Toxicology Mechanisms and Methods最新文献

Alveolar macrophages (AMs), the first line against the invasion of foreign invaders, play a predominant role in the pathogenesis of silicosis. Studies have shown that inhaled silica dust is recognized and engulfed by AMs, resulting in the production of large amounts of silica-induced reactive oxygen species (ROS), including particle-derived ROS and macrophage-derived ROS. These ROS change the microenvironment of the AMs where the macrophage phenotype is stimulated to swift from M0 to M1 and/or M2, and ultimately emerge as the M2 phenotype to trigger silicosis. This is a complex process accompanied by various molecular biological events. Unfortunately, the detailed processes and mechanisms have not been systematically described. In this review, we first systematically introduce the process of ROS induced by silica in AMs. Then, describe the role and molecular mechanism of M2-type macrophage polarization caused by silica-induced ROS. Finally, we review the mechanism of pulmonary fibrosis induced by M2 polarized AMs. We conclude that silica-induced ROS initiate the fibrotic process of silicosis by inducing macrophage into M2 phenotype, and that targeted intervention of silica-induced ROS in AMs can reprogram the macrophage polarization and ameliorate the pathogenesis of silicosis.

New approach methodologies (NAMs) offer information tailored to the intended application while reducing the use of animals. NAMs aim to develop quantitative structure-activity relationship (QSAR) and quantitive-Read-Across structure-activity relationship (q-RASAR) models to predict and categorize the acute toxicity of known and unknown endocrine-disrupting chemicals (EDCs) against zebrafish. EDCs are a diverse group of toxic substances that disrupt the endocrine system of humans and animals. The q-RASAR model was constructed and verified using validation metrics (R² = 0.886 and Q² = 0.814) which found to be more reliable model compare to QSAR model. The substructure fingerprint was well-fitted for the classification model and it was validated using 10-fold average accuracy (Q = 86.88%), specificity (Sp = 88.89%), Matthew's correlation curve (MCC = 0.621) and receiver operating characteristics (ROC = 0.828). The dataset of unknown substances revealed that phenolphthalein (Php) exhibited a significant level of toxicity based on q-RASAR model. The docking and simulation study indicated that the computationally derived important features successfully bound to the target zebrafish sex hormone binding globulin (zfSHBG). The experimental LC50 value of 0.790 mg L^-1 was very close to the predicted value of 0.763 mg L^-1, which provides high confidence to the developed model.

Objectives: Five solvent extracts (n-hexane, ethyl acetate, ethanol, ethanol/water (70%), and water) of Gladiolus italicus Mill. from Turkey were evaluated for chemical and biological properties.

Methods: Antioxidant activities, inhibitory properties against key enzymes involved in the etiology of chronic diseases were tested, as well as cytotoxic effects on different cell lines. Chemical characterization was also carried out to determine the most abundant compounds of each extract.

Results: The highest total phenolic content (TPC) was observed in the water extract while highest TFC in ethanol/water extract. The most abundant compounds in the extracts were hyperoside (69041.06 mg kg^-1), isoquercitrin (46239.49 mg kg^-1), delphindin-3,5-diglucoside (42043.81 mg kg^-1), myricetin (21486.61 mg kg^-1), and kaempferol-3-glucoside (21199.76 mg kg^-1). Molecular dynamic (MD) simulations confirmed the structural stability and dynamic conformational integrity of these complexes over a period of 100 ns. In network pharmacology, A total of 657 unique target genes were screened: 52 associated with programmed cell death-1 (PD-1), 85 with vascular endothelial growth factor receptor-2 (VEGFR2), and 130 with fibroblast growth factor receptor-2 (FGFR2), identifying crucial gene interactions for these proteins. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted, revealing significant interactions and pathways such as the advanced glycation end products (AGE) and their receptors (RAGE) signaling pathway in diabetic complications and T- helper 17 (Th17) cell differentiation, among others. This elucidation of complex networks involving key genes like AKT Serine/Threonine Kinase 1 (AKT1), MYC proto-oncogene (MYC), tumor protein 53 (TP53), Interleukin 6 (IL6), and tumor necrosis factor (TNF) provides a promising foundation for the development of targeted therapies in the treatment of non-communicable diseases.

Conclusion: These results show that G. italicus could be a natural source of potent antioxidants and enzyme inhibitors which need to be further explored for the development of biopharmaceuticals.

The endocannabinoid (eCB) system comprises endogenous ligands, cannabinoid receptors (CBRs), and their regulatory proteins; its alteration leads to many diseases including cancer. Thus, becomes a therapeutic target for synthetic cannabinoids aimed to control cancer cell proliferation, migration, adhesion, and invasion. However, little is known about adhesion molecules regulation through CBRs activation. The aim of this study was to evaluate the effects of a CB1/CB2 agonist, WIN-55, 212-2 (WIN), on the regulation of adhesion molecules platelet endothelial cell adhesion molecule-1 (PECAM-1) and vascular endothelial cadherin (VE-cadherin) in HeLa cells. CBRs expression was evaluated by immunofluorescence staining in HeLa cells and cell viability (thiazolyl blue tetrazolium bromide), cell adhesion (crystal violet), adhesion molecules expression and location (Western blot and immunofluorescence staining assays) were all assessed on cells treated with different WIN concentrations. Receptors CB1, CB2, and G-protein-coupled receptor 55 were expressed in HeLa cells. Additionally, biphasic effects were observed in their metabolic activity and adhesive properties: low WIN concentrations resulted in significant increases whereas, high ones decreased them compared to controls (p < 0.0001), demonstrating that WIN elicits opposite effects depending on the concentration and exposure time. PECAM-1 was detected in HeLa cell's cytoplasm, membrane, and perinuclear region, whereas VE-cadherin had a nuclear distribution. There were no significant differences in PECAM-1 and VE-cadherin expression and location, suggesting that WIN does not modulate these proteins. These findings support the potential use of WIN due to its anticancer properties without dysregulating adhesion molecules. WIN possible contribution to inhibit cancer progression should be further investigated.

The study aimed to assess the toxic effect of cadmium (Cd) on the exocrine and endocrine functions of pancreas, the changes in pancreatic tissue after Cd withdrawal, and the protective effects of vitamin C (VC) and Nigella sativa (NS) against Cd-induced damage. Rats were assigned to: control, Cd-treated (0.5 mg/kg/d intraperitoneal [IP] injection), VC and Cd-treated (receiving 100 mg/kg/d VC orally and Cd concomitantly), NS and Cd-treated (receiving 20 mg/kg/d NS and Cd, simultaneously), and Cd withdrawal (receiving Cd for 30 d then living free for recovery for other 30 d). Blood samples were collected and post-sacrifice pancreatic specimens were processed for light and electron microscope study. Quantitative analyses of pancreatic collagen area%, pancreatic islet parameters, β cell density, and insulin immunoexpression were done. Fasting blood glucose was significantly increased in Cd-treated and Cd-withdrawal groups, while co-treatment with VC and NS caused significant reductions (p < 0.05). Cd-induced extensive degenerative changes in pancreatic acini and islets at light and ultrastructure levels. Obvious fibrosis and congestion of blood vessels were noticed. Significant reductions in pancreatic islet number, volume, and surface area and diminished beta cell count and insulin immunoexpression were observed. After withdrawal of Cd, the whole pancreatic tissue still showed a serious impact. Concomitant treatment with VC or NS obviously reduced these degenerative changes and significantly improved pancreatic islet parameters and insulin immunoexpression. VC showed a better amendment than NS, but this difference was statistically insignificant. Therefore, VC and NS could be used as prophylactic agents that lessen Cd consequences on the pancreas.

Benzoic acid, the most basic aromatic carboxylic acid, is produced industrially and used in cosmetic, hygiene, and pharmaceutical items as a flavoring ingredient and/or preservative. The significance of sodium benzoate, a metabolite of cinnamon, used as a food preservative and FDA-approved medication to treat urea cycle abnormalities in humans, has been shown to raise the levels of neurotrophic factors. Valproic acid (VPA), a commonly used anti-epileptic and mood-stabilizing medication, causes behavioral and intellectual problems and is a commonly used agent to induce animal model for autism. Aim of this study is to determine the effects of benzoic acid synthesized from Cinnamomum Cassia by green chemistry method on gene expressions related to autism development in case of VPA toxicity. Zebrafish embryos were exposed to low and high doses of benzoic acid for 72 h post-fertilization. Locomotor activities were determined. Acetylcholinesterase (AchE), lipid peroxidation, nitric oxide (NO), sialic acid (SA), glutathione (GSH)-S-transferase, catalase (CAT), and superoxide dismutase (SOD) activities were determined spectrophotometrically. eif4b, adsl, and shank3a expressions were determined by RT-PCR as autism-related genes. Although high-dose benzoic acid inhibited locomotor activity, benzoic acid at both doses ameliorated VPA-induced disruption in oxidant-antioxidant balance and inflammation in zebrafish embryos and was effective in improving the impaired expression of autism-related genes.

A vast variety of chemical compounds have been fabricated and commercialized, they not only result in industrial exposure during manufacturing and usage, but also have environmental impacts throughout their whole life cycle. Consequently, attempts to assess the risk of chemicals in terms of toxicology have never ceased. In-silico toxicology, also known as predictive toxicology, has advanced significantly over the last decade as a result of the drawbacks of experimental investigations. In this study, ProTox-III was applied to predict the toxicity of the ligands used for metal-organic framework (MOF) design and synthesis. Initially, 35 ligands, that have been frequently utilized for MOF synthesis and fabrication, were selected. Subsequently, canonical simplified molecular-input line-entry system (SMILES) of ligands were extracted from the PUBCHEM database and inserted into the ProTox-III online server. Ultimately, webserver outputs including LD₅₀ and the probability of toxicological endpoints (cytotoxicity, carcinogenicity, mutagenicity, immunotoxicity, and ecotoxicity) were obtained and organized. According to retrieved LD₅₀ data, the safest ligand was 5-hydroxyisophthalic. In contrast, the most hazardous ligand was 5-chlorobenzimidazole, with an LD₅₀ of 8 mg/kg. Among evaluated endpoints, ecotoxicity was the most active and was detected in several imidazolate ligands. This data can open new horizons in design and development of green MOFs.