Toxicol. Appl. Pharmacol. [JOURNAL]
Sun
200 papers
Unveiling the therapeutic potential and leukemia risk of PD-166866 in sepsis via an integrated computational-experimental strategy.
Chang M, Shang Y, Zheng J … +2 more , Wang W, Zhao T
Toxicol Appl Pharmacol · 2026 Feb · PMID 41478319 · Publisher ↗
OBJECTIVE: This study evaluates the anti-sepsis efficacy and potential risks of the FGFR1 inhibitor PD-166866 by integrating network pharmacology, transcriptome sequencing, and network toxicology. METHODS: In terms of dr...
OBJECTIVE: This study evaluates the anti-sepsis efficacy and potential risks of the FGFR1 inhibitor PD-166866 by integrating network pharmacology, transcriptome sequencing, and network toxicology. METHODS: In terms of druggability, network pharmacology was used to screen drug-disease common targets and conduct enrichment analysis. Meanwhile, transcriptome sequencing was performed on the LPS-induced Raw264.7 cell model for target validation. In terms of toxicology, network toxicology was applied to predict the potential toxicity of small molecules, which was further verified by gene expression and survival analysis using the TCGA and Kaplan-Meier Plotter databases. RESULTS: A total of 39 common targets between PD-166866 and sepsis were identified. The core pathways include the Rap1 signaling pathway, and the core targets are SRC, EGFR, and CCND1; molecular docking showed stable binding between PD-166866 and these targets. Transcriptomic analysis confirmed that PD-166866 can significantly regulate the expression of inflammation-related genes and inhibit the Rap1 pathway. Network toxicology indicated a significant risk of hematological toxicity associated with this drug. Transcriptome sequencing revealed that PD-166866 treatment led to the downregulation of IRAK3 and IKBKE, and the low expression of these two genes was significantly associated with poor prognosis in leukemia patients, confirming the potential hematological toxicity of PD-166866. CONCLUSION: This study confirms that PD-166866 exerts anti-sepsis effects by regulating pathways such as Rap1, but it also has the potential risk of inducing leukemia. More importantly, this study successfully established a comprehensive evaluation framework integrating in silico and in vitro experiments. It provides a feasible methodological reference for systematically evaluating the dual attributes of "efficacy-risk" in the early stage of drug development and reducing the initial reliance on traditional animal models.
Benign cardiac troponin I release induced by elevated beat rate is associated with membrane bleb formation.
Hatahet J, Nonarath HJ, Zafiratos MT … +4 more , Jasiek G, Kohnken R, Treadway J, Foley CM
Toxicol Appl Pharmacol · 2026 Feb · PMID 41478318 · Publisher ↗
Cardiac troponin I (cTnI), a key regulatory protein of cardiomyocyte contraction, serves as a clinical biomarker for cellular necrosis. Measuring circulating cTnI in preclinical studies is used to assess cardiotoxicity o...
Cardiac troponin I (cTnI), a key regulatory protein of cardiomyocyte contraction, serves as a clinical biomarker for cellular necrosis. Measuring circulating cTnI in preclinical studies is used to assess cardiotoxicity of new chemical entities (NCEs) and gate their advancement into clinical trials. Recent studies showed benign troponin release due to reversible myocyte injury post-exercise, that could be primarily driven by sustained elevations in heart rate. However, mechanisms linking increased heart rate to troponin release without necrotic damage remain undetermined. In this study we investigated the relationship between sustained beat rate increases and cTnI release using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and zebrafish models. Beat rate was increased in hiPSC-CMs with forskolin, and a concomitant increase in cTnI release was observed without impacting cell viability. To evaluate the translatability of benign troponin release from in vivo contexts, we established methods for quantifying systemic troponin levels in zebrafish and evaluated the effects of forskolin on heart rate and troponin release. Similarly, forskolin treatment increased heart rate and circulating troponin in zebrafish. To investigate the molecular mechanisms involved, hiPSC-CMs were co-treated with forskolin and (±)-blebbistatin, a Myosin II and membrane blebbing inhibitor. We found (±)-blebbistatin to significantly reduce cTnI release, suggesting membrane bleb formation as a possible mechanism of benign troponin release triggered by elevated beat rates. These findings provide a better understanding of troponin release mechanisms in cardiomyocytes. Further, these results may support refinement of cardiotoxicity assessment of NCEs, preventing misinterpretations that might lead to unnecessary termination of promising therapeutics.
Doxorubicin-induced cardiotoxicity under 28 GHz 5G-band electromagnetic radiation in rats: Insights into the mitigative role of vitamin C.
Rahimi A, Rafati A, Mortazavi SMJ … +8 more , Edalat F, Jooyan N, Naseh M, Keshavarz S, Jahromi HM, Nabizadeh A, Dastghaib S, Karbalaei N
Toxicol Appl Pharmacol · 2026 Feb · PMID 41478317 · Publisher ↗
Doxorubicin (DOX), an effective anthracycline chemotherapeutic agent, induces cardiotoxicity through oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways. As millimeter-wave frequencies used...
Doxorubicin (DOX), an effective anthracycline chemotherapeutic agent, induces cardiotoxicity through oxidative stress, mitochondrial dysfunction, and activation of apoptotic pathways. As millimeter-wave frequencies used in fifth-generation (5G) communication systems continue to expand, experimental data on potential biological interactions under clinically relevant conditions remain limited. This study investigated whether short-term 28-GHz electromagnetic radiation (EMR) modifies the cardiac response to DOX and evaluated the potential protective role of vitamin C. Thirty male Sprague-Dawley rats were assigned to five groups (n = 6): Sham, DOX, DOX + Vit C, DOX + 5G, and DOX + 5G + Vit C. DOX (15 mg/kg intraperitoneally, six injections) induced cardiotoxicity, while vitamin C (250 mg/kg orally) was administered daily for 14 days. EMR exposure consisted of three 10-min cycles per day at 28 GHz for 14 days. Cardiac injury was assessed using electrocardiography, serum cTnI, oxidative markers (MDA, GSH, SOD, CAT), apoptotic and inflammatory gene expression (BAX, CASP3, BCL-2, TNF-α), and design-based stereology. DOX induced significant functional, biochemical, molecular, and structural alterations. Co-exposure to 28-GHz EMR amplified reductions in CAT (p < 0.001), and enhanced pro-apoptotic BAX gene expression (p < 0.0001), accompanied by QT interval prolongation (p < 0.05). Vitamin C provided partial protection across these endpoints. Under the specific short-term pre-clinical conditions tested, these findings indicate that 28-GHz EMR can modulate the severity of DOX-induced cardiotoxicity, while vitamin C confers modest attenuation. Further long-term and clinical studies are needed to clarify mechanisms and refine translational relevance.
Resveratrol mitigates TOCP-induced spinal cord neurotoxicity by suppressing ferroptosis, a process mediated through the p62/Keap1/Nrf2 pathway.
Li S, Tan S, Tian X … +4 more , Ou Y, Hu S, Zhao W, Long D
Toxicol Appl Pharmacol · 2026 Feb · PMID 41475526 · Publisher ↗
This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2...
This study investigated the protective effects of resveratrol (Res) against tri-o-cresyl phosphate (TOCP)-induced spinal cord neurotoxicity in adult hens, focusing on its modulation of ferroptosis via the p62/Keap1/Nrf2 pathway. Resveratrol is a classical neuroprotective compound with antioxidant properties and the ability to activate Nrf2. Adult hens were assigned to six groups: Control, TOCP, Ferrostatin-1 (Fer-1), Ferrostatin-1 + TOCP, Resveratrol, and Resveratrol + TOCP. Spinal cord tissues were analyzed using behavioral OPIDN scoring, histology (hematoxylin-eosin and Nissl staining), biochemical assays, and Western blotting for ferroptosis- and p62/Keap1/Nrf2-related proteins. TOCP exposure induced severe ultrastructural damage, including myelin sheath disruption and neuronal degeneration, along with increased malondialdehyde (MDA) and Fe levels and decreased glutathione (GSH) and superoxide dismutase (SOD) activity. Western blot analysis demonstrated upregulation of NCOA4, ACSL4, Nrf2, P62, and LC3 II, with downregulation of GPX4, SLC7A11, FTH1, and Keap1. Resveratrol treatment significantly attenuated these molecular, biochemical, and histopathological alterations, mitigating oxidative stress and ferroptotic changes.
Repurposing of bithionol as a potential anxiolytic agent through NF-κB suppression: Insights from behavioural, biochemical, and molecular modelling studies.
Satao K, Borkar M, Godad A … +1 more , Doshi G
Toxicol Appl Pharmacol · 2026 Feb · PMID 41475092 · Publisher ↗
Chronic stress activates neuroinflammatory responses through the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, rendering anxiety disorders the leading psychological disease. Fo...
Chronic stress activates neuroinflammatory responses through the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, rendering anxiety disorders the leading psychological disease. For the current investigation, an anxiety-related mouse model of restraint stress was adopted to analyse the potential anxiolytic activities of bithionol, a Food and Drug Administration (FDA) an approved anthelmintic drug. It is expected that bithionol should act through inhibiting the process of NF-κB activation, which reduces pro-inflammatory cytokines production. Three dosages of bithionol (25, 50, 100 mg/kg) were administered in male Swiss albino mice subjected to chronic restraint stress, of which diazepam served as the comparator anxiolytic. The behavioural tests, like the Marble Burying Test, Open Field Test (OFT), Elevated Plus Maze (EPM), Light and Dark Transition Screening test, were used for determining anxiety-like behaviours. Therapy with bithionol significantly reduced NF-κB, Tumor necrosis factor- alpha (TNF-α), as well as (Interleukin-1beta) IL-1β, while enhancing serotonin levels primarily at the highest dose of 100 mg/kg, as revealed through biochemical analysis of brain homogenates. These observations suggest that bithionol exhibits dose-dependent anxiolytic activity, possibly through suppression of the NF-κB pathway as well as neuroinflammatory reductions. Molecular modelling study has been performed to gain the insights of molecular level interactions between bithionol and NF-κB, TNF-α and IL-1β. Thus, the repurposing of bithionol for anxiety disorders is investigated.
Inhaled polystyrene nanoparticles may cause fibrotic lesions via immune dysregulation and energy metabolism disturbance.
Jung W, Kim MS, Kim BG … +10 more , Hong SM, Yu S, Kwon K, Yang MJ, Heo MB, Kwon IH, Choi SJ, Choi H, Lee JA, Park EJ
Toxicol Appl Pharmacol · 2026 Feb · PMID 41461255 · Publisher ↗
Microplastics have emerged as a major risk to human health. In this study, we dosed polystyrene nanoparticles (PS-NPs) via the pharynx for 90 days and assessed local and systemic toxicity. PS-NPs increased white blood ce...
Microplastics have emerged as a major risk to human health. In this study, we dosed polystyrene nanoparticles (PS-NPs) via the pharynx for 90 days and assessed local and systemic toxicity. PS-NPs increased white blood cell counts and decreased blood potassium levels, and they were widely distributed in the lungs and hearts. The total count of pulmonary cells increased with dose, whereas the proportion of macrophages decreased. Levels of immune regulation-related cytokines increased markedly in the lungs of male and female mice exposed to PS-NPs, accompanied by infiltration of inflammatory cells and the aggregation of foamy macrophages. Collagen fiber-and lamellar body-like structures were notably observed in the lungs and hearts of PS-NP-treated mice, accompanied by elevations in both blood total cholesterol and pulmonary IL-11 levels. We also investigated cellular responses in alveolar macrophages (MH-S cells), bronchial epithelial cells (BEAS-2B), and cardiomyocytes (H9C2), which are considered primary target organs for inhaled PS-NPs. PS-NPs inhibited the proliferation of H9C2 cells but not that of BEAS-2B or MH-S cells. In addition, PS-NPs disrupted the expression of energy metabolism-related genes, including those involved in oxidative phosphorylation and respiratory electron transport, across all three cell types, inducing a proteotoxic stress response that involved both mitochondrial and endoplasmic reticulum stress. Based on these results, we propose that chronic inhalation of PS-NPs may lead to fibrotic lesions via immune dysregulation and energy metabolism dysfunction.
Dapagliflozin regulates kynurenine metabolism and microglial activation to alleviate diabetes-associated cognitive impairment.
Jia Y, Pang J, Sun C … +4 more , Wang P, Huang Q, Zhao X, Zhang D
Toxicol Appl Pharmacol · 2026 Feb · PMID 41453497 · Publisher ↗
Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has shown significant therapeutic potential in alleviating Diabetes-associated cognitive dysfunction (DACD). However, its specific effects on microglia r...
Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has shown significant therapeutic potential in alleviating Diabetes-associated cognitive dysfunction (DACD). However, its specific effects on microglia remain to be further explored. In this study, a type 2 diabetes mellitus (T2DM) mouse model induced by a high-fat diet/streptozotocin (HFD/STZ) was used. It was found that dapagliflozin could significantly reduce fasting blood glucose levels, alleviate weight loss, and improve cognitive function performance in behavioral tests (Y-maze, Morris water maze, and novel object recognition). Histological and biochemical analyses indicated that dapagliflozin could reduce hippocampal neuronal damage, enhance antioxidant capacity (manifested as increased levels of superoxide dismutase and catalase, and decreased malondialdehyde content), and effectively inhibit neuroinflammation (significantly reduced levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6). Transcriptomic and metabolomic analyses revealed that dapagliflozin rebalanced the kynurenine pathway by down-regulating indoleamine 2,3-dioxygenase (IDO1) and kynurenine monooxygenase (KMO), while up-regulating kynurenic acid transaminase 1 (KYAT1), promoting the transformation of metabolic products from neurotoxic substances (such as 3-hydroxykynurenine and kynurenic acid) to neuroprotective substances (kynurenic acid). Additionally, in vitro experiments in high glucose (HG)-stimulated BV-2 microglia further verified that dapagliflozin exerted anti-inflammatory effects by inhibiting the Toll-like receptor/myeloid differentiation factor 88 (TLR/MyD88) signaling pathway and regulating kynurenine metabolic reprogramming. At the same time, overexpression of KMO reversed these effects. In conclusion, these results reveal the multi-dimensional neuroprotective mechanisms of dapagliflozin in DACD, providing substantial evidence for its potential as a therapeutic agent for diabetes-related cognitive dysfunction.
Saxagliptin mitigates doxorubicin-induced cardiotoxicity by modulating NLRP3/caspase-1/IL-1β and TLR-4/NF-κB pathways.
Abdel-Fattah MM, Abozaid YM, Messiha BAS … +1 more , Khalaf MM
Toxicol Appl Pharmacol · 2026 Feb · PMID 41453496 · Publisher ↗
Doxorubicin (DOX) is a powerful anthracycline utilized in the management of several malignant disorders, involving both solid and hematological tumors. Despite its effectiveness as cytotoxic agent, its therapeutic use is...
Doxorubicin (DOX) is a powerful anthracycline utilized in the management of several malignant disorders, involving both solid and hematological tumors. Despite its effectiveness as cytotoxic agent, its therapeutic use is restricted as cardiac toxicity proportional to the drug dosage. Saxagliptin (SAXA) is a selective and potent member of the dipeptidyl peptidase (DPP)-IV inhibitor family utilized in the management of type two diabetes. It also possesses several biological actions, involving anti-inflammatory and antioxidant properties. This work sought to ascertain the underlying molecular mechanisms and determine the shielding role of SAXA against DOX-induced cardiotoxicity. Thirty-two rats were randomly assigned to four experimental groups, including a normal control group administered the vehicle only, a SAXA group receiving SAXA alone (10 mg/kg), a DOX control group receiving DOX (20 mg/kg) as a single dose, and a SAXA treatment group receiving SAXA plus DOX. Compared to DOX control group, pretreatment with SAXA (10 mg/kg) significantly reduced serum concentrations of CK-MB and CTnI by 37.11 % and 46.32 %, respectively, in addition to a marked improvement in the histopathological features of heart tissues. Moreover, SAXA significantly decreased MDA by 56.05 % and increased GSH and SOD in DOX-intoxicated rats by 493.28 % and 458.32 %, respectively. Additionally, western blot analysis revealed that SAXA pretreatment significantly down-regulated TLR-4 and NLRP3 by 34.9 % and 33.99 %, respectively. Furthermore, ELISA analysis showed that SAXA pretreatment significantly down-regulated NF-κB, caspase-1, and IL-1β by 44.04 %, 78.7 %, and 57.7 %, respectively. The findings of this study suggest that SAXA may exert a cardioprotective effect against DOX-induced toxicity, likely through its antioxidant and anti-inflammatory properties.
Establishment of a real-time monitored animal model to evaluate novel therapeutic strategies for organophosphorus nerve agent poisonings.
Jonasson S, Gustafsson Å, Qvarnström J … +4 more , Carlsson M, Forsgren N, Ekström F, Elfsmark L
Toxicol Appl Pharmacol · 2026 Feb · PMID 41421588 · Publisher ↗
Preclinical evaluation of oximes as antidotes for organophosphorus nerve agent (OPNAs) poisoning is predominantly based on protection ratio of the antidote against lethal doses. Developing protection indexes involves con...
Preclinical evaluation of oximes as antidotes for organophosphorus nerve agent (OPNAs) poisoning is predominantly based on protection ratio of the antidote against lethal doses. Developing protection indexes involves considerable animal distress and, due to the limited precision, requires large animal cohorts. This study aimed to establish an in vivo model for evaluating new therapeutic substances more aligned with the 3R principles that also enables detailed quantification of specific biological effects to better understand the impact of treatment. Anesthetized Sprague-Dawley rats were tracheostomized and connected to a small animal ventilator allowing simultaneous registration of respiratory function. Rats were exposed to 1xLD VX or tabun, and progression of poisoning was monitored in real-time through measurements of respiratory resistance (R) over a 30-min period. Additional assessments included clinical symptoms and acetylcholine esterase (AChE) inhibition in blood. Pre-treatment with oxime (obidoxime, HI-6, RS194B) or atropine were used to validate the model. Exposure to OPNAs resulted in rapid increases in R to 250-300 % above baseline. HI-6 and obidoxime were the most effective treatments, mitigating both respiratory and enzymatic effects of OPNA poisoning, while RS194B treatment delayed onset of symptoms but did not fully reverse toxicity. Tabun-inhibited AChE was generally more resistant to reactivation with oximes than VX- inhibited enzymes. The findings indicate that maintaining AChE activity above 15-20 % is sufficient to restore respiratory function and alleviate symptoms to levels comparable to unexposed controls. This study highlights the value of high-sensitivity, real-time monitoring of physiological metrics like respiratory resistance in evaluating novel antidotes for OPNA poisoning.
Shionone ameliorates pulmonary fibrosis by activating mitophagy via PINK1-Parkin pathway.
Su Y, Fu Q, Wu X … +3 more , Che X, Jiang Z, Li X
Toxicol Appl Pharmacol · 2026 Feb · PMID 41421587 · Publisher ↗
Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited clinical treatment options. Shionone (SHI), a major active compound derived from Ligularia fischeri Turcz (LF), has shown pharmaco...
Pulmonary fibrosis (PF) is a progressive and fatal interstitial lung disease with limited clinical treatment options. Shionone (SHI), a major active compound derived from Ligularia fischeri Turcz (LF), has shown pharmacological potential; however, its mechanism of action against PF remains unclear. This study investigates the anti-fibrotic effects and underlying pathways of SHI using a bleomycin (BLM)-induced PF mouse model and a Transforming Growth Factor-β (TGF-β)-stimulated A549 cell model. The results demonstrate that SHI treatment markedly alleviates BLM-induced alveolar damage, collagen accumulation, and inflammatory responses, while significantly improving survival rates in mice. At the molecular level, SHI activates the PTEN-induced putative kinase 1 (PINK1)-Parkin-mediated mitophagy pathway, leading to increased expression of autophagy-related proteins such as LC3II/LC3I and Beclin1, decreased levels of p62 and pro-fibrotic markers, enhanced clearance of dysfunctional mitochondria, restoration of mitochondrial membrane potential (MMP), and reduction of reactive oxygen species (ROS) accumulation. In vitro experiments further confirm that SHI inhibits fibrosis in TGF-β-challenged A549 cells through the same mechanism. This study is the first to elucidate that SHI mitigates PF by regulating mitophagy, offering a promising therapeutic target and potential drug candidate for PF. Future research may focus on optimizing the clinical application strategies of SHI.
CYP genetic polymorphism, and CYP3A inducers and inhibitors regulate apatinib metabolism: Consequences for drug exposure and toxicity risks.
Wang Z, Jin LH, Pang NH … +5 more , Xu JE, Xu XY, Sun W, Zhang XD, Qian JC
Toxicol Appl Pharmacol · 2026 Feb · PMID 41407268 · Publisher ↗
Apatinib is a tyrosine kinase inhibitor metabolized by hepatic cytochromes P450 (CYPs). This study investigated how CYP genetic variations affect apatinib metabolism and response. We employed a multi-scale approach inclu...
Apatinib is a tyrosine kinase inhibitor metabolized by hepatic cytochromes P450 (CYPs). This study investigated how CYP genetic variations affect apatinib metabolism and response. We employed a multi-scale approach including enzyme kinetic studies with recombinant human CYP variants (n = 3), cellular proliferation assays in CYP3A4-overexpressing A549 cells (n = 3), and pharmacokinetic studies in rats treated with CYP3A modulators (n = 6 per group). CYP3A4*18, CYP2D6*10, and CYP2C9*3 variants showed markedly reduced metabolic activity. CYP3A4*18 overexpression enhanced apatinib's anti-proliferative effect in A549 cells. In rats, dexamethasone decreased apatinib exposure by inducing CYP3A expression, while ketoconazole increased exposure without altering CYP3A levels. Both CYP genetic polymorphisms and drug interactions significantly influence apatinib metabolism, highlighting the importance of personalized dosing strategies for optimizing therapy.
Celastrol delays the progression of hepatocellular carcinoma by suppressing SLC1A5-mediated glutamine dependence.
Xiao S, Zhao Y, Chen Z … +4 more , Xiong Y, Zhang D, Zhou G, Zhang C
Toxicol Appl Pharmacol · 2026 Feb · PMID 41401867 · Publisher ↗
Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the...
Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the cellular vital activities, has become a promising direction for HCC management. Celastrol is a terpenoids natural product isolated from the Tripterygium wilfordii Hook F. and catches attention for its multiple pharmacological activities including anti-HCC therapeutic potential. However, its effects in regulating glutamine metabolism to suppress HCC progression have not been investigated. In this study, Hep3B and HepG2 cells were used to investigate the inhibitory effects of celastrol on hepatoma cells. Subsequently, the biosafety and inhibitory effects of celastrol on tumor growth were investigated in a xenograft animal model of liver cancer. Our results showed that celastrol restrained the proliferation of hepatoma cells which was tightly associated with reduction of glutamine metabolic flux. Mechanistically, celastrol restricted glutamine uptake by inhibiting the SLC1A5 expression to reduce the content of glutamine metabolism intermediates in hepatoma cells thereby interrupting the energy source for cell proliferation. Consistently, similar results were observed in a transplanted HCC tumor mouse model. Interestingly, overexpression of SLC1A5 reversed the efficacy of celastrol in decreasing glutamine metabolic flux to suppress the malignant proliferation of hepatoma cells in vitro and in vivo. Overall, this study provides compelling evidence to demonstrate the efficacy of celastrol in inhibiting hepatocarcinogenesis by suppressing SLC1A5-mediated glutamine dependence, suggesting that celastrol as a natural active compound is expected to be developed as a therapeutic agent for HCC.
Pioglitazone attenuates cardiovascular remodeling cadmium-induced through the MAPK pathway.
Sarmiento-Ortega VE, Moroni-González D, Avelino-Cruz JE … +4 more , Garcia-Gonzalez M, Vázquez-Roque R, Brambila E, Treviño S
Toxicol Appl Pharmacol · 2026 Feb · PMID 41401866 · Publisher ↗
Cadmium (Cd) is an environmental pollutant increasingly linked to cardiovascular morbidity. While its toxic effects have been well documented at high doses, the impact of chronic exposure to the minimal risk level remain...
Cadmium (Cd) is an environmental pollutant increasingly linked to cardiovascular morbidity. While its toxic effects have been well documented at high doses, the impact of chronic exposure to the minimal risk level remains underexplored. This study aimed to investigate the mechanistic basis of Cadmium-induced cardiotoxicity at low doses and to evaluate the cardioprotective potential of pioglitazone, a PPARγ agonist with anti-inflammatory and antioxidant properties. Male Wistar rats were exposed chronically to Cd in drinking water (Cd, 15 mg/L) for 3 and 5 months, with or without pioglitazone co-treatment (2.5 mg/kg bw/day). Hemodynamic parameters, serum biomarkers (hs-TnI, NT-proBNP, sST2, IL-6, TNF-α), ventricular morphometry, histology, and activation of MAPK signaling (p-ERK1/2, p-JNK, p-p38) were evaluated. At 5 months, Cd exposure significantly increased systolic and diastolic blood pressure, hs-TnI, and NT-proBNP, without affecting CK-MB or hs-PCR. Structural changes included selective left ventricular hypertrophy, increased cardiomyocyte size, and elevated HW/BW and LVW/BW ratios. Cadmium also disrupted the IL-33/sST2 axis, elevating IL-6 and TNF-α, which indicates the presence of chronic inflammation. Mechanistically, Cd activated the MAPK pathway, with marked increases in p-p38 and p-JNK. Pioglitazone partially reversed these alterations by reducing inflammatory cytokines, restoring IL-33 levels, downregulating MAPK activation, and attenuating cardiac remodeling. Chronic exposure to the minimal risk of cadmium dosage induces subclinical yet progressive cardiotoxicity through inflammatory and MAPK-dependent pathways. Pioglitazone confers partial protection by modulating these mechanisms, underscoring its therapeutic potential in mitigating environmentally induced cardiovascular injury.
Corrigendum to "Toxicokinetics and in vivo genotoxicity after single dose oral gavage and intravenous administration of N-Nitrosonornicotine in Sprague Dawley rats" [Toxicology and Applied Pharmacology 505 (2025), 117572].
De M, Fields A, Lagaud G
Toxicol Appl Pharmacol · 2026 Mar · PMID 41391730 · Publisher ↗
Abstract loading — click title to view on PubMed.
Mechanistic insights into trimetazidine's protection against bladder ischemia-reperfusion injury via mirR-211/CHOP modulation and SIRT1/AMPK/PGC1α-mediated mitochondrial biogenesis.
Alrashdi S, Mohamed SK, Elbaz M … +1 more , El-Sayed EK
Toxicol Appl Pharmacol · 2026 Feb · PMID 41386315 · Publisher ↗
Bladder ischemia, frequently associated with vascular insufficiency, contributes to lower urinary tract symptoms via oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial defect, and apoptosis....
Bladder ischemia, frequently associated with vascular insufficiency, contributes to lower urinary tract symptoms via oxidative stress, inflammation, endoplasmic reticulum (ER) stress, mitochondrial defect, and apoptosis. Ischemia-reperfusion (I/R) injury exacerbates these effects by generating excessive reactive oxygen species. Trimetazidine (TMZ), an anti-ischemic agent, has shown protective effects in several I/R models; however, its role in bladder injury remains insufficiently characterized. This study investigated the protective effect of TMZ against bladder I/R injury in rats, focusing on oxidative stress, inflammation, ER stress, mitochondrial biogenesis, microRNA regulation, and apoptosis. Forty rats were allocated into four groups: sham control, I/R, and two TMZ-pretreated groups (10 or 20 mg/kg/day, p.o., for 14 days) prior to I/R induction. Controls received Tween 80 vehicle. Bladder tissues were collected for biochemical, molecular, and histopathological analyses. TMZ showed protection by lowering MDA (∼43.5-60.8 %) and enhancing GSH (∼2-2.6 fold) and SOD activity (∼2-3.2 fold). ER stress was attenuated, with reduced p-PERK (∼29.4-63 %) and CHOP (∼29.1-60 %), alongside upregulation of mirR-211 (∼1.4-1.9 fold). TMZ restored mitochondrial biogenesis through increased SIRT1 (∼1.9-2.4 fold), PGC1α (∼2.1-4.3 fold), p-AMPK (∼3-6.3 fold), and ATP (∼2-2.8 fold). It also downregulated pro-apoptotic (Bax, Caspase 3) and pro-inflammatory (TNF-α, IL-1β) mediators. Histopathology revealed marked preservation of bladder architecture, particularly at 20 mg/kg. TMZ exerts strong antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective effects in bladder I/R injury via modulation of oxidative stress, ER stress, mitochondrial pathways, and the mirR-211/CHOP axis. These findings suggest that TMZ may represent a promising therapeutic candidate for ischemia-associated bladder dysfunction, providing a mechanistic basis for future translational and clinical investigation.
Rupestonic acid targets ENO1 to exert antitumor activity and synergizes with paclitaxel in hepatocellular carcinoma.
Mulati S, Maimaitiming M, Ma J … +4 more , Zhang M, Jiang R, Aibai S, Tuerxun X
Toxicol Appl Pharmacol · 2026 Feb · PMID 41386314 · Publisher ↗
Rupestonic acid, a sesquiterpene, has protective properties against liver damage, inflammation, and tumor formation. Despite these known effects, its specific role and mechanism of action in combating hepatocellular carc...
Rupestonic acid, a sesquiterpene, has protective properties against liver damage, inflammation, and tumor formation. Despite these known effects, its specific role and mechanism of action in combating hepatocellular carcinoma (HCC) remain insufficiently understood. This study aimed to investigate the anti-HCC effects of rupestonic acid and to identify its potential molecular targets. We employed cell counting kit-8 (CCK-8), colony formation, and flow cytometry assays to assess its impact on cell viability, proliferation, and apoptosis in HCC cell lines. Additionally, target fishing, cellular thermal shift assays (CETSA), ribonucleic acid interference, and Western blot (WB) were employed to identify rupestonic acid's protein targets in HCC cells. Our results showed that rupestonic acid significantly inhibited HCC cell proliferation, induced G0/G1 phase cell cycle arrest, and promoted apoptosis through the mitochondrial pathway. Target engagement studies employing an alkyne-rupestonic acid probe combined with mass spectrometry identified enolase 1 (ENO1) as a direct binding target, with CETSA confirming its destabilization. Furthermore, rupestonic acid inhibited the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/Forkhead box protein O (FOXO) signaling pathway, and rupestonic acid demonstrated a synergistic cytotoxic effect with paclitaxel (PTX). These findings suggest that rupestonic acid is a promising candidate for HCC treatment. They also underscore the potential of rupestonic acid in the design and development of lead compounds for HCC treatment and identify ENO1 as a viable therapeutic target.
Evaluation of 2-isopropyl-N-2,3-trimethylbutyramide by a comprehensive toxicity study using gpt delta rats.
Mitsumoto T, Ishii Y, Takimoto N … +4 more , Takasu S, Namiki M, Toyoda T, Ogawa K
Toxicol Appl Pharmacol · 2026 Feb · PMID 41380784 · Publisher ↗
2-Isopropyl-N-2,3-trimethylbutyramide (ITB) is a food-flavoring agent classified as an aliphatic amide. In 2016, the Joint FAO/WHO Expert Committee on Food Additives evaluated ITB and concluded that additional data on to...
2-Isopropyl-N-2,3-trimethylbutyramide (ITB) is a food-flavoring agent classified as an aliphatic amide. In 2016, the Joint FAO/WHO Expert Committee on Food Additives evaluated ITB and concluded that additional data on toxicity and in vivo genotoxicity are required for its safety evaluation. In this study, we comprehensively investigated ITB toxicity using reporter gene transgenic animals. Male F344 gpt delta rats were administered ITB by oral gavage at doses of 0, 5, 50, or 500 mg/kg/day for 13 weeks. Neurological symptoms were observed in the early phase of treatment at doses ≥50 mg/kg. Periportal hepatocellular vacuolation was observed histopathologically at doses ≥50 mg/kg, along with increased liver weight and serum alanine aminotransferase levels. Kidney weight increased and serum chloride levels decreased at doses ≥5 mg/kg, indicating that ITB exerted potential nephrotoxic effects at lower doses. Accordingly, the lowest observed adverse effect level in the present study was at 5 mg/kg/day. No significant changes in gpt and red/gam mutant frequencies were detected in the liver or kidney, demonstrating a lack of ITB genotoxicity. Immunohistochemical analysis of GST-P-positive foci also suggested that ITB showed no hepatocarcinogenic potential. Overall, our findings demonstrate that ITB induces hepatic and renal toxicity but shows no evidence of in vivo genotoxicity or hepatocarcinogenic potential, providing essential information for safety assessment.
Gastrodin alleviates alcohol-induced developmental and neurotoxic effects in zebrafish larvae by suppressing ferroptosis via regulating the Nrf2/GPX4 signaling pathway.
Li R, Yang W, Zheng L … +4 more , Yan X, Liu C, Zhang Y, Li J
Toxicol Appl Pharmacol · 2026 Feb · PMID 41371372 · Publisher ↗
Prenatal alcohol exposure is a leading cause of developmental abnormalities and neurobehavioral deficits, collectively known as fetal alcohol spectrum disorder (FASD). The underlying molecular mechanisms, however, are no...
Prenatal alcohol exposure is a leading cause of developmental abnormalities and neurobehavioral deficits, collectively known as fetal alcohol spectrum disorder (FASD). The underlying molecular mechanisms, however, are not fully elucidated, hindering the development of effective therapeutic strategies. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key pathological process in various diseases. Gastrodin (GAS), the primary bioactive component of Gastrodia elata, has demonstrated potent antioxidant and neuroprotective properties. This study aimed to investigate the protective effects of GAS against alcohol-induced developmental and neurotoxic damage and to elucidate the underlying molecular mechanisms. Using a zebrafish larval model, we found that exposure to 200 mM alcohol from 2 to 24 hours post-fertilization (hpf) induced significant developmental toxicity, including a decreased hatching rate, body length and eye diameter, and increased morphological malformations in larvae. Alcohol-exposed larvae also exhibited severe neurobehavioral deficits, characterized by a reduction in movement distance and average velocity in dark conditions. Mechanistically, alcohol exposure triggered ferroptosis, evidenced by an increase in intracellular Fe, malondialdehyde (MDA), and reactive oxygen species (ROS) levels, alongside a decrease in the levels of glutathione (GSH) and reduced glutathione peroxidase 4 (GPX4) and the nuclear factor erythroid 2-related factor 2 (Nrf2) activities. Co-treatment with GAS (200 mg/L) significantly ameliorated these alcohol-induced developmental and neurobehavioral defects. GAS administration effectively suppressed the hallmarks of ferroptosis by restoring the ROS level and altering the expression of genes related to oxidative stress. In addition, GAS suppressed alcohol-induced cell apoptosis, downregulated caspase3b, bax, caspase8, and upregulated bcl2 in mRNA levels. Molecular analysis revealed that GAS exerts its anti-ferroptotic effect by activating Nrf2/GPX4 signaling pathway, which was suppressed by alcohol. Our findings indicate that ferroptosis plays a key role in alcohol-induced developmental neurotoxicity, and GAS provides protection by activating the Nrf2/GPX4 axis. This suggests that GAS could be a potential therapeutic option for reducing the negative effects of prenatal alcohol exposure.
Duloxetine-induced inhibition of voltage-gated K 3.1 (Kv3.1) channels and underlying electrophysiological mechanisms.
An JR, Jeong J, Kim HR … +10 more , Lee S, Sultana A, Das R, Woo J, Choi SW, Bae YM, Lim Y, Park H, Seo MS, Park WS
Toxicol Appl Pharmacol · 2026 Feb · PMID 41371371 · Publisher ↗
Duloxetine is a serotonin-norepinephrine reuptake inhibitor that has been widely used to treat major depression; however, it has also been associated with severe neuropsychiatric side effects, including hallucinations, c...
Duloxetine is a serotonin-norepinephrine reuptake inhibitor that has been widely used to treat major depression; however, it has also been associated with severe neuropsychiatric side effects, including hallucinations, confusion, and suicide attempts. Nevertheless, the electrophysiological mechanisms underlying these adverse effects remain poorly understood. In this study, we investigated the effect of duloxetine on cloned neuronal rat voltage-gated K (Kv) channel subunit Kv3.1, stably expressed in Chinese hamster ovary (CHO) cells. Duloxetine inhibited the Kv3.1 current in a concentration-dependent manner with a half-maximal inhibitory concentration (IC) of 2.04 ± 0.27 μM (approximately 5-fold higher than the peak therapeutic plasma concentration of 0.4 μM) and a Hill coefficient of 0.94 ± 0.08. This inhibitory effect was associated with accelerated current inactivation. The association and dissociation rate constants for duloxetine were 43.43 ± 4.57 μM·s and 122.12 ± 68.2 s, respectively. In addition, duloxetine shifted the voltage dependence of Kv3.1 steady-state inactivation toward a more negative direction and led to use-dependent inhibition upon repetitive stimulation (1 and 2 Hz). Duloxetine also slowed recovery from inactivation. Docking analysis predicted that duloxetine binds to the central pore and interface between the voltage-sensing and pore domains on Kv3.1 channel, supporting the inhibitory mechanisms of duloxetine. Furthermore, duloxetine inhibited Kv3.1-mediated currents in SH-SY5Y human neuroblastoma cells. Taken together, our results indicate that duloxetine inhibits Kv3.1 expressed in CHO cells in concentration-, time-, and use (open and inactivated states)-dependent manners, independently of its anti-depressive effects.
Targeting sonic hedgehog (shh) signaling pathways by the concentration-dependent topical resveratrol for protection from cyclophosphamide-induced alopecia in a mouse model.
El-Din AA, Tahoon DM, Abd Elmaaboud MA … +2 more , Abd Elmoniem FF, Abdin AA
Toxicol Appl Pharmacol · 2026 Feb · PMID 41371370 · Publisher ↗
BACKGROUND: Chemotherapy-induced alopecia (CIA) is a common and inevitable side effect of systemic cancer treatment. There is an urgent need for novel therapies for cancer patients suffering from hair loss to improve the...
BACKGROUND: Chemotherapy-induced alopecia (CIA) is a common and inevitable side effect of systemic cancer treatment. There is an urgent need for novel therapies for cancer patients suffering from hair loss to improve their quality of life. This study aimed to investigate the potential protective effect of concentration-dependent topical resveratrol on hair follicles via targeting sonic hedgehog (Shh) signaling and its related downstream regulatory (Sirt-1), proliferative (Ki-67), and apoptotic status (caspase-3 and Bcl-2) pathways in cyclophosphamide-induced alopecia in female C57BL/6 mice model. METHODS: All animals were subjected to depilation at the start of the experiment, then mice were divided into 5 equal groups as follows: Control group, cyclophosphamide (CPA)-untreated alopecia group, minoxidil (MXL) + CPA-alopecia, Resveratrol low concentration (RSV L10) + CPA-alopecia, Resveratrol high concentration (RSV H80) + CPA-alopecia. The effects of these drugs on hair coverage score, Shh signaling, Sirt-1, proliferation, and apoptosis were assessed. RESULTS: Low concentration of topical RSV showed a significant increase in hair coverage score. Shh, Sirt-1, immunohistochemical expression levels of Ki-67, and Bcl-2 were significantly elevated, significantly decreasing caspase-3 expression in skin tissue. Moreover, the superiority extended to include histopathological findings and dermatoscopic skin monitoring compared to the groups that received either topical minoxidil 2 % or RSV at high concentration. CONCLUSION: Topical low-dose resveratrol protects against CIA by activating Shh signaling and modulating follicular proliferative and apoptotic pathways.
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