Cisplatin-induced activation of TGF-βsignaling contributes to drug resistance

Growing evidence suggests an association between epithelial-mesenchymal transition(EMT),a hallmark of tumor malignancy,and chemoresistance to a number of anti-cancer drugs.However,the mechanism of EMT induction in the process of acquiring anti-cancer drug resistance remains unclear.To address this issue,we obtained a number of cisplatin-resistant clones from LoVo cells and found that almost all of them lost cell-cell contacts.In these clones,the epithelial marker E-cadherin was downregulated,whereas the mesenchymal marker N-cadherin was upregulated.Moreover,the expression of EMT-related transcription factors,including Slug,was elevated.On the other hand,the upregulation of other mesenchymal marker Vimentin was weak,suggesting that the mesenchymal-like phenotypic changes occurred in these cisplatin-resistant clones.These mesenchymal-like features of cisplatin-resistant clones were partially reversed to parental epithelial-like features by treatment with transforming growth factor-β(TGF-β)receptor kinase inhibitors,indicating that TGF-βsignaling is involved in cisplatin-induced the mesenchymallike phenotypic changes.Moreover,cisplatin was observed to enhance the secretion of TGF-βinto the culture media without influencing TGF-βgene transcription.These results suggest that cisplatin may induce the mesenchymal-like phenotypic changes by enhancing TGF-βsecretion,ultimately resulting in drug resistance.

六道木属六道木组种间关系的AFLP分析和黄花六道木中国分布新记录的认定

用荧光标记AFLP技术对东亚产六道木属六道木组作了系统关系分析。我们采用 5对AFLP引物 ,对六道木属 9个物种 ,锦带花属和猬实属各 1个物种共 16份样品进行分析 ,共获得 988个位点。不同引物所获得的结果具有很高的相容性 ,Mantel相关系数为 0 72 5～0 919,说明AFLP技术适用于六道木属的种间关系分析。用邻接法 (neighbor joining)对 16个样品 988个位点的分析生成的系统树获得很高的自展分析 (bootstrap)支持率。树系图表明 ,猬实属与六道木属管花六道木组有密切的关系。在六道啪组内 ,温州六道木与糯米条的关系密切 ,单花六道木与大花六道木差异很小 ,黄花六道木与日本产的近缘种组成一单系分支。本文认定 ,根据形态特征鉴定浙江永嘉的标本为黄花六道木 (AbeliaserrataSieb .etZucc .)是正确的 ,属中国分布新记录。文章最后补充描述了中国产的黄花六道木。黄花六道木在中国的发现进一步证明中国植物区系与日本植物区系的密切关系。

中国忍冬科分布新记录——温州六道木(英文)

温州六道木AbeliaspathulataSieb.&Zucc.原来被认为特产于日本,最近发现也分布在我国浙江省永嘉县四海山。温州六道木与糯米条A.chinensisR.Brown的亲缘关系最近,但温州六道木聚伞花序仅2花,生于小枝顶端;花冠白色或粉红色,长2–3cm,钟状,裂片二唇形;雄蕊不伸出花冠筒外。糯米条聚伞花序多花,集生于小枝顶部叶腋成圆锥花序状;花冠白色,长0.5–1cm,漏斗状,裂片近辐射对称;雄蕊显著伸出花冠筒外。

Eubacterium limosum ameliorates experimental colitis and metabolite of microbe attenuates colonic inflammatory action with increase of mucosal integrity

AIM： To examine the effect of Eubacteriuro Iiroosuro （E.Iiroosuro） on colonic epithelial cell line in vitro, and to evaluate the effect of E.limosum on experimental colitis.METHODS： E.Iimosum was inoculated anaerobically and its metabolites were obtained. The growth stimulatory effect of the E.limosum metabolites on T84 cells was evaluated by SUDH activity, and the anti-inflammatory effect by IL-6 production. The change in mRNA of toll like receptor 4 （TLR4） was evaluated by real time PCR. Colitis was induced by feeding BALB/C mice with 2.0% dextran sodium sulfate. These mice received either 5% lyophilized E.lirnosum （n=7） or control diet （n=7）. Seven days after colitis induction, clinical and histological scores, colon length, and cecal organic acid levels were determined.RESULTS： The E.Iimosum produced butyrate, acetate, propionate, and lactate at 0.25, 1.0, 0.025 and 0.07 retool/L, respectively in medium. At this concentration, each acid had no growth stimulating activity on T84 cells; however, when these acids were mixed together at the above levels, it showed significantly high activity than control. Except for lactate, these acids significantly attenuated IL-6 production at just 0.1 mmol/L. In addition, under TNF-α stimulation, butyrate attenuated the production of TLR4 mRNA. The treatment with E.limosum significantly attenuated clinical and histological scores of colitis with an increase of cecal butyrate levels, compared with the control group.CONCLUSION： E.limosum can ameliorate experimental colonic inflammation. In part, the metabolite of E.lirnosurn, butyrate, increases mucosal integrity and shows anti-inflammatory action modulation of mucosal defense system via TLR4.

Role of Cathepsin G in the Degradation of Glyceraldehyde-3-Phosphate Dehydrogenase Triggered by 4-Hydroxy-2-Nonenal in U937 Cells

Degradation of oxidized or oxidatively modified proteins is an essential part of the cellular antioxidant defense system. 4-Hydroxy-2-nonenal (HNE), a major reactive aldehyde formed by lipid peroxidation, causes many types of cellular damage. HNE-modified proteins are degraded by the ubiquitin-proteasome pathway or the lysosomal pathway. However, our previous studies using U937 cells showed that HNE-modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is degraded by cathepsin G. In the present study, we examined whether GAPDH in U937 cells treated with HNE in culture is degraded similarly to that incubated with HNE and U937 cell extract. Treatment with HNE for 10 min in culture decreased GAPDH activity in a concentration dependent manner, but did not affect GAPDH degradation. The proteasome activities were not affected by HNE, but culturing with HNE decreased cathepsin G activity and protein level in a concentration dependent manner. These results suggest that HNE-induced oxidative stress leads to decreased cathepsin G activity and results in the loss of GAPDH degradation. Taken together, our findings indicate that cathepsin G has an important role in the degradation of oxidatively modified GAPDH in U937 cells.

Effects of ADH1C, ALDH2, and CYP2A6 Polymorphisms on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers

Recent genome-wide association studies have identified several lung cancer susceptibility loci. We previously carried out a replication study in male Japanese smokers that focused on chromosome 5p15 (telomerase reverse transcriptase) and 3q28 (tumor protein p63) (Shimizu et al., Journal of Cancer Therapy, Vol. 2, No. 5, 2011, pp. 690-696). The current study was performed to confirm the association of traditional susceptibility loci [i.e., alcohol dehydrogenase 1C (ADH1C) and aldehyde dehydrogenase 2 (ALDH2)] in 1039 male Japanese smokers (573 lung cancer patients and 466 healthy control subjects) who were previously enrolled in a study to investigate the low odds ratio for lung cancer risk associated with functionally impaired and deletion polymorphisms in cytochrome P450 2A6 (CYP2A6). The minor allele frequency of rs671 in ALDH2 (0.304) was significantly higher in lung cancer cases than in controls (0.226), with an odds ratio of 1.42 [95% confidence interval (CI) of 1.12 - 1.80, p = 0.0033]. No significant association of rs698 in ADH1C with lung cancer risk was found in this population of male Japanese smokers. For light smokers categorized according to the 50th percentile Brinkman index value among the control subjects (620 daily cigarettes × years) and for the CYP2A6*1 wild-type non-carrier sub-population, significantly high odds ratios of 1.98 and 1.68 (95% CI of 1.28 - 3.06, p = 0.0022, and 1.07 - 2.66, p = 0.025), respectively, were observed for rs671 in ALDH2. The present results support the association of ALDH2 loci with lung cancers and suggest a specific effect of ALDH2 loci resulting in a higher risk of lung cancer in light smokers. CYP2A6 polymorphisms, including copy number polymorphisms, may lower the risk of heavy tobacco use-related lung cancer.

Effect of Silver-Loaded Zeolite on the Susceptibility of <i>Escherichia Coli</i>Against Antibiotics

We investigated the effect of silver-loaded zeolite (Ag-Z) on antibacterial activity of some antibiotics against Es-cherichia coli against antibiotics. We treated the bacterial suspension of E. coli by Ag-Z to be the level which the decrease of viable cell count was not observed. Susceptibility test of E. coli treated with Ag-Z was carried out against four antibiotics with different mode of action. Apparent increase in susceptibility was found in the case of rifampicin, not in others. The result suggests that application of Ag-Z to ward environment might give a good outcome at the treatment with rifampicin and at the treatment for pathogenic microbe spread through the air, such as tubercle bacilli.

Electrochemical Analysis of the Redox State of Silver Contained in Antibacterial Material

Introduction of silver into some inorganic material causes the resulting mixture to have antibacterial activity. Here, we investigated the role of silver in the bactericidal activity of silver-loaded zeolite, by measuring the effects of silver-loaded zeolite on Escherichia coli cell viability under conditions in which the oxidation state of the silver was controlled electrochemically. Bactericidal activity was observed when the sweeping voltage between 0 and 0.7 V was applied to the silver electrode. When nitrogen gas bubbling or reactive oxygen scavengers were added to the experimental system, bactericidal activity decreased. These results indicated that the redox cycle, Ag0 Ag+, caused the dissolved oxygen to form reactive oxygen species.

Effects of Meat Intake Frequency and Polymorphic Cytochrome P450 2A6 Activity on Individual Colorectal Tumour Risk in a Japanese Cohort

The relationships among meat consumption, smoking habits, and phenotypic cytochrome P450 2A6 variation with respect to colorectal cancer risk remain unclear. In this study, the relationships among colorectal tumour risk, meat consumption by questionnaire, and phenotypic P450 2A6 activity by genotyping in a case-control study (299 cases and 170 controls) were analyzed for never-smokers and ever-smokers. In never-smokers consuming ≥1 serving per day of total meat, a significant odds ratio of 4.42 (95% confidence interval, 1.29 - 15.2), adjusted by logistic regression for age and gender, was observed, compared with the group consuming ≤2 servings per week. Furthermore, in Japanese never-smokers, the susceptibility to colorectal tumours was dependent on the frequency of meat intake (trend test p = 0.011). In never-smokers who were P450 2A6 poor metabolizers and had a high frequency of meat intake, the apparent odds ratio was 3.57 (95% confidence interval, 0.30 - 42.2) compared with the P450 2A6 normal group with a low meat intake frequency. These results suggested that colorectal tumour risk was inversely associated with the phenotypic P450 2A6 activities in Japanese never-smokers with a high meat intake.

Measurement of the integrated luminosity of the Phase 2 data of the Belle Ⅱ experiment

From April to July 2018,a data sample at the peak energy of the T(4 S) resonance was collected with the Belle Ⅱ detector at the SuperKEKB electron-positron collider.This is the first data sample of the Belle Ⅱ experiment.Using Bhabha and digamma events,we measure the integrated luminosity of the data sample to be(496.3±0.3±3.0) pb-1,where the first uncertainty is statistical and the second is systematic.This work provides a basis for future luminosity measurements at Belle Ⅱ.