleep apnea is often attributed to craniofacial anatomy, and patients with obstructive sleep apnea are not necessarily obese. In the present study, we investigated whether there is an association between obstructive sleep apnea and gastroesophageal reflux after adjusting for obesity.Method: The subjects were 230 patients with sleep disorders who visited the Sleep Center at Osaka Kaisei Hospital between May 2016 and November 2017. All patients underwent esophagogastroduodenoscopy. They were diagnosed with sleep disorders by a respiratory specialist, and all patients with suspected OSAS underwent polysomnography/portable monitoring. BMI was measured from the height and weight of all patients, and they were categorized into three groups: non-obese OSAS, obese OSAS, and control (non-OSAS). The presence or absence of reflux esophagitis in each group was compared using the Los Angeles classification.Results: There were 138 patients in the obese OSAS group, 71 patients in the non-obese OSAS group, and 21 patients in the control group. There was a greater prevalence of reflux esophagitis both in the obese and non-obese OSAS groups compared with the control group (both ppp=0.64).Conclusions: In patients with sleep disorders, OSAS is associated with gastroesophageal reflux regardless of obesity. Alcohol consumption is also a major factor in non-obese patients with OSAS. Since alcohol consumption is associated with the risk of esophageal squamous cell carcinoma and gastroesophageal reflux is associated with the risk of esophageal adenocarcinoma, regular upper gastrointestinal endoscopy is thought to be necessary in patients at risk.

A 77-year-old man complained of postmeal vomiting and sustained general fatigue. An abdominal computed tomography scan showed massive gastric expansion and fluid storage. Gastroscopy revealed four gastric bezoars that were considered to have caused pyloric ring obstruction. The patient was asked to drink 500 mL per day of Coca-Cola

α-Galactosyl ceramide (GalCer) is an anticancer glycolipid consisting of d-galactose and phytosphingosine-based ceramide. Although the amphiphilic structure of GalCer is expected to form self-associates in water, the self-assembly behaviors of GalCer and its derivatives have not been systematically investigated at this moment in spite of its great importance. The evaluation of morphologies and properties of the associates should open new insights into glycolipid chemistry such as the application of GalCer derivatives to a nanocarrier and the elucidation of the detailed pharmacological mechanism of GalCer. Herein, we show the synthesis of the aglycon fragment (Aglycon) of GalCer and the self-assembly behaviors of both GalCer and Aglycon in water. The critical aggregation concentrations of Aglycon and GalCer were determined using UV-vis spectral measurements at various concentrations. The transmission electron microscopy observations of the aqueous sample solutions indicated that the solution of GalCer includes vesicles, while that of Aglycon comprises giant micelles in the absence of vesicles. The vesicle formation in the solution of GalCer was also confirmed by Triton X-100-triggered dye-release experiments. To reveal the effects of glycon on the self-assembly behaviors in detail, we performed the measurements of dynamic light scattering, temperature-dependence of turbidity, differential scanning calorimetry, and wide-angle X-ray diffraction. The results clarify that the glycon moiety of GalCer has a significant role in the formation inhibition of second associates and the plasticization of the hydrophobe. This work will shed light on the other natural glycosides to evaluate the self-assembly behaviors for supramolecular and pharmacological applications in the near future.

Recently, conversion of lignocellulose into useful substances has attracted increasing attention. In our previous investigations, microcrystalline cellulose was successfully converted to methyl glucopyranosides (MeGlc) by the combined use of ionic liquid (IL) and microwave irradiation under moderate reaction conditions. In this study, lignocelluloses, including softwood, hardwood, and rice straw, were directly converted to methyl glycopyranosides (MG), including MeGlc, methyl mannopyranosides (MeMan), and methyl xylopyranosides (MeXyl) using acid-catalyzed methanolysis under microwave irradiation in ILs. Lignocellulose ball-milling was quite effective as a crucial process of increasing the yield of MG. Under the optimized reaction conditions, the molar yield of MeGlc reached 40% from softwood, which was a comparable yield from microcrystalline cellulose. MeXyl was also obtained in a 48% yield. These results showed that the combination of the dissolution of ball-milled lignocellulose in IL and the microwave-assisted methanolysis was an effective method of converting lignocellulose into a high-value-added substance.

Lignin acylated with acetate and/or

Conversion of lignocellulose into useful chemicals is an important research topic in the area of biomass utilization. In this study, microcrystalline cellulose (MC) was dissolved in a mixed-solvent system containing the ionic liquid (IL) 1-allyl-3-methylimidazolium chloride ([Amim]Cl) and N-methyl-pyrrolidone (NMP), and the cellulose was directly converted into methyl glucoside (MG) by acid-catalyzed methanolysis aided by microwave irradiation (μWIr). Under moderate reaction temperature and pressure, and in the presence of acetyl chloride/methanol (in situ formed HCl) as an acid catalyst, MG was obtained in a 42% yield. In contrast, in the absence of either IL or μWIr, the MG yield was only 5 or 21%, respectively. Both μWIr and the dissolution of cellulose in IL were quite effective for the conversion of cellulose into MG.

We previously reported the total synthesis of procyanidin B6 by using the stereo- and regioselective C-C bond formation of tethered catechin moieties as the key step. The reaction afforded the product bearing a new C4α-C6' bond linkage instead of the inherently preferable C4α-C8' bond. However, the origin of this selectivity remained unclear due to the complex structure of the substrate. Here we report the results of computational exploration of this C-C bond formation to gain mechanistic insights into the selectivity. The computational study of highly flexible compounds was realized by an exhaustive search of transition states. A large library of candidate transition states was generated by a conformational search of constrained models using molecular mechanics simulations and semiempirical molecular orbital calculations. Subsequent DFT-based transition state calculations provided 367 transition states for C4-C6' and C4-C8' bond formations. Comparison of the geometries and energies showed that the C4α-C6' linkage is preferentially formed via two competing transition states, leading to a C6'-diastereomeric mixture. Interactive atomic distances and visualization of the nonbonding interactions suggest the importance of nonclassical hydrogen bonding and CH-π, π-π, and lone pair-π interactions in stabilizing the two transition states. The present study supports preferential C4α-C6' bond formation of the tethered catechins.

A new approach for the enzymatic synthesis of methyl β-d-glucoside was proposed, based on commercially available cellulase and cellulose pretreated with phosphonium-based amino acid ionic liquid/cosolvent. The pretreatments were quite effective and methyl β-d-glucoside was successfully synthesized with 40% yield from cellulose (Avicel) pretreated with tetrabutylphosphonium glycine/dimethyl sulfoxide (DMSO), whereas the yield was only 1.4% from untreated cellulose. Preparative-scale synthesis from 1 g cellulose with a reduced amount of cellulase was also conducted, achieving a 33% isolated yield. Results of additional studies with cellobiose and glucose as substrates have been interpreted as cellulose being first enzymatically hydrolyzed to cellobiose, which then reacted with methanol to produce methyl β-d-glucoside by transglycosylation.

The potential of halogen-free and imidazolium-free phosphonium-based amino acid ionic liquids (AAILs) has been investigated as new solvents for cellulose pretreatment for the subsequent enzymatic hydrolysis of cellulose. AAILs alone did not dissolve cellulose (Avicel), even at 120°C. However, when polar solvents such as dimethylsulfoxide (DMSO) were added as cosolvents, AAILs became an acceptable solvent for cellulose at 30°C. The solubility of cellulose in tetrabutylphosphonium glycine ([TBP][Gly])/cosolvent reached 15%. The enzymatic hydrolysis of cellulose was dramatically enhanced by pretreatment with AAIL/cosolvent, and the glucose yield reached 100% when the novel AAIL tetrabutylphosphonium N,N-dimethylglycine ([TBP][DMGly]) was used in combination with DMSO as cosolvent. The enzymatic conversion of cellulose to glucose in 6% and 13% [TBP][DMGly]/DMSO buffer solutions reached 98% and 79%, respectively. The decrease in cellulase activity owing to residual [TBP][DMGly]/DMSO was not significant. Hence, it is possible to conduct the dissolution and enzymatic hydrolysis of cellulose in a one-batch process in a phosphonium-based AAIL/cosolvent system.

Proanthocyanidins, which are composed of oligomeric flavan-3-ol units, are contained in various foodstuffs (e.g., fruits, vegetables, and drinks) and are strongly biologically active compounds. We investigated which element of the proanthocyanidin structure is primarily responsible for this functionality. In this study, we elucidate the importance of the upper-unit of 4–8 condensed dimeric flavan-3-ols for antimicrobial activity against Saccharomyces cerevisiae (S. cerevisiae) and cervical epithelioid carcinoma cell line HeLa S3 proliferation inhibitory activity. To clarify the important constituent unit of proanthocyanidin, we synthesized four dimeric compounds, (−)-epigallocatechin-[4,8]-(+)-catechin, (−)-epigallocatechin-[4,8]-(−)-epigallocatechin, (−)-epigallocatechin-[4,8]-(−)-epigallocatechin-3-O-gallate, and (+)-catechin-[4,8]-(−)-epigallocatechin and performed structure–activity relationship (SAR) studies. In addition to antimicrobial activity against S. cerevisiae and proliferation inhibitory activity on HeLa S3 cells, the correlation of 2,2-diphenyl-l-picrylhydrazyl radical scavenging activity with the number of phenolic hydroxyl groups was low. On the basis of the results of our SAR studies, we concluded that B-ring hydroxyl groups of the upper-unit of the dimer are crucially important for strong and effective activity.

To improve the solubility of cellulose at lower temperatures, several polar organic solvents were examined as cosolvents in imidazolium ionic liquid (IL). All tested cosolvents increased the solubilization efficiency of ILs at lower temperatures. Among these, N-methylimidazole, N-methyl-2-pyrrolidone, and dimethyl sulfoxide (DMSO) were notably efficient; in case of Avicel the solubility was increased, with 12–15% cellulose dissolution in 1-allyl-3-methylimidazolium chloride ([Amim]Cl) at 30°C. IR spectra of the regenerated celluloses from IL/cosolvent systems showed characteristic features of cellulose II and/or amorphous cellulose. Thermogravimetric analyses showed significantly higher thermal stability of regenerated cellulose from [Amim]Cl/DMSO compared with that without DMSO. Moreover, dimethylacetamide (DMAc) increased the solubility of filter paper pulp in 1-ethyl-3-methylimidazolium acetate ([Emim]OAc), with 12% pulp dissolution at 30°C. No decrease in the degree of polymerization (DP) of cellulose was observed with [Emim]OAc/DMAc, whereas 8–9% DP decrease was observed with [Emim]OAc, even at 30°C. These results indicate that some cosolvents including DMSO and DMAc increase solubilization efficiency and have superior cellulose-protective effects during enhanced dissolution in ILs.

Quercetin is a major flavonoid, present as its glycosidic forms in plant foods. In this study, quercetin-3-glucoside (Q3G) was administered intraduodenally to thoracic lymph-cannulated rats, and its lymphatic transport was investigated. The resulting lymphatic and plasma metabolites were identified with LC-MS/MS and compared with those after administration of quercetin aglycone. The total concentration of quercetin metabolites in the lymph was about four times lower than that in the plasma, and quercetin and its methylated form isorhamnetin were detected as their glucuronides, sulfates and diglucuronides both in the lymph and the plasma after Q3G and quercetin administrations. The lymph levels of the glucuronides after Q3G administration were lower than those after quercetin administration, whereas those in the plasma showed the opposite pattern. Both the lymph and plasma levels of the sulfates after Q3G administration were lower than those after quercetin administration. Some of the intestinal metabolites like quercetin monoglucuronides were transported directly into the lymph and the hepatic metabolites like the diglucuronides were eventually transferred from the plasma into the lymph. These results indicate that the absorbed Q3G is partly transported into the intestinal lymph as quercetin metabolites. Deglycosylation in the enterocyte is also suggested to affect the subsequent metabolic pathways.

Flavan-3-ol derivatives are common plant-derived bioactive compounds with strong various biological activities. In particular, (–)-epigallocatechin-3-O-gallate exhibits a variety of moderate biological activities without severe toxicity. Its health-promoting effects have been widely studied because it is a main ingredient in green tea and is commercially available at low cost. In general, the galloyl moieties of flavan-3-ol derivatives are thought to be essential to their strong biological activities. However, it is not clear which position is most effective for modification with the galloyl moiety to strengthen the biological activities because various galloylated analogs are difficult to obtain in pure form in a quantity large enough for assays. Therefore, we synthesized various galloylated flavan-3-ol derivatives in a stereoselective and regioselective manner. We reported in a previous paper that 3,5-digalloyl-(–)-epicatechin displayed much stronger inhibitory activity than 3,5-digalloyl-(+)-catechin did against HeLa S3 cell proliferation. In this study, we describe synthetic studies of 7-galloyl- and 3,7-digalloyl-modified (–)-epicatechin and (+)-catechin and compared their biological activities, HeLa S3 cell proliferation inhibitory activity and DPPH radical scavenging activity with those of 3,5- digalloyl- (–)-epicatechin. The results indicated that 3,7-digalloyl derivative did not inhibit HeLa S3 cell proliferation. Furthermore, 3,5-digalloyl- (–)-epigallocatechin was synthesized to evaluate the importance of the number of phenolic hydroxyl groups on the B-ring. Contrary to our expectations, 3,5-digalloyl-(–)-epigallocatechin exhibited a weaker inhibition of HeLa S3 cell proliferation than 3,5-digalloyl- (–)-epicatechin did. The DPPH radical scavenging activity of the synthesized compounds suggested that the galloyl-modified position and the number of phenolic hydroxyl groups on B-ring affected to the radical scavenging ability. In conclusion, we found that 3,5-digalloyl-(–)-epicatechin exhibited a superlative HeLa S3 cell proliferation inhibitory effect among the galloylated flavan-3-ol derivatives we synthesized and DPPH radical scavenging activity was affected by the galloyl-moiety-introduced position and the number of phenolic hydroxyl groups on the B-ring.

The intramolecular [4–8] coupling of silyl-protected catechin and epicatechins is examined. Coupling reaction of silyl-protected epicatechin/catechin, epicatechin/epicatechin, catechin/catechin and catechin/epicatechin worked well to afford the corresponding dimers with excellent selectivity and yield. The series of procyanidin B analogues synthesis are achieved. We also carried out the synthesis of 3-O- and/or 5-O-acyl-catechin and epicatechin derivatives on a gram scale.

Tea catechins such as epicatechin, epigallocatechin, epicatechin gallate and epigallocatechin gallate afford many metabolites, including γ-valerolactone derivatives, through metabolic pathways in the human body. Two of these γ-valerolactone metabolite analogues with a 2′-hydroxyphenyl group were synthesized as optically active authentic standards.

Recently, a method was presented for the dissolution and nuclear magnetic resonance analysis of cell wall components in lignocellulosic biomass, which involves cell wall ball-milling, dissolution in ionic liquids (ILs), in situ acetylation, and the recovery of acetylated materials. However, the dissolution in ILs and the relatively long ball-milling times may partially degrade the plant cell wall components. In the present study, the molecular weight (MW) distributions of acetylated biomasses from fir (Abies sachalinensis), birch (Betula platyphylla), and bamboo (Phyllostachys nigra) recovered from IL systems were examined by size exclusion chromatography. The effects of IL types, cosolvents, dissolution temperatures and times, and ball-milling times were evaluated. The MW of acetylated fir woods recovered from 1-allyl-3-methylimidazolium chloride at 30–80°C or from 1-butyl-3-methylimidazolium chloride at 100°C for 2 h were similar to those materials that were recovered from the N-methylimidazole/dimethyl sulfoxide system. In contrast, a significant decrease in MW was observed with 1-ethyl-3-methylimidazolium acetate ([Emim]OAc) even at 30°C. The degradation of cell wall components in [Emim]OAc was reduced to some extent in the presence of N,N-dimethylacetamide or pyridine. The MW decreased gradually with increased ball-milling time.

A facile synthetic route is described to cyanogenic glycosides (R)-prunasin, linamarin and (S)-heterodendrin from O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)trichloroace- timidate and the corresponding α-hydroxyamides by a 3-step reaction of glycosylation, cyanohydrin formation by dehydration of carboxamides, and deprotection.

Glucuronidation is one of the most common pathways in mammals for detoxification and elimination of hydrophobic xenobiotic compounds, including many drugs. Metabolites, however, can form active or toxic compounds, such as acyl glucuronides, and their safety assessment is often needed. The absence of efficient means for in vitro synthesis of correct glucuronide metabolites frequently limits such toxicological analyses. To overcome this hurdle we have developed a new approach, the essence of which is a coexpression system containing a human, or another mammalian UDP-glucuronosyltransferases (UGTs), as well as UDP-glucose-6-dehydrogenase (UGDH), within the budding yeast, Saccharomyces cerevisiae. The system was first tested using resting yeast cells coexpressing UGDH and human UGT1A6, 7-hydroxycoumarin as the substrate, in a reaction medium containing 8% glucose, serving as a source of UDP-glucuronic acid. Glucuronides were readily formed and recovered from the medium. Subsequently, by selecting suitable mammalian UGT enzyme for the coexpression system we could obtain the desired glucuronides of various compounds, including molecules with multiple conjugation sites and acyl glucuronides of several carboxylic acid containing drugs, namely, mefenamic acid, flufenamic acid, and zomepirac. In conclusion, a new and flexible yeast system with mammalian UGTs has been developed that exhibits a capacity for efficient production of various glucuronides, including acyl glucuronides.

Nuclear magnetic resonance (NMR) analysis of entire plant cell walls without isolating their components gained importance over the last decade. Recently, a dissolution method and an NMR analysis of entire plant cell walls were reported, in which finely ball-milled lignocellulosic biomass was dissolved at 100°C in the ionic liquid (IL) 1-butyl-3-methylimidazolium chloride. In the present study, several ILs were examined with or without co-solvent to find milder dissolution conditions to mitigate possible degradation processes. Co-solvents, including N,N-dimethylacetamide, pyridine, and dimethyl sulfoxide, increased the solubilization efficiency of ILs. For example, ball-milled fir wood was completely dissolved in 1-allyl-3-methylimidazolium chloride ([Amim]Cl) at 30°C in the presence of these co-solvents. The heteronuclear single-quantum coherence NMR spectra of acetylated fir, birch, and bamboo cell walls, which were recovered from [Amim]Cl/pyridine (1:1, w/w) solution, had a high analytical power.

A method for nuclear magnetic resonance (NMR) characterization of whole cell wall components, including lignin, cellulose and hemicelluloses, was recently developed in our laboratory. The method described for fir (Abies sachalinensis) as a softwood consists of ball-milling of cell wall, dissolution in an ionic liquid 1-butyl-3-methylimidazolium chloride ([Bmim]Cl), in situ acetylation, recovery of the material from the solution, and characterization of the product by 1H-13C correlation heteronuclear single quantum coherence (HSQC) NMR spectroscopy in dimethyl sulfoxide (DMSO)-d6. In the present paper, the performance of the method should be tested for a hardwood and a bamboo. Thus, Japanese white birch (Betula platyphylla) and hachiku bamboo (Phyllostachys nigra) have been investigated. Finely ball-milled birch and bamboo materials were completely dissolved in [Bmim]Cl at 100°C without severe chemical modification of the cell wall components. The dissolved cell walls were then subjected to in situ acetylation, and the ball-milled and fully acetylated cell walls were recovered from [Bmim]Cl. Longer ball-milling time was required for birch and bamboo cell walls, because of the lower solubility of acetylated birch and bamboo materials in DMSO-d6compared to the acetylated fir material. However, HSQC NMR experiments were successfully conducted, and the acetylated whole cell wall components in the birch and bamboo could be fully characterized. This method is applicable for the analysis of cell wall components of various plant biomasses without previous isolation. Further studies are necessary to improve the method.

Ethanol extracts from 15 kinds of marine algae collected from the coast of the Noto Peninsula in Japan were examined for their inhibitory effects on human salivary α-amylase. Four extracts significantly suppressed the enzyme activity. An inhibitor was purified from the extract of Sargassum patens . The compound was a new phloroglucinol derivative, 2-(4-(3,5-dihydroxyphenoxy)-3,5-dihydroxyphenoxy) benzene-1,3,5-triol (DDBT), which strongly suppressed the hydrolysis of amylopectin by human salivary and pancreatic α-amylases. The 50% inhibitory activity (IC(50)) for α-amylase inhibition of DDBT (3.2 μg/mL) was much lower than that of commercially available α-amylase inhibitors, acarbose (26.3 μg/mL), quercetagetin (764 μg/mL), and α-amylase inhibitor from Triticum aestivum (88.3 μg/mL). A kinetic study indicated that DDBT was a competitive α-amylase inhibitor with a K(i) of 1.8 μg/mL. DDBT also inhibited rat intestinal α-glucosidase with an IC(50) value of 25.4 μg/mL for sucrase activity and 114 μg/mL for maltase activity. These results suggest that DDBT, a potent inhibitor of carbohydrate-hydrolyzing enzymes, may be useful as a natural nutraceutical to prevent diabetes.

Catechins in green tea display anti-cancer and anti-angiogenesis activities. We previously found that some catechins, such as epigallocatechin-3-O-gallate (EGCG), inhibit the activities of eukaryotic DNA polymerases (pols) (Y. Mizushina et al.: Structural analysis of catechin derivatives as mammalian DNA polymerase inhibitors. Biochem Biophys Res Commun 333, 101-109 (2005)). In this study, we discuss the effects of chemical modifications of catechin and epicatechin that enhance their anti-cancer and anti-angiogenic activities based on pol inhibition. Catechins conjugated with fatty acid (3-O-acylcatechins) are stronger inhibitors of mammalian pol than epicatechins conjugated with fatty acid (3-O-acylepicatechins). Moreover, 3-O-acylcatechins are more potent inhibitors of cultured cell growth both of the human colon carcinoma cell line (HCT116 cells) and human umbilical vein endothelial cell (HUVEC) line, as well as angiogenesis by comparison with 3-O-acylepicatechins. Catechin conjugated with stearic acid ((2R,3S)-3',4',5,7-tetrahydroxyflavan-3-yl octadecanoate; C-C18) was the strongest inhibitor in replicative pol alpha and repair-related pol beta, as well as the cultured cell growth and angiogenesis assays in the compounds tested. C-C18 also suppressed HUVEC tube formation on reconstituted basement membrane suggesting that it affected not only pols but also signal transduction pathways in HUVECs. These data indicate that the acylated catechins target both pols and angiogenesis as anti-cancer agents. Moreover, the results suggest that acylation of catechin is an effective chemical modification to improve the anti-cancer activity of catechin.

Inosine monophosphate dehydrogenases (IMPDHs) are the committed step in de novo guanine nucleotide biosynthesis. There are two separate, but very closely related IMPDH isoenzymes, termed type I and type II. IMPDHs are widely believed to be major targets for cancer and transplantation therapy. Mycophenolic acid (MPA) is a potent inhibitor of IMPDHs. Previously, we found that MPA acted as a latent agonist of this nuclear hormone receptor in U2OS cells, and 6'-hydroxamic acid derivatives of MPA inhibited tubulin-specific histone deacetylase[s] (HDAC[s]) in HeLa cells. Although MPA is a promising lead compound, structure-activity relationships (SARs) for inhibition of IMPDH, and the mechanism action of MPA derivatives have not well been understood. We therefore synthesized, evaluated MPA derivatives as IMPDH inhibitor in vitro and cellular level, and explored their biological function and mechanism in cultured cells. This paper exhibits that (i) functional groups at C-5, C-7, and C-6' positions in MPA are important for inhibitory activity against IMPDH, (ii) it is difficult to improve specificity against IMPDH II by modification of 5-, 7-, and 6'-group, (iii) demethylation of 5-OMe results in increasing hydrophilicity, and lowering cell permeability, (iv) ester bonds of protective groups at C-7 and C-6' positions are hydrolyzed to give MPA in cultures, (v) the effects of a tubulin-specific HDAC[s] inhibitor on proliferation and differentiation are weaker than its inhibitory activity against IMPDH. The present work may provide insight into the development of a new class of drug lead for treating cancer and transplantation.

滲出性中耳炎の滲出液中にエンドトキシンが検出される事は知られている.エンドトキシンが正円窓より蝸牛に浸透するならば,内耳障害を起こし急性感音難聴となりうる.エンドトキシンの影響による内耳出血部位を検討する事は重要である.350 gのモルモットを10匹用いた.E. coliより抽出したエンドトキシン0.02 mg を腹腔投与し24時間後にエンドトキシン0.04 mg を含んだGelformⓇを正円窓膜上に留置した.24時間後正円窓より2%グルタルアルデヒドで蝸牛内を灌流固定後断頭し,蝸牛を摘出した.一側は光顕用に10 %EDTA で脱灰し,他側は電顕用に非脱灰とした.2%オスミウム酸で固定後,エポン812に包埋した.出血は蝸牛全ての領域で認め,最も出血が顕著であった部位は鼓室階ラセン靱帯の集合静脈付近であり,最も強くエンドトキシンに影響されたと考えられた.この部位にはしばしばblood sludgeを認めた.血管条が破綻し赤血球が内リンパ液中に漏出する像も観察できた.蝸牛軸血管周囲の広範囲に出血を認め,蝸牛神経の変性像も観察できた.蝸牛軸血管からの出血は蝸牛全体の機能に大きく影響を及ぼすと考えられた., It was reported that endotoxin was detected in middleear effusions from patients of otitis media with effusion. Ifthe bacterial endotoxin penetrates into the cochlea throughthe round window inner ear trouble causes, which willcause the acute hearing loss. It is important to make clearwhich area of cochlea the hemorrhage caused by endotoxin.Ten guinea pigs weighing 350 g each were used in thisstudy. A small piece of GelformⓇ containing 0.04mg ofE.coli-derived endotoxin was set on the round window, 24hours after intrapertoneal injection of 0.02mg endotoxin. 24hours after the inoculation of endotoxin, the cochleas wereinfused with 2 % glutaraldehyde through the round window.After decapitation, the cochleas were removed. Onecochlea was decalcified in 10 % EDTA for light microscopy,and the other was not decalcified for electron microscopy.They were postfixed for 40 min in 2 % osmium tetroxideand embedded in Epon 812.Hemorrhage was observed in all turns of cochlea, and themost remarkable hemorrhage was recognized in the vicinityof collecting venules of spiral ligament of scala tympani,where the blood sludge was also observed in many vessles.Therefore, the endotoxin most strongly influenced this portion.It was observed the stria vascularis was collapsed andthe red blood cells escaped to the endolymphatic space.Hemorrhage was observed in the wide area of the modiolusblood vessels. In addition, the nerves of modiolus were degenerated.It was thought the bleeding in modiolus vesselsgreatly affected the function of whole cochlea.

The catechins, a family of polyphenols found in tea, can evoke various responses, including apoptosis. In this study we investigated whether the chemical modification of (-)-epigallocatechin gallate (EGCG) could enhance its apoptosis activity. We found that one of the catechin conjugated with capric acid [(2R,3S)-3',4',5,7-tetrahydroxyflavan-3-yl decanoate; catechin-C10] was most potent to induce apoptosis in U937 cells. C10 treatment resulted in a significant increase in reactive oxygen species (ROS) formation, mitochondrial membrane potential (MMP) loss, cytochrome c release caspase-9 and caspase-3 activation. In addition to this C10 also activated extrinsic pathway significantly as evident by time-dependent increase in Fas expression and caspase-8 activity. C10 mediated cleavage of Bid may be an important event for cross talk between intrinsic and extrinsic signaling. Moreover, pre-treatment of cells with anti-oxidant N-acetyl-L-cysteine (NAC) significantly prevented C10-induced apoptosis but did not protect MMP loss. Treatment of cells with pan-caspase inhibitor significantly inhibited apoptosis indicating that caspases are playing key role. In addition to this C10 was found to induce apoptosis in human colon cancer (HCT116) cells while it showed resistance to human keratinocytes (HaCat). In short our results showed that the optimal fatty acid side chain length is required for the apoptosis inducing activity of catechin derivatives in U937 cells.

Catechins and epicatechins are extremely useful compounds in the context of biological activities. These compounds afford many metabolites, including γ-valerolactone derivatives, through metabolic pathways in the human body. Several of these γ-valerolactone metabolites were synthesized as optically pure authentic standards.

Proanthocyanidins, also known as condensed tannins or oligomeric flavonoids, are found in many edible plants and exhibit interesting biological activities. Herein, we report a new, simple method for the stereoselective synthesis of procyanidin B6, a (+)-catechin-(4-6)-(+)-catechin dimer, by Lewis acid-catalyzed intramolecular condensation. The 5-O-t-butyldimethylsilyl (TBDMS) group of 5,7,3′4′-tetra-O-TBDMS-(+)-catechin was regioselectively removed using trifluoroacetic acid, leading to the “regio-controlled” synthesis of procyanidin B6. The 5-hydroxyl group of the 7,3′,4′-tri-O-TBDMS-(+)-catechin nucleophile and the 3-hydroxyl group of 5,7,3′,4′-tetra-O-benzylated-(+)-catechin electrophile were connected with an azelaic acid. The subsequent SnCl4-catalyzed intramolecular condensation proceeded smoothly to give the 4-6-condensed catechin dimer. This is the first report on the complete regioselective synthesis of a 4-6-connected oligomer without modifying the 8-position.

Proanthocyanidins, known as condensed tannins or oligomeric flavonoids, exist in many edible plants and show various interesting biological activities. We have developed a simple and versatile method of synthesizing procyanidin oligomers consisting of (−)-epicatechin and (+)-catechin. This method is applicable to the synthesis of various 3- O -substituted oligomers. We report here the stereoselective and length controlled synthesis of [4–8]-condensed (−)-epicatechin series procyanidin oligomers. We described the details of the synthesis of an two tetramers, (−)-epicatechin-(−)-epicatechin-(−)-epicatechin-(−)-epicatechin and (−)-epicatechin-(−)-epicatechin-(−)-epicatechin-(+)-catechin (arecatannin A1), (−)-epicatechin pentamer and two 3,3″,3⁗-tri- O -galloyl trimers, (−)-epicatechin-(−)-epicatechin-(−)-epicatechin-3,3″,3⁗-tri- O -gallate and (−)-epicatechin-(−)-epicatechin-(+)-catechin-3,3″,3⁗-tri- O -gallate with the condensation method using TMSOTf as a catalyst. The ability of DPPH radical scavenging activity and DNA polymerase inhibitory activity of these oligomeric compounds were investigated.

胃酸による食道外の粘膜上皮障害の機序をより明らかにするため，摘出モルモット気管上皮の初代培養細胞を作成し，上皮膜抵抗を測定することで酸による電気的バリアの変化を検索した。塩酸を頂膜側より投与しpHを徐々に変化させると，pH 3より上皮膜抵抗は低下し，初代培養気管粘膜上皮細胞の電気的バリアのdown regulationが有意に認められた。培養液中にプロトンポンプインヒビターであるランソプラゾールを投与していた群では，pHを変化させても，上皮膜抵抗の有意な変動はみられなかった。この細胞の上皮膜抵抗が，どの因子から構成されているかの手がかりを得るため，代表的なイオンチャネルであるクロライドイオンおよびナトリウムイオンチャネルのブロッカーを頂膜側より順次投与し，上皮膜抵抗を測定した。それぞれ，上皮膜抵抗の有意な上昇効果をきたしたが，これらの効果はランソプラゾール投与群，非投与群との間では，有意な差を認めなかった。また，その後，酸を投与したところ，上皮膜抵抗は減少した。これらの結果から，酸暴露により，気道上皮の電気的バリアの破綻が惹起されることが示され，この反応は一部上皮の頂膜側のイオンチャネルを介していることが示唆された。また，プロトンポンプインヒビター投与は，酸暴露時の電気的バリアの障害を部分的に防止する効果を持つ可能性が証明された。