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Molecular signatures associated with diuron exposure on rat urothelial mitochondria 大鼠尿路上皮线粒体暴露与迪乌隆相关的分子特征
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-04-04 DOI: 10.1080/15376516.2022.2062271
T. R. R. Lima, Estela de Oliveira Lima, J. Delafiori, Rodrigo Ramos Catharino, J. L. Viana de Camargo, L. C. Pereira
Abstract Diuron, 3-(3,4-dichlorophenyl)-1,1-dimethylurea, is a worldwide used herbicide whose biotransformation gives rise to the metabolites, 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU) and 3,4-dichloroaniline (DCA). Previous studies indicate that diuron and/or its metabolites are toxic to the bladder urothelium of the Wistar rats where, under certain conditions of exposure, they may induce successively urothelial cell degeneration, necrosis, hyperplasia and eventually tumors. The hypothesis was raised that the molecular initiating event (MIE) of this Adverse Outcome Pathway is the mitochondrial toxicity of those compounds. Therefore, this study aimed to investigate in vitro the metabolic alterations resulting from urothelial mitochondria isolated from male Wistar rats exposure to diuron, DCPMU and DCA at 10 and 100 µM. A non-targeted metabolomic analysis using mass spectrometry showed discriminative clustering among groups and alterations in the intensity abundance of membrane-associated molecules phosphatidylcholine, phosphatidylinositol and phosphatidylserine, in addition to methylhexanoyl-CoA and, particularly for diuron 100 µM, dehydro-L-gulonate, all of them involved in critical mitochondrial metabolism. Collectively, these data indicate the mitochondrial dysfunction as an MIE that triggers cellular damage and death observed in previous studies.
摘要:Diuron, 3-(3,4-二氯苯基)-1,1-二甲基脲是一种广泛使用的除草剂,其生物转化产生代谢物3-(3,4-二氯苯基)-1-甲基脲(DCPMU)和3,4-二氯苯胺(DCA)。既往研究表明,迪乌隆和/或其代谢物对Wistar大鼠膀胱尿路上皮具有毒性,在一定的暴露条件下,可先后诱导尿路上皮细胞变性、坏死、增生,最终诱发肿瘤。我们提出的假设是,这个不良结果通路的分子起始事件(MIE)是这些化合物的线粒体毒性。因此,本研究旨在研究雄性Wistar大鼠尿路上皮线粒体在10和100µM浓度下暴露于diuron、DCPMU和DCA对其代谢的影响。使用质谱进行的非靶向代谢组学分析显示,不同组之间存在区别性聚类,膜相关分子磷脂酰胆碱、磷脂酰肌醇和磷脂酰丝氨酸的强度丰度也发生了变化,此外还有甲基己醇辅酶A和脱氢l-谷gulate,特别是对于100µM的二脲,所有这些分子都参与了关键的线粒体代谢。总的来说,这些数据表明,线粒体功能障碍是先前研究中观察到的触发细胞损伤和死亡的MIE。
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引用次数: 3
The protective effect of co-administration of platelet-rich plasma (PRP) and pentoxifylline (PTX) on cyclophosphamide-induced premature ovarian failure in mature and immature rats 富血小板血浆(PRP)和己酮茶碱(PTX)联合给药对环磷酰胺诱导的成熟和未成熟大鼠卵巢早衰的保护作用
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-04-04 DOI: 10.1080/15376516.2022.2057264
H. Aboutalebi, F. Alipour, A. Ebrahimzadeh-Bideskan
Abstract Cyclophosphamide (CP), as an antineoplastic agent, causes premature ovarian failure (POF) due to ovarian toxicity and subsequent infertility in women. Platelet-rich plasma (PRP) has accumulated significant attention in regenerative medicine. Pentoxifylline (PTX) as a methylxanthine derivative has been shown to have antioxidant and antiapoptotic properties. The aim of this study was to evaluate the protective effect of PRP and PTX on CP-induced POF. Fifty mature and immature female rats were assigned into five groups: control, CP (75 mg/kg, intraperitoneal [ip] on days 1 and 10 to induce POF), CP + PRP (200 μl, ip, half an hour after CP injection on day 1 and 10), CP + PTX (50 mg/kg, orally, half an hour after CP injection daily for 21 day), and CP + PRP + PTX. At the end of experiments on day 21, measurement of body weight, ovarian parameters (ovarian volume, follicular granulosa cell layers diameter, oocyte diameter, and the number of granulosa cells), measurement of ovarian hormone in sera for estradiol (E2), and anti-Mullerian hormone (AMH), as well as biochemical assessment were performed. The results showed that CP significantly reduced the ovarian parameters, E2, AMH, superoxide dismutase (SOD) activity and increased Malondialdehyde (MDA) levels compared to the control group (p < 0.001). Our results also indicated that all histomorphometric parameters and biochemical markers in CP-induced POF, were preserved close to normal by PRP and PTX treatments in both mature and immature rats (p < 0.001). Therefore, it is concluded that the co-administration of PRP and PTX can protect the ovary from CP-induced POF. Graphical Abstract
摘要环磷酰胺(Cyclophosphamide, CP)是一种抗肿瘤药物,可导致卵巢毒性导致卵巢早衰(POF),进而导致女性不孕。富血小板血浆(PRP)在再生医学中引起了广泛的关注。己酮可可碱(PTX)作为甲基黄嘌呤衍生物已被证明具有抗氧化和抗凋亡的特性。本研究的目的是评价PRP和PTX对cp诱导的POF的保护作用。将50只成熟和未成熟雌性大鼠分为5组:对照组、CP (75 mg/kg,腹腔注射[ip],第1天和第10天诱导POF)、CP + PRP (200 μl, ip, CP注射后半小时,第1天和第10天)、CP + PTX (50 mg/kg,口服,CP注射后半小时,每天,连续21天)、CP + PRP + PTX。实验第21天结束时,测定大鼠体重、卵巢参数(卵巢体积、卵泡颗粒细胞层径、卵母细胞直径、颗粒细胞数),测定血清中卵巢激素雌二醇(E2)、抗苗勒管激素(AMH),并进行生化评价。结果表明,与对照组相比,CP显著降低卵巢参数、E2、AMH、超氧化物歧化酶(SOD)活性,升高丙二醛(MDA)水平(p < 0.001)。我们的研究结果还表明,PRP和PTX处理的成熟和未成熟大鼠POF的所有组织形态学参数和生化指标都保持接近正常(p < 0.001)。由此可见,PRP和PTX联合用药可保护卵巢免受cp诱导的POF。图形抽象
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引用次数: 2
Implications for herbal polypharmacy: coumarin-induced hepatotoxicity increased through common herbal phytochemicals astragaloside IV and atractylenolide I 对草药多药的影响:香豆素诱导的肝毒性通过常见的草药植物化学物质黄芪甲苷IV和白术内酯I增加
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-03-30 DOI: 10.1080/15376516.2022.2057267
Susan M. Britza, I. Musgrave, R. Byard
Abstract Hepatotoxicity is a well-known adverse effect of many substances, with toxicity often resulting from interactions of drugs with other drug-like substances. With the increased availability of complementary and alternative medicines, including herbal medicines, the likelihood of adverse interactions between drugs and drug-like substances in herbs increases. However, the impact of potential herb-herb interactions is little understood. To assess the potential of two cytochrome P450 enzyme modulating phytochemicals common to many herbal medicines, atractylenolide I (ATR-I) and astragaloside IV (AST-IV), to interact with coumarin, another phytochemical common in many foods, a hepatocyte function model with a liver carcinoma cell line, HepG2, was exposed to these agents. To determine the effects of cytochrome P450 modulation by these phytochemicals certain cells were induced with rifampicin to induce cytochrome P450. Increasing concentrations of ATR-I combined with a fixed, nontoxic concentration of coumarin (200 µM), demonstrated significant additive interactions. 300 µM ATR-I produced a 31% reduction in cell viability (p < 0.01) with coumarin in rifampicin uninduced cells. In rifampicin-induced cells, ATR-I (100–300 µM) produced a significant reduction in cell viability (p < 0.01) with coumarin (200 µM). AST-IV with fixed coumarin (200 µM) showed 27% toxicity at 300 µM AST-IV in rifampicin uninduced cells (p < 0.05) and 30% toxicity in rifampicin induced cells (p < 0.05). However, when fixed coumarin and AST-IV were combined with increasing concentrations of ATR-I no further significant increase in toxicity was observed (p > 0.05). These results demonstrate the potential toxic interactive capabilities of common traditional Chinese herbal medicine phytochemicals and underline the potential importance of coumarin-mediated toxicity.
摘要肝毒性是许多物质的一种众所周知的不良反应,其毒性通常是由药物与其他类药物的相互作用引起的。随着包括草药在内的补充和替代药物的供应增加,药物与草药中的类药物之间发生不良相互作用的可能性增加。然而,人们对潜在的中草药相互作用的影响知之甚少。为了评估许多草药中常见的两种细胞色素P450酶调节植物化学物质,白术内酯I(ATR-I)和黄芪甲苷IV(AST-IV)与许多食物中常见的另一种植物化学物质香豆素相互作用的潜力,将肝癌细胞系HepG2的肝细胞功能模型暴露于这些药物中。为了确定这些植物化学物质对细胞色素P450的调节作用,用利福平诱导某些细胞诱导细胞色素P450%。增加ATR-I的浓度与固定无毒浓度的香豆素(200 µM),表现出显著的添加剂相互作用。300 µM ATR-I使细胞活力降低31%(p  0.05)。这些结果证明了常见中草药植物化学物质的潜在毒性相互作用能力,并强调了香豆素介导的毒性的潜在重要性。
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引用次数: 3
Chronic oral exposure of aluminum chloride in rat modulates molecular and functional neurotoxic markers relevant to Alzheimer’s disease 大鼠慢性口服氯化铝暴露可调节与阿尔茨海默病相关的分子和功能神经毒性标志物
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-03-27 DOI: 10.1080/15376516.2022.2058898
M. Dey, R. Singh
Abstract Aluminum is an environmentally abundant potential neurotoxic agent that may result in oxidative damage to a range of cellular biomarkers. The potential sources of aluminum accumulation in the body include drinking water, food, medicines, vaccines, and aluminum cookware utensils, etc. The accumulation of aluminum in the brain is reported to be associated with cholinergic dysfunction, oxidative stress and neuronal damage, which may ultimately cause Alzheimer’s disease. Since chronic exposure to aluminum leads to its accumulation in the brain, so this study was done by a long-term (24 weeks) low dose (20 mg/kg) oral exposure of aluminum chloride in rats. In this chronic model, we have evaluated the major hallmarks of Alzheimer’s disease including amyloid-beta (Aβ1–42) and phosphorylated-tau (p231-tau) protein in brain tissue. Furthermore, we evaluated the level of acetyl cholinesterase activity, inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and oxidative stress biomarkers in the rat brain in this model. The neurobehavioral parameters were also assessed in animals by using spontaneous locomotor activity, passive avoidance, rotarod test and novel object recognition test to evaluate alteration in learning, memory and muscle co-ordination. We found that chronic oral exposure to aluminum chloride causes a significant increase in structural hallmarks such as Aβ1–42 and p231-tau levels along with pro-inflammatory cytokines (TNF-α and IL-6), oxidative stress, and a decrease in antioxidant markers such as GSH and catalase in the brain tissue. These biomarkers significantly affected neurobehavioral parameters in animals. This study provides a mechanistic understanding of chronic aluminum-induced neuronal toxicity in the brain with relevance to Alzheimer’s disease.
摘要铝是一种环境丰富的潜在神经毒性物质,可能对一系列细胞生物标志物造成氧化损伤。铝在体内积聚的潜在来源包括饮用水、食物、药品、疫苗和铝制炊具等。据报道,铝在大脑中的积聚与胆碱能功能障碍、氧化应激和神经元损伤有关,最终可能导致阿尔茨海默病。由于长期接触铝会导致其在大脑中积累,因此这项研究是由一名长期(24 周)低剂量(20 mg/kg)经口暴露于大鼠中的氯化铝。在这个慢性模型中,我们评估了阿尔茨海默病的主要特征,包括脑组织中的淀粉样蛋白β(Aβ1-42)和磷酸化tau(p231-tau)蛋白。此外,我们评估了该模型中大鼠大脑中乙酰胆碱酯酶活性、炎性细胞因子如TNF-α、IL-6和IL-1β以及氧化应激生物标志物的水平。动物的神经行为参数也通过自发运动活动、被动回避、旋转棒测试和新型物体识别测试来评估学习、记忆和肌肉协调的变化。我们发现,长期口服氯化铝会导致结构特征显著增加,如aβ1-42和p231 tau水平,以及促炎细胞因子(TNF-α和IL-6)、氧化应激,以及脑组织中抗氧化标志物(如GSH和过氧化氢酶)的减少。这些生物标志物显著影响动物的神经行为参数。这项研究提供了对铝诱导的大脑中与阿尔茨海默病相关的慢性神经元毒性的机制理解。
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引用次数: 1
Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and Parkin in Pb and β-amyloid peptide induced toxicity 铅和β-淀粉样肽中PINK1和Parkin水平的降低诱导线粒体自噬缺陷和细胞凋亡
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-03-17 DOI: 10.1080/15376516.2022.2054749
Lakshmi Jaya Madhuri B, Neelima Ayyalasomayajula, Lokesh Murumulla, P. K. Dixit, C. Suresh
Abstract Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer’s Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/Parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and Parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and Parkin in cells exposed to Pb and β–amyloid peptides, both Aβ (25-35) and Aβ (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aβ peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and β–amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/Parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity.
铅(Pb)是一种环境污染物,通过氧化应激诱导和线粒体功能改变与神经退行性疾病的发生密切相关。线粒体受损可能是阿尔茨海默病(AD)恶化的原因之一。线粒体自噬对保持细胞健康至关重要。为了了解其在铅诱导AD中的作用,我们通过研究SH-SY5Y分化细胞中特异性的线粒体自噬标记蛋白PINK1和Parkin来研究PINK1/Parkin依赖通路。我们的数据表明,暴露于Pb和β -淀粉样肽(a β(25-35)和a β(1-40)单独或不同组合)的细胞中,PINK1和Parkin的水平显著降低,导致线粒体自噬缺陷。此外,本研究还揭示了单独和不同组合Pb和Aβ肽处理细胞时线粒体通透性过渡孔(MPTP)、线粒体质量、线粒体膜电位(MMP)和线粒体ROS生成的状况。暴露组线粒体ROS生成增加,MPTP开放增强,膜电位去极化,线粒体质量减少。此外,在本研究中,我们发现Pb和β -淀粉样肽可以通过激活Bak蛋白来触发细胞凋亡,Bak蛋白通过MPTP从线粒体释放细胞色素c,进而激活细胞溶胶中的AIF(凋亡诱导因子)和caspase-3蛋白。上述发现揭示了PINK1/Parkin介导的线粒体自噬和功能失调线粒体介导的细胞凋亡等机制在铅诱导的神经毒性中的潜在作用。
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引用次数: 5
The searching for agents for Alzheimer’s disease treatment via the system of self-consistent models 通过自洽模型系统寻找阿尔茨海默病治疗药物
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-03-14 DOI: 10.1080/15376516.2022.2053918
A. Toropov, A. Toropova, P. Achary, M. Rasková, I. Raška
Abstract Robust quantitative structure-activity relationships (QSARs) for hBACE-1 inhibitors (pIC50) for a large database (n = 1706) are established. New statistical criteria of the predictive potential of models are suggested and tested. These criteria are the index of ideality of correlation (IIC) and the correlation intensity index (CII). The system of self-consistent models is a new approach to validate the predictive potential of QSAR-models. The statistical quality of models obtained using the CORAL software (http://www.insilico.eu/coral) for the validation sets is characterized by the average determination coefficient R2 v= 0.923, and RMSE = 0.345. Three new promising molecular structures which can become inhibitors hBACE-1 are suggested.
在一个大型数据库(n = 1706)中建立了hBACE-1抑制剂(pIC50)的稳健定量构效关系(QSARs)。提出并检验了模型预测潜力的新统计准则。这两个指标分别是相关理想指数(IIC)和相关强度指数(CII)。自洽模型系统是验证qsar模型预测潜力的一种新方法。使用CORAL软件(http://www.insilico.eu/coral)对验证集获得的模型统计质量的特征是平均决定系数R2 v= 0.923, RMSE = 0.345。提出了三种新的有希望成为hBACE-1抑制剂的分子结构。
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引用次数: 10
Combinative ex vivo studies and in silico models ProTox-II for investigating the toxicity of chemicals used mainly in cosmetic products 联合离体研究和硅模型ProTox-II用于调查主要用于化妆品的化学品的毒性
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-03-14 DOI: 10.1080/15376516.2022.2053623
Priyanka Banerjee, O. C. Ulker
Abstract Human data on remains sparse and of varying quality and reproducibility. Ex vivo experiments and animal experiments currently is the most preferred way to predict the skin sensitization approved by the regulatory agencies across the world. However, there is a constant need and demand to reduce animal experiments and provide the scope of alternative methods to animal testing. In this study, we have compared the predictive performance of the published computational tools such as ProTox-II, SuperCYPsPred with the data obtained from ex-vivo experiments. From the results of the retrospective analysis, it can be observed that the computational predictions are in agreement with the experimental results. The computational models used here are generative models based on molecular structures and machine learning algorithms and can be applied also for the prediction of skin sensitization. Besides prediction of the toxicity endpoints, the models can also provide deeper insights into the molecular mechanisms and adverse outcome pathways (AOPs) associated with the chemicals used in cosmetic products.
摘要关于的人类数据仍然稀少,质量和再现性各不相同。目前,离体实验和动物实验是预测皮肤致敏的最首选方法,已获得世界各地监管机构的批准。然而,不断需要和要求减少动物实验,并为动物试验提供替代方法的范围。在这项研究中,我们将已发表的计算工具(如ProTox II、SuperCYPsPred)的预测性能与从离体实验中获得的数据进行了比较。从回顾性分析的结果可以看出,计算预测与实验结果一致。这里使用的计算模型是基于分子结构和机器学习算法的生成模型,并且也可以应用于皮肤致敏的预测。除了预测毒性终点外,这些模型还可以更深入地了解化妆品中使用的化学物质的分子机制和不良反应途径。
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引用次数: 10
Hematotoxic, oxidative and genotoxic damage in rainbow trout (Oncorhynchus mykiss) after exposure to 3-benzoylpyridine 虹鳟暴露于3-苯甲酰吡啶后的血毒、氧化和基因毒性损伤
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-03-10 DOI: 10.1080/15376516.2022.2049413
Veysel Parlak, Bunyamin Ozgeris, A. Uçar, A. ÇİLİNGİR YELTEKİN, F. B. Ozgeris, O. Caglar, G. Alak, H. Turkez, M. Atamanalp
Abstract Pyridine is a basic heterocyclic organic compound. The pyridine ring is present in many important compounds, including agricultural chemicals, medicines and vitamins. Due to their widespread industrial use, bioaccumulation and non-target toxic effects are being considered as a great risk to human and environmental health. In this study, we aimed to evaluate the hematological, oxidative and genotoxic damage potentials by different concentrations (1, 1.5, and 2 g/L) of the ketone 3-Benzoylpyridine (3BP) on rainbow trout (Oncorhynchus mykiss). Alterations in the biomarker levels of oxidative DNA damage (8-hydroxy-2′-deoxyguanosine (8-OHdG)), apoptosis (Caspase-3), malondialdehyde (MDA) as well as antioxidant enzyme activities including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), myeloperoxidase (MPO), paraoxonase (PON), and arylesterase (AR) were assessed in brain, liver, gill and blood tissues. Acetylcholinesterase (AChE) activity was also determined in brain tissue. In addition, we analyzed micronucleus (MN) rates and hematological indices of total erythrocyte count (RBC), total leukocyte count (WBC), hemoglobin (Hb), hematocrit (Hct), total platelet count (PLT), mean cell hemoglobin concentration (MCHC), mean cell hemoglobin (MCH), and mean cell volume (MCV) in blood. LC50-96h value of 3BP was calculated as 5.2 g/L from the data obtained. A significant decrease in brain AChE activity was determined in clear time and dose dependent manners. While SOD, CAT, GPx, PON, and AR levels were decreased, MDA, MPO, 8-OHdG and Caspase-3 levels were increased in all tissues (p < 0.05). Again, the 3BP led to increases of MN formation at all applied concentrations in the rates of between 45.4 and 72.7%. Significant differences (p < 0.05) were found out in between all studied hematology parameters between 3BP-exposed and the control fish. In conclusion, ours study firstly indicated that the treatment doses of 3BP induced distinct hematological and oxidative alterations as well as genotoxic damage in rainbow trout.
摘要吡啶是一种碱性杂环有机化合物。吡啶环存在于许多重要的化合物中,包括农用化学品、药物和维生素。由于其广泛的工业用途,生物累积和非目标毒性作用被认为是对人类和环境健康的巨大风险。在本研究中,我们旨在评估不同浓度(1、1.5和2 g/L)酮3-苯甲酰基吡啶(3BP)对虹鳟(Oncorhynchus mykiss)的作用。评估了大脑、肝脏、鳃和血液组织中氧化性DNA损伤(8-羟基-2′-脱氧鸟苷(8-OHdG))、细胞凋亡(Caspase-3)、丙二醛(MDA)以及抗氧化酶活性(包括超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、谷胱甘肽过氧化物酶(GPX)、髓过氧化物酶(MPO)、对氧酶(PON)和芳基酯酶(AR))的生物标志物水平的变化。还测定了脑组织中乙酰胆碱酯酶(AChE)的活性。此外,我们还分析了血液中红细胞总数(RBC)、白细胞总数(WBC)、血红蛋白(Hb)、红细胞比容(Hct)、血小板总数(PLT)、平均细胞血红蛋白浓度(MCHC)、平均血红蛋白(MCH)和平均细胞体积(MCV)的微核率和血液学指标。3BP的LC50-96h值计算为5.2 g/L。以明确的时间和剂量依赖性方式测定了脑AChE活性的显著降低。SOD、CAT、GPx、PON和AR水平降低,MDA、MPO、8-OHdG和Caspase-3水平升高(p < 0.05)。同样,3BP在所有施用浓度下都导致MN形成的增加,增加率在45.4%和72.7%之间 < 0.05)在暴露于3BP和对照鱼之间的所有研究的血液学参数之间发现。总之,我们的研究首次表明,3BP的治疗剂量对虹鳟产生了明显的血液学和氧化改变以及遗传毒性损伤。
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引用次数: 2
Toxicity effects evaluation of green synthesized silver nanoparticles on intraperitoneally exposed male Wistar rats 绿色合成纳米银对雄性Wistar大鼠腹腔注射的毒性作用评价
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-03-06 DOI: 10.1080/15376516.2022.2049412
S. Tarbali, Saeed Karami Mehrian, Shiva Khezri
Abstract Objective: During the last decades, the widespread use of silver nanoparticles (AgNPs) has been considered because of their small size and antimicrobial effects. The main concern about these particles is that they can induce oxidative stress. In this study, the dose-dependent effects of green synthesized silver nanoparticles (Green-AgNPs) were evaluated on adult male rats. Methods: Animals were injected intraperitoneally (I.P) with the vehicle (deionized water) and different doses of Green-AgNPs (50, 100, 200, and 400 ppm), daily for 21 days. For the safety assessment, body weight and organ coefficient (liver, kidney, spleen, and brain) were measured. The effects of Green-AgNPs administration on working memory, anxiety behavior, novel object recognition, and spatial memory were analyzed. The lipophilic fluorescent products (LFPs), as an indicator of oxidative stress, were also evaluated in the liver, kidney, spleen, and hippocampus. Results: After 21 days of exposure, significant changes were not observed in body weight and organ coefficients. Green-AgNPs at the doses of 100, 200, and 400 ppm caused memory impairment and anxieties as well as altered liver, kidney, spleen, and hippocampus redox status. All tissues of the exposed animals showed an increased LFPs level compared to those of the rats in the vehicle group. Conclusions: This study indicated that the consumption of Green-AgNPs in higher doses (>50 ppm), not only had negative effects on behavioral indices but also caused memory impairment in rats and was toxic. This might be due to the induction of oxidative stress demonstrated by increased LFPs levels in tissues. Graphical Abstract Cascade events after I.P. injection of different doses of Green-AgNPs in rats After I.P. administration of green synthesized AgNPs in rats, these particles can pass through endothelial cells to various organs, such as the liver, kidney, spleen, and brain. Then caused oxidative stress and increased production of free radicals in the tissues. Overload free radicals result in the initiation of lipid peroxidation and result in the production of aldehydes. Following changes in the redox state in the neurons, these events caused memory impairment in high doses of green synthesized AgNPs. Aldehydes produced are unstable and react with amino groups of proteins, amino acids, or phospholipids. Assessment of generated lipophilic fluorescent products (LFPs) as stress oxidative marker.
摘要目的:在过去的几十年里,银纳米颗粒(AgNPs)由于其小尺寸和抗菌作用而被广泛应用。对这些颗粒的主要担忧是它们会引起氧化应激。在本研究中,研究了绿色合成银纳米颗粒(green - agnps)对成年雄性大鼠的剂量依赖性。方法:动物腹腔注射不同剂量的Green-AgNPs(50、100、200、400 ppm)和去离子水,连续注射21 d。为了进行安全性评估,测量了体重和器官系数(肝、肾、脾和脑)。分析Green-AgNPs给药对工作记忆、焦虑行为、新物体识别和空间记忆的影响。作为氧化应激指标的亲脂性荧光产物(LFPs)也在肝脏、肾脏、脾脏和海马中进行了评估。结果:暴露21天后,大鼠体重和脏器系数无明显变化。100,200和400ppm剂量的绿色agnps引起记忆障碍和焦虑,以及肝脏,肾脏,脾脏和海马氧化还原状态的改变。与车辆组大鼠相比,暴露动物的所有组织均显示lfp水平升高。结论:大鼠大剂量(50 ~ 50 ppm)摄入绿agnps不仅对大鼠的行为指标有负面影响,还会引起记忆障碍,并具有毒性。这可能是由于组织中lfp水平增加所证明的氧化应激的诱导。大鼠ig注射不同剂量的绿色合成AgNPs后,这些颗粒可以通过内皮细胞到达肝、肾、脾、脑等各器官。然后引起氧化应激并增加组织中自由基的产生。过量的自由基导致脂质过氧化的开始,并导致醛的产生。随着神经元氧化还原状态的变化,这些事件导致高剂量绿色合成AgNPs的记忆损伤。产生的醛是不稳定的,与蛋白质、氨基酸或磷脂的氨基发生反应。生成的亲脂性荧光产物(LFPs)作为应激氧化标志物的评价。
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引用次数: 3
Mitigative impact of bradykinin potentiating factor isolated from Androctonus amoreuxi scorpion venom and low doses of γ-irradiation on doxorubicin induced hepatotoxicity through ang II/AMPK crosstalk 阿莫鲁西雄蛾蝎子毒液缓激肽增强因子及低剂量γ辐照对阿霉素诱导肝毒性的影响
IF 3.2 4区 医学 Q2 TOXICOLOGY Pub Date : 2022-03-06 DOI: 10.1080/15376516.2022.2049941
H. Hasan, S. Galal, Rania A. Ellethy
Abstract In this study, the mitigative impact of bradykinin potentiating factor (BPF) and low doses of γ-irradiation (LDR) were evaluated against doxorubicin (DOX) hepatotoxicity through Ang II/AMPK crosstalk. Rats have received a single dose of DOX (10 mg/kg, i.p.). BPF administration at a dose of 1 μg/g (b.wt./twice a week) was started one week before the administration of DOX and followed throughout the study for another consecutive week where LDR rats were subjected to two low fractions of γ-irradiation; 0.5 Gy/fraction/week up to the cumulative dose of 1 Gy at 7 days before and after doxorubicin administration. DOX produced a remarkable disturbance in serum hepatic enzymes activities, hepatic oxidative stress indices, as well as hepatic inflammatory and fibrotic markers in response to a marked elevation in hepatic angiotensin II (Ang II) together with marked depression in hepatic AMP-activated protein kinase (AMPK) expressions. The combination of BPF and LDR produced a significant improvement in all examined parameters as well as mitigates hepatic toxicity through inhibition of Ang II induced by DOX, which might also be mediated by AMPK activation. Furthermore, histopathological and immunohistochemical examination reinforced the previous results. In conclusion, these findings shed new light on the mechanism underlying the anti-inflammatory and anti-fibrosis consequence of our remedy and support the potential use of it as a preventive and therapeutic candidate against hepatic toxicity through Ang II/AMPK crosstalk. Graphical Abstract
摘要本研究通过Ang II/AMPK串扰评价了缓激肽增强因子(BPF)和低剂量γ辐照(LDR)对阿霉素(DOX)肝毒性的缓解作用。大鼠接受单剂量DOX (10mg /kg, i.p.)。给药剂量为1 μg/g (b.wt)。/每周两次)在给药前一周开始,并在整个研究中连续一周,LDR大鼠接受两次低剂量γ辐射;0.5 Gy/分数/周,直至阿霉素给药前后7天累积剂量1 Gy。DOX对血清肝酶活性、肝脏氧化应激指标以及肝脏炎症和纤维化标志物产生显著干扰,以响应肝血管紧张素II (Ang II)的显著升高和肝amp活化蛋白激酶(AMPK)表达的显著降低。BPF和LDR联合使用可显著改善所有检测参数,并通过抑制DOX诱导的Ang II减轻肝毒性,这也可能是由AMPK激活介导的。组织病理学和免疫组化检查进一步证实了上述结果。总之,这些发现揭示了我们的药物抗炎和抗纤维化作用的机制,并支持其作为通过Ang II/AMPK串扰预防和治疗肝毒性的潜在用途。图形抽象
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引用次数: 1
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Toxicology Mechanisms and Methods
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