A meta-analysis of the impact of traffic-related air pollution on health and the factors affecting exposure

ISSN 1743-354

Preclinical pharmacokinetics and metabolism of a novel prototype DNA-PK inhibitor NU7026

In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 μM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg−1, NU7026 underwent rapid plasma clearance (0.108 l h−1) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg−1 was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg−1 i.p. in order to obtain the drug exposure required for radiosensitisation

Effect of light on skeletal δ13C and δ18O, and interaction with photosynthesis, respiration and calcification in two zooxanthellate scleractinian corals

International audienc

Therapeutic effects of proteoliposomes on X-linked chronic granulomatous disease: proof of concept using macrophages differentiated from patient-specific induced pluripotent stem cells

Julie Brault,1,2 Guillaume Vaganay,3 Aline Le Roy,4–6 Jean-Luc Lenormand,1 Sandra Cortes,3 Marie José Stasia1,2 1UMR CNRS 5525, University of Grenoble Alpes, Grenoble, France; 2CGD Diagnosis and Research Centre, University Hospital Centre of Grenoble Alpes, Grenoble, France; 3Synthelis SAS, La Tronche, France; 4IBS, University of Grenoble Alpes, Grenoble, France; 5CNRS, IBS, University Grenoble Alpes, Grenoble, France; 6CEA, IBS, University of Grenoble Alpes, Grenoble, France Abstract: Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency due to dysfunction of the phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex leading to severe and recurrent infections in early childhood. The main genetic form is the X-linked CGD leading to the absence of cytochrome b558 composed of NOX2 and p22phox, the membrane partners of the NADPH oxidase complex. The first cause of death of CGD patients is pulmonary infections. Recombinant proteoliposome-based therapy is an emerging and innovative approach for membrane protein delivery, which could be an alternative local, targeted treatment to fight lung infections in CGD patients. We developed an enzyme therapy using recombinant NOX2/p22phox liposomes to supply the NADPH oxidase activity in X0-linked CGD (X0-CGD) macrophages. Using an optimized prokaryotic cell-free protein synthesis system, a recombinant cytochrome b558 containing functional hemes was produced and directly inserted into the lipid bilayer of specific liposomes. The size of the NOX2/p22phox liposomes was estimated to be around 700 nm. These proteoliposomes were able to generate reactive oxygen species (ROS) in an activated reconstituted cell-free NADPH oxidase activation assay in the presence of recombinant p47phox, p67phox and Rac, the cytosolic components of the NADPH oxidase complex. Furthermore, using flow cytometry and fluorescence microscopy, we demonstrated that cytochrome b558 was successfully delivered to the plasma membrane of X0-CGD-induced pluripotent stem cell (iPSC)-derived macrophages. In addition, NADPH oxidase activity was restored in X0-CGD iPSC-derived macrophages treated with NOX2/p22phox liposomes for 8 h without any toxicity. In conclusion, we confirmed that proteoliposomes provide a new promising technology for the delivery of functional proteins to the membrane of targeted cells. This efficient liposomal enzyme replacement therapy will be useful for future treatment of pulmonary infections in CGD patients refractory to conventional anti-infectious treatments. Keywords: protein therapy, proteoliposomes, chronic granulomatous disease, NADPH oxidase, induced pluripotent stem cells, macrophages&nbsp

A novel culture technique for scleractinian corals:application to investigate changes in skeletal δ18O as a function of temperature

International audiencenovel experimental protocol is described that assists investigations of the effect of environmental parameters on records from the carbonate skeletons of scleractinian corals. It involves the culture of coral colonies on glass slides so as to time the skeletal deposition and environmental records precisely. The value of the technique is demonstrated via calibration of the relationship between skeletal δ18O and seawater temperature in 2 species of coral obtained from the Gulf of Aqaba. Colonies were grown at 5 temperatures between 21 and 29°C. For Acropora sp. this relationship gave a slope of -0.27o/oo °C-1, a value close to previous estimates. The δ18O signature of Stylophora pistillata displayed a high variability between colonies and gave an average slope much lower than previous estimates (-0.13o/oo °C-1). These data may indicate a taxonomic difference and the need to re-examine the systematics of this genus. Nevertheless, such variability in colonies of a single species or of a set of closely related species may have implications for the use of coral skeleton as proxy records

Calcification does not stimulate photosynthesis in the zooxanthellate scleractinian coral Stylophora pistillata

The interaction between photosynthesis and calcification remains poorly known in zooxanthellate scleractinian corals. We tested whether calcification is a significant source of CO2 for photosynthesis in Stylophora pistillata. Rates of net photosynthesis, respiration, add calcification were measured on colonies incubated in synthetic seawater (SSW) controlled with respect to the inorganic carbon system and containing standard (11.40 mmol kg(-1)) and low (2.85 mmol kg(-1)) calcium concentrations. Net photosynthesis and respiration are not significantly different in standard and low-Ca2+ SSW despite a rate of calcification 2.0-2.4 times lower in Ca2+-depleted SSW. Additional experiments carried out on the noncalcifying zooxanthellate Anthozoa Anemonia viridis demonstrate that a low calcium concentration has no direct effect on rates of photosynthesis and respiration. It is suggested that calcification is not a significant source of photosynthetic CO2 and that photosynthesis stimulates calcification rather than the opposite

"Adaptive response" - some underlying mechanisms and open questions

Organisms are affected by different DNA damaging agents naturally present in the environment or released as a result of human activity. Many defense mechanisms have evolved in organisms to minimize genotoxic damage. One of them is induced radioresistance or adaptive response. The adaptive response could be considered as a nonspecific phenomenon in which exposure to minimal stress could result in increased resistance to higher levels of the same or to other types of stress some hours later. A better understanding of the molecular mechanism underlying the adaptive response may lead to an improvement of cancer treatment, risk assessment and risk management strategies, radiation protection, e. g. of astronauts during long-term space flights. In this mini-review we discuss some open questions and the probable underlying mechanisms involved in adaptive response: the transcription of many genes and the activation of numerous signaling pathways that trigger cell defenses - DNA repair systems, induction of proteins synthesis, enhanced detoxification of free radicals and antioxidant production.Publisher PDFPeer reviewe