Glioblastoma multiforme (GBM) is the most aggressive form of adult primary malignant brain tumour with poor prognosis. Extracellular vesicles (EVs) are a key-mediator through which GBM cells promote ...a pro-oncogenic microenvironment. Peptidylarginine deiminases (PADs), which catalyze the post-translational protein deimination of target proteins, are implicated in cancer, including via EV modulation. Pan-PAD inhibitor Cl-amidine affected EV release from GBM cells, and EV related microRNA cargo, with reduced pro-oncogenic microRNA21 and increased anti-oncogenic microRNA126, also in combinatory treatment with the chemotherapeutic agent temozolomide (TMZ). The GBM cell lines under study, LN18 and LN229, differed in PAD2, PAD3 and PAD4 isozyme expression. Various cytoskeletal, nuclear and mitochondrial proteins were identified to be deiminated in GBM, including prohibitin (PHB), a key protein in mitochondrial integrity and also involved in chemo-resistance. Post-translational deimination of PHB, and PHB protein levels, were reduced after 1 h treatment with pan-PAD inhibitor Cl-amidine in GBM cells. Histone H3 deimination was also reduced following Cl-amidine treatment. Multifaceted roles for PADs on EV-mediated pathways, as well as deimination of mitochondrial, nuclear and invadopodia related proteins, highlight PADs as novel targets for modulating GBM tumour communication.
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A series of polyvinylpyrrolidone fibers loaded with paracetamol (PCM) and caffeine (CAF) was fabricated by electrospinning and explored as potential oral fast-dissolving films. The ...fibers take the form of uniform cylinders with smooth surfaces, and contain the drugs in the amorphous form. Drug–polymer intermolecular interactions were evidenced by infrared spectroscopy and molecular modeling. The properties of the fiber mats were found to be highly appropriate for the preparation of oral fast dissolving films: their thickness is around 120–130μm, and the pH after dissolution in deionized water lies in the range of 6.7–7.2. Except at the highest drug loading, the folding endurance of the fibers was found to be >20 times. A flavoring agent can easily be incorporated into the formulation. The fiber mats are all seen to disintegrate completely within 0.5s when added to simulated saliva solution. They release their drug cargo within around 150s in a dissolution test, and to undergo much more rapid dissolution than is seen for the pure drugs. The data reported herein clearly demonstrate that electrospun PCM/CAF fibers comprise excellent candidates for oral fast-dissolving films, which could be particularly useful for children and patients with swallowing difficulties.
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A series of 5-fluorouracil (5-FU) loaded core/shell electrospun fibers is reported. The fibers have shells made of Eudragit S100 (ES-100), and drug-loaded cores comprising ...poly(vinylpyrrolidone), ethyl cellulose, ES-100, or drug alone. Monolithic 5-FU loaded ES-100 fibers were also prepared for comparison. Electron microscopy showed all the fibers to have smooth cylindrical shapes, and clear core–shell structures were visible for all samples except the monolithic fibers. 5-FU was present in the amorphous physical form in all the materials prepared. Dissolution studies showed that the ES-100 shell was not able to prevent drug release at pH 1.0, even though the polymer is completely insoluble at this pH: around 30–80% of the maximum drug release was reached after 2h immersion at pH 1.0. These observations are ascribed to the low molecular weight of 5-FU permitting it to diffuse through pores in the ES-100 coating, and the relatively high acid solubility of the drug providing a thermodynamic impetus for this to happen. In addition, the fibers were observed to be broken or merged following 2h at pH 1.0, giving additional escape routes for the 5-FU.
Glioblastoma multiforme (GBM) is the most common and aggressive form of primary malignant brain tumor in adults, with poor prognosis. Extracellular vesicles (EVs) are key-mediators for cellular ...communication through transfer of proteins and genetic material. Cancers, such as GBM, use EV release for drug-efflux, pro-oncogenic signaling, invasion and immunosuppression; thus the modulation of EV release and cargo is of considerable clinical relevance. As EV-inhibitors have been shown to increase sensitivity of cancer cells to chemotherapy, and we recently showed that cannabidiol (CBD) is such an EV-modulator, we investigated whether CBD affects EV profile in GBM cells in the presence and absence of temozolomide (TMZ). Compared to controls, CBD-treated cells released EVs containing lower levels of pro-oncogenic miR21 and increased levels of anti-oncogenic miR126; these effects were greater than with TMZ alone. In addition, prohibitin (PHB), a multifunctional protein with mitochondrial protective properties and chemoresistant functions, was reduced in GBM cells following 1 h CBD treatment. This data suggests that CBD may, via modulation of EVs and PHB, act as an adjunct to enhance treatment efficacy in GBM, supporting evidence for efficacy of cannabinoids in GBM.
The objective of this investigation was to develop a new class of antibacterial material in the form of nanofibers coated with silver nanoparticles (AgNPs) using a modified coaxial electrospinning ...approach. Through manipulation of the distribution on the surface of nanofibers, the antibacterial effect of Ag can be improved substantially.
Using polyacrylonitrile (PAN) as the filament-forming polymer matrix, an electrospinnable PAN solution was prepared as the core fluid. A silver nitrate (AgNO₃) solution was exploited as sheath fluid to carry out the modified coaxial electrospinning process under varied sheath-to-core flow rate ratios.
Scanning electron microscopy and transmission electron microscopy demonstrated that the sheath AgNO₃ solution can take a role in reducing the nanofibers' diameters significantly, a sheath-to-core flow rate ratio of 0.1 and 0.2 resulting in PAN nanofibers with diameters of 380 ± 110 nm and 230 ± 70 nm respectively. AgNPs are well distributed on the surface of PAN nanofibers. The antibacterial experiments demonstrated that these nanofibers show strong antimicrobial activities against Bacillus subtilis Wb800, and Escherichia coli dh5α.
Coaxial electrospinning with AgNO₃ solution as sheath fluid not only facilitates the electrospinning process, providing nanofibers with reduced diameters, but also allows functionalization of the nanofibers through coating with functional ingredients, effectively ensuring that the active antibacterial component is on the surface of the material, which leads to enhanced activity. We report an example of the systematic design, preparation, and application of a novel type of antibacterial material coated with AgNPs via a modified coaxial electrospinning methodology.
The nature of metal silane σ-bond interaction has been investigated in several key systems by a range of experimental and computational techniques. The structure of Cp′Mn(CO)2(η2-HSiHPh2) 1 has been ...determined by single crystal neutron diffraction, and the geometry at the Si atom is shown to approximate a trigonal bipyramid; salient bond distances and angles are Mn−H(1) 1.575(14), Si−H(1) 1.806(14), Si−H(2) 1.501(13) Å, and H(1)−Si−H(2) 148.5(8)°. This complex is similar to Cp′Mn(CO)2(η2-HSiFPh2) 2, whose structure and bonding characteristics have recently been determined by charge density studies based on high-resolution X-ray and neutron diffraction data. The geometry at the Si atom in these σ-bond complexes is compared with that in other systems containing hypercoordinate silicon. The Mn−H distances for 1 and 2 in solution have been estimated using NMR T 1 relaxation measurements, giving a value of 1.56(3) Å in each case, in excellent agreement with the distances deduced from neutron diffraction. Density functional theory calculations have been employed to explore the bonding in the Mn−H−Si unit in 1 and 2 and in the related system Cp′Mn(CO)2(η2-HSiCl3) 3. These studies support the idea that the oxidative addition of a silane ligand to a transition metal center may be described as an asymmetric process in which the Mn−H bond is formed at an early stage, while both the establishment of the Mn−Si bond and also the activation of the η2-coordinated Si−H moiety are controlled by the extent of Mn → σ*(X−Si−H) back-donation, which increases with increasing electron-withdrawing character of the X substituent trans to the metal-coordinated Si−H bond. This delocalized molecular orbital (MO) approach is complemented and supported by combined experimental and theoretical charge density studies: the source function S(r,Ω), which provides a measure of the relative importance of each atom’s contribution to the density at a specific reference point r, clearly shows that all three atoms of the Mn(η2-SiH) moiety contribute to a very similar extent to the density at the Mn−Si bond critical point, in pleasing agreement with the MO model. Hence, we advance a consistent and unifying concept which accounts for the degree of Si−H activation in these silane σ-bond complexes.
Based on a modified coaxial electrospinning process and suitable selection of solvent mixtures as sheath fluid, a new strategy is presented for systematically improving polymer nanofiber quality. A ...concentric spinneret with an indented inner capillary is designed for the modified coaxial electrospinning. With a solution of 12% w/v PVP K60 in ethanol as the core electrospinning fluid, six solvents are used as sheath fluids to investigate the impact of solvent properties on the resultant PVP nanofiber quality. The PVP nanofiber quality is closely related to solvent physical‐chemical properties. High quality PVP nanofibers of average diameter 130 ±10 nm with homogeneous structures and smooth surfaces are created using a solvent mixture of acetone, ethanol and DMAc in the ratio of 3:1:1(v/v/v).
A new strategy is put forward for improving electrospun polymer nanofiber quality. A concentric spinneret with indented inner capillary and suitable selection of the solvent mixture as sheath fluid are key factors to fulfill a modified coaxial electrospinning process, by which PVP nanofibers with a diameter of 130±10nm, homogeneous structure and smooth surface are successfully created.
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