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Ephedrine attenuates LPS-induced M1 polarization of alveolar macrophages via the PKM2-mediated glycolysis. 麻黄碱可通过 PKM2 介导的糖酵解减轻 LPS 诱导的肺泡巨噬细胞 M1 极化。
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-10 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae166
Yijin Xiang, Zaifeng Jiang, Zhigang Yang, Shaomin Gong, Weiran Niu

Background: Asthma is one of chronic inflammatory lung diseases in world. The important role of macrophage polarization and glycolysis in lung inflammation has attracted considerable attention. Ephedrine (EP) is a compound isolated from Ephedra and plays a regulatory role in inflammatory response, but its role in asthma and mechanism involved are not clear. Therefore, the purpose of this study was to investigate the molecular mechanism and effect of EP on lipopolysaccharide (LPS)-induced alveolar macrophage polarization and glycolysis.

Methods: We investigated the expression of Tnf-a, Nos2, Il10, and Arg1 using RT-PCR, as well as PKM2 and LDHA protein expression with Western blot. A CCK-8 assay was performed to determine the viability of the cells. The extracellular acidification rate (ECAR), ATP and lactate level were detected using commercial kits.

Results: The results revealed that EP alleviated LPS-induced NR8383 cell glycolysis and M1 polarization. Further studies found that EP enhanced the effect of 2-DG on NR8383 cell glycolysis and M1 polarization. More importantly, PKM2 inhibitor alleviated LPS-induced NR8383 cell glycolysis and M1 polarization. In addition, EP alleviated LPS-induced NR8383 cell glycolysis and M1 polarization by targeting PKM2.

Conclusion: It is suggested that EP alleviates LPS-induced glycolysis and M1 polarization in NR8383 cells by regulating PKM2, thereby alleviating lung injury, suggesting the involvment of alveolar macrophage polarization and glycolysis in the role of EP in asthma.

背景:哮喘是世界上慢性肺部炎症性疾病之一。巨噬细胞极化和糖酵解在肺部炎症中的重要作用引起了广泛关注。麻黄碱(Ephedrine,EP)是从麻黄中分离出来的一种化合物,在炎症反应中起调节作用,但其在哮喘中的作用及其机制尚不清楚。因此,本研究旨在探讨麻黄碱对脂多糖(LPS)诱导的肺泡巨噬细胞极化和糖酵解的分子机制和影响:方法:用RT-PCR检测Tnf-a、Nos2、Il10和Arg1的表达,用Western印迹检测PKM2和LDHA蛋白的表达。CCK-8试验测定了细胞的活力。使用商业试剂盒检测细胞外酸化率(ECAR)、ATP和乳酸水平:结果表明,EP 可减轻 LPS 诱导的 NR8383 细胞糖酵解和 M1 极化。进一步研究发现,EP 增强了 2-DG 对 NR8383 细胞糖酵解和 M1 极化的影响。更重要的是,PKM2 抑制剂减轻了 LPS 诱导的 NR8383 细胞糖酵解和 M1 极化。此外,EP通过靶向PKM2缓解了LPS诱导的NR8383细胞糖酵解和M1极化:结论:EP通过调节PKM2减轻LPS诱导的NR8383细胞糖酵解和M1极化,从而减轻肺损伤,表明EP在哮喘中的作用涉及肺泡巨噬细胞极化和糖酵解。
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引用次数: 0
Cytotoxicity induced by three commercial neonicotinoid insecticide formulations in differentiated human neuroblastoma SH-SY5Y cells. 三种商用新烟碱类杀虫剂制剂在分化的人神经母细胞瘤 SH-SY5Y 细胞中诱导的细胞毒性。
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-10 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae171
Karol Ferreira Honatel, Aline Mocellin Conte, Solange Cristina Garcia, Bruno Dutra Arbo, Marcelo Dutra Arbo

Background: Neonicotinoid insecticides are used worldwide for crop protection. They act as agonists at postsynaptic nicotinic acetylcholine receptors (nAChRs), disrupting normal neurotransmission in target insects. Human exposure is high due to the widespread use of neonicotinoids and their residues in food. This study aimed to evaluate the in vitro neurotoxicity of three neonicotinoid commercial formulations Much 600 FS® (imidacloprid 600 g L-1), Evidence 700 WG® (imidacloprid 700 g kg-1), and Actara 250 WG® (thiamethoxam 250 g kg-1) in differentiated human neuroblastoma SH-SY5Y cell line.

Methods: Cells were incubated with the pesticides for 96 h, and the cytotoxicity was evaluated through the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium·bromide (MTT) reduction and neutral red (NR) uptake assays. Toxicological pathways such as reactive oxygen (ROS) and nitrogen species (RNS) production, mitochondrial membrane potential, cell death mode, and the expression of the pro-apoptotic protein Bax were also evaluated.

Results: EC50 values of 266.4, 4,175, and 653.2 mg L-1 were found for Much®, Evidence® and Actara®, respectively. Significant increases in ROS and RNS generation were observed for all pesticides, while mitochondrial membrane potential and Bax protein expression showed no significant changes. Analysis of cell death mode revealed an increase in early apoptotic cells.

Conclusion: Therefore, neonicotinoid insecticides are potentially neurotoxic, reinforcing concerns about human exposure to these commercial formulations.

背景:新烟碱类杀虫剂在全球范围内用于作物保护。它们是突触后烟碱乙酰胆碱受体(nAChRs)的激动剂,会破坏目标昆虫的正常神经传递。由于新烟碱类化合物及其在食物中的残留物被广泛使用,人类的接触量很高。本研究旨在评估三种新烟碱类商用制剂 Much 600 FS®(吡虫啉 600 g L-1)、Evidence 700 WG®(吡虫啉 700 g kg-1)和 Actara 250 WG®(噻虫嗪 250 g kg-1)在分化的人神经母细胞瘤 SH-SY5Y 细胞系中的体外神经毒性:方法:将细胞与农药培养 96 小时,通过 3-(4,5-二甲基-2-噻唑基)-2,5-二苯基-2H-溴化四氮唑(MTT)还原和中性红(NR)吸收试验评估细胞毒性。此外,还评估了活性氧(ROS)和氮物种(RNS)的产生、线粒体膜电位、细胞死亡模式以及促凋亡蛋白 Bax 的表达等毒理学途径:结果:Much®、Evidence® 和 Actara® 的 EC50 值分别为 266.4、4,175 和 653.2 mg L-1。所有杀虫剂产生的 ROS 和 RNS 都显著增加,而线粒体膜电位和 Bax 蛋白表达则无明显变化。对细胞死亡模式的分析表明,早期凋亡细胞有所增加:因此,新烟碱类杀虫剂具有潜在的神经毒性,这加深了人们对人类接触这些商业制剂的担忧。
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引用次数: 0
Repeated radon exposure induced ATM kinase-mediated DNA damage response and protective autophagy in mice and human bronchial epithelial cells. 反复氡照射诱导小鼠和人类支气管上皮细胞发生 ATM 激酶介导的 DNA 损伤反应和保护性自噬。
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae165
Xiaoyu Chen, Shan Shan, Aiqing Wang, Cheng Tu, Jianmei Wan, Chengjiao Hong, Xiaohan Li, Xueying Wang, Jieyun Yin, Jian Tong, Hailin Tian, Lili Xin

Objective: Radon ( 222 Rn) is a naturally occurring radioactive gas that has been closely linked with the development of lung cancer. In this study, we investigated the radon-induced DNA strand breaks, a critical event in lung carcinogenesis, and the corresponding DNA damage response (DDR) in mice and human bronchial epithelial (BEAS-2B) cells.

Methods: Biomarkers of DNA double-strand breaks (DSBs), DNA repair response to DSBs, ataxia-telangiectasia mutated (ATM) kinase, autophagy, and a cell apoptosis signaling pathway as well as cell-cycle arrest and the rate of apoptosis were determined in mouse lung and BEAS-2B cells after radon exposure.

Results: Repeated radon exposure induced DSBs indicated by the increasing expressions of γ-Histone 2AX (H2AX) protein and H2AX gene in a time and dose-dependent manner. Additionally, a panel of ATM-dependent repair cascades [i.e. non-homologous DNA end joining (NHEJ), cell-cycle arrest and the p38 mitogen activated protein kinase (p38MAPK)/Bax apoptosis signaling pathway] as well as the autophagy process were activated. Inhibition of autophagy by 3-methyladenine pre-treatment partially reversed the expression of NHEJ-related genes induced by radon exposure in BEAS-2B cells.

Conclusions: The findings demonstrated that long-term exposure to radon gas induced DNA lesions in the form of DSBs and a series of ATM-dependent DDR pathways. Activation of the ATM-mediated autophagy may provide a protective and pro-survival effect on radon-induced DSBs.

目的:氡(222 Rn)是一种天然放射性气体,与肺癌的发生密切相关。本研究调查了氡诱导的 DNA 链断裂(肺癌发生的一个关键事件)以及小鼠和人类支气管上皮细胞(BEAS-2B)中相应的 DNA 损伤反应(DDR):方法:测定氡照射后小鼠肺细胞和BEAS-2B细胞中DNA双链断裂(DSB)的生物标志物、DSB的DNA修复反应、共济失调-特朗吉赛突变(ATM)激酶、自噬、细胞凋亡信号通路以及细胞周期停滞和细胞凋亡率:结果:重复氡照射可诱导DSB,表现为γ-组蛋白2AX(H2AX)蛋白和H2AX基因的表达增加,且呈时间和剂量依赖性。此外,一系列依赖于ATM的修复级联[即非同源DNA末端连接(NHEJ)、细胞周期停滞和p38丝裂原活化蛋白激酶(p38MAPK)/Bax凋亡信号通路]以及自噬过程也被激活。通过3-甲基腺嘌呤预处理抑制自噬,可部分逆转氡暴露在BEAS-2B细胞中诱导的NHEJ相关基因的表达:研究结果表明,长期暴露于氡气可诱导DSB形式的DNA损伤和一系列依赖于ATM的DDR途径。激活ATM介导的自噬可对氡诱导的DSB起到保护和促进生存的作用。
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引用次数: 0
Proteomic analysis of toxic effects of short-term cadmium exposure on goat livers. 短期镉暴露对山羊肝脏毒性效应的蛋白质组分析
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae162
Guangyang Liu, Xiaoyun Shen, Yuanfeng Li

Food safety is closely related to environmental pollution. It is worth noting that the long-term accumulation of Cd, a toxic heavy metal, in animals may pose a threat to human health through food chain. Previous studies have found that Cd exposure may cause liver metabolic disorders of black goats, but the mechanism of its impact on liver proteome of goats has not been widely studied. Therefore, in this study, ten male goats (Nubian black goat × native black goat) were exposed to Cd via drinking water containing CdCl2 (20 mg Cd·kg - 1·BW) for 30 days (five male goats per group). Blood physiology and liver antioxidant indices in black goats were determined and differentially expressed proteins (DEPs) in the livers of Cd-exposed goats were profiled by using TMT-labelled proteomics. It was found that plasma Hb and RBC levels as well as PCV values were decreased, liver SOD, GSH-Px, T-AOC and CAT levels were decreased, and MDA level was increased in Cd-treated goats, and 630 DEPs (up 326, down 304) in the livers of Cd-treated goats. Proteomics analysis revealed that Cd exposure affected glutathione metabolism and drug metabolism-cytochrome P450. We identified GP×2, GSTM3, and TBXAS1 as potential protein markers of early Cd toxicity in goats. This study provided theoretical basis for early diagnosis of Cd poisoning in goats.

食品安全与环境污染密切相关。值得注意的是,有毒重金属镉在动物体内的长期积累可能会通过食物链对人类健康造成威胁。以往的研究发现,接触镉可能导致黑山羊肝脏代谢紊乱,但镉对黑山羊肝脏蛋白质组的影响机制尚未得到广泛研究。因此,在本研究中,十只雄性山羊(努比亚黑山羊×本地黑山羊)通过饮用含氯化镉(20 毫克镉-千克-1-体重)的水暴露于镉,为期 30 天(每组五只雄性山羊)。采用 TMT 标记的蛋白质组学方法测定了黑山羊的血液生理指标和肝脏抗氧化指标,并分析了镉暴露山羊肝脏中的差异表达蛋白(DEPs)。结果发现,经 Cd 处理的山羊血浆 Hb 和 RBC 水平以及 PCV 值下降,肝脏 SOD、GSH-Px、T-AOC 和 CAT 水平下降,MDA 水平升高,经 Cd 处理的山羊肝脏中有 630 个 DEPs(上升 326 个,下降 304 个)。蛋白质组学分析表明,镉暴露影响了谷胱甘肽代谢和药物代谢-细胞色素 P450。我们发现 GP×2、GSTM3 和 TBXAS1 是山羊早期镉中毒的潜在蛋白质标记物。这项研究为山羊镉中毒的早期诊断提供了理论依据。
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引用次数: 0
Serum glucose/potassium ratio as an indicator of early and delayed outcomes of acute carbon monoxide poisoning. 血清葡萄糖/钾比率作为急性一氧化碳中毒早期和延迟预后的指标。
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-07 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae168
Alshaimma Mahmoud Elmansy, Dalia Mustafa Hannora, Heba K Khalifa

Background: Carbon monoxide (CO) poisoning is a major health problem associated with a high rate of severe morbidity and mortality.

Aims: This study aimed to evaluate the validity of the serum glucose/potassium (Glu/K) ratio as a quick predictor of both early and delayed unfavorable outcomes following acute CO poisoning.

Patients and methods: This prospective cohort study included 136 patients with acute CO poisoning admitted at Tanta Poison Control Center, Egypt, between January 2023 and June 2024. The serum Glu/K ratio was calculated for all patients. The primary outcome was a prediction of mortality. Secondary outcomes were the prediction of delayed neurological sequelae (DNS) within six months after CO exposure, the need for mechanical ventilation, and the need for hyperbaric oxygen. A receiver operating curve analysis was applied to test the performance of the Glu/K ratio in predicting acute CO poisoning outcomes.

Results: The mortality rate was 12.5% of patients with acute CO poisoning. Meanwhile, 14.7% of patients developed DNS. Furthermore, mechanical ventilation was required in 16.9% of patients. An elevated Glu/K ratio was significantly associated with the severity of acute CO poisoning. At a cut-off value of >31.62, the Glu/K ratio demonstrated an AUC of 0.649 for predicting mortality. The Glu/K ratio was employed to predict DNS at a cut-off value of 33.10, with a sensitivity of 60.0%, a specificity of 82.76%, and an AUC of 0.692.

Conclusions: Early Glu/K ratio may be an effective, reliable, and convenient laboratory predictor of mortality, DNS, and the need for mechanical ventilation in patients with acute CO poisoning.

背景:目的:本研究旨在评估血清葡萄糖/钾(Glu/K)比值作为急性一氧化碳中毒早期和延迟不良后果快速预测指标的有效性:这项前瞻性队列研究纳入了 2023 年 1 月至 2024 年 6 月期间埃及坦塔中毒控制中心收治的 136 名急性一氧化碳中毒患者。研究计算了所有患者的血清 Glu/K 比值。主要结果是预测死亡率。次要结果是预测接触一氧化碳后 6 个月内的迟发性神经系统后遗症 (DNS)、机械通气需求和高压氧需求。应用接收器操作曲线分析法检验了 Glu/K 比值在预测急性一氧化碳中毒结果方面的性能:结果:急性 CO 中毒患者的死亡率为 12.5%。同时,14.7%的患者出现 DNS。此外,16.9%的患者需要进行机械通气。Glu/K比值升高与急性一氧化碳中毒的严重程度明显相关。在临界值大于 31.62 时,Glu/K 比值预测死亡率的 AUC 为 0.649。采用 Glu/K 比值预测 DNS 的临界值为 33.10,灵敏度为 60.0%,特异度为 82.76%,AUC 为 0.692:早期 Glu/K 比值可能是预测急性 CO 中毒患者死亡率、DNS 和机械通气需求的有效、可靠和便捷的实验室指标。
{"title":"Serum glucose/potassium ratio as an indicator of early and delayed outcomes of acute carbon monoxide poisoning.","authors":"Alshaimma Mahmoud Elmansy, Dalia Mustafa Hannora, Heba K Khalifa","doi":"10.1093/toxres/tfae168","DOIUrl":"https://doi.org/10.1093/toxres/tfae168","url":null,"abstract":"<p><strong>Background: </strong>Carbon monoxide (CO) poisoning is a major health problem associated with a high rate of severe morbidity and mortality.</p><p><strong>Aims: </strong>This study aimed to evaluate the validity of the serum glucose/potassium (Glu/K) ratio as a quick predictor of both early and delayed unfavorable outcomes following acute CO poisoning.</p><p><strong>Patients and methods: </strong>This prospective cohort study included 136 patients with acute CO poisoning admitted at Tanta Poison Control Center, Egypt, between January 2023 and June 2024. The serum Glu/K ratio was calculated for all patients. The primary outcome was a prediction of mortality. Secondary outcomes were the prediction of delayed neurological sequelae (DNS) within six months after CO exposure, the need for mechanical ventilation, and the need for hyperbaric oxygen. A receiver operating curve analysis was applied to test the performance of the Glu/K ratio in predicting acute CO poisoning outcomes.</p><p><strong>Results: </strong>The mortality rate was 12.5% of patients with acute CO poisoning. Meanwhile, 14.7% of patients developed DNS. Furthermore, mechanical ventilation was required in 16.9% of patients. An elevated Glu/K ratio was significantly associated with the severity of acute CO poisoning. At a cut-off value of >31.62, the Glu/K ratio demonstrated an AUC of 0.649 for predicting mortality. The Glu/K ratio was employed to predict DNS at a cut-off value of 33.10, with a sensitivity of 60.0%, a specificity of 82.76%, and an AUC of 0.692.</p><p><strong>Conclusions: </strong>Early Glu/K ratio may be an effective, reliable, and convenient laboratory predictor of mortality, DNS, and the need for mechanical ventilation in patients with acute CO poisoning.</p>","PeriodicalId":105,"journal":{"name":"Toxicology Research","volume":null,"pages":null},"PeriodicalIF":2.2,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457236/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142386488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"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
"Exploring therapeutic potential and toxicological profiles of Cuscuta species: insights from pharmacological studies and an anti-cholinergic toxicity report." "探索菟丝子的治疗潜力和毒理学特征:药理学研究的启示和抗胆碱能毒性报告"。
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae160
Saurabh Dilip Bhandare

This study examines the therapeutic potential and toxicological profiles of Cuscuta species based on recent pharmacological investigations: "a therapeutic potential vs. toxicological risks of Cuscuta species: a pharmacological-toxicology dilemma." The study encompasses diverse research areas, including the mitigation of Bisphenol A (BPA)-induced ovarian damage using Cuscuta chinensis flavonoids (CCFs), acute and sub-acute toxicity assessments of Cuscuta chinensis Lam. water extract (CLW), and observations on Cuscuta campestris toxicity in horses. In addition, this scientific study discusses the interplant communication dynamics between soybean and the parasitic dodder (Cuscuta australis) under nutrient deficiency conditions. Key significant findings highlight the efficacy of CCFs in alleviating BPA-induced ovarian damage, the safety profile of CLW within specified doses, and clinical manifestations of C. campestris toxicity in horses. Moreover, insights into interplant communication mechanisms emphasise the significance of protein-mediated interactions in nutrient-deficient environments. The report illustrates the potential toxicity of Dodder in humans, and further research findings into its chemical composition and toxicological profiles reveal great data on its phytotoxicity. Greater awareness and understanding of the risks associated with consuming Dodder and other similar plant species are crucial for preventing plant intoxication and have been a significant major focus of the present toxicology study of Cuscuta species. Hence, by addressing these objectives, the scientific study aims to balance the therapeutic benefits of Cuscuta species with their potential toxicological risks, contributing to a more nuanced understanding of their role in pharmacology and toxicology. This dual focus is crucial for guiding future research and informing safe usage practices.

本研究根据最近的药理学调查,探讨了菟丝子的治疗潜力和毒理学特征:"菟丝子的治疗潜力与毒理学风险:药理学与毒理学的两难选择"。该研究涵盖多个研究领域,包括使用菟丝子黄酮类化合物(CCFs)减轻双酚 A(BPA)诱导的卵巢损伤、菟丝子水提取物(CLW)的急性和亚急性毒性评估,以及观察菟丝子对马的毒性。此外,这项科学研究还讨论了大豆与寄生菟丝子(Cuscuta australis)在营养缺乏条件下的植物间交流动态。主要的重要发现强调了CCFs在减轻双酚A诱导的卵巢损伤方面的功效、CLW在特定剂量内的安全性概况以及菟丝子毒性在马身上的临床表现。此外,对植物间交流机制的深入研究强调了在营养缺乏的环境中蛋白质介导的相互作用的重要性。报告说明了菟丝子对人类的潜在毒性,对其化学成分和毒理学特征的进一步研究结果揭示了有关其植物毒性的大量数据。提高对食用菟丝子和其他类似植物物种相关风险的认识和理解,对于预防植物中毒至关重要,也是目前菟丝子毒理学研究的一个重要重点。因此,通过实现这些目标,这项科学研究旨在平衡菟丝子的治疗功效与其潜在的毒理学风险,从而有助于更细致地了解菟丝子在药理学和毒理学中的作用。这种双重关注对于指导未来研究和告知安全使用方法至关重要。
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引用次数: 0
Impacts of gentamycin toxicity: nephroprotective role of guarana through different signaling pathways. 庆大霉素毒性的影响:瓜拉纳纳通过不同信号通路发挥肾保护作用
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae167
Adel Qlayel Alkhedaide

Gentamicin is a widely used aminoglycosidic antibiotic since its discovery. Like any other medication gentamicin causes unwanted side effects such as hepatotoxicity and nephrotoxicity. This study aims to examine the antioxidant effect of the guarana seed extract in protecting renal tissue. Forty male mice were divided into four groups (group one was control with free access to food and water, group two was treated orally with 300 mg/kg of guarana seed extract daily, group three was injected intraperitoneally with 100 mg/kg of gentamicin daily and the fourth group was co-treated with both 300 mg/kg of guarana seed extract orally and injected intraperitoneally with 100 mg/kg of gentamicin daily) for two weeks. Serum levels of urea, creatinine, AST, ALT, IL-1β and IL-6 have significantly elevated in the gentamicin treated group and those changes were not found in the guarana co-treated group. In gentamicin treated mice, a significant reduction was observed in two antioxidants SOD and GPX accompanied by downregulation of Ho-1 and Nrf2 while, that did not happen in the guarana seed extract co-treated group. Histopathology and immunohistochemistry slides show that the guarana seed extract prevents degenerative and necrotic events in tubular epithelial tissues caused by gentamicin toxicity. In conclusion, current data suggest that gentamicin can damage renal tissues when given at 100 mg/kg/day, however, the guarana seed extract may be capable of preventing that event when cotreated with the gentamicin as a supplement.

自发现以来,庆大霉素是一种广泛使用的氨基糖苷类抗生素。与其他药物一样,庆大霉素也会产生不良副作用,如肝毒性和肾毒性。本研究旨在探讨瓜拉纳种子提取物在保护肾组织方面的抗氧化作用。研究人员将 40 只雄性小鼠分为四组(第一组为对照组,自由进食和饮水;第二组每天口服 300 毫克/千克瓜拉纳种子提取物;第三组每天腹腔注射 100 毫克/千克庆大霉素;第四组每天同时口服 300 毫克/千克瓜拉纳种子提取物和腹腔注射 100 毫克/千克庆大霉素),为期两周。庆大霉素治疗组小鼠血清中的尿素、肌酐、谷草转氨酶、谷丙转氨酶、IL-1β和IL-6水平明显升高,而瓜拉那籽提取物联合治疗组小鼠则没有出现这些变化。在庆大霉素治疗组中,观察到两种抗氧化剂 SOD 和 GPX 明显降低,同时伴随着 Ho-1 和 Nrf2 的下调,而在瓜拉纳种子提取物联合治疗组中则没有出现这种情况。组织病理学和免疫组化切片显示,瓜拉纳种子提取物能防止庆大霉素毒性引起的肾小管上皮组织变性和坏死。总之,目前的数据表明,庆大霉素的剂量为 100 毫克/千克/天时,会对肾组织造成损害,但是瓜拉纳种子提取物作为庆大霉素的补充剂与庆大霉素共用时,可能能够防止这种情况的发生。
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引用次数: 0
Dose-dependent effects of silver nanoparticles on cell death modes in mouse blastocysts induced via endoplasmic reticulum stress and mitochondrial apoptosis. 纳米银粒子对通过内质网应激和线粒体凋亡诱导的小鼠胚泡细胞死亡模式的剂量依赖性影响
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae158
Cheng-Kai Lee, Fu-Ting Wang, Chien-Hsun Huang, Wen-Hsiung Chan

In view of the rapidly expanding medical and commercial applications of silver nanoparticles (AgNPs), their potential health risks and environmental effects are a significant growing concern. Earlier research by our group uncovered the embryotoxic potential of AgNPs, showing detrimental impacts of these nanoparticles on both pre- and post-implantation embryonic development. In the current study, we showed that low (50-100 μM) and high (200-400 μM) dose ranges of AgNPs trigger distinct cell death programs affecting mouse embryo development and further explored the underlying mechanisms. Treatment with low concentrations of AgNPs (50-100 μM) triggered ROS generation, in turn, inducing mitochondria-dependent apoptosis, and ultimately, harmful effects on embryo implantation, post-implantation development, and fetal development. Notably, high concentrations of AgNPs (200-400 μM) evoked more high-level ROS generation and endoplasmic reticulum (ER) stress-mediated necrosis. Interestingly, pre-incubation with Trolox, a strong antioxidant, reduced ROS generation in the group treated with 200-400 μM AgNPs to the level induced by 50-100 μM AgNPs, resulting in switching of the cell death mode from necrosis to apoptosis and a significant improvement in the impairment of embryonic development. Our findings additionally indicate that activation of PAK2 is a crucial step in AgNP-triggered apoptosis and sequent detrimental effects on embryonic development. Based on the collective results, we propose that the levels of ROS generated by AgNP treatment of embryos serve as a critical regulator of cell death type, leading to differential degrees of damage to embryo implantation, post-implantation development and fetal development through triggering apoptosis, necrosis or other cell death signaling cascades.

鉴于银纳米粒子(AgNPs)的医疗和商业应用正在迅速扩大,其潜在的健康风险和环境影响日益受到人们的关注。我们小组的早期研究发现了银纳米粒子的胚胎毒性潜力,显示了这些纳米粒子对胚胎植入前和植入后发育的不利影响。在目前的研究中,我们发现低(50-100 μM)和高(200-400 μM)剂量范围的AgNPs会引发不同的细胞死亡程序,影响小鼠胚胎发育,并进一步探讨了其潜在机制。低浓度(50-100 μM)的AgNPs会引发ROS生成,进而诱导线粒体依赖性凋亡,最终对胚胎着床、着床后发育和胎儿发育产生有害影响。值得注意的是,高浓度的 AgNPs(200-400 μM)会诱发更高水平的 ROS 生成和内质网(ER)应激介导的坏死。有趣的是,用强抗氧化剂 Trolox 预孵育可将 200-400 μM AgNPs 处理组的 ROS 生成量降至 50-100 μM AgNPs 诱导的水平,从而使细胞死亡模式从坏死转向凋亡,并显著改善胚胎发育障碍。我们的研究结果还表明,PAK2 的活化是 AgNP 触发细胞凋亡并继而对胚胎发育产生不利影响的关键步骤。基于上述综合结果,我们提出,AgNP 处理胚胎所产生的 ROS 水平是细胞死亡类型的关键调节因子,通过引发细胞凋亡、坏死或其他细胞死亡信号级联,对胚胎植入、植入后发育和胎儿发育造成不同程度的损害。
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引用次数: 0
Di(2-ethylhexyl) phthalate exposure aggravates hypoxia/reoxygenation injury in cerebral endothelial cells by downregulating epithelial cadherin expression. 接触邻苯二甲酸二(2-乙基己酯)会通过下调上皮粘连蛋白的表达加重脑内皮细胞的缺氧/复氧损伤。
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae163
Jin Hee Kim, Jae Hoon Lee, Zhengyu Nan, Ja Woo Choi, Jong Wook Song

Di-(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that has adverse health effects. Most phthalates exhibit reproductive toxicity and are associated with diseases such as cardiovascular disorders. However, the effect of DEHP exposure on acute hypoxia/reperfusion injury remains unknown. Therefore, we assessed whether hypoxia/reperfusion injury is aggravated by exposure to DEHP and investigated plausible underlying mechanisms, including oxidative stress and expression of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) and endothelial junctional proteins. bEnd.3 cells were exposed to DEHP and subsequently subjected to oxygen-glucose deprivation (OGD). Cell viability was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) proliferation assay. The effect of DEHP/OGD/reoxygenation (R) was evaluated by assessing the levels of NO, reactive oxygen species (ROS), and PGE2. The expression of COX-2, cleaved caspase-3, cleaved PARP, inducible nitric oxide synthase (iNOS), and the endothelial tight junction proteins claudin-5 and ZO-1 was evaluated using quantitative polymerase chain reaction and western blotting. OGD/R decreased cell viability, and DEHP exposure before OGD/R further aggravated cell viability. DEHP/OGD/R significantly increased NO, PGE2, and ROS production following OGD/R. In the DEHP/OGD/R group, iNOS, COX-2, cleaved caspase-3, and cleaved PARP expression increased, and claudin-5 and ZO-1 levels decreased compared with those in the OGD/R group. E-Cadherin expression decreased significantly after DEHP/OGD/R exposure compared with that after OGD/R; this decrease in expression was recovered by treatment with the COX-2 inhibitor indomethacin and antioxidant N-acetylcysteine. Exposure to DEHP exacerbated hypoxia-reoxygenation injury. The enhanced damage upon DEHP exposure was associated with increased oxidative stress and COX-2 expression, leading to E-cadherin downregulation and increased apoptosis.

邻苯二甲酸二(2-乙基己基)酯(DEHP)是一种广泛使用的增塑剂,对健康有不良影响。大多数邻苯二甲酸盐具有生殖毒性,并与心血管疾病等疾病有关。然而,DEHP 暴露对急性缺氧/再灌注损伤的影响仍然未知。因此,我们评估了暴露于 DEHP 是否会加重缺氧/再灌注损伤,并研究了可能的潜在机制,包括氧化应激和环氧化酶-2(COX-2)/前列腺素 E2(PGE2)及内皮连接蛋白的表达。bEnd.3 细胞暴露于 DEHP,随后进行氧-葡萄糖剥夺(OGD)。使用 3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺酸苯基)-2H-四唑鎓(MTS)增殖试验分析细胞活力。通过评估 NO、活性氧(ROS)和 PGE2 的水平来评估 DEHP/OGD/ 复氧(R)的效果。使用定量聚合酶链式反应和 Western 印迹法评估了 COX-2、裂解的 Caspase-3、裂解的 PARP、诱导型一氧化氮合酶(iNOS)以及内皮紧密连接蛋白 claudin-5 和 ZO-1 的表达。OGD/R 降低了细胞存活率,而在 OGD/R 之前暴露于 DEHP 会进一步恶化细胞存活率。OGD/R后,DEHP/OGD/R明显增加了NO、PGE2和ROS的产生。与 OGD/R 组相比,DEHP/OGD/R 组 iNOS、COX-2、裂解的 Caspase-3 和裂解的 PARP 表达增加,Claudin-5 和 ZO-1 水平降低。与OGD/R组相比,暴露于DEHP/OGD/R组后E-Cadherin的表达量明显下降;经COX-2抑制剂吲哚美辛和抗氧化剂N-乙酰半胱氨酸处理后,表达量的下降得以恢复。暴露于 DEHP 会加剧缺氧-复氧损伤。暴露于DEHP时损伤的加剧与氧化应激和COX-2表达的增加有关,导致E-cadherin下调和细胞凋亡增加。
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引用次数: 0
Role of bone marrow mesenchymal stem cell-derived exosomes in reducing neurotoxicity and depression-like behaviors induced by doxorubicin in rats. 骨髓间充质干细胞衍生的外泌体在减少多柔比星诱导的大鼠神经毒性和抑郁样行为中的作用
IF 2.2 4区 医学 Q3 TOXICOLOGY Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1093/toxres/tfae159
Doaa R I Abdel-Gawad, Fatma Khalil, Olfat Shehata, Marwa A Ibrahim, SalmaI El-Samannoudy, Emad A Mahdi, Nema S Shaban

Background: Doxorubicin (DOX) is a broad-spectrum antitumor drug while its use is limited nowadays due to its neurobiological side effects associated with depression. Bone marrow mesenchymal stem cells (BM-MSCs) derived exosomes are a promising regenerative therapy. In this study, we investigated the therapeutic potentiality of BM-MSCs derived exosomes against the neurotoxicity induced by DOX.

Methods: Twenty-four male albino rats were divided equally in to three groups as follow: group 1 (control), group 2 (rats injected intraperitoneally (i.p|) with DOX at a dose 2.5mg/Kg), and group 3 (rats injected with DOX and BM-MSCs derived exosomes i.p at a dose 1.5ml/Kg). During the experiment the behavior tests were noted, after three weeks rats were sacrificed, serum and brain samples were collected for biochemical, molecular and histopathological examinations.

Results: The results revealed that DOX causing impairment of the locomotor and increasing the anxiety like behavior of rats, marked neuropathological changes, significant elevation of MDA content and TNF-α concentration, reduction of phospholipase (PLD) and acetylcholinesterase (AChE) protein concentration in addition, there were up regulation of JNK, NF-κB and p38 genes and down regulation of Erk1.

Conclusion: Exosomal therapy improved the substantial neurotoxicity of DOX through modulating the markers involved in the neurotoxic signalling pathway of DOX that resulting in improving the pathological lesions and the animal behaviours.

背景:多柔比星(DOX)是一种广谱抗肿瘤药物,但由于其与抑郁症相关的神经生物学副作用,如今其使用已受到限制。骨髓间充质干细胞(BM-MSCs)衍生的外泌体是一种很有前景的再生疗法。在这项研究中,我们探讨了骨髓间充质干细胞衍生的外泌体对DOX诱导的神经毒性的治疗潜力:将 24 只雄性白化大鼠平均分为以下三组:第 1 组(对照组)、第 2 组(腹腔注射 DOX,剂量为 2.5 毫克/千克)和第 3 组(腹腔注射 DOX 和 BM-MSCs 派生外泌体,剂量为 1.5 毫升/千克)。实验期间对大鼠进行行为测试,三周后将大鼠处死,采集血清和脑样本进行生化、分子和组织病理学检查:结果显示:DOX会导致大鼠运动能力受损,焦虑行为增加,神经病理变化明显,MDA含量和TNF-α浓度显著升高,磷脂酶(PLD)和乙酰胆碱酯酶(AChE)蛋白浓度降低,此外,JNK、NF-κB和p38基因上调,Erk1基因下调:结论:外泌体疗法通过调节参与 DOX 神经毒性信号通路的标记物,改善了 DOX 的实质性神经毒性,从而改善了病理损伤和动物行为。
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引用次数: 0
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Toxicology Research
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