Toxicology Mechanisms and Methods最新文献

Nanoplastics (NPs) are emerging as environmental pollutants with the capacity to penetrate biological barriers, distribute systemically, and cause toxicity to multiple organs. Although early studies have primarily focused on localized organ damage, growing evidence suggests that NPs exert broader biological effects by disrupting interorgan communication through established physiological axes. In this review, we examined NP-induced toxicity through seven critical organ-organ pathways, including the gut-liver, gut-brain, gut-endocrine, liver-kidney, hypothalamus-pituitary-gonadal (HPG), hypothalamus-pituitary-adrenal (HPA), and placenta-fetus. NPs initiate damage at primary exposure sites, such as the intestinal epithelium or hypothalamic neurons, which propagates to secondary organs through hormonal, immunologic, and metabolic signaling. Shared histopathological features, including epithelial or parenchymal degeneration, inflammatory infiltration, and fibrotic remodeling, are consistently observed across axis-linked tissues. Moreover, bidirectional feedback mechanisms within these axes amplify NP-induced dysfunction and promote system-wide pathology. The ability of NPs to cross the placental barrier, accumulate in fetal tissues, and disrupt organ development is of particular concern and suggesting a potential for transgenerational toxicity. Overall, this axis-based framework highlights NPs as systemic toxicants that compromise the integrity of interconnected biological systems. In addition to single-organ perspectives, this review proposes an integrative model for understanding the complex and often indirect effects of chronic NP exposure on organismal health.

Glioblastoma cells exhibit a pronounced dependence on glutamine uptake, primarily via the alanine‑serine‑cysteine transporter 2, since its deletion prevents glioma growth, making this transporter an attractive therapeutic target. This study aimed to evaluate 6‑pentadecyl salicylic acid, a natural antineoplastic and immunomodulatory compound, for its ability to impair alanine‑serine‑cysteine transporter 2‑mediated glutamine transport and by these means reduce glioblastoma cells viability. Human U373MG glioma cells and primary chick cerebellar Bergmann glia (non‑malignant control) were exposed to increasing concentrations of 6SA for 24 h. Viability, measured by the MTT assay, declined in a dose‑dependent manner in U373MG cells while Bergmann glia remained largely unaffected (p < 0.001). L-[³H]-glutamine uptake assays revealed that 100 µM 6SA functioned as a potent inhibitor, increasing the Michaelis constant (K_M) more than four-fold (from 7.11 mM to 31.79 mM). This indicates a mixed-type or competitive inhibition mechanism that dramatically reduces the transporter's apparent affinity for glutamine and prevents saturation within the tested substrate range. Additionally, quantitative PCR showed a dose‑dependent down‑regulation of ASCT2 mRNA, suggesting post‑transcriptional control. Blind docking of 6SA onto the cryo‑EM ASCT2 structure identified nine peripheral cavities that could serve as allosteric sites, however, these predictions are computational and require experimental validation; binding to these sites would stabilize a low‑affinity transporter conformation, consistent with the kinetic data. Collectively, 6‑pentadecyl salicylic acid selectively impairs glutamine transport and viability in glioblastoma cells while sparing normal glial cells, supporting its potential as a lead compound for alanine‑serine‑cysteine transporter 2 ‑targeted glioma therapy.

Drug abuse screening is a public health and legal priority in the United Arab Emirates (UAE), where rapid and accurate detection is critical in workplaces, healthcare, and forensic settings. This study evaluates the diagnostic performance of the ACCU-TELL^® Multi 7 Drug Panel Cup Test (Urine) as a rapid screening tool for detecting seven commonly abused substances. A total of 228 urine samples from diverse clinical and occupational contexts were analyzed using the ACCU-TELL^® test and compared with the Atellica^® Immunoassay System. The test demonstrated high sensitivity (92.5%), specificity (92.6%), and an overall accuracy of 92.1%. The area under the ROC curve (AUC) was 0.926, confirming excellent diagnostic performance. The ACCU-TELL^® Cup Test offers practical advantages such as affordability, ease of use, and immediate results, making it suitable for high-throughput screening where timely decisions are essential. Its application is particularly relevant in the UAE, where drug violations carry significant legal consequences and early detection aids both preventive and rehabilitative interventions. These findings support the ACCU-TELL^® test as a reliable alternative to conventional lab-based methods for preliminary drug abuse screening in resource-limited or time-sensitive environments.

Constipation and gastrointestinal (GI) dysmotility are prevalent disorders often associated with impaired gut-brain axis regulation and limited therapeutic options. This study investigated the safety and gastrokinetic efficacy of CL18100F4 (Digexin^®), a standardized polyherbal formulation comprising extracts of Withania somnifera (Ashwagandha) root and Abelmoschus esculentus (Okra) pods. Ex vivo assays using isolated rat ileum demonstrated that CL18100F4 significantly enhanced intestinal contractility in a dose-dependent manner, with muscarinic receptor involvement confirmed by atropine inhibition. In vivo administration of CL18100F4 (200- and 300 mg/kg body weight for eight days) to Wistar rats showed significant improvements in gastric emptying (73.97 ± 15.12%, p = 0.0410), intestinal transit (80.43 ± 4.76%, p = 0.0184), and fecal moisture content (57.42 ± 5.05%, p = 0.0101), without affecting fecal pellet count. Serum corticosterone levels were significantly reduced, while serotonin levels increased, suggesting modulation of the gut-brain axis. No adverse alterations were observed in liver, kidney, or metabolic biochemical parameters, indicating systemic safety. Collectively, these findings demonstrate that CL18100F4 exerts synergistic gastrokinetic and neuroendocrine regulatory effects while maintaining a good safety profile. The formulation shows promise as a functional food or nutraceutical for managing GI motility disorders by modulating the gut-brain axis-associated biomarkers.

Mercury (Hg) remains a prominent global contaminant despite regulatory interventions such as the Minamata Convention. Inorganic mercury (Hg²⁺), particularly mercuric chloride (HgCl₂), persists in aquatic ecosystems and poses significant risks to both environmental and human health. While its neurotoxicity is well recognized, the systemic interplay between brain and liver responses under sub-lethal exposure remains poorly understood. Here, we exposed zebrafish (Danio rerio) to an environmentally relevant concentration of HgCl₂ (0.04 ppm) for 15 days to examine behavioural, neurochemical, molecular, and hepatic alterations. Mercury exposure induced pronounced anxiety-like behavior and delayed social recognition, accompanied by decreased locomotor activity. These behavioural deficits are supported with depletion of dopamine, serotonin, and acetylcholinesterase activity, implicating disrupted monoaminergic and cholinergic signaling. Molecular profiling revealed downregulation of aldh1l1 and ugt8, indicating glial dysfunction, and upregulation of il6, consistent with neuroinflammation. In the liver, mercury triggered a shift toward apoptosis (bax/bcl2 ratio increase), inflammation (il6 elevation), and loss of junctional integrity (cldn7a downregulation). Biochemically, exposure to HgCl₂ elevated serum SGPT levels, enhanced lipid peroxidation, and caused dyslipidaemia characterized by reduced HDL, triglyceride, and cholesterol levels. Immunohistochemistry confirmed strong hepatic Hsp90 overexpression, marking oxidative and proteotoxic stress, while histological analysis revealed steatosis, parenchymal disorganization, and nuclear pyknosis. Together, these findings establish that even low-level inorganic mercury exposure perturbs both central and peripheral systems through convergent oxidative and inflammatory mechanisms. Our study highlights mercury as a systemic toxicant disrupting the liver-brain axis and underscores the importance of integrating multi-organ endpoints in environmental risk assessment of heavy metals.

Methotrexate (METX) is a widely used chemotherapeutic and immunosuppressive agent, frequently employed as a first-line treatment for various malignancies and autoimmune disorders. Despite its clinical efficacy, METX is known to induce cardiotoxicity primarily through mechanisms involving oxidative stress, inflammation, and apoptosis. Apigenin (API), a natural dietary flavonoid, exhibits potent antioxidant and anti-inflammatory properties. The current study evaluated the protective effects of API against METX-induced cardiotoxicity in mice, focusing on the modulation of transforming growth factor-β (TGF-β)/(SMAD2) signaling. Molecular docking was done to investigate the possible inhibition of TGF-β by API and bioinformatic tools were utilized to investigate the correlation between the target proteins. Male Swiss albino mice were randomly distributed to four groups: Group I: a saline group, Group II: a METX control group (20 mg/kg, per week), Group III: METX + API (40 mg/kg, per day) and Group IV: METX + API (80 mg/kg, per day, via oral gavage); the study continued for three weeks. Our findings suggest that API administration significantly mitigated METX cardiotoxicity and serum CK-MB, likely through attenuation of the inflammatory cytokines (NF-κB, IL-1β, TNF-α, and IL-6) and suppression of cardiac TGF-β/SMAD2 signaling. The congruence between bioinformatics and experimental validation findings strongly highlighted API as a promising therapeutic candidate for alleviating METX cardiotoxicity. While the current data reveals key underlying molecular mechanisms for API's cardioprotective effect, further comprehensive studies across diverse cardiotoxicity models are essential to fully elucidate cardioprotective effect of API.

The hepatotoxicity of zinc oxide nanoparticles(ZnO NPs) is of great concern. Connexin32 (Cx32), as a crucial mediator for various kinds of liver injuries, has little investigation on ZnO NPs-induced hepatotoxicity. In the present study, small interfering RNA were performed to specific knockdown of Cx32 in BRL-3A rat liver cells and AML12 mouse liver cells. The observation indicated that the hepatocyte survivals were improved when Cx32 suppressed. The blockage of ROS transmission between neighboring cells as well as attenuated oxidative stress might be responsible for the protection of Cx32 deficiency on hepatocytes. Furthermore, ROS-related signal proteins, such as JNK, Nrf2/HO-1 and Gli1, were found to be downregulated in the absence of Cx32. These findings indicated that Cx32 knockdown could decrease ZnO NPs-induced hepatotoxicity by weakening oxidative stress, where JNK, Nrf2 and hedgehog signaling pathways might be involved.

Pesticides are metabolized in mammals by phase-I reactions (through cytochrome P450) and phase-II reactions. The parent molecule or its metabolites produced during phase-I reactions can be toxic, which are detoxified by phase-II reactions. However, superoxide anions and hydrogen peroxide generated by Cytochrome P450 during pesticide metabolism, and superoxide anions generated from mitochondrial-ETC enhance the toxicity by causing redox imbalance and oxidative stress. Much of the research conducted on pesticide toxicity has measured lipid oxidation in terms of TBARS or other indirect measures of oxidative stress, while increasing the chances of overestimating ROS-mediated damage. The current study employed relatively sensitive and accurate method to specifically evaluate lipid peroxidation in plasma and tissues by using HPLC-based detection of MDA. The data in this study compare MDA and nitric oxide levels in plasma, liver, and kidneys of Wistar rats treated with different classes of pesticides including imidacloprid (neonicotinoid), cypermethrin (pyrethroid), or chlorpyrifos (organophosphate) at equivalent dose (0.1 LD₅₀). The lipid peroxidation augmented in rats treated with different classes of pesticides at equivalent dose of 0.1 LD₅₀, with chlorpyrifos causing the maximum lipid oxidation and tissue damage. Pesticide treatments drastically elevated plasma NO levels by more than double. Chlorpyrifos treatment augmented liver NO levels by more than double. The magnitude of histoarchitectural changes in liver and kidneys correlates with the extent of lipid peroxidation, oxidative and nitrative stress induced by imidacloprid, cypermethrin or chlorpyrifos. Conclusively and comparatively, maximum adverse effects were imposed by chlorpyrifos, followed by imidacloprid and cypermethrin.

Exposure to ionizing radiation during medical diagnostics and cancer therapy often results in collateral damage to healthy cells, primarily due to the generation of free radicals. Moringa oleifera (MO), known for its rich antioxidant profile, may offer protective effects against such damage. This study investigates the radioprotective potential of MO leaf extract against DNA damage induced by bleomycin and X-irradiation. The antioxidant capacity of the extract was evaluated using DPPH radical scavenging assays, which revealed a dose-dependent increase in free radical inhibition, from 21.51% at 0.2 mg/mL to 51.07% at 1 mg/mL. UV-Vis spectral analysis showed strong absorbance around 370 nm, indicating the presence of flavonoid compounds. HPLC profiling further confirmed the phytochemical composition, with prominent peaks corresponding to kaempferol and related flavonoids, indicating their substantial abundance in the extract. In vitro experiments using human peripheral blood lymphocytes treated with MO demonstrated a significant (p < 0.0001) reduction in chromosomal aberrations and DNA strand breaks following exposure to bleomycin (40 µg/mL) and X-irradiation (2 Gy). Furthermore, molecular docking and 200 ns molecular dynamics simulations revealed that kaempferol, a major MO constituent, exhibited strong binding affinity with the Keap1-Nrf2 complex, suggesting activation of antioxidant gene expression. Overall, the findings support MO's role as a natural, low-toxicity radioprotective agent and highlight the complementary value of computational approaches alongside cytogenetic assays in validating therapeutic potential.

This article presents a new, more efficient and accurate method for assessing fire and toxic smoke losses to structures, the risks associated with such, and the scope necessary to restore an affected property to its pre-fire loss condition. While the commonly utilized field practice of handling fires, using the S700 as a guide, has been to focus on visible damage and particulate accumulations, to test for the presence of soot, char, and ash (sometimes referred to as fire residue), and to attempt remediation and cleaning of the property. The method proposed herein is to test for microscopic particulates commonly produced by fire, including heavy metals, dioxins, and furans, to determine if toxic levels of identified particulates are present. When toxic levels are present, standard airflow and waterflow dynamics, as well as secondary contamination circulate the toxic particles throughout the property rendering the property effectively totaled as a result of the impracticality of alternative handling methods.