Characterization and applicability of a novel physiologically relevant 3D-tetraculture bronchial model for in vitro assessment of respiratory sensitization.

Chemical Respiratory Allergy (CRA) is triggered after exposure to Low Molecular Weight (LMW) sensitizers and manifests clinically as asthma and rhinitis. From a risk/toxicity assessment point of view, there are few methods, none of them validated, for evaluating the respiratory sensitization potential of chemicals once the in vivo-based models usually employed for inhalation toxicity addressment do not comprise allergenicity endpoints specifically. Based on that, we developed, characterized, and evaluated the applicability of a 3D-tetraculture airway model reconstructed with bronchial epithelial, fibroblasts, endothelial and monocytic cell lines.

Mitochondrial impairment related to the immunotoxicity of the herbicides clomazone, glyphosate and sulfentrazone in THP-1 cells.

Background: Pesticides are indispensable for the cultivation of crops, especially those of economic importance, such as soybeans. Data on the annual use of herbicides in crops show that they correspond to 50%, making it the most used in agriculture.

Aim: Therefore, the aim of this study was to evaluate the toxicity of the three commercial herbicides (clomazone, glyphosate, and sulfentrazone) in THP-1 cells.

Biological effects triggered by chemical respiratory sensitizers on THP-1 monocytic cells.

Respiratory sensitization encompasses a group of diseases that manifest through airway hyperresponsiveness and airflow limitation. Although the concerns regarding human health, to date there are still no validated methods for preclinical assessment of this class of toxicants once the chemical respiratory allergy mechanistic framework is not fully understood. As Dendritic Cells (DCs) are the bridging elements between innate and adaptative immune responses, we preliminarily investigated the biological alterations triggered by seven different LMW respiratory allergens in the DC model THP-1.

The Application of New Approach Methodologies in Respiratory Disease Research: Their Role in Improving Translational Medicine from Bench to Bedside.

The SARS-CoV-2 outbreak focused global attention on the shortcomings of the drug discovery process. It led to its acceleration in several areas, particularly in the processes associated with the development and approval of COVID-19 vaccines. This situation contrasts with the low approval rates of new drugs for respiratory system diseases (e.

Paclitaxel-Loaded Lipid-Coated Magnetic Nanoparticles for Dual Chemo-Magnetic Hyperthermia Therapy of Melanoma.

Melanoma is the most aggressive and metastasis-prone form of skin cancer. Conventional therapies include chemotherapeutic agents, either as small molecules or carried by FDA-approved nanostructures. However, systemic toxicity and side effects still remain as major drawbacks.

Safety and efficacy of a mucoadhesive phytomedication containing curcuminoids and Bidens pilosa L. extract in the prevention and treatment of radiochemotherapy-induced oral mucositis: Triple-blind, randomized, placebo-controlled, clinical trial.

Background: Oral mucositis (OM) is the significant complication of radio/chemotherapy treatment. This study evaluated the safety and efficacy of a mucoadhesive phytomedication containing curcuminoids and Bidens pilosa L. (FITOPROT) in the prevention/treatment of OM.

Anxiolytic- and antidepressant-like effects of new phenylpiperazine derivative LQFM005 and its hydroxylated metabolite in mice.

The current treatments available for anxiety and depression are only palliative. Full remission has remained elusive, characterizing unmet medical needs. In the scope of an academic drug discovery program, we describe here the design, synthesis, in vitro metabolism prediction and pharmacological characterization of a new piperazine compound, 1-(4-methoxyphenyl)-4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazine (LQFM005), and of its main putative metabolite, 4-(4-((4-(4-methoxyphenyl)piperazin-1-yl)methyl)- 1H-pyrazol-1-yl)phenol (LQFM235).

Strategy Combining Nonanimal Methods for Ocular Toxicity Evaluation.

Historically, the ocular toxicity of manufactured consumer materials has been evaluated using the rabbit in vivo Draize rabbit eye test. The animal data obtained were used by the United Nations Globally Harmonized System of Classification and Labelling of Chemicals (UN GHS) to define the classification and labelling (C&L) for eye damage/irritation endpoint. However, the Draize test, a method which was never formally validated, has been widely criticized because of its technical limitations.

Assessing Agricultural Toxicity in Brazil: Advances and Opportunities in the 21st Century.

Agriculture in the 21st century faces multiple challenges to produce food for the growing population using ethical/sustainable and efficient methods safely for humans and the environment. Brazil today is a world leader in terms of production of food of plant origin, both for human consumption and animal feed. Agriculture and livestock raising are critical economic activities in maintaining a positive balance in its economy.

Anti-inflammatory and antinociceptive activity profile of a new lead compound - LQFM219.

LQFM219 is a molecule designed from celecoxibe (COX-2 inhibitor) and darbufelone (inhibitor of COX-2 and 5-LOX) lead compounds through a molecular hybridisation strategy. Therefore, this work aimed to investigate the antinociceptive and anti-inflammatory activities of this new hybrid compound. The acute oral systemic toxicity of LQFM219 was evaluated via the neutral red uptake assay.

Application of the adverse outcome pathway framework for investigating skin sensitization potential of nanomaterials using new approach methods.

Background: Currently, considerable efforts to standardize methods for accurate assessment of properties and safety aspects of nanomaterials are being made. However, immunomodulation effects upon skin exposure to nanomaterial have not been explored.

Objectives: To investigate the immunotoxicity of single-wall carbon nanotubes, titanium dioxide, and fullerene using the current mechanistic understanding of skin sensitization by applying the concept of adverse outcome pathway (AOP).

Innovative strategy based on mechanisms to substitute animal testing for ocular toxicity assessment of agrochemical formulations market in Brazil.

Considering the successful employment of alternative methods for eye toxicity assessment of products for regulatory purposes, and the recent advances in Brazilian legislative scenario, which adopted the UN GHS classification system for agrochemical formulations toxicity assessment, there is an emerging demand for strategies that allow the evaluation of such products. Based on this, the present study aimed to address the applicability of a mechanistic-based defined approach for eye toxicity assessment of agrochemical formulations. It was investigated the opacity/permeability, depth and location of corneal injury in bovine cornea, and vascular events in chorioallantoic membrane induced for different Brazilian agrochemicals using a Sequential Testing Strategy (STS).

Small-molecule MDM2 inhibitor LQFM030-induced apoptosis in p53-null K562 chronic myeloid leukemia cells.

Our group designed and synthesized the N-phenyl-piperazine LQFM030 [1-(4-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl) piperazin-1-yl) ethanone], a small molecule derived from molecular simplification of the Nutlin-1, an inhibitor of the human homologue of murine double minute 2 (MDM2) protein that is expressed in several types of cancer. To better investigate the effects of LQFM030 regarding the p53 mutation status, this study investigated the antiproliferative activity of LQFM030 against the p53-null K562 leukemia cells as well as the cell death pathways involved. In addition, the effects of LQFM030 on the levels of the p53/MDM2 complex were also carried out using 3T3 cells as a p53 wild-type model.

A new corneal epithelial biomimetic 3D model for in vitro eye toxicity assessment: Development, characterization and applicability.

In vitro eye toxicity assessment using reconstructed corneal epithelial models has emerged highlighting its applicability domain for Classification and Labeling of products and chemicals. However, due to bureaucratic issues, such models are not commercially available in Brazil and Latin America. In this work, we developed, characterized and evaluated the applicability of a new corneal epithelial biomimetic model using a cell lineage for in vitro eye toxicity assessment.

Corneal histomorphometric analysis: The depth of damage induced in the bovine cornea correlates with the severity of the ocular toxicity.

The Bovine Corneal Opacity and Permeability (BCOP) assay is an alternative method used to ocular toxicity potential assessment of chemicals and mixtures. The standard BCOP test provides information about permeability and opacity, however, corneal histopathological analysis has been recommended as an additional parameter to better categorize eye irritants. Moreover, such analysis associated with depth of substance-induced corneal injury analysis may provide additional scientific measurement for the refinement of BCOP test.

Increased Nose-to-Brain Delivery of Melatonin Mediated by Polycaprolactone Nanoparticles for the Treatment of Glioblastoma.

Purpose: Intranasal administration has been extensively applied to deliver drugs to the brain. In spite of its unfavorable biopharmaceutic properties, melatonin (MLT) has demonstrated anticancer effects against glioblastoma. This study describes the nose-to-brain delivery of MLT-loaded polycaprolactone nanoparticles (MLT-NP) for the treatment of glioblastoma.

Mechanistic-based non-animal assessment of eye toxicity: Inflammatory profile of human keratinocytes cells after exposure to eye damage/irritant agents.

Eye toxicity is a mandatory parameter in human risk and safety evaluation for products including chemicals, pesticides, medicines and cosmetics. Historically, this endpoint has been evaluated using the Draize rabbit eye test, an in vivo model that was never formally validated. Due to advances in scientific knowledge, economic and ethical issues, non-animal methods based on mechanisms of toxicity are being developed and validated for increasing the capability of these models to predict eye toxicity.

Chemopreventive effects of FITOPROT against 5-fluorouracil-induced toxicity in HaCaT cells.

Aims: This study evaluated the mechanisms involved in the chemopreventive effects of a mucoadhesive formulation (FITOPROT), containing curcuminoids from Curcuma longa L. (Zingiberaceae) and Bidens pilosa L. (Asteraceae) extract, against 5-FU-induced cellular toxicity using an in vitro oral mucositis model.

A novel chalcone derivative, LQFM064, induces breast cancer cells death via p53, p21, KIT and PDGFRA.

This study shows the design, synthesis and antitumoral potential evaluation of a novel chalcone-like compound, (E)-3- (3, 5-di-ter-butyl-4-hydroxyphenyl)-1- (4-hydroxy-3-methoxyphenyl) prop-2-en-1-one [LQFM064) (4)], against human breast adenocarcinoma MCF7 cells. Some toxicological parameters were also investigated. LQFM064) (4) exhibited cytotoxic activity against MCF7 cells (IC=21μM), in a concentration dependent-manner, and triggered significant changes in cell morphology and biochemical/molecular parameters, which are suggestive of an apoptosis inductor.