Egr-1 Activation by Cancer-Derived Extracellular Vesicles Promotes Endothelial Cell Migration via ERK1/2 and JNK Signaling Pathways

Various mammalian cells, including cancer cells, shed extracellular vesicles (EVs), also known as exosomes and microvesicles, into surrounding tissues. These EVs play roles in tumor growth and metastasis by promoting angiogenesis. However, the detailed mechanism of how cancer-derived EVs elicit endothelial cell activation remains unknown. Here, we provide evidence that early growth response-1 (Egr-1) activation in endothelial cells is involved in the angiogenic activity of colorectal cancer cell-derived EVs. Both RNA interference-mediated downregulation of Egr-1 and ERK1/2 or JNK inhibitor significantly blocked EV-mediated Egr-1 activation and endothelial cell migration. Furthermore, lipid raft-mediated endocytosis inhibitor effectively blocked endothelial Egr-1 activation and migration induced by cancer-derived EVs. Our results suggest that Egr-1 activation in endothelial cells may be a key mechanism involved in the angiogenic activity of cancer-derived EVs. These findings will improve our understanding regarding the proangiogenic activities of EVs in diverse pathological conditions including cancer, cardiovascular diseases, and neurodegenerative diseases.open11617sciescopu

New arylated benzo[h]quinolines induce anti-cancer activity by oxidative stress-mediated DNA damage

© 2016 The Author(s).The anti-cancer activity of the benzo[h]quinolines was evaluated on cultured human skin cancer (G361), lung cancer (H460), breast cancer (MCF7) and colon cancer (HCT116) cell lines. The inhibitory effect of these compounds on the cell growth was determined by the MTT assay. The compounds 3e, 3f, 3h and 3j showed potential cytotoxicity against these human cancer cell lines. Effect of active compounds on DNA oxidation and expression of apoptosis related gene was studied. We also developed a quantitative method to measure the activity of cyclin-dependent kinases-2 (CDK2) by western blotting in the presence of active compound. In addition, molecular docking revealed that benzo[h]quinolines can correctly dock into the hydrophobic pocket of the targets receptor protein aromatase and CDK2, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. These findings reveal that benzo[h]quinolines act as anti-cancer agents by inducing oxidative stress-mediated DNA damage

No association between islet cell antibodies and coxsackie B, mumps, rubella and cytomegalovirus antibodies in non-diabetic individuals aged 7–19 years

Viral antibodies were tested in a cohort of 44 isletcell antibody-positive individuals age 7–19 years, and 44 of their islet cell antibody-negative age and sex-matched classmates selected from a population study of 4208 pupils who had been screened for islet cell antibodies. Anti-coxsackie B1-5 IgM responses were detected in 14 of 44 (32%) of the islet cell antibody-positive subjects and in 7 of 44 (16%) control subjects. This difference did not reach the level of statistical significance. None of the islet cell antibody-positive subjects had specific IgM antibodies to mumps, rubella, or cytomegalovirus. There was also no increase in the prevalence or the mean titres of anti-mumps-IgG or IgA and anti-cytomegalovirus-IgG in islet cell antibody-positive subjects compared to control subjects. These results do not suggest any association between islet cell antibodies, and possibly insulitis, with recent mumps, rubella or cytomegalo virus infection. Further studies are required to clarify the relationship between islet cell antibodies and coxsackie B virus infections

Chiral nematic self-assembly of minimally surface damaged chitin nanofibrils and its load bearing functions

Chitin is one of the most abundant biomaterials in nature, with 1010 tons produced annually as hierarchically organized nanofibril fillers to reinforce the exoskeletons of arthropods. This green and cheap biomaterial has attracted great attention due to its potential application to reinforce biomedical materials. Despite that, its practical use is limited since the extraction of chitin nanofibrils requires surface modification involving harsh chemical treatments, leading to difficulties in reproducing their natural prototypal hierarchical structure, i.e. chiral nematic phase. Here, we develop a chemical etching-free approach using calcium ions, called "natural way", to disintegrate the chitin nanofibrils while keeping the essential moiety for the self-assembly, ultimately resulting in the reproduction of chitin's natural chiral structure in a polymeric matrix. This chiral chitin nanostructure exceptionally toughens the composite. Our resultant chiral nematic phase of chitin materials can contribute to the understanding and use of the reinforcing strategy in nature.open119sciescopu

Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

This article has been made available through the Brunel Open Access Publishing Fund - Copyright @ 2009 Orton et al.BACKGROUND: The Epidermal Growth Factor Receptor (EGFR) activated Extracellular-signal Regulated Kinase (ERK) pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF) stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. RESULTS: We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF) receptors. CONCLUSION: Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications for drug selection strategies. We also conducted a comparison of the critical differences between signalling from different growth factor receptors (namely EGFR, mutated EGFR, NGF, and Insulin) with our results suggesting the difference between the systems are large scale and can be attributed to the presence/absence of entire pathways rather than subtle difference in individual rate constants between the systems.This work was funded by the Department of Trade and Industry (DTI), under their Bioscience Beacon project programme. AG was funded by an industrial PhD studentship from Scottish Enterprise and Cyclacel

Nanoemulsion and Encapsulation Strategy of Hydrophobic Oregano Essential Oil Increased Human Prostate Cancer Cell Death via Apoptosis by Attenuating Lipid Metabolism

Origanum vulgare essential oil (EO) is traditionally well-known for its aromatic properties and biomedical applications, including anticancer. This was the first report where oregano essential oil-based nano emulsion (OENE) was synthesized for studying its effects on prostate cancer cell lines (PC3). At first, we have synthesized OENE and characterized using various spectroscopic analyses. The toxicity and inhibitory concentration (IC50) of OENE toward prostate cancer by MTT analysis were performed. The lipid biogenesis mediated, molecular target pathway analyses were performed using fluorescence cellular staining techniques, real-time RT-PCR, or western blotting analysis. OENE showed IC50 at 13.82 µg/mL and significantly induced distinct morphological changes, including cell shrinkage, cell density, and cell shape reduction. In addition, OENE could also significantly decreased lipid droplet accumulation which was confirmed by studying mRNA transcripts of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (0.31-fold), fatty acid synthase (FASN) (0.18-fold), and sterol regulatory element-binding protein (SREPB1) (0.11-fold), respectively. Furthermore, there is a significant upregulation BAX (BCL2 associated X) and caspase 3 expressions. Nevertheless, OENE decreased the transcript level of BCL2 (B-cell lymphoma 2), thus resulting in apoptosis. Overall, our present work demonstrated that OENE could be a therapeutic target for the treatment of prostate cancer and warrants in vivo studies.</jats:p

Multiple Causes for Delay in Arrival at Hospital in Acute Stroke Patients in Aydin, Turkey

This descriptive, hospital-based study, performed in western Turkey, was designed to assess the level of pre-hospital delay and reasons for such delay in acute stroke patients, taking into consideration certain factors such as socioeconomic status, availability of transport options at onset of symptoms. Data were collected from hospital records, and a questionnaire was administered that included questions about socio-demographics, self-reported risk factors and questions related to hospital arrival. The rate of patients arriving at the hospital more than 3 hours after symptom onset was found to be 31.6% for this study. Approximately 1/3 of patients delayed going to the hospital because they were waiting for symptoms to go away while 1/3 of patients were not aware of the importance of seeking immediate medical help. There was a significant relationship between the use of ambulance transportation and length of time before arrival at the hospitals, though there was no statistically significantly relationship between the existence of stroke risk factors and hospital arrival delay. These results will likely be helpful to health care decision makers as they develop a model for stroke health care and community based training

Directed self-assembly of a helical nanofilament liquid crystal phase for use as structural color reflectors

The fabrication of molecular structures with a desired morphology, e.g., nanotubes, nanoribbons, nanosprings, and sponges, is essential for the advancement of nanotechnology. Unfortunately, realization of this objective is expensive and complicated. Here, we report that irradiating a film comprising azobenzene derivatives with UV light produces oriented arrays of helical nanofilaments via the photoisomerization-induced Weigert effect. As a result, structural colors are observed due to the extrinsic chiral reflection in the visible wavelength range, and the reflected color can be tuned by adjusting the molecular length of the azobenzene derivative. This simple fabrication method can be used for fabricating large, reversible, and patternable color reflectors, providing a new platform for interference-based structural coloration as it exists in nature, such as morpho butterflies, green-winged teal, and various beetles

Mussel-Inspired Anisotropic Nanocellulose and Silver Nanoparticle Composite with Improved Mechanical Properties, Electrical Conductivity and Antibacterial Activity

Materials for wearable devices, tissue engineering and bio-sensing applications require both antibacterial activity to prevent bacterial infection and biofilm formation, and electrical conductivity to electric signals inside and outside of the human body. Recently, cellulose nanofibers have been utilized for various applications but cellulose itself has neither antibacterial activity nor conductivity. Here, an antibacterial and electrically conductive composite was formed by generating catechol mediated silver nanoparticles (AgNPs) on the surface of cellulose nanofibers. The chemically immobilized catechol moiety on the nanofibrous cellulose network reduced Ag+ to form AgNPs on the cellulose nanofiber. The AgNPs cellulose composite showed excellent antibacterial efficacy against both Gram-positive and Gram-negative bacteria. In addition, the catechol conjugation and the addition of AgNP induced anisotropic self-alignment of the cellulose nanofibers which enhances electrical and mechanical properties of the composite. Therefore, the composite containing AgNPs and anisotropic aligned the cellulose nanofiber may be useful for biomedical applications.open11128sciescopu