Toxicol. Appl. Pharmacol. [JOURNAL]
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200 papers
Mitotic abnormality induced by evodiamine, a tryptamine indole alkaloid.
Shigefuji R, Komatsu S, Terabayashi T … +4 more , Ishizaki T, Tomo T, Nishida Y, Hanada K
Toxicol Appl Pharmacol · 2026 Jun · PMID 41935754 · Publisher ↗
Inhibitors of mitosis are used extensively in studies of cell biology and as chemotherapy agents in clinical settings. Such inhibitors may be present in certain East Asian herbal medicines that have been administered as...
Inhibitors of mitosis are used extensively in studies of cell biology and as chemotherapy agents in clinical settings. Such inhibitors may be present in certain East Asian herbal medicines that have been administered as anticancer treatments. In this study, we screened compounds that were discovered in herbal medicines and we identified evodiamine as a new anticancer drug candidate. The cytotoxic effects of evodiamine were observed only in proliferating cells, which is an excellent property for an anticancer drug candidate. As a negative control, cells were treated with rutaecarpine, an alkaloid with a similar structure to evodiamine; however, rutaecarpine did not show any cytotoxicity up to 10 μM. To understand the molecular action of evodiamine, chromosome segregation during mitosis was analyzed. First, cells were treated with a low concentration of evodiamine (1 μM) or with 10 μM rutaecarpine for 16 h. In evodiamine-treated metaphase cells, several chromatids were prematurely distributed to both poles without sister chromatid separation. In contrast, cells treated with rutaecarpine did not show this abnormality. Cells treated with evodiamine also displayed micronucleus formation but this was not observed in cells treated with rutaecarpine. Cells treated with a higher concentration of evodiamine (5 μM) showed a higher rate of prophase arrest. Based on these results, we suggest that evodiamine induces chromosomal segregation abnormalities, which are thought to cause cell death exclusively in proliferating cells.
Early-life exposure to Cannabidiol: Safety assessment of a chronic exposure in Caenorhabditis elegans.
Padilha HA, Reginatto JF, Saleh JD … +5 more , Jardim NS, Crippa JA, Hallak JEC, Campos A, Ávila DS
Toxicol Appl Pharmacol · 2026 Jun · PMID 41935753 · Publisher ↗
The use of cannabidiol (CBD) for therapeutic purposes encompasses a wide range of diseases and disorders. Following the discovery of the endocannabinoid system in humans, interest has been sparked in investigating the ph...
The use of cannabidiol (CBD) for therapeutic purposes encompasses a wide range of diseases and disorders. Following the discovery of the endocannabinoid system in humans, interest has been sparked in investigating the pharmacological activities of Cannabis spp. and its possible mechanisms of action. However, studies indicate adverse effects associated with cannabinoid use, particularly in early-life treatments, highlighting the need for clinical trials and risk assessments before the widespread recommendation of CBD for different age groups. Therefore, we used Caenorhabditis elegans to carry out toxicological analysis of isolated CBD during long-term exposure, starting from the early life stages. After chronic exposure (48 h) of first larval stage animals, we found that CBD treatment early in life was safe at the lowest concentration. Although the highest CBD concentrations tested showed toxicity by reducing worm survival and causing delayed reproduction, probably due to oxidative stress as indicated by increased ROS levels, the other parameters analyzed were not affected by these concentrations. In line with this, the lowest concentration tested did not produce detectable adverse effects in the evaluated endpoints under the experimental conditions used, indicating tolerability within this model. Finally, our research contributed to the assessment of potential risks associated with cannabinoid exposure during early life stages, which are particularly vulnerable to chemical insults, and highlights the need to identify appropriate exposure ranges during development.
Corrigendum to 'Carnosic acid prevents COL1A2 transcription through the reduction of Smad3 acetylation via the AMPKα1/SIRT1 pathway' [Toxicology and Applied Pharmacology 339 (2018) 172-180].
Zhao Y, Shi X, Ding C … +7 more , Feng D, Li Y, Hu Y, Wang L, Gao D, Tian X, Yao J
Toxicol Appl Pharmacol · 2026 Jun · PMID 41933738 · Publisher ↗
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Nickel exposure disrupts epigenetic repression of developmental genes in mouse embryonic stem cells.
Bradford B, Filipovic D, Zhang X … +2 more , Goriainova V, Cuddapah S
Toxicol Appl Pharmacol · 2026 Jun · PMID 41932553 · Full text
Nickel (Ni) is a naturally occurring heavy metal whose environmental levels have been steadily rising due to industrial activities and the widespread use of Ni-containing products. Ni exposure poses significant health ri...
Nickel (Ni) is a naturally occurring heavy metal whose environmental levels have been steadily rising due to industrial activities and the widespread use of Ni-containing products. Ni exposure poses significant health risks, and studies in vertebrate models and human populations link Ni to developmental toxicity. However, the mechanisms by which Ni perturbs early developmental programs remain poorly understood. Here, we examined the effects of Ni exposure on pluripotency in mouse embryonic stem cells (mESCs) maintained under pluripotency-supporting conditions. Ni exposure led to aberrant upregulation of genes associated with mesodermal and endodermal lineages, while ectodermal gene expression remained largely unaffected. However, the expression of core pluripotency factors was preserved, indicating that Ni does not induce differentiation but instead disrupts normal transcriptional control within the pluripotent state. Mechanistically, Ni exposure caused a selective loss of the repressive histone modification H3K27me3 at bivalent promoters of mesoderm-associated genes without altering global H3K27me3 levels. Pharmacological inhibition of H3K27me3 demethylases attenuated Ni-induced gene activation, suggesting that localized H3K27me3 removal contributes to this aberrant activation of developmental genes. ESCs normally exist as heterogeneous populations that dynamically fluctuate between naïve and lineage-primed pluripotent states. Our findings indicate that Ni exposure perturbs this equilibrium through aberrant activation of lineage-associated genes while core pluripotency remains preserved. Such dysregulation of early transcriptional programs may predispose cells to abnormal fate decisions. These findings suggest a mechanistic link between Ni exposure and developmental abnormalities.
Alpha-terpineol induced developmental toxicity in Wistar rats: Embryotoxic, teratogenic, and targeted gene expression effects.
Hegde SS, Malashetty VB
Toxicol Appl Pharmacol · 2026 Jun · PMID 41932552 · Publisher ↗
Alpha-terpineol (α-terpineol), a ubiquitous monoterpenoid alcohol found in numerous essential oils, is widely employed in cosmetics, perfumes, and aromatic therapies. Despite its extensive application, concerns regarding...
Alpha-terpineol (α-terpineol), a ubiquitous monoterpenoid alcohol found in numerous essential oils, is widely employed in cosmetics, perfumes, and aromatic therapies. Despite its extensive application, concerns regarding its potential reproductive and developmental toxicity remain inadequately characterized, particularly concerning specific teratogenic effects and underlying molecular mechanisms. This study presents novel findings, demonstrating that α-terpineol exposure during the critical organogenesis period significantly induces developmental toxicity in Wistar rat fetuses. α-terpineol was administered at the doses of 0, 75, 150, and 300 mg/kg with a dose volume of 5 mL/kg. We report dose-dependent embryotoxic and teratogenic effects, including reduced fetal weight and a spectrum of severe skeletal malformations such as anophthalmia, club foot, micrognathia, phocomelia, and irregularities in the vertebral column, ribs, and limb bones. Crucially, our comprehensive gene expression analysis revealed statistically significant alterations in the expression patterns of HOXD13 and GDF11, two pivotal genes essential for skeletal patterning and limb development. The observed downregulation of these genes suggests a potential molecular association into α-terpineol-induced teratogenesis. These findings underscore the significant developmental risks associated with α-terpineol exposure during pregnancy and provides insights into potential molecular changes underlying its teratogenic potential, warranting further investigation into human health implications and the establishment of safe exposure limits for this widely used compound.
Ghrelin as a candidate molecule in translational pharmacology: Physiopharmacological actions, therapeutic pros and cons, and delivery challenges.
Bukhari SMS, Shah M, Ali R … +3 more , Rehman NU, Ahmad P, Shah FA
Toxicol Appl Pharmacol · 2026 Jun · PMID 41932551 · Publisher ↗
Ghrelin is a peptide hormone consisting of 28 amino acids, characterized by octanoylation, and is primarily secreted by gastric X/A-like cells and is recognized as the sole circulating orexigenic hormone. Ghrelin, via it...
Ghrelin is a peptide hormone consisting of 28 amino acids, characterized by octanoylation, and is primarily secreted by gastric X/A-like cells and is recognized as the sole circulating orexigenic hormone. Ghrelin, via its receptor growth hormone secretagogue receptor 1a, modulates key biological functions such as appetite, growth hormone release, glucose regulation, gastrointestinal motility, cardiovascular activity, immune, and stress reactivity. The characteristics of O-octanoyl substitution at Ser3 are not only crucial for receptor activation, but this alteration also makes it susceptible to enzymatic breakdown and therefore leads to a short plasma half-life, bridging both therapeutic possibilities and pharmacological constraints. This review summarizes the structural features of ghrelin, its receptor biology, and its significant physiological and pharmacological actions, particularly its differential effects on the hypothalamic pituitary adrenal axis and stress behaviors. We also discussed the hurdles associated with ghrelin-based treatments, and, therefore, briefly mentioned new delivery methods that could potentially address issues with pharmacokinetics and targeting constraints. There are numerous potential clinical applications, including metabolic disorders, gastrointestinal disease, neurodegeneration, chronic pain, psychiatric disorders, and wasting syndromes. The limitations, such as metabolic adverse effects, receptor desensitization, differential effects, and safety considerations, were critically evaluated. In translational pharmacology, ghrelin is a potential but challenging target that requires careful integration of physiopharmacological knowledge with prudent treatment design.
Ginkgolide B inhibits non-small cell lung cancer cells by modulating the integrin β3 pathway.
Shao L, Song Z, Cong J … +2 more , Ma J, Du A
Toxicol Appl Pharmacol · 2026 Jun · PMID 41921594 · Publisher ↗
OBJECTIVE: Ginkgolide B (GB) exhibits anti-tumor activity. However, the inhibitory effect of GB on non-small cell lung cancer (NSCLC) and its specific molecular mechanisms remain unclear. This study aimed to analyze the...
OBJECTIVE: Ginkgolide B (GB) exhibits anti-tumor activity. However, the inhibitory effect of GB on non-small cell lung cancer (NSCLC) and its specific molecular mechanisms remain unclear. This study aimed to analyze the pharmacological mechanism of GB for NSCLC. METHODS: Two NSCLC cells, A549 and H1299, were treated with different doses of GB for 48 h. Cell apoptosis, cell viability, and integrin β3 expression were measured to analyze the inhibitory effect of GB. The binding affinity between GB and integrin β3 was analyzed using microscale thermophoresis (MST). An integrin αβ blocker, LM609, was used as a positive control to analyze the effects of GB on integrin αβ. Meanwhile, the silence of integrin β3 (ITGB3) in NSCLC cells was established by ITGB3 siRNA transfection to analyze the role of integrin β3 in GB-mediated inhibition. Changes in cell viability, integrin β3, and the Akt/PI3K/mTOR pathway were measured. In A549-injected nude mice, animals were treated with GB or LM609 to observe the changes in tumor growth, integrin β3, and the Akt/PI3K pathway. RESULTS: GB treatment promoted the apoptosis of NSCLC cells, inhibited cell viability, and suppressed the integrin β3 expression in a dose-dependent manner. Meanwhile, a good binding affinity was found between GB and integrin β3. GB or LM609 treatment not only inhibited the integrin αβ expression but also suppressed the phosphorylation of the Akt/PI3K pathway. Meanwhile, the silence of integrin β3 attenuated the GB-induced effects. In vivo, GB treatment suppressed tumor growth, as well as suppressed the integrin β3 expression and the phosphorylation of the Akt/PI3K pathway. CONCLUSIONS: GB inhibited NSCLC by inhibiting the integrin β3 pathway, providing a theoretical basis for the application of GB in NSCLC.
Cellular redox disruption and apoptosis: Differential effects of RFR frequencies on Leydig cells.
Jangid P, Rai U, Sevak JK … +2 more , Singh S, Singh R
Toxicol Appl Pharmacol · 2026 Jun · PMID 41921593 · Publisher ↗
Radiofrequency radiation (RFR), widely emitted from modern wireless devices, has raised questions regarding its possible impact on male reproductive health. In this comparative study, we examined the redox and apoptotic...
Radiofrequency radiation (RFR), widely emitted from modern wireless devices, has raised questions regarding its possible impact on male reproductive health. In this comparative study, we examined the redox and apoptotic responses of TM3 Leydig cells following exposure to mobile phone radiation, as well as 2450 MHz, and 1800 MHz frequencies for 15, 30, 45, 60, 90 & 120 min, and redox imbalance was assessed by quantifying nitric oxide (NO) and intracellular superoxide (SO) levels. Apoptotic cell percentages were evaluated by dual labeling with Annexin V-FITC/PI using flow cytometry. Mobile phone and 2450 MHz exposures induced biphasic alterations in NO levels, while 1800 MHz exposure resulted in a sustained reduction in NO. SO levels increased progressively in a time- and frequency-specific manner. Apoptotic analysis revealed early apoptotic activation in mobile and 2450 MHz groups, whereas 1800 MHz exposure led to delayed but sustained late-stage apoptosis. These findings demonstrate that RFR triggers redox imbalance and apoptosis in TM3 cells, with effects varying by frequency and exposure duration. This comparative analysis underscores the biological risks of chronic low-intensity RFR exposure and highlights the growing concerns about RFR-associated testicular stress and its implications for male reproductive toxicity.
Effects of music on hepatic cytochrome P450 1A enzymes in Sprague Dawley rats.
Shalaby AH, Adhiya J, Al-Dajani AR … +6 more , El-Mahrouk SR, Olympus C, Seubert J, Ahonen H, El-Kadi AOS, Kiang TKL
Toxicol Appl Pharmacol · 2026 Jun · PMID 41905667 · Publisher ↗
The cytochrome P450 (CYP) 1A subfamily, regulated by the aryl hydrocarbon receptor (AhR), is central to the bioactivation or deactivation of xenobiotics, endogenous substrates, and carcinogens. Music can alter hormonal a...
The cytochrome P450 (CYP) 1A subfamily, regulated by the aryl hydrocarbon receptor (AhR), is central to the bioactivation or deactivation of xenobiotics, endogenous substrates, and carcinogens. Music can alter hormonal and neurotransmitter concentrations, which are partly regulated by CYP-dependent pathways. This study investigated whether defined musical elements modulate hepatic CYP1A in male and female Sprague-Dawley rats. Animals were exposed for 24 h to music containing variations of rhythm, tempo, and harmony. Of all conditions tested, fast-tempo, irregular-rhythm, and atonal-harmony (FT-IR-AH) produced the greatest increases in hepatic CYP1A1 (7-ethoxyresorufin O-deethylase) and CYP1A2 (7-methoxyresorufin O-demethylase) activities. In the combined-sex cohort, FT-IR-AH music increased CYP1A1 maximum velocity (V) and intrinsic clearance (CL) by 3.2- and 3.1-fold, respectively, and increased CYP1A2 V and CL by 1.9- and 1.8-fold, respectively, without altering enzyme affinities. FT-IR-AH also increased CYP1A1 protein expression by 1.9-fold in females and 2.6-fold in males, and CYP1A2 by 1.6-fold and 1.7-fold, respectively, with concordant elevations in mRNA levels. Replication of the same music elements across different music composers yielded consistent findings, with variations in effects potentially attributed to percentages of gaps (i.e., staccato) and frequency patterns. Selective induction of AhR-regulated genes in the absence of nuclear factor erythroid 2-related factor 2-dependent antioxidant gene activation suggests that FT-IR-AH music selectively engages AhR signaling without a generalized oxidative stress response. These data identify specific music features as an external stimulus capable of modulating CYP1A expression and function, with potential implications for therapeutic responses, toxicological effects, and drug interactions.
Aluminum maltolate induced cellular stress is associated with ER stress related responses and alterations in NMDAR2B levels: Modulatory effects of coenzyme Q10.
Sahin-Mazlumoglu B, Palabiyik-Yucelik SS
Toxicol Appl Pharmacol · 2026 Jun · PMID 41905666 · Publisher ↗
Chronic aluminum (Al) exposure has been implicated as a significant environmental risk factor in the development and progression of neurodegenerative diseases. This study aimed to investigate the Al maltolate (Al-Malt) i...
Chronic aluminum (Al) exposure has been implicated as a significant environmental risk factor in the development and progression of neurodegenerative diseases. This study aimed to investigate the Al maltolate (Al-Malt) induced cellular stress responses in SH-SY5Y cells in vitro by evaluating the changes in endoplasmic reticulum (ER) stress related markers and NMDAR2B levels, and to assess the modulatory effects of coenzyme Q10 (CoQ10). Cellular viability and metabolic activity following exposure to Al-Malt were assessed using the MTT assay. NMDAR2B levels were measured by the ELISA, while GRP78 and CHOP mRNA expression levels, which are ER stress biomarkers, were analyzed by the RT-PCR. 250 and 500 μ Al-Malt exposure resulted in reduced cellular viability and metabolic activity by approximately ∼18% and ∼ 30% respectively. GRP78 mRNA expression increased ∼2.2 and ∼ 2.6 fold, while CHOP mRNA expression increased by ∼1.86 and ∼ 2.31 fold at 250 and 500 μ Al-Malt, respectively. NMDAR2B levels decreased by approximately ∼26% and ∼ 40% compared to control. CoQ10 pretreatment attenuated these cellular responses. These findings suggest an association between Al exposure, ER stress related responses, and alterations in NMDAR2B levels in an in vitro neuronal model, and indicate that CoQ10 may modulate Al-induced cellular stress. However, further studies using primary neuronal cultures and in vivo models are warranted to validate and extend these results.
Saikosaponin D protects against isoproterenol-induced kidney injury in rats by regulating the intrarenal renin-angiotensin system.
Yi X, Song S, Yang H … +3 more , Tan W, Yu J, Xu C
Toxicol Appl Pharmacol · 2026 Jun · PMID 41903810 · Publisher ↗
Saikosaponin D (SSD), a triterpene saponin isolated from Bupleurum falcatum, exhibits diverse pharmacological activities and has been shown to alleviate kidney-related diseases in rodent models. However, its effects on i...
Saikosaponin D (SSD), a triterpene saponin isolated from Bupleurum falcatum, exhibits diverse pharmacological activities and has been shown to alleviate kidney-related diseases in rodent models. However, its effects on isoproterenol (ISO)-induced kidney injury and the underlying mechanisms have not been fully elucidated. Herein, SSD administration effectively mitigated ISO-induced kidney injury in Sprague-Dawley rats, as evidenced by improvements in renal function parameters (e.g., reduced plasma creatinine and blood urea nitrogen) and histopathological structure. Specifically, SSD significantly suppressed ISO-induced upregulation of inflammatory cytokines, fibrotic markers, and kidney injury biomarkers in renal tissues. SSD treatment downregulated renal expression of angiotensinogen (AGT), renin, and angiotensin-converting enzyme (ACE), reduced renal ACE activity and urinary angiotensin II (AngII) excretion, and upregulated renal angiotensin-converting enzyme 2 (ACE2) activity (without altering its expression) while increasing urinary angiotensin 1-7 (Ang1-7) excretion. Notably, no significant changes in plasma AngII or Ang1-7 concentrations were observed, indicating SSD specifically modulates the intrarenal renin-angiotensin system. Functional validation experiments showed that co-administration of SSD with the ACE inhibitor enalapril or AngII type 1 receptor (ATR) antagonist losartan further potentiated its protective effects against ISO-induced kidney injury. In contrast, co-treatment with the ACE2 inhibitor MLN-4760 or Mas receptor (MasR) antagonist A779 completely abrogated SSD's renoprotective effects. In conclusion, our findings demonstrate that SSD exerts renoprotective effects against ISO-induced kidney injury by inhibiting renal fibrosis and inflammation. Mechanistically, SSD shifts the intrarenal RAS balance from the pro-inflammatory/fibrotic ACE/AngII/ATR axis to the protective ACE2/Ang1-7/MasR axis, providing a novel therapeutic target for ISO-related kidney damage.
Camizestrant-induced heart rate reduction is mediated via a sinoatrial node pacemaker channel mechanism.
Hall A, El-Haou S, Villar IC … +15 more , Molla D, Kwan M, Purbrick S, Henry D, Kirk J, Hawthorne G, Canzolino S, Harding J, Harmer A, Bucchi A, Roberts L, Pointon A, Protze S, Baruscotti M, Wright L
Toxicol Appl Pharmacol · 2026 Jun · PMID 41903809 · Publisher ↗
Camizestrant, a next-generation selective estrogen receptor (ER) degrader and complete ER antagonist, has been associated with a reversible dose- and time-dependent heart rate (HR) reduction in clinical studies. This non...
Camizestrant, a next-generation selective estrogen receptor (ER) degrader and complete ER antagonist, has been associated with a reversible dose- and time-dependent heart rate (HR) reduction in clinical studies. This nonclinical investigation aimed to understand the mechanism of camizestrant-induced HR reduction. The effects of camizestrant on HR in vivo were assessed in rat and dog telemetry studies. Effects on pacemaker channel function in vitro were assessed using patch-clamp electrophysiology in Chinese hamster ovary cells expressing human hyperpolarization-activated cyclic nucleotide-gated channel 4 (hHCN4), human embryonic stem cell (hESC)-derived sinoatrial node (SAN) cardiomyocytes, and primary rat SAN cardiomyocytes. In dogs, 28-day repeat-dose camizestrant administration caused a reversible dose- and time-dependent HR reduction (maximum reduction of 53 beats per min [bpm] on Day 25 vs pre-study levels at 20 mg/kg). HR reduction was also noted in rats (maximum reduction 89 bpm vs vehicle [23%] on Day 5 of a 7-day study at 75 mg/kg). Responses to chronotropic stimuli (e.g., atropine and isoprenaline) were reduced in dogs treated with camizestrant. Camizestrant-induced HR reduction was still present following combined sympathetic (atenolol) and parasympathetic (atropine) inhibition in dogs, as well as vagotomy in rats. Camizestrant reduced hHCN4 current density in Chinese hamster ovary cells, as well as beat rate and "funny" pacemaker (I) current activity in hESC-derived SAN cardiomyocytes. Camizestrant at 75 mg/kg for 7 days significantly reduced I current activity versus vehicle in isolated SAN cardiomyocytes. These results support the hypothesis that camizestrant exerts a pharmacologic, reversible reduction in HR by decreasing SAN pacemaker current activity.
Acute exercise activates hepatic Nrf2 signaling by ROS, AMPK and epinephrine to protect against acute liver injuries.
Yang S, Zhao R, Lei L … +8 more , An X, Xu J, Xu H, Wang J, Xiao H, Zhang Y, Yang X, Yu S
Toxicol Appl Pharmacol · 2026 Jun · PMID 41861854 · Publisher ↗
While exercise is well-established as a protective strategy against non-alcoholic fatty liver disease, its role in acute liver injury (ALI) remains poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2), a...
While exercise is well-established as a protective strategy against non-alcoholic fatty liver disease, its role in acute liver injury (ALI) remains poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of antioxidant response element (ARE)-dependent gene expression, plays an important role in the pathogenesis of liver diseases, where oxidative stress contributes significantly to both chronic progression and acute injury. This study investigated whether exercise confers protection against ALI via the Nrf2 signaling pathway and elucidated the underlying molecular mechanisms. We found that acute treadmill exercise time- and intensity-dependently activated hepatic Nrf2 signaling in mouse, conferring significant protection against ALI induced by alcohol, acetaminophen, or carbon tetrachloride. Conversely, exercise failed to protect against and even exacerbated ALI in Nrf2-deficient mice. Furthermore, using antioxidant Trolox and AMPKα2-knockout mice, we demonstrated that exercise activated hepatic Nrf2 primarily via ROS and AMPK signaling. Additionally, we identified exercise-induced elevation of epinephrine as a novel mechanism for activating hepatic Nrf2. In conclusion, our study demonstrates that exercise protects against ALI by activating the hepatic Nrf2/ARE signaling axis and delineates the associated molecular mechanisms, providing a scientific rationale for exercise-based therapeutic interventions.
Sodium fluoride induces cardiotoxicity via TGF-β-mediated suppression of the Wnt/β-catenin signaling pathway.
Cheng J, Liu Y, Li Y … +8 more , Yang B, Yang X, Chen X, Zhou Y, Li B, Liu Y, Wang F, Tang D
Toxicol Appl Pharmacol · 2026 Jun · PMID 41861853 · Publisher ↗
This study aims to delineate the specific mechanism through which TGF-β mediates NaF-induced cardiotoxicity, with a focus on its regulatory role in the Wnt/β-catenin signaling pathway. We assessed NaF-induced cytotoxicit...
This study aims to delineate the specific mechanism through which TGF-β mediates NaF-induced cardiotoxicity, with a focus on its regulatory role in the Wnt/β-catenin signaling pathway. We assessed NaF-induced cytotoxicity in AC16 cardiomyocytes by CCK-8, crystal violet staining, and EdU assays; determined cell cycle progression and apoptosis by flow cytometry; and systematically evaluated ROS levels, mitochondrial function, oxidative stress, inflammation, and expression using fluorescent probes, enzymatic assays, RT-qPCR, and Western Blot. The in vivo cardiotoxic mechanism of NaF was further verified in a rat model. NaF triggers cardiotoxicity in AC16 cardiomyocytes by inhibiting the Wnt/β-catenin pathway and activating TGF-β signaling, leading to suppressed proliferation, cell cycle arrest, and apoptosis. These changes further intensify oxidative stress, mitochondrial dysfunction, and inflammation. In rats, NaF exposure caused abnormal ECG patterns and cardiac tissue damage, linked to upregulated TGF-β signaling and downregulated Wnt/β-catenin activity. Corresponding molecular changes included decreased expression of antioxidant factors (NQO1, HO-1), increased levels of inflammatory mediators (IL-6, IL-8), and P16, MMP3, P53, P21. Together, these findings clarify key mechanisms of fluoride-induced cardiotoxicity and offer a theoretical basis for managing fluorosis-related cardiac injury. NaF inhibits AC16 cardiomyocyte proliferation and induces apoptosis, cell cycle arrest, oxidative stress, mitochondrial damage, and inflammatory responses. These effects are mediated through upregulation of the TGF-β signaling pathway and concurrent inhibition of the Wnt/β-catenin pathway.
Urinary NGAL as an early marker of subclinical kidney injury in adults with substance use disorder: A case-control study.
Hemeda MS, Moustafa AA, El-Aal BEA … +1 more , Sayed HY
Toxicol Appl Pharmacol · 2026 Jun · PMID 41856332 · Publisher ↗
Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is a sensitive marker of tubular stress and injury that may detect early renal involvement before overt changes in conventional kidney function tests. This case-...
Urinary neutrophil gelatinase-associated lipocalin (uNGAL) is a sensitive marker of tubular stress and injury that may detect early renal involvement before overt changes in conventional kidney function tests. This case-control study evaluated uNGAL as an early biomarker of subclinical kidney injury among adults with substance use disorder (SUD). Adults with SUD and no known kidney disease (n = 31) were compared with age-matched controls (n = 31). uNGAL was measured by ELISA together with serum creatinine and estimated glomerular filtration rate (eGFR; Cockcroft-Gault). uNGAL was markedly higher in participants with SUD than in controls (1913.1 ± 770.9 vs 71.5 ± 26.5 ng/mL; p < 0.001). Serum creatinine was higher, and eGFR was lower in the SUD group, although both remained within generally non-severe ranges. uNGAL demonstrated excellent discrimination between groups (AUC = 1.00; cutoff = 611.5 ng/mL; sensitivity and specificity = 100% in this sample). These findings suggest that uNGAL may reflect early or subclinical renal tubular injury in adults with SUD even when conventional renal markers show only limited changes. Larger prospective studies are needed to validate these findings and clarify prognostic utility.
A comparative study on the developmental toxicity of three dihydroxynaphthalene positional isomers in zebrafish embryos.
Li Z, Xu K, Wang Z … +8 more , Zhi W, Fu D, Zhou X, Hu W, Xiao Z, Cao Z, Li H, Shi X
Toxicol Appl Pharmacol · 2026 Jun · PMID 41850535 · Publisher ↗
Dihydroxynaphthalenes (DHNs) are widely detected in combustion-derived pollution. However, their isomer-specific developmental toxicity remains poorly understood. In this study, we systematically compared the development...
Dihydroxynaphthalenes (DHNs) are widely detected in combustion-derived pollution. However, their isomer-specific developmental toxicity remains poorly understood. In this study, we systematically compared the developmental toxicity of three DHN isomers-1,5-dihydroxynaphthalene (1,5-DHN), 2,3-dihydroxynaphthalene (2,3-DHN), and 2,7-dihydroxynaphthalene (2,7-DHN)-using zebrafish embryos as a vertebrate model. Exposure to DHNs induced distinct, isomer-dependent developmental abnormalities, with 2,3-DHN exerting the most severe effects. Prominent phenotypes included cranial hemorrhage, disrupted cerebrovascular architecture, abnormal erythrocyte distribution, impaired hematopoietic stem cell development, and selective suppression of immune cell populations. In addition, DHN exposure resulted in pronounced neurodevelopmental and craniofacial defects, particularly in the 2,3-DHN treated group. Biochemical analyses revealed significant accumulation of reactive oxygen species (ROS), elevated lipid peroxidation, and disruption of antioxidant enzyme activities, indicating oxidative stress as an important toxicological response. Consistent with these findings, transcriptional analysis demonstrated isomer-specific alterations in genes associated with vascular development, apoptosis, and neurodevelopment, whereas proliferation-related gene expression remained largely unaffected. These results demonstrate that DHN exposure induces multisystem developmental toxicity in zebrafish in a strongly isomer-dependent manner, following the toxicity ranking of 2,3-DHN > 1,5-DHN > 2,7-DHN. Subtle differences in hydroxyl substitution position translate into pronounced differences in redox reactivity and biological outcomes, highlighting oxidative stress as a key contributing mechanism associated with DHN-induced developmental toxicity. These findings demonstrate that environmental transformation of polycyclic aromatic hydrocarbons does not necessarily attenuate toxicity, but may generate derivatives with distinct and potentially enhanced toxicological profiles. Collectively, this study underscores the necessity of incorporating oxygenated PAHs and isomer-specific effects into environmental toxicology and ecological risk assessment.
Melanocyte proliferation gene 1 regulated metabolic reprogramming in acute myocardial infarction based on the AMPK/mTOR pathway.
Zhu S, Qu T, Liu Z … +3 more , Gao Y, Chang X, Yu H
Toxicol Appl Pharmacol · 2026 Jun · PMID 41833858 · Publisher ↗
Melanocyte proliferation gene 1 (MYG1) has been implicated in cellular metabolic regulation; however, its role in cardiomyocyte metabolic reprogramming during acute myocardial infarction (AMI) remains unclear. In this st...
Melanocyte proliferation gene 1 (MYG1) has been implicated in cellular metabolic regulation; however, its role in cardiomyocyte metabolic reprogramming during acute myocardial infarction (AMI) remains unclear. In this study, a rat AMI model was established, and MYG1 knockdown was achieved by lentiviral injection to investigate its effects on myocardial injury and metabolism. Myocardial infarct size, apoptosis, and the expression of metabolic- and autophagy-related proteins were assessed using TTC staining, Western blotting, immunohistochemistry, and TUNEL assays. In parallel, an oxygen-glucose deprivation (OGD) model was generated in H9C2 cells, in which MYG1 was overexpressed alone or in combination with the glycolysis inhibitor 2-deoxy-d-glucose (2-DG), the AMPK activator AICAR, or the mTOR inhibitor rapamycin. MYG1 expression was significantly upregulated in myocardial tissues following AMI. MYG1 knockdown attenuated cardiomyocyte apoptosis, enhanced the expression of mitophagy-related proteins PINK1 and Parkin, reduced the levels of key glycolytic enzymes hexokinase 2 and enolase 1, and promoted mitochondrial oxidative phosphorylation. In vitro, MYG1 overexpression facilitated glycolysis and aggravated OGD-induced cellular injury, whereas inhibition of glycolysis by 2-DG effectively reversed these effects. Furthermore, modulation of the AMPK/mTOR pathway influenced MYG1-associated metabolic alterations, as evidenced by changes in cellular metabolic flux and improved mitochondrial autophagy and ultrastructural integrity. These findings suggest that MYG1 participates in cardiomyocyte metabolic reprogramming during AMI, potentially through regulation of the AMPK/mTOR pathway, and may represent a candidate target for therapeutic intervention.
Ophiopogonin B inhibits triple-negative breast cancer progression via suppressing PTP1B and regulating the PI3K/Akt pathway.
Cheng Y, Luo X, Lin L … +2 more , Xu Y, Zhao S
Toxicol Appl Pharmacol · 2026 Jun · PMID 41831498 · Publisher ↗
OBJECTIVE: This study aimed to investigate whether ophiopogonin B (OP-B), suppresses the progression of triple-negative breast cancer (TNBC) by modulating protein tyrosine phosphatase 1B (PTP1B) activity and the downstre...
OBJECTIVE: This study aimed to investigate whether ophiopogonin B (OP-B), suppresses the progression of triple-negative breast cancer (TNBC) by modulating protein tyrosine phosphatase 1B (PTP1B) activity and the downstream PI3K/Akt signaling pathway. METHODS: The anti-TNBC effects of OP-B on MDA-MB-231 and BT549 cells were evaluated using CCK-8, colony formation, wound healing, and Transwell assays. Cell apoptosis was assessed by TUNEL staining. PTP1B gain- and loss-of-function models were established via lentiviral transduction. Protein expression of PTP1B, PI3K, p-PI3K, Akt, and p-Akt was examined by Western blot. The in vivo antitumor activity of OP-B was investigated in a TNBC xenograft model, with subsequent IHC, TUNEL, and Western blot analyses of tumor tissues. RESULTS: OP-B inhibited the proliferation, migration, and invasion of TNBC cells in a concentration-dependent manner and induced apoptosis. Western blot analysis revealed that OP-B treatment down-regulated the expression of PTP1B protein and suppressed the activity of the PI3K/Akt pathway. Genetic rescue experiments confirmed the critical role of PTP1B: knocking down PTP1B both mimicked and potentiated the antitumor effects of OP-B and its inhibition of the PI3K/Akt pathway, whereas overexpressing PTP1B antagonized these effects. In the MDA-MB-231 cell xenograft mouse model, OP-B treatment significantly inhibited tumor growth, reduced the percentage of Ki67-positive cells in tumor tissues, increased apoptosis, and recapitulated the suppression of the PTP1B/PI3K/Akt signaling axis. CONCLUSION: Collectively, these findings indicate that ophiopogonin B exerts anti-tumor effects against triple-negative breast cancer both in vitro and in vivo through modulating PTP1B and suppressing the downstream PI3K/Akt signaling pathway.
Ezetimibe counteracts lipopolysaccharide-induced liver injury in mice via modulating TLR4-mediated MYD88/TRAF-6/NF-kB signaling pathway.
Sakr AG, Kafl HE, El-Kashef DH
Toxicol Appl Pharmacol · 2026 Jun · PMID 41831497 · Publisher ↗
Sepsis-associated liver injury is one of the signs of multiple organ damage brought on by sepsis. Acute liver injury (ALI) is a potentially fatal acute inflammatory disease that causes necrotic cell death and immediate h...
Sepsis-associated liver injury is one of the signs of multiple organ damage brought on by sepsis. Acute liver injury (ALI) is a potentially fatal acute inflammatory disease that causes necrotic cell death and immediate hepatocyte destruction. This study aimed to investigate the protective effect of ezetimibe (EZE) against lipopolysaccharide (LPS)-induced acute liver injury. Five days prior to a single intraperitoneal injection of LPS (3 mg/kg), male Swiss albino mice weighing 18-25 g were pre-treated orally with EZE at two different dosages (5 and 10 mg/kg), while animals of the control group received only the vehicles. Serum was used to test liver function, while mouse tissue homogenates were used to measure oxidative stress and inflammatory mediators. EZE improved histological changes and dramatically reduced serum liver transaminases. Reduced levels of malondialdehyde (MDA) and increased levels of reduced glutathione (GSH) in hepatic tissues are further indications of its antioxidant action. Moreover, EZE pretreatment significantly reduced the hepatic expression of toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB)p65, interleukin (IL)-1β and tumor necrosis factor (TNFα). Additionally, myeloid differentiation primary-response protein 88 (MYD88), TNF Receptor Associated Factor 6 (TRAF-6) and IL-6 were markedly reduced in the liver by EZE. Collectively, EZE may be a promising candidate in sepsis-related liver injury following further clinical studies.
Hyperoside impairs mitochondrial respiration in chronic myeloid leukemia by promoting STUB1-mediated ubiquitination and degradation of NOX4.
Che H, Zhao B, Yi W … +2 more , Liu P, Hu L
Toxicol Appl Pharmacol · 2026 Jun · PMID 41825841 · Publisher ↗
Chronic myeloid leukemia (CML) cells exhibit a distinct reliance on oxidative phosphorylation (OXPHOS), presenting a metabolic vulnerability for therapeutic intervention. While Hyperoside, a natural flavonol, demonstrate...
Chronic myeloid leukemia (CML) cells exhibit a distinct reliance on oxidative phosphorylation (OXPHOS), presenting a metabolic vulnerability for therapeutic intervention. While Hyperoside, a natural flavonol, demonstrates anti-leukemic activity, its precise molecular targets and impact on mitochondrial bioenergetics remain elusive. In this study, we combined in silico modeling and biophysical validation to identify NADPH oxidase 4 (NOX4) as a direct molecular target of Hyperoside. Surface plasmon resonance and cellular thermal shift assays confirmed high-affinity binding between Hyperoside and NOX4. Hyperoside promotes the proteasomal degradation of NOX4 by enhancing its interaction with the E3 ubiquitin ligase STUB1. This Hyperoside-induced recruitment of STUB1 accelerates NOX4 ubiquitination and turnover in K562 and Meg-01 cells. Functionally, Hyperoside treatment resulted in a severe impairment of mitochondrial respiration, including reduced oxygen consumption rates, diminished ATP production, and inhibitory phosphorylation of the pyruvate dehydrogenase complex. Importantly, these metabolic defects were reversed by NOX4 overexpression or STUB1 knockdown. In summary, our findings characterize a novel STUB1/NOX4 signaling axis and establish Hyperoside as a targeted metabolic modulator that dismantles the bioenergetic machinery essential for CML cell survival.
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