Toxicology in Vitro最新文献_第2页

The effects of flavored vaped e-liquids on cultured human macrophages derived from the central and peripheral nervous systems

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-01-31 DOI: 10.1016/j.tiv.2025.106013

Ciani C. Bradley , Imari Walker-Franklin , Alex Kovach , Vijay Sivaraman , Rob U. Onyenwoke

The use of the electronic cigarette (e-cig) to consume an aerosol is referred to as “vaping” and has become the most popular method for nicotine consumption amongst youth and many adults worldwide. This popularity is at least partially attributable to the availability of 1000s of distinctly flavored e-liquids. At present, a large number of studies have evaluated the potential negative effects of e-cig use in relation to pulmonary disease. These studies have demonstrated that vaping can lead to immune activation and cell death but typically include only epithelial cell line studies. At present, significantly less is known about the effects of vaped e-liquids on the central nervous system (CNS) and peripheral nervous system (PNS). To investigate this gap, we utilized the human macrophage cell lines KG-1 (PNS-resident macrophages) and DBTRG-05MG (CNS-resident macrophages) and examined their exposure to vaped e-liquids. To carry out these investigations, measurements of: cell viability, expression of inflammatory cytokines, phagocytosis and reactive oxygen species (ROS) were employed. Our findings illustrate that when exposed to e-liquid, and especially flavored e-liquids, both peripheral and central macrophage cell lines decrease in cell viability, showcase an upregulated level of expression of pro-inflammatory cytokines, a diminished level of phagocytic activity and an overall increased level of reactive oxidative species. Thus, our study further indicates that the use of the e-cig can cause phenotype and immune disruptions within both the CNS and PNS.

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引用次数: 0

Predicting the skin sensitizing potential of pesticides using Pred-skin 3.0–A web-based prediction tool

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-01-30 DOI: 10.1016/j.tiv.2025.106015

Ajay Godwin Potnuri , Lingesh Allakonda , Ajith Kakaraparthi

Pesticide usage is increasing due to growing needs of agriculture and horticulture. Occupational dermal exposure to pesticides at an acute or chronic low-level could result in contact dermatitis and various skin cancers. Hence, detailed understanding about the Adverse Outcome Pathways (AOP) or Chemical Sensitization Pathway (CSP) behind pesticides belonging to various categories has to be investigated. Animal models of skin sensitization testing at times either over or under predict the human responses due to species-to-species variability. This necessitates the need for prediction tools for skin sensitizing potential of various chemicals. Pred-skin 3.0, is a consensus Naïve Bayes model-based prediction tool which utilizes various human, LLNA, and non-animal data to predict skin sensitization. Although, this tool was never used for predicting skin sensitizing potential of pesticides. Henceforth, the current study aims to test the applicability of this prediction tool in predicting skin sensitizing potential of 96 pesticides belonging to three Major classes. The Bayesian outcome of Pred Skin prediction tool provided a good concordance of 72.72 % with the existing animal skin sensitizing data as well as 63.46 % with the non-sensitizer data.

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引用次数: 0

TCDD inhibits the proliferation of C17.2 cells through the activation of the c-Cbl/β-catenin signaling pathway

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-01-27 DOI: 10.1016/j.tiv.2025.106014

Yewen Cong , Yue Wu , Yue Liu , Yongjun Ai , Xiping Wang , Chunxi Wei , Haoyu Ding , Guangfei Xu , Wenxing Sun

2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD) belongs to the category of persistent environmental pollutants, and gestational exposure to TCDD can lead to cognitive, memory, and motor deficits, as well as altered neuron development in rodents. However, the molecular mechanisms underlying TCDD's neurotoxicity remain unclear. Neural stem cells (NSCs) possess the capacity for self-renewal and can generate various cell types within the brain, playing fundamental roles in brain development and regeneration. This study investigated the impact of TCDD on the proliferation of mouse NSCs, specifically focusing on the C17.2 cell line. The results demonstrated that TCDD inhibited the proliferation of C17.2 cells in a dose-dependent manner. Even low doses of TCDD (5 nM) significantly reduced C17.2 cell proliferation. Regarding the molecular mechanisms, it was found that TCDD induced the degradation of β-catenin, a key regulator of cell proliferation, through the upregulation of the E3 ubiquitin ligase, casitas B-lineage lymphoma (c-Cbl), which was dependent on the aryl-hydrocarbon Receptor (AhR). Furthermore, knockdown of c-Cbl alleviated the TCDD-induced inhibition of C17.2 proliferation and of the reduction of β-catenin expression. Our research provides foundational data to understand the mechanism of TCDD-induced neurotoxicity through the inhibition of NSCs proliferation, and suggests that the c-cbl/β-catenin pathway may serve as a potential therapeutic target for countering the neurotoxicants of TCDD.

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引用次数: 0

Sex steroid disrupting effects of nonsteroidal anti-inflammatory drugs on the Persian Gulf Arabian Sea bream, Acanthopagrus arabicus: In vitro model of environmental drug contamination

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-01-24 DOI: 10.1016/j.tiv.2025.106008

Zahra Beitgader , Negin Salamat , Mohammad Ali Salarialiabadi , Hoda Mojiri-Forushani , Asma Mohammadi

The presence of pharmaceuticals in aquatic ecosystems and their impact on humans and the environment are growing concerns in environmental health. This study aimed to evaluate the potential reproductive effects of diclofenac, ibuprofen, and aspirin on dissociated ovarian and testicular cells from Arabian Sea bream, Acanthopagrus arabicus. The cells were exposed to varying concentrations of the pharmaceuticals for 48 h. Steroid (17-β-estradiol (E2) and 11-ketotestosterone (11-KT)) production by the cells was assessed at 0, 12, 24, and 48 h of the experiment. The findings showed that diclofenac did not impact the production of E2 and 11-KT by ovarian cells, but it did significantly decrease the secretion of 11-KT from testicular cells. Ibuprofen and aspirin, on the other hand, both increased the production of the studied steroid hormones by ovarian cells and reduced the secretion of 11-KT by testicular cells in a dose- and time-dependent manner. The pharmaceuticals studied were potent inhibitors of 11-KT secretion, particularly at higher concentrations in the cultured testicular cells. However, they were also found to stimulate steroid production from fish ovarian cells. In conclusion, the results suggest that analgesics (diclofenac, ibuprofen, and aspirin) have the potential to disrupt estrogen biosynthesis and impact reproduction in fish.

水生生态系统中存在的药物及其对人类和环境的影响是环境健康领域日益关注的问题。本研究旨在评估双氯芬酸、布洛芬和阿司匹林对阿拉伯鲷离体卵巢和睾丸细胞的潜在生殖影响。将细胞暴露在不同浓度的药物中 48 小时。在实验的 0、12、24 和 48 小时评估细胞产生的类固醇（17-β-雌二醇（E2）和 11-酮睾酮（11-KT））。结果表明，双氯芬酸不会影响卵巢细胞产生 E2 和 11-KT，但会显著减少睾丸细胞分泌 11-KT。另一方面，布洛芬和阿司匹林都能增加卵巢细胞产生所研究的类固醇激素，并以剂量和时间依赖的方式减少睾丸细胞分泌 11-KT。所研究的药物是 11-KT 分泌的强效抑制剂，尤其是在培养的睾丸细胞中浓度较高时。不过，研究还发现，这些药物还能刺激鱼卵巢细胞分泌类固醇。总之，研究结果表明，镇痛药（双氯芬酸、布洛芬和阿司匹林）有可能破坏雌激素的生物合成，影响鱼类的繁殖。

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引用次数: 0

Risk assessment of chlorophenols (CPs) exposure in vitro:Inhibition of sulfotransferases (SULTs) activity

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-01-23 DOI: 10.1016/j.tiv.2025.106012

Kai Yang , Guo-Qiang Qin , Zi-Zhuo Jia , Qiangqiang Gan , Ruo-Yong Jia , Wei Zhang , Yong-Zhe Liu , Zhong-Ze Fang

Chlorophenols (CPs) are common organic pollutants widely used in many industries. The current study seeks to examine the inhibition of sulfotransferases (SULTs) by CPs. Four SULT isoforms were significantly inhibited by multiply CPs. Furthermore, half inhibition concentration (IC₅₀) was calculated to be 0.31 μM, 0.11 μM and 1.86 μM for the inhibition of PCP (pentachlorophenol) towards SULT1A1, SULT1B1 and SULT1E1. PCP showed competitive inhibition towards SULT1B1 and SULT1E1.The inhibition kinetics (inhibition type and parameters (K_i)) values were calculated to be 0.34 μM and 0.56 μM for the inhibition of PCP towards SULT1B1 and SULT1E1, respectively. In silico docking was used to explain the inhibition difference among CPs. The binding free energy between 4-CP and SULT1A3 was −4.92 kcal/mol, and the binding free energy between 2.4-DCP and SULT1A3 was −5.63 kcal/mol. Therefore, 2.4-DCP exerted stronger inhibition activity towards SULT1A3 compared with 4-CP, which can well explain the experimental result. These results are crucial for exploring the risks associated with CPs exposure from a novel perspective.

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引用次数: 0

Studying the intracellular bile acid concentration and toxicity in drug-induced cholestasis: Comprehensive LC-MS/MS analysis with human liver slices

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-01-22 DOI: 10.1016/j.tiv.2025.106011

R.E.H. Karsten , K. Gier , V.E. de Meijer , W.H.C. Huibers , H.P. Permentier , E. Verpoorte , P. Olinga

Drug-induced cholestasis (DIC) is a leading cause of drug-induced liver injury post-drug marketing, characterized by bile flow obstruction and toxic bile constituent accumulation within hepatocytes. This study investigates the toxicity associated with intracellular bile acid (BA) accumulation during DIC development. Using liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, we examined intracellular BA concentrations in human precision-cut liver slices (PCLS) following the administration of cyclosporin A and chlorpromazine, both with and without an established BA mixture.

Our findings indicate toxicity of cyclosporin A upon BA addition, while chlorpromazine's toxicity remained unaffected. Although neither drug led to the accumulation of all BAs intracellularly, BA mixture addition resulted in the accumulation of unconjugated BAs associated with DIC, such as deoxycholic acid (DCA) and cholic acid (CA). Additionally, cyclosporin A increased taurolithocholic acid (TLCA) concentrations. In the absence of the BA mixture, a decrease in conjugated BAs was observed, suggesting inhibition of BA metabolism by cholestatic drugs and warranting further investigation. The evident increase in CA and DCA for both drugs (and TLCA for cyclosporin A), despite not exacerbating toxicity with chlorpromazine, suggests these increases may be related to DIC development and possible toxicity.

In conclusion, the current human PCLS model is appropriate for investigating and detecting essential contributors to DIC and can be used in future studies elucidating DIC ex vivo.

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引用次数: 0

The obesogenic effects of Bisphenol A and its analogues are differentially regulated via PPARγ transactivation in mouse 3T3-L1 cells

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-01-20 DOI: 10.1016/j.tiv.2025.106009

Jennifer Crosthwait , Syed Syeddan , Ella Atlas

Exposure to environmental pollutants with obesogenic activity is being recognised as one of the contributing factors to the obesity epidemic. Bisphenol A (BPA) has been shown to stimulate adipogenesis in both human and mouse preadipocytes, to increase body weight and affect lipid metabolism in animal and epidemiological studies. Regulatory action and public concern has prompted industry to replace BPA with other structurally similar analogues that may have similar effects.

In this study we investigated the effects of fifteen BPA analogues on adipogenesis in the mouse 3 T3-L1 pre-adipocyte cell model in order to determine their adipogenic activity relative to BPA. 3 T3-L1 cells were treated with increasing concentrations of BPA and replacements and mRNA expression of the mature adipocyte markers fatty acid binding protein 4 (Fabp4), perilipin (Plin) lipoprotein lipase (Lpl)and peroxisome proliferator-activated receptor (Ppar)γ and lipid accumulation were assessed. In addition, a luciferase reporter assay for PPARγ transactivation was employed to investigate mechanism of action.

Our results show that BPC, BPS-MAE, BPS-MPE and TGSA, were the most adipogenic bisphenols, as shown by a robust increase in lipid accumulation and mRNA expression of adipogenic markers. BPS-MPE, BPC, BTUM, TGSA and D8 increased PPARγ transcriptional activity. Despite its ability to activate PPARγ in the transcriptional assay D8 did not affect adipogenesis in this cell model.

{"title":"The obesogenic effects of Bisphenol A and its analogues are differentially regulated via PPARγ transactivation in mouse 3T3-L1 cells","authors":"Jennifer Crosthwait , Syed Syeddan , Ella Atlas","doi":"10.1016/j.tiv.2025.106009","DOIUrl":"10.1016/j.tiv.2025.106009","url":null,"abstract":"<div><div>Exposure to environmental pollutants with obesogenic activity is being recognised as one of the contributing factors to the obesity epidemic. Bisphenol A (BPA) has been shown to stimulate adipogenesis in both human and mouse preadipocytes, to increase body weight and affect lipid metabolism in animal and epidemiological studies. Regulatory action and public concern has prompted industry to replace BPA with other structurally similar analogues that may have similar effects.</div><div>In this study we investigated the effects of fifteen BPA analogues on adipogenesis in the mouse 3 T3-L1 pre-adipocyte cell model in order to determine their adipogenic activity relative to BPA. 3 T3-L1 cells were treated with increasing concentrations of BPA and replacements and mRNA expression of the mature adipocyte markers fatty acid binding protein 4 (<em>Fabp4</em>), perilipin (<em>Plin</em>) lipoprotein lipase (<em>Lpl)</em>and peroxisome proliferator-activated receptor (<em>Ppar</em>)γ and lipid accumulation were assessed. In addition, a luciferase reporter assay for PPARγ transactivation was employed to investigate mechanism of action.</div><div>Our results show that BPC, BPS-MAE, BPS-MPE and TGSA, were the most adipogenic bisphenols, as shown by a robust increase in lipid accumulation and mRNA expression of adipogenic markers. BPS-MPE, BPC, BTUM, TGSA and D8 increased PPARγ transcriptional activity. Despite its ability to activate PPARγ in the transcriptional assay D8 did not affect adipogenesis in this cell model.</div></div>","PeriodicalId":54423,"journal":{"name":"Toxicology in Vitro","volume":"104 ","pages":"Article 106009"},"PeriodicalIF":2.6,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143025684","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

DTPA and anti-inflammatory drug associations to alleviate Pu-induced response of macrophages in vitro DTPA与抗炎药物联合减轻巨噬细胞pu诱导的体外反应。

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2025-01-19 DOI: 10.1016/j.tiv.2025.106007

Alexandra Bourgois , Guillaume Cosler , Diane Riccobono , Clélia Le Gallic , Sabine François , Anne Van der Meeren

Internal contamination by inhalation of plutonium poorly soluble compounds leads to their long time retention in alveolar macrophages inducing delayed pathology development. As previous studies highlighted co-localization of retained Pu and inflammatory lesions, this study was designed to assess the combined effect of the reference treatment (DTPA) and anti-inflammatory drugs on Pu-induced early response of macrophages in vitro.

Pu colloids, mimicking poorly soluble Pu, were characterized using filtration and solid-state nuclear track detectors CR39. Their bioavailability was determined using a biphasic acellular model. Treatment effects on Pu dissolution and release as well as on Pu-induced pro-inflammatory response were assessed over 7 days on macrophage-like cells.

DTPA treatment, associated or not with anti-inflammatory drug, increased Pu dissolution and release from contaminated THP-1 differentiated cells after 7 days. Significant decreases in Pu-induced IL-8 and MCP-1 secretions were also observed with anti-inflammatory treatment associated or not with DTPA.

This study highlighted the ability of DTPA to partially dissolve a poorly soluble form of Pu as well as the ability of anti-inflammatory drugs to modulate Pu-induced pro-inflammatory response in macrophage-like cells. These treatments seem a promising strategy to improve the clinical management of Pu pulmonary contaminations and to limit delayed pulmonary pathology occurrence.

吸入钚难溶性化合物的内部污染导致其在肺泡巨噬细胞中长时间滞留，从而导致病理发展延迟。鉴于既往研究强调残留Pu与炎性病变的共定位，本研究旨在评估参考治疗（DTPA）和抗炎药物联合使用对体外巨噬细胞Pu诱导的早期反应的影响。采用过滤和固体核径迹探测器CR39对模拟难溶性Pu的Pu胶体进行了表征。采用双相脱细胞模型测定其生物利用度。在7 天的巨噬细胞样细胞上评估治疗对Pu溶解和释放以及Pu诱导的促炎反应的影响。DTPA治疗，无论是否联合抗炎药物，在7 天后，污染的THP-1分化细胞中Pu的溶解和释放增加。与DTPA相关或不相关的抗炎治疗也观察到pu诱导的IL-8和MCP-1分泌显著降低。这项研究强调了DTPA部分溶解难溶性Pu的能力，以及抗炎药物调节巨噬细胞样细胞中Pu诱导的促炎反应的能力。这些治疗似乎是一种有希望的策略，以改善肺部污染的临床管理和限制延迟的肺部病理发生。

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引用次数: 0

Protective effects of methylnissolin and methylnissolin-3-O-β-d-glucopyranoside on TNF-α-induced inflammation in human dermal fibroblasts 甲基尼索林和甲基尼索林-3- o -β-d-葡萄糖吡喃苷对TNF-α-诱导的人真皮成纤维细胞炎症的保护作用。

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2024-12-31 DOI: 10.1016/j.tiv.2024.106005

Yea Jung Choi , Xiaohua Wu , Sullim Lee , Jae Sung Pyo , Jaejin Cho , Shugeng Cao , Ki Sung Kang

Methylnissolin-3-O-β-d-glucopyranoside (MNG) and methylnissolin (MN) are pterocarpan derivatives that are found in plants, such as Astragalus membranaceus. There are limited existing studies on the potential health benefits of MNG, and currently there is no evidence to suggest that MNG has any impact on skin-aging. Tumor necrosis factor-alpha (TNF-α) plays a significant role in skin aging by promoting chronic inflammation, damaging skin cells, and impairing the skin's natural repair mechanisms. Targeting TNF-α or its downstream signaling pathways may be a promising strategy for preventing or reversing skin-aging. We tested the effect of MNG and MN on skin-aging by inducing cell inflammation and oxidative stress with TNF-α in HDFs. MNG and MN significantly reduced the TNF-α-induced secretion of matrix metalloproteinase-1 (MMP-1). However, MNG has more beneficial compound for oral administration than MN in pharmacokinetics analysis. The mechanism underlying the anti-skin-aging effect of MNG is related to the suppression of TNF-α-induced reactive oxygen species (ROS) generation and mitogen-activated protein kinase (MAPKs) phosphorylation. Our results suggest that MNG is a potential candidate for preventing skin-aging induced by TNF-α.

methylnissolin -3- o -β-d-glucopyranoside （MNG）和methylnissolin （MN）是在黄芪等植物中发现的翼龙碱衍生物。关于MNG的潜在健康益处的现有研究有限，目前没有证据表明MNG对皮肤老化有任何影响。肿瘤坏死因子-α (Tumor necrosis factor -α, TNF-α)通过促进慢性炎症、破坏皮肤细胞和损害皮肤的自然修复机制，在皮肤衰老中发挥重要作用。靶向TNF-α或其下游信号通路可能是预防或逆转皮肤老化的有希望的策略。我们通过在HDFs中使用TNF-α诱导细胞炎症和氧化应激来检测MNG和MN对皮肤衰老的影响。MNG和MN显著降低TNF-α-诱导的基质金属蛋白酶-1 （MMP-1）的分泌。然而，在药代动力学分析中，口服MNG比MN有更多的有益化合物。MNG抗皮肤衰老作用的机制与抑制TNF-α-诱导的活性氧（ROS）生成和丝裂原活化蛋白激酶（MAPKs）磷酸化有关。我们的研究结果表明，MNG是预防TNF-α诱导的皮肤衰老的潜在候选者。

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引用次数: 0

Washing with buffered vitamin C after corrosive chemical (sodium hypochlorite) exposure reduces ocular depth of injury 在腐蚀性化学物质（次氯酸钠）暴露后，用缓冲的维生素C洗涤可减少眼部损伤深度。

IF 2.6 3区医学 Q3 TOXICOLOGY

Toxicology in Vitro

Pub Date : 2024-12-31 DOI: 10.1016/j.tiv.2024.106006

Stewart Lebrun, Linda Nguyen, Joana Romero, Roxanne Chan

Chemical eye injuries occur in home, industrial, and military settings. The standard recommended treatment after exposure of the eyes to chemical toxins is washing with tap water for at least 15 min. An estimated 80 % of ocular toxins are associated with reactive oxygen species and/or extreme pH. Using food-source eyes and a commercially available test kit for depth of injury (IVD EIT^TM) that measures the depth of dead corneal keratocytes by fragmented DNA staining, washing the eye with a buffered vitamin C solution significantly reduced corneal keratocyte cell death and depth of injury compared to control. When eyes were washed (using a 500-mL eyewash bottle) for 15 min with water after exposure to 32 % sodium hypochlorite (chlorine bleach), the depth of injury was 59.6 ± 3.6 %, a level of damage predicted to cause extreme/permanent eye injury or even blindness in vivo (extreme or irreversible injury, GHS category 1), but washing with 0.2 % buffered vitamin C after bleach exposure reduced damage to13.8 ± 1.4 %, which is significantly less (P < 0.001) and predicted by the IVD EIT method to be reversible irritation (GHS category 2) that will heal within 21 days in vivo.

化学眼睛伤害发生在家庭、工业和军事环境中。眼睛接触化学毒素后的标准建议治疗方法是用自来水冲洗至少15 分钟。估计80% %的眼部毒素与活性氧和/或极端ph值有关。使用食物来源的眼睛和市售的损伤深度测试试剂盒（IVD EITTM），通过碎片化DNA染色测量死亡角膜角质细胞的深度，用缓冲的维生素C溶液冲洗眼睛，与对照组相比，明显减少了角膜角质细胞的死亡和损伤深度。眼睛洗时(使用一瓶500毫升的无稽之谈) 15分钟后与水接触32 %次氯酸钠(含氯漂白剂)损伤的深度是59.6 ±3.6  %,预计将造成一定程度的破坏极限/永久眼睛受伤甚至失明体内(极端或不可逆损伤,gh类别1),但洗后0.2 %缓冲维生素C漂白剂暴露减少损害to13.8 ±1.4  %,显著减少(P

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引用次数: 0