Agerskovziegler5349

Therefore, the importance of the spacer chemistry in BC deprotection and PS stability and cargo release is herein highlighted. We have also evaluated the impact of spacer chemistry on the PS-specific release of the chemotherapeutic drug doxorubicin (DOX) into tumors in vitro and in vivo. We demonstrate that by spacer chemistry design one can enhance the efficacy of DOX treatments (decrease in tumor growth and prolonged animal survival) in mice bearing EL4 T cell lymphoma. Side effects (weight loss and cardiotoxicity) were also reduced compared to free DOX administration, highlighting the potential of the well-defined ROS-responsive PSs as TME-selective nanomedicines. The PSs could also find applications in other environments with high ROS levels, such as chronic inflammations, aging, diabetes, cardiovascular diseases, and obesity.Much effort has been devoted to clarifying the comparative toxicity of ZnO nanoparticles (NPs) and Zn ions; however, little is known about their toxicodynamic processes at the metabolic level. Here, we investigated the acute (2d) and chronic (7d) effects to a soil species, Enchytraeus crypticus, of two sublethal doses of ZnO-NPs and ZnCl2 (10 and 30 mg/L Zn) using ultrahigh performance liquid chromatography-quadrupole-time-of-flight/mass spectrometry-based metabolomics. The metabolomics analysis identified 99, 128, 121, and 183 significantly changed metabolites (SCMs) in E. crypticus exposed to ZnO-NPs for 2d, ZnCl2 for 2d, ZnO-NPs for 7d, and ZnCl2 for 7d, respectively, suggesting that ZnCl2 induced stronger metabolic reprogramming than ZnO-NPs, and a longer exposure time caused greater metabolite changes. Among the SCMs, 67 were shared by ZnO-NPs and ZnCl2 after 2d and 84 after 7d. These metabolites were mainly related to oxidative stress and antioxidant defense, membrane disturbance, and energy expenditure. The targeted analysis on physiological and biochemical responses further proved the metabolic observations. Nevertheless, 32 (33%) and 37 (31%) SCMs were found only in ZnO-NP treatments after 2 and 7d, respectively, suggesting that the toxicity of ZnO-NPs cannot be solely attributed to the released Zn ions. Metabolic pathway analysis revealed significant perturbations of galactose metabolism, amino sugar and nucleotide sugar metabolism, and glycerophospholipid metabolism in all test groups. Based on involvement frequency, glucose-1-phosphate, glycerol 3-phosphate, and phosphorylcholine could serve as universal biomarkers for exposure to different Zn forms. Four pathways perturbed by ZnO-NPs were nanospecific upon acute exposure and three upon chronic exposure. find more Our findings demonstrated that metabolomics is an effective tool for understanding the molecular toxicity mechanism and highlighted that time-series measurements are essential for discovering and comparing modes of action of metal ions and NPs.A compact isotope ratio sensor based on laser absorption spectroscopy at 2.7 μm was developed for high precision and simultaneous measurements of the D/H, 18O/16O and 17O/16O isotope ratios in glacier water. Measurements of the oxygen and hydrogen isotope ratios in glacier water demonstrate a 1σ precision of 0.3‰ for δ18O, 0.2‰ for δ17O, and 0.5‰ for δ2H, respectively. The δ values of the working standard glacier water obtained by the calibrated sensor system is basically identical to the IRMS measurement results with a very high calibration accuracy from 0.17‰ to 0.75‰. Preliminary results on the reproducibility measurements display a standard deviation of 0.13‰ for δ18O, 0.13‰ for δ17O, and 0.64‰ for δ2H, respectively.Pesticide biotransformation, especially by cytochrome P450 enzymes (CYPs), may produce metabolites with substantially altered toxicological and physicochemical profiles, which has drawn great attention as a basis for environmental risk assessment. CYPs are active in the metabolism of various reactions of pesticides, and there are potentially different short-lived oxidant species in CYPs (Compound I vs Compound 0), which make elucidating their biotransformation mechanism challenging. To facilitate this task, we performed density functional theory (DFT) calculations to explore the puzzling bifurcation pathways of dieldrin by CYPs. The results show that the two-oxidant mechanism does not work, while the bifurcation pathways are within the mechanistic framework of a two-state reactivity of Compound I. Specifically, 9-hydroxy-dieldrin as a hydroxylation product is formed via H-abstraction and essentially barrierless C-9 alkyl radical rebound in the doublet state; while 3-ketone-dieldrin as a dechlorination product is formed via H-abstraction, C-9 alkyl radical cyclization, and C-3 cyclized radical rebound in the quartet state followed by HCl elimination, originating from a significant barrier for C-9 alkyl radical rebound in the quartet state to provide this radical sufficient lifetime for cyclization. Thus, the ratio [dechlorination]/[hydroxylation] can be estimated as 135, consistent with the experimental findings. We envision that application of computational chemistry has a great potential in revealing the complex biotransformation mechanisms of pesticides.Dissolved organic matter (DOM) is ubiquitous in raw drinking water and can efficiently scavenge oxidants, such as permanganate. Here, changes to DOM induced by permanganate oxidation under typical drinking water treatment conditions (6 μM, 1 h) to bulk DOM properties, DOM functional groups, and DOM chemical formulae were examined for two DOM isolate types (terrestrial and microbial). Permanganate oxidation did not mineralize DOM, rather changes were compositional in nature. Optical properties suggest that permanganate oxidation decreased DOM aromaticity (decreased SUVA-254), decreased DOM electron-donating capacity, and decreased DOM average molecular weight (increased E2/E3 ratios). Fourier-transform-infrared spectroscopy second derivative analyses revealed that permanganate does not oxidize DOM alkene groups, suggesting permanganate access to functional groups may be important. Four ionization techniques were used with ultrahigh-resolution mass spectrometry negative and positive ion mode electrospray ionization and negative and positive ion mode laser/desorption ionization.