Eco-Friendly Hydrogels Loading Polyphenols-Composed Biomimetic Micelles for Topical Administration of Resveratrol and Rutin.

In this study, we describe the development of hydrogel formulations composed of micelles loading two natural antioxidants-resveratrol and rutin-and the evaluation of the effect of a by-product on the rheological and textural properties of the developed semi-solids. This approach aims to associate the advantages of hydrogels for topical administration of drugs and of lipid micelles that mimic skin composition for the delivery of poorly water-soluble compounds in combination therapy. Biomimetic micelles composed of L-α-phosphatidylcholine loaded with two distinct polyphenols (one non-flavonoid and one flavonoid) were produced using hot shear homogenisation followed by the ultrasonication method.

Attribute ranging as a coordinated strategy between drug substance and drug product to accelerate commercial process nomination.

To make investigational drug candidates available to patients sooner, timelines for drug development are becoming shorter. Synthesis route scouting for active pharmaceutical ingredients (API) and drug product development often must occur simultaneously, requiring formulators to make decisions regarding drug product process selection before commercial API route finalization. Alternatively, the formulation strategy may be locked, thereby constraining drug substance processes with strict API attribute requirements.

Natural compounds-based nanomedicines for cancer treatment: Future directions and challenges.

Several efforts have been extensively accomplished for the amelioration of the cancer treatments using different types of new drugs and less invasives therapies in comparison with the traditional therapeutic modalities, which are widely associated with numerous drawbacks, such as drug resistance, non-selectivity and high costs, restraining their clinical response. The application of natural compounds for the prevention and treatment of different cancer cells has attracted significant attention from the pharmaceuticals and scientific communities over the past decades. Although the use of nanotechnology in cancer therapy is still in the preliminary stages, the application of nanotherapeutics has demonstrated to decrease the various limitations related to the use of natural compounds, such as physical/chemical instability, poor aqueous solubility, and low bioavailability.

The Use of Multiple Biomarkers to Assess the Health of Anuran Amphibians in the Brazilian Cerrado Savanna: An Ecotoxicological Approach.

Changes in the natural landscape and the indiscriminate use of pesticides can have a major impact on aquatic environments and have contributed to the worldwide decline of amphibian populations. In the present study, we sampled tadpoles of three anuran amphibians (Boana albopunctata, Physalaemus cuvieri, and Dendropsophus minutus) from ponds in six different agricultural landscapes of the Brazilian Cerrado savanna and evaluated whether and to what extent genotoxic and mutagenic damage was related to land use (the amount of forest and agricultural remnants, and related physicochemical factors) and the presence of pesticides in the water of the study ponds. We also evaluated the hepatotoxicity in P.

Leaf Aqueous Extract Differentially Inhibits the Growth of Three Bacterial Tomato Pathogens.

As available tools for crop disease management are scarce, new, effective, and eco-friendly solutions are needed. So, this study aimed at assessing the antibacterial activity of a dried leaf Labill. aqueous extract (DLE) against pv.

DiSiR: fast and robust method to identify ligand-receptor interactions at subunit level from single-cell RNA-sequencing data.

Most cell-cell interactions and crosstalks are mediated by ligand-receptor interactions. The advent of single-cell RNA-sequencing (scRNA-seq) techniques has enabled characterizing tissue heterogeneity at single-cell level. In the past few years, several methods have been developed to study ligand-receptor interactions at cell type level using scRNA-seq data.

Preparation, Characterization, and Environmental Safety Assessment of Dithiocarbazate Loaded Mesoporous Silica Nanoparticles.

Dithiocarbazates comprise an important class of Schiff bases with remarkable biological applications due to the imine group present in their structure. However, full exploitation of the biological activity of 3-methyl-5-phenyl-pyrazoline-1-(-benzyldithiocarbazate) (DTC) is limited due to its easy degradation and poor solubility in aqueous solutions. The loading of DTC into mesoporous silica nanoparticles (MSiNPs) can be an excellent strategy to improve the solubility of DTC in the aqueous medium.

Neurotoxicity Assessment of Four Different Pesticides Using In Vitro Enzymatic Inhibition Assays.

Pesticides affect different organs and tissues according to their bioavailability, chemical properties and further molecular interactions. In animal models exposed to several classes of pesticides, neurotoxic effects have been described, including the reduction of acetylcholinesterase activity in tissue homogenates. However, in homogenates, the reduction in enzymatic activity may also result from lower enzymatic expression and not only from enzymatic inhibition.

Expression and subcellular localization of USH1C/harmonin in human retina provides insights into pathomechanisms and therapy.

Usher syndrome (USH) is the most common form of hereditary deaf-blindness in humans. USH is a complex genetic disorder, assigned to three clinical subtypes differing in onset, course and severity, with USH1 being the most severe. Rodent USH1 models do not reflect the ocular phenotype observed in human patients to date; hence, little is known about the pathophysiology of USH1 in the human eye.

Environmental Safety Assessments of Lipid Nanoparticles Loaded with Lambda-Cyhalothrin.

Lipid nanoparticles (LN) composed of biodegradable lipids and produced by green methods are candidates for the encapsulation of pesticides, potentially contributing to decreasing their release in the environment. From a safety-by-design concept, this work proposes LN for the encapsulation of insecticide active ingredients (AI). However, given the complexity of nanoparticles, ecotoxicological studies are often controversial, and a detailed investigation of their effects on the environment is required.

Molecular Physicochemical Properties of Selected Pesticides as Predictive Factors for Oxidative Stress and Apoptosis-Dependent Cell Death in Caco-2 and HepG2 Cells.

In this work, three pesticides of different physicochemical properties: glyphosate (GLY, herbicide), imidacloprid (IMD, insecticide), and imazalil (IMZ, fungicide), were selected to assess their cytotoxicity against Caco-2 and HepG2 cells. Cell viability was assessed by the Alamar Blue assay, after 24 and 48 h exposure to different concentrations, and IC50 values were calculated. The mechanisms underlying toxicity, namely cellular reactive oxygen species (ROS), glutathione (GSH) content, lipid peroxidation, loss of mitochondrial membrane potential (MMP), and apoptosis/necrosis induction were assessed by flow cytometry.

In Vitro Assessment of Pesticides Toxicity and Data Correlation with Pesticides Physicochemical Properties for Prediction of Toxicity in Gastrointestinal and Skin Contact Exposure.

In this work, three pesticides of different physicochemical properties, namely, glyphosate (herbicide), imidacloprid (insecticide) and imazalil (fungicide), were selected to assess their cytotoxicity against distinct cell models (Caco-2, HepG2, A431, HaCaT, SK-MEL-5 and RAW 264.7 cells) to mimic gastrointestinal and skin exposure with potential systemic effect. Cells were subjected to different concentrations of selected pesticides for 24 h or 48 h.

Benchmarking computational methods for B-cell receptor reconstruction from single-cell RNA-seq data.

Multiple methods have recently been developed to reconstruct full-length B-cell receptors (BCRs) from single-cell RNA sequencing (scRNA-seq) data. This need emerged from the expansion of scRNA-seq techniques, the increasing interest in antibody-based drug development and the importance of BCR repertoire changes in cancer and autoimmune disease progression. However, a comprehensive assessment of performance-influencing factors such as the sequencing depth, read length or number of somatic hypermutations (SHMs) as well as guidance regarding the choice of methodology is still lacking.

Single-cell specific and interpretable machine learning models for sparse scChIP-seq data imputation.

Motivation: Single-cell Chromatin ImmunoPrecipitation DNA-Sequencing (scChIP-seq) analysis is challenging due to data sparsity. High degree of sparsity in biological high-throughput single-cell data is generally handled with imputation methods that complete the data, but specific methods for scChIP-seq are lacking. We present SIMPA, a scChIP-seq data imputation method leveraging predictive information within bulk data from the ENCODE project to impute missing protein-DNA interacting regions of target histone marks or transcription factors.

Circadian programming of the ellipsoid body sleep homeostat in .

Homeostatic and circadian processes collaborate to appropriately time and consolidate sleep and wake. To understand how these processes are integrated, we scheduled brief sleep deprivation at different times of day in and find elevated morning rebound compared to evening. These effects depend on discrete morning and evening clock neurons, independent of their roles in circadian locomotor activity.

Lipid-Drug Conjugates and Nanoparticles for the Cutaneous Delivery of Cannabidiol.

Lipid nanoparticles are currently used to deliver drugs to specific sites in the body, known as targeted therapy. Conjugates of lipids and drugs to produce drug-enriched phospholipid micelles have been proposed to increase the lipophilic character of drugs to overcome biological barriers. However, their applicability at the topical level is still minimal.

Glyphosate vs. Glyphosate-Based Herbicides Exposure: A Review on Their Toxicity.

Glyphosate-based herbicide has been the first choice for weed management worldwide since the 1970s, mainly due to its efficacy and reported low toxicity, which contributed to its high acceptance. Many of the recent studies focus solely on the persistence of pesticides in soils, air, water or food products, or even on the degree of exposure of animals, since their potential hazards to human health have raised concerns. Given the unaware exposure of the general population to pesticides, and the absence of a significant number of studies on occupational hazards, new glyphosate-induced toxicity data obtained for both residual and acute doses should be analyzed and systematized.

Characterization of Stress Responses in a Model of Werner Syndrome.

As organisms age, their resistance to stress decreases while their risk of disease increases. This can be shown in patients with Werner syndrome (WS), which is a genetic disease characterized by accelerated aging along with increased risk of cancer and metabolic disease. WS is caused by mutations in , a gene involved in DNA replication and repair.

The E3 ubiquitin ligase adaptor links the core circadian clock to neuropeptide and behavioral rhythms.

Circadian transcriptional timekeepers in pacemaker neurons drive profound daily rhythms in sleep and wake. Here we reveal a molecular pathway that links core transcriptional oscillators to neuronal and behavioral rhythms. Using two independent genetic screens, we identified mutants of () with poor behavioral rhythmicity.

Ecotoxicity to Freshwater Organisms and Cytotoxicity of Nanomaterials: Are We Generating Sufficient Data for Their Risk Assessment?

The aim of the present study was to investigate the eco-cytotoxicity of several forms of nanomaterials (NM), such as nano-CuO, nano-TiO, nano-SiO and nano-ZnO, on different aquatic species (, and ) following standard protocols and on human cell lines (Caco-2, SV-80, HepG2 and HaCaT). Predicted no-effect concentrations (PNEC) or hazard concentrations for 5% of the species (HC) were also estimated based on the compilation of data available in the literature. Most of the NM agglomerated strongly in the selected culture media.

Five-Step Enantioselective Synthesis of Islatravir via Asymmetric Ketone Alkynylation and an Ozonolysis Cascade.

A 5-step enantioselective synthesis of the potent anti-HIV nucleoside islatravir is reported. The highly efficient route was enabled by a novel enantioselective alkynylation of an α,β-unsaturated ketone, a unique ozonolysis-dealkylation cascade in water, and an enzymatic aldol-glycosylation cascade.

Discovery of hydroxy pyrimidine Factor IXa inhibitors.

The synthesis and structure activity relationship development of a pyrimidine series of heterocyclic Factor IXa inhibitors is described. Increased selectivity over Factor Xa inhibition was achieved through SAR expansion of the P1 element. Select compounds were evaluated in vivo to assess their plasma levels in rat.

Synthesis of Islatravir Enabled by a Catalytic, Enantioselective Alkynylation of a Ketone.

The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition of an alkyne nucleophile to a ketone through ligand-accelerated catalysis that was performed on a greater than 100 g scale.