TOXICOLOGY AND APPLIED PHARMACOLOGY毒理学与应用药理学
TOXICOLOGY AND APPLIED PHARMACOLOGY(英文缩写 TOXICOL APPL PHARM),ISSN 0041-008X,eISSN 1096-0333,中文译名:毒理学与应用药理学 是一本学术期刊。本页汇总该期刊的最新影响因子、分区信息以及最新收录于 PubMed 的文献,帮助您快速了解期刊全貌。
发文量统计区间：2025-11-01 至 2026-10-31，按本站收录文献的发表日期统计。
期刊介绍
历年影响因子趋势
| JCR 数据年份 | 影响因子 | JCR 分区 |
|---|---|---|
| 2021 | 4.460 | Q2 |
| 2022 | 3.800 | Q2 |
| 2023 | 3.300 | Q2 |
| 2024 | 3.400 | Q2 |
| 2025 | 3.600 | Q2 |
TOXICOLOGY AND APPLIED PHARMACOLOGY 最新收录文献
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1. Tubuloside A alleviates sepsis-associated kidney injury by modulating the mTOR-NF-κB pathway.
1. 管花苷A通过调控mTOR-NF-κB通路减轻脓毒症相关肾损伤PMID:日期:2026-10-02Sepsis-associated kidney injury (S-AKI) is a severe complication of sepsis, yet effective targeted therapies remain limited. We investigated the renoprotective effects of Tubuloside A (TA) and its mechanisms. S-AKI was induced in mice by cecal ligation and puncture, whereas an in vitro model was established using HK-2 cells exposed to lipopolysaccharide. Network pharmacology and molecular docking were used to explore potentially relevant targets and signaling pathways, and the involvement of autophagy-related processes was further examined using 3-methyladenine (3-MA). TA attenuated renal histopathological injury, reduced serum blood urea nitrogen and creatinine levels, and decreased the expression of the kidney injury markers KIM-1 and NGAL. TA also suppressed IL-1β, IL-6, and TNF-α expression while increasing IL-10 expression. TA also reduced ROS and MDA levels and increased CAT, GSH, and T-AOC activities, indicating antioxidant capacity. TA reduced Bax, cleaved caspase-3, and cleaved caspase-9 expression, increased Bcl-2 expression, and decreased the proportion of Annexin V-FITC/PI-positive cells. TA decreased the p-mTOR/mTOR ratio and p62 expression while increasing the LC3B-II/LC3B-I ratio, indicating modulation of mTOR-associated autophagy-related markers. TA also inhibited NF-κB activation, as evidenced by reduced p-p65 and p-IκBα levels, restored IκBα expression, and decreased nuclear p-p65 accumulation. CETSA further showed that TA altered the thermal stability profile of p65, providing experimental support for potential cellular target engagement of p65 by TA. Notably, 3-MA partially reversed these effects. Collectively, TA protects against S-AKI by alleviating inflammation, oxidative stress, and apoptosis, possibly through modulation of mTOR-associated autophagy-related processes and NF-κB signaling.
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2. NRF2 activation mediates the protective effects of capsaicin against MGO/STZ-induced chondrocyte apoptosis and diabetic articular cartilage injury.
2. NRF2激活介导了辣椒素对MGO/STZ诱导的软骨细胞凋亡和糖尿病关节软骨损伤的保护作用PMID:日期:2026-10-01Diabetes mellitus is an independent risk factor for osteoarthritis (OA), and the molecular mechanisms underlying diabetic cartilage damage remain unclear. This study investigated the role of oxidative stress in diabetes-induced chondrocyte injury, especially chondrocyte apoptosis, explored the protective role of the NRF2 antioxidant system, and evaluated the therapeutic potential of capsaicin for diabetic OA. In vivo experiments were conducted on streptozotocin (STZ)-induced diabetic mice, in which cartilage degeneration and subchondral bone remodeling were assessed via Safranin O/Fast Green staining, OARSI scoring and micro-CT, while chondrocyte apoptosis and protein expression were detected by TUNEL staining and immunohistochemistry. In vitro, methylglyoxal (MGO)-treated primary mouse chondrocytes and ATDC5 chondrogenic precursor cells were combined with Nrf2 knockdown/overexpression and N-acetylcysteine (NAC) rescue assays to verify the ROS/NRF2 regulatory mechanism. In vivo, STZ-induced hyperglycemia caused severe cartilage erosion, aberrant subchondral bone remodeling and excessive chondrocyte apoptosis. In vitro, MGO elevated intracellular ROS levels and triggered chondrocyte apoptosis in a concentration-dependent manner, and NAC-mediated ROS scavenging reversed this injury, confirming a ROS-dependent pathogenic mechanism. MGO activated NRF2 signaling time-dependently, and Nrf2 knockdown aggravated whereas Nrf2 overexpression attenuated chondrocyte apoptosis. Importantly, capsaicin activated NRF2 signaling, rescued MGO-induced chondrocyte apoptosis in vitro, and alleviated STZ-elicited articular cartilage degeneration in vivo. In conclusion, diabetes induces ROS-mediated chondrocyte apoptosis and cartilage damage. Capsaicin exerts potent chondroprotective effects against diabetic OA via NRF2 activation, offering a promising therapeutic strategy.
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3. Mechanistic study of cycloastragenol in improving heart failure by regulating PI3K/AKT/mTOR signaling and ferroptosis.
3. 环黄芪醇通过调控PI3K/AKT/mTOR信号通路和铁死亡改善心力衰竭的机制研究PMID:日期:2026-09-29Heart failure (HF) is the end stage of various cardiovascular diseases, and persistent myocardial injury and adverse remodeling are major causes of its high hospitalization and mortality rates worldwide. Therefore, it is important to identify key molecules and effective agents that can slow or reverse HF progression. Cycloastragenol (CAG) is an active compound derived from Astragalus and has anti-inflammatory, antioxidant, and tissue-protective effects. The present study aimed to clarify the protective role of CAG in HF and to determine whether this effect is related to the regulation of ferroptosis through the PI3K/AKT/mTOR signaling pathway. The results showed that PI3K/AKT/mTOR signaling activity was markedly decreased in myocardial tissue from HF rats, accompanied by impaired cardiac function, aggravated myocardial injury, enhanced inflammatory response, and increased myocardial fibrosis and hypertrophic remodeling. At the same time, GSH levels were decreased, whereas ROS, MDA, and Fe levels were increased. In addition, GPX4 and FTH1 expression was downregulated, ACSL4 expression was upregulated, and the Prussian blue-positive area was increased, indicating marked ferroptosis-related abnormalities. After CAG treatment, these changes were improved to different degrees. CAG restored cardiac function, reduced serum NT-proBNP, CK-MB, and cTnI levels, decreased inflammatory factor expression, and alleviated myocardial fibrosis and hypertrophy. Meanwhile, PI3K/AKT/mTOR signaling activity was restored, and iron deposition, lipid peroxidation, and ferroptosis-related molecular abnormalities were alleviated. In vitro experiments further showed that, in an OGD-induced H9c2 cell injury model, CAG increased cell viability, reduced LDH release, attenuated the inflammatory response, and alleviated mitochondrial membrane potential loss, ROS accumulation, and ferroptosis-related protein abnormalities. C11-BODIPY 581/591 flow cytometry further demonstrated that CAG reduced OGD-induced lipid ROS accumulation and lipid peroxidation. In addition, the ferroptosis inhibitor ferrostatin-1 partially rescued OGD-induced cell injury, restored cell viability, reduced LDH release, and suppressed lipid ROS accumulation, further supporting the involvement of ferroptosis-related processes. Further intervention with the AKT inhibitor MK-2206 partially weakened the protective effects of CAG, supporting the involvement of AKT signaling in its protective action. In conclusion, the present study showed that CAG improved HF-related myocardial injury and myocardial remodeling by restoring PI3K/AKT/mTOR signaling activity and inhibiting ferroptosis-related processes, suggesting that CAG may be a potential therapeutic agent for HF.
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4. Shikonin suppresses fibrotic phenotype and oxidative stress in keloid fibroblasts via EGFR-targeted AKT/STAT3/PTGS2 modulation.
4. 紫草素通过靶向EGFR的AKT/STAT3/PTGS2调控通路抑制瘢痕疙瘩成纤维细胞的纤维化表型及氧化应激PMID:日期:2026-09-28Keloids are fibroproliferative disorders with excessive extracellular matrix (ECM) deposition, fibroblast hyperproliferation, oxidative stress, and a lack of effective therapies. Shikonin, a natural naphthoquinone, exhibits anti-tumor and antioxidant activities, yet its role in keloid fibroblasts (KFs) remains unclear. In this study, putative Shikonin targets were predicted from public databases and intersected with keloid-associated genes, followed by PPI network construction and GO enrichment analysis. Primary KFs and normal skin fibroblasts (NFs) were treated with Shikonin and assessed for proliferation by CCK-8 assay, apoptosis by flow cytometry, ECM-related protein and HIF-1α expression by Western blotting/immunofluorescence, and intracellular ROS by DCFH-DA staining. Target engagement and functional dependence were validated through molecular docking, molecular dynamics simulations, MM-PBSA analysis, biotin pull-down, CETSA, proteasome inhibition, and EGFR overexpression rescue experiments. Network analysis identified AKT1, EGFR, CASP3, STAT3, BCL2, PTGS2, and HIF-1α as core targets, with enrichment in oxidative stress and PI3K-centered pathways. Shikonin inhibited KF proliferation, induced apoptosis, downregulated Bcl-2 while upregulating Cleaved caspase-3, and suppressed ECM proteins (α-SMA, Fibronectin, Collagen I) and HIF-1α expression. Mechanistically, Shikonin directly bound to EGFR and promoted its proteasomal degradation, consequently suppressing p-AKT, p-STAT3, and PTGS2 expression. EGFR overexpression significantly reversed Shikonin's inhibitory effects on proliferation, ECM production, and oxidative stress, as well as its pro-apoptotic activity. To conclude, Shikonin exerts anti-KF effects by directly targeting EGFR, inducing its proteasomal degradation, and thereby inhibiting downstream AKT/STAT3 signaling and PTGS2 expression.
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5. Tuberostemonine produces antidepressant effects via the BDNF/TrkB/Erk/CREB signaling pathway.
5. 百部碱通过BDNF/TrkB/Erk/CREB信号通路产生抗抑郁作用PMID:日期:2026-09-28Depression is a highly prevalent, debilitating psychiatric disorder that imposes severe global public health and socioeconomic burdens, greatly compromising patients' quality of life and social function. Current clinical antidepressants suffer from several critical drawbacks, including delayed therapeutic onset, limited efficacy, high relapse rates, and widespread treatment resistance that affects over 30% of patients. This creates an urgent demand for novel, safe antidepressant drug candidates. Natural products, with favorable safety profiles and unique neuropharmacological activities, are promising resources for psychiatric drug development. Herein, we screened an in-house natural product library and identified tuberostemonine as a potential antidepressant agent, and systematically validated its therapeutic effects and molecular mechanisms through integrated in vitro and in vivo experiments. In corticosterone-injured PC12 cells, tuberostemonine effectively mitigated neuronal apoptosis and excessive reactive oxygen species accumulation. In a mouse depression model, tuberostemonine significantly rescued depressive-like behaviors, as evidenced by elevated sucrose preference and shortened immobility time in tail suspension and forced swim tests. Mechanistically, tuberostemonine exerted its antidepressant effects by restoring the corticosterone-induced downregulation of the BDNF/TrkB/ERK /CREB signaling pathway. In PC12 cells, ERK inhibitor treatment effectively abrogated its protective effects, confirming the involvement of this signaling cascade. In conclusion, tuberostemonine ameliorates corticosterone-induced neuronal injury and depressive behaviors via restoration of the BDNF/TrkB/ERK/CREB pathway. This study reveals a novel antidepressant role of tuberostemonine and provides preclinical evidence supporting further investigation of its potential as an innovative natural antidepressant candidate.
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6. Retraction notice to "Apple polyphenol phloretin complexed with ruthenium is capable of reprogramming the breast cancer microenvironment through modulation of PI3K/Akt/mTOR/VEGF pathways" [Toxicol. Appl. Pharmacol. 434 (2022) 115822].
6. 关于“苹果多酚根皮素与钌络合物可通过调节PI3K/Akt/mTOR/VEGF通路重编程乳腺癌微环境”的撤稿通知 [Toxicol. Appl. Pharmacol. 434 (2022) 115822]PMID:日期:2026-09-27该文献暂无摘要。
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7. Myocardial senescence as a mechanistic endpoint of arsenic cardiotoxicity: Cysteine-associated p53/p21 activation and reversal by quercetin.
7. 心肌衰老作为砷心脏毒性的机制终点：半胱氨酸相关的p53/p21激活及槲皮素的逆转作用PMID:日期:2026-09-26This study investigates how environmental arsenic exposure induces cardiotoxicity via myocardial senescence by in vivo/in vitro models and evaluates the protective effects of quercetin. In vivo, 3-week-old male C57BL/6 mice were exposed to sodium arsenite (NaAsO) in drinking water at 10 or 20 mg/L for 6 weeks, with 22-month-old mice serving as a natural aging reference. In vitro, H9C2 rat cardiomyoblasts were treated with 6 μM NaAsO for 24 h to establish a sub-lethal senescence model, followed by PBS or 60 μM quercetin for a further 24 h. Arsenic-exposed mice exhibited dose-dependent aging-like behavioral impairment, left ventricular systolic and diastolic dysfunction, and myocardial fibrosis, driven by P53/P21 upregulation. Network toxicology and in vitro assays revealed that arsenic directly binds a p53 cysteine residue, initiating senescence through the p53/p21 axis and altering pathways including PI3K-Akt and HIF-1. At 6 μM, NaAsO increased the proportion of SA-β-gal-positive H9C2 cells and upregulated P53, P21, and IL-6 at both mRNA and protein levels. Network pharmacology identified TP53, AKT1, and EGFR as quercetin's core targets, with molecular docking and 100 ns dynamics simulations confirming stable, spontaneous binding. Co-treatment with 60 μM quercetin for 24 h reversed arsenic-induced senescence and downregulated these overactivated targets. Ultimately, this study provides evidence that arsenic drives myocardial senescence and associated with upregulation of the p53/p21 axis, highlighting quercetin as a promising multi-target botanical countermeasure for cardiovascular protection in arsenic-exposed populations.
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8. Translation from mice to monkeys toward human: species differences in endothelial-dependent vasorelaxation in various isolated vascular beds.
8. 从 mice 到 monkeys 再到 human 的转化：不同离体血管床中内皮依赖性血管舒张的物种差异PMID:日期:2026-09-26Compounds inducing effects on the blood pressure may act on arteries. The endothelium is frequently involved in these vascular effects, and its influence may depend on vascular beds and species, making translational interpretation challenging. This study aimed to assess the endothelial responses and reactivity across various vascular beds from different animal species (rats, mice and monkeys) and human. Endothelium-dependent vasorelaxation due to acetylcholine in large and resistance arteries from healthy rats, mice, monkeys and human were evaluated using isolated organ bath or wire myography. Contraction induced by serotonin have been also investigated in various human vessels. Mice aorta, but not mesenteric arteries, was more sensitive to acetylcholine compared to rat arteries. Monkey abdominal aorta displayed a weak relaxation, whereas a potent relaxation was observed in mammary, mesenteric and subcutaneous arteries. Human and monkey subcutaneous arteries exhibited similar vasorelaxations. Interesting, human veins exhibited potent contraction to serotonin compared to resistance and large arteries. Overall, resistance arteries were more sensitive and responsive to endothelial stimulation by acetylcholine, compared to large arteries. This study provides evidences of the variability of endothelium-dependent vasorelaxant responses across various vascular beds and species. This work underlines the importance of selecting the most appropriate vascular bed and species based on the scientific /pharmacological rationales (molecular target, in vivo pharmacodynamic, therapeutic indication and target organ) to enable a translational interpretation of findings.
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9. {"_":"Environmental blood cadmium tracks with albuminuria at concentrations far below ToxCast ACs.","sub":["50"]}
PMID:日期:2026-09-25Cadmium is a cumulative nephrotoxicant that injures the proximal tubule through oxidative stress and disrupted metal handling. Whether contemporary low-level exposure associates with albuminuria, and how those internal concentrations compare with in vitro bioactivity, remains incompletely defined. In NHANES 2011-2018 adults aged ≥40 years (n=8921; median whole-blood cadmium 0.31μg/L, 0.0028μM), survey-weighted logistic models estimated odds ratios (ORs) for albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g) per doubling of whole-blood cadmium, adjusted for age, sex, race/ethnicity, poverty-income ratio, body mass index, smoking, diabetes, and hypertension. Internal concentrations were anchored to ToxCast cadmium chloride (CAS 10108-64-2) ACs as a bioactivity exposure ratio (BER). The adjusted OR was 1.25 (95% CI 1.13-1.37) overall, a 25% higher odds of albuminuria per doubling, and 1.29 (1.09-1.52) in never-smokers; albuminuria rose across cadmium quartiles from 8.2% to 15.9%. The estimate was unchanged after further adjustment for estimated glomerular filtration rate. Median whole-blood cadmium lay about 110-fold below the 5th percentile of active ACs (0.30 μM) but only 1.2-fold below the most potent active AC (0.0034 μM). Environmentally relevant cadmium therefore tracks with albuminuria at internal concentrations below most in vitro bioactivity. The BER is a screening-level scaling comparison rather than a margin of safety, and does not on its own establish an accumulation-driven mechanism.
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10. Acute or developmental exposure of primary rat cortical cells to Emamectin Benzoate disrupts gene expression.
10. 原代大鼠皮层细胞急性或发育期暴露于甲氨基阿维菌素苯甲酸盐会破坏基因表达PMID:日期:2026-09-22As the number of chemicals lacking neurotoxicity assessment increases, there is an increased demand for data and tools that can quickly prioritize and identify hazardous chemicals. Using sub-cytotoxic concentrations of Emamectin Benzoate (EMB), an avermectin class pesticide, we explored the use of transcriptomic assessment to provide foundational molecular data for understanding the modes of action for the toxic effects of these chemicals. Primary cortical cell cultures from Long Evans rats were exposed to varying concentrations of EMB and assessed for toxicity following a short-term exposure and a continuous exposure during a key developmental differentiation and synapse formation window. The goals of this study were to determine if EMB exposure disrupted gene expression, whether those changes varied across cortical cell development, compare with proteomic and phenotypic changes, and understand how these gene expression changes could provide critical information on molecular initiating and key events for developmental neurotoxicity. At acute exposure concentrations up to 2.5 μM, minimal transcriptomic effects were observed under the presented analysis framework. Following prolonged developmental exposure, concentration-responsive differential expression was observed across all timepoints, with notable overlap in some key pathways and distinct expression patterns in others. Gene expression changes occurred at similar concentration with proteomic and phenotypic changes. DIV7 emerged as the most sensitive developmental window, with strong dose-responsive effects affecting synaptic and myelin-related genes. These data link transcriptomic and multi-omic molecular changes to apical endpoints and support mechanisms related to GABA signaling, ribosomal protein disruption, inflammation, neurite outgrowth, and synaptogenesis.