Toxicol. Appl. Pharmacol. [JOURNAL]
Sun
200 papers
Highly efficient discovery of CYP1B1 inhibitors from licorice as novel anti-fibrotic agents via integrating interdisciplinary methodologies.
Li Z, Hao Y, Yang Y … +8 more , Lei J, Zhang F, Song Y, Yin H, Dai Z, Qi S, Cao Y, Ge G
Toxicol Appl Pharmacol · 2026 Jun · PMID 42303053 · Publisher ↗
Aberrant CYP1B1 activity has been implicated in various metabolic disorders, while targeted inhibition on CYP1B1 has been validated as an emerging therapeutic strategy for hepatic fibrosis. Although a range of edible her...
Aberrant CYP1B1 activity has been implicated in various metabolic disorders, while targeted inhibition on CYP1B1 has been validated as an emerging therapeutic strategy for hepatic fibrosis. Although a range of edible herbs including Licorice (the root of Glycyrrhiza glabra) have been widely used for treating liver diseases, identifying the key anti-CYP1B1 constituents in these herbs and elucidating their mechanisms of action remain challenging. This study presents a comprehensive interdisciplinary framework for discovering CYP1B1 inhibitors from herbal medicines (HMs) via integrating interdisciplinary methodologies. An initial fluorescence-based screening of 65 herbal extracts revealed that licorice aqueous extract (LAE) exhibited potent CYP1B1 inhibitory activity. Docking-based virtual screening predicted 23 phytochemicals in LAE as potential CYP1B1 inhibitors, 18 of which were experimentally confirmed as potent CYP1B1 inhibitors (IC < 1 μM). Further investigations showed that the nine most potent phytochemicals in LAE (IC < 260 nM) inhibited CYP1B1 in a competitive manner, with the K values below 560 nM. Cellular assays further demonstrated that three of these phytochemicals (glycyrol, licoflavonol, and licochalcone C) effectively blocked intracellular CYP1B1 activity in living cells (IC < 3 μM). Anti-fibrotic assays showed that glycyrol significantly reduced cell migration and downregulated the expression of key fibrotic genes in TGF-β1-stimulated JS-1 cells. Collectively, this work establishes a practical and efficient strategy for discovering potent anti-CYP1B1 agents from HMs against liver fibrosis, while glycyrol emerges as a promising anti-fibrotic therapeutic.
Growth-mode-independent glutamine/glutamate/aspartate metabolic shift and urea cycle remodeling driven by FOXA1 in benzo[a]pyrene-transformed human bronchial epithelial cells.
Fu Y, Qi Y, Xing Y … +5 more , Lin Y, Liu Z, Fu J, Yao B, Zhao P
Toxicol Appl Pharmacol · 2026 Jun · PMID 42303052 · Publisher ↗
To characterize the amino acid metabolic remodeling in THBEc1 cells malignantly transformed by benzo[a]pyrene (BaP) relative to parental human bronchial epithelial HBE cells, and to delineate the role of FOXA1 in this re...
To characterize the amino acid metabolic remodeling in THBEc1 cells malignantly transformed by benzo[a]pyrene (BaP) relative to parental human bronchial epithelial HBE cells, and to delineate the role of FOXA1 in this remodeling, the amino acid metabolic phenotypes and gene expression patterns of HBE, THBEc1, THBEc1-ctrl (knockout control), and THBEc1-FOXA1 KO (FOXA1 knockout) cells were profiled under 2D, 3D spheroid, and in vivo conditions. Differential metabolic amino acids across these growth modes were identified. THBEc1 cells exhibited a glutamine/glutamate/aspartate metabolic shift and urea cycle remodeling that were conserved across all growth modes, representing key metabolic features of BaP-induced malignant transformation. FOXA1 knockout partially reversed these metabolic alterations across growth modes. Mechanistically, FOXA1 transcriptionally regulated GLUL, SLC6A14, CPS1, and SLC7A2 in a growth-mode-independent manner. These findings establish FOXA1 as a key mediator of the glutamine/glutamate/aspartate metabolic shift and urea cycle remodeling during BaP-induced malignant transformation, with GLUL, SLC6A14, CPS1, and SLC7A2 as critical downstream targets. This work advances the understanding of amino acid metabolic reprogramming in BaP-induced lung carcinogenesis.
Advanced glycation end products promote diabetic retinopathy through the p65-p300/SMAD4-miR-409-5p-HIF-1α-VEGF signaling pathway.
Liu J, Zhang X, Qi X … +3 more , Huang D, Ju J, Li J
Toxicol Appl Pharmacol · 2026 Jun · PMID 42303051 · Publisher ↗
Diabetic retinopathy (DR) is a major complication of diabetes, with advanced glycation end products (AGEs) implicated in its pathogenesis, although the underlying mechanisms remain unclear. This study investigated the ro...
Diabetic retinopathy (DR) is a major complication of diabetes, with advanced glycation end products (AGEs) implicated in its pathogenesis, although the underlying mechanisms remain unclear. This study investigated the role of AGEs in DR using streptozotocin-induced diabetic mice and AGEs-treated human retinal microvascular endothelial cells (hRMECs). ELISA, PAS staining, qRT-PCR, Western blot, and functional assays were conducted to assess molecular and cellular changes. Our results showed that AGEs and VEGF levels were significantly elevated in the retinas and serum of diabetic mice, accompanied by increased retinal neovascularization. Mechanistically, we found that microR-409-5p was found to be upregulated both in diabetic retinas and AGEs-induced hRMECs, where it promoted cellular proliferation, migration, and tube formation. AGEs activated p65 to induce p300 expression, which subsequently interacted with SMAD4 in the nucleus to enhance the transcription of miR-409-5p. Upregulated miR-409-5p in turn induced HIF-1α expression, leading to VEGF upregulation. These findings demonstrated that AGEs contribute to DR progression via the p65-p300/SMAD4-miR-409-5p-HIF-1α-VEGF signaling pathway, identifying miR-409-5p as a potential therapeutic target for DR intervention.
In-depth in vivo and in vitro investigation of metabolism and detectability of three novel methylprolintane psychostimulants by hyphenated mass spectrometry.
Wagmann L, Herter A, Dybek MB … +4 more , Adejare A, Wallach J, Brandt SD, Meyer MR
Toxicol Appl Pharmacol · 2026 Jun · PMID 42303050 · Publisher ↗
Amphetamine-type stimulants (ATS) remain a major group among internationally misused psychostimulants. Prolintane (1-(1-phenylpentan-2-yl)pyrrolidine) is one representative historically applied in clinical settings. Rece...
Amphetamine-type stimulants (ATS) remain a major group among internationally misused psychostimulants. Prolintane (1-(1-phenylpentan-2-yl)pyrrolidine) is one representative historically applied in clinical settings. Recently, 2-, 3-, and 4-methylprolintane, structurally related prolintane analogs, have been identified as inhibitors of monoamine reuptake, prompting the need for detailed toxicological and analytical characterization. To explore their metabolic transformation and assess their detectability in urine, we analyzed rat samples collected over 24 h following oral administration (2 mg/kg) of each isomer, as well as human liver S9 incubations (25 μM; 1 h and 6 h). Metabolites were tentatively assigned using liquid chromatography-high-resolution tandem mass spectrometry (LC-HRMS/MS). Complementary isoenzyme-specific incubations with 11 human phase I monooxygenases enabled mapping of the primary biotransformation routes. The same in vivo samples were subsequently evaluated with commonly used urine screening strategies, including gas chromatography-MS, LC-ion trap MS, and LC-HRMS/MS. Across all isomers, metabolism was extensive, yielding 95 distinct metabolites. Initial hydroxylation and oxidation reactions were mainly linked to the activity of CYP1A2, CYP2B6, CYP2C19, and CYP3A4, followed by conjugation through glucuronidation, sulfation, or O-methylation. Each screening platform successfully detected the compounds via their metabolites; however, the high degree of overlap in the metabolic profiles limits the ability to distinguish between the three isomers. These results provide essential analytical reference data and contribute to toxicological risk assessment of these emerging ATS derivatives.
Aureusidin protects against osteoarthritis via Caspase-3/gasdermin E-mediated pyroptosis.
Feng S, Song K, Zhang H … +4 more , Wang Z, Zhao Y, Zhao Z, Wan C
Toxicol Appl Pharmacol · 2026 Jun · PMID 42297245 · Publisher ↗
This study investigated the effects of Aureusidin on extracellular matrix (ECM) degradation and pyroptosis of chondrocytes in osteoarthritis. Network pharmacology, molecular docking, and pull-down assays were initially c...
This study investigated the effects of Aureusidin on extracellular matrix (ECM) degradation and pyroptosis of chondrocytes in osteoarthritis. Network pharmacology, molecular docking, and pull-down assays were initially conducted to explore the target of Aureusidin. Subsequently, Sprague-Dawley rats underwent anterior cruciate ligament transection (ACLT) received oral administration of Aureusidin. Cartilage damage was evaluated histopathologically by H&E and Safranin O-fast green staining. Primary rat chondrocytes were treated with Aureusidin under IL-1β stimulation. Pyroptotic morphology was observed under light microscopy. Propidium iodide staining and flow cytometry were conducted to evaluate membrane rupture. The expression of markers associated with ECM degradation and pyroptosis was analyzed by qRT-PCR, Western blot, immunohistochemistry, and ELISA. Caspase-3 was identified as a target for Aureusidin. Aureusidin (5, 10, 20 mg/kg) alleviated ACLT-induced cartilage damage and ECM degradation. It reduced the OARSI score and serum levels of CTX-II and COMP, while upregulating the expression of Col2a1 and Acan, and downregulating Adamts5, Mmp13, and Mmp3. Aureusidin also mitigated atypical pyroptosis, evidenced by inhibited expression of GSDME-N, Caspase-3, and Cleaved-Caspase-3, and decreased levels of IL-1β and IL-18. In IL-1β-stimulated primary chondrocytes, Aureusidin (5, 10, 20 μM) attenuated ECM degradation and Caspase-3/GSDME-mediated pyroptosis. Treating chondrocytes with the Caspase-3 inhibitor Z-DEVD-FMK under IL-1β-stimulated conditions alleviated ECM degradation and pyroptosis, but the additional application of Aureusidin did not provide further inhibition. Aureusidin has the potential to inhibit ECM degradation and Caspase-3/GSDME-mediated chondrocyte pyroptosis during osteoarthritis progression. Its therapeutic effects are dependent on binding to and modulating the Caspase-3.
Targeting NFS1-mediated ferroptosis mitigates alveolar injury in experimental idiopathic pulmonary fibrosis.
Li J, Cao Y, Wang Y … +1 more , Shi H
Toxicol Appl Pharmacol · 2026 Jun · PMID 42297244 · Publisher ↗
Idiopathic pulmonary fibrosis (IPF), a lethal form of interstitial lung disorder, has recently been recognized as a ferroptosis-associated disorder, with the inhibition of ferroptosis offering promising therapeutic poten...
Idiopathic pulmonary fibrosis (IPF), a lethal form of interstitial lung disorder, has recently been recognized as a ferroptosis-associated disorder, with the inhibition of ferroptosis offering promising therapeutic potential. Cysteine desulfurase (NFS1) is a pivotal ferroptosis-related gene involved in regulating ferroptotic processes in multiple diseases. Nonetheless, the involvement of NFS1-mediated ferroptosis in the pathogenesis of IPF is still not well understood. The objective of this research was to explore the role of NFS1 in the advancement of IPF and to elucidate the mechanisms that contribute to this process. Significantly reduced levels of NFS1 were identified in the lungs of bleomycin (BLM)-challenged mice and BLM-exposed alveolar epithelial cells. The upregulation of NFS1 in alveolar epithelial cells markedly mitigated BLM-induced cell injury and ferroptosis, whereas NFS1 silencing exacerbated these effects. Moreover, BLM stimulation induced an iron-starvation response, as indicated by increased levels of IRP1 and TFR1 and decreased expression of FTH1. Notably, NFS1 overexpression reversed these changes by reducing IRP1 and TFR1 expression while upregulating FTH1 levels in BLM-stimulated alveolar epithelial cells. Furthermore, the exacerbation of ferroptosis caused by NFS1 silencing was abolished by IRP1 knockdown. In a BLM-induced IPF mouse model, NFS1 overexpression effectively alleviated lung injury and fibrosis, accompanied by suppression of the iron-starvation response and ferroptosis. Collectively, these findings demonstrate that NFS1 exerts a protective role against IPF by suppressing ferroptosis of alveolar epithelial cells through the modulation of iron-starvation response-induced iron overload. This research clarifies a previously unrecognized mechanism that governs the regulation of ferroptosis in IPF and emphasizes the potential of NFS1 as a promising therapeutic target for addressing this severe condition.
A fully human antibody A140 neutralizes abrin toxin via lysosomal intracellular mechanisms, confers potent protection in vitro and in vivo, and reverses transcriptomic dysregulation with a Favorable safety profile.
Qin F, Chen SY, Lin P … +5 more , Wang B, Fu X, Jiang JL, Cui HY, Wang SJ
Toxicol Appl Pharmacol · 2026 Jun · PMID 42297243 · Publisher ↗
Abrin is a type II ribosome-inactivating protein extracted from the seeds of Abrus precatorius. Due to its extreme toxicity and ease of acquisition, it is classified as a Category B bioterrorism agent, and no effective a...
Abrin is a type II ribosome-inactivating protein extracted from the seeds of Abrus precatorius. Due to its extreme toxicity and ease of acquisition, it is classified as a Category B bioterrorism agent, and no effective antidote is currently available. In this study, a fully human antibody against abrin, designated A140, was generated via screening of a fully human phage-display antibody library and subsequent expression. The A140 antibody demonstrates high affinity while maintaining specificity for its target antigen. It exhibited potent neutralizing efficacy against abrin toxin in both in vitro and in vivo assays. Intriguingly, the A140 antibody, which enters cells via clathrin-dependent and macropinocytic pathways and is subsequently trafficked to lysosomes, does not prevent the cellular entry of abrin, suggesting that its intracellular neutralization activity may function within the lysosomal compartment. Molecular docking studies based on AlphaFold 3 (AF3) indicate that A140 primarily recognizes residues Ser14, Arg169, and Asn173 of the alpha chain of abrin-a. Transcriptomic analysis based on Vero E6 cells showed that A140 antibody treatment was able to reverse almost 80% of the transcriptomic changes induced by abrin. Preliminary toxicity analysis shows that a high dose of the A140 antibody has no impact on the heart, liver, spleen, lungs, kidneys, and other major organs in mice. Our findings indicate that the A140 antibody, as a novel fully human antibody, holds promise as a key therapeutic agent for the treatment of abrin intoxication.
Biodistribution and toxicity of inhaled nickel oxide nanoparticles: Potential application to realistic exposure.
Jung W, Park H, Yoon C … +3 more , Lee GH, Kim JB, Park EJ
Toxicol Appl Pharmacol · 2026 Jun · PMID 42288192 · Publisher ↗
As industrial applications of nickel oxide nanoparticles (NiONPs) increase due to their high surface energy and magnetic properties, their potential adverse health effects are emerging as a public concern. We administere...
As industrial applications of nickel oxide nanoparticles (NiONPs) increase due to their high surface energy and magnetic properties, their potential adverse health effects are emerging as a public concern. We administered NiONPs to mice via pharyngeal aspiration for 90 days and investigated their biodistribution and toxicity. NiONPs were primarily deposited in lung tissues, with translocation into other tissues. Blood triglyceride levels decreased significantly in male mice but increased in female mice, and glucose levels were elevated in both male and female mice. NiONPs increased the total number of pulmonary immune cells, accompanied by increases in the proportions of neutrophils and lymphocytes. Similarly, the concentrations of proinflammatory cytokines and tissue damage-related mediators increased notably in the lungs of male and female mice exposed to NiONPs (50 μg/mouse) compared with controls. Collagen fibers, lamellar body-like structures, and tubular myelin were frequently observed in the lung tissues of mice exposed to NiONPs. Given that toxicity test results at unrealistic doses are used only to a limited extent in setting permissible exposure limits, we also compared differences across exposure frequencies for the same amount. The lung burden was 2.51-fold higher in mice administered a 50 μg single dose than in mice administered 10 μg five times, and the pulmonary level of inflammatory mediators and the proportion of neutrophils were also higher in mice administered a 50 μg single dose. Meanwhile, the effects on each test item showed a similar trend between the two groups. Collectively, we conclude that chronic airway exposure to NiONPs may cause lung tissue damage by activating inflammatory mediators and may also result in systemic adverse health effects, depending on their distribution. Considering the unique lamellar body-like structures observed in the lungs, we also believe that further study is needed to elucidate their formation process and chronic health effects.
Novel peptide Aurein1.2 derivative induces cytotoxicity in cervical cancer SiHa and HeLa cells by apoptosis and cell cycle arrest.
Zhang Y, Sun M, Li M … +3 more , Zhang M, Liu Y, Han Y
Toxicol Appl Pharmacol · 2026 Jun · PMID 42276299 · Publisher ↗
Cervical cancer remains one of the most common diseases among women worldwide. Although its incidence rate has been on the decline due to widespread vaccination and other preventive measures, significant disparities in p...
Cervical cancer remains one of the most common diseases among women worldwide. Although its incidence rate has been on the decline due to widespread vaccination and other preventive measures, significant disparities in prevalence persist across different age groups. Antimicrobial peptides (AMPs) have garnered considerable attention as potential alternative chemotherapeutic agents. The present study aimed to investigate the cytotoxic effect of the Aurein1.2 variant (Aurein1.2 m) on cervical cancer cells and elucidate its underlying mechanism. Results demonstrated that Aurein1.2 m exerted significant cytotoxicity against two cervical cancer cell lines (SiHa and HeLa) while exhibiting relatively low toxicity toward normal cells. Flow cytometry analysis with Annexin V-FITC/PI double staining revealed that Aurein1.2 m induced apoptosis and arrested the cell cycle at the G0/G1 phase in SiHa and HeLa cells. Mechanistically, Aurein1.2 m impaired mitochondrial function by disrupting the mitochondrial membrane potential (Δψm), elevating reactive oxygen species (ROS) levels, and regulating the expression of Bax, Bcl-2, Cleaved caspase 3, and PARP, ultimately leading to mitochondria-dependent apoptosis in SiHa and HeLa cells. Additionally, Aurein1.2 m modulated the expression of CDK4 and Cyclin D1 through inhibiting c-Myc, thereby contributing to G0/G1 phase cell cycle arrest. In vivo experiments showed that Aurein1.2 m effectively suppressed the growth of SiHa-derived tumors without inducing any adverse effects. In conclusion, Aurein1.2 m exerts cytotoxicity against cervical cancer cells by promoting mitochondria-dependent apoptosis and arresting the cell cycle via c-Myc inhibition, highlighting its potential for development as an anti-cervical cancer therapeutic agent.
Artemisinin alleviates cardiac and cerebral injury after cardiopulmonary resuscitation in pigs by regulating the HMGB1/TLR4/NF-κB mediated inflammatory pathway.
Liang L, Wang C, Luo C … +4 more , You B, Hu Y, Xu J, Chen Q
Toxicol Appl Pharmacol · 2026 Jun · PMID 42264193 · Publisher ↗
Artemisinin (Art), a sesquiterpene lactone for malaria therapy, attenuates ischemia-reperfusion-induced inflammation in vital organs. This study explored its protective effects and molecular mechanisms against cardiac an...
Artemisinin (Art), a sesquiterpene lactone for malaria therapy, attenuates ischemia-reperfusion-induced inflammation in vital organs. This study explored its protective effects and molecular mechanisms against cardiac and cerebral injury in male white pigs after cardiac arrest (CA)/cardiopulmonary resuscitation (CPR). Twenty-two pigs were randomized into sham (n = 6), CPR (n = 8), and Art (CPR + Art, n = 8) groups. A CPR model was established via ventricular fibrillation in the latter two groups, with Art intravenously administered to the Art group post return of spontaneous circulation (ROSC). Hemodynamics, blood gas, cardiac function, cardio-cerebral injury markers, neurological deficit score (NDS), inflammatory cytokines, and HMGB1/TLR4/NF-κB pathway protein expression were compared among groups. No intergroup differences were observed in baseline indices and coronary perfusion pressure during resuscitation (P>0.05), while the Art group had a higher 24-h survival rate (100%) than the CPR group (75%). Compared with the sham group, both the CPR and Art groups exhibited elevated heart rate, reduced blood pressure, decreased PaO₂ and pH, and increased lactic acid levels post-CA/CPR, indicative of acidosis. However, the Art group presented superior hemodynamic profiles, improved post-resuscitation cardiac function, reduced cardio-cerebral injury markers, and lower NDS compared with the CPR group (P < 0.05). We also found that Art downregulated the expression of cardio-cerebral tissue inflammatory cytokines and HMGB1/TLR4/NF-κB pathway proteins (P < 0.05). Collectively, Art treatment facilitates hemodynamic recovery and exerts a protective effect against CA/CPR-induced cardio-cerebral injury. The underlying mechanism may involve the inhibition of CA/CPR triggered inflammatory response via suppressing the HMGB1/TLR4/NF-κB signaling pathway.
Brefeldin A induces apoptosis in cisplatin-resistant ovarian cancer cells independent of ABCC2-mediated drug efflux.
Haghi SM, Tavakkoli A, Iranshahi M … +4 more , Kalalinia F, Hashemi M, Najafzadeh MJ, Mosaffa F
Toxicol Appl Pharmacol · 2026 Jun · PMID 42263956 · Publisher ↗
BACKGROUND: Resistance to platinum chemotherapy remains a major obstacle in ovarian cancer treatment and is often associated with overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters such as...
BACKGROUND: Resistance to platinum chemotherapy remains a major obstacle in ovarian cancer treatment and is often associated with overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) transporters such as ABCC2. Agents that retain cytotoxic efficacy in resistant cells through transporter-independent mechanisms may provide a therapeutic advantage. METHODS & MATERIALS: Brefeldin A (BFA), a fungal metabolite with known anticancer activity, was isolated from the endophytic fungus Dactylonectria torresensis and characterized by nuclear magnetic resonance (NMR) spectroscopy. Cytotoxicity and chemosensitization were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assays in cisplatin-sensitive (A2780) and cisplatin-resistant ovarian cancer cell line (A2780/RCIS). Cisplatin efflux transporter expression level was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), while transporter activity was assessed by flow cytometry using 5-carboxyfluorescein diacetate (5-CFDA). Cell cycle distribution and apoptosis-associated cell death (based on Sub-G1 accumulation) were examined by propidium iodide (PI) staining and flow cytometry. RESULTS: BFA exhibited comparable cytotoxicity in sensitive and resistant cells (inhibitory concentration (IC)₅₀ 47.2 ± 2.3 and 53.6 ± 3.8 nM, respectively), indicating that ABCC2 overexpression in resistant cells did not affect cellular responsiveness. Treatment with a non-cytotoxic concentration of BFA did not alter ABCC1/ABCC2 expression or transporter activity. Instead, co-treatment with cisplatin and BFA enhanced G2/M cell cycle arrest and increased the Sub-G1 population in both cell lines, consistent with apoptosis-associated cell death. Co-treatment resulted in a modest increase in cisplatin-induced growth inhibition, suggesting apoptotic priming rather than efflux inhibition. CONCLUSION: BFA maintains cytotoxic efficacy in cisplatin-resistant ovarian cancer cells through apoptosis-associated mechanisms that are independent of ABCC2-mediated drug efflux. These findings indicate that BFA avoids classical transporter-mediated resistance and could be a candidate for targeting drug-resistant ovarian cancer.
Matrine ameliorated myocardial ischemia-reperfusion injury through lipid accumulation reduction by activating JAK2-STAT3-CPT1 signaling pathway.
Liu M, Cheng X, Jiang H … +7 more , Mao Y, Li J, Qiao C, Wang X, Wang W, Gao S, Zhou K
Toxicol Appl Pharmacol · 2026 Jun · PMID 42263955 · Publisher ↗
Matrine (MT), the most abundant active compound derived from Sophora flavescens Ait, has demonstrated promising cardioprotective effects against myocardial ischemia-reperfusion (MIR) injury, and is known to reduce excess...
Matrine (MT), the most abundant active compound derived from Sophora flavescens Ait, has demonstrated promising cardioprotective effects against myocardial ischemia-reperfusion (MIR) injury, and is known to reduce excessive triglyceride (TG) level in hyperlipidemia. However, the specific effects and molecular mechanism of MT in regulating cardiac lipid metabolism have remained elusive. This study investigated the role and underlying mechanism of MT in restoring disrupted lipid metabolism in cardiomyocytes. Our results indicate that MT treatment significantly improved MIR-induced cardiac insufficiency and reduced TG accumulation in the heart. Mechanistically, MT significantly promoted CPT1b expression by activating the JAK2-STAT3 phosphorylation pathway, which consequently restored fatty acid oxidation and alleviated lipid droplet deposition. Crucially, the cardioprotective effects of MT, including the reduction of mitochondrial damage and the inhibition of apoptosis, were significantly attenuated when the JAK2 inhibitor was co-administered. In summary, this study suggests a critical role for the JAK2-STAT3-CPT1b signaling pathway in mediating the protective effects of MT against MIR-induced lipid metabolism dysfunction in cardiomyocytes.
Pyrazole permethrin-induced liver toxicity in mice involves the PI3K/AKT/NF-κB pathway: Integrated network pharmacology and experimental validation.
Chen J, Liu B, Li Y … +5 more , Zhuang B, Su D, Sang Y, Dong Z, Liu H
Toxicol Appl Pharmacol · 2026 Jun · PMID 42259493 · Publisher ↗
Pyrazole permethrin (also known as pyraclostrobin, abbreviated as PP) is a widely used fungicide that is chemically stable and fat-soluble; however, due to its accumulation in the environment and bioaccumulation, it pose...
Pyrazole permethrin (also known as pyraclostrobin, abbreviated as PP) is a widely used fungicide that is chemically stable and fat-soluble; however, due to its accumulation in the environment and bioaccumulation, it poses potential health risks.This study systematically elucidates PP-induced liver injury through a combination of network toxicology and in vitro/in vivo investigations. Network toxicology identified 328 potential targets and 12 core genes associated with PP-induced liver injury. GO and KEGG enrichment analyses revealed pathway enrichment emphasizing biological processes such as inflammation, oxidative stress, apoptosis, and lipid metabolism. In vivo experiments in mice revealed that after 28 days of exposure, histopathological analysis showed minor local inflammatory cell infiltration and extensive hepatocyte necrosis and vacuolation in both low- and high-dose groups. High-dose PP significantly elevated serum transaminase (AST and ALT) activity. Biochemical analysis revealed that PP treatment reduced antioxidant enzyme activity (CAT, T-AOC, GSH-Px) while increasing malondialdehyde (MDA) levels, inducing oxidative stress. Additionally, PP exposure enhanced the expression of inflammatory cytokines (IL-1β, TNF-α). This indicates activation of oxidative stress and inflammatory pathways: oxidative damage occurs via depletion of the antioxidant enzyme system, while inflammatory cascades are mediated through the PI3K/AKT/NF-κB signaling axis. This study reveals key molecular targets and pathways involved in PP-induced hepatotoxicity, suggesting that subacute exposure risks should be fully considered when establishing safety standards for agricultural chemical use.
Closantel mitigates acute kidney injury by preserving ATP-dependent sodium transport and renal hemodynamics via antioxidant mechanisms.
Silva JK, Siqueira LCS, Cirilo MAS … +13 more , Farias TSP, Ribeiro FPB, Carvalho JM, Santos VBS, Calzerra NTM, Chávez-Canales M, Pérez-Villalva R, Barragán-Jiménez K, Castañeda-Bueno M, Bobadilla NA, Gamba G, Wanderley AG, Vieira LD
Toxicol Appl Pharmacol · 2026 Jun · PMID 42252028 · Publisher ↗
Renal ischemia-reperfusion (IR) injury increases the production of reactive oxygen species (ROS), alters tubular sodium transport, and activates tubuloglomerular feedback (TGF). Closantel is an allosteric inhibitor of th...
Renal ischemia-reperfusion (IR) injury increases the production of reactive oxygen species (ROS), alters tubular sodium transport, and activates tubuloglomerular feedback (TGF). Closantel is an allosteric inhibitor of the SPAK/OSR1 signaling pathway. This study investigated whether closantel mitigates IR-induced acute kidney injury (AKI) by modulating the SPAK/NKCC2 pathway, renal redox balance and hemodynamics. Male Wistar rats underwent 30 min of bilateral renal ischemia and 72 h of reperfusion. Closantel (2.5, 5, or 10 mg/kg) was administered 24 h before and after ischemia. Renal IR resulted in increased serum creatinine (∼70%), albuminuria (∼400%), tubulointerstitial injury score (8-fold), and fractional excretion of Na, K, and Cl (by 200-450%). Cortical (Na+K) ATPase activity decreased by 40%, while medullary activity increased by 133%. Oxidative stress markers (ROS, lipid peroxidation, NADPH oxidase) were elevated, and antioxidant defenses (SOD, catalase) were impaired. Closantel (10 mg/kg) significantly inhibited the SPAK/NKCC2 pathway, reducing protein levels of SPAK, total NKCC2, and phosphorylated NKCC2 (p-NKCC2) by ∼70%. This was accompanied by normalized fractional excretion of Na, K, and Cl, reflecting restored tubular reabsorptive efficiency. In the cortex, closantel induced a supraphysiological upregulation of (Na+K)ATPase activity, whereas medullary activity was restored to Sham levels. Furthermore, closantel improved glomerular filtration rate and renal blood flow while reducing renal vascular resistance. In conclusion, closantel protects against AKI by inhibiting the SPAK/p-NKCC2 signaling axis, mitigating oxidative stress, and restoring renal reabsorptive efficiency and hemodynamics.
EGFR suppression mediates aurantio-obtusin-induced autophagy-dependent ferroptosis in breast cancer cells.
Wang Y, Zhou S, Yu X … +2 more , Cui J, Wu T
Toxicol Appl Pharmacol · 2026 Jun · PMID 42235648 · Publisher ↗
Emerging evidence suggests that triggering ferroptosis could be a promising approach for combating breast cancer. Here, we investigated the role of aurantio-obtusin (AO), a key bioactive compound sourced from Cassiae sem...
Emerging evidence suggests that triggering ferroptosis could be a promising approach for combating breast cancer. Here, we investigated the role of aurantio-obtusin (AO), a key bioactive compound sourced from Cassiae semen, in the treatment of breast cancer. Cell viability and death were determined via a CCK-8 assay and propidium iodide (PI) staining. Ferroptosis was determined by the levels of Fe2+, lipid ROS, and GSH. Autophagy was assessed by immunofluorescence staining. An MDA-MB-231 cell transplantation tumor model was established in vivo. AO inhibited breast cancer cell growth in a concentration-dependent manner while promoting cell death. Ferroptotic changes, including blockage of the GSH-GPX4 antioxidation system, massive iron release, and lipid ROS accumulation, were evident in AO-treated breast cancer cells. Antioxidant N-acetylcysteine (NAC) treatment markedly restored GSH content and suppressed lipid ROS overproduction to relieve AO-triggered ferroptosis. The introduction of the iron scavenger deferoxamine or the ferroptosis inhibitor ferrostatin-1 weakened AO-induced ferroptosis in breast cancer cells. Moreover, AO treatment promoted autophagosome formation in breast cancer cells via the mTOR-ULK1 pathway. AO-induced autophagy and ferroptosis were both reversed by Atg7 knockdown or mTOR activator MHY1485 treatment. Network pharmacology and molecular docking investigations suggested that EGFR was a potential target of AO in breast cancer and that its protein expression was suppressed by AO. Selective EGFR inhibitor gefitinib exacerbated AO-mediated ferroptosis and autophagy, while genetic overexpression of EGFR completely reversed these AO-mediated phenotypes. In vivo assays confirmed the antitumor effects of AO. Our study revealed that AO facilitated autophagy-dependent ferroptosis in breast cancer cells through the downregulation of EGFR. This work provides a new perspective on the antitumor activity of AO, which is valuable for further investigations of the practical application of AO in breast cancer.
mTORC1-mediated inhibition of AMBRA1/PINK1/Parkin-dependent mitophagy contributes to renal podocyte injury in trichloroethylene-sensitized mice.
Bai Q, You C, Qin Z … +2 more , Zhu Q, Xie H
Toxicol Appl Pharmacol · 2026 Aug · PMID 42225213 · Publisher ↗
Trichloroethylene (TCE) is extensively utilized within industrial settings. Certain individuals with occupational exposure may develop occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT), with rena...
Trichloroethylene (TCE) is extensively utilized within industrial settings. Certain individuals with occupational exposure may develop occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT), with renal injury being a predominant clinical manifestation among OMDT patients. Prior research has demonstrated that TCE-sensitized mice exhibit glomerular podocyte damage and activation of the mTOR signaling pathway, although the precise mechanisms remain unclear. In the present study, we employed Rapamycin, an mTORC1 inhibitor, to intervene in a TCE-sensitized mouse model. This was complemented by TCE-sensitized mice serum-induced mouse podocyte clone-5 (MPC5) cell model to elucidate the mechanism through which mTORC1 contributes to podocyte damage during TCE sensitization. The findings indicate that activation of mTORC1 results in the downregulation of autophagy/beclin-1 regulator-1 (AMBRA1) expression. Following intervention with Rapamycin, there was a significant restoration of AMBRA1 expression in mice, accompanied by increased mitophagy and decreased apoptosis levels. In vitro studies using cell culture models demonstrated that MPC5 cells exposed to serum from TCE-sensitized mice showed markedly reduced expression of PINK1 and Parkin proteins, along with suppressed mitophagy levels. Treatment with Rapamycin or si-AMBRA1 effectively enhanced cellular mitophagy and diminished apoptosis. This study elucidates that TCE sensitization activates the mTORC1 signaling pathway, leading to the downregulation of AMBRA1. The suppression of AMBRA1 impedes the PINK1/Parkin-dependent mitophagy pathway, hindering the timely clearance of damaged mitochondria in podocytes. Consequently, this results in the release of cytochrome C into the cytoplasm, which triggers podocyte apoptosis signaling, compromises the integrity of the glomerular filtration barrier, and ultimately leads to renal dysfunction.
Therapeutic mechanism of imperatorin in allergic rhinitis via anti-inflammatory action and restoration of nasal epithelial barrier integrity.
Zhang Y, Wang J, Li S … +3 more , Zeng Z, Bu Y, Wang N
Toxicol Appl Pharmacol · 2026 Jun · PMID 42219115 · Publisher ↗
Allergic rhinitis (AR) is a highly prevalent allergic disease worldwide, significantly impairing patients' quality of life. Current clinical management focuses primarily on symptom control, while natural compounds derive...
Allergic rhinitis (AR) is a highly prevalent allergic disease worldwide, significantly impairing patients' quality of life. Current clinical management focuses primarily on symptom control, while natural compounds derived from herbal medicines offer a valuable complementary therapeutic strategy. This study investigates the therapeutic effect and underlying mechanism of imperatorin (IMP), a furanocoumarin derived from the traditional Chinese medicine Bai Zhi (Angelica Dahurica), in an ovalbumin (OVA)-induced murine model of AR. The efficacy of IMP was evaluated based on nasal mucosal histopathology, allergy-related behavioral changes, and cytokine levels in nasal lavage fluid. Furthermore, the protective effect of IMP on nasal epithelial barrier function was assessed both in vivo and in vitro. RNA sequencing of nasal epithelial tissue revealed several key differentially expressed genes in AR mice, including Gucy2c and Chac1, whose aberrant expression was significantly reversed following IMP treatment and were further confirmed participated in cytokine release and barrier integrity. Our findings indicates that IMP may alleviate AR symptoms through dual mechanisms: exerting anti-inflammatory effects and restoring nasal epithelial barrier integrity, thereby supporting its potential as a multi-target complementary agent for AR treatment.
Oral toxicokinetics of the indoor air pollutant, α-pinene, and its genotoxic metabolite, α-pinene oxide, in rodents and comparison to inhalation route of exposure.
Waidyanatha S, Fennell TR, Black SR … +4 more , Silinski MR, Knudsen GA, Fernando RA, Rider CV
Toxicol Appl Pharmacol · 2026 Aug · PMID 42217586 · Publisher ↗
α-Pinene is a monoterpene with potential human exposure via oral and inhalation routes and has been associated with bladder hyperplasia and decrease in sperm counts in rodents following inhalation exposure. The toxicokin...
α-Pinene is a monoterpene with potential human exposure via oral and inhalation routes and has been associated with bladder hyperplasia and decrease in sperm counts in rodents following inhalation exposure. The toxicokinetics of α-pinene and α-pinene oxide was investigated following 7-day oral administration of α-pinene in rats (10, 50, and 150 mg/kg) and mice (50 mg/kg). α-Pinene was absorbed following oral administration. In rats, α-pinene systemic exposure (maximum concentration (C) and area the under the concentration versus time curve (AUC)) increased less than dose-proportionally, except for C in females, which increased proportionally with dose. While no sex difference was apparent at 10 mg/kg, female rats exhibited 2- to 3-fold higher exposure than males at 150 mg/kg. Oral bioavailability in rats was moderate at 10 mg/kg and higher in females (49%) than in males (32.7%)-bioavailability decreased at 150 mg/kg (females, 22.4%; males 4.89%). In mice, bioavailability was lower and similar between sexes (female, 18.5%; male, 19.8%). In both species, α-pinene was metabolized to α-pinene oxide. In rats, α-pinene oxide systemic exposure was similar to α-pinene, in contrast to inhalation exposure where α-pinene oxide concentration was lower than α-pinene. In mice, α-pinene oxide exposure was lower than that of α-pinene following oral administration. No apparent sex difference in α-pinene oxide systemic exposure were observed in either species. Both α-pinene and α-pinene oxide were distributed to mammary tissues. These findings will allow extrapolation of inhalation toxicology data to oral exposures and subsequent assessment of potential adverse human health impact to α-pinene exposure.
Expression and functional role of NAD(P)H:quinone oxidoreductase 1 (NQO1) in glycidyl methacrylate-induced malignant transformation of lung epithelial cells.
Liu X, Wu H, Cui Y … +9 more , Liu Y, Liu Z, Sun J, Ge Y, Jin Y, Gan J, Yao W, Bi Y, Sun G
Toxicol Appl Pharmacol · 2026 May · PMID 42214696 · Publisher ↗
Glycidyl methacrylate (GMA), a widely used industrial epoxy monomer, is classified as a Group 2A carcinogen by the International Agency for Research on Cancer. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a critical phase...
Glycidyl methacrylate (GMA), a widely used industrial epoxy monomer, is classified as a Group 2A carcinogen by the International Agency for Research on Cancer. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a critical phase II detoxifying enzyme that maintains cellular redox homeostasis and is frequently upregulated in lung cancer. However, the molecular mechanism of GMA-induced lung adenocarcinoma remains unclear, particularly the regulatory role of NQO1 in this malignant process. This study aimed to investigate NQO1 expression and function during GMA-induced malignant transformation of lung epithelial cells and its correlation with oxidative stress signaling. A malignant cell model was established by chronic GMA exposure. Functional assays and xenograft tumor experiments were performed to evaluate malignant phenotypes, while transcriptomic sequencing and molecular verification were applied to screen and validate key molecules. Long-term GMA exposure significantly promoted the malignant transformation of lung epithelial cells. NQO1 was markedly upregulated in transformed cells, and NQO1 knockdown suppressed malignant behaviors and induced apoptosis. GMA increased intracellular reactive oxygen species and activated Nrf2/HO-1 signaling, which was reversed by antioxidant treatment. NQO1 was also highly expressed in clinical lung adenocarcinoma tissues. Collectively, NQO1 facilitates GMA-induced malignant transformation via the reactive oxygen species-Nrf2/HO-1 signaling pathway.
Physio-transcriptomic perspectives on midgut structural disruption and metabolic imbalance underlying neodymium oxide toxicity in Bombyx mori.
Chen L, Yin J, Li W … +5 more , Xiao J, Xie Q, Ma L, Fang Y, Zeng X
Toxicol Appl Pharmacol · 2026 May · PMID 42208909 · Publisher ↗
The Bombyx mori (B. mori) is an economically important insect and toxicological model. Neodymium oxide (Nd₂O₃), a widely used rare earth oxide, has unclear biological effects. Fifth-instar B. mori larvae were exposed to...
The Bombyx mori (B. mori) is an economically important insect and toxicological model. Neodymium oxide (Nd₂O₃), a widely used rare earth oxide, has unclear biological effects. Fifth-instar B. mori larvae were exposed to Nd₂O₃ (0-3.2 μg/μL), and growth, oxidative stress, midgut morphology, and transcriptomic profiles were evaluated. High-concentration exposure inhibited weight gain and induced oxidative stress. This was evidenced by elevated ROS, reduced SOD activity, and GSH depletion. Histopathology and TEM revealed the midgut as a primary target, showing epithelial thinning, villus disruption, mitochondrial swelling, and vacuolization. RNA-seq identified 922 differentially expressed genes. RT-qPCR validated the dysregulation of representative metabolism-related DEGs, including fatty acid metabolism-associated BMSK0006934 (BglB) and BMSK0009525 (uncharacterized metabolism-related gene), PPAR signaling-related BMSK0003301 (Scd3) and BMSK0011688 (Pepck), and cholesterol digestion-related BMSK0004756 (ALLC) and BMSK0003704 (Tryp_SPc). Conserved domain analysis confirmed these genes encode critical metabolic enzymes (Δ9-desaturase, PEPCK, allantoinase). Our findings demonstrate that Nd₂O₃ impairs B. mori growth through oxidative stress, midgut structural damage, and transcriptomic reprogramming of metabolic pathways. This study provides new insights into the ecotoxicology of rare earth oxides.
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