Cigarette smoke is a complex mixture that affects toxicological and pharmacological mechanisms in multiple organs, including liver, intestine, and lung. Therefore, an integrated multi-omics approach was applied to characterize cigarette smoke extract (CSE)-induced effects across human in vitro models of liver, intestine and lung. Primary human hepatocytes, biopsy-derived intestinal organoids, alveolar A549 cells, primary bronchial and small airway epithelial cells were exposed to CSE and analyzed using RNA sequencing and untargeted proteomics. Across tissues and omics-layers, activation of aryl hydrocarbon receptor (AHR) signaling and strong induction of CYP1A1 and CYP1B1 was identified as cross-tissue response. CYP1A1 was the only overlapping molecule among deregulated proteins across all in vitro models. Consistent deregulation of G protein-coupled receptor-signaling was observed. Overall, tissue-specific adaptations were identified. Liver models showed upregulation of xenobiotic and metabolic pathways, intestine models displayed downregulation of cell cycle processes consistent with growth arrest. Lung models should be considered cautiously because of heterogeneity between cell models but demonstrated a shared response of CYP1A1 and CYP1B1 deregulation. Cross-omics comparisons of RNA sequencing and proteomics data revealed moderate correlations (ρ = 0.43-0.64) and limited overlap of individual molecules, highlighting the importance of post-transcriptional regulation. Network and upstream regulator analyses predicted a coordinated stress response accompanied by modulation of inflammatory signaling. These findings demonstrate that cigarette smoke induces shared pathway-level responses, alongside tissue-specific adaptations. This underscores the importance of considering multiple organ systems in toxicological and pharmacological assessments. This comprehensive dataset provides a resource that may support further hypothesis-driven analysis of cigarette smoke-related mechanisms.

Tributyl phosphate (TBP), a widely used organophosphate ester, exhibits lipophilic characteristics that enable it to cross the blood-brain barrier. Although its neurotoxicity has been confirmed, the underlying molecular pathways remain unclear. This study examined whether TLR4-associated autophagy disruption contributes to TBP-induced neuronal damage. Autophagy was activated with rapamycin (RAPA) and TLR4 was knocked down using siRNA. TBP exposure upregulated TLR4 expression and downregulated autophagy-related markers. Autophagic flux analysis assays using bafilomycin A1 further revealed that TBP impaired autophagosome biogenesis instead of lysosomal dysfunction. Autophagy activation and TLR4 knockdown each partially attenuated TBP-induced oxidative stress, inflammation, and alterations in neuroinjury markers. Moreover, inhibiting TLR4 partially reversed the decrease in autophagy levels caused by TBP. Molecular docking predicted TBP may bind to the TLR4 extracellular domain, providing a testable framework for future validation. These findings identify TLR4-regulated autophagy suppression as a candidate mechanism for TBP neurotoxicity.

Macrolide antibiotics (MLAs) are widely utilized in both human and veterinary medicine. Their extensive use has led to ubiquitous contamination in aquatic environments, posing significant risks to public health and ecosystems. Despite their prevalence, comprehensive analyses of their environmental fate, diverse exposure pathways, and potential molecular toxicological mechanisms remain insufficient. This study systematically reviewed MLAs in global drinking water sources from 2005 to 2025 and their potential impacts on health. Using VOSviewer for bibliometric analysis, key research clusters focusing on ecological risks, antimicrobial resistance development, and health outcomes were identified. MLAs are frequently detected in surface and groundwater, with concentrations exceeding 1000 ng/L in specific regions, primarily influenced by seasonal variations and regional industrial activities. Additionally, we assessed how MLAs through the food chain into human dietary sources such as seafood and dairy products. Clinically, MLAs exposure correlates with a range of adverse health outcomes including cardiotoxicity (QT interval prolongation), hearing loss, obesity, and developmental defects. Five representative toxicity pathways were reviewed: mitochondrial dysfunction and impaired mitophagy/apoptosis, hERG potassium channel blockade, altered bile acid homeostasis, nicotinic acetylcholine receptor (nAChR) inhibition, and oxidative stress. The evidence supporting these pathways varies across individual macrolides, and their relevance to exposure through drinking water remains uncertain. By identifying existing research gaps, this review establishes a robust scientific foundation for risk assessment and calls for enhanced oversight to mitigate the environmental and health risks associated with MLAs.

Coumarin derivatives are structurally diverse benzopyrone-based compounds with broad relevance to medicinal chemistry, redox biology, mitochondrial pharmacology and photobiology. Their biological effects are highly context-dependent and are shaped by substitution pattern, concentration, metabolic activation, intracellular localization, metal coordination and light exposure. This review critically examines the chemico-biological mechanisms through which coumarin derivatives influence oxidative stress signaling, mitochondrial function and regulated cell death. Particular emphasis is placed on the distinction between chemical radical-scavenging activity observed in simplified assays and biologically relevant redox modulation in cells. Although hydroxy- and methoxycoumarins may display antioxidant capacity in chemical systems, their cellular effects are more plausibly mediated through redox-sensitive signaling pathways, including NRF2/KEAP1/ARE, NF-κB and MAPK, and through modulation of enzymatic antioxidant defenses rather than direct stoichiometric scavenging of oxidants in vivo. Conversely, selected synthetic hybrids, metal complexes, mitochondria-targeted derivatives and photoactivatable coumarins may promote ROS/RNS accumulation, nitric oxide-related signaling, calcium dysregulation, mitochondrial membrane depolarization, cytochrome c release, apoptosis, ferroptosis-associated lipid peroxidation, autophagy-associated responses and photodynamic cytotoxicity. We also discuss how tumor-cell heterogeneity, basal redox state, NRF2 activity, NF-κB dependence, metabolic context and antioxidant reserve may determine whether coumarin exposure results in cytoprotection, growth inhibition or cell death. Finally, we evaluate major translational and toxicological barriers, including metabolic liability, hepatotoxicity, phototoxicity, photogenotoxicity, limited in vivo validation, insufficient target-engagement data and mechanistic overinterpretation of ROS-related endpoints. A more critical chemico-biological framework is required to guide the rational development of coumarin-based therapeutic, phototherapeutic and theranostic candidates.

Cadmium (Cd) and lead (Pb) frequently co-occur in contaminated environments, yet the toxicological interaction between them remains unclear. Here, we established a rat model of combined Cd and Pb exposure and used FTIR, synchrotron XAFS, and DFT calculations to examine the coordination mechanism underlying Pb-mediated modulation of Cd hepatotoxicity. Pb co-exposure significantly attenuated Cd-induced liver injury, as shown by reduced serum ALT, ALP, and GGT levels and alleviated histopathological damage. Spectroscopic and computational analyses revealed that Pb alters the local coordination environment of Cd by competing for oxygen-containing ligands in GSH and bridging sulfur atoms in MT, thereby weakening Cd-S interactions and promoting Cd redistribution from LCF-derived free Cd[2+] fraction to GSH-/MT-bound forms. Pb co-exposure alleviates Cd-induced hepatotoxicity, and this effect is associated with changes in Cd coordination chemistry, underscoring the importance of metal speciation in assessing mixed-metal exposure risk.

Toluene diisocyanate (TDI) is a prevalent cause of occupational asthma. Although mitophagy contributes to various pulmonary diseases, its role and downstream signaling in TDI-induced asthma remain unclear. In this study, we first utilized BALB/c mice to investigate the effects of TDI exposure on pulmonary injury, mitophagy, and associated regulatory mechanisms. Based on these findings, we constructed an adverse outcome pathway (AOP) network for TDI-induced asthma. Mechanistic connections predicted by the AOP were validated in vitro using PINK1-knockdown bronchial epithelial cells, assessing PINK1-related mitophagy, mitochondrial function, cytosolic mtDNA release, attenuated the increased expression of cGAS/STING pathway-related proteins, and necroptosis. Finally, we predicted potential natural product therapeutics through bioactivity screening and toxicity profiling, targeting key genes implicated in TDI-induced asthma. Integration of in vivo, in vitro, and AOP network analyses indicated that TDI exposure induced airway hyperresponsiveness and pulmonary histopathological changes, along with elevated Th2 cytokine production. This exposure selectively upregulated PINK1 and Parkin expression, without altering levels of BNIP3, NIX, or FUNDC1. PINK1 knockdown mitigated TDI-induced mitophagy-related alterations, restored mitochondrial function, reduced cytosolic mtDNA release, attenuated the increased expression of cGAS/STING pathway-related proteins, and reduced necroptosis. In silico screening predicted β-lapachone, genistein, and apigenin as promising candidate therapeutics for TDI-induced asthma. Overall, PINK1-related mitophagy may contribute to TDI-induced occupational asthma, and natural compounds identified via in silico screening are potential candidates that require further in vitro and in vivo validation of their safety and efficacy.

Di-2-ethylhexyl phthalate (DEHP), as the most common member of phthalic acid esters (PAEs), is considered an endocrine-disrupting compound (EDC) and causes prominent developmental, reproductive toxicity, metabolic dysfunctions, and neurotoxicity. However, the potential neurotoxicity associated with chronic DEHP exposure at concentrations below the no-observed-adverse-effect level (NOAEL) in adult zebrafish remains poorly understood, largely due to a lack of experimental evidence from animal studies. Thus, to comprehensively characterize the potential neurological effects of DEHP, adult zebrafish were used as an animal model to evaluate neurotoxicity following 4 weeks of exposure to DEHP at concentrations within the NOAEL range (5, 50, and 200 mg/L). Behavioral assessments included the light-dark preference test, novel tank diving test, novel object exploration test, social interactions test, and conditioned place preference (CPP) test. After 4 weeks of chronic exposure to DEHP, zebrafish exhibited marked neurobehavioral alterations, including increased time spent and distance traveled in the dark zone and reduced exploratory behavior in unfamiliar environments (reduced exploration of the top zone in the novel tank and of the novel object zone); DEHP exposure also disrupted social interactions and impaired learning and memory in zebrafish. The LC-MS/MS results revealed that changes in neuro-behavioral profiles were closely associated with neurotransmitter levels in the brain of zebrafish. The present study provides a valuable reference for drawing attention to the assessment of DEHP neurotoxicity under the NOAEL.

Di(2-ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant that has been implicated in immune and inflammatory dysregulation, but its potential role in psoriasis-related skin inflammation remains unclear. In this study, we integrated bioinformatics, network toxicology, and machine-learning analyses to identify candidate genes associated with DEHP-exacerbated psoriasis-like inflammation, followed by experimental validation in in vivo and in vitro models. Public transcriptomic datasets were analyzed to screen differentially expressed genes and prioritize key candidates. S100A9 and FABP5 were identified as high-priority genes by machine learning and were further examined in an imiquimod (IMQ)-induced psoriasis-like mouse model and in DEHP-treated HaCaT keratinocytes. Our results showed that DEHP exposure exacerbated IMQ-induced psoriasiform skin inflammation in mice and was associated with increased expression of S100A9, FABP5, and IL-17A-related inflammatory markers in mouse skin. In HaCaT cells, DEHP treatment was also associated with increased S100A9/FABP5 expression under the tested conditions. These exploratory findings suggest that DEHP exposure may exacerbate psoriasis-like skin inflammation and is associated with increased keratinocyte S100A9/FABP5 expression and IL-17A-related signaling. Translation to human psoriasis remains uncertain. Further functional studies are needed to clarify the causal role and mechanistic significance of this pathway.

Polycyclic aromatic hydrocarbons (PAHs), as widespread environmental contaminants, exhibit neurotoxicity. Because PAHs often co-occur with dietary lipids in foods, those lipids might serve as vehicles that alter PAH biotransport and accumulation in the brain. In this work, we systematically investigated how three common dietary fatty acids-oleic acid, linoleic acid (LA), and linolenic acid-differently influence the transport steps (including cellular uptake, efflux, and clearance) of benzo[a]pyrene (BaP) and benzo[b]fluoranthene (BbF) across the blood-brain barrier, using a bEnd.3 cell-based model, and explored the potential underlying molecular mechanisms. Results revealed that dietary lipids, acting as carriers, significantly enhanced cellular uptake of PAHs, with LA increasing the uptake of BaP and BbF by 20.36% and 17.90%, respectively, and accelerated transmembrane transport dynamics. Simultaneously, distinct lipids differentially affected PAH clearance and efflux. Notably, LA delayed the clearance of PAHs, prolonging the elimination half-life of BaP from 10.117 h to 17.696 h and that of BbF from 7.418 h to 14.964 h, thereby increasing overall brain exposure. Mechanistically, LA was observed to upregulate the fatty acid transporter CD36, and functional inhibition studies suggested that P-glycoprotein and CD36 may jointly contribute to lipid-modulated effects. This study suggests that dietary lipids influence brain exposure to PAHs through a multi-level network, highlighting a factor that warrants consideration when assessing their neurotoxicity risks.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder worldwide. Accumulating evidence has linked environmental polycyclic aromatic hydrocarbons (PAHs), with benzo[a]pyrene (B[a]P) as a representative ubiquitous member, to elevated PD risk and disease pathogenesis. The present study aimed to investigate whether B[a]P can trigger typical PD-like lesions in mice, and further dissects the functional role of microglial senescence as well as its underlying regulatory mechanism, using complementary systems in vivo mouse model and in vitro BV2 microglia cell. Behavioral assessments revealed that B[a]P exposure induced significant, dose-dependent impairments in motor coordination and cognitive function compared with the control group. Moreover, the degree of functional impairments measured in the high-dose B[a]P group was comparable to that observed in the MPTP positive-control group. Following B[a]P treatment, brain-resident microglia cells exhibited signs of cell senescence, as evidenced by typical ultrastructural alterations, increased senescence-associated β-galactosidase (SA-β-gal) activity, and elevated expression of the core senescence markers p16, p21, and p53 proteins. Consistent with these in vivo observations, B[a]P was confirmed to also induce cell cycle arrest in cultured BV2 microglia cells. This pro-senescent effect was significnatly attenuated by Triggering receptor expressed on myeloid cells 2 (TREM2) overexpression, whereas it was markedly exacerbated following TREM2 knockout. Subsequent experiments further validated that insulin-like growth factor 1 (IGF-1), as a direct downstream effector regulated by TREM2, is functionally required for B[a]P-triggered microglial senescence. Collectively, these findings demonstrate that B[a]P exposure can induce PD-like lesions and microglial senescence, and which is primarily mediated via the TREM2/IGF-1 signaling axis.

Arsenite can impair pancreatic β-cell function, but the mechanisms linking mitochondrial metabolic disturbances to this toxicity remain incompletely understood. Therefore, mitophagy, which removes dysfunctional mitochondria by lysosomal degradation, has attracted much attention. Mitochondrial (cis)aconitase 2 (ACO2) is a critical enzyme in the tricarboxylic acid cycle responsible for coordinating mitochondrial functions and is involved in energy metabolism. However, the role of ACO2 in arsenite-induced mitochondrial dysfunction and altered mitophagy in pancreatic β cells remains unclear. In this study, we demonstrated that arsenic exposure leads to the downregulation of mitochondrial ACO2. As expected, ACO2 overexpression reversed the arsenic-induced MIN6 cells dysfunction. In addition, arsenic induced the inhibition of mitophagy in islets β-cells characteristic with the downregulation of PTEN-induced putative kinase 1 (PINK1) , Parkin RBR E3 ubiquitin protein ligase (Parkin) and sequestosome 1 (p62/SQSTM1), accompanied by an increased level of microtubule-associated protein 1 light chain 3-II (LC3-II). ACO2 reversed these alterations in protein expression. Simultaneously, ACO2 overexpression elevated adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP) levels, decreased mitochondrial reactive oxygen species (mtROS) production, and alleviated the functional impairment of β-cells induced by arsenic. Moreover, supplementation with α-ketoglutarate (α-KG), a downstream metabolite of ACO2, similarly mitigated arsenic-induced mitophagy inhibition and functional impairment of MIN6 cells. In conclusion, this study identified a novel mechanism by which inorganic arsenic can lead to pancreatic β cell dysfunction via the ACO2-αKG-mitophagy pathway. These findings advance the mechanistic understanding of arsenite-induced β-cell toxicity.

Euphorbia umbellata latex is used in Brazilian traditional medicine, including empirically for cancer treatment. However, its chemical composition, molecular targets, pharmacological properties, and biological effects in triple-negative breast cancer (TNBC) remain insufficiently characterized. This study investigated the TNBC-related biological activity and toxicity of E. umbellata crude latex by integrating computational analyses with experimental evaluation in a 4T1 cell model. Eighteen compounds previously identified in E. umbellata crude latex were curated from phytochemical studies and evaluated for predicted pharmacokinetic and toxicological properties. Compound-associated human targets were integrated with TNBC-related genes, followed by protein-protein interaction network construction, functional enrichment analysis, hub-gene identification, and molecular docking. The effects of crude latex on cell viability, post-treatment recovery, and wound closure were evaluated in 4T1 murine TNBC cells, while acute toxicity was assessed using the Artemia salina lethality assay. The latex-derived compounds exhibited heterogeneous ADMET profiles, with generally low predicted mutagenic, carcinogenic, and hepatotoxic potential. A total of 357 compound-associated targets were identified, of which 204 overlapped with TNBC-related genes. Enrichment analyses highlighted pathways associated with apoptosis, inflammatory responses, oxidative stress, and immune checkpoint regulation. Molecular docking indicated favorable predicted interactions with EGFR, AKT1, and PARP1, whereas PTGS2 showed a more restricted interaction profile. Experimentally, crude latex markedly reduced 4T1 cell viability, with an estimated IC50 interval of 2.15-2.76 mg/mL, and impaired wound closure during acute exposure. However, both effects were partially reversed after treatment removal. The latex also induced concentration-dependent lethality in A. salina, with an estimated LC50 of 3.25 mg/mL. Together, these findings indicate that E. umbellata latex represents a chemically diverse source of bioactive compounds capable of interacting with TNBC-associated molecular networks, while also showing biological activity in a 4T1 murine TNBC model. Nevertheless, the partial recovery of 4T1 cells after treatment removal and the toxicity observed in A. salina indicate that crude latex should not be considered directly suitable for therapeutic use and that further fractionation, chemical standardization, mechanistic validation, and safety studies are required.

Prostate cancer continues to be an important therapeutic challenge that demands the development of new apoptosis-inducing agents. In the present study, a series of N-(3-trifluoromethylphenyl)sulfonyl-indole-3-carbaldehyde thiosemicarbazone derivatives (5a-s) was synthesized and evaluated for their biological activity against the LNCaP prostate cancer cell line. Among the synthesized compounds, 5a and 5g showed strong antiproliferative activity and favorable selectivity toward non-malignant HEK293 cells, with IC50 values of 7.56 and 5.81 μM, respectively. Compound 5g increased the expression of TP53, CDKN1A, BBC3, and BAX, whereas compound 5a significantly reduced the expression of the anti-apoptotic BCL2 gene. Both compounds also modulated the expression of cancer- and DNA damage response-related genes, including c-MYC, KRAS, PTEN, ATM, and ATR. Molecular docking studies predicted favorable interactions of compound 5g with MDM2 (IFD score = -7.951 kcal/mol; ΔG_bind = -56.75 kcal/mol) and compound 5a with BCL-2 (IFD score = -8.636 kcal/mol; ΔG_bind = -59.55 kcal/mol). 500-nanosecond molecular dynamics simulations further supported the dynamic stability and persistence of the proposed ligand-protein interactions. ADME and DFT analyses further indicated favorable pharmacokinetic and electronic properties of the lead compounds. Overall, the integrated experimental and computational findings identify compounds 5a and 5g as promising lead candidates for further investigation as apoptosis-inducing agents against prostate cancer.

Ferroptosis is an iron-dependent, non-apoptotic form of programmed cell death closely associated with various diseases. It is characterized by intracellular lipid peroxidation (LPO) and glutathione depletion. The process of lipid peroxidation is regulated by reactive oxygen species (ROS) and reactive sulfur species (RSS). Detecting ROS and RSS species during ferroptosis is particularly crucial for related research. However, the continuous temporal monitoring of these substances during ferroptosis remains an area that has not received sufficient attention. In this study, we constructed fluorescent probes ISE and ISEO to detect HClO and HSO3[-] during ferroptosis. Probe ISE enables dual-channel detection of HClO and HSO3[-] in yellow and blue channels, respectively. Probe ISE exhibits response times of 3 s for HClO and 45 s for HSO3[-], with detection limits of 23 nM and 7 nM, respectively. Probe ISEO detects HSO3[-] through a change in the yellow-to-blue ratio. Probe ISEO has a response time of 80 s for HSO3[-], with a detection limit of 26 nM. Both the probe ISE and ISEO demonstrate excellent imaging performance for detecting exogenous and endogenous targets within cells. Furthermore, the robust performance of the probes ISE and ISEO during ferroptosis in cells and zebrafish makes them extremely valuable for ferroptosis research.