A novel mitochondria-targeting tetrapeptide for subcellular delivery of nanoparticles

A novel mitochdrial-targeting tetrapeptide, RF-2(D-Arg-Dmt-Arg-Phe-NH₂) had been developed, which showed controlled toxicity and excellent protection against gentamicin-induced hair cell damage, and more importantly, exhibited superior guidance towards mitochondrion achieved by its modified nanoparticles.     

The efficacy of sono-electro-Fenton process for removal of Cefixime antibiotic from aqueous solutions by response surface methodology (RSM) and evaluation of toxicity of effluent by microorganisms

The increasing use of antibiotics by humans and their persistence in the environment leads to the development of drug resistance, which is nowadays considered as an environmental problem. The aim of this study was to determine the efficacy of sono-electro-Fenton process for removal of Cefixime antibiotic from aqueous solutions by Response Surface Methodology (RSM) and to evaluate the toxicity of effluent by microorganisms. In the present study, the degradation of synthetic wastewater containing Cefixime was investigated in a reactor (with a useful volume of 1 L) located in the chamber of the ultrasonic device. The effects of pH, hydrogen peroxide concentration, voltage, initial antibiotic concentration, and electrolysis time were investigated using the Box-Behnken model, and the optimal conditions for elimination were obtained by analyzing the variance. The performance of the electro-Fenton and ultrasonic process was evaluated separately and in combination under optimal conditions. Toxicity of inlet and outlet was tested by Escherichia coli and Staphylococcus aureus, and growth inhibition percentage was calculated. The intermediates were determined by LC-MS with the lowest molecular mass. The results showed that the sono-electro-Fenton process under optimum conditions, including pH of 3.07, hydrogen peroxide concentration of 0.85 mL/L, voltage 15 V, initial antibiotic concentration 10.4 mg/L and electrolysis time of 81.5 min has a percentage of removal of 97.5%. Under optimum conditions, the percentage of removal by electro-Fenton and ultrasonic separately were 81.7% and 9%, respectively, and in the hybrid process of sono-electro-Fenton, the percentage of removal increased to 97.5%. The results also showed that the biological toxicity of the outlet effluent from the sono-electro-Fenton process, compared to the inlet solution, was significantly reduced. So, we conclude that the Sono-electro-Fenton process has a significant effect on the removal of Cefixime from aqueous solutions and can also significantly reduce the biological toxicity of the effluent.     

Behavioral,electrophysiological and histopathological consequences of systemic manganese administration in MEMRI

Manganese (Mn²⁺)-enhanced magnetic resonance imaging (MEMRI) offers the possibility to generate longitudinal maps of brain activity in unrestrained and behaving animals. However, Mn²⁺ is a metabolic toxin and a competitive inhibitor for Ca²⁺, and therefore, a yet unsolved question in MEMRI studies is whether the concentrations of metal ion used may alter brain physiology. In the present work we have investigated the behavioral, electrophysiological and histopathological consequences of MnCl₂ administration at concentrations and dosage protocols regularly used in MEMRI. Three groups of animals were sc injected with saline, 0.1 and 0.5 mmol/kg MnCl₂, respectively. In vivo electrophysiological recordings in the hippocampal formation revealed a mild but detectable decrease in both excitatory postsynaptic potentials (EPSP) and population spike (PS) amplitude under the highest MnCl₂ dose. The EPSP to PS ratio was preserved at control levels, indicating that neuronal excitability was not affected. Experiments of pair pulse facilitation demonstrated a dose dependent increase in the potentiation of the second pulse, suggesting presynaptic Ca²⁺ competition as the mechanism for the decreased neuronal response. Tetanization of the perforant path induced a long-term potentiation of synaptic transmission that was comparable in all groups, regardless of treatment. Accordingly, the choice accuracy tested on a hippocampal-dependent learning task was not affected. However, the response latency in the same task was largely increased in the group receiving 0.5 mmol/kg of MnCl₂. Immunohistological examination of the hippocampus at the end of the experiments revealed no sign of neuronal toxicity or glial reaction. Although we show that MEMRI at 0.1 mmol/Kg MnCl₂ may be safely applied to the study of cognitive networks, a detailed assessment of toxicity is strongly recommended for each particular study and Mn²⁺ administration protocol.     

Decision tree SAR models for developmental toxicity based on an FDA/TERIS database

Humans are exposed to thousands of environmental chemicals for which no developmental toxicity information is available. Structure-activity relationships (SARs) are models that could be used to efficiently predict the biological activity of potential developmental toxicants. However, at this time, no adequate SAR models of developmental toxicity are available for risk assessment. In the present study, a new developmental database was compiled by combining toxicity information from the Teratogen Information System (TERIS) and the Food and Drug Administration (FDA) guidelines. We implemented a decision tree modeling procedure, using Classification and Regression Tree software and a model ensemble approach termed bagging. We then assessed the empirical distributions of the prediction accuracy measures of the single and ensemble-based models, achieved by repeating our modeling experiment many times by repeated random partitioning of the working database. The decision tree developmental SAR models exhibited modest prediction accuracy. Bagging tended to enhance the accuracy of prediction. Also, the model ensemble approach reduced the variability of prediction measures compared to the single model approach. Further research with data derived from animal species- and endpoint-specific components of an extended and refined FDA/TERIS database has the potential to derive SAR models that would be useful in the developmental risk assessment of the thousands of untested chemicals.     

Molecular Modification of Benzophenone Derivatives for Lower Bioenrichment and Toxicity Through the Pharmacophore Model

In this study, we used the improved extreme-difference normalization method to calculate the comprehensive evaluation values of bioenrichment and toxicity of benzophenone UV light absor-bers(BPs). Based on this parameter, a 3D-QSAR(QSAR=quantitative structure activity relationship) pharmacophore model was constructed using Discovery Studio software and applied to the mole-cular modification of BPs. With three commonly used ingredients in sunscreen 2-hydroxy-4-methoxybenzophenone(BP-3), 2,2'-dihydroxy-4,4'-dimethoxybenzophenone(BP-6) and 2,2'-dihydroxy-4-methoxybenzophenone(BP-8) as target molecules, we performed BPs substitution reaction based on the binding positions of characteristic elements of the pharmacophore model and designed BP derivatives with reduced bioenrichment and toxicity. Stability and function evaluation showed that while the stability of 6 BP derivatives was enhanced, the light absorption capacity was also significantly enhanced(from 9.16% to 43.16%). Molecular dynamics simulation results showed that the binding ability of BP-609 molecule with serum albumin was reduced by 16.37% compared with BP-6, and the binding with collagen could not occur spontaneously, which could be used as an explanation for the simultaneous reduction of its bioenrichment and toxicity. Besides, through the simulation of human metabolism, it was found that the liver metabolites of BP-609 were less toxic, which reduced the potential risk of human metabolism. It proved that the molecular modification scheme of BPs was environment-friendly.     

New understanding of aconitine hydrolysis pathway: Isolation,identification and toxicity evaluation based on intermediate products

Aconitine hydrolysis is deemed to be the guarantee for the safe application of Aconitum phytomedicine. Studies have suggested that hydrolysates of aconitine not only include benzoylaconitine and aconine, but other hydrolysates. Moreover, these hydrolysates maybe have a mutual transformation relationship, which has not been confirmed. Herein, hydrolysates of aconitine and their mutual transformation relationship were studied by the theoretical quantum chemistry, UPLC-Q-TOF-MS, the separation and identification of target products, etc. Then the toxicity of its hydrolysates was evaluated. The results demonstrate that the probability is the same for aconitine hydrolysis to pyroaconitine and benzoylaconitine, but they are difficult to convert to each other. Aconitine hydrolysis has three independent hydrolysis pathways, 1) to indaconitine, 2) to benzoylaconitine, and aconine, 3) to pyroaconitine and to 16-epi-pyroaconine. The result of embryotoxicity evaluation on zebrafish was aconitine > indaconitine > benzoylaconitine > α-pyroaconitine > β- pyroaconitine > aconine > 16-epi-pyroaconine. In conclusion, aconitine have three independent hydrolysis pathways and the hydrolysates of different pathways cannot be transformed into each other. Pyroaconitine is a hydrolysate of aconitine except for benzoylaconitine, and its toxicity is lower than benzoylaconitine. More importantly, it clarifies the long-standing debate and provides scientific evidence for the processing and detoxification of Aconitum phytomedicine.     

Ecotoxicity and analysis of nanomaterials in the aquatic environment

Nanotechnology is a major innovative scientific and economic growth area. However nanomaterial residues may have a detrimental effect on human health and the environment. To date there is a lack of quantitative ecotoxicity data, and recently there has been great scientific concern about the possible adverse effects that may be associated with manufactured nanomaterials. Nanomaterials are in the 1- to 100-nm size range and can be composed of many different base materials (carbon, silicon and metals, such as gold, cadmium and selenium) and they have different shapes. Particles in the nanometer size range do occur both in nature and as a result of existing industrial processes. Nevertheless, new engineered nanomaterials and nanostructures are different because they are being fabricated from the “bottom up”. Nanomaterial properties differ compared with those of the parent compounds because about 40–50% of the atoms in nanoparticles (NPs) are on the surface, resulting in greater reactivity than bulk materials. Therefore, it is expected that NPs will have different biological effects than parent compounds. In addition, release of manufactured NPs into the aquatic environment is largely an unknown. The surface properties and the very small size of NPs and nanotubes provide surfaces that may bind and transport toxic chemical pollutants, as well as possibly being toxic in their own right by generating reactive radicals. This review addresses hazards associated and ecotoxicological data on nanomaterials in the aquatic environment. Main weaknesses in ecotoxicological approaches, controversies and future needs are discussed. A brief discussion on the scarce number of analytical methods available to determinate nanomaterials in environmental samples is included.     

Toxicological study of pesticides in air and precipitations of Paris by means of a bioluminescence method

A detailed toxicological study on several pesticides, including chlorothalonil, cyprodynil, dichlobénil, pendimethaline, trifluraline, and α-endosulfan, present at trace levels in air and total atmospheric precipitations of Paris is presented. The pesticides contained in the atmospheric samples, collected during sampling campaigns in February–March 2007, are identified and quantified by a high-performance liquid chromatographic (HPLC)-UV detection method. The toxicity measurements are performed by means of the Microtox® bioluminescence method, based on the evaluation of the bioluminescence inhibition of the Vibrio fischeri marine bacteria at two exposure times to the pesticide solutions. The specific toxicity, corresponding to the particular toxicity of the compound under study and represented by the EC₅₀ parameter, is determined for these pesticides. Also, the global toxicity, which is the toxicity of all micro-pollutants present in the sample under study, is estimated for the extracts of air and atmospheric precipitation (rainwater) samples. The specific toxicities strongly vary with the nature of the pesticide, the EC₅₀ parameter values being comprised between 0.17 and 0.83 mg/mL and 0.15 and 0.66 mg/mL, respectively, for exposure times of 5 and 15 min. The importance of the atmospheric samples’ global toxicity and the respective contribution of the toxic potency of the various pesticides contained in these samples are discussed.

Spectroscopic Studies on the Interaction of Acid Yellow With Bovine Serum Albumin

Azo dyes, which are common in the environment, can be toxic to various organisms. In order to determine the molecular mechanism of acid yellow 11(AY) toxicity, we studied the effect of AY exposure to the common protein bovine serum albumin (BSA) by several spectroscopic techniques including fluorescence spectroscopy, ultraviolet spectrophotometry (UV) and circular dichroism (CD). It could be concluded from the fluorescence spectra that the quenching effect of BSA by AY was mainly due to complex formation which was unrelated to the absorption of AY. The enthalpy change (ΔH) and entropy change (ΔS) were found to be −21.94 kJ/mol and 30.04 Jmol^-1 K^-1, respectively. The results confirm that electrostatic attraction was the predominant intermolecular force between BSA and AY. Furthermore, the binding distance (r) between AY and the inner tryptophan residue of BSA was determined to be 3.541 nm on the basis of Forster theory of non-radiative energy transfer. In addition, the conformational changes of BSA in the presence of AY were also analyzed by UV and CD. These results indicated that AY could interact with BSA by complex formation, which also affected the structure of BSA.