Toxicology and applied pharmacology最新文献_第3页

Bisphenol AP inhibits mouse oocyte maturation in vitro by disrupting cytoskeleton architecture and cell cycle processes 双酚 AP 通过破坏细胞骨架结构和细胞周期过程抑制小鼠卵母细胞的体外成熟。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-01 DOI: 10.1016/j.taap.2024.117118

{"title":"Bisphenol AP inhibits mouse oocyte maturation in vitro by disrupting cytoskeleton architecture and cell cycle processes","authors":"","doi":"10.1016/j.taap.2024.117118","DOIUrl":"10.1016/j.taap.2024.117118","url":null,"abstract":"<div><div>Bisphenol A (BPA) is among the extensively researched environmental endocrine-disrupting chemicals (EDCs), and its utilization is restricted owing to the detrimental impacts it has on human health. Bisphenol AP (BPAP) is one of the alternatives to BPA, but the influence of BPAP on human health has not been elucidated. The objective of the current research was to determine the influence of BPAP exposure on the <em>in vitro</em> maturation of mouse oocytes and to explore its potential reproductive toxicity. BPAP exposure was found to inhibit polar body extrusion during mouse oocyte maturation, resulting in an arrest at the metaphase I stage of meiosis. Exposure to BPAP led to sustained activation of BubR1, preventing the degradation of both Securin and Cyclin B1. Mechanistically, BPAP exposure disrupts spindle assembly and chromosome alignment. Levels of acetylated α-tubulin were significantly elevated in BPAP-treated oocytes, reflecting decreased spindle stability. Exposure to BPAP also induced DNA damage and impaired DNA damage repair. In addition, BPAP exposure altered histone modification levels. In summary, this investigation suggests that exposure to BPAP can influence cytoskeletal assembly, interfere with cell cycle progression, induce DNA damage, alter histone modifications, and ultimately impede oocyte meiotic maturation. This investigation enhances understanding of the impact of bisphenol analogs on female gametes, underscoring that BPAP cannot be considered a reliable replacement for BPA.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Alcohol promotes hepatocyte injury via ER stress sensor XBP1s mediated regulation of autophagy and lysosomal activity 酒精通过ER应激传感器XBP1s介导的自噬和溶酶体活性调节促进肝细胞损伤。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-10-01 DOI: 10.1016/j.taap.2024.117117

{"title":"Alcohol promotes hepatocyte injury via ER stress sensor XBP1s mediated regulation of autophagy and lysosomal activity","authors":"","doi":"10.1016/j.taap.2024.117117","DOIUrl":"10.1016/j.taap.2024.117117","url":null,"abstract":"<div><h3>Objective</h3><div>Endoplasmic reticulum stress (ERS) plays an important role in the development of Alcoholic liver injury (ALI), but the exact mechanism needs further exploration. This study aims to investigate the role of ERS-XBP1s in ALI, and providing new target for the treatment of liver injury.</div></div><div><h3>Method</h3><div>The ALI model was constructed using the NIAAA method and was validated by several methods. ERS was detected using western-blot, RT-qPCR and immunohistochemistry. Apoptosis was measured by TUNEL staining, Hoechst staining, western-blot and Annexin V-FITC. Lysosomal function and autophagy were measured by Lyso-Tracker Green probe, western-blot and immunofluorescence, respectively.</div></div><div><h3>Results</h3><div>The ALI model was successfully constructed as demonstrated by increased liver steatosis, inflammation and oxidative stress, and higher levels of serum ALT, AST and TG. Alcohol significantly increased the expression of ERS-related molecules, such as PERK, IRE1α, GRP78 and XBP1s, and promoted the nuclear translocation of XBP1s. Moreover, alcohol significantly increased apoptosis and inhibition of XBP1s could reverse this effect <em>in vivo</em> and <em>in vitro</em>. Interestingly, we found that alcohol significantly elevated hepatocyte LC3-II/I levels and concomitantly accumulation of P62, and this phenomenon was reversed by inhibiting XBP1s both <em>in vivo</em> and <em>in vitro</em>. Mechanistically, we found that alcohol activation of ER stress sensor XBP1s which promoted liver injury <em>via</em> inhibiting lysosomal function and autophagy activity in hepatocytes, whereas inhibition of XBP1s reduces hepatocyte apoptosis by restoring lysosomal activity and activating of autophagy.</div></div><div><h3>Conclusion</h3><div>Alcohol promotes hepatocytes injury <em>via</em> ER stress sensor XBP1s mediated inhibition of autophagy. Therefore, inhibition of XBP1 may protect the liver from alcohol-induced damage.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ameliorative effect of Schisandrol B against Diosbulbin B-induced hepatotoxicity via inhibiting CYP3A4-mediated bioactivation 通过抑制 CYP3A4 介导的生物活化，五味子醇 B 对黄独素 B 诱导的肝毒性具有改善作用。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-09-30 DOI: 10.1016/j.taap.2024.117116

{"title":"Ameliorative effect of Schisandrol B against Diosbulbin B-induced hepatotoxicity via inhibiting CYP3A4-mediated bioactivation","authors":"","doi":"10.1016/j.taap.2024.117116","DOIUrl":"10.1016/j.taap.2024.117116","url":null,"abstract":"<div><div>Diosbulbin B (DBB), the major component isolated from herbal medicine <em>Dioscorea bulbifera</em> L. (DBL), can trigger severe hepatotoxicity. The previous studies demonstrated that DBB-induced hepatotoxicity is closely relevant to the bioactivation mediated by CYP3A4 and subsequent generation of adducts with cellular proteins. Schisandrol B (SchB), the primary lignan ingredient in herbal medicine <em>Schisandra chinensis</em> (SC), is able to inhibit CYP3A activity. The objective of this study is to investigate the protective effect of SchB against hepatotoxicity induced by DBB and to explore the underlying mechanism. Biochemical and histopathological analysis demonstrated that SchB exerted dose-dependent protective effect against DBB-induced hepatotoxicity. <em>In vitro</em> metabolism assay showed that the formation of pyrrole-glutathione (GSH) conjugates of DBB was inhibited by SchB in a concentration dependent manner, suggesting SchB inhibited the bioactivation of DBB <em>in vitro</em>. Pharmacokinetic studies demonstrated that SchB enhanced C<sub>max</sub> and AUCs of DBB in mouse blood and liver, resulting in accelerating the accumulation of DBB in the circulation. In addition, pretreatment with SchB alleviated DBB-induced hepatic GSH depletion, obviously facilitated the excretion of DBB in urine, and reduced the urinary excretion of DBB-GSH conjugates, indicating that SchB affected absorption, distribution, metabolism, and excretion (ADME) of DBB by inhibiting the bioactivation of DBB <em>in vivo</em>. In conclusion, our findings demonstrated the amelioration of SchB against DBB-induced hepatotoxicity was correlated with the inhibition of CYP3A4-mediated bioactivation of DBB. Thus, the findings indicated that SchB may serve as a potential candidate drug for the treatment of DBB intoxication.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Integration of network pharmacology and transcriptomics to explore the mechanism of isoliquiritigenin in treating heart failure induced by myocardial infarction 整合网络药理学和转录组学，探索isoliquiritigenin治疗心肌梗死诱发的心力衰竭的机制。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-09-30 DOI: 10.1016/j.taap.2024.117114

{"title":"Integration of network pharmacology and transcriptomics to explore the mechanism of isoliquiritigenin in treating heart failure induced by myocardial infarction","authors":"","doi":"10.1016/j.taap.2024.117114","DOIUrl":"10.1016/j.taap.2024.117114","url":null,"abstract":"<div><h3>Background</h3><div>The inflammatory response and myocardial remodeling play critical roles in the progression of heart failure (HF) following myocardial infarction (MI). Isoliquiritigenin (ISL) possesses anti-inflammatory properties and has been investigated in cardiovascular diseases such as atherosclerosis. However, the effects and mechanism of ISL on MI-induced HF remain unclear. This research aimed to explore the effects and mechanism of ISL in the treatment of HF on the basis of network pharmacology, transcriptomics, and experimental verification.</div></div><div><h3>Methods and results</h3><div>We established an MI-induced HF mouse model in which ISL was administered via gavage for 28 days. Ultrasonic cardiogram data were collected from the mice, and pathological staining was conducted. Then, network pharmacology and molecular docking were performed. Transcriptomic analysis was also conducted on mouse myocardial tissue. Ultimately, we integrated transcriptomic data and network pharmacology to reveal the underlying mechanism, with the results verified through in vivo experiments. Our experiments indicated that ISL improved cardiac function, preserved myocardial structure, inhibited collagen fiber accumulation, reduced inflammatory factor secretion, and mitigated myocardial cell apoptosis in mice with MI-induced HF. A combination of transcriptomics and network pharmacology analysis revealed that core targets of ISL related to HF were significantly enriched in the Tumor Necrosis Factor (TNF) signaling pathway. Molecular docking validation demonstrated that ISL shows strong binding to these core targets. Additionally, in vivo experiments verified that ISL protects against HF post-MI by inhibiting the TNF signaling pathway.</div></div><div><h3>Conclusion</h3><div>We clarified the anti-inflammatory and antimyocardial remodeling mechanisms of ISL in the treatment of HF post-MI, which involves the TNF signaling pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Trivalent arsenicals induce skin toxicity through thiol depletion 三价砷通过消耗硫醇诱发皮肤中毒。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-09-30 DOI: 10.1016/j.taap.2024.117115

{"title":"Trivalent arsenicals induce skin toxicity through thiol depletion","authors":"","doi":"10.1016/j.taap.2024.117115","DOIUrl":"10.1016/j.taap.2024.117115","url":null,"abstract":"<div><div>Arsenic, a widespread environmental contaminant, is highly toxic to human health. Arsenic exposure is associated with the occurrence of skin lesions and diseases. This study investigated the dermal toxicity of trivalent arsenicals (As<sup>III</sup> and MMA<sup>III</sup>) and its underlying mechanism using human keratinocyte cell line and <em>ex vivo</em> porcine skin. As<sup>III</sup> and MMA<sup>III</sup> induced concentration-dependent cell apoptosis and necrosis in HaCaT cells, which was confirmed in <em>ex vivo</em> porcine skin. As<sup>III</sup> and MMA<sup>III</sup> increased reactive oxygen species generation and GSH depletion. Interestingly, radical scavenger antioxidants such as Vitamin C failed to mitigate arsenic-induced cytotoxicity, while thiol-containing compounds effectively alleviated it, suggesting a key role of thiol depletion in the trivalent arsenical-induced dermal toxicity. DMSA showed the strongest protective effects against As<sup>III</sup> and MMA<sup>III</sup>-induced cytotoxicity in HaCaT cells. Of note, DMSA restored arsenical-induced tissue damage, and reduced the apoptosis in <em>ex vivo</em> porcine skin, highlighting its potential use to alleviate arsenic-induced skin lesions and diseases.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142366553","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CBR-470-1 protects against cardiomyocyte death in ischaemia/reperfusion injury by activating the Nrf2–GPX4 cascade CBR-470-1 通过激活 Nrf2-GPX4 级联，防止心肌细胞在缺血/再灌注损伤中死亡。

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-09-27 DOI: 10.1016/j.taap.2024.117113

{"title":"CBR-470-1 protects against cardiomyocyte death in ischaemia/reperfusion injury by activating the Nrf2–GPX4 cascade","authors":"","doi":"10.1016/j.taap.2024.117113","DOIUrl":"10.1016/j.taap.2024.117113","url":null,"abstract":"<div><div>Cardiac ischaemia/reperfusion (I/R) impairs mitochondrial function, resulting in excessive oxidative stress and cardiomyocyte ferroptosis and death. Nuclear factor E2-related factor 2 (Nrf2) is a key regulator of redox homeostasis and has cardioprotective effects against various stresses. Here, we tested whether CBR-470-1, a noncovalent Nrf2 activator, can protect against cardiomyocyte death caused by I/R stress. Compared with vehicle treatment, the administration of CBR-470-1 (2 mg/kg) to mice significantly increased Nrf2 protein levels and ameliorated the infarct size, the I/R-induced decrease in cardiac contractile performance, and the I/R-induced increases in cell apoptosis, ROS levels, and inflammation. Consistently, the beneficial effects of CBR-470-1 on cardiomyocytes were verified in a hypoxia/reoxygenation (H/R) model in vitro, but this cardioprotection was dramatically attenuated by the GPX4 inhibitor RSL3. Mechanistically, CBR-470-1 upregulated Nrf2 expression, which increased the expression levels of antioxidant enzymes (NQO1, SOD1, Prdx1, and Gclc) and antiferroptotic proteins (SLC7A11 and GPX4) and downregulated the protein expression of p53 and Nlrp3, leading to the inhibition of ROS production and inflammation and subsequent cardiomyocyte death (apoptosis, ferroptosis and pyroptosis). In summary, CBR-470-1 prevented I/R-mediated cardiac injury possibly through inhibiting cardiomyocyte apoptosis, ferroptosis and pyroptosis via Nrf2-mediated inhibition of p53 and Nlrp3 and activation of the SLC7A11/GPX4 pathway. Our data also highlight that CBR-470-1 may serve as a valuable agent for treating ischaemic heart disease.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142354440","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hesperidin attenuates radiation-induced ovarian failure in rats: Emphasis on TLR-4/NF-ĸB signaling pathway 橙皮甙可减轻辐射诱导的大鼠卵巢功能衰竭：强调TLR-4/NF-ĸB信号通路

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-09-24 DOI: 10.1016/j.taap.2024.117111

{"title":"Hesperidin attenuates radiation-induced ovarian failure in rats: Emphasis on TLR-4/NF-ĸB signaling pathway","authors":"","doi":"10.1016/j.taap.2024.117111","DOIUrl":"10.1016/j.taap.2024.117111","url":null,"abstract":"<div><div>Young women suffering from premature ovarian failure after radiotherapy carry a huge burden in the field of cancer therapy including reproductive loss, emotional stress, and physical troubles that reduce their long-term quality of life. Hesperidin (HSP) exhibited antioxidant, anti-inflammatory, and anti-apoptotic properties. HSP enhanced in vitro follicular maturation and preserved in vivo ovarian stockpile. In this research, the role of HSP in radiation-induced POF in rats was investigated besides ascertaining its underlying mechanisms. Female Sprague-Dawley rats were arbitrarily allocated into four groups: control-group, ϒ-irradiated-group (3.2 Gy once on the 7th day), HSP-group (100 mg/kg, orally for 10 days), and HSP/ϒ-irradiated-group (ϒ-radiation was applied one hour after HSP). At the end of experiment, the whole ovaries were collected for histological and biochemical analyses. Administration of HSP preserved the ovarian histoarchitecture and follicular stock, retained ovarian weight, and conserved serum estradiol and AMH levels following radiation exposure. HSP ameliorated the ovarian oxidative damage mediated by radiation through augmenting the activities of glutathione peroxidase, glutathione reductase, and catalase antioxidant enzymes. HSP exhibited remarkable anti-inflammatory activity by downregulating the expression of ovarian TLR-4, NF-ĸB, and TNF-α. Moreover, HSP suppressed the apoptotic machinery triggered by radiation by reducing p53 and Bax while increasing Bcl-2 mRNA expressions alongside diminishing caspase-3 expression. Additionally, HSP regulated estrous cycle disorder of irradiated rats and improved their reproductive capacity reflected by enhancing pregnancy outcomes. Therefore, HSP represents an appealing candidate as an adjunct remedy for female cancer patients during radiotherapy protocols owing to its antioxidant, anti-inflammatory, anti-apoptotic, and hormone-regulatory effects.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human trophoblast organoids for improved prediction of placental ABC transporter-mediated drug transport 人类滋养层有机体用于改进对胎盘 ABC 转运体介导的药物转运的预测

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-09-24 DOI: 10.1016/j.taap.2024.117112

{"title":"Human trophoblast organoids for improved prediction of placental ABC transporter-mediated drug transport","authors":"","doi":"10.1016/j.taap.2024.117112","DOIUrl":"10.1016/j.taap.2024.117112","url":null,"abstract":"<div><div>ATP-binding cassette (ABC) transporters, the important transmembrane efflux transporters, play an irreplaceable role in the placenta barrier. The disposition and drug-drug interaction of clinical drugs are also closely related to the functions of ABC transporters. The trophoblast is a unique feature of the placenta, which is crucial for normal placentation and maintenance during pregnancy. ABC transporters are abundantly expressed in placental syncytiotrophoblast, especially P-gp, BCRP, and MRPs. However, due to the lack of appropriate modeling systems, the molecular mechanisms of regulation between ABC transporters and trophoblast remains unclear. In this report, trophoblast organoids were cultured from human placental villi and developed into three-dimension structures with cavities. Trophoblast organoids exhibited transporter expression and localization comparable to that in villous tissue, indicating their physiological relevance for modeling drug transport. Moreover, fluorescent substrates can accumulate in organoids and be selectively inhibited by inhibitors, indicating the efflux function of ABC transporters (P-gp, BCRP, MRP1, and MRP2) in organoids. Two commonly used hypertension drugs and three antipsychotics were chosen to further validate this drug transport model and demonstrate varying degrees of inhibitory effects on ABC transporters. Overall, a new drug transport model mediated by ABC transporter has been successfully established based on human trophoblast organoids, which can be used to study drug transport in the placenta.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142323007","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Protective effects of alpinetin against interleukin-1β-exposed nucleus pulposus cells: Involvement of the TLR4/MyD88 pathway in a cellular model of intervertebral disc degeneration 羊胎素对暴露于白细胞介素-1β的髓核细胞的保护作用椎间盘退化细胞模型中 TLR4/MyD88 通路的参与

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-09-23 DOI: 10.1016/j.taap.2024.117110

{"title":"Protective effects of alpinetin against interleukin-1β-exposed nucleus pulposus cells: Involvement of the TLR4/MyD88 pathway in a cellular model of intervertebral disc degeneration","authors":"","doi":"10.1016/j.taap.2024.117110","DOIUrl":"10.1016/j.taap.2024.117110","url":null,"abstract":"<div><div>Intervertebral disc degeneration (IDD) causes a variety of symptoms such as low back pain, disc herniation, and spinal stenosis, which can lead to high social and economic costs. Alpinetin has an anti-inflammatory potential, but its effect on IDD is unclear. Herein, we investigated the effect of alpinetin on IDD. To mimic an <em>in vitro</em> model of IDD, nucleus pulposus cells (NPCs) were exposed to interleukin 1β (IL-1β). The viability of NPCs was assessed by CCK-8 assay. The expression of Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein 88 (MyD88), aggrecan, collagen-2, and matrix metalloproteinase-3 (MMP-3) was examined by qRT-PCR and western blotting. The protein levels of B cell lymphoma-2 (Bcl-2), Bcl-2-associated protein X (Bax), and cleaved caspase-3 were scrutinized by western blotting. The flow cytometry assay was performed to assess apoptosis of NPCs. The contents of inflammatory factors were examined by ELISA kits. Results showed that alpinetin repressed IL-1β-tempted activation of the TLR4/MyD88 pathway and apoptosis in NPCs. Alpinetin alleviated IL-1β-tempted inflammatory responses and oxidative stress in NPCs. Moreover, alpinetin lessened IL-1β-tempted extracellular matrix (ECM) degeneration in NPCs by enhancing the expression of aggrecan and collagen-2 and reducing the expression of MMP-3. The effects of alpinetin on IL-1β-exposed NPCs were neutralized by TLR4 upregulation. In conclusion, alpinetin repressed IL-1β-tempted apoptosis, inflammatory responses, oxidative stress, and ECM degradation in NPCs through the inactivation of the TLR4/MyD88 pathway.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Strengths and limitations of the worm development and activity test (wDAT) as a chemical screening tool for developmental hazards 蠕虫发育和活动试验（wDAT）作为发育危害化学筛选工具的优势和局限性

IF 3.3 3区医学

Toxicology and applied pharmacology Pub Date : 2024-09-23 DOI: 10.1016/j.taap.2024.117108

{"title":"Strengths and limitations of the worm development and activity test (wDAT) as a chemical screening tool for developmental hazards","authors":"","doi":"10.1016/j.taap.2024.117108","DOIUrl":"10.1016/j.taap.2024.117108","url":null,"abstract":"<div><div>The worm Development and Activity Test (wDAT) measures <em>C. elegans</em> developmental milestone acquisition timing and stage-specific spontaneous locomotor activity (SLA). Previously, the wDAT identified developmental delays and SLA level changes in <em>C. elegans</em> with mammalian developmental toxicants arsenic, lead, and mercury. 5-fluorouracil (5FU), cyclophosphamide (CP), hydroxyurea (HU), and ribavirin (RV) are teratogens that also induce growth retardation in developing mammals. In at least some studies on each of these chemicals, fetal weight reductions were seen at mammalian exposures below those that had teratogenic effects, suggesting that screening for developmental delay in a small alternative whole-animal model could act as a general toxicity endpoint to identify chemicals for further testing for more specific adverse developmental outcomes. Consistent with mammalian developmental effects, 5FU, HU, and RV were associated with developmental delays with the wDAT. Exposures associated with developmental delay induced hypoactivity with 5FU and HU, but slight hyperactivity with RV. CP is a prodrug that requires bioactivation by cytochrome P450s for both therapeutic and toxic effects. CP tests as a false negative in several <em>in vitro</em> assays, and it was also a false negative with the wDAT. These results suggest that the wDAT has the potential to identify some developmental toxicants, and that a positive wDAT result with an unknown may warrant further testing in mammals. Further assessment with larger panels of positive and negative controls will help qualify the applicability and utility of this <em>C. elegans</em> wDAT assay within toxicity test batteries or weight of evidence approaches for developmental toxicity assessment<strong>.</strong></div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142326517","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0