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Agaricus bisporus (white button mushroom, WBM) is widely consumed in most countries and is reported to have anti-inflammatory and antioxidant activities. However, little is known regarding its effects in dextran sulfate sodium (DSS)-induced colitis, which are related to dysfunction of intestinal immunity. The aim of the present study was to investigate the effects of WBMs in an animal model of DSS-induced colitis. Male, 4-week-old ICR mice (n=10 per group) were fed a normal diet with or without 10% WBM for 4 weeks, and colitis was induced by 3% DSS in drinking water for 7 days. WBMs prevented DSS-induced shortening of colon length (P=.033) and diminished diarrhea (P=.049) and gross bleeding (P=.001), resulting in a decreased disease activity index. Results of histological analysis showed that WBMs suppressed mucosal damage. In addition, WBMs attenuated the DSS-induced increase in myeloperoxidase activity (P=.012) and upregulation of proinflammatory cytokine tumor necrosis factor-α (P=.020) in the colon segment. Taken together, these findings suggest a possible role for the WBM as an immunomodulator that can prevent and/or treat ulcerative colitis.

Background: Ginger leaf (GL) has long been used as a vegetable, tea and herbal medicine. However, its pharmacological properties are still poorly understood. Thus, we performed in vitro studies to evaluate anti-cancer properties of ginger leaf and then elucidate the potential mechanisms involved. Methods: Cell viability was measured by MTT assay. ATF3 expression level was evaluated by Western blot or RT-PCR and ATF3 transcriptional activity was determined using a dual-luciferase assay kit after the transfection of ATF3 promoter constructs. In addition, ATF3-dependent apoptosis was evaluated by Western blot after ATF3 knockdown using ATF3 siRNA. Results: Exposure of GL to human colorectal cancer cells (HCT116, SW480 and LoVo cells) reduced the cell viability and induced apoptosis in a dose-dependent manner. In addition, GL reduced cell viability in MCF-7, MDA-MB-231 and HepG-2 cells. ATF3 knockdown attenuated GL-mediated apoptosis. GL increased activating transcription factor 3 (ATF3) expressions in both protein and mRNA level and activated ATF3 promoter activity, indicating transcriptional activation of ATF3 gene by GL. In addition, our data showed that GL-responsible sites might be between -318 and -85 region of the ATF3 promoter. We also observed that ERK1/2 inhibition by PD98059 attenuated GL-mediated ATF3 expression but not p38 inhibition by SB203580, indicating ERK1/2 pathway implicated in GL-induced ATF3 activation. Conclusions: These findings suggest that the reduction of cell viability and apoptosis by GL may be a result of ATF3 promoter activation and subsequent increase of ATF3 expression through ERK1/2 activation in human colorectal cancer cells.

Background/Aims: C-reactive protein (CRP) is a serologic activity marker in Crohn’s disease (CD), but it may be less useful in evaluating CD activity in ileal CD patients. We aimed to investigate the usefulness of CRP as a disease activity marker in CD according to disease location. Methods: Korean CD patients in a single hospital were evaluated. Factors associated with elevated CRP concentration at the time of diagnosis of CD and the association between the physician’s prediction regarding upcoming surgery and the sites of the lesions directly related to surgery were analyzed. Results: Of 435 CD patients, 25.7%, 6.9%, and 67.4% had ileal, colonic, and ileocolonic CD, respectively. Multivariate analysis revealed that an elevated erythrocyte sedimentation rate, reduced serum albumin, CD activity index (CDAI) >220, and ileocolonic/colonic location were associated with an elevated CRP level and that the CRP level was significantly correlated with the CDAI in all CD patients (γ=0.466, p

The purpose of this study is to investigate the effects of euphorbiasteroid, a component of Euphorbia lathyris L., on adipogenesis of 3T3-L1 pre-adipocytes and its underlying mechanisms. Euphorbiasteroid decreased differentiation of 3T3-L1 cells via reduction of intracellular triglyceride (TG) accumulation at concentrations of 25 and 50 μM. In addition, euphorbiasteroid altered the key regulator proteins of adipogenesis in the early stage of adipocyte differentiation by increasing the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. Subsequently, levels of adipogenic proteins, including fatty acid synthase, peroxisome proliferator-activated receptor-γ and CCAAT/enhancer-binding protein α, were decreased by euphorbiasteroid treatment at the late stage of adipocyte differentiation. The anti-adipogenic effect of euphorbiasteroid may be derived from inhibition of early stage of adipocyte differentiation. Taken together, euphorbiasteroid inhibits adipogenesis of 3T3-L1 cells through activation of the AMPK pathway. Therefore, euphorbiasteroid and its source plant, E. lathyris L., could possibly be one of the fascinating anti-obesity agent.

PURPOSE To evaluate the effectiveness of endoscopic submucosal resection with a ligation device (ESMR-L) on histologic complete resection for the treatment of small rectal carcinoid tumors in comparison with the treatment with endoscopic mucosal resection (EMR) alone. METHODS Thirty-five patients with small rectal carcinoid tumors were enrolled prospectively for ESMR-L, and we retrospectively reviewed 74 carcinoid tumor patients who underwent EMR. The comparison between ESMR-L and EMR groups was analyzed including endoscopic and histologic complete resection and complications after resection. We also evaluated the associations of histologic complete resection with clinical and procedure-related factors. RESULTS The histologic complete resection rate was significantly higher in ESMR-L than in EMR (94.3% vs. 75.7%, P=0.019). In addition, the resection time was significantly shorter in ESMR-L than in EMR (4.16±1.48 min vs. 5.11±2.47 min, respectively, P=0.014). Moreover, previously biopsied rectal carcinoid tumors were significantly associated with histologic incomplete resection, especially in patients who underwent EMR (odds ratio, 6.28; 95% confidence interval, 1.92-20.58; P=0.002). CONCLUSIONS Compared with EMR, ESMR-L is a safe and effective method for histologic complete resection of small rectal carcinoid tumors, especially in patients with previously biopsied carcinoid tumors.

Double balloon enteroscopy (DBE)-assisted endoscopic retrograde cholangiopancreatography (ERCP) is frequently performed in patients with surgically altered intestinal anatomy. Moreover, it is also utilized in some cases with pancreatic indications, particularly patients with Roux-en-Y anatomy following Whipple’s procedure or pylorus-preserving pancreaticoduodenectomy. Here, we present our experiences using DBE-assisted ERCP in patients with Roux-en-Y anatomy, with a focus on pancreatic indications.Peroral DBE was attempted in 10 patients with Roux-en-Y anatomy. Conventional ERCP had previously been unsuccessful in all 10 patients. We retrospectively analyzed the relevant data of these patients.Four patients were male (40%) and the median age of the patients was 68 years. A complete evaluation of the afferent loops was possible in eight cases (80%) and selective cannulation was successful in six cases (60%). Therapeutic interventions were tried in four patients, and were successful in all of them. We tried to approach pancreatic duct through pancreaticojejunal anastomosis and performed therapeutic intervention successfully such as removal of pancreaticoliths or dilation of stricture of pancreaticojejunostomy site in two of three patients.DBE-assisted ERCP appears to be a useful tool for the diagnosis and treatment of pancreatobiliary lesions in patients with a Roux-en-Y reconstruction, especially those with pancreatic indications.

With the explosive growth of battery-operated portable devices, the demand for low power and small size has been increasing for system-on-a-chip (SoC). The FinFET is considered as one of the most promising technologies for future low-power mobile applications because of its good scaling ability, high on-current, better SCE and subthreshold slope, and small leakage current [1]. As a key approach for low-power, supply-voltage (VDD) scaling has been widely used in SoC design. However, SRAM is the limiting factor of voltage-scaling, since all SRAM functions of read, write, and hold-stability are highly influenced by increased variations at low VDD, resulting in lower yield. In addition, the width-quantization property of FinFET device reduces the design window for transistor sizing, and increases the failure probability due to the un-optimized bitcell sizing [1]. In order to overcome the bitcell challenges to high yield, peripheral-assist techniques are required. In this paper, we present 14nm FinFET-based 128Mb 6T SRAM chips featuring low-VMIN with newly developed assist techniques.

Background: Root bark of mulberry (Morus alba L.) has been used in herbal medicine as anti-phlogistic, liver protective, kidney protective, hypotensive, diuretic, anti-cough and analgesic agent. However, the anti-cancer activity and the potential anti-cancer mechanisms of mulberry root bark have not been elucidated. We performed in vitro study to investigate whether mulberry root bark extract (MRBE) shows anti-inflammatory and anti-cancer activity. Methods: In anti-inflammatory activity, NO was measured using the griess method. iNOS and proteins regulating NF-kappa B and ERK1/2 signaling were analyzed by Western blot. In anti-cancer activity, cell growth was measured by MTT assay. Cleaved PARP, ATF3 and cyclin D1 were analyzed by Western blot. Results: In anti-inflammatory effect, MRBE blocked NO production via suppressing iNOS over-expression in LPS-stimulated RAW264.7 cells. In addition, MRBE inhibited NF-kappa B activation through p65 nuclear translocation via blocking I kappa B-alpha degradation and ERK1/2 activation via its hyper-phosphorylation. In anti-cancer activity, MRBE deos-dependently induced cell growth arrest and apoptosis in human colorectal cancer cells, SW480. MRBE treatment to SW480 cells activated ATF3 expression and down-regulated cyclin D1 level. We also observed that MRBE-induced ATF3 expression was dependent on ROS and GSK3 beta. Moreover, MRBE-induced cyclin D1 down-regulation was mediated from cyclin D1 proteasomal degradation, which was dependent on ROS. Conclusions: These findings suggest that mulberry root bark exerts anti-inflammatory and anti-cancer activity.

Background: Recently, Abeliophyllum distichum Nakai (A. distichum) has been reported to exert the inhibitory effect on angiotensin converting enzyme. However, no specific pharmacological effects from A. distichum have been described. We performed in vitro study to evaluate anti-cancer properties of A. distichum and then elucidate the potential mechanisms. Methods: Cell viability was measured by MTT assay. ATF3 expression level was evaluated by Western blot or RT-PCR and ATF3 transcriptional activity was determined using a dual-luciferase assay kit after the transfection of ATF3 promoter constructs. In addition, ATF3-dependent apoptosis was evaluated by Western blot after ATF3 knockdown using ATF3 siRNA. Results: Exposure of ethyl acetate fraction from the parts of A. distichum including flower, leaf and branch to human colorectal cancer cells, breast cancer cells and hepatocellular carcinoma reduced the cell viability. The branch extracts from A. distichum (EAFAD-B) increased the expression of activating transcription factor 3 (ATF3) and promoter activity, indicating transcriptional activation of ATF3 gene by EAFAD-B. In addition, our data showed that EAFAD-B-responsible sites might be between -147 and -85 region of the ATF3 promoter. EAFAD-B-induced ATF3 promoter activity was significantly decreased when the CREB site was deleted. However, the deletion of Ftz sites did not affect ATF3 promoter activity by EAFAD-B. We also observed that inhibition of p38MAPK and GSK3 beta attenuated EAFAD-B-mediated ATF3 promoter activation. Also, EAFAD-B contributes at least in part to increase of ATF3 accumulation. Conclusion: These findings suggest that the anti-cancer activity of EAFAD-B may be a result of ATF3 promoter activation and subsequent increase of ATF3 expression.

Microsatellite alteration (MSA) has been observed in a fraction of non-small cell lung cancer (NSCLC). Most prior studies regarding MSA in lung cancer have usually used adjacent non-malignant lung tissues as a source of constitutional DNA. However, these normal tissues might have genetic alterations because the entire field of bronchial tree is exposed to the same carcinogenic insult. The aim of this study was to search if MSA is present in the histologically normal lung tissue of patients with NSCLC. Tumor and corresponding normal lung tissue specimens were obtained from 20 patients with NSCLC. Normal lung tissue specimens were obtained from either the opposite end of resected surgical samples or as distant from the tumor as possible. They were examined histopathologically and confirmed as normal by H-E stain. Patients' peripheral lymphocytes were used as the source for the normal DNA. Sixteen markers on 3p and 9p (nine and seven markers, respectively) were used. MSA was detected in seven of 20 (35%) histologically normal lung tissue specimens at a frequency similar to that observed in tumor tissue (eight of 20, 40%). Five cases showed MSA in both normal lung tissue and the corresponding tumor. In these five cases, MSA in normal lung tissue was detected at the same microsatellite markers which MSA was detected in the corresponding tumor. The number and size of novel bands in normal lung tissue was identical to that in tumor tissue except in one case. In which case, the same pattern of MSA was found in both normal lung tissue and corresponding tumor tissue at two markers. However, at one marker, while one identical novel band was detected in normal lung tissue and corresponding tumor tissue, another novel band was found only in tumor tissue. In two of 12 patients whose tumor was negative for the presence of MSA, MSA was detected in normal lung tissue. These results indicate that genetic alterations are widely distributed in the lung tissue of patients with lung cancer and provide considerable support for the field cancerization theory. Screening for MSA in resected normal lung tissue might be a new method to identify patients at high risk for developing second primary lung cancers.

Computer-assisted database analysis of sequences homologous to human acid ceramidase (ASAH) revealed a 1233-bp cDNA (previously designated cPj-LTR) whose 266-amino-acid open reading frame had approximately 36% identity with the ASAH polypeptide. Based on this high degree of homology, we undertook further molecular characterization of cPj-LTR and now report the full-length cDNA sequence, complete gene structure (renamed human ASAHL since it is a human acid ceramidase-like sequence), chromosomal location, primer extension and promoter analysis, and transient expression results. The full-length human ASAHL cDNA was 1825 bp and contained an open-reading frame encoding a 359-amino-acid polypeptide that was 33% identical and 69% similar to the ASAH polypeptide over its entire length. Numerous short regions of complete identity were observed between these two sequences and two sequences obtained from the Caenorhabditis elegans genome database. The 30-kb human ASAHL genomic sequence contained 11 exons, which ranged in size from 26 to 671 bp, and 10 introns, which ranged from 150 bp to 6.4 kb. The gene was localized to the chromosomal region 4q21.1 by fluorescence in situ hybridization analysis. Northern blotting experiments revealed a major 2.0-kb ASAHL transcript that was expressed at high levels in the liver and kidney, but at relatively low levels in other tissues such as the lung, heart, and brain. Sequence analysis of the 5'-flanking region of the human ASAHL gene revealed a putative promoter region that lacked a TATA box and was GC rich, typical features of a housekeeping gene promoter, as well as several tissue-specific and/or hormone-induced transcription regulatory sites. 5'-Deletion analysis localized the promoter activity to a 1. 1-kb fragment within this region. A major transcription start site also was located 72 bp upstream from the ATG translation initiation site by primer extension analysis. Expression analysis of a green fluorescence protein/ASAHL fusion protein in COS-1 cells revealed a punctate, perinuclear distribution, although no acid ceramidase activity was detected in the transfected cells using a fluorescence-based in vitro assay system.

Objective To determine the presence of specific immune recognition of type II collagen (CII) and its immunodominant epitope CII (255–274) in patients with rheumatoid arthritis (RA). Methods T cell proliferative responses to bovine CII and a synthetic peptide encompassing CII (255–274) in peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) from RA patients, and in PBMC from osteoarthritis (OA) patients and healthy controls were assayed by mixed lymphocyte culture. Results The stimulation index (SI) and the number of positive (SI ≥2) T cell responses to CII were higher in RA patients (n = 106) than in OA patients (n = 26) and healthy controls (n = 34). T cell responses to CII (255–274) were also enhanced in RA patients and correlated well with those to CII. In SFMC, positive responses to CII or CII (255–274) were detected in 61.9% of 42 RA patients. T cell responses to CII in SFMC were stronger and more prevalent than peripheral responses. The SI and positive responses to CII were higher in early RA than in late RA. Levels of IgG antibodies to CII in synovial fluid inversely correlated with T cell responses to CII. Conclusion T cell responses to CII or CII (255–274) were enhanced in RA, especially in early disease. Synthetic peptide CII (255–274), as well as native CII, could be recognized as immunogenic antigens by T cells, particularly in the synovial fluid. These observations suggest that CII-reactive T cells play an important role in the pathogenesis of RA. Peripheral tolerance induction using CII (255–274) might be useful in the treatment of RA.

Acid ceramidase (N-acylsphingosine amidohydrolase) is the lysosomal enzyme required to hydrolyze the N-acyl linkage between the fatty acid and sphingosine moieties in ceramide. A deficiency of acid ceramidase activity results in the lipid storage disorder, Farber disease. This study reports a new assay method to detect acid ceramidase activity in vitro using Bodipy or lissamine rhodamine-conjugated ceramide (C12 ceramide; dodecanoylsphingosine). Using mouse kidney extracts as the source of acid ceramidase activity, this new method was compared with an assay using radioactive C12 ceramide (N-[(14)C]-dodecanoylsphingosine) as a substrate. The Bodipy C12 ceramide substrate provided data very similar to those of the radioactive substrate, but under the experimental conditions tested, it was significantly more sensitive. Using Bodipy C12 ceramide, femtomole quantities of the product, Bodipy dodecanoic acid, could be detected, providing an accurate measure of acid ceramidase activity as low as 0.1 pmol/mg protein/h. Acid ceramidase activities in skin fibroblasts and EBV-transformed lymphoblasts from Farber disease patients were around 7.8 and 10% of those in normal cells, respectively, confirming the specificity of this new assay method. Based on these results, we suggest that this fluorescence-based, high-performance liquid chromatographic technique is a reliable, rapid, and highly sensitive method to determine acid ceramidase activity, and that it could be useful wherever the in vitro detection of acid ceramidase activity is of importance.

Low TNF production and its association with TNF gene restriction fragment length polymorphism (RFLP) was demonstrated in (NZW/NZB) F1mice. However, little is known about the significance of TNF production in association with TNF gene polymorphism in human SLE. This study was designed to evaluate the role of TNF production of peripheral blood mononuclear cells (PBMC) and its association with TNFB gene polymorphism in SLE, particularly lupus nephritis. TNFB gene polymorphism was defined by PCR- NcoI RFLP. TNF productions of phytohemagglutinin (PHA)- stimulated PBMC and T cells were examined by bioassay using L929 cell line and ELISA. The PBMC stimulated by PHA from patients with SLE ( n = 60) tended to secrete less amounts of TNF by bioassay (1032±184pg/ml vs 1524±224pg/ml, P=0.094), and TNF-β by ELISA ( P = 0.0082) than that from normal controls ( n = 38). The low TNF-α producer was more frequent in nephritis than non-nephritis (34.4% vs 7.1% respectively, P

The antidiabetic effect of the Citrus junos Tanaka (also known as yuja or yuzu) was examined. Ethanol extract of yuja peel (YPEE) significantly stimulated 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG) uptake in C2C12 myotubes. However, ethanol extract of yuja pulp (YpEE) and water extract of yuja peel (YPWE) or pulp (YpWE) did not stimulate glucose uptake. In addition, peroxisome proliferator-activated receptor gamma (PPAR-γ) and AMP-activated protein kinase (AMPK) activities were increased by YPEE in a dose-dependent manner. Pretreatment of AMPK inhibitor decreased the glucose uptake stimulated by YPEE in C2C12 myotubes. We confirmed the anti-diabetic effect of YPEE in mice fed a high fat-diet (HFD). Compared with control mice on a normal diet (ND), these mice showed increased body weight, liver fat, insulin resistance, triacylglycerol (TG), and total cholesterol content. Addition of 5% YPEE significantly reduced the weight gain and rise in liver fat content, serum triacylglycerol (TG), total cholesterol, and insulin resistance found in mice fed a high-fat diet (HFD). Moreover, YPEE reduced the secretion of HFD-induced adipocytokines such as leptin and resistin. YPEE also resulted in increased phosphorylation of AMPK in muscle tissues. These results suggest that ethanol extract of yuja peel exerts anti-diabetic effects via AMPK and PPAR-γ in both cell culture and mouse models.

We examined the antidiabetic property ofBoehmeria nivea(L.) Gaud. Ethanolic extract ofBoehmeria nivea(L.) Gaud. (EBN) increased the uptake of 2-[N-(nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose in C2C12 myotubes. To examine the mechanisms underlying EBN-mediated increase in glucose uptake, we examined the transcriptional activity and expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), a pivotal target for glucose metabolism in C2C12 myotubes. We found that the EBN increased both the transcriptional activity and mRNA expression levels of PPAR-γ. In addition, we measured phosphorylation and expression levels of other targets of glucose metabolism, such as AMP-activated protein kinase (AMPK) and protein kinase B (Akt/PKB). We found that EBN did not alter the phosphorylation or expression levels of these proteins in a time- or dose-dependent manner, which suggested that EBN stimulates glucose uptake through a PPAR-γ-dependent mechanism. Further, we investigated the antidiabetic property of EBN using mice fed a high-fat diet (HFD). Administration of 0.5% EBN reduced the HFD-induced increase in body weight, total cholesterol level, and fatty liver and improved the impaired fasting glucose level, blood insulin content, and glucose intolerance. These results suggest that EBN had an antidiabetic effect in cell culture and animal systems and may be useful for preventing diabetes.

Novel asiaticoside mimetics simplified the sugar moiety by alkoxyalkyl groups were synthesized, and tested their wound healing effects by tensile strength measurement.

We investigated the hepatoprotective effects of the extract of dandelion leaves (EDL) on a murine model of methionine- and choline-deficient (MCD) diet-induced nonalcoholic steatohepatitis (NASH). C57BL/6 mice were fed for 4 weeks with one of the following diets: control diet (Cont), MCD diet (MCD), MCD diet supplemented with EDL at 200 mg/kg body weight·daily (MCD+D200), and MCD diet supplemented with EDL at 500 mg/kg body weight·daily (MCD+D500). Hepatic function was assessed by evaluating the following parameters: liver histology; plasma levels of alanine aminotransferase (ALT), triglyceride (TG), malondialdehyde (MDA), and reduced glutathione (GSH); expression levels of TNF-α and IL-6; and levels of caspase-3 and pJNK/JNK protein. Histopathological evaluations revealed that addition of EDL to the MCD diet dampens the severity of the clinical signs of NASH. Moreover, EDL led to a significant decrease in the serum levels of ALT, hepatic TG, and MDA, and in the expression levels of TNF-α, and IL-6; on the contrary, the levels of reduced GSH increased. At the post-transcriptional level, EDL significantly decreased the activation of procaspase-3 to active caspase-3, and the phosphorylation of JNK. These results suggest that the beneficial effects of EDL on NASH are mainly due to its antioxidant and anti-inflammatory activities.

The purpose of this study is to determine the protective effect of Taraxacum official (dandelion) leaf extract (DLE) on high-fat-diet (HFD)-induced hepatic steatosis, and elucidate the molecular mechanisms behind its effects. To determine the hepatoprotective effect of DLE, we fed C57BL/6 mice with normal chow diet (NCD), high-fat diet (HFD), HFD supplemented with 2g/kg DLE DLE (DL), and HFD supplemented with 5 g/kg DLE (DH). We found that the HFD supplemented by DLE dramatically reduced hepatic lipid accumulation compared to HFD alone. Body and liver weights of the DL and DH groups were significantly lesser than those of the HFD group, and DLE supplementation dramatically suppressed triglyceride (TG), total cholesterol (TC), insulin, fasting glucose level in serum, and Homeostatic Model Assessment Insulin Resistance (HOMA-IR) induced by HFD. In addition, DLE treatment significantly increased activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) in liver and muscle protein. DLE significantly suppressed lipid accumulation in the liver, reduced insulin resistance, and lipid in HFD-fed C57BL/6 mice via the AMPK pathway. These results indicate that the DLE may represent a promising approach for the prevention and treatment of obesity-related nonalcoholic fatty liver disease.

This study was designed to evaluate the effects and mechanism of Platycodi radix, having white balloon flower (Platycodon grandiflorum for. albiflorum (Honda) H. Hara) on obesity and insulin resistance. The extracts of Platycodi radix with white balloon flower were tested in cultured cells and administered into mice on a high-fat diet. The Platycodi radix activated the AMPK/ACC phosphorylation in C2C12 myotubes and also suppressed adipocyte differentiation in 3T3-L1 cells. In experimental animal, it suppressed the weight gain of obese mice and ameliorated obesity-induced insulin resistance. It also reduced the elevated circulating mediators, including triglyceride (TG), T-CHO, leptin, resistin, and monocyte chemotactic protein (MCP)-1 in obesity. As shown in C2C12 myotubes, the administration of Platycodi radix extracts also recovered the AMPK/ACC phosphorylation in the muscle of obese mice. These results suggest that Platycodi radix with white balloon flower ameliorates obesity and insulin resistance in obese mice via the activation of AMPK/ACC pathways and reductions of adipocyte differentiation.

As angiogenesis plays important roles in tumor growth and metastasis, searching for antiangiogenic compounds is a promising tactic for treating cancers. Cafestol, a diterpene found mainly in unfiltered coffee, provides benefit through varied biological activity, including antitumorigenic, antioxidative, and anti-inflammatory effects. This study aimed to investigate the effects of cafestol on angiogenesis and to uncover the associated mechanism. We show that cafestol inhibits angiogenesis of human umbilical vascular endothelial cells. This inhibition affects the following specific steps of the angiogenic process: proliferation, migration, and tube formation. The inhibitory effects of cafestol are accompanied by decreasing phosphorylation of FAK and Akt and by a decrease in nitric oxide production. Overall, cafestol inhibits angiogenesis by affecting the angiogenic signaling pathway.

We used UPLC-Q-TOF MS to analyze hepatic metabolites of rats aged 6, 12, 18, and 24 months; the MS data were processed by partial least-squares discriminant analysis (PLS-DA) to investigate the discrimination among sample groups. Rats were significantly separated with increasing age, except those aged between 6 and 12 months. We identified only 25 of 120 metabolites contributing to the separation: lipid metabolites (glycerol-3-phosphate, linolenic acid, lysophosphatidylcholines [lysoPCs]), energy metabolism intermediates (betaine, carnitine, acylcarnitines, creatine, pantothenic acid), nucleic acid metabolites (inosine, xanthosine, uracil, hypoxanthine, xanthine), and tyrosine. Aging accumulated energy metabolism intermediates, hypoxanthine, xanthine, and 2 major lysoPCs (C18:0 and C22:6). The NAD level and NAD/NADH ratio decreased with age. It was indicated that aging might decrease energy production through β-oxidation because of a decrease in NAD despite the accumulation of lipid energy metabolism intermediates. In addition to energy dysregulation, hypoxanthine and xanthine, which are elevated with age, might accumulate reactive oxygen species in the liver. These results strongly support two aging theories: those of energy dysregulation and free radicals. Additionally, we propose a metabolic pathway related to aging based on these hepatic metabolites. These metabolites and the proposed aging pathway could be used to understand aging and related diseases better, and increase the predictability of aging risk.

Luteolin is a flavonoid in many fruits and vegetables. Although luteolin has important biological functions, including antioxidant, anti-inflammatory, antimicrobial, and neuroprotective activities, little is known about the functions of luteolin in the olfactory system. Various odorants can be detected and distinguished by using several molecular processes, including the binding of odorants to odorant receptors, activation of adenylyl cyclase (AC), changes of cyclic adenosine monophosphate (cAMP) and Ca(2+) levels in olfactory sensory neurons, as well as changes in membrane potentials and the transmission of electric signals to the brain. Because AC-cAMP signal transduction plays a pivotal role in the olfactory system, we evaluated the effects of luteolin on the AC-cAMP pathway that had been stimulated by the odorant eugenol. We demonstrated that eugenol caused an upregulation of the cAMP level and the phosphorylation of phosphokinase A (PKA, a downstream target of cAMP) in human embryonic kidney 293 (HEK293) cells expressing the murine eugenol receptor. This upregulation significantly decreased in the presence of luteolin, suggesting that luteolin inhibited the odorant-induced production of cAMP and affected the downstream phosphorylation of PKA.

Background Acute severe lower gastrointestinal bleeding in Crohn's disease is uncommon, but is a diagnostic and therapeutic challenge. We aimed to identify risk factors for acute lower gastrointestinal bleeding in patients with Crohn's disease and assess the cumulative probability of rebleeding in relation to therapeutic modality. Methods We retrospectively reviewed the medical records of 70 Crohn's patients (4.0%) with acute severe lower gastrointestinal bleeding and compared these with matched 140 Crohn's patients without bleeding. Results The cumulative probability of bleeding after diagnosis of Crohn's disease was 1.7%, 3.6%, 6.5%, and 10.3% after 1, 5, 10, and 20 years respectively. At presentation, the median haemoglobin concentration was 8.4 g/dL (range, 4.7–11.6 g/dL). Use of azathioprine/6-mercaptopurine decreased the risk of lower gastrointestinal bleeding (OR: 0.525, 95% CI: 0.304–0.906, p = 0.021). Bleeding recurred in 29 patients (41.4%) after a median time of 3.2 months (range, 15 days–94.7 months). One out of eleven patients treated with infliximab rebled. The cumulative probability of rebleeding tended to be lower in patients treated with infliximab than in those receiving other treatments (p = 0.076). Conclusions Azathioprine/6-mercaptopurine may reduce the risk of acute severe lower gastrointestinal bleeding. The rebleeding is common, but infliximab may decrease rebleeding.

Ga-doped ZnO [GZO] thin films were employed for the transparent electrodes in dye-sensitized solar cells [DSSCs]. The electrical property of the deposited GZO films was as good as that of commercially used fluorine-doped tin oxide [FTO]. In order to protect the GZO and enhance the photovoltaic properties, a TiO2 blocking layer was deposited on the GZO surface. Then, TiO2 nanoparticles were coated on the blocking layer, and dye was attached for the fabrication of DSSCs. The fabricated DSSCs with the GZO/TiO2 glasses showed an enhanced conversion efficiency of 4.02% compared to the devices with the normal GZO glasses (3.36%). Furthermore, they showed better characteristics even than those using the FTO glasses, which can be attributed to the reduced charge recombination and series resistance.

Decursin (De), an active component of Angelica gigas, is known to exert anticancer and neuroprotective effects. However, its antiobesity and antidiabetic potential has not yet been investigated. This study evaluated the antiobesity effect of decursin, particularly focusing on its ability to inhibit adipocyte differentiation in 3T3-L1 cells. Decursin treatment resulted in the inhibition of adipocyte differentiation and the expression of fatty acid synthase. The study further investigated these antiobesity effects using mice fed a normal diet (ND), a high-fat diet (HFD) and a HFD plus decursin 200 mg/kg diet (HFD + De) for 7 weeks. Mice administered HFD plus decursin showed a drastic decrease in weight gain, triglyceride content, total cholesterol content and fat size compared with those that received the HFD alone; this was observed despite similar quantities of total food intake. Furthermore, decursin improved glucose tolerance in mice fed a HFD. Finally, administration of decursin along with the HFD significantly reduced the secretion of HFD-induced adipocytokines such as leptin, resistin, IL-6 and MCP-1. These results suggest that decursin might be useful for the treatment of obesity and diabetes.

9 páginas, 6 figuras.-- et al., [Background]: The lower incidence of breast cancer among Asian women compared with Western countries has been partly attributed to soy in the Asian diet, leading to efforts to identify the bioactive components that are responsible. Soy Bowman Birk Inhibitor Concentrate (BBIC) is a known cancer preventive agent now in human clinical trials. [Methodology/Principal Findings]: The objectives of this work are to establish the presence and delineate the in vitro activity of lunasin and BBI found in BBIC, and study their bioavailability after oral administration to mice and rats. We report that lunasin and BBI are the two main bioactive ingredients of BBIC based on inhibition of foci formation, lunasin being more efficacious than BBI on an equimolar basis. BBI and soy Kunitz Trypsin Inhibitor protect lunasin from in vitro digestion with pancreatin. Oral administration of 3H-labeled lunasin with lunasin-enriched soy results in 30% of the peptide reaching target tissues in an intact and bioactive form. In a xenograft model of nude mice transplanted with human breast cancer MDA-MB- 231 cells, intraperitoneal injections of lunasin, at 20 mg/kg and 4 mg/kg body weight, decrease tumor incidence by 49% and 33%, respectively, compared with the vehicle-treated group. In contrast, injection with BBI at 20 mg/kg body weight shows no effect on tumor incidence. Tumor generation is significantly reduced with the two doses of lunasin, while BBI is ineffective. Lunasin inhibits cell proliferation and induces cell death in the breast tumor sections. [Conclusions/Significance]: We conclude that lunasin is actually the bioactive cancer preventive agent in BBIC, and BBI simply protects lunasin from digestion when soybean and other seed foods are eaten by humans., Project number 05B087 awarded by the American Institute for Cancer Research (http://www.aicr.org/site/PageServer). Project number W81XWH-04-1- 0128 awarded by the United States Department of Defense Congressionally Directed Medical Research Program (https://cdmrp.org). Project LUNAMICE 039241 awarded by the European Commission and the Spanish National Research Council for the Marie-Curie postdoctoral fellowship of BHL.

Lunasin is a unique 43-amino acid peptide that has been shown to be chemopreventive in mammalian cells and in a skin cancer mouse model against oncogenes and chemical carcinogens. In search for new sources of lunasin and to better understand the role of cereals in cancer prevention, we report here the properties of lunasin from rye. The stability and bioavailability were measured by in vitro digestibility assay using pepsin and pancreatin and feeding rats with lunasin-enriched rye (LER). Inhibition of histone acetyl transferase (HAT) and nuclear localization in mammalian cells were used to measure lunasin bioactivity. Lunasin is present in 15 out of 21 cultivars of rye analyzed. Lunasin present in rye crude protein preparation is stable to pepsin and pancreatin in in vitro digestion. The liver, kidney, and blood of rats fed LER show the presence of lunasin in Western blot. Lunasin extracted from these tissues inhibits the activities of HATs, confirming that the peptide is intact and bioactive. Lunasin purified from rye internalizes in the nuclei of mouse fibroblast cells. We conclude that lunasin in rye is bioavailable and bioactive and that consumption of rye may play an important role of cancer prevention in rye-consuming populations.

The dried rhizomes of Cnidium officinale are used as herbal drugs in the treatment of pain, inflammation, menstrual disturbance and antivitamin deficiency disease, and also act as a blood pressure depressant. In addition, there are several reports suggesting that they have pharmacological properties to tumor metastasis and angiogenesis, and that they act as an inhibitor of high glucose-induced proliferation of glomerular mesangial cells. However, little has been known about the functional role of the extracts from C. officinale on oxidative DNA damage and apoptosis caused by ROS. In this work, we have investigated the DPPH radical, hydroxyl radical and intracellular ROS scavenging capacity, and Fe(2+) chelating activity of the extracts from C. officinale. In addition, we evaluated whether the extracts are capable of reducing H(2)O(2)-induced DNA and cell damage in the human skin fibroblast cell. These extracts showed a dose-dependent free-radical scavenging capacity and a protective effect on DNA damage and the lipid peroxidation causing the cell damage by ROS. These antioxidant activities and inhibitory effects of the extracts on DNA and cell damage may further explain that C. officinale is useful as a herbal medicine for cancer chemoprevention.

A number of genome-wide linkage analyses have identified the 2q33.3-2q37.2 region as most likely to contain the genes that contribute to the susceptibility to chronic obstructive pulmonary disease (COPD). It was hypothesized that the SERPINE2 gene, which is one of the genes located at the 2q33.3-2q37.2 region, may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, the associa- tion of four SERPINE2 single nucleotide polymorphisms (SNPs; rs16865421A>G, rs7583463A>C, rs729631C>G, and rs6734100C>G) with the risk of COPD was investigated in a case-control study of 311 COPD patients and 386 controls. The SNP rs16865421 was associated with a significantly decreased risk of COPD in a dominant model for the polymorphic allele (adjusted odds ratio (OR)=0.66, 95% con- fidence interval (CI)=0.45-0.97, P=0.03). In haplotype analysis, the GACC haplo- type carrying the polymorphic allele at the rs16865421 was associated with a sig- nificantly decreased risk of COPD when compared to the AACC haplotype (adjust- ed OR=0.58, 95% CI=0.38-0.89, P=0.01), and this effect was evident in younger individuals (adjusted OR=0.30, 95% CI=0.14-0.64, P=0.002). This study suggests that the SERPINE2 gene contributes to the susceptibility to COPD.

Background Adiponectin is an antiatherogenic adipocyte-derived proteins. The level of plasma adiponectin is inversely correlated to cardiovascular risk in patients with end-stage renal disease (ESRD). The aim of this study was to elucidate the changes of adiponectin concentrations in newly diagnosed ESRD patients after peritoneal dialysis. Methods In 16 newly diagnosed ESRD patients, total concentrations of adiponectin and high molecular weight (HMW) adiponectin, the HMW ratio (HMWR; ratio of the plasma level of HMW adiponectin to that of total adiponectin), the body mass index (BMI), insulin concentrations, blood glucose and estimation of the insulin sensitivity index by the homeostasis model assessment (HOMR(IR)) were compared before and after 1 year of peritoneal dialysis. Results Plasma total adiponectin was decreased from 15.52 +/- 9.35 microg/mL to 11.80 +/- 6.84 microg/mL (P = 0.046), HMW adiponectin was decreased from 9.05 +/- 6.48 microg/mL to 4.83 +/- 4.15 microg/mL (P = 0.009), and HMWR was decreased from 0.51 +/- 0.18 to 0.35 +/- 0.20 (P = 0.008). Total and HMW adiponectin/BMI ratio was decreased. The BMI was increased from 25.2 +/- 5.7 to 25.8 +/- 6.2 (P = 0.036). The HOMR(IR), insulin level and lipid profile were not changed. Conclusion Total adiponectin, HMW adiponectin and HMWR were decreased in newly diagnosed ESRD patients after 1 year of peritoneal dialysis. The factors that influence the decrease of the level of adiponectin should be studied in a larger prospective study.

Lunasin, a unique 43 amino acid, 4.8 kDa cancer-chemopreventive peptide initially reported in soybean and now found in barley and wheat, has been shown to be cancer-chemopreventive in mammalian cells and in a skin cancer mouse model against oncogenes and chemical carcinogens. To identify bioactive components in traditional herbal medicines and in search for new sources of lunasin, we report here the properties of lunasin from Solanum nigrum L. (SNL), a plant indigenous to northeast Asia. Lunasin was screened in the crude extracts of five varieties of the medicinal plants of Solanaceae origin and seven other major herbal plants. An in vitro digestion stability assay for measuring bioavailability was carried out on SNL crude protein and autoclaved SNL using pepsin and pancreatin. A nonradioactive histone acetyltransferase (HAT) assay and HAT activity colorimetric assay were used to measure the inhibition of core histone acetylation. The inhibitory effect of lunasin on the phosphorylation of retinoblastoma protein (Rb) was determined by immunoblotting against phospho-Rb. Lunasin isolated from autoclaved SNL inhibited core histone H3 and H4 acetylation, the activities of the HATs, and the phosphorylation of the Rb protein. Lunasin in the crude protein and in the autoclaved crude protein was very stable to pepsin and pancreatin in vitro digestion, while the synthetic pure lunasin was digested at 2 min after the reaction. We conclude that lunasin is a bioactive and bioavailable component in SNL and that consumption of SNL may play an important role in cancer prevention.

Recent studies suggest that the lipid, ceramide, induces the default apoptosis process in eggs. Yet, it is obscure how newly formed embryos overcome this fate. Acid ceramidase (AC) is a key regulatory enzyme involved in ceramide metabolism, and mutations in the AC gene (Asah1) result in Farber Lipogranulomatosis, a fatal human genetic disorder. Our previous studies revealed that AC knockout (Asah1-/-) mice had a lethal phenotype, and herein we reveal the mechanism underlying this observation. A single-cell, polymerase chain reaction (PCR) genotyping method was developed to analyze individual embryos from Asah1 +/- intercrosses. Combined with Annexin V staining, this genotype analysis demonstrated that Asah1-/- embryos could not survive beyond the 2-cell stage, and underwent apoptotic death. Notably, sphingosine-1-phosphate (S1P) treatment of early 2-cell embryos from the Asah1 +/- intercrosses rescued Asah1-/- embryos, and enabled their progression from the 2-cell to 4-8-cell stage. Quantitative PCR also revealed that expression of the Asah1 gene in healthy embryos was initiated at the 2-cell stage, coincident with embryonic genome activation (EGA). AC activity and Western blot analyses further demonstrated high expression and activity of the enzyme in normal, unfertilized eggs, which likely provide the protein to newly formed embryos prior to EGA. Based on these observations, we suggest that AC is an essential factor required for embryo survival that functions by removing ceramide from the newly formed embryos, thus inhibiting the default apoptosis pathway.

Diseases of the peripheral nervous system are the most prevalent in patients with end-stage renal disease (ESRD). Although increased blood levels of lead in ESRD have been reported, the role of lead remains to be elucidated. The purpose of this study was to determine the connection of blood lead concentration with peripheral nerve conduction velocity. One hundred ninety-eight healthy subjects (control group) and 68 patients with ESRD undergoing hemodialysis (ESRD group) were enrolled. Nerve conduction was measured within two hours after hemodialysis. Orthodromic sensory nerve action potentials and compound muscle action potentials were recorded on the median, ulnar, and radial nerves. Hemoglobin-corrected blood lead was significantly higher in ESRD patients than in controls (9.1+/-2.8 microgram/dL vs. 5.9+/-2.3 microgram/dL, p0.001). 32.4% of 68 ESRD patients with diabetes mellitus were significantly related to poorer motor and sensory nerve conduction velocity (p0.001). However, blood lead was not a significant predictor of the nerve conduction velocity (p0.05). Our result suggested that even though the blood lead levels were high in ESRD, they were not associated with the decline of peripheral nerve function. Diabetes mellitus is a primary independent risk of neuropathy in ESRD patients.

Acid sphingomyelinase (ASM) is the lipid hydrolase that is deficient in types A and B Niemann-Pick disease (NPD). Here, we demonstrate that the gene encoding ASM (SMPD1) is paternally imprinted and that differential expression of the mutant alleles in patients with ASM-deficient NPD and in carriers influences the disease phenotype. Comparison of the results of genomic sequencing versus reverse-transcriptase polymerase chain reaction sequencing for several patients with NPD revealed preferential expression of one mutant allele. Further analysis of one family showed that the expressed allele was maternally inherited and that the distinct clinical presentations of the individual patients were correlated with the amount of residual ASM activity expressed from the maternal mutation. Treatment of NPD cell lines with 5-aza-2'-deoxycytidine enhanced the expression of the paternal SMPD1 allele, and bisulfite genomic sequencing identified which CpG dinucleotides within the SMPD1 promoter were methylated. In a related set of studies, we identified a carrier individual who had approximately 15% of normal ASM activity and clinical features of ASM-deficient NPD. DNA sequencing confirmed that this individual carried a single SMPD1 mutation and that this mutant allele was preferentially expressed. These data thus demonstrate, for the first time, imprinting at the SMPD1 gene and reveal the influence of this epigenetic modification on the presentation of ASM-deficient NPD.

Polymorphisms in DNA repair genes may be associated with differences in the repair capacity of DNA damage and may influence an individual's susceptibility to smoking-related cancer. We investigated the association between two polymorphisms of the DNA repair gene XPA and risk of lung cancer in the Korean population. Two XPA polymorphisms (A23G and G709A) were typed in 265 lung cancer patients and 185 healthy controls who were frequency-matched on age and sex. The XPA G709A polymorphism was not detected in cases and controls. The XPA 23 GG genotype was associated with a significantly decreased risk for lung cancer [odds ratio (OR), 0.56; 95% confidence interval (CI), 0.35-0.90] when the combined AA and AG genotype was used as the reference. The reduction in risk for the XPA 23 GG genotype was significant in males (OR, 0.51; 95% CI, 0.30-0.86), younger individuals (OR, 0.39; 95% CI, 0.19-0.80), and current smokers (OR, 0.46; 95% CI, 0.25-0.83). These results suggest that the XPA A23G polymorphism contributes to genetic susceptibility for lung cancer.

a Department of Internal Medicine, School of Medicine, Kyungpook National Uni ersity Hospital, Samduk 2ga 50, Taegu 700-412, South Korea b Cancer Research Institute, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea c Department of Biochemistry, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea d Department of Thoracic Surgery, School of Medicine, Kyungpook National Uni ersity Hospital, Samduk 2ga 50, Taegu 700-412, South Korea e Department of Internal Medicine, School of Medicine, Keimyung Uni ersity, Dongsan Dong 194, Taegu 700-712, South Korea f Department of Pre enti e Medicine, School of Medicine, Kyungpook National Uni ersity, Dong In 2Ga 101, Taegu 700-422, South Korea

Ceramide is an important cellular lipid involved in signal transduction and the biosynthesis of complex sphingolipids. It can be hydrolyzed into sphingosine, another important signaling lipid, by the activity of ceramidases. Point mutations in the gene (Asah1) encoding one ceramidase, acid ceramidase (AC), lead to the lysosomal storage disorder Farber disease (FD). To investigate the role of AC in mammalian development, we disrupted the mouse gene Asah1 in embryonic stem cells by homologous recombination mediated insertion of an AC targeting vector into the wild-type sequence. Genotype analysis of over 150 offspring or embryos from heterozygous intercrosses revealed an absence of Asah1−/− individuals at embryonic day (E) 8.5 or later, although the ratio of wild-type to Asah1+/− individuals from these intercrosses was 1:2. Northern blot analysis showed that AC expression was turned on early in development, by E7.0, and continued through at least E17. In contrast, expression of the related lipid hydrolase, acid sphingomyelinase, was shut down by E11. Asah1+/− mice survived and lived a normal lifespan, but developed a progressive lipid storage disease in several of their organs, particularly the liver. These histopathological findings in Asah1+/− animals correlated with an up to twofold increase in the ceramide content of these tissues and a reduction n AC activity, confirming that the gene insertion event disrupted AC activity and ceramide metabolism. These results provide direct in vivo evidence that normal ceramide metabolism, and AC activity in particular, is essential for mammalian development. The animals and embryos described here should be a valuable resource for investigators studying the role of ceramide in cell growth and development, as well as those interested in the pathogenesis of FD and other sphingolipid storage disorders.

DNA repair plays a critical role in protecting the genome of the cell from insults of cancer-causing agents, such as those found in tobacco smoke. Reduced DNA repair capacity, therefore, can increase the susceptibility to smoking-related cancers. Recently, three coding polymorphisms in X-ray cross-complementing group 1 (XRCC1) DNA repair gene have been identified, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility. We investigated the relationship between the codon 399 polymorphism in XRCC1 gene and lung cancer risk in male smokers. The study population consisted of 192 lung cancer patients and 135 healthy controls. The distribution of XRCC1 genotypes was not significantly different between cases and controls. When the cases were categorized by histological type, however, the presence of at least one Gln allele was associated with a significant increased risk for squamous cell carcinoma [crude odds ratio (OR) = 1.77, 95% confidence interval (CI) = 1.06-2.93 and adjusted OR = 1.66, 95% CI = 0.99-2.79]. The risk for the disease increased as the number of Gln alleles increased (Arg/Gln genotype: adjusted OR = 1.45, 95% CI = 0.84-2.5; Gln/Gln genotype: adjusted OR = 3.26, 95% CI = 1.17-9.15). When the subjects dichotomized by cigarette consumption into two pack-year groups (or =40 pack-years,40 pack-years), the Gln allele was associated with an increased risk for squamous cell carcinoma only in the group of individuals havingor =40 pack-years of smoking (Arg/Gln genotype: adjusted OR = 1.48, 95% CI = 0.78-2.8; Gln/Gln genotype: adjusted OR = 5.75, 95% CI = 1.46-22.69). These results suggest that XRCC1 codon 399 polymorphism may be an important genetic determinant of squamous cell carcinoma of the lung in persons with lower degrees of cigarette use.

Allyl isothiocyanate (AITC) is a phytochemical found in cruciferous vegetables that has known chemopreventive and chemotherapeutic activities. Thus far, the antiangiogenic activity of AITC has not been reported in in vivo studies. Herein, we investigated the effect of AITC on angiogenesis and inflammation in a mouse model of colitis. Experimental colitis was induced in mice by administering 3% dextran sulfate sodium via drinking water. To monitor the activity of AITC in this model, we measured body weight, disease activity indices, histopathological scores, microvascular density, myeloperoxidase activity, F4/80 staining, inducible nitric oxide synthase (iNOS) expression, cyclooxygenase-2 (COX-2) expression, and vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (VEGFR2) expression in the mice. We found that AITC-treated mice showed less weight loss, fewer clinical signs of colitis, and longer colons than vehicle-treated mice. AITC treatment also significantly lessened the disruption of colonic architecture that is normally associated with colitis and repressed the microvascularization response. Further, AITC treatment reduced both leukocyte recruitment and macrophage infiltration into the inflamed colon, and the mechanism these activities involved repressing iNOS and COX-2 expression. Finally, AITC attenuated the expression of VEGF-A and VEGFR2. Thus, AITC may have potential application in treating conditions marked by inflammatory-driven angiogenesis and mucosal inflammation.

Acid ceramidase (AC) is the lysosomal enzyme that degrades ceramide into sphingosine and fatty acid. A deficiency in human AC activity leads to the lysosomal storage disorder, Farber disease (FD). The human AC gene (HGMW-approved symbol ASAH) was cloned and characterized, revealing an organization similar to that of the murine AC gene. The human gene spans about 30 kb in length and contains 14 exons ranging in size from 46 to 1201 bp. The exon/intron junctions were determined and found to follow the GT-AG rule. The putative promoter region had a GC content over 60%, lacked a TATA box, and contained several sequences matching transcription factor binding sites, including nine SP-1 sites, one AP-1 site, and three CACC boxes. The promoter activity of a 475-bp fragment from within this region was demonstrated by chloramphenicol acyltransferase assays. Northern blotting revealed variable expression of the human AC RNA; i.e., expression of the major 2.4-kb transcript was high in heart and kidney, followed by lung and placenta, but low in pancreas, liver, brain, and skeletal muscle. Two minor AC transcripts of 1.7 and 1.2 kb also were detected in heart and skeletal muscle. The human AC gene was mapped to the chromosomal region 8p21.3–p22 by in situ hybridization and FISH analyses, syntenic with the mouse chromosomal location. Finally, three new missense mutations, E138V, R254G, and P362R, were identified in the human AC gene from FD patients. Mutant AC cDNAs containing these point mutations were constructed and examined using the FLAG-tagged expression system. Although the levels of protein expression for these mutant ACs were about equivalent to that of the controls, their enzymatic activity was markedly reduced, confirming their authenticity.

candidates referring to training in endoscopic mucosal resection (EMR). The median number of formative colonoscopy assessments was 3 (range 0-16). In the year since DOPyS was introduced there were 150 applications for certification. The median number of procedures per candidate was 206. All of these candidates had evidence of polypectomy assessment with a median number of DOPyS of 7 (range 3-27). 89 per cent of applicants had evidence of assessed EMR. The median number of formative colonoscopy assessments in this cohort was 32 (range 9-199). There was a significant increase in the number of logged polypectomy assessments (p 0.001), experience of EMR (p 0.001) and formative colonoscopy assessments (p 0.001). There was no significant difference in the total number of colonoscopy procedures performed. Conclusions: These data the largest in the literature to date show that structured polypectomy assessment improves trainees’ documented exposure to therapeutic endoscopy as well as providing formal evidence of skills acquisition. As polypectomy plays an increasing role globally in colorectal cancer prevention, the DOPyS provides an effective means of assessing and certifying polypectomy in order to minimize the well-recognized risks associated with this technique. Reference: 1. Gupta S et al. Development and validation of a novel method for assessing competency in polypectomy: direct observation of polypectomy skills. Gastrointest Endosc. 2011 Jun ;73(6):1232-9.e2.

Background: The High resolution manometry (HRM) provides a colorful representation of esophageal motility based on its spatiotemporal plot (STP) compared to the previously used conventional linear plot (LP). The diagnostic accuracy of STP compared to the LP has been reported to be increased, especially higher diagnostic yield in novice than advanced learners. Three-dimensional animation plot (3-DP) (SandhillTM, Highland Ranch, CO) can aggregate the information from the STP profiles and regenerate the esophageal motion as threedimensional model with moving pictures. However, the clinical usefulness and diagnostic yield of 3-DP have not been fully validated. We aimed to investigate the additional diagnostic yield and ease of interpretation of 3-DP compared to STP and LP among nurses, medical students, and gastrointestinal (GI) fellows. Methods: After standardized electronic tutorials, 20 medical students, 10 nurses, and 6 GI fellows, all of whom were never spoiled from the conventional manometry or HRM previously, were asked to answer to the questionnaire regarding diagnosis to the classified 30 examples of esophageal motility findings in LP, STP, and 3-DP formats in random order ((normalcy (n=15), type I achalasia (n=6), type II or III achalasia (n=7), ineffective esophageal motility (IEM) (n=2)), and asked about subjective preference and availability of interpretation among 3 formats. The diagnostic accuracy was compared among the 3 different display formats, as well as a subjective rating of preference in the diagnosis. The diagnostic accuracy in 3 formats was calculated and compared by logistic regression with generalized estimating equation. Results: The diagnostic accuracy was significantly higher in fellow group (OR=1.62, 95%CI: 1.12 to 2.35, P=0.01), especially in case of normalcy (OR=2.42, 95% CI: 1.42 to 4.11, P