Chelated iron sources are inhibitors of Pseudomonas aeruginosa biofilms and distribute efficiently in an in vitro model of drug delivery to the human lung

Aims:  To determine whether chelated sources of ferric iron were efficient inhibitors of biofilm formation in Pseudomonas aeruginosa and might be suitable for drug delivery to the lungs of cystic fibrosis (CF) patients via nebulization.
Methods and Results:  The response of P. aeruginosa biofilms to elevated iron concentrations in the form of eight structurally varied iron chelators in a microtitre plate assay for biofilm production was examined in the lab. Among these iron chelates, picolinic acid and acetohydroxamic acid-chelated iron were able to effectively thwart biofilm production in P. aeruginosa PA14 and in 20 clinical isolates of P. aeruginosa from a local hospital. The chelated iron sources showed excellent distribution in an Anderson cascade impactor model of particle size distribution in the human lung.
Conclusions:  Ferric picolinate and ferric acetohydroxamate are effective anti-biofilm compounds against both lab and clinical strains of P. aeruginosa and are readily nebulized into particles of suitable size for lung delivery.
Significance and Impact of the Study:  The data herein serve both to solidify the growing base of literature correlating high iron levels with biofilm inhibition in P. aeruginosa and to highlight the potential of these chelators as nebulized agents to combat biofilms of P. aeruginosa in CF patients.     

RBM10 inhibits cell proliferation of lung adenocarcinoma via RAP1/AKT/CREB signalling pathway

Initial functional studies have demonstrated that RNA‐binding motif protein 10 (RBM10) can promote apoptosis and suppress cell proliferation; however, the results of several studies suggest a tumour‐promoting role for RBM10. Herein, we assessed the involvement of RBM10 in lung adenocarcinoma cell proliferation and explored the potential molecular mechanism. We found that, both in vitro and in vivo, RBM10 overexpression suppresses lung adenocarcinoma cell proliferation, while its knockdown enhances cell proliferation. Using complementary DNA microarray analysis, we previously found that RBM10 overexpression induces significant down‐regulation of RAP1A expression. In this study, we have confirmed that RBM10 decreases the activation of RAP1 and found that EPAC stimulation and inhibition can abolish the effects of RBM10 knockdown and overexpression, respectively, and regulate cell growth. This effect of RBM10 on proliferation was independent of the MAPK/ERK and P38/MAPK signalling pathways. We found that RBM10 reduces the phosphorylation of CREB via the AKT signalling pathway, suggesting that RBM10 exhibits its effect on lung adenocarcinoma cell proliferation via the RAP1/AKT/CREB signalling pathway.     

Antitumor effect of miR-197 targeting in p53 wild-type lung cancer

Lung cancer is the leading cause of tumor-related death. The lack of effective treatments urges the development of new therapeutic approaches able to selectively kill cancer cells. The connection between aberrant microRNA (miRNA – miR) expression and tumor progression suggests a new strategy to fight cancer by interfering with miRNA function. In this regard, LNAs (locked nucleic acids) have proven to be very promising candidates for miRNA neutralization. Here, we employed an LNA-based anti-miR library in a functional screening to identify putative oncogenic miRNAs in non-small-cell lung cancer (NSCLC). By screening NIH-H460 and A549 cells, miR-197 was identified as a new functional oncomiR, whose downregulation induces p53-dependent lung cancer cell apoptosis and impairs the capacity to establish tumor xenografts in immunodeficient mice. We further identified the two BH3-only proteins NOXA and BMF as new miR-197 targets responsible for induction of apoptosis in p53 wild-type cells, delineating miR-197 as a key survival factor in NSCLC. Thus, we propose the inhibition of miR-197 as a novel therapeutic approach against lung cancer.     

Induction of SCEs in CHL cells by dichlorobiphenyl derivative water pollutants, 2-phenylbenzotriazole (PBTA) congeners and river water concentrates

We recently identified dichlorobiphenyl (DCB) derivatives and 2-phenylbenzotriazole (PBTA) congeners as major mutagenic constituents of the waters of the Waka River and the Yodo River system in Japan, respectively. In this study we examined sister chromatid exchange (SCE) induction by two dichlorobiphenyl derivatives, 3,3′-dichlorobenzidine (DCB, 4,4′-diamino-3,3′-dichlorobiphenyl) and 4,4′-diamino-3,3′-dichloro-5-nitrobiphenyl (5-nitro-DCB); three PBTA congeners, 2-[2-(acetylamino)-4-[bis(2-methoxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-1), 2-[2-(acetylamino)-4-[N-(2-cyanoethyl)ethylamino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-2), and 2-[2-(acetylamino)amino]-4-[bis(2-hydroxyethyl)amino]-5-methoxyphenyl]-5-amino-7-bromo-4-chloro-2H-benzotriazole (PBTA-6); and water concentrates from the Waka River in Chinese hamster lung (CHL) cells. Concentration-dependent induction of SCE was found for all DCBs and PBTAs examined in the presence of S9 mix, and statistically significant increases of SCEs were detected at 2 μg per ml of medium or higher concentrations. SCE induction of MeIQx was examined to compare genotoxic activities of these water pollutants. According to the results, a ranking of the SCE-inducing potency of these compounds is the following: 5-nitro-DCB ≈ MeIQx > PBTA6 > PBTA-1 ≈ PBTA-2 > DCB.Water samples collected at a site at the Waka River showed concentration-related increases in SCEs at 6.25–18.75 ml-equivalent of river water per ml of medium with S9 mix. The concentrations of 5-nitro-DCB and DCB in the river water samples were from 2.5 to 19.4 ng/l and from 4100 to 18,900 ng/l, respectively. However, these chemicals showed only small contribution to SCE induction by the Waka River water.     

采用蛋白质组学技术筛选大肠癌转移相关蛋白

采用对同一亲本来源、不同转移潜能细胞株SW480和SW620的蛋白质表达谱进行双向凝胶电泳和质谱技术分析,并在蛋白质和mRNA水平进行验证,成功鉴定了10个大肠癌转移相关蛋白,其中SW620细胞株表达上调的蛋白质有磷酸甘油酸变位酶1,磷脂酰乙醇胺结合蛋白和高迁移率族蛋白B-1,而热休克蛋白27,膜联蛋白Ⅰ,甲硫腺苷磷酸化酶,切丝蛋白1和表皮型脂肪酸结合蛋白在SW620中表达下调.大多数差异蛋白质功能涉及肿瘤细胞生长、运动、粘附、凋亡等过程,研究结果为阐明大肠癌转移机制及寻找预测大肠癌转移的潜在标志物提供了理论依据.     

Autophagic Degradation of NBR1 Restricts Metastatic Outgrowth during Mammary Tumor Progression

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Circulating and local nuclear expression of survivin and fibulin-3 genes in discriminating benign from malignant respiratory diseases: correlation analysis

Survivin is an inhibitor of apoptosis as well as a promoter of cell proliferation. Fibulin-3 is a matrix glycoprotein that displays potential for tumor suppression or propagation. The present study aimed to validate the expression levels of survivin and fibulin-3 in benign and malignant respiratory diseases. This case–control study included 219 patients categorized into five groups. Group A included 63 patients with lung cancer, group B included 63 patients with various benign lung diseases, group D included 45 patients with malignant pleural mesothelioma (MPM), and group E included 48 patients with various benign pleural diseases. Group C included 60 healthy individuals (control group). Serum survivin and fibulin-3 levels were measured by ELISA, whereas their nuclear expressions in the lung and pleura were assessed via Western blot analysis. The results showed significantly higher survivin serum levels and significantly lower fibulin-3 levels in group A compared with in group B and controls (P<0.001). There were significantly higher serum levels of survivin and fibulin-3 in group D compared with in group E and controls (P<0.001), consistent with observed nuclear survivin and fibulin-3 expression levels. Fibulin-3 was determined to have higher value than survivin in discriminating lung cancer from MPM (P<0.05). Survivin and fibulin-3 could be useful diagnostic markers for lung and pleural cancers, and fibulin-3 expression was particularly useful in differentiating lung cancer from MPM.     

Killing cancer with platycodin D through multiple mechanisms

Cancer is a multi‐faceted disease comprised of a combination of genetic, epigenetic, metabolic and signalling aberrations which severely disrupt the normal homoeostasis of cell growth and death. Rational developments of highly selective drugs which specifically block only one of the signalling pathways have been associated with limited therapeutic success. Multi‐targeted prevention of cancer has emerged as a new paradigm for effective anti‐cancer treatment. Platycodin D, a triterpenoid saponin, is one the major active components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties including, anti‐nociceptive, anti‐atherosclerosis, antiviral, anti‐inflammatory, anti‐obesity, immunoregulatory, hepatoprotective and anti‐tumour activities. Recently, the anti‐cancer activity of platycodin D has been extensively studied. The purpose of this review was to give our perspectives on the current status of platycodin D and discuss its anti‐cancer activity and molecular mechanisms which may help the further design and conduct of pre‐clinical and clinical trials to develop it successfully into a potential lead drug for oncological therapy. Platycodin D has been shown to fight cancer by inducing apoptosis, cell cycle arrest, and autophagy and inhibiting angiogenesis, invasion and metastasis by targeting multiple signalling pathways which are frequently deregulated in cancers suggesting that this multi‐target activity rather than a single effect may play an important role in developing platycodin D into potential anti‐cancer drug.