Journal of Xenobiotics最新文献

The vascular endothelial growth factor receptor 2 (VEGFR2) and the hepatocyte growth factor receptor (C-Met) are critical receptors for signaling pathways controlling crucial cellular processes such as cell growth, angiogenesis and tissue regeneration. However, dysregulation of these proteins has been reported in different diseases, particularly cancer, where these proteins promote tumour growth, invasiveness, metastasis and resistance to conventional therapies. The identification of dual inhibitors targeting both VEGFR-2 and c-Met has emerged as a strategic therapeutic approach to overcome the limitations and resistance mechanisms associated with single-target therapies in clinical settings. Through molecular dynamics simulations and comparative docking analysis, we tested the inhibitory potential of 2,016 Food and Drug Administration (FDA)-approved drugs targeting VEGFR-2 and/or c-Met receptors. The results revealed that entacapone and telmisartan are potent and selective inhibitors for c-Met and VEGFR-2, respectively. Interestingly, triamterene was identified as a promising dual inhibitor, demonstrating specific and significant binding affinity to both proteins. Molecular dynamics simulations revealed key interactions between the identified compounds and critical residues in the catalytic domains of both VEGFR-2 (e.g., Lys868, Asp1028, Asp1046) and c-Met (e.g., Asp1204, His1202, Asp1222), providing insights into their mechanism of action. These findings underscore the therapeutic potential of triamterene in targeting multiple signaling pathways involved in cancer progression, metastasis and poor prognosis in patients. Our study provides a foundational framework for the development of novel anticancer compounds able to target multiple pathways in cancer. Further preclinical and clinical investigations are needed to validate the efficacy of these compounds in clinical settings and to test their ability to overcome resistance and improve patient outcome.

The Silway River has historically failed to meet safe fecal coliform levels due to improper waste disposal. The river mouth is located in General Santos City, the tuna capital of the Philippines and a leading producer of hogs, cattle, and poultry. The buildup of contaminants due to direct discharge of waste from chicken farms and existing water quality conditions has led to higher fecal matter in the Silway River. While there were technical reports in the early 2000s about poultry farming, this is the first study where fecal coliform from poultry farming was detected in the Silway River using highly sensitive protocols like qPCR. This study characterized the effect of flow velocity and physicochemical water quality parameters on chicken fecal contamination. Gene markers such as Ckmito and ND5-CD were used to detect and quantify poultry manure contamination through microbial source tracking (MST) and environmental DNA (eDNA) profiling. The results of this study showed the presence of chicken fecal bacteria in all stations along the Silway River. The results revealed that normal levels of water quality parameters such as temperature, pH, and high TSS concentrations create favorable conditions for chicken fecal coliforms to thrive. Multiple regression analysis showed that flow velocity and DO significantly affect chicken fecal contamination. A lower cycle threshold (Ct) value indicated higher concentration of the marker ND5-CD, which means higher fecal contamination. It was found that there was an inverse relationship between the Ct value and both velocity (R² = 0.55, p = 0.01) and DO (R² = 0.98, p = 0.2), suggesting that low flow velocity and low DO can lead to higher fecal contamination. Findings of fecal contamination could negatively impact water resources, the health of nearby residents, and surrounding farms and industries, as well as the health and growth of fish.

Nanoplastics are known to represent a threat to marine ecosystems. Their combination with other contaminants of emerging concerns (CECs) may amplify ecotoxic effects, with unknown impacts on marine biodiversity. This study investigates the effects, single and combined, of bisphenol A (BPA)-one of the most hazardous CECs-and polystyrene nanoparticles (PS NPs)-as a proxy for nanoplastics, being among the most commonly found asmarine debris-on cholinesterase (ChE) activities of the ascidian Ciona robusta. ChE activity was first measured in the siphons, tunic, and viscera of wild-caught adult specimens and exposed in vitro to BPA (0.01, 0.21, 0.69 mM) and PS NPs (0.0096-0.096 mM; 8.096 × 10⁹-10¹⁰ particles, respectively) alone and combined for 15 min of incubation. PS NPs' behavior in milliQ water and in the ChE assay reaction buffer was characterized alone, combined with BPA, and analyzed through ζ-potential measurements via Dynamic Light Scattering. The results revealed that ChE activity was predominant in the viscera and siphons of C. robusta; PS NPs did not affect the ChE activity alone or combined, while BPA caused a concentration-dependent inhibition of ChE activity in the viscera. No changes in ζ-potential were observed for PS NPs alone or combined with BPA in the ChE buffer, suggesting no interaction. Further investigations are needed to understand the potential neurotoxic consequences for C. robusta and ecological risk scenarios due to exposure to BPA and nanoplastics in marine coastal waters.

The present study focused, for the first time, on the adverse effects of nine REEs on the marine copepod Tigriopus fulvus. For this purpose, copepod mortality, immobilization, and naupliar development were assessed. Overall, the results demonstrated that all REEs tested exerted significant adverse effects on T. fulvus, with LC50 values ranging from 0.56 to 1.99 mg/L. Concentration-dependent increases in mortality and immobilization for all tested REEs were observed. Following exposure of nauplii to REEs, a significant slowing of nauplii development was shown with all REEs tested. The results obtained clearly highlight the potential toxicity of REEs, and, in particular, of Lanthanum, which could have consequences on the survival and development of T. fulvus, affecting the copepod population.

In the field of computational chemistry, computer models are quickly and cheaply constructed to predict toxicology hazards and results, with no need for test material or animals as these computational predictions are often based on physicochemical properties of chemical structures. Multiple methodologies are employed to support in silico assessments based on machine learning (ML) and deep learning (DL). This review introduces the development of computational toxicology, focusing on ML and DL and emphasizing their importance in the field of toxicology. A fine balance between target potency, selectivity, absorption, distribution, metabolism, excretion, toxicity (ADMET) and clinical safety properties should be achieved to discover a potential new drug. It is advantageous to perform virtual predictions as early as possible in drug development processes, even before a molecule is synthesized. Currently, there are numerous commercially available and free web-based programs for toxicity prediction, which can be used to construct various predictive models. The key features of the QSAR method are also outlined, and the selection of appropriate physicochemical descriptors is a prerequisite for robust predictions. In addition, examples of open-source tools applied to toxicity prediction are included, as well as examples of the application of different computational methods for the prediction of toxicity in drug design and environmental toxicology.

Temephos is an organophosphorus pesticide widely used as a larvicide in public health campaigns to control vector-borne diseases. Data on the urinary elimination of temephos metabolites are limited, and there is no validated biomarker of exposure for its evaluation. This study aimed to determine the urinary excretion kinetics of temephos and its metabolites in adult male rats. Hence, adult male Wistar rats were administered orally with a single dose of temephos (300 mg/kg). Urine samples were collected at different time intervals after dosing and enzymatically hydrolyzed using β-glucuronidase/sulfatase from H. pomatia. The metabolites were extracted and analyzed by HPLC-DAD. The metabolites detected were 4,4'-thiodiphenol (TDP), 4,4'-sulfinyldiphenol (SIDP), 4,4'-sulfonyldiphenol (SODP), or bisphenol S (BPS), a non-identified metabolite, and only traces of the parent compound. The mean urine concentrations of metabolites were used for kinetic analysis. Urinary levels of TDP were fitted to a two-compartmental model, and its half-lives (t_{1/2 Elim-U}) were 27.8 and 272.1 h for the first and second phases, respectively. The t_{1/2 Elim-U} of BPS was 17.7 h. TDP, the main metabolite of temephos, was eliminated by urine and is specific and stable. Therefore, it may be used as a biomarker of temephos exposure.

Over the last decades, the human species has seen an increase in the incidence of pathologies linked to the genitourinary tract. Observations in animals have allowed us to link these increases, at least in part, to changes in the environment and, in particular, to an increasing presence of endocrine disruptors. These can be physical agents, such as light or heat; natural products, such as phytoestrogens; or chemicals produced by humans. Endocrine disruptors may interfere with the signaling pathways mediated by the endocrine system, particularly those linked to sex hormones. These factors and their general effects are presented before focusing on the male and female genitourinary tracts by describing their anatomy, development, and pathologies, including bladder and prostate cancer.

The increasing consumption of chia seeds is followed by a growing interest in their nutritional and toxicological characterization. To assess the characterization of the essential and PTEs of this novel food, 20 samples of conventional and organic chia seeds available on the European market were analyzed using ICP-OES. Then, the dietary exposure to these elements was assessed. An exhaustive investigation into the metal content of this food serves to elucidate the paucity of existing knowledge. The results show that the levels of essential elements are similar in both types of production, while the levels of PTEs are higher in the organic samples. The exposure assessment indicates that Mn contributes the most among the essential elements, followed by Cu in women. Exposure to PTEs through doses of 50 g/day of chia seeds analyzed would hardly pose short-term health risks as the contributions are below 10%, except for Sr, although they could produce a long-term toxicological risk. To promote safety in chia seed consumption, it is recommended to encourage responsible and moderate consumption, continue monitoring PTE levels in this novel food, and establish concentration limits for PTEs in future European regulations.

Polyethylene and polystyrene are massively used around the world in various applications and are the most abundant plastic waste. Once in the marine environment, under the influence of physical and chemical factors, plastic products degrade, changing from the size category of macroplastics to microplastics. In order to study the effect of plastic on marine organisms, we modeled the conditions of environmental pollution with different-sized plastic-polystyrene microparticles of 0.9 µm and macro-sized polyethylene fragments of 10 cm-and compared their effect on biochemical parameters in the tissues of the bivalve mollusk Mytilus trossulus. Using biomarkers, it was found that regardless of the size and type of polymer, polystyrene microparticles and polyethylene macrofragments induced the development of oxidative stress in mussels. A significant decrease in the level of lysosomal stability in mussel hemocytes was observed. Increases in the level of DNA damage and the concentration of malonic dialdehyde in the cells of gills and the digestive gland were also shown. The level of total antiradical activity in cells varied and had a tissue-specific character. It was shown that both ingested polystyrene particles and leachable chemical compounds from polyethylene are toxic for mussels.

Pharmaceutical residues in aquatic ecosystems pose significant environmental and public health challenges. Identifying the presence and levels of these pharmaceuticals is crucial. This study developed an analytical method to detect pharmaceuticals used for Alzheimer's (AD) and Parkinson's (PD) disease, including psychiatric drugs and the stimulant caffeine, targeting 30 compounds. Optimized mass spectrometric and liquid chromatographic parameters enabled robust detection and quantification. The methodology was applied to 25 surface and wastewater samples. Twenty-one compounds were detected including eight psychiatric drugs, five metabolites (citalopram N-oxide, citalopram propionic acid, desmethylcitalopram, O-desmethylvenlafaxine, and 10,11-epoxycarbamazepine), and seven AD/PD pharmaceuticals along with caffeine. Nine compounds (apomorphine, benserazide, donepezil, didemethylcitalopram, carbidopa, norfluoxetine, galantamine, pramipexole, and safinamide) were not detected. Fluoxetine was found in all samples, and caffeine had the highest concentration at 76,991 ng/L, reflecting its high consumption. Concentrations ranged from 29.8 to 656 ng/L for caffeine,