Toxicol. Appl. Pharmacol. [JOURNAL]
Sun
200 papers
Doxorubicin-induced apoptosis and mitochondrial fission are promoted by LncRNA TGFB2-AS1 through BMP7/Smad signaling.
Gao H, Lan K, Gong H
Toxicol Appl Pharmacol · 2026 Jun · PMID 42031322 · Publisher ↗
Doxorubicin-induced cardiotoxicity (DIC) features cardiomyocyte loss and maladaptive remodeling. Mitochondrial damage, oxidative stress, autophagy, and different types of cell death, including ferroptosis, pyroptosis, an...
Doxorubicin-induced cardiotoxicity (DIC) features cardiomyocyte loss and maladaptive remodeling. Mitochondrial damage, oxidative stress, autophagy, and different types of cell death, including ferroptosis, pyroptosis, and apoptosis, are recognized as the principal biological mechanisms contributing to DIC, in which disrupted mitochondrial dynamics play a pivotal role. The role of long noncoding RNAs (lncRNAs) in DIC is becoming more well understood; however, the function of TGFB2-AS1 remains unclear. Here, DIC was established in doxorubicin-treated male C57BL/6 mice and in doxorubicin-treated AC16/HL-1 cardiomyocytes. TGFB2-AS1 expression and subcellular localization were determined, and gain- and loss-of-function analyses were performed. Flow cytometry was used to quantify apoptosis and intracellular reactive oxygen species (ROS), and apoptosis-associated proteins and mitochondrial dynamics regulators were assessed by immunoblotting. Mitochondrial morphology was visualized using MitoTracker staining. Bone morphogenic protein 7 (BMP7) signaling was evaluated via recombinant BMP7 supplementation and BMP7 knockdown. Cardiac structure and injury were evaluated by echocardiography and histology. TGFB2-AS1 expression was markedly upregulated in DIC models, and TGFB2-AS1 overexpression exacerbated doxorubicin-induced hypertrophy, apoptosis, ROS accumulation, and mitochondrial fragmentation, whereas TGFB2-AS1 silencing partially reversed these effects. Mechanistically, TGFB2-AS1 knockdown restored BMP7/Smad1/5/9- inhibitor of DNA binding protein 2 (Id2) signaling, and BMP7 depletion attenuated the cardioprotective effects of TGFB2-AS1 silencing. Consistently, BMP7 supplementation mitigated cardiomyocyte apoptosis and Drp1-associated mitochondrial fission in vitro and improved doxorubicin-induced remodeling in vivo through the activation of BMP7/Smad signaling. Collectively, TGFB2-AS1 promotes DIC by suppressing BMP7/Smad/Id2 signaling and enhancing mitochondrial fission, positioning TGFB2-AS1 as a candidate intervention point.
Incorporating inter-individual variability to improve the reliability of predicted outcomes in in silico cardiac safety assessment.
Olivia Y, Park H, Ariyadi … +5 more , Qauli AI, Fuadah YN, Marcellinus A, Heikhmakhtiar AK, Lim KM
Toxicol Appl Pharmacol · 2026 Jun · PMID 42019890 · Publisher ↗
Preclinical assessment of torsades de pointes (TdP) risk increasingly relies on in silico electrophysiological models within the Comprehensive in vitro Proarrhythmia Assay (CiPA) framework. Most current implementations e...
Preclinical assessment of torsades de pointes (TdP) risk increasingly relies on in silico electrophysiological models within the Comprehensive in vitro Proarrhythmia Assay (CiPA) framework. Most current implementations evaluate drug effects under homogeneous assumptions and do not explicitly account for inter-individual variability in ionic conductances. We hypothesized that TdP risk classifiers trained without considering inter-individual variability would exhibit reduced generalization when evaluated on data incorporating variability, and aimed to verify the necessity of integrating variability during the training phase to mitigate this degradation. Drug-induced electrophysiological responses were simulated for 28 CiPA recommended drugs using the CiPAORdv1.0 human ventricular myocyte model with dynamic hERG parameters. Inter-individual variability was introduced by varying key ionic conductances within physiological ranges. Drug effects were quantified using the qNet biomarker, and TdP risk classification was performed using ordinal logistic regression. Predictive performance was evaluated under four scenario based training and testing strategies. Under homogeneous conditions, cumulative AUC values ranged from 0.90 to 0.95. When evaluated under heterogeneous electrophysiological conditions without incorporating variability during the training phase, discrimination declined substantially to 0.60-0.63. Incorporating inter-individual variability during training improved AUC values to 0.80-0.87, including when testing on previously unseen individuals. Discrimination under heterogeneous conditions remained lower than under homogeneous assumptions. These findings indicate that high accuracy under homogeneous assumptions does not necessarily ensure consistent performance across heterogeneous electrophysiological conditions. Incorporating inter-individual variability during model development improved the stability of risk classification across individuals, supporting a variability-aware approach to TdP risk assessment within the CiPA framework.
Translating in vitro mechanistic findings to in vivo toxicity outcomes: A case study of Usnic acid hepatotoxicity.
Liu Y, Chen S, Gao X … +4 more , Eckstrum K, Guo L, Campasino K, Headrick K
Toxicol Appl Pharmacol · 2026 Jul · PMID 42019889 · Publisher ↗
New Approach Methodologies (NAMs) utilizing cellular models provide mechanistic insight into chemical hazards, but their utility in human health risk assessment depends on demonstrating how effectively in vitro findings...
New Approach Methodologies (NAMs) utilizing cellular models provide mechanistic insight into chemical hazards, but their utility in human health risk assessment depends on demonstrating how effectively in vitro findings translate to real-world outcomes. Quantitative in-vitro-to-in-vivo extrapolation (QIVIVE), supported by physiologically based pharmacokinetic (PBPK) modeling, enables this translation by linking in vitro concentration-response data to in vivo dose-response relationships. Here, we evaluated QIVIVE performance using usnic acid as a model compound. Usnic acid was selected because in vitro data and clinical case reports are available, enabling direct assessment of translational accuracy. Bayesian Benchmark Doses (BBMDs) were derived from in vitro toxicity data spanning thirteen endpoints in three hepatic cell models. Freely dissolved concentrations were estimated using a mass balance distribution model and incorporated into QIVIVE to predict equivalent administered doses (EADs), the in vivo doses expected to reproduce observed in vitro effects. Three PBPK platforms (GastroPlus, Berkeley Madonna, and httk R package) were applied. Predicted EADs aligned with reported exposure levels associated with hepatotoxicity, supporting the translational relevance of QIVIVE. Results indicated activation of multiple hepatotoxicity pathways, including redox disturbance, stress response, and DNA damage, across 1-384 mg oral doses. At human relevant intake levels, these mechanisms may explain the progression to liver injury in consumers of usnic acid. This study demonstrates that QIVIVE has the potential to translate in vitro mechanisms into possible human health outcomes, offering more mechanistically informed evidence for safety assessments of botanical constituents.
Metabolomics and exploratory mendelian randomization identify indole-3-propionic acid associated with doxorubicin-induced testicular injury.
Duan J, Li X, Li F
Toxicol Appl Pharmacol · 2026 Jun · PMID 42013983 · Publisher ↗
Doxorubicin (DOX) exhibits severe side effects that restrict its clinical application. In the testes, DOX triggers apoptosis and excessive oxidative stress. Modulation of the metabolic microenvironment may contribute to...
Doxorubicin (DOX) exhibits severe side effects that restrict its clinical application. In the testes, DOX triggers apoptosis and excessive oxidative stress. Modulation of the metabolic microenvironment may contribute to the amelioration of testicular injury. However, the relationship between DOX and alterations in testicular metabolites remains elusive. In this study, the metabolic profiles of the testes and plasma were analyzed in mice with DOX-induced testicular injury. Mendelian randomization (MR) analysis was employed to prioritize candidate metabolites associated with the risk of male infertility in human cohorts. Furthermore, the roles of prioritized metabolites were validated in cells. A total of 76 metabolites in the testes and 48 metabolites in the plasma exhibited alterations, with 24 metabolites showing changes in both tissues. Although statistical significance was not maintained following FDR correction, the exploratory MR analysis prioritized indole-3-propionic acid (IPA) for its potential inverse association with male infertility. In TM4 cells, IPA attenuated DOX-induced reactive oxygen species accumulation and regulated the protein expression of the NRF2/HO-1 pathway. Collectively, these findings characterize the metabolic disturbances underlying DOX-induced testicular injury and highlight IPA as a candidate metabolite for further investigation.
Analysis of the effect of high doses of vitamin D on gene and protein expression in the intestine of pigs (Sus scrofa).
Oczkowicz M, Wierzbicka A, Świątkiewicz M … +3 more , Szmatoła T, Steg A, Smołucha G
Toxicol Appl Pharmacol · 2026 Jun · PMID 42013982 · Publisher ↗
Vitamin D is one of the most popular supplements worldwide, yet its appropriate dosage and full impact on health of humans and animals are still debatable. In this study, 30 pigs were divided into three groups, differing...
Vitamin D is one of the most popular supplements worldwide, yet its appropriate dosage and full impact on health of humans and animals are still debatable. In this study, 30 pigs were divided into three groups, differing in the amount of vitamin D in the diet (Group A - no supplementation, group B-5000 IU/Kg of vitamin D, and group C 10000 IU/Kg). After 3 months of fattening, animals were slaughtered, and samples of jejunum (the longest part of the small intestine in pigs) and colon were collected for transcriptome analysis. Comparison of the transcriptomes between jejunum and colon identified 3872 Differentially Expressed Genes (DEGs). In contrast, transcriptomic changes under the influence of vitamin D were subtle in both parts of the intestine. RNA-seq results showed that vitamin D supplementation with 5000 IU/Kg enhanced the expression of 7 genes in the jejunum and one gene (MEP1B) in the colon (FDR < 0.05, base mean > 10, and log2fold change>0.6), while supplementation with 10,000 IU/Kg increased the expression of one gene (OASL) in the jejunum. No DEGs with FDR < 0.05 were identified after supplementation with 10,000 IU/kg of vitamin D in the colon, however qPCR analysis showed that genes connected to cell cycle control (PLK1, PLK3, KIF4A, KIFC1, AURKB) are upregulated in this group. Gene Set enrichment analysis of the whole RNA-seq dataset revealed that among the most affected by vitamin D processes are that connected to immunity, especially antiviral response in the jejunum, and that connected to cell cycle control in the colon. Despite the use of very high dietary vitamin D doses, no evidence of overt intestinal toxicity was observed at the transcriptomic level. Nevertheless, the activation of molecular pathways involved in calcium handling and cell cycle regulation suggests that prolonged exposure to supraphysiological vitamin D levels may trigger adaptive responses whose long-term consequences remain unknown.
10-Gingerol induces ferroptosis via TFEB-mediated NRF2 lysosomal degradation in NSCLC.
Li S, Shi K, Huang L … +10 more , Li Z, Qin Z, Sun Y, Qin C, Wang C, Li H, Sun J, Liu W, Wu J, Zhang Z
Toxicol Appl Pharmacol · 2026 Jun · PMID 42013981 · Publisher ↗
10-Gingerol (10-G) exhibits antitumor activity, yet its mechanism in non-small cell lung cancer (NSCLC) remains unclear. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abn...
10-Gingerol (10-G) exhibits antitumor activity, yet its mechanism in non-small cell lung cancer (NSCLC) remains unclear. Ferroptosis, a mode of programmed cell death resulting from lipid peroxidation, is regulated by abnormalities in the antioxidant system and iron metabolism. This study investigated the antitumor mechanism of 10-G in NSCLC, emphasizing its dual role in activating lysosomes and inducing ferroptosis. In this study, we found 10-G induced ferroptosis in NSCLC by increasing iron accumulation, lipid peroxidation, intracellular ROS levels, and malondialdehyde (MDA) production, while depleting glutathione (GSH) and rising Fe levels. Mechanistically, 10-G induced the dephosphorylation of Transcription Factor EB (TFEB) and TFEB dissociation from the 14-3-3 protein, thereby promoting the nuclear translocation of TFEB and the activation of lysosomal gene expression. Subsequently, the activation of lysosomes promoted the degradation of Nuclear factor erythroid 2-related factor 2 (NRF2), thereby affecting the expression levels of downstream targets Glutathione Peroxidase 4 (GPX4) and cystine/glutamate antiporter SLC7A11 (xCT), ultimately leading to ferroptosis. In vivo, 10-G suppressed tumor growth by inhibiting the TFEB-mediated NRF2/xCT/GPX4 axis and promoting ferroptosis. These findings demonstrated that 10-G suppressed the progression of NSCLC by promoting TFEB-mediated lysosomal degradation of NRF2, thereby inducing ferroptosis, which provides a rationale for a novel potential therapeutic strategy.
Proteome profiling of emamectin-treated primary rat cortical cells following up to twelve days in vitro exposure.
Winnik WM, Padgett W, Freeborn D … +8 more , Jackson T, Cherukury H, Valdez J, Valdez M, Mack C, Shafer TJ, Herr DW, Kodavanti PRS
Toxicol Appl Pharmacol · 2026 Jun · PMID 42009082 · Publisher ↗
This study identifies altered proteomic pathways that may be involved in mechanistic pathways for neurotoxicity (NT) and developmental neurotoxicity (DNT), using primary rat cortical cultures. Emamectin benzoate (EMB) in...
This study identifies altered proteomic pathways that may be involved in mechanistic pathways for neurotoxicity (NT) and developmental neurotoxicity (DNT), using primary rat cortical cultures. Emamectin benzoate (EMB) insecticide was chosen as a test chemical. To compare the proteomic expression data to previously described effects related to Neurite Outgrowth (NOG) and alterations in cortical cell culture multielectrode array electrical activity produced by EMB, data was retrieved from the CompTox Chemicals Dashboard. In the current acute EMB experiments, starting the exposure at DIV7 for up to 24 h. 241 proteins were significantly changed at a high EMB dose. However, only two proteins demonstrated significant protein abundance change at all three EMB concentrations at 24 h after treatment. In the developmental paradigm involving continuous EMB treatment from 2 h after plating to collection day, the largest number of significant protein ratios (104) were recorded for the longest treatment duration and highest concentration, 1.25 μM, day in vitro 12 (DIV12), where 85 proteins were downregulated and 20 proteins were upregulated. Major protein alterations were detected in neurological development and neurite outgrowth, neuronal processes involving GABA and glutamate, microtubules, mitochondria - oxidative phosphorylation, and in the calcium management pathways. The data show that a proteomic-based approach might facilitate understanding of how toxins can initiate neurotoxicity and physiological effects and can possibly be used to propose AOP pathways as models for future screening and prioritizing large number of chemicals for NT/DNT.
ALDH2 deficiency increases susceptibility to acetaminophen-induced liver injury through gut microbiota dysbiosis and altered bile acid metabolism.
Li ZM, Du M, Wei N … +3 more , Li JW, Zhang XN, Wang XY
Toxicol Appl Pharmacol · 2026 Jun · PMID 42009081 · Publisher ↗
Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), largely driven by mitochondrial dysfunction and oxidative stress. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) detoxifies lipid peroxidation...
Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), largely driven by mitochondrial dysfunction and oxidative stress. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) detoxifies lipid peroxidation-derived reactive aldehydes; however, its role in APAP-induced hepatotoxicity, particularly in light of the high prevalence of ALDH2 deficiency in East Asian populations, remains incompletely understood. Fasted wild-type (WT) and ALDH2 knockout (KO) mice were challenged with APAP (500 mg/kg). Liver injury was evaluated by histopathological analysis, serum aminotransferase levels, and survival. Intestinal barrier integrity, gut microbiota composition (16S rRNA sequencing), fecal bile acid profiles (LC-MS/MS), and hepatic Nrf2 signaling were systematically examined. ALDH2 deficiency markedly exacerbated APAP-induced liver injury, as evidenced by extensive hepatic necrosis, elevated serum ALT and AST levels, and reduced survival. KO mice exhibited compromised intestinal barrier function, characterized by reduced expression of Claudin-1 and ZO-1 and increased accumulation of 4-hydroxynonenal. Gut microbiota analysis revealed pronounced microbial instability and a significant depletion of Lactobacillus, which was negatively correlated with the severity of liver injury. Consistently, fecal bile acid profiling demonstrated increased levels of tauro-β-muricholic acid in KO mice, which positively correlated with liver damage and inversely correlated with Lactobacillus abundance. Mechanistically, APAP robustly induced hepatic Nrf2-dependent antioxidant gene expression in WT mice, whereas this adaptive response was markedly blunted in ALDH2-deficient mice. Collectively, ALDH2 deficiency heightens susceptibility to APAP-induced ALI by impairing Nrf2-mediated antioxidant defenses and disrupting the gut-liver axis. These findings identify ALDH2 as a critical determinant of APAP sensitivity and a potential therapeutic target.
Nanoencapsulation modulates aspartame metabolite exposure: Toxicokinetic, mechanistic, and pharmacological evaluation in a glucocorticoid dysfunction model.
Fawzy SF, Newairy AA, Ghareeb DA … +6 more , Abdulmalek SA, Hussien HM, Allam M, Eweda SM, Saleh SR, Raafat K
Toxicol Appl Pharmacol · 2026 Jun · PMID 42002150 · Publisher ↗
Aspartame is a widely consumed artificial sweetener that undergoes rapid metabolic conversion to phenylalanine, aspartic acid, and methanol, metabolites that may contribute to oxidative stress and inflammatory responses...
Aspartame is a widely consumed artificial sweetener that undergoes rapid metabolic conversion to phenylalanine, aspartic acid, and methanol, metabolites that may contribute to oxidative stress and inflammatory responses under conditions of metabolic vulnerability. This study evaluated whether nanoencapsulation using chitosan nanoparticles could modulate systemic metabolite exposure and attenuate metabolite-associated biological stress responses. Aspartame-loaded chitosan nanoparticles (Asp@CS-NPs) were prepared by ionic gelation and characterized for physicochemical properties, release kinetics, and pharmacokinetic behavior. Nanoencapsulation produced sustained release profiles and significantly reduced peak plasma concentrations (C) and systemic exposure (AUC) of phenylalanine compared with free aspartame, indicating altered toxicokinetic behavior. In a glucocorticoid-induced metabolic dysfunction and osteoporosis rat model, reduced metabolite exposure was associated with attenuation of oxidative stress biomarkers, suppression of pro-inflammatory cytokines, preservation of hepatic and renal function, and improvement in metabolic and skeletal endpoints. These effects were accompanied by normalization of redox-sensitive signaling markers, suggesting mitigation of metabolite-induced oxidative and inflammatory cascades. Collectively, the findings indicate that nanoencapsulation can influence toxicokinetic parameters and downstream toxicodynamic responses associated with metabolite exposure. This approach provides a framework for toxicokinetic modulation, whereby controlled absorption reduces peak metabolite exposure and downstream stress responses without altering the intrinsic properties of the parent compound.
Impaired autophagy from TRPV4 activation drives α-synuclein pathology in a Parkinson's disease model: A toxicological insight.
Hu J, Zang H, Li H … +5 more , Yang W, Luo J, Tan Y, Zhuan L, Liu N
Toxicol Appl Pharmacol · 2026 Jun · PMID 41997430 · Publisher ↗
The environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical agent for modeling Parkinson's disease (PD). Our previous study demonstrated that calcium channel transient receptor potential...
The environmental toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a prototypical agent for modeling Parkinson's disease (PD). Our previous study demonstrated that calcium channel transient receptor potential vanilloid 4 (TRPV4) mediates MPTP-induced endoplasmic reticulum (ER) stress and inflammation, leading to loss of dopamine neurons and movement disorder. Here, we investigated whether TRPV4 activation impairs clearance of pathological α-Synuclein (α-Syn) via the autophagy-lysosomal pathway (ALP), contributing to cognitive deficits in PD. We used C57BL/6J mice subjected to intracerebral injection of adeno-associated virus in substantia nigra to knockdown or overexpress TRPV4, followed by MPTP treatment. Novel object recognition and Morris water maze tests, immunohistochemistry, electron microscopy, and western blot were employed to assess the role of TRPV4 in modulating α-Syn via ALP. We found that targeting TRPV4 to counteract neurotoxicity improved cognitive dysfunction in PD mice. Mechanistically, MPTP-triggered toxic stress and TRPV4 overexpression induced accumulation of α-Syn and autophagosomes in hippocampus. Critically, TRPV4 knockdown significantly alleviated MPTP-induced α-Syn accumulation. Western blot analysis revealed that TRPV4 impaired α-Syn clearance via the ALP, as evidenced by dysregulation of key ALP components: LC3B, p62, lysosome-associated membrane protein 1, and transcription factor EB. In conclusion, our data are consistent with a model in which TRPV4 contributes to α-Syn accumulation through impairment of the ALP. This work establishes a direct link between TRPV4 and impaired α-Syn clearance, identifying TRPV4 not only as a mediator of ER stress and inflammation but as a critical molecular sensor that disrupts proteostasis. This positions TRPV4 as a promising therapeutic target for counteracting MPTP-induced neurodegeneration.
PGAM5 modulates PI3K/AKT/mTOR-dependent mitochondrial homeostasis in sepsis-induced acute kidney injury.
Jin X, Sheng L, Jiang D … +3 more , Tian D, Jia H, Wu X
Toxicol Appl Pharmacol · 2026 Jun · PMID 41985761 · Publisher ↗
Sepsis-induced acute kidney injury (S-AKI) is a frequent and life-threatening complication in critically ill patients and is largely driven by mitochondrial metabolic dysfunction in renal tubular epithelial cells, yet th...
Sepsis-induced acute kidney injury (S-AKI) is a frequent and life-threatening complication in critically ill patients and is largely driven by mitochondrial metabolic dysfunction in renal tubular epithelial cells, yet the upstream regulatory mechanisms remain incompletely understood. In this study, we investigated the role of phosphoglycerate mutase family member 5 (PGAM5) in S-AKI using lipopolysaccharide (LPS)-treated renal tubular epithelial cells and murine models of sepsis. PGAM5 expression was markedly upregulated under septic conditions. Functional gain- and loss-of-function analyses demonstrated that PGAM5 exacerbated tubular cell injury and mitochondrial dysfunction, whereas PGAM5 knockdown preserved mitochondrial homeostasis, as evidenced by improved cell viability, reduced LDH release and pro-inflammatory cytokine production, decreased apoptosis, restored mitochondrial membrane potential, increased ATP generation, and reduced ROS and MDA levels. Mechanistically, PGAM5 dysregulation was associated with modulation of the PI3K/AKT/mTOR signaling pathway, and pharmacological inhibition of PI3K abolished the protective effects conferred by PGAM5 depletion, indicating pathway involvement. Consistently, in vivo PGAM5 knockdown alleviated sepsis-induced renal dysfunction, histopathological injury, and mitochondrial impairment, accompanied by restoration of PI3K/AKT/mTOR activity. Together, these findings suggest that PGAM5 contributes to S-AKI, at least in part via modulation of PI3K/AKT/mTOR-dependent mitochondrial metabolic homeostasis, while the precise molecular interactions underlying this regulation remain to be elucidated.
Chronic arsenic exposure promotes cell migration via KEAP1-mediated F-actin cytoskeletal rearrangement.
Fang X, Wang J, Yin X … +5 more , Fu M, Hu Y, Wang H, Pi J, Xu Y
Toxicol Appl Pharmacol · 2026 Jun · PMID 41967613 · Publisher ↗
Chronic arsenic exposure is a known environmental risk factor for lung cancer, yet the mechanisms underlying arsenite-induced malignant transformation remain unclear. Kelch-like ECH-associated protein 1 (KEAP1) has been...
Chronic arsenic exposure is a known environmental risk factor for lung cancer, yet the mechanisms underlying arsenite-induced malignant transformation remain unclear. Kelch-like ECH-associated protein 1 (KEAP1) has been shown to directly bind to F-actin, suggesting its potential role in cytoskeletal organization and thus involvement of oncogenic phenotypes. In this study, chronic exposure to 0.1 μM arsenite for up to 36 weeks led to malignant transformation accompanied with a significant decrease in KEAP1 protein level and F-actin cytoskeletal rearrangement in human bronchial epithelial (BEAS-2B) cells. The actin polymerization inhibitor cytochalasin D attenuated arsenite-induced cell migration. Immunofluorescence showed limited spatial association between KEAP1 and the actin cytoskeleton. KEAP1 overexpression suppressed F-actin cytoskeletal rearrangement and arsenic-induced elevation of migratory capacity, while NRF2 knockout did not rescue F-actin cytoskeletal rearrangement in arsenite-transformed cells. These data suggest that arsenite induces the malignant transformation of BEAS-2B cells, and this process involves KEAP1- associated rearrangement of the F-actin cytoskeleton, highlighting a critical role of KEAP1 in cytoskeletal dynamics and cell migration during transformation. Moreover, the role of KEAP1 may be independent of the classical KEAP1-NRF2 axis.
Prenatal amoxicillin exposure impairs mouse alveolar development via Tet3-mediated hypo-hydroxymethylation of Nkx2-1 promoter.
Li W, Xia B, Geng X … +2 more , Liu X, Wang M
Toxicol Appl Pharmacol · 2026 Jun · PMID 41967612 · Publisher ↗
Prenatal exposure to antibiotics is an emerging environmental risk factor for fetal development; however, the impact of amoxicillin (Amo)-one of the most frequently prescribed antibiotics-on alveolarization remains poorl...
Prenatal exposure to antibiotics is an emerging environmental risk factor for fetal development; however, the impact of amoxicillin (Amo)-one of the most frequently prescribed antibiotics-on alveolarization remains poorly understood. In the present study, we established a mouse model of maternal Amo exposure to investigate its developmental toxicity and underlying mechanisms. Histological and ultrastructural examinations revealed that prenatal Amo exposure resulted in marked alveolar simplification and injury to alveolar type II (AT2) epithelial cells, characterized by mitochondrial swelling and compromised lamellar bodies. Mechanistically, we demonstrated that Amo exposure disrupted the Tet3-Nkx2-1 axis. Specifically, Amo exposure downregulated the DNA dioxygenase Tet3, leading to a reduction in 5-hydroxymethylcytosine (5-hmC) (hypo-hydroxymethylation) levels at the Nkx2-1 promoter region, thereby silencing the transcription of Nkx2-1 and its downstream target Sftpc. Notably, administration of Vitamin C, a cofactor for Tet enzymes, effectively reinstated Tet3-mediated hydroxymethylation, restored Nkx2-1 expression, and alleviated the observed pulmonary defects both in vitro and in vivo. These findings uncover a novel epigenetic mechanism linking maternal Amo exposure to impaired alveolar development and suggest Vitamin C supplementation as a potential therapeutic strategy to mitigate antibiotic-induced developmental toxicity.
In vitro exposure to atomoxetine hydrochloride reduces testosterone biosynthesis, induces cell death and DNA damage, as well as altering the oxidative profile and gene expression in TM3 Leydig cells.
Quadreli DH, Sakai AH, Martins SH … +7 more , Bomfim LP, Ikeda Kawasaki JA, Bertozzi MM, Colodro IM, Verri WA, Serpeloni JM, Fernandes GSA
Toxicol Appl Pharmacol · 2026 Jun · PMID 41967611 · Publisher ↗
Atomoxetine, a drug used in the treatment of Attention Deficit/Hyperactivity Disorder, acts by increasing the availability of neurotransmitters, which can act on the male genital system. The effects of this substance on...
Atomoxetine, a drug used in the treatment of Attention Deficit/Hyperactivity Disorder, acts by increasing the availability of neurotransmitters, which can act on the male genital system. The effects of this substance on Leydig cells, which are responsible for testosterone production, have not been described. This study aimed to investigate the in vitro effects of atomoxetine hydrochloride (250, 1000 or 1750 ng/mL) on DNA damage (4 h), gene expression (12h), and after 24 h, cell viability and death, oxidative profile, cytokines and testosterone levels, and the colony-forming capacity in TM3 Leydig cells. Although cell viability was not altered, a reduction in testosterone biosynthesis, an increase in apoptosis and necrosis, a decrease in clonogenic capacity, and an increase in DNA damage were observed at higher concentrations. An alteration in the redox profile was noted, evidenced by a decrease in reduced glutathione and catalase enzyme activity, an increase in total, oxidized, and S-transferase glutathione enzymes, in addition to superoxide dismutase activity and increased lipid peroxidation. Genes involved in apoptotic pathways (BAX, Tp53) were upregulated, as were those related to oxidative stress (HO-1 and Nrf2). Conversely, the androgen receptor gene (AR), especially at the concentration of 1000 ng/mL, downregulated. Furthermore, there was a reduction in IL-33 levels. Even without directly compromising cell viability, possibly due to a limitation of the MTT test, or altering levels of TNF-α and IL-1β, atomoxetine hydrochloride caused important functional alteration in Leydig cells through oxidative stress, genotoxicity, and cytostatic effects, with potential implications for male reproductive function.
Scoparone alleviates cisplatin-induced acute kidney injury by inhibiting 5-lipoxygenase-mediated ferroptosis.
Dai C, Huang S, Huang N … +9 more , Mu S, Liu S, Xie M, Mei J, Tang Y, Yu H, Yue P, Li Y, Ou J
Toxicol Appl Pharmacol · 2026 Jun · PMID 41967610 · Publisher ↗
Ferroptosis, a regulated form of cell death, plays a critical role in renal tubular epithelial cells during acute kidney injury (AKI). Scoparone, a bioactive coumarin, confers organ protection in cardiovascular, hepatic,...
Ferroptosis, a regulated form of cell death, plays a critical role in renal tubular epithelial cells during acute kidney injury (AKI). Scoparone, a bioactive coumarin, confers organ protection in cardiovascular, hepatic, and inflammatory disorders. However, its therapeutic potential in AKI and its role in regulating ferroptosis remain unexplored. This study aimed to investigate the role of scoparone in cisplatin-induced AKI using mouse models and human renal tubular epithelial (HK-2) cells. Integrative analyses, incorporating network pharmacology, bioinformatics, and machine learning, identified arachidonate 5-lipoxygenase (ALOX5) as a key target. In vivo, scoparone treatment markedly improved renal function and preserved histopathological architecture in cisplatin-induced AKI mice. In vitro, scoparone attenuated cisplatin-induced cytotoxicity in HK-2 cells without compromising cisplatin's antitumor efficacy in four human tumor cell lines. Mechanistically, scoparone downregulated ALOX5, suppressed lipid peroxidation, and inhibited ferroptosis. Pharmacological inhibition of ALOX5 with zileuton recapitulated these protective effects, with no additional benefit from co-treatment. Altogether, the findings of this study show that scoparone ameliorates cisplatin-induced AKI by suppressing ALOX5-mediated ferroptosis, positioning ALOX5 as a potential therapeutic target and supporting scoparone as a promising therapeutic candidate for AKI management.
The N-butyl isothiocyanate inhibited breast cancer by suppressing MIF-CD74 interaction.
Zhou Q, Xia Q, Kuang Z … +7 more , Zhu W, Deng Y, Qi X, Zhang H, Wang Y, Xiong X, Zhou S
Toxicol Appl Pharmacol · 2026 Jun · PMID 41966309 · Publisher ↗
Breast cancer ranks as the most common malignant tumor in women across the globe, and triple-negative breast cancer (TNBC) has the worst prognostic outcome among all its molecular subtypes. In the present study, we found...
Breast cancer ranks as the most common malignant tumor in women across the globe, and triple-negative breast cancer (TNBC) has the worst prognostic outcome among all its molecular subtypes. In the present study, we found that BI exerted inhibitory effects on cell proliferation and migration, triggered cellular apoptosis, and also promoted autophagic activity in both MCF7 and 4T1 breast cancer cell lines. Further investigations suggested that BI likely targeted MIF and disrupted the MIF-CD74 interaction, thereby suppressing activation of JAK2/STAT3 signaling axis and transcription of downstream genes such as Il-6 and Socs3. Notably, BI inhibited MEK/ERK and NF-κB activation while increasing ROS levels specifically in 4T1 cells, but not in MCF7 cells. In a 4T1 xenograft tumor model, BI reduced tumor weight and volume without affecting body weight or major organ integrity. To summarize, our research provides the first documentation of the anti-breast cancer effects exerted by BI, laying a foundation for further exploration of isothiocyanate compounds (ITCs) as a potential source of novel therapeutic agents against breast cancer.
Clomiphene citrate induces changes in human fallopian tube secretory epithelial cells: An in vitro study.
Roy O, Hegde S, Ritting ML … +9 more , Hebbar S, Gowda J, Agarwal J, Nair AS, Joshi MB, Kumar A, Adiga SK, Kannan N, Kalthur G
Toxicol Appl Pharmacol · 2026 Jun · PMID 41962809 · Publisher ↗
The fallopian tube microenvironment supports gamete transport, fertilization and early embryo development. Any disturbances in this microenvironment can lead to fertilization failure, infertility or ectopic pregnancy. In...
The fallopian tube microenvironment supports gamete transport, fertilization and early embryo development. Any disturbances in this microenvironment can lead to fertilization failure, infertility or ectopic pregnancy. In this study, we systematically investigated the effects of clomiphene citrate (CC) on human PAX8-positive fallopian tube secretory epithelial cells (hPFTSECs) to assess CC-induced alterations in the tubal microenvironment. Human fallopian tube tissues obtained from women undergoing postpartum tubectomy were enzymatically digested, and the isolated hPFTSECs were cultured with CC. CC exposure reduced hPFTSEC viability, clonogenicity, proliferation and organoid forming efficiency while inducing apoptosis, DNA damage, and senescence in a dose-dependent manner. Further, delayed cell-cycle progression and impaired DNA replication were observed in CC-exposed hPFTSECs. CC when administered to adult female Swiss albino mice, both single-dose (25, 50, and 100 mg/kg; intraperitoneally) and multiple-dose (10 mg/kg; intraperitoneally for four consecutive days) exposure caused several oviductal abnormalities, including epithelial disorganization, loss of ciliation, dysplasia, and hyperplasia. Our findings reveal that CC induces a spectrum of cytotoxic, genotoxic, and structural alterations in the fallopian tube epithelium, with potential implications for tubal function impairment and disruption of the optimal microenvironment essential for fertilization and early embryo development, which might negatively impact overall reproductive outcomes.
Neuropeptide analog PD149163 ameliorates metabolic endotoxemia-driven thyroid inflammation by targeting LPS-LBP signalling in murine model: Insights from in vivo, in silico and network pharmacology analyses.
Singh P, Mohanty B
Toxicol Appl Pharmacol · 2026 Jun · PMID 41956324 · Publisher ↗
The present study elucidates the efficacy of the neuropeptide neurotensin/NTS analog PD149163 in ameliorating chronic thyroid inflammation and metabolic endotoxemia induced by E. coli endotoxin lipopolysaccharide/LPS. NT...
The present study elucidates the efficacy of the neuropeptide neurotensin/NTS analog PD149163 in ameliorating chronic thyroid inflammation and metabolic endotoxemia induced by E. coli endotoxin lipopolysaccharide/LPS. NTS, a gastrointestinal-tract tri-decapeptide, has anti-inflammatory and anti-oxidative effects. Swiss-albino mice (female/7-8 weeks/25 ± 2.5 g) were divided into six groups: GI/control; GII and GIII were treated with 50 and 100 μg/kg bw of PD149163, respectively, for 4 weeks. GIV-VI was injected with LPS (1 mg/kg bw; 5 days), followed by PD149163 exposure to GV/END+PD (50 μg/kg bw) and GVI/END+PD (100 μg/kg bw) for 4 weeks. Both the LPS and PD149163 were given intraperitoneally. PD treatment has shown efficacy in counteracting chronic thyroid inflammation, metabolic endotoxemia and hormonal impairments. The LPS-induced histopathological alterations in thyroid and visceral adipose tissue are characteristics of inflammation, ameliorated following PD supplementation. LPS-exposure elevates cytokines (IL-6/TNF-α), apoptotic protein/CAS3, adipokine/leptin and decreases IL-10, Bcl-2 and NTS, indicating inflammation and cellular apoptosis, normalised by PD. Supplementation with PD reduces LPS-mediated increase in acute-phase protein/CRP and anti-thyroid peroxidase/TPO antibodies in plasma and tissue. The LPS-induced hormonal impairment of the HPT axis (TSH/T/T) and metabolic endotoxemia, reflected in altered triglycerides (TAG)/total cholesterol (TC)/high and low-density lipoproteins (HDL-c/LDL-c), were also counteracted by PD. Molecular docking predicted that LPS/LBP may compete with T for its receptors (TRα/TRβ) and can disrupt the thyroid receptor's functioning. Also, docking of PD149163-LBP suggests that PD149163 directly binds to LBP, thereby inhibiting LPS-LBP interaction and attenuating LPS-induced effects. Thus, PD149163 emerges as a potential modulator of endotoxemia-induced thyroid inflammation, hormonal imbalance, and metabolic dysfunction by inhibiting LPS-LBP interaction and downstream signalling.
Pristimerin drives ROS-dependent apoptosis in cutaneous T-cell lymphoma via inhibition of the AKT-SKP2 axis.
Kuttikrishnan S, Anver R, Ahmad F … +10 more , Mariyam Z, Habeeba U, Akhtar S, Salameh I, Siddiqui SS, Prabu KS, Ansari AW, Bhat AA, Khan AQ, Uddin S
Toxicol Appl Pharmacol · 2026 Jun · PMID 41936986 · Publisher ↗
Cutaneous T-cell lymphoma (CTCL) is a skin-predominant form of non-Hodgkin lymphoma for which improved therapeutic options are needed. Here, we investigated the anti-lymphoma effects of pristimerin (PS) and defined its u...
Cutaneous T-cell lymphoma (CTCL) is a skin-predominant form of non-Hodgkin lymphoma for which improved therapeutic options are needed. Here, we investigated the anti-lymphoma effects of pristimerin (PS) and defined its underlying mechanism in H9 and HH CTCL cell lines. PS strongly reduced cell growth and induced apoptosis, with hallmarks of mitochondrial (intrinsic) pathway activation, including caspase processing. PS also decreased basal AKT activity and downregulated pro-survival factors such as XIAP. In addition, PS reduced the abundance of S-phase kinase-associated protein 2 (SKP2) and was accompanied by increased levels of the cyclin-dependent kinase inhibitors p21 and p27. Genetic suppression of AKT intensified apoptosis-associated signaling, reflected by increased H2AX activation and PARP cleavage. Notably, PS elevated intracellular reactive oxygen species (ROS), and scavenging ROS with N-acetylcysteine (NAC) significantly attenuated PS-driven cytotoxicity, supporting a ROS-dependent mechanism. Finally, PS combined with the proteasome inhibitor bortezomib produced greater anti-CTCL activity than either agent alone, consistent with a synergistic interaction. Together, these findings show that PS promotes ROS-dependent, mitochondria-mediated apoptosis in CTCL and support further evaluation of PS-based strategies for this malignancy.
Impact of renal hypoxia on OAT1 expression and adefovir-induced cytotoxicity in human 3D-RPTEC spheroids.
Yokoseki I, Nakano M, Takahashi E … +9 more , Morimura K, Nishioka Y, Araki A, Jimbo Y, Ishiguro N, Arakawa H, Tamai I, Fukami T, Nakajima M
Toxicol Appl Pharmacol · 2026 Jun · PMID 41936985 · Publisher ↗
Drug transporters such as organic anion transporter (OAT) 1 in renal proximal tubule epithelial cells (RPTECs) play a pivotal role in drug disposition. Renal hypoxia, a hallmark of chronic kidney disease (CKD), is known...
Drug transporters such as organic anion transporter (OAT) 1 in renal proximal tubule epithelial cells (RPTECs) play a pivotal role in drug disposition. Renal hypoxia, a hallmark of chronic kidney disease (CKD), is known to alter drug disposition; however, the molecular mechanisms underlying altered transporter expression in human RPTECs under hypoxic conditions remain poorly understood. This study aimed to elucidate these mechanisms using three-dimensional (3D) human RPTECs that maintain stable expression of key transporters, including OAT1. Quantitative PCR analysis revealed that hypoxia (1% O, 72 h) significantly decreased the mRNA levels of major drug transporters, such as OAT1 and organic cation transporter 2 (OCT2), indicating transcriptional suppression. Consistent with this, global proteomic analysis confirmed that the protein levels of these transporters were significantly downregulated, and further revealed a broad suppression of proteins involved in the "transport of small molecules". Focusing on OAT1 to elucidate the regulatory mechanism, our findings suggest that this suppression is associated with a potential dual mechanism: activation of the repressive nuclear factor-kappa B (NF-κB) signaling pathway and decreased expression of hepatocyte nuclear factor 1α (HNF1α). The hypoxia-induced OAT1 reduction diminished cellular accumulation of the OAT1 substrate adefovir and consequently mitigated its cytotoxicity. Collectively, these findings clarify the molecular basis by which renal hypoxia alters drug transporter expression, emphasizing the importance of renal oxygen status in determining drug efficacy and toxicity in CKD patients.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe