Neural Wiskott-Aldrich syndrome protein(N-WASP)promotes distant metastasis in pancreatic ductal adenocarcinoma via activation of LOXL2

Pancreatic ductal adenocarcinoma(PDAC)is one of the most aggressive solid malignancies.A specific mechanism of its metastasis has not been established.In this study,we investigated whether Neural Wiskott-Aldrich syndrome protein(N-WASP)plays a role in distant metastasis of PDAC.We found that N-WASP is markedly expressed in clinical patients with PDAC.Clinical analysis showed a notably more distant metastatic pattern in the N-WASP-high group compared to the N-WASP-low group.N-WASP was noted to be a novel mediator of epithelialmesenchymal transition(EMT)via gene expression profile studies.Knockdown of N-WASP in pancreatic cancer cells significantly inhibited cell invasion,migration,and EMT.We also observed positive association of lysyl oxidase-like 2(LOXL2)and focal adhesion kinase(FAK)with the N-WASP-mediated response,wherein EMT and invadopodia function were modulated.Both N-WASP and LOXL2 depletion significantly reduced the incidence of liver and lung metastatic lesions in orthotopic mouse models of pancreatic cancer.These results elucidate a novel role for N-WASP signaling associated with LOXL2 in EMT and invadopodia function,with respect to regulation of intercellular communication in tumor cells for promoting pancreatic cancer metastasis.These findings may aid in the development of therapeutic strategies against pancreatic cancer.

Regulation of sleep by astrocytes in the hypothalamic ventrolateral preoptic nucleus

Astrocytes are functionally dynamic cells that support neurons in multiple ways throughout an organism’s lifespan.The astrocytic regulation of neuronal activity has been increasingly recognized in recent years.Astrocytes are now recognized as playing a more complex role than mere bystanders in the central nervous system.However,their role in regulating the sleep neurocircuitry is not well understood.From this perspective,we highlight the role of astrocytes in sleep modulation,with a particular focus on regulatory mechanisms related to the ventrolateral preoptic nucleus(VLPO)of the hypothalamus.We briefly discuss recent literature reporting the role of VLPO astrocytes in regulating sleep-associated behaviors.

Hepatocellular carcinoma in Budd-Chiari syndrome:A single center experience with long-term follow-up in South Korea

AIM:To evaluate long-term clinical course of BuddChiari syndrome(BCS) and predictive factors associated with the development of hepatocellular carcinoma(HCC) and survival.METHODS:We analyzed 67 patients with BCS between June 1988 and May 2008.The diagnosis of BCS was confirmed by hepatic venous outflow obstruction shown on abdominal ultrasound sonography,computed tomography,magnetic resonance imaging,or venography.The median follow-up period was 103 ± 156 [interquartile range(IQR)] mo.RESULTS:The median age of the patients was 47 ± 16(IQR) years.At diagnosis,54 patients had cirrhosis,25(37.3%) Child-Pugh class A,23(34.3%) Child-Pugh class B,and six(9.0%) patients Child-Pugh class C.During the follow-up period,HCC was developed in 17 patients,and the annual incidence of HCC in patients with BCS was 2.8%.Patients in HCC group(n = 17) had higher hepatic venous pressure gradient(HVPG) than those in non-HCC group(n = 50)(21 ± 12 mmHg vs 14 ± 7 mmHg,P = 0.019).The survival rate of BCS patients was 86.2% for 5 years,73.8% for 10 years,and 61.2% for 15 years.In patients with BCS and HCC,survival was 79% for 5 years,43.1% for 10 years,and 21.5% for 15 years.CONCLUSION:The incidence of HCC in patients with BCS was similar to that in patients with other etiologic cirrhosis in South Korea.The HVPG is expected to provide additional information for predicting HCC development in BCS patients.

Single patient classifier as a prognostic biomarker in pT1N1 gastric cancer:Results from two large Korean cohorts

Objective:Benefits of adjuvant treatment in pT1 N1 gastric cancer(GC)remain controversial.Additionally,an effective biomarker for early GC is the need of the hour.The prognostic and predictive roles of single patient classifier(SPC)were validated in stageⅡ/ⅢGC.In this study,we aimed to elucidate the role of SPC as a biomarker for pT1 N1 GC.Methods:The present retrospective biomarker study(NCT03485105)enrolled patients treated for pT1 N1 GC between 1996 and 2012 from two large hospitals(the Y cohort and S cohort).For SPC,mRNA expression of four classifier genes(GZMB,WARS,SFRP4 and CDX1)were evaluated by real-time reverse transcription-polymerase chain reaction assay.The SPC was revised targeting pT1 stages and the prognosis was stratified as high-and lowrisk group by the expression of SFRP4,a representative epithelial-mesenchymal transition marker.Results:SPC was evaluated in 875 patients(n=391 and 484 in the Y and S cohorts,respectively).Among 864 patients whose SPC result was available,41(4.7%)patients experience GC recurrence.According to revised SPC,254(29.4%)patients were classified as high risk[123(31.5%)and 131(27.1%)in the Y and S cohorts,respectively].The high risk was related to frequent recurrence in both Y and S cohort(log-rank P=0.023,P<0.001,respectively),while there was no difference by GZMB and WARS expression.Multivariable analyses of the overall-cohort confirmed the high risk of revised SPC as a significant prognostic factor[hazard ratio(HR):4.402(2.293-8.449),P<0.001]of GC.A significant difference was not detected by SPC in the prognosis of patients in the presence and absence of adjuvant treatment(log-rank P=0.670).Conclusions:The present study revealed the revised SPC as a prognostic biomarker of pT1 N1 GC and suggested the use of the revised SPC for early-stage GC as like stageⅡ/Ⅲ.

Prediction models of hepatocellular carcinoma development in chronic hepatitis B patients

Chronic hepatitis B virus(HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma(HCC). Applying the same strategies for antiviral therapy and HCC surveillance to all chronic hepatitis B(CHB) patients would be a burden worldwide. To properly manage CHB patients, it is necessary to identify and classify the risk for HCC development in such patients. Several HCC risk scores based on risk factors such as cirrhosis, age, male gender, and high viral load have been used, and have negative predictive values of ≥ 95%. Most of these have been derived from, and internally validated in, treatment-na?ve Asian CHB patients. Herein, we summarized various HCC prediction models, including IPM(Individual Prediction Model), CU-HCC(Chinese University-HCC), GAG-HCC(Guide with Age, Gender, HBV DNA, Core Promoter Mutations and Cirrhosis-HCC), NGM-HCC(NomogramHCC), REACH-B(Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B), and Page-B score. To develop a noninvasive test of liver fibrosis, we also introduced a new scoring system that uses liver stiffness values from transient elastography, including an LSM(Liver Stiffness Measurement)-based model, LSM-HCC, and mR EACH-B(modified REACH-B).

Isolation and characterization of Pseudomonas otitidis WL-13 and its capacity to decolorize triphenylmethane dyes

Pseudomonas otitidis WL-13, which has a high capacity to decolorize triphenylmethane dyes, was isolated from activated sludge obtained from a wastewater treatment plant of a dyeing industry. This strain exhibited a remarkable color-removal capability when tested against several triphenylmethane dyes under both shaking and static conditions at high concentrations of dyes. More than 95% of Malachite Green and Brilliant Green was removed within 12 h at 500 μmol/L dye concentration under shaking conditions. Crystal Violet lost about 13% of its color under the same conditions tested. The rate of decolorization increased when the M9 medium was supplemented with yeast extract. The optimum pH and temperature for color removal were 7-9 and 35-40℃, respectively. The observed changes in the visible spectra and the inspection of bacterial growth indicated the color-removal by the adsorption of dye to the cells during incubation with strains.

Oxidative stress and inflammatory signaling in cerulein pancreatitis

Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-&#x003ba;B (NF-&#x003ba;B) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-&#x003ba;B, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.

Increased intestinal macromolecular permeability and urine nitrite excretion associated with liver cirrhosis with ascites

AIM： To determine intestinal permeability, the serum tumor necrosis factor （TNF）-α level and urine nitric oxide （NO） metabolites are altered in liver cirrhosis （LC） with or without ascites. METHODS： Fifty-three patients with LC and 26 healthy control subjects were enrolled in the study. The intestinal permeability value is expressed as the percentage of polyethylene glycol （PEG） 400 and 3350 retrieval in 8-h urine samples as determined by high performance liquid chromatography. Serum TNF-α concentrations and urine NO metabolites were determined using an enzyme-linked immunosorbent assay （ELISA） and Greiss reaction method, respectively. RESULTS： The intestinal permeability index wassignificantly higher in patients with LC with ascites than in healthy control subjects or patients with LC without ascites （0.88 ± 0.12 vs 0.52 ± 0.05 or 0.53 ± 0.03, P 〈 0.05） and correlated with urine nitrite excretion （r = 0.98）. Interestingly, the serum TNF-α concentration was significantly higher in LC without ascites than in control subjects or in LC with ascites （198.9 ± 55.8 pg/mL vs 40.9 ± 12.3 pg/mL or 32.1 ± 13.3 pg/mL, P 〈 0.05）. Urine nitrite excretion was significantly higher in LC with ascites than in the control subjects or in LC without ascites（ 1170.9± 28.7 μmol/L vs 903.1 ± 55.1 μmol/L or 956.7 ± 47.7 μmol/L, P 〈 0.05）. COMCLUSIOM： Increased intestinal macromolecular permeability and NO is probably of importance in the pathophysiology and progression of LC with ascites, but the serum TNF-α concentration was not related to LC with ascites.

Cloning,expression in Escherichia coli,and enzymatic properties of laccase from Aeromonas hydrophila WL-11

A strain WL-11 with high laccase activity was isolated from activated sludge collected from the effluent treatment plant of a textile and dyeing industry. It was identified as Aeromonas hydrophila by physiological test and 16S rDNA sequence analysis. A gene encoding of laccase from a newly isolated Aeromonas hydrophila WL-11 was cloned and characterized. Nucleotide sequence analysis showed an open reading frame of 1605 bp encoding a polypeptide comprised of 534 amino acids. The primary structure of the enzyme predicted the structural features characteristic of other laccases, including the conserved regions of four histidine-rich copper-binding sites. The predicted amino acid sequence showed a high homology （more than 60%） with bacterial laccases in the genome and protein databases and the highest degree of similarity （61% identity） was observed with the multicopper oxidase of KlebsieUa sp. 601. When expressed in Escherichia coli, the recombinant enzyme was overproduced in the cytoplasm as soluble and active form. The purified enzyme had an optimum pH of 2.6 and 8.0 for ABTS （2,2＇-azino-bis（3-ethylbenzthiazolinesulfonic acid） and DMP （2,6-dimethoxyphenol）, respectively. The kinetic study on ABTS revealed a higher affinity of this enzyme to this substrate than DMP.

Primary intestinal lymphangiectasia diagnosed by capsule endoscopy and double balloon enteroscopy

Primary intestinal lymphangiectasia(PIL)is a rare disorder characterized by dilated intestinal lymphatics and the development of protein-losing enteropathy.Patients with PIL develop hypoalbuminemia,hypocalcemia,lymphopenia and hypogammaglobulinemia,and present with bilateral lower limb edema,fatigue,abdominal pain and diarrhea.Endoscopy reveals diffusely elongated,circumferential and polypoid mucosae covered with whitish enlarged villi,all of which indicate intestinal lymphangiectasia.Diagnosis is conf irmed by characteristic tissue pathology,which includes dilated intestinal lymphatics with diffusely swollen mucosa and enlarged villi.The prevalence of PIL has increased since the introduction of capsule endoscopy.The etiology and prevalence of PIL remain unknown.Some studies have reported that several genes and regulatory molecules for lymphangiogenesis are related to PIL.We report the case of a patient with PIL involving the entire small bowel that was confirmed by capsule endoscopy and double-balloon enteroscopy-guided tissue pathology who carried a deletion on chromosome 4q25.The relationship between this deletion on chromosome 4 and PIL remains to be investigated.

Transient elastography in chronic hepatitis B: An Asian perspective

Transient elastography (TE) is a new non-invasive tool for assessing liver stiffness, which is correlated with the histologic stage of liver fibrosis. Many studies have reported a good accuracy of TE in predicting signif icant fibrosis and an optimal accuracy in predicting cirrhosis. Furthermore, the potential role of TE in screening the general population has also been proven. TE thus helps physicians to decide treatment strategies, predict prog-nosis, and monitor disease progression in patients with chronic liver disease and to screen the general popula-tion to identify high risk patients with potential liver disease. However, most data on the clinical roles of TE have been gathered in European patients with chronic hepatitis C (CHC), because TE was first developed in France. Accordingly, much data on the usefulness of TE in patients with CHC has accumulated. Recently, however, vigorous efforts have been made to apply TEto patients with chronic hepatitis B (CHB), and TE has also proved to have acceptable accuracy in diagnosing liver fibrosis and cirrhosis in these patients. Thus, we focused on TE in the Asian population with CHB in comparison with the European population with CHC and found that the diagnostic performance and cutoff values were different between the 2 populations possibly as a result of several different confounders between Asian and European populations (the etiology of chronic liver disease, histologic features, major fluctuation in alanine aminotransferase levels, and the prevalence of high body mass index and metabolic syndrome). Therefore, further studies tailored to the Asian population with CHB should be performed before the widespread application of TE in Asian populations with CHB.

Survival outcome of patients with spontaneously ruptured hepatocellular carcinoma treated surgically or by transarterial embolization

AIM: To evaluate clinical outcomes of patients that underwent surgery, transarterial embolization (TAE), or supportive care for spontaneously ruptured hepatocellular carcinoma (HCC). METHODS: A consecutive 54 patients who diagnosed as spontaneously ruptured HCC at our institution between 2003 and 2012 were retrospectively enrolled. HCC was diagnosed based on the diagnostic guidelines issued by the 2005 American Association for the Study of Liver Diseases. HCC rupture was defined as disruption of the peritumoral liver capsule with enhanced fluid collection in the perihepatic area adjacent to the HCC by dynamic liver computed tomography, and when abdominal paracentesis showed an ascitic red blood cell count of > 50000 mm 3 /mL in bloody fluid. RESULTS: Of the 54 patients, 6 (11.1%) underwent surgery, 25 (46.3%) TAE, and 23 (42.6%) supportive care. The 2-, 4and 6-mo cumulative survival rates at 2, 4 and 6 mo were significantly higher in the surgery (60%, 60% and 60%) or TAE (36%, 20% and 20%) groups than in the supportive care group (8.7%, 0% and 0%), respectively (each, P < 0.01), and tended to be higher in the surgical group than in the TAE group. Multivariate analysis showed that serum bilirubin (HR = 1.09, P < 0.01), creatinine (HR = 1.46, P = 0.04), and vasopressor requirement (HR = 2.37, P = 0.02) were significantly associated with post-treatment mortality, whereas surgery (HR = 0.41, P < 0.01), and TAE (HR = 0.13, P = 0.01) were inversely associated with posttreatment mortality. CONCLUSION: Post-treatment survival after surgery or TAE was found to be better than after supportive care, and surgery tended to provide better survival benefit than TAE.

A pilot study of single-use endoscopy in screening acute gastrointestinal bleeding

AIM:To investigate the feasibility of a single-use endoscopy as an alternative procedure to nasogastric lavage in patients with acute gastrointestinal(GI) bleeding.METHODS:Patients who presented with hematemesis,melena or hematochezia were enrolled in this study.EG scan and conventional esophagogastroduodenoscopy(EGD) were subsequently performed.Active bleeding was defined as blood in the stomach,and inactive bleeding was defined as coffee ground clots and clear fluid in the stomach.The findings were recorded and compared.RESULTS:Between January and March,2011,13 patients that presented with hematemesis(n = 4),melena(n = 6),or bleeding from a previous nasogastric feeding tube(n = 3),were enrolled in this study.In 12 patients with upper GI bleeding,the EG scan device revealed that 7 patients had active bleeding and 5 patients had inactive bleeding,whereas conventional EGD revealed that 8 patients had active bleeding and 4 patients had inactive bleeding.The sensitivity and specificity of the EG scan device was 87.5% and 100% for active bleeding,with conventional EGD serving as a reference.No complication were reported during the EG scan procedures.CONCLUSION:The EG scan is a feasible device for screening acute upper GI bleeding.It may replace nasogastric lavage for the evaluation of acute upper GI bleeding.

Clinical outcomes and predictive factors in oral corticosteroid-refractory active ulcerative colitis

AIM:To evaluate the clinical outcomes and prognostic factors after intravenous corticosteroids following oral corticosteroid failure in active ulcerative colitis patients.METHODS:Consecutive patients with moderate to severe ulcerative colitis who had been treated with a course of intravenous corticosteroids after oral corticosteroid therapy failure between January 1996 and July 2010 were recruited at Severance Hospital,Seoul,South Korea.The disease activity was measured by the Mayo score,which consists of stool frequency,rectal bleeding,mucosal appearance at flexible sigmoidoscopy,and Physician Global Assessment.We retrospectively evaluated clinical outcomes at two weeks,one month,three months,and one year after the initiation of intravenous corticosteroid therapy.Two weeks outcomes were classified as responders or non-responders.One month,three month and one year outcomes were classified into prolonged response,steroid dependency,and refractoriness.RESULTS:Our study included a total of 67 eligible patients.At two weeks,56(83.6%) patients responded to intravenous corticosteroids.At one month,complete remission was documented in 18(32.1%) patients and partial remission in 26(46.4%).Eleven patients(19.7%) were refractory to the treatment.At three months and one year,we found 37(67.3%) and 25(46.3%) patients in prolonged response,ten(18.2%) and 23(42.6%) patients in corticosteroid dependency,8(14.5%) and 6(11.1%) patients with no response,respectively.Total 9 patients were underwent elective proctocolectomy within 1 year.The duration of oral corticosteroid therapy(> 14 d vs ≤ 14 d,P = 0.049) and lower hemoglobin level(≤ 11.0 mg/dL vs >11.0 mg/dL,P = 0.02) were found to be poor prognostic factors for response at two weeks.For one year outcome,univariate analysis revealed that only a partial Mayo score(≥ 6 vs <6,P = 0.057) was found to be associated with a poor response.CONCLUSION:The duration of oral corticosteroid therapy and lower hemoglobin level were strongly associated with poor outcome.

Efficacy of switching to telbivudine plus adefovir in suboptimal responders to lamivudine plus adefovir

AIM:To examine the efficacy of telbivudine(LdT)+adefovir(ADV)vs continuation of lamivudine(LAM)+ADV in patients with LAM-resistant chronic hepatitis B(CHB)who show a suboptimal response to LAM+ADV.METHODS:This was a randomized,active-control,open-label,single-center,parallel trial.All eligible patients were enrolled in this study in Severance Hospital,Yonsei University College of Medicine,Seoul,South Korea,between March 2010 and March 2011.Hepatitis Be antigen(HBeAg)-positive CHB patients whose serum hepatitis B virus(HBV)DNA remained detectable despite at least 6 mo of LAM+ADV therapy were included.Enrolled patients were randomized to either switching to LdT(600 mg/d orally)plus ADV(10 mg/d orally)(LdT+ADV group)or to continuation with LAM(100 mg/d orally)plus ADV(10 mg/d orally)(LAM+ADV group),and were followed for 48 wk.One hundred and six patients completed the 48-wk treatment period.Serum HBV DNA,HBeAg status,liver biochemistry and safety were monitored at baseline and week 12,24,36 and 48.RESULTS:The duration of prior LAM+ADV treatment was 18.3(LdT+ADV)and 14.9 mo(LAM+ADV),respectively(P=0.131).No difference was seen in baseline serum HBV DNA between the two groups[3.66(LdT+ADV)vs 3.76(LAM+ADV)log10IU/mL,P=0.729].At week 48,although there was no significant difference in the mean reduction of serum HBV DNA from baseline between LdT+ADV group and LAM+ADV group(-0.81 vs-0.47 log10IU/mL,P=0.167),more patients in the LdT+ADV group had undetectable HBV DNA levels compared to those in the LAM+ADV group(30.2%vs 11.5%,P=0.019).Three patients with LdT+ADV treatment and 2 patients with LAM+ADV treatment achieved HBeAg loss.The patients in both groups tolerated the treatment well without serious adverse events.The proportion of patients with estimated glomerular filtration rate≥90 mL/min per 1.73 m2in the LdT+ADV group increased from 49.1%(26/53)at baseline to 58.5%(31/53)at week 48,while that in the LAM+ADV group decreased from 37.7%(20/53)at baseline to 30.2%(16/53)at week 48.CONCLUSION:The switch to LdT+ADV in suboptimal responders to LAM+ADV showed a significantly higher rate of virologic response at week 48.These results suggest that LdT+ADV could be a therapeutic option for patients who are unable to use enofovir disoproxil fumarate for any reason.

Targeted yield concept and a framework of fertilizer recommendation in irrigated rice domains of subtropical India

Soil test crop response （STCR） correlation studies were carried out in Vindhyan alluvial plain during 2001 to 2004 taking IR-36 as test crop to quantify rice production in the context of the variability of soil properties and use of balanced fertilizers based on targeted yield concept. The soils were developed on gently sloping alluvial plain with different physiographic settings and notable variation in drainage condition. Soil properties show moderate variation in texture （loamy to clay）, organic carbon content （4.4 to 9.8 g/kg）, cation exchange capacity （10,2 to 22.4 cmol （p＋）/kg） and pH （5.3 to 6,4）, Soil fertility status for N is low to medium （224 to 348 kg/ha）, P is medium to high （87 to 320 kg/ha） and K ranges from medium to high （158 to 678 kg/ha）. Database regarding nutrient requirement in kg/t of grain produce （NR）, the percent contribution from the soil available nutrients [CS （%）] and the percent contribution from the applied fertilizer nutrients [CF （%）] were computed for calibrating and fbrmulating fertilizer recommendations. Validity of the yield target for 7 and 8 t/ha was tested in farmers＇ fields and yields targets varied at less than 10%. The percent achievement of targets aimed at different level was more than 90%, indicating soil test based fertilizer recommendation approach was economically viable within the agro-ecological zone with relatively uniform cropping practices and socio-economic conditions.

Placement of a fully covered self-expandable metal stent in a young patient with chronic pancreatitis

Plastic stent insertion is a treatment option for pancreatic duct stricture with chronic pancreatitis.However, recurrent stricture is a limitation after removing the plastic stent.Self-expandable metal stents have long diameters and patency.A metal stent has become an established management option for pancreatic duct stricture caused by malignancy but its use in benign stricture is still controversial.We introduce a young patient who had chronic pancreatitis and underwent several plastic stent insertions due to recurrent pancreatic duct stricture.His symptoms improved after using a fully covered self-expandable metal covered stent and there was no recurrence found at follow-up at the outpatient department.

Ovalicin attenuates atopic dermatitis symptoms by inhibiting IL-31 signaling and intracellular calcium influx

Atopic dermatitis(AD)is a common skin disorder difficult to be treated with medication.This study investigated the potential of ovalicin extracted from Cordyceps militaris for the treatment of AD using in vitro and in vivo models.We found that,in canine macrophage cell line DH82,lipopolysaccharide(LPS)upregulated the expression of genes associated with inflammation and pruritic responses through activating calcium and interleukin-31(IL-31)signaling,and the upregulation could be suppressed by ovalicin,with an effect significantly stronger than dexamethasone.Ovalicin also reduced the expression of IL-31 downstream genes,including JAK2(Janus kinase 2),TRPV1(transient receptor potential vanilloid receptor-1),and HRH2(histamine receptor H2).Ovalicin significantly alleviated the allergic symptoms in the AD mouse model.Histologically,the number of macrophages and mast cells infiltrated in the dermis was significantly reduced by ovalicin treatment.In the skin tissue of AD mice,reduction of IL-31 receptor was observed in the ovalicin treated group compared to the group without ovalicin treatment.To our knowledge,this is the first study to elucidate the anti-atopic mechanism of ovalicin,which could be an alternative to steroidal drugs commonly used for AD treatment.

Identifying multi-component drug candidates in natural products via association rule mining

OBJECTIVE To identify compound combinations as candidate multi-component drugs for the type 2 diabetes from natural product information.METHODS Chemical composition information of herbs in natural medicine was acquired by integrating conventional databases;Traditional Chinese Medicine Information Database(TCM-ID)and Traditional Chinese Medicine Integrated Database(TCMID).Therapeutic effect of each herb on the type 2 diabetes was examined by analyzing annotated function information with a text-mining method.The Apriori algorithm,which is a classical method for extracting associations between object in large-scale databases,was employed to infer association rules between compound combinations and therapeutic effect on the target disease.The chemical composition and therapeutic information of each herb was used as a transaction,which consists of the chemical compound combination as an antecedent item set and the therapeutic effect as a consequent item.The association rules with high support and confidence value were suggested as candidate multi-component drugs for the type 2 diabetes.RESULTS Totally 40 941 association rules were inferred with support lower bound 0.05% and maximum rule length 4.With respect to support and confidence,the top-ranked compound combination was puerarin and daidzin(support=0.15%,confidence=100%).In addition,the top 16 compound combinations were composed of 11 individual chemical compounds;puerarin,daidzin,abscisic acid,batatisine,dopamine,cholesterol,daidzein,gamma-aminobutyric acid,stigmasterol,campesteryl ferulate,and campesterol.To validate therapeutic effect of the proposed compound combinations,literature evidences of each individual compound were investigated.Among the 11 individual compounds,six compounds were reported to be effective for the treatment of the diabetes mellitus.CONCLUSION By analyzing natural product in formation with association rule mining,16 compound combinations are suggested as candidate multi-component drugs for the type 2 diabetes.These compound combinations are recommended for further investigation in the context of drug development.

Agmatine reduces nitric oxide synthase expression and peroxynitrite formation in the cerebral cortex in a rat model of transient global cerebral ischemia

Agmatine, an analog of L-arginine, is an endogenous substance synthesized by arginine decarboxylase, which has been shown to possess neuroprotective effects following brain ischemia. Nitric oxide is generated by sequential oxidation of the guanidinium group in L-arginine, and agmatine might protect the brain from ischemic injury by interfering with nitric oxide signaling. This study investigated the effects of agmatine on cerebral cortex neuronal injury following transient global cerebral ischemia and also detected nitric oxide synthase expression and peroxynitrite formation. Results demonstrated that intraperitoneal injection of agmatine in global cerebral ischemia/reperfusion alleviated ischemia/reperfusion-induced cerebral cortical cortex neuronal injury and cellular apoptosis, decreased neuronal and inducible nitric oxide synthase expression at 24, 48, and 72 hours following global cerebral ischemia and reperfusion, and greatly inhibited nitrotyrosine levels, which reflect the amount of peroxynitrite formed. These findings indicated that agmatine alleviates cerebral cortex neuronal injury following global cerebral ischemia and decreases nitric oxide synthase expression and peroxynitrite formation following ischemia/repeffusion.