A bioinspired peptide scaffold with high antibiotic activity and low in vivo toxicity.

Bacterial resistance to almost all available antibiotics is an important public health issue. A major goal in antimicrobial drug discovery is the generation of new chemicals capable of killing pathogens with high selectivity, particularly multi-drug-resistant ones. Here we report the design, preparation and activity of new compounds based on a tunable, chemically accessible and upscalable lipopeptide scaffold amenable to suitable hit-to-lead development. Such compounds could become therapeutic candidates and future antibiotics available on the market. The compounds are cyclic, contain two D-amino acids for in vivo stability and their structures are reminiscent of other cyclic disulfide-containing peptides available on the market. The optimized compounds prove to be highly active against clinically relevant Gram-negative and Gram-positive bacteria. In vitro and in vivo tests show the low toxicity of the compounds. Their antimicrobial activity against resistant and multidrug-resistant bacteria is at the membrane level, although other targets may also be involved depending on the bacterial strain.

Oxidative stress, genotoxicity and histopathology biomarker responses in Mugil cephalus and Dicentrarchus labrax gill exposed to persistent pollutants. A field study in the Bizerte Lagoon: Tunisia.

The use of biomarkers has become an important tool for modern environmental assessment as they can help to predict pollutants involved in the monitoring program. Despite the importance of fish gill in several functions (gaseous exchange, osmotic and ionic regulation, acid-base balance and nitrogenous waste) its use in coastal water biomonitoring focusing on protection and damage is scarce. This field study investigates biochemical (catalase, superoxide dismutase, lipid peroxidation), molecular (DNA integrity) and morphological (histology) parameters in gill of mullet (Mugil cephalus) and sea bass (Dicentrarchus labrax) and originating from Bizerte lagoon (a coastal lagoon impacted by different anthropogenic activities) and from the Mediterranean Sea (a reference site). Remarkable alterations in the activities of oxidative stress enzymes and DNA integrity in the tissue of the two studied fish species were detected in Bizerte Lagoon. The study of histopathological alterations of gills in both two fish species from Bizerte Lagoon suggest thickening of primary lamellae, cellular hyperplasia, aneurism, curving, shortening and fusion of secondary lamellae. The adopted approach, considering simultaneously protection responses and damaging effects, revealed its usefulness on the pollution assessment.

Developmental effects and genotoxicity of 10 water disinfection by-products in zebrafish.

Disinfection by-products are contaminants produced during drinking water disinfection. Several DBPs have been implicated in a variety of toxic effects, mainly carcinogenic and genotoxic effects. Moreover, DBPs exposure has also been associated with an increased risk of developmental effects. In this study, the developmental toxicity and genotoxicity of 10 DBPs (four trihalomethanes [THMs], five haloacetic acids [HAAs] and sodium bromate) in the zebrafish embryo model were evaluated. Embryos exposed for 72 hours were observed for different endpoints such as growth, hatching success, malformations and lethality. THMs exposure resulted in adverse developmental effects and a significant reduced tail length. Two HAAs, tribromoacetic acid and dichloroacetic acid, along with sodium bromate were found to cause a significant increase in malformation rate. Chloroform, chlorodibromomethane and sodium bromate produced a weak induction of DNA damage to whole embryos. However, developmental effects occurred at a range of concentrations (20-100 µg/mL) several orders of magnitude above the levels that can be attained in fetal blood in humans exposed to chlorinated water. In conclusion, the teratogenic and genotoxic activity observed by some DBPs in zebrafish reinforce the view that there is a weak capacity of disinfection products to cause developmental effects at environmentally relevant concentrations.

Ultra-high-pressure homogenization (UHPH) system for producing high-quality vegetable-based beverages: physicochemical, microbiological, nutritional and toxicological characteristics.

BACKGROUND: A relatively new technology based on a continuous system of ultra-high-pressure homogenization (UHPH) was used for producing high-quality soy and almond beverages as an alternative to conventional heat treatments (pasteurization and UHT). The aim of this study was to compare those treatments by analyzing the most relevant quality parameters with a broad vision from the production to the potential toxicological changes, passing through the main nutritional characteristics. RESULTS: UHPH treatment at 200 MPa, 55 °C T(in) produced a higher reduction of microorganisms than pasteurization. UHPH treatment at 300 MPa, 75 °C T(in) led to complete inactivation of microorganisms, similar to UHT treatment. A much better colloidal stability was observed in both UHPH-treated almond and soy beverages compared with those processed by conventional heat treatments. UHPH treatments led to the same increase in digestibility as heat treatments and did not produce a reduction in the availability of lysine. In addition, UHPH samples of soy beverage seem to be less allergenic based on their lower gut immune response in comparison with heat-treated samples. CONCLUSION: UHPH treatments could be used to produce high-quality commercial vegetable beverages with different quality standards (fresh or long-life storage) according to consumer preference.

Oxidative stress, genotoxicity and histopathology biomarker responses in mullet (Mugil cephalus) and sea bass (Dicentrarchus labrax) liver from Bizerte Lagoon (Tunisia).

The aim of the study was to evaluate the impact of environmental contaminants on oxidative stress, genotoxic and histopathologic biomarkers in liver of mullet (Mugil cephalus) and sea bass (Dicentrarchus labrax) collected from a polluted coastal lagoon (Bizerte Lagoon) in comparison to a reference site (the Mediterranean Sea). Antioxidant enzyme activities were lower in fish from the polluted site compared with fish from the reference site, suggesting deficiency of the antioxidant system to compensate for oxidative stress. DNA damage was higher in both fish species from the contaminated site indicating genotoxic effects. The liver histopathological analysis revealed alterations in fish from Bizerte Lagoon. Hepatocytes from both fish species featured extensive lipid-type vacuolation and membrane disruption. Results suggest that the selected biomarkers in both fish species are useful for the assessment of pollution impacts in coastal environments influenced by multiple pollution sources.

Gemini imidazolium amphiphiles for the synthesis, stabilization, and drug delivery from gold nanoparticles.

Gold nanoparticles (AuNPs) are considered useful vehicles for medical therapy and diagnosis. Despite the progress made in this field, there is need to find direct, reliable, and versatile synthetic procedures for their preparation as well as new multifunctional coating agents. In this sense, we have explored the use of imidazolium amphiphiles to prepare new AuNPs designed for anion recognition and transport. Thus, in this work we describe (a) the synthesis, by a phase transfer method, of new gold nanoparticles using gemini-type surfactants as ligands based on imidazolium salts, those ligands acting as transfer agents into organic media and also as nanoparticle stabilizers, (b) the examination of their stability in solution, (c) the chemical and physical characterization of the nanoparticles, using a variety of techniques, including UV-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS), (d) toxicity data concerning both the imidazolium ligands and the imidazolium coated nanoparticles, (e) the assessment of their molecular recognition ability toward molecules of biological interest, such as anions and carboxylate containing model drugs, such as ibuprofen, (f) the study of their toxicity and those of their coating ligands, as well as their ability for cell internalization, and (g) the study of their ability for delivering anionic pharmaceuticals. The structurally governed triple role of those new gemini-type surfactants is responsible for the preparation, remarkable stability, and delivery properties of these functional AuNPs.

Chronic exposure to MDMA (ecstasy) increases DNA damage in sperm and alters testes histopathology in male rats.

3,4-Methylenedioxymethamphetamine (MDMA or "ecstasy") is consumed mainly by young population. For this reason, it is especially relevant to take into consideration the effects on the reproductive system. The influence of MDMA on the fertility and reproduction of the male rat was assessed in this study. MDMA was administered subcutaneously at 0 mg/kg (control), 0.5 mg/kg, 5 mg/kg and 10 mg/kg to SD male rats once a day, 3 consecutive days a week during 12 weeks, simulating human weekend associated consumption. Hormonal, haematological, biochemical, histological, genotoxicological and testicular and sperm parameters were evaluated in half of the rats. The remaining animals were mated with untreated sexually receptive females to evaluate the mating and pregnancy rates. A significantly higher incidence of DNA damage in Comet Test in sperm, tubular degeneration and interstitial oedema in testes was found. At all doses tested, sperm motility, morphology, mating and pregnancy rates, and number of implantation sites were not affected. This study fills the existing gap of knowledge about the chronic effects of MDMA in reproductive function using a realistic experimental design. Taking into account the higher sensitivity of human males, some concerns about the effects on the reproductive health still remain.

Use of transduction proteins to target trabecular meshwork cells: outflow modulation by profilin I.

PURPOSE: Fusion proteins containing a protein transduction domain (PTD4) are able to cross biological membranes. We tested the applicability of the protein transduction method for study of the aqueous humor trabecular outflow pathway by targeting the actin cytoskeleton, which is known to be involved in outflow facility regulation. METHODS: Expression vectors useful for generating fusion proteins with the PTD4 domain and the actin-binding protein Profilin I were constructed. The transductional and functional properties of these proteins were tested in bovine trabecular meshwork cells in culture. The effects of PTD4-Profilin I on outflow facility were evaluated in perfused bovine anterior segments. PTD4-beta-galactosidase was used to visually check correct delivery of fusion proteins to trabecular meshwork cells. RESULTS: The fusion proteins generated were characterized by western blot. Immunocytochemistry experiments showed intracellular staining for PTD4-Profilin I in trabecular meshwork cells in culture. The fusion protein was found in the cytoplasm associated with actin filaments and in the leading edge of the cellular membrane. In contrast, control Profilin I, without the PTD4 domain, was unable to cross the cell membrane. In perfused anterior segments, 2 microM PTD4-Profilin I increased trabecular outflow facility in a reversible manner, while Profilin I had no significant effect. Anterior segments perfused with PTD4-beta-galactosidase showed positive staining in the trabecular meshwork tissue. CONCLUSIONS: Protein transduction technology is a valuable tool for targeting trabecular meshwork tissue, not only for performing physiological studies, but also as a potential drug-delivery method. Profilin I action on the actin cytoskeleton further reinforces the importance of this structure in outflow facility regulation.

The genetic network of prototypic planarian eye regeneration is Pax6 independent.

We report the presence of two Pax6-related genes, Pax6A and Pax6B, which are highly conserved in two planarian species Dugesia japonica and Girardia tigrina (Platyhelminthes, Tricladida). Pax6A is more similar to other Pax6 proteins than Pax6B, which is the most divergent Pax6 described so far. The planarian Pax6 homologs do not show any clear orthology to the Drosophila duplicated Pax6 genes, eyeless and twin of eyeless, which suggests an independent Pax6 duplication in a triclad or platyhelminth ancestor. Pax6A is expressed in the central nervous system of intact planarians, labeling a subset of cells of both cephalic ganglia and nerve cords, and is activated during cephalic regeneration. Pax6B follows a similar pattern, but shows a lower level of expression. Pax6A and Pax6B transcripts are detected in visual cells only at the ultrastructural level, probably because a limited amount of transcripts is present in these cells. Inactivation of both Pax6A and Pax6B by RNA-mediated gene interference (RNAi) inhibits neither eye regeneration nor eye maintenance, suggesting that the genetic network that controls this process is not triggered by Pax6 in planarians.