Toxicology Mechanisms and Methods最新文献

This paper studies the toxic effect of micron-sized quartz silica particles on primary human airway epithelial cells (AECs) and the molecular mechanism of its induction of apoptosis. Studies have found that micron-sized quartz silica particles cause AECs damage by activating cell apoptosis. By constructing a competitive endogenous RNA (ceRNA) network, it was identified that three circRNAs (hsa_circ_0052203, hsa_circ_0022429, hsa_circ_0052264) and four key miRNAs (hsa-miR-4646-5p, hsa-miR-150-3p, hsa-miR-6798-3p, hsa-miR-6756-5p) play key roles in regulating apoptosis. In addition, seven mRNAs (LMNB1, TP53AIP1, CASP10, BCL2, LMNB2, CFLAR and ITPR1) were significantly associated with the apoptosis. Functional enrichment analysis indicated that these genes were involved in biological processes such as nuclear lysis, hypoxia response and DNA damage. This study has for the first time revealed the role of the ceRNA network in the apoptosis of AECs induced by micron-sized quartz silica particles, providing new molecular targets and therapeutic ideas for the early pathogenesis of silicosis.

Crizotinib, a first-generation tyrosine kinase inhibitor, demonstrates excellent clinical efficacy in treating non-small cell lung cancer (NSCLC). However, its clinical application is often limited by severe hepatotoxicity, the underlying mechanisms of which remain poorly understood. This study aimed to investigate the molecular mechanisms of crizotinib-induced hepatotoxicity in mice using transcriptomic analysis. Male ICR mice were orally administered crizotinib at doses of 100, 200, and 300 mg/kg for 7 consecutive days. Hepatotoxicity was assessed by measuring serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, along with histopathological evaluation via hematoxylin and eosin (H&E) staining. Transcriptomic and bioinformatics analyses of liver tissues were conducted to identify potential toxicological pathways. Oxidative stress markers were quantified using biochemical assay kits. Hepatic macrophage activation was examined by F4/80 immunostaining, and protein expression levels were analyzed by western blotting. Crizotinib administration resulted in dose-dependent liver injury, as indicated by elevated serum ALT and AST levels, body weight loss, and histological abnormalities. Transcriptomic profiling revealed significant enrichment of oxidative stress-related pathways, with protein-protein interaction (PPI) analysis identifying Jun as a key hub gene. Crizotinib significantly increased hepatic reactive oxygen species (ROS), malondialdehyde (MDA), and oxidized glutathione (GSSG) levels, while reducing reduced glutathione (GSH) levels and the GSH/GSSG ratio. Additionally, crizotinib significantly upregulated Bax and downregulated Bcl-2 expression, promoted macrophage infiltration, and increased the expression of JNK and NLRP3 proteins. These findings suggest that crizotinib-induced hepatotoxicity may be mediated by ROS-induced activation of the JNK/NLRP3 signaling pathway, which subsequently promotes hepatic inflammation and apoptosis.

Plastics are extensively used materials with a long environmental lifespan, posing significant risks to human health and the environment. Global plastic consumption has surged, with plastic waste expected to triple by 2060. The primary concern is the breakdown of plastics into nano and micro-sized particles, which can enter the body and have been detected in various organs and tissues. This review systematically examines the effects of micro and nanoplastics (MNPs) on the endocrine system using in vitro and in vivo experimental models. Following PRISMA guidelines, articles were sourced from databases like PubMed, Web of Science, and Scopus. After screening for relevance and removing duplicates and non-English articles, 103 articles focusing on the endocrine effects of MNPs were selected. MNPs can disrupt endocrine functions, altering reproductive hormones and gene expression patterns. In vivo exposure to MNPs increases inflammatory markers such as TNF-α, IL-6, IL-1β, and NF-κB, leading to apoptosis, inflammation, and oxidative stress. These disruptions impact the gonads, thyroid glands, and hormone secretion from the pituitary and hypothalamus. Most studies focus on terrestrial animals, with polystyrene being the most commonly used polymer. Future research should explore various plastic polymers, longer exposure durations, a broader range of concentrations, and human-level studies to better understand the toxicity of plastic particles. Reducing exposure to these pollutants requires legal changes, consumer behavior adjustments, and increased public awareness. Understanding the underlying processes can help propose methods to mitigate risks and protect human health.

Oroxylum indicum extract (OIE), prepared from its dried bark, known for neuroprotective and cognitive health support, is evaluated. Oroxylum indicum, the Indian Trumpet Tree, is traditionally known for its numerous medicinal benefits. Almost every part of the plant has been traditionally applied to treat many conditions such as stomachache, rheumatism, jaundice, cough, pharyngitis, acute and chronic bronchitis. Various researchers have demonstrated biological activities including antioxidant, and anti-inflammatory, immunomodulatory, analgesic, anti-cancer, anthelmintic, hepatoprotective, antiulcer, anti-diarrheal, cardioprotective, anti-diabetic, anti-epileptic, wound healing, properties. Since very little scientific evidence was available on safety assessment of OIE, a detailed toxicological evaluation of OIE was executed to ensure its safety for human administration and to harness its potential therapeutic applications. The present study evaluated the acute, subacute, subchronic, and reproductive toxicity of OIE in rodents. Also, the mutagenic potential was evaluated with the bacterial reverse mutation assay and the mammalian bone marrow micronucleus test.

No treatment-related study findings were observed, and a No Observed Adverse Effect Level of 400 mg/kg body weight was established in subacute, subchronic, reproductive/developmental toxicity studies. In addition, the findings of genotoxicity as evaluated by in vitro bacterial reverse mutation assay, and in vivo mammalian bone marrow micronucleus test in mice showed that OIE did not induce any mutagenic effects. Henceforth, this toxicological evaluation confirms that oral administration of OIE was found to be safe in rodents, non-mutagenic, without any adverse effects. This study positively impacts in encouraging the use of OIE in various therapeutic applications ensuring its safety.

Bromism is a syndrome that results from bromide intoxication. It is difficult to diagnose since it mimics a myriad of psychiatric and dermatological disturbances. Historically, the most common sources have been drug ingestion or contaminated drinks. This work aims to thoroughly review all the state-of-the-art aspects of bromism and bromoderma, including its pathophysiology, diagnosis, treatment, and other relevant clinical and forensic features. In this context, a comprehensive search was conducted in PubMed (U.S. National Library of Medicine) without time restrictions. Bromism may occur in individuals of any age or gender, but it is more frequent in women. In children, it usually occurs under therapy for resistant epilepsy or is breastfed by mothers who ingested bromide and may manifest as bromoderma. In adults, bromism manifests with psychiatric and neurological signs such as hallucinations, delusions, or ataxia. Pseudohyperchloremia with a negative anion gap is highly suggestive of the diagnosis. Treatment requires the removal of bromide, which is achieved by per os or intravenous saline administration or even hemodialysis. Although bromism is not usually observed in clinical and forensic practice, it is still related to the administration of controlled or immediate-release formulations, mainly analgesics or antiepileptic drugs, as well as internet-purchased supplements.

Background: Neodymium, as a strategic rare earth element (REE), has demonstrated bioaccumulative potential and can permeate human systems through inhalation of airborne particulates, ingestion of contaminated food/water, and dermal absorption from soil matrices, ultimately eliciting multi-organ toxicological manifestations. However, the hepatotoxicological profile of neodymium species and their pathophysiological mechanisms remain inadequately characterized. Neodymium nitrate (Nd(NO₃)₃), the predominant water-soluble neodymium species, exhibits marked bioavailability with particular hepatic tropism.

Objective: This study aims to investigate the effects of neodymium nitrate on apoptosis of mouse liver cells and its underlying molecular mechanisms.

Results: Mouse liver cell line AML12 was treated with gradient concentrations of neodymium nitrate. The results showed that neodymium nitrate inhibited liver cell proliferation, induced apoptosis, and exhibited a dose-dependent relationship. Western blotting and quantitative real-time PCR (qRT-PCR) revealed that neodymium nitrate suppressed Bcl2l1 transcription and activated the proteolysis of Caspase 3. To further explore the molecular mechanism, Bcl2l1 protein was overexpressed in mouse liver cells. The findings indicated that overexpression of Bcl2l1 rescued neodymium nitrate-induced apoptotic phenotypes and attenuated Caspase 3 cleavage.

Conclusion: The present data suggest that neodymium nitrate induces apoptosis of mouse liver cells through the Bcl2l1/Caspase 3 pathway. However, further studies are called for to substantiate this view, as the findings may provide critical mechanistic evidence for revising the toxicological risk assessment frameworks of rare earth elements.

Trans fatty acids (TFAs) are potential health risk factors generated during food processing, and their mechanisms of association with digestive diseases remain incompletely elucidated. This study focused on elaidic acid (EA), integrating computational toxicology and molecular docking to systematically analyze its molecular mechanisms in regulating functional dyspepsia (FD), gastric cancer (GC), nonalcoholic fatty liver disease (NAFLD), and colorectal cancer (CRC) through multi-target networks. Protein Interaction Networks were constructed by screening EA and disease-intersecting targets, enriching and analyzing key pathways, and validating the binding ability of core targets. Results showed that EA shared 22, 67, 56, and 72 common targets with FD, GC, NAFLD, and CRC, respectively. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that EA acts through pathways including lipid metabolism dysregulation, inflammatory response, and chemical carcinogenesis-receptor activation. Molecular docking confirmed binding affinities between EA and core targets. The present study suggests that EA may promote the progression of digestive diseases through a multi-target-multi-pathway model, providing a new perspective for the study of the toxicity mechanism of TFA and food safety prevention and control.

Microplastics (MPs) have emerged as a serious global environmental threat due to their resistance to degradation and persistence in ecosystems. Given their potential risks to human health, it is essential to thoroughly investigate the mechanisms of toxicity and associated health consequences. This study examined the toxicological and reproductive effects of varying doses of polyethylene microplastics (PE-MPs) in 120 male and female Sprague Dawley rats. A statistically significant, dose-dependent increase in malondialdehyde levels was observed, along with a reduction in catalase activity. Furthermore, alterations were detected in sexual hormone levels and disruptions were noted in both the Kelch-like ECH-associated protein 1 (Keap1)-Nrf2-ARE (antioxidant response element) and p38 MAPK-Nrf2 signaling pathways. PE-MP exposure also produced marked histopathological changes in the testes and ovaries. These findings indicate that reproductive toxicity from PE-MPs is associated with impairments in the Keap1-Nrf2-ARE and p38 MAPK-Nrf2 pathways. The results underscore the importance of limiting MP exposure to mitigate potential health hazards and provide new data on the potential mechanisms of toxicity of MPs.