Toxicology Research最新文献

The protective effects of sevoflurane (Sev) in cardiovascular disease have been well documented in studies. The investigation aimed to clarify the contribution of miR-1291 to the pathophysiological process of hypoxia-reoxygenation (H/R)-induced cardiomyocyte injury in the setting of Sev preconditioning. H/R cell models were constructed with AC16 cells and the cell models were pretreated with 1%, 1.5% and 2% concentrations of Sev. Quantitative reverse transcription polymerase chain reaction was performed to detect miR-1291 and NF2 expression in cells. Cell viability was assessed using the cell counting kit-8 assay. Apoptosis was evaluated via flow cytometry. Cellular cardiac troponin I (cTnI), lactate dehydrogenase (LDH), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels were detected by enzyme-linked immunosorbent assay. Dual luciferase reporter gene assay and RIP analysis were applied to validate the binding of miR-1291 to NF2. In the H/R cell model, miR-1291 was downregulated, and this was accompanied by reduced cell viability, increased apoptosis, and elevated levels of cTnI, LDH, IL-6 and TNF-α. In contrast, inhibition of miR-1291 expression impaired the protective effect of Sev on cardiomyocytes. NF2 was a downstream target gene of miR-1291, and miR-1291 negatively regulated the expression of NF2. Knockdown of NF2 expression alleviated the effects of miR-1291 inhibition on Sev-treated cells. Sev attenuates H/R-induced cardiomyocyte injury by regulating miR-1291/NF2 expression and inhibiting apoptosis and inflammatory responses. This study unveils a novel mechanism of Sev-mediated myocardial protection, offering theoretical support and potential therapeutic targets for myocardial injury prevention and treatment.

Perfluorooctanoic acid (PFOA) is a synthetic chemical belonging to per and poly-fluoroalkyl substances. It persists in the environment and accumulates in human bodies, leading to significant health concerns. Allium sativum (garlic) is acknowledged for its nutritional and anti-oxidative properties. Current research investigated the efficacy of A. sativum ethanolic extract against PFOA-induced cardiotoxicity. Fifty adult albino rats were grouped equally into five groups: control, vehicle, A. sativum (300 mg/kg), PFOA (25 mg/kg), and PFOA and A. sativum. Rats were daily gavaged with treatments for 8 weeks. Serum samples were used for measuring lactate dehydrogenase (LDH), total cholesterol, and triglycerides (TG) levels. Cardiac tissues were used for assessing oxidative stress biomarkers (heme oxygenase1 (HO1), catalase (CAT), superoxide dismutase (SOD), and malondialdehyde (MDA)), and nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB). Also, the gene expression for nuclear factor erythroid-derived 2-like 2 (Nrf2), Kelch-like ECH-associated protein1 (Keap1), and peroxisome proliferator-activated receptor α (PPAR α) was determined. Cardiac tissues had undergone histopathological and immunohistochemical examination for caspase-3. Results revealed that PFOA exposure decreased the anti-oxidant enzymes (HO1, CAT, SOD), and markedly elevated levels of both MDA and NF-κB. PFOA inhibited the Nrf2 pathway as presented by the downregulated Nrf2 and upregulated Keap1 genes. Additionally, PFOA disturbed lipid metabolism via PPAR α downregulation. These changes were supported by histopathological changes and increased caspase-3 immunoexpression. A combination of A. sativum extract with PFOA provided significant protection against the aforementioned changes. Results suggested that A. sativum is an effective natural product that can attenuate PFOA-induced cardiotoxicity.

Lipopolysaccharide (LPS; a bacterial endotoxin) treatment causes acute inflammatory conditions. Acute inflammation causes the brain to activate neurons in some brain nuclei known as circumventricular organs. The c-Fos immunoreaction could be used to assess this neural activity. The current study aimed to check the activated neurons in time and site effect during toxicity and inflammation induced by LPS. The c-Fos antibody immunofluorescence labeling was checked at one, three, and six hours after LPS intoxication. Moreover, a retrograde viral tracing approach was employed to verify the neuronal connections among certain brain nuclei that were activated. The results indicated the activation of several brain nuclei in the hippocampus, epithalamus, thalamus, hypothalamus, basal ganglia, midbrain, and medulla oblongata. The type of brain nuclei and the number of neurons that were activated in relation to the duration of acute inflammation were clearly different. Furthermore, this research demonstrated that these active brain nuclei were connected neuronally. Ultimately, acute inflammatory responses induced by LPS treatment activated dorsal raphe serotonergic neurons. Twenty-two brain nuclei were shown to be involved in the neuroinflammatory response via whole-brain mapping. One hour after LPS administration, neurons in the dorsomedial hypothalamic nucleus (DM), lateral septal nucleus (LS), and solitary tract nucleus (SOL) were significantly activated. However, the sensory circumventricular organs (CVOs) were activated three hours after LPS treatment. It was also demonstrated that dorsal raphe serotonergic neurons play a vital role in the body's reaction to acute inflammation. This study confirmed the involvement of dorsal raphe serotonergic neurons in response to acute inflammation and toxicity induced by LPS.

Tobacco production lasts about 10 months and various pesticides are used, including growth inhibitors, which flumetralin is the most used. This is an herbicide that acts as a synthetic and plant growth regulator. Therefore, this work aimed to evaluate the toxicity of the growth regulator flumetralin in RAW 264.7 and 3T3 cell lines. Cytotoxicity was assessed by MTT reduction and neutral red uptake assays after 24 h of incubation with flumetralin. Mitochondrial integrity, production of reactive species and cytokine profile were evaluated in both cell lines. Furthermore, NO production was evaluated in RAW 264.7 cells, while comet assay was evaluated in 3T3 cells. An increase in reactive species production was observed in both cell lines. In RAW 264.7 cells were observed an increase in mitochondrial membrane potential, while 3T3 cells presented a mitochondrial depolarization. At all tested concentrations, flumetralin increased TNF-α levels and decreased IL-10 levels in RAW 264.7, and increased TNF and IL-1ß in 3T3 cells. In addition, at all tested concentrations, flumetralin induced DNA damage in 3T3 cells. It was possible to observe the cytotoxic effect of flumetralin on the tested cell lines, as well as a possible generation of an inflammatory response and immune deregulation.

Curcumin is a well-known anticancer agent used for many malignancies; however, its low bioavailability and solubility limit its use in clinical applications. To enhance its efficacy, we synthesized a novel curcumin-benzoquinone analog, JWB1 (3), and evaluated its anticancer potential against triple-negative breast cancer (TNBC) in vitro. We designed JWB1 (3) and structurally identified it using NMR, FTIR, MS, and UV-Vis techniques. The MTT assay was used to evaluate JWB1 (3) cytotoxicity in the MDA-MB-231, MCF-7, and HUVEC cell lines. Flow cytometry was used to examine apoptotic activation and reactive oxygen species (ROS) levels. Global DNA methylation was measured using an ELISA kit. Docking studies and molecular dynamics simulations revealed potential JWB1 (3) interactions with double-stranded DNA (dsDNA). JWB1 (3) showed selective cytotoxicity towards MDA-MB-231 cells (IC₅₀: 2.94 μg/mL, SI: 23.5 in 24 h), with minimal effects on HUVECs. Treatment with 10 μg/mL JWB1 (3) increased global DNA methylation levels in MDA-MB-231 cells (from 0.87% to 1.92%) more than in MCF-7 cells. The apoptosis assay showed that JWB1 (3) significantly induced MDA-MB-231 cells in the early apoptosis phase (early apoptosis: 45.65% vs. 2.95% in the controls). Furthermore, post-treatment, cancer cells showed a notable decrease in ROS levels. Supported by 100 ns molecular dynamics simulation, molecular docking investigations also showed a stable 3D structure and intercalation of JWB1 (3) with DNA. These findings imply that JWB1 (3) has notable anticancer potential against TNBC by inducing apoptosis, epigenetic modification, and DNA interaction.

The accumulation of misfolded proteins inside the cells has been considered to be an important contributor to the development of cigarette smoke-mediated diseases. Since endocytosis plays a crucial role in protein trafficking and clearance, impaired endocytosis may contribute to cigarette smoke-mediated protein accumulation. Therefore, the current study investigated the effects of cigarette smoke extract (CSE) on the endocytosis process in the yeast Saccharomyces cerevisiae. The current study demonstrated that treatment of cells with CSE resulted in reduced uptake of the FM4-64 stain, indicating impaired endocytosis. Further analysis revealed that CSE treatment resulted in a defect in the recruitment of proteins involved in endocytosis. Also, aberrant actin filament morphology was found upon CSE treatment, which might interfere with vesicle budding from the membrane. Moreover, the current study showed that the PI(4,5)P2 level in the plasma membrane in CSE-treated cells is reduced due to the failed translocation of MSS4 kinase to the membrane. This reduced PI(4,5)P2 results in aberrant actin filament morphology. Thus, the current study demonstrates that CSE treatment causes endocytosis defects and provides insight into this defective process.

Tanshinone IIA (Tan IIA), a pleiotropic bioactive natural compound, has a general anti-tumor effect, as well as in bladder cancer. However, little is known about its mechanism. This work attempts to explore the mechanism of Tan IIA promoting cuproptosis in bladder cancer cells and the effective targets. Copper concentration and total m6A quantification were determined using test kits. Cell viability was tested by CCK-8. Gene expression was evaluated by western blot or qRT-PCR. The m6A methylation level of FDX1 was detected by methylated RNA immunoprecipitation. FDX1 3'UTR activity was evaluated by luciferase activity assay. YTHDC1 binding to FDX1 was detected by RNA immunoprecipitation assay. Inhibition of tumor growth by Tan IIA was verified using a mouse xenograft tumor model. Tan IIA inhibits cell viability and induces the expression of FDX1 and lip-DLAT, key regulators of cuproptosis, in bladder cancer cells. The copper chelator tetrathiomolybdate weakens the inhibiting effect of Tan IIA on cell viability; while Tan IIA enhances the inhibiting effect of elesclomol-Cu on cell viability. FDX1 knockdown reverses Tan IIA-induced cuproptosis. Tan IIA increases FDX1 m6A modification, which is reversed by S-adenosylhomocysteine, an inhibitor of METTL3/METTL14, and this event mediates Tan IIA-induced cuproptosis of bladder cancer cells. The effectiveness of SAH in Tan IIA promoting cuproptosis and antitumor utility is demonstrated in a xenograft tumor model. Tan IIA exerts an anti-bladder cancer effect by promoting the cuproptosis of tumor cells, and the possible mechanism is to promote the expression of FDX1 by METTL3/METTL14-mediated the increasing FDX1 m6A modification.

Bisphenol A (BPA), widely used in plastics and resins, has raised health concerns for its endocrine-disrupting effects. BPA analogues such as bisphenol S (BPS) and bisphenol F (BPF) emerged as alternatives but exhibit similar risks. Despite regulations on BPA in many countries, alternatives remain insufficiently controlled. Although the safety of BPS and BPF has not been sufficiently verified, these compounds have already been detected in various environmental sources and human urine, raising serious concerns. While bisphenols are expected to have various adverse effects, research remains limited. This study investigates the adverse effects of bisphenols mixture on rats from fetal stage to young adulthood by analyzing transcriptomes in multiple tissues-liver, kidney, thyroid gland, and reproductive organs-and by gender, to identify key genes affected by bisphenol exposure. Dams were orally administered test substances from gestational day 6 to lactation day 6, and F1 pups received the same substances at half the concentration from postnatal day 7 to day 63. Transcriptome analysis of the collected tissues identified core genes related to high-density lipoprotein metabolism and hormone secretion, providing insights into mechanisms through which BPA may disrupt hormonal balance. Furthermore, the study suggests that combined exposure to BPA, BPS, and BPF produces distinct effects compared to BPA alone, with pronounced impacts on the thyroid and reproductive organs, despite individual concentrations being below the no-observed-adverse-effect-level. These findings highlight the potential cumulative impact of endocrine disrupting chemicals in the body.

This study investigated the association between exposure to organophosphate flame retardants (OPFRs) and serum omega-3 fatty acid levels in the general U.S. population, using data from 1,350 adults in the 2011-2014 National Health and Nutrition Examination Survey (NHANES). OPFRs are widely used in consumer and industrial products, and emerging evidence has linked them to disruptions in lipid metabolism. In this study, urinary concentrations of five OPFR metabolites were analyzed in relation to serum levels of key omega-3 fatty acids, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and docosapentaenoic acid (DPA), with adjustment for potential confounders. We observed significant negative associations between higher levels of diphenyl phosphate (DPhP) and the concentrations of EPA, DHA, and DPA. Similarly, bis(1,3-dichloro-2-propyl) phosphate (BDCPP) was negatively associated with EPA, bis(1-chloro-2-propyl) phosphate (BCEP) with DHA, and dibutyl phosphate (DBUP) with alpha-linolenic acid and DPA. Participants in the highest quartiles of DPhP and BDCPP exposure showed 18.2 and 18.4% lower EPA levels compared to the lowest quartiles, respectively. DHA levels declined by 17.5% with increasing DPhP and by 9.4% with sum of OPFRs (ΣOPFRs). These findings suggest that environmental OPFR exposure may interfere with omega-3 fatty acid metabolism and highlight potential metabolic and cardiovascular risks associated with these widely used flame retardants. These results underscore the importance of continued environmental monitoring and research into the health effects of OPFRs, particularly as their global use and human exposure continue to rise.

Sucrose is a common ingredient in many foods. However, intake of High-Sucrose Diet (HSD) for a longer duration can fuel metabolic and physiological issues. Hence, continuous efforts implying animal models are essential to mitigate the adverse impacts of HSD on health. Rutin is a bioactive compound with greater biocompatibility and health-promoting effects. Nonetheless, studies investigating the protective efficacy of rutin against HSD-induced health hazards are scarce. Hence, the present work aims to explore the ameliorative potential of rutin against the HSD-mediated hazards in Drosophila melanogaster. First instar larvae of D. melanogaster were orally exposed to control, HSD (30%-sucrose), and rutin-supplemented foods. D. melanogaster exposed to HSD for prolonged periods exhibited reduced survivability, physical fitness, and growth, while rutin co-supplementation significantly mitigated these effects. Rutin co-treatment also normalized HSD-induced eye morphology defects and light insensitivity, alleviated oxidative stress, and normalized sub-cellular endogenous antioxidants. Moreover, rutin supplementation improved cell survivability in visceral organs, reduced protein and lipid oxidation as evidenced by down-regulated protein carbonyl and MDA contents, and boosted CYP4501A1 and GST functions. Thus, co-administration of rutin, mainly at 150, 200, and 250 μM concentrations, effectively mitigated HSD-induced oxidative stress and associated organismal and sub-organismal level adverse outcomes in D. melanogaster, suggesting a protective dietary intervention of rutin against HSD-induced organismal and sub-organismal-level health hazards. Moreover, rutin can be considered as a promising bioactive compound in diets for artificial insect rearing in a controlled environment.