Toxicology Mechanisms and Methods最新文献

The potential of Trigonella foenum-graecum or fenugreek seed extract in alleviating chronic hyperglycemia is supported by scientific evidence. In addition to its role in optimizing the insulin signaling pathway, fenugreek extract can also prevent the generation of Advanced Glycation End products (AGE) by sequestration of reactive carbonyl groups involved in the formation of Schiff base with lysine and arginine residues of protein side chains. In the present work, a patented and standardized extract of Fenfuro^® was found to reduce AGE fluorescence by 75%, along with a corresponding decrease in Thioflavin T fluorescence of nearly 85%. It was determined that these significant spectral changes were due to a combined effect of the protein as well as non-protein part of the extract and not attributable to any single bioactive component. The precipitated protein from the extract itself showed Thio-T fluorescence and gave a single band around the 65 kD MW range. The non-protein supernatant, when incubated with the glycated protein, gave an enhanced AGE as well as Thio-T fluorescence thus negating any possibility of plant extract mediated quenching of fluorescence leading to false interpretations. 8-Anilinonaphthalene-1-sulfonic acid (ANS) fluorescence spectra indicated that the extract provided substantial protection against thermal denaturation.The results collectively provided significant insights for exploring newer avenues of fenugreek-based therapeutics for treating both diabetes and neurodegeneration.

Brominated flame retardants (BFRs) are ubiquitous and persistent environmental contaminants owing to their extensive use in consumer products. Although linked to various adverse health effects, the underlying molecular mechanisms remain complex. This review consolidates scientific evidence positioning mitochondria as a central target of BFR toxicity, unraveling the pathways that drive cellular damage. The analysis revealed that BFRs converge on the fundamental mechanisms of mitochondrial injury. They consistently impair bioenergetics by disrupting the electron transport chain and uncoupling oxidative phosphorylation, leading to ATP depletion and collapse of the mitochondrial membrane potential (ΔΨm). This energetic failure triggers a surge in reactive oxygen species, overwhelming antioxidant defenses, and causing severe oxidative damage. Beyond these common effects, this review highlights remarkable mechanistic plasticity. Tetrabromobisphenol A can induce distinct cell death programs, including apoptosis, necroptosis, and ferroptosis, depending on the cellular context of the study. Furthermore, BFR biotransformation can yield metabolites such as hydroxylated polybrominated diphenyl ethers (PBDEs) that exhibit significantly greater toxicity than their parent compounds. Finally, mitochondrial dysfunction is a central hub that orchestrates cellular damage by BFRs. This is critically highlighted by the replacement of BDE-209 with decabromodiphenyl ethane, a regrettable substitution, where the new compound shares similar mitotoxic mechanisms and has become a widespread pollutant. This underscores the urgent need for a paradigm shift toward mechanism-based risk assessment to prevent future cycles of hazardous chemical replacements and to guide the design of genuinely safer alternatives.

2,4-dichlorophenoxyacetic acid (2,4-D), a common herbicide, is widely used in agricultural activities. Prolonged and low-level exposure to 22,4-D increases the likelihood of adverse effects on human health. Nonetheless, the intricate toxicological mechanisms behind its influence on hypertension remain poorly understood. This study utilized ADMET, network toxicology, molecular docking, molecular dynamics, and gut microbiota analyses to explore the toxicological mechanisms underlying hypertension induced by 2,4-D. Common targets of 2,4-D and hypertension were retrieved from ChEMBL, SwissTargetPrediction, GeneCards, and OMIM databases. The ADMETlab (2.0) database was utilized to conduct ADMET analysis, which indicated potential health risks associated with 2,4-D. Eighteen potential targets associated with the toxicity of 2,4-D in relation to hypertension were identified and subsequently narrowed down to five key targets: ACE, REN, TNF, PPARG, and ADRB2 via STRING database and Cytoscape software. Enrichment analyses through GO and KEGG revealed that 2,4-D primarily affects renin secretion and the renin-angiotensin system in its hypertensive toxicity. Molecular docking analysis results showed that 2,4-D has significant binding affinities with both ACE and REN. Molecular dynamics simulations indicated that the structural stability of the ACE-2,4-D complex was notably higher than that of the REN-2,4-D complex. Finally, 2,4-D may also interact with gut microbiota and their metabolites, potentially influencing TNF and PPARG pathways and contributing to the development of hypertension. This research offers a thorough assessment using computational techniques on the toxic effects of 2,4-D on hypertension, presenting approaches for systematically evaluating the health risks posed by 2,4-D.

Reactive oxygen species (ROS)-induced DNA oxidative damage is a significant manifestation of oxidative stress in the body and is closely associated with the onset and progression of various diseases. Although Pyripyropene A (PPPA) exhibits anti-tumor and anti-inflammatory activities, its antioxidant and protective effects against DNA oxidative injury remain unclear. In this study, using a hydrogen peroxide-induced oxidative injury model of L02 cells, it was found that PPPA could significantly reduce intracellular ROS and malondialdehyde (MDA) levels, enhance the activities of catalase (CAT) and reduced glutathione (GSH), and increase the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) clearance rate, confirming its antioxidant effect. Comet assay showed a reduction in DNA breakage, and down-regulation of phosphorylated histone (γ-H2AX) and 8-hydroxydeoxyguanosine (8-oxodG), indicating that it effectively alleviates DNA oxidative injury. Meanwhile, the upregulated expression of poly ADP-ribose polymerase (PARP) suggests that PPPA may promote repair by activating the DNA damage response (DDR). This study systematically clarify for the first time that PPPA exerts a protective effect by synergistically antioxidizing, reducing DNA injury, and potentially activating repair pathways, providing a theoretical basis for its application in neoplasm and oxidative stress-related diseases.

Fluoropyrimidines are a class of chemotherapy drugs used to treat various solid tumors. 5-Fluorouracil (5-FU) an antimetabolite in the fluoropyrimidine family, which has shown remarkable efficacy against a variety of solid tumors, is a crucial medication in the treatment of cancer. However, severe organ toxicities frequently restrict its therapeutic potential. Our current knowledge of the intricate processes underlying 5-FU-induced toxicities, such as cellular absorption, metabolism, disruption of DNA synthesis, interference with RNA processing, and cell cycle regulation, is consolidated in this thorough study. 5-FU toxicity affects the cardiovascular, neurological, gastrointestinal, hepatic, renal, hematological, and pulmonary systems and includes a number of mechanisms, including oxidative stress, inflammation, and endothelial dysfunction. With documented severe toxicity occurrences varying from 0.55% to 40% depending on the affected organ, genetic differences, especially in drug-metabolizing enzymes like dihydropyrimidine dehydrogenase (DPD), are important in predicting toxicity risk. Individual susceptibility to these toxicities has been found to be significantly influenced by patterns of polymorphism peculiar to a population. While new research points to the possible advantages of certain protective agents, current management approaches mostly focus on supportive care and dose modifications. Pharmacogenomic testing has demonstrated potential in lowering the risk of serious toxicities, particularly for variations in the DPYD gene. Improved therapy techniques, such as genetic profile-based individualized dosing and improved monitoring protocols, have been made possible by a clearer knowledge of these pathways.

Caffeine, a widely consumed phytochemical, exhibits a dual and paradoxical role in modulating cellular responses to radiation, acting as both a radioprotector and radiosensitizer depending on context. This comprehensive review synthesizes evidence from in vitro, in vivo, and clinical studies to elucidate caffeine's multifaceted interactions with ionizing (gamma rays, X-rays) and non-ionizing (UV) radiation. Mechanistically, caffeine influences DNA repair pathways-notably inhibiting ATM/ATR checkpoint kinases-overrides G2/M cell cycle arrest, and modulates apoptosis through p53-dependent and independent pathways. While caffeine demonstrates radioprotective potential by mitigating oxidative stress, enhancing antioxidant defenses, and reducing chromosomal aberrations in normal tissues, it concurrently sensitizes cancer cells to radiation by disrupting DNA repair and amplifying mitotic catastrophe. Intriguingly, its effects vary by radiation type, dose, cell lineage (e.g. p53 status), and administration timing, underscoring its context-dependent utility. Preclinical studies highlight caffeine's capacity to attenuate radiation-induced hepatotoxicity, skin damage, and cataract formation, yet caution is warranted due to risks of exacerbating chromosomal instability and teratogenicity. Clinically, retrospective data suggest caffeine may reduce late radiotherapy toxicity in cervical cancer patients, though evidence remains sparse. This review underscores caffeine's potential as an adjuvant in radiotherapy but emphasizes the necessity for precision in its application, balancing therapeutic benefits against risks. Further research is critical to unravel dose-response dynamics, optimize timing, and validate clinical translatability across diverse radiation modalities.

While agriculture is essential for food security, the intensive use of pesticides in modern farming practices raises concerns on their impact, in particular from a One Health perspective. In 2024, Brazil approved 663 new pesticides, a 19% increase in comparison with 2023. The occupational exposure of rural workers is known to be associated with a range of health outcomes, including cancer. Despite this, considerable knowledge gaps persist with regard to the impact of pesticides on the expression of target genes, in particular those involved in the regulation of the cell cycle, apoptosis, and xenobiotic detoxification. The present study used an in silico approach to investigate the impacts of insecticides, herbicides, and fungicides on gene regulation and the biological pathways that are fundamental to the stability of the genome and cell homeostasis. The study focused on the interactions between the 10 most widely used pesticides in the State of Goiás and genes that are sensitive to these compounds were analyzed using data from the Comparative Toxicogenomics Database (CTD). The analyses indicated alterations in pathways associated with oxidative stress, DNA damage, Mitogen-Activated Protein Kinase (MAPK) signaling, and apoptosis. The genes TP53 and GADD45A (cell cycle control), CYP3A4 (xenobiotic detoxification), and BAX (pro-apoptotic) showed increased expression, while BCL2 (anti-apoptotic) had reduced expression. The results highlight the impacts of pesticides on gene expression and potential cellular dysfunctions associated with cancer and neurodegenerative diseases. They also reinforce the need for functional studies and more effective regulatory policies to protect workers and promote sustainable agricultural practices.

Background: Cardiovascular diseases are often driven by oxidative stress and endothelial dysfunction, particularly under heavy metal exposure such as HgCl₂. It disrupts NO signaling and RAS balance, impairing vascular function. L-arginine (LA) and tetrahydrobiopterin (BH₄) as essential regulators of eNOS, are potential therapeutic agents for restoring vascular reactivity.

Objective: This study aimed to evaluate the protective effects of LA and BH₄, individually and in combination, on Ang II-induced vascular reactivity in isolated rat aortic rings under normal and HgCl₂-induced oxidative stress conditions. The interaction of Ang-II receptors (AT₁, AT₂) and ACE2 activity were explored.

Methods: Aortic rings were pretreated with LA, BH₄, or both, followed by stimulation with Ang II (10^-11-10^-6 M). Pharmacological inhibitors were used to assess the roles of AT₁ (1 µM), AT₂ (10 µM), and ACE2 (1 µM) receptors. Vascular responsiveness was analyzed through Emax, pD₂, and AUC values in the presence and absence of HgCl₂ (1 µM).

Results: HgCl₂ significantly impaired Ang II-induced vasoconstriction. LA and BH₄ partially restored vascular responsiveness, with the combination producing the most substantial improvements, indicating synergistic NO-mediated effects. AT₁ receptor blockade abolished Ang II responses, confirming its central role, while AT₂ inhibition increased contraction, revealing its vasodilatory function. ACE2 inhibition enhanced Ang II-induced contraction, particularly after HgCl₂ exposure. Co-treatment with LA and BH₄ mitigated this effect, restoring balance.

Conclusion: LA and BH₄ can reverse HgCl₂-induced vascular dysfunction by enhancing NO signaling and modulating Ang II receptor pathways. Their combined use offers therapeutic promise in conditions involving oxidative stress and RAS dysregulation.

Chronic kidney disease and its complications, including renal fibrosis, diabetic nephropathy, and renal cell carcinoma represent a major global health burden with limited therapeutic options. Resveratrol, a naturally occurring polyphenol found in grapes and berries, has emerged as a promising therapeutic candidate due to its multifaceted biological activities. Extensive research demonstrates resveratrol's remarkable renoprotective properties across various renal pathologies. It effectively attenuates tissue scarring, mitigates diabetes-related kidney damage, inhibits cancer progression, and protects against drug-induced nephrotoxicity. These broad-spectrum benefits stem from its unique ability to simultaneously target oxidative stress, inflammation, angiogenesis, apoptosis, and cellular damage pathways. Clinical investigations have confirmed resveratrol's potential to improve renal function markers in patients, while advanced formulation strategies are enhancing its therapeutic effectiveness. The compound's excellent safety profile further supports its clinical translation potential. This comprehensive review evaluates the current evidence for the renoprotective effects of resveratrol, focusing on its mechanisms of action in kidney diseases.

Asbestiform fibers and cleavage fragments of the same mineral have different origins, though distinguishing between samples of fibers and fragments is often complicated. This study aims to demonstrate an efficient method for distinguishing between samples of two commercial amphibole asbestos types (crocidolite and amosite) and their non-asbestiform varieties. For the study, 15 dimensional datasets were used. For classification, two metrics were used: the fraction of elongate mineral particles with 2.99log₁₀(length)-5.82log₁₀(width)-3.80 ≥ 0, and the Pearson Index, which is the linear correlation coefficient between log₁₀(width) and log₁₀(length) of elongate mineral particles in the set. The decision boundary of CriteriaParticlesFraction ≥ 0.34PearsonIndex + 0.35 was found to predict the correct habit for amphibole datasets with an average error rate of 0.4% (Cohen's Kappa statistics 0.992). Additionally, several quantitative characteristics were used that have been demonstrated to be predictive of mesothelioma potency factors of elongate particles. These include dimensional coefficient of carcinogenicity (DCC), found as 1 - exp(-A x Surface Area^K/(B x width^T +C)), EMPA (fraction of particles longer than 5 µm with diameter not higher than 0.15 µm), EMPB (fraction of particles longer than 5 µm with diameter not higher than 0.25 µm), and aerodynamic diameter of the particles. It was demonstrated that asbestiform and non-asbestiform datasets have significantly different dimensional parameters that can be related to dissimilar toxicological effects.