Zafirlukast Induces VHL- and HIF-2α-Dependent Oxidative Cell Death in 786-O Clear Cell Renal Carcinoma Cells

Mutations in the Von Hippel–Lindau (VHL) gene are the driving force in many forms of clear cell renal cell carcinoma (ccRCC) and promote hypoxia-inducible factor (HIF)-dependent tumor proliferation, metastasis and angiogenesis. Despite the progress that has already been made, ccRCC generally remain resistant to conventional therapies and ccRCC patients suffer from metastasis and acquired resistance, highlighting the need for novel therapeutic options. Cysteinyl leukotriene receptor 1 (CysLTR1) antagonists, like zafirlukast, are administered in bronchial asthma to control eicosanoid signaling. Intriguingly, long-term use of zafirlukast decreases cancer risk and leukotriene receptor antagonists inhibit tumor growth, but the mechanisms still remain unexplored. Therefore, we aim to understand the mechanisms of zafirlukast-mediated cell death in ccRCC cells. We show that zafirlukast induces VHL-dependent and TNFα-independent non-apoptotic and non-necroptotic cell death in ccRCC cells. Cell death triggered by zafirlukast could be rescued with antioxidants and the PARP-1 inhibitor Olaparib, and additionally relies on HIF-2α. Finally, MG-132-mediated proteasome inhibition sensitized VHL wild-type cells to zafirlukast-induced cell death and inhibition of HIF-2α rescued zafirlukast- and MG-132-triggered cell death. Together, these results highlight the importance of VHL, HIF and proteasomal degradation in zafirlukast-induced oxidative cell death with potentially novel therapeutic implications for ccRCC.     

The Role of Plasma Extracellular Vesicles in Remote Ischemic Conditioning and Exercise-Induced Ischemic Tolerance

Ischemic conditioning and exercise have been suggested for protecting against brain ischemia-reperfusion injury. However, the endogenous protective mechanisms stimulated by these interventions remain unclear. Here, in a comprehensive translational study, we investigated the protective role of extracellular vesicles (EVs) released after remote ischemic conditioning (RIC), blood flow restricted resistance exercise (BFRRE), or high-load resistance exercise (HLRE). Blood samples were collected from human participants before and at serial time points after intervention. RIC and BFRRE plasma EVs released early after stimulation improved viability of endothelial cells subjected to oxygen-glucose deprivation. Furthermore, post-RIC EVs accumulated in the ischemic area of a stroke mouse model, and a mean decrease in infarct volume was observed for post-RIC EVs, although not reaching statistical significance. Thus, circulating EVs induced by RIC and BFRRE can mediate protection, but the in vivo and translational effects of conditioned EVs require further experimental verification.     

Results of irradiation treatment in patients with non-resectable oesophageal cancer

Forty-eight patients with non-resectable cancer of the oesophagus and oesophagogastric junction (Group A: Stage I/II, 32; Group B: Stage III/IV, 16) underwent intraluminal Iridium-192 high dose-rate afterloading therapy (5-7 Gy/session, total dose: 5-21 Gy, mean: 12.4 Gy) and external beam irradiation (Karnofsky > or = 80% 50-60 Gy/2 Gy per day; Karnofsky 60-79%: 30 Gy/3 Gy per day). Durable satisfactory palliation (intake of at least semi-solid food) was demonstrated in 96% of patients. The mean survival for group A was 19.1 months and that for group B, 6.9 months, with a 12-month survival rate of 66% (group A) and 0% (group B) (P < 0.001). Local tumour response and complication rate were significantly dose-related with a predicted response rate of 70.5%, and a complication rate of 50% at ERD 129.3 Gy.     

Solubility of poly(n-alkylmethacrylate)s in hydrocarbons and in alcohols

Poly(methylmethacrylate) (PMMA), poly(butylmethacrylate) (PBMA), and poly(decylmethacrylate) (PDMA) are completely miscible with toluene at normal pressure from room temperature up to the boiling point of the solvent. In alkanes (C₆ to C₁₀) and 1-pentanol the solubility increases with the length of the side chain of the polymer: PMMA always exhibits a solubility gap within the above temperature range, PBMA shows upper critical solution temperatures (except n-hexane, which is a non-solvent), and PDMA mixes completely with all alkanes under consideration. Alcohols (up to C₄) are non-solvents for PMMA but theta solvents for PBMA and PDMA (except ethanol which is a non-solvent for the latter). The low temperature demixing of ethanol/PBMA is shifted towards lower temperatures by pressure.     

Katalysatoruntersuchungen an einer Technikumsanlage für Biomasse‐Kleinfeuerungen

In addition to the reduction of particulate matter, a catalytic supported emission reduction in small scale biomass combustion systems can also enable a conversion of toxic organic components into carbon dioxide and water. For catalyst investigations under practical conditions a special test facility was designed. The results show that products of incomplete combustion like carbon monoxide from stoves can be reduced by catalytic processes. Further developments and studies are necessary to achieve the targeted emission limits.     

Viscosity‐molecular weight relationship for cellulose solutions in either NMMO monohydrate or cuen

The intrinsic viscosities, [η], of nine cellulose samples, with molar masses from 50 × 10³ to 1 390 × 10³ were determined in the solvents NMMO*H₂O (N‐methyl morpholin N‐oxide hydrate) at 80°C and in cuen (copper II‐ethlenediamine) at 25°C. The evaluation of these results with respect to the Kuhn–Mark–Houwink relations shows that the data for NMMO*H₂O fall on the usual straight line in the double logarithmic plots only for M ≤ 158 10³; the corresponding [η]/M relation reads log ([η]/mL g⁻¹) = –1.465 + 0.735 log M. Beyond that molar mass [η] remains almost constant up to M ≈ 10⁶ and increases again thereafter. In contrast to NMMO*H₂O the cellulose solutions in cuen behave normal and the Kuhn–Mark–Houwink relation reads log ([η]/mL g⁻¹) = −1.185 + 0.735 log M. Possible reasons for the dissimilarities of the behavior of cellulose in these two solvents are being discussed. The comparison of three different methods for the determination of [η] from viscosity measurements at different polymer concentrations, c, demonstrates the advantages of plotting the natural logarithm of the relative viscosities as a function of c. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Synthesis of hybrid nanocomposites based on new triazeno copolymers and montmorillonite used for detecting metal ions

The modern synthesis of novel functional materials with improved properties includes that of hybrid nanocomposites composed of inorganic nanoparticles and organic derivatives, where controlling the molecular structure at atomic and macroscopic dimensions is a key factor, with a major effect on performance. An extension of this approach to the field of nanocomposites containing photopolymers with triazene groups attached on a methacrylic backbone could be of great interest in the future development of chemosensors and photoresists, among others. Photopolymer/clay nanocomposites were prepared by in situ free radical copolymerization of 1‐(phenyl)‐3‐(2‐methacryloyloxyethylcarbamoyloxyethyl)‐3‐methyltriazene‐1 or 1‐(p‐methoxyphenyl)‐3‐(2‐methacryloyloxyethylcarbamoyloxyethyl)‐3‐methyltriazene‐1 and vinyl acetate or styrene in solution and in the presence of 3 and 5 wt% of organically modified montmorillonite. The characterization of the nanocomposites and pure copolymers was achieved through ¹H NMR and Fourier transform infrared spectroscopy, gel permeation chromatography, thermogravimetric analysis, X‐ray diffraction, atomic force microscopy and fluorescence analysis. The morphologies and properties of the nanocomposites are dependent on the nature of the triazene, on the co‐monomer structure and on the organoclay content. Also, the fluorescence response of these nanocomposites towards certain metal ions (Fe³⁺, Cu²⁺, Hg²⁺, Ni²⁺) in dimethylformamide solution was investigated. The effect of uranyl ions on the fluorescence intensity of the nanocomposites in solution or as films could be exploited in the development of ‘turn‐off’ or ‘turn‐on’ chemosensors for this type of analyte. Triazeno copolymer/organophilic montmorillonite nanocomposites with exfoliated (not completely exfoliated) or exfoliated and intercalated structures exhibit distinct characteristics concerning their fluorescence behaviour, a higher sensing ability towards certain target compounds (Fe³⁺, UO₂²⁺) being evidenced for those incorporating 3 wt% organoclay in solution and as films. Copyright © 2010 Society of Chemical Industry     

Experimental and numerical investigation of supported rhodium catalysts for partial oxidation of methane in exhaust gas diluted reaction mixtures

The partial oxidation of methane/oxygen mixtures with large exhaust gas dilution (46.3 vol% H₂O and 23.1 vol% CO₂) has been investigated experimentally and numerically over Rh/CeO₂-ZrO₂, Rh/ZrO₂ and Rh/α-Al₂O₃ catalysts. Experiments were carried out in a short-contact-time reactor at 5 bar and included exhaust gas analysis, temperature measurements along the reactor, and catalyst characterization. Additional experiments were performed in an optically accessible channel-flow reactor and involved in situ Raman measurements of major gas-phase species concentrations over the catalyst boundary layer and laser-induced fluorescence (LIF) of formaldehyde. A full elliptic two-dimensional numerical code that included elementary hetero-/homogeneous chemical reaction schemes and relevant heat transfer mechanisms in the solid was used in the simulations. The employed heterogeneous reaction mechanism, including only active Rh sites, reproduced the experiments with good accuracy. The ratio of active to geometrical surface area, deduced from hydrogen chemisorption measurements, was the single model parameter needed to account for the effect of different supports. This indicated that water activation occurring on support sites, resulting in inverse OH spillover from the support to the noble metal sites, could be neglected under the present conditions with high water dilution. An evident relationship between noble metal dispersion and catalytic behavior, in terms of methane conversion and synthesis gas yields, could be established. Both measurements and predictions indicated that an increasing Rh dispersion (in the order Rh/α-Al₂O₃, Rh/ZrO₂, and Rh/CeO₂-ZrO₂) resulted in higher methane conversions, lower surface temperatures, and higher synthesis gas yields.