Chemico-biological interactions最新文献

Perfluorooctane sulfonate (PFOS) is a persistent and bioaccumulative member of the per- and polyfluoroalkyl substances (PFAS) family widely used in various industrial applications and consumer products. In this study we present a comprehensive analysis of the effects of PFOS exposure on zebrafish embryos with respect to possible role of the organic anion transporting polypeptide 1d1 (Oatp1d1) membrane transporter, focusing on the differential responses between wild-type (WT) and Oatp1d1 mutant embryos. Significant differences in mortality rates were observed, with LC₅₀ values of 23.57 μM for WT and 16.71 μM for oatp1d1 mutants, indicating a higher susceptibility of the mutants to PFOS toxicity. Developmental abnormalities, particularly in the swim bladder, were more pronounced in mutant embryos. In addition, gene expression analysis showed changes in expression of genes involved in biotransformation processes, including members of the cytochrome P450 and glutathione S-transferase families. In summary, results of this study emphasize the complexity of PFOS-induced developmental toxicity mechanisms, implying important protective role of the Oatp1d1 transporter possibly related to detoxification processes or regulation of bioavailability. The findings improve our understanding of the toxicokinetic and toxicodynamic mechanisms of PFOS, emphasizing potential need for additional regulatory measures to address PFOS contamination and protect both aquatic life and human populations.

Cyflumetofen is a highly effective acaricide, and both it and its metabolites are often present in the environment as pollutants. Therefore, the safety of cyflumetofen for non-target organisms requires further attention. This study used zebrafish larvae to evaluate the effects of cyflumetofen on liver development. After 72-hour exposure, cyflumetofen specifically manifested as significantly reduced liver area and histological damage (cellular vacuolization, nuclear loss) in the 2.0 and 4.0 μg/mL exposure groups. Concurrently, Oil Red O, Nile Red, and BODIPY 493/503 staining all showed that cyflumetofen induced hepatic and systemic lipid accumulation, accompanied by increased levels of TG, CH, FC, and LDL-C, and decreased HDL-C levels. qPCR analysis further revealed the molecular mechanism by which it disrupts lipid metabolism: promoting the expression of fatty acid synthesis genes (srebp-1c, fas) and inhibiting the expression of catabolism genes (cpt-1a, pparα) and lipid transport (fabp2). These integrated results demonstrate that cyflumetofen can cause abnormal liver development and induce systemic lipid metabolism disorder in zebrafish larvae.

Methylglyoxal (MG) is a precursor of advanced glycation end-products produced during glycolysis. MG accumulation is linked to various pathophysiological conditions through the production of reactive oxygen species (ROS). This investigation uncovers the mechanism of MG-induced hepatotoxicity in vitro and in vivo. We assessed MG's dose- and time-dependent cytotoxicity (0.001-10 μM) in HepG2 cells using the cell viability assay. We examined the protective effects of N-acetylcysteine (NAC) against MG toxicity using MTT reagent, monitoring ROS generation, apoptosis (via flow cytometry), and mitochondrial membrane potential (with JC1 dye staining). For the in vivo study, BALB/c mice received MG (290 mg/kg and 400 mg/kg) at 6 h and 14 h intervals to induce hepatotoxicity. We conducted liver histopathology and protein expression analysis for apoptotic markers (Bax, Bcl-2, and caspase-3) and gluconeogenesis regulators (SIRT1, PGC1α, and glucose 6-phosphatase or G6Pase) in both cell lines and liver tissues. MG caused significant dose- and time-dependent toxicity in HepG2 cells by promoting cell death, increasing ROS and apoptosis, and altering the mitochondrial membrane potential at 5 μM. NAC (5 and 10 mM) protected against MG-induced toxicity. In mice, MG led to elevated spleen and liver weight, aspartate transferase (AST), alanine transaminase (ALT), glucose, malondialdehyde, and decreased superoxide dismutase levels. MG upregulated pro-apoptotic and gluconeogenic proteins in HepG2 cells, while NAC significantly reduced their levels. MG also increased the expression of proteins involved in apoptosis and gluconeogenesis. MG-induced caspase-dependent hepatotoxicity was mediated by the production of ROS and the activation of gluconeogenesis via SIRT1-dependent PGC1α activation.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a prevalent environmental pollutant, has been associated with an increased risk of Parkinson's disease (PD), yet the underlying molecular mechanisms remain poorly understood. To systematically elucidate these mechanisms, we employed an integrated computational and experimental approach. Network toxicology and molecular docking initially identified endothelial PAS domain protein 1 (EPAS1) as a high-priority target of TDCPP, exhibiting the strongest predicted binding affinity (-8.3 kcal/mol). This prediction was rigorously validated through in vivo experiments. Subchronic exposure of C57BL/6J mice to TDCPP (0, 0.03 0.3, 3, 30, and 300 mg/kg/day for 30 days) induced dose-dependent motor deficits, including reduced locomotor activity, impaired coordination in the pole test, and anxiety-like behavior. Pathological analysis revealed a substantial loss of tyrosine hydroxylase-positive (TH⁺) dopaminergic neurons in the substantia nigra (nearly 50% in the high-dose group) and a significant decrease in TH protein levels. Crucially, TDCPP exposure consistently upregulated EPAS1 protein expression in the midbrain. Finally, 100-ns molecular dynamics simulations confirmed the stability of the TDCPP-EPAS1 complex, demonstrating a rigid binding pocket and identifying Cys339 as a key interacting residue (96% contact fraction). Our study demonstrates that TDCPP promotes PD-like motor dysfunction and dopaminergic neurodegeneration, likely through a mechanism involving the direct targeting and upregulation of EPAS1 within the neurovascular unit. These findings provide novel, multi-layered evidence linking this common environmental contaminant to PD pathogenesis.

In this paper we have made efforts to compile and critically review the existing scientific evidence on the efficacy of combined oxime treatment as potential alternative or interim solution in organophosphate poisonings in the absence of universal single oxime. Literature review identified binary combinations of oximes that included apart from standard four (pralidoxime, trimedoxime, obidoxime and asoxime) also promising experimental oximes (K203 and phenoxyalkyl pyridinium oximes). Their effectiveness was confronted to nerve agents, and some organophosphate insecticides. Although few in vitro studies were found, the most studies were done in vivo on intoxicated mice, rats or guinea pigs. Some beneficial effects of combined oxime treatment were found for particular organophosphate poisonings. However, the majority of studies are incomparable due to interspecies differences or differences in the experimental setups. The need for appropriate oxime dosing was found via extrapolation of animal doses to human relevant doses. Thus, the further and rational approach is need to confirm or disprove advantages of the combined oxime treatment for organophosphate poisoning.

Background & aims: Artesunate (Art), a semisynthetic derivative of Artemisinin isolated from the traditional Chinese medicinal plant Artemisia annua L., has recently emerged as a candidate agent for hepatocellular carcinoma (HCC) therapy. Although accumulating preclinical evidence suggests its potent antitumor efficacy against HCC, the precise molecular mechanisms underlying its therapeutic effects remain poorly characterized. This investigation employs a multimodal approach to delineate the pharmacodynamic mechanism of Art in HCC pathogenesis, while establishing a mechanistic foundation for developing targeted combination therapies against this malignancy.

Methods: In vitro metastatic potential was quantified through standardized wound-healing assays and Matrigel-based transwell invasion systems. Autophagic flux dynamics and ferroptosis biomarkers were systematically profiled using commercial assay kits coupled with live-cell confocal imaging and Western blot. Mechanistic interrogation employed RIP-seq analysis and dual-luciferase reporter systems with in situ mutation controls. In vivo therapeutic efficacy was validated using orthotopic HCC xenograft models in immunocompromised BALB/c nude mice.

Results: Art demonstrated antitumor efficacy, significantly attenuating HCC cell motility and suppressing orthotopic xenograft growth. Mechanistic profiling revealed Art-induced ferroptosis through autophagy, mediated by m⁶A-dependent post-transcriptional regulation. Specifically, Art enhanced WTAP-mediated deposition of m⁶A modifications at the RRACH motif of ATG5 mRNA, facilitating YTHDC2-dependent translation. This epitranscriptomic reprogramming increased ATG5 protein synthesis, triggering autophagy dependent ferritin degradation and subsequent ferroptosis.

Conclusion: Art emerges as a clinically potential HCC therapeutic that elicits its oncosuppressive activity through WTAP/YTHDC2-mediated m⁶A methylation of ATG5 transcripts, thereby causes ferroptosis of HCC mediated by autophagy.

Per- and polyfluoroalkyl substances (PFAS), including legacy compounds (PFOA, PFOS) and their alternatives (HFPO-DA, OBS), pose potential risks for hypertensive disorders of pregnancy (HDP). This study systematically evaluated their mechanisms using network toxicology and molecular docking. Toxicity predictions indicated that alternatives exhibit significant multi-organ toxicity risks comparable to legacy PFAS. Network analysis revealed that alternatives not only share core HDP-related targets (STAT3, CASP3) with legacy PFAS but also engage unique targets (e.g., MTOR, AKT1), indicating broader pathogenic networks. Molecular docking demonstrated strong binding affinities, with OBS showing higher affinity for STAT3 and CASP3 than PFOS. Pathway enrichment analysis further implicated disruptions in placental development, immune inflammation, and vascular function. These findings suggest that PFAS alternatives do not present a superior safety profile and may introduce novel risks via distinct molecular pathways, underscoring the need for rigorous health risk assessments of these emerging contaminants.

Sepantronium bromide (YM155) emerged as one of the earliest small molecules designed to selectively suppress survivin (BIRC5), a key regulator of apoptosis and cell-cycle progression in cancer. Over the past two decades, YM155 has provided a unique translational framework to investigate the molecular crosstalk between survivin, cellular stress responses, and therapy resistance that shape cell-death outcomes. This mini-review integrates preclinical and clinical data to delineate how YM155 modulates transcriptional networks, mitochondrial integrity, DNA damage signaling, and autophagy. Particular attention is given to adaptive redox and metabolic programs that limit its efficacy in solid and hematological tumors. The article also revisits the outcomes of early clinical trials, highlighting both the safety profile and the challenges that hindered durable patient responses. Beyond oncology, emerging findings have repositioned YM155 as a probe to interrogate survivin-regulated processes in vascular and immune pathologies. By bridging molecular and clinical evidence, this review contextualizes YM155 within the broader landscape of targeted small molecules, emphasizing its value as a model for developing next-generation survivin modulators and precision-based therapeutic strategies.

Diisocyanates are intermediates required for the production of polyurethane, a foam and coating material with widespread use across many industries. Knowledge regarding the potential health hazards associated with exposure to the two most widely used diisocyanates, 4,4'-Methylene diphenyl diisocyanate (MDI) and toluene diisocyanate (TDI), has evolved since their popularization in the early 20th century. Both compounds have been used in industry for polyurethane manufacturing for many decades. As new studies have been published, it has been shown that MDI has a similar toxicological profile to TDI. This review provides an overview of the general body of literature on the potential health hazards resulting from exposure to diisocyanates, including MDI and TDI, in the occupational environment. This review provides an understanding of what was known, by decade, about the animal and human health effects identified through laboratory and epidemiological studies, and action taken by regulatory agencies to protect workers' health as knowledge on their sensitizing effects evolved over time. The findings of this historical review indicate that the incidence of adverse health effects resulting from diisocyanate exposure has been declining since the 1950s; improved industrial controls and increased efforts by regulatory agencies and stakeholders to protect worker health are responsible for the decline.

Abnormal activity level of human butyrylcholinesterase (BChE) was detected in patients with cardiovascular disease and neurodegenerative disorders, however, the specific role of BChE in the pathology of these diseases are not known yet. Homocysteine thiolactone (HTL) is a toxic thioester metabolite of homocysteine in conditions of hyperhomocysteinemia (HHcy). Experimental evidences suggest that HTL and resultant N-Hcy proteins that disrupt normal protein function, are associated with the pathology of HHcy-related complications such as cardiovascular diseases. Given the abundance of BChE in the blood and its esterase capacity, it is worthy to investigate the hydrolytic ability of BChE and its genetic polymorphism effects towards the endogenous toxic HTL in order to delineate its function in the complex disease network. In this study, human BChE and acetylcholinesterase were examined for their ability in HTL hydrolysis, and BChE demonstrates higher catalytic efficiency than reported serum paraoxonase 1. Furthermore, the catalytic mechanism uncovered by Quantum mechanics/Molecular mechanics molecular dynamics method helps to understand and substantiate the function of BChE in HTL metabolism. Six frequent BChE nonsynonymous coding single nucleotide polymorphisms (SNPs) variants were recombinantly produced and their catalytic activity was assessed. Differential catalytic efficiency toward HTL was observed among these variants, suggesting their distinct metabolic capability in vivo. These findings highlight the potential protection role of BChE against HTL-induced toxicity, and pave a way for future investigation into BChE's contribution in HTL metabolism and the possible correlation between specific BChE SNPs and susceptibility for developing HTL-associated diseases.