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In-silico green toxicology approach toward discovering safer ligands for development of safe-by-design metal-organic frameworks. 为开发安全设计的金属有机框架发现更安全配体的硅学绿色毒理学方法。
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-09-01 Epub Date: 2024-05-23 DOI: 10.1080/15376516.2024.2353364
Reyhane Khezri, Seyed Jamaleddin Shahtaheri, Elahe Khezri, Mahdi Niknam Shahrak, Monireh Khadem

A vast variety of chemical compounds have been fabricated and commercialized, they not only result in industrial exposure during manufacturing and usage, but also have environmental impacts throughout their whole life cycle. Consequently, attempts to assess the risk of chemicals in terms of toxicology have never ceased. In-silico toxicology, also known as predictive toxicology, has advanced significantly over the last decade as a result of the drawbacks of experimental investigations. In this study, ProTox-III was applied to predict the toxicity of the ligands used for metal-organic framework (MOF) design and synthesis. Initially, 35 ligands, that have been frequently utilized for MOF synthesis and fabrication, were selected. Subsequently, canonical simplified molecular-input line-entry system (SMILES) of ligands were extracted from the PUBCHEM database and inserted into the ProTox-III online server. Ultimately, webserver outputs including LD50 and the probability of toxicological endpoints (cytotoxicity, carcinogenicity, mutagenicity, immunotoxicity, and ecotoxicity) were obtained and organized. According to retrieved LD50 data, the safest ligand was 5-hydroxyisophthalic. In contrast, the most hazardous ligand was 5-chlorobenzimidazole, with an LD50 of 8 mg/kg. Among evaluated endpoints, ecotoxicity was the most active and was detected in several imidazolate ligands. This data can open new horizons in design and development of green MOFs.

大量的化学物质被制造和商业化,它们不仅在制造和使用过程中造成工业接触,而且在整个生命周期中对环境产生影响。因此,从毒理学角度评估化学品风险的尝试从未停止过。由于实验研究的弊端,在过去十年中,硅毒理学(又称预测毒理学)得到了长足的发展。在这项研究中,ProTox-III 被用来预测用于金属有机框架设计和合成的配体的毒性。最初,研究人员选择了 35 种配体,这些配体经常用于 MOF 的合成和制造。随后,从 PUBCHEM 数据库中提取配体的规范 SMILES,并将其插入 ProTox-III 在线服务器。最终,获得并整理了包括半数致死剂量(LD50)和毒理学终点(细胞毒性、致癌性、致突变性、免疫毒性和生态毒性)概率在内的网络服务器输出结果。根据检索到的半数致死剂量数据,最安全的配体是 5-羟基间苯二甲酸酯。相反,最危险的配体是 5-氯苯并咪唑,半数致死剂量为 8 毫克/千克。在评估的终点中,生态毒性最为活跃,在几种咪唑配体中都检测到了生态毒性。这些数据为设计和开发绿色 MOFs 开辟了新的视野。
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引用次数: 0
Silver nanoparticle-induced cell damage via impaired mtROS-JNK/MnSOD signaling pathway. 银纳米粒子通过受损的 mtROS-JNK/MnSOD 信号通路诱导细胞损伤。
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-09-01 Epub Date: 2024-05-13 DOI: 10.1080/15376516.2024.2350595
Mei Jing Piao, Kyoung Ah Kang, Pincha Devage Sameera Madushan Fernando, Herath Mudiyanselage Udari Lakmini Herath, Jin Won Hyun

This study investigated the mechanism of silver nanoparticle (AgNP) cytotoxicity from a mitochondrial perspective. The effect of AgNP on manganese superoxide dismutase (MnSOD), a mitochondrial antioxidant enzyme, against oxidative stress has not been studied in detail. We demonstrated that AgNP decreased MnSOD mRNA level, protein expression, and activity in human Chang liver cells in a time-dependent manner. AgNP induced the production of mitochondrial reactive oxygen species (mtROS), particularly superoxide anion. AgNP was found to increase mitochondrial calcium level and disrupt mitochondrial function, leading to reduced ATP level, succinate dehydrogenase activity, and mitochondrial permeability. AgNP induced cytochrome c release from the mitochondria into the cytoplasm, attenuated the expression of the anti-apoptotic proteins phospho Bcl-2 and Mcl-1, and induced the expression of the pro-apoptotic proteins Bim and Bax. In addition, c-Jun N-terminal kinase (JNK) phosphorylation was significantly increased by AgNP. Treatment with elamipretide (a mitochondria-targeted antioxidant) and SP600125 (a JNK inhibitor) showed the involvement of MnSOD and JNK in these processes. These results indicated that AgNP damaged human Chang liver cells by destroying mitochondrial function through the accumulation of mtROS.

本研究从线粒体的角度研究了银纳米粒子(AgNP)的细胞毒性机制。AgNP对线粒体抗氧化酶锰超氧化物歧化酶(MnSOD)的影响尚未得到详细研究。我们证实,AgNP 会降低人 Chang 肝细胞中 MnSOD 的 mRNA 水平、蛋白表达量和活性,且呈时间依赖性。AgNP 诱导线粒体活性氧(mtROS)的产生,尤其是超氧阴离子。研究发现,AgNP 会增加线粒体钙水平并破坏线粒体功能,导致 ATP 水平、琥珀酸脱氢酶活性和线粒体通透性降低。AgNP 可诱导细胞色素 c 从线粒体释放到细胞质中,降低抗凋亡蛋白 phospho Bcl-2 和 Mcl-1 的表达,并诱导促凋亡蛋白 Bim 和 Bax 的表达。此外,AgNP 还显著增加了 c-Jun N 端激酶(JNK)的磷酸化。线粒体靶向抗氧化剂 Elamipretide 和 JNK 抑制剂 SP600125 的处理表明,MnSOD 和 JNK 参与了这些过程。这些结果表明,AgNP 通过 mtROS 的积累破坏线粒体功能,从而损害人 Chang 肝细胞。
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引用次数: 0
Evaluating the possible genotoxicity of nanoaluminum incorporated in human vaccines and the potential protective role of nanocurcumin: an in vivo study. 评估人类疫苗中加入的纳米铝可能具有的遗传毒性以及纳米姜黄素的潜在保护作用:一项体内研究。
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-09-01 Epub Date: 2024-05-22 DOI: 10.1080/15376516.2024.2352736
Nevine Khairy Elkady, Abrar Roshdy Abouelkheir, Sherien S Ghaleb, Olfat Gamil Shaker, Heba Abd ElMonem Ibrahim, Eman Mohamed Ibraheim Moawad, Asmaa Mohammad Moawad

For nearly 90 years, aluminum (Al) salts have been utilized as vaccination adjuvants. Nevertheless, there is a risk of adverse effects associated with the amount of nanoaluminum used in various national pediatric immunization regimens. This study aimed to investigate the possible genotoxic effects of nanoaluminum incorporated in human vaccines on the brains of newborn albino rats and whether nanocurcumin has a potential protective effect against this toxicity. Fifty newborn albino rats were randomly assigned to 5 groups, with 10 in each group. Groups 1 and 2 received "high" and "low" Al injections corresponding to either the American or Scandinavian pediatric immunization schedules, respectively, as opposed to the control rats (group 5) that received saline injections. Groups 3 and 4 received the same regimens as groups 1 and 2 in addition to oral nanocurcumin. The expression of both the cell breakdown gene tumor protein (P53) and the cell stress gene uncoupling protein 2 (UCP2) was significantly greater in groups 1 and 2 than in group 5. Groups 1 and 2 exhibited severe DNA fragmentation, which was observed as DNA laddering. Nanocurcumin significantly reduced the expression of the P53 and UCP2 genes in groups 3 and 4, with very low or undetectable DNA laddering in both groups. Vaccination with nanoaluminum adjuvants can cause genotoxic effects, which can be mediated by the inflammatory response and oxidative stress, and nanocurcumin can protect against these toxic effects through the modulation of oxidative stress regulators and gene expression.

近 80 年来,纳米铝(Al)盐一直被用作疫苗佐剂。然而,各国儿科免疫接种方案中使用的纳米铝的数量可能会产生不良影响。本研究旨在调查人类疫苗中添加的纳米铝对新生白化大鼠大脑可能产生的基因毒性影响,以及纳米古柯碱是否对这种毒性具有潜在的保护作用。50 只新生白化大鼠被随机分配到 5 组,每组 10 只。第 1 组和第 2 组分别接受与美国或斯堪的纳维亚儿科免疫计划相对应的 "高 "和 "低 "Al 注射,而对照组(第 5 组)则接受生理盐水注射。第 3 组和第 4 组除了口服纳米姜黄素外,还接受了与第 1 组和第 2 组相同的治疗方案。细胞破坏基因肿瘤蛋白(P53)和细胞应激基因解偶联蛋白 2(UCP2)在第 1 组和第 2 组的表达量明显高于第 5 组。纳米古柯碱明显降低了第 3 组和第 4 组中 P53 和 UCP2 基因的表达,而这两组的 DNA 梯状化程度很低或检测不到。使用纳米铝佐剂接种疫苗会导致基因毒性效应,这种效应可能是由炎症反应和氧化应激介导的,而纳米姜黄素可以通过调节氧化应激调节因子和基因表达来抵御这些毒性效应。
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引用次数: 0
Assessment of TGx-DDI genes for genotoxicity in a comprehensive panel of chemicals. 评估综合化学品组中 TGx-DDI 基因的遗传毒性。
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-09-01 Epub Date: 2024-04-15 DOI: 10.1080/15376516.2024.2335966
A Rasim Barutcu

Background: The TGx-DDI biomarker identifies transcripts specifically induced by primary DNA damage. Profiling similarity of TGx-DDI signatures can allow clustering compounds by genotoxic mechanism. This transcriptomics-based approach complements conventional toxicology testing by enhancing mechanistic resolution.

Methods: Unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding (tSNE) were utilized to assess similarity of publicly-available per- and polyfluoroalkyl substances (PFAS) and ToxCast chemicals based on TGx-DDI modulation. TempO-seq transcriptomic data after highest chemical concentrations were analyzed.

Results: Clustering discriminated between genotoxic and non-genotoxic compounds while drawing similarity among chemicals with shared mechanisms. PFAS largely clustered distinctly from classical mutagens. However, dynamic range across PFAS types and durations indicated variable potential for DNA damage. tSNE visualization reinforced phenotypic groupings, with genotoxins clustering separately from non-DNA damaging agents.

Discussion: Unsupervised learning approaches applied to TGx-DDI profiles effectively categorizes chemical genotoxicity potential, aiding elucidation of biological response pathways. This transcriptomics-based strategy gives further insight into the role and effect of individual TGx-DDI biomarker genes and complements existing assays by enhancing mechanistic resolution. Overall, TGx-DDI biomarker profiling holds promise for predictive safety screening.

背景TGx-DDI 生物标志物可识别原发性 DNA 损伤特异性诱导的转录本。通过分析 TGx-DDI 特征的相似性,可以按基因毒性机制对化合物进行分类。这种基于转录组学的方法可提高机理分辨率,是对传统毒理学测试的补充:方法:利用无监督分层聚类和 t 分布随机邻域嵌入(tSNE)来评估公开的全氟和多氟烷基物质(PFAS)与基于 TGx-DDI 调节的 ToxCast 化学品的相似性。对最高化学浓度后的 TempO-seq 转录组数据进行了分析:结果:聚类区分了基因毒性和非基因毒性化合物,同时得出了具有共同机制的化学品之间的相似性。全氟辛烷磺酸在很大程度上有别于传统的诱变剂。tSNE 可视化强化了表型分组,将基因毒性物质与非 DNA 损伤物质分开聚类:讨论:应用于 TGx-DDI 图谱的无监督学习方法有效地对化学物质的潜在遗传毒性进行了分类,有助于阐明生物反应途径。这种基于转录组学的策略可进一步深入了解单个 TGx-DDI 生物标记基因的作用和影响,并通过提高机理分辨率对现有检测方法进行补充。总之,TGx-DDI 生物标志物分析有望用于预测性安全性筛选。
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引用次数: 0
Obesity aggravates neuroinflammatory and neurodegenerative effects of bisphenol A in female rats. 肥胖会加重双酚 A 对雌性大鼠神经炎症和神经退行性病变的影响。
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-09-01 Epub Date: 2024-05-16 DOI: 10.1080/15376516.2024.2349538
Anuradha Mangla, Poonam Goswami, Bhaskar Sharma, Suramya Suramya, Garima Jindal, Mehjbeen Javed, Mohd Anas Saifi, Suhel Parvez, Tapas Chandra Nag, Sheikh Raisuddin

Bisphenol A (BPA), a common plasticizer, is categorized as a neurotoxic compound. Its impact on individuals exhibits sex-linked variations. Several biological and environmental factors impact the degree of toxicity. Moreover, nutritional factors have profound influence on toxicity outcome. BPA has been demonstrated to be an obesogen. However, research on the potential role of obesity as a confounding factor in BPA toxicity is lacking. We studied the neurodegenerative effects in high-fat diet (HFD)-induced obese female rats after exposure to BPA (10 mg/L via drinking water for 90 days). Four groups were taken in this study - Control, HFD, HFD + BPA and BPA. Cognitive function was evaluated through novel object recognition (NOR) test. Inflammatory changes in brain, and changes in hormonal level, lipid profile, glucose tolerance, oxidative stress, and antioxidants were also determined. HFD + BPA group rats showed a significant decline in memory function in NOR test. The cerebral cortex (CC) of the brain showed increased neurodegenerative changes as measured by microtubule-associated protein-2 (MAP-2) accompanied by histopathological confirmation. The increased level of neuroinflammation was demonstrated by microglial activation (Iba-1) and protein expression of nuclear factor- kappa B (NF-КB) in the brain. Obesity also caused significant (p < 0.05) increase in lipid peroxidation accompanied by reduced activities of antioxidant enzymes (glutathione S-transferase, catalase and glutathione peroxidase) and decrease in reduced-glutathione (p < 0.05) when compared to non-obese rats with BPA treatment. Overall, study revealed that obesity serves as a risk factor in the toxicity of BPA which may exacerbate the progression of neurological diseases.

双酚 A(BPA)是一种常见的增塑剂,被归类为一种神经毒性化合物,其对个体的影响表现出性别差异。多种生物和环境因素会影响毒性程度。此外,营养因素对毒性结果也有深远影响。双酚 A 已被证明是一种肥胖诱因。然而,有关肥胖作为双酚 A 中毒混杂因素的潜在作用的研究还很缺乏。我们研究了高脂饮食(HFD)诱导的肥胖雌性大鼠暴露于双酚 A(10 毫克/升,通过饮用水暴露 90 天)后的神经退行性影响。本研究分为四组:对照组、高脂饮食组、高脂饮食 + 双酚 A 组和双酚 A 组。认知功能通过新物体识别(NOR)测试进行评估。此外,还测定了脑部炎症变化、荷尔蒙水平、血脂、葡萄糖耐量、氧化应激和抗氧化剂的变化。HFD + BPA 组大鼠的 NOR 测试结果明显下降。根据微管相关蛋白-2(MAP-2)的测量结果,大脑皮层(CC)的神经退行性变化增加,组织病理学也证实了这一点。大脑中的小胶质细胞活化(Iba-1)和核因子卡巴B(NF-КB)蛋白表达显示神经炎症水平升高。肥胖也会引起明显的(p
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引用次数: 0
Farnesoid X receptor modulator 12β-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid represses liver fibrosis by inhibiting ERK/p38 signaling pathways. 类arnesoid X受体调节剂12β-(甲基苯甲酰基)-11,12-二氢齐墩果酸通过抑制ERK/p38信号通路抑制肝纤维化
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-09-01 Epub Date: 2024-05-14 DOI: 10.1080/15376516.2024.2349551
Yiming Li, Yunyang Bao, Simin Guo, Yang Li, Weishuo Fang, Na Zhang, Hongwei He

Liver fibrosis is a common pathological process in the progression of several chronic liver diseases to cirrhosis and hepatocellular carcinoma. Therefore, the development of medications that can repress the progress of liver fibrosis is essential. We discovered that initially, 12β-(m-methyl-benzoyl)-11,12-dihydro oleanolic acid (12d-OA), a farnesoid X receptor (FXR) modulator, possessed potential anti-fibrotic properties. Through an in-depth study, we revealed that 12d-OA not only inhibited the expression of fibrogenic markers in the LX-2 cells and HSC-T6 cells but also exhibited significant protective effects against liver injury and liver fibrosis in bile duct ligation (BDL) rats. Further exploration of its molecular mechanism indicated that 12d-OA exerted antifibrotic activity by inhibiting the extracellular signal-regulated kinase (ERK)/stress-activated protein kinase (p38) signaling pathways. Consequently, the great effects of 12d-OA in vitro and in vivo suggest that it may be a good candidate for liver fibrosis.

肝纤维化是多种慢性肝病发展为肝硬化和肝细胞癌的常见病理过程。因此,开发能够抑制肝纤维化进程的药物至关重要。我们最初发现,12β-(间甲基苯甲酰基)-11,12-二氢齐墩果酸(12d-OA)是一种法尼类固醇 X 受体(FXR)调节剂,具有潜在的抗肝纤维化特性。通过深入研究,我们发现 12d-OA 不仅能抑制 LX-2 细胞和 HSC-T6 细胞中纤维化标志物的表达,而且对胆管结扎(BDL)大鼠的肝损伤和肝纤维化具有显著的保护作用。对其分子机制的进一步研究表明,12d-OA是通过抑制细胞外信号调节激酶(ERK)/应激激活蛋白激酶(p38)信号通路来发挥抗肝纤维化活性的。因此,12d-OA在体外和体内的巨大作用表明,它可能是一种治疗肝纤维化的良好候选药物。
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引用次数: 0
Leflunomide-induced cardiac injury in adult male mice and bioinformatic approach identifying Nrf2/NF-κb signaling interplay. 来氟米特诱导成年雄性小鼠心脏损伤以及识别 Nrf2/NF-κB 信号相互作用的生物信息学方法。
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-07-01 Epub Date: 2024-03-11 DOI: 10.1080/15376516.2024.2322666
Abeer A Rahman, Ann Hegazy, Lamiaa M Elabbasy, Mohamed Z Shoaeir, Tarek M Abdel-Aziz, Awad S Abbas, Heba W Z Khella, Amira H Eltrawy, Reem Alshaman, Sheka Yagub Aloyouni, Afaf A Aldahish, Sawsan A Zaitone

Leflunomide (LFND) is an immunosuppressive and immunomodulatory disease-modifying antirheumatic drug (DMARD) that was approved for treating rheumatoid arthritis. LFND-induced cardiotoxicity was not fully investigated since its approval. We investigated the cardiac injury in male mice and identified the role of nuclear factor erythroid 2-related factor 2/nuclear factor-κ B (Nrf2/NF-κB) signaling. Male albino mice were assigned into five groups as control, vehicle, and LFND (2.5, 5, and 10 mg/kg). We investigated cardiac enzymes, histopathology, and the mRNA expression of Nrf2, NF-κB, BAX, and tumor necrosis factor-α (TNF-α). The bioinformatic study identified the interaction between LFND and Nrf2/NF-κB signaling; this was confirmed by amelioration in mRNA expression (0.5- to 0.34-fold decrease in Nrf2 and 2.6- to 4.61-fold increases in NF-κB genes) and increased (1.76- and 2.625-fold) serum creatine kinase (CK) and 1.38- and 2.33-fold increases in creatine kinase-MB (CK-MB). Histopathological results confirmed the dose-dependent effects of LFND on cardiac muscle structure in the form of cytoplasmic, nuclear, and vascular changes in addition to increased collagen deposits and apoptosis which were increased compared to controls especially with LFND 10 mg/kg. The current study elicits the dose-dependent cardiac injury induced by LFND administration and highlights, for the first time, dysregulation in Nrf2/NF-κB signaling.

来氟米特(LFND)是一种免疫抑制和免疫调节疾病修饰抗风湿药(DMARD),已被批准用于治疗类风湿性关节炎。自获得批准以来,尚未对 LFND 诱导的心脏毒性进行全面研究。我们研究了雄性小鼠的心脏损伤,并确定了核因子红细胞2相关因子2/核因子-κB(Nrf2/NF-κB)信号传导的作用。雄性白化小鼠分为 5 组,分别为对照组、药物组和 LFND 组(2.5、5 和 10 mg/kg)。我们研究了心脏酶、组织病理学以及 Nrf2、NF-κB、BAX 和肿瘤坏死因子-α(TNF-α)的 mRNA 表达。生物信息学研究确定了 LFND 与 Nrf2/NF-κB 信号之间的相互作用;mRNA 表达的改善(Nrf2 减少 0.5 至 0.34 倍,NF-κB 基因增加 2.6 至 4.61 倍)和血清肌酸激酶(CK)的增加(1.76 和 2.625 倍)以及肌酸激酶-MB(CK-MB)的增加(1.38 和 2.33 倍)证实了这一点。组织病理学结果证实了 LFND 对心肌结构的剂量依赖性影响,表现为细胞质、细胞核和血管的变化,以及胶原沉积和细胞凋亡的增加。目前的研究表明,服用 LFND 会诱发剂量依赖性心肌损伤,并首次强调了 Nrf2/NF-κB 信号的失调。
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引用次数: 0
Renoprotective effect of hyperin against CdCl2 prompted renal damage by activation of Nrf-2/Keap-1 ARE pathway in male mice. 金丝桃素通过激活 Nrf-2/Keap-1 ARE 通路对雄性小鼠氯化镉肾损伤的保护作用
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-07-01 Epub Date: 2024-03-20 DOI: 10.1080/15376516.2024.2329655
Iserhienrhien O Lucky, Iyoha I Aisuhuehien, Memudu E Adejoke

Objectives: This study explored the mitigating properties of hyperin (HYP) on renotoxicity induced by cadmium chloride (CdCl2).

Methods: Four groups of seven male albino mice each were used in this experiment. Group 1 served as the control, receiving no treatment. Group 2 received daily oral gavage of CdCl2 at 0.3 mg/kg body weight for 28 d. Group 3 received both CdCl2 (0.3 mg/kg) and HYP (100 mg/kg) daily using the same administration method. Finally, Group 4 received only HYP (100 mg/kg) daily.

Results: Cd exposure significantly increased kidney dysfunction markers (blood urea nitrogen and creatinine) and oxidative stress (reactive oxygen species [ROS] and malondialdehyde [MDA]). Conversely, it decreased antioxidant enzyme activities (glutathione peroxidase (GPx] and catalase [CAT]) and glutathione (GSH) levels. Nuclear factor erythroid 2-related factor 2 (Nrf-2) and antioxidant gene expression decreased, while Kelch-like ECH-associated protein 1 expression increased. Additionally, Cd exposure increased inflammatory mediators (nuclear factor kappa B, tumor necrosis factor alpha [TNF-α], interleukin-1β [IL-1β], and cyclooxygenase-2) and apoptotic markers (Bax and caspase-3), alongside decreased Bcl-2 expression and renal tissue abnormalities. Mitochondrial dysfunction manifested with diminished activities of Krebs cycle and respiratory chain enzymes, and reduced mitochondrial membrane potential. Co-treatment with HYP significantly attenuated these detrimental effects through its anti-apoptotic, antioxidant, and anti-inflammatory properties.

Conclusion: HYP co-treatment significantly attenuated CdCl2-induced renal damage in mice, suggesting its potential as a protective agent against Cd-induced kidney toxicity.

研究目的本研究探讨了金丝桃素对氯化镉(CdCl2)诱导的再中毒的缓解作用:实验共分四组,每组七只雄性白化小鼠。第 1 组为对照组,不接受任何治疗。第 2 组每天口服 0.3 毫克/千克体重的氯化镉(CdCl2),连续 28 天。第 3 组采用相同的给药方法,每天同时服用氯化镉(0.3 毫克/千克)和金丝桃素(100 毫克/千克)。最后,第 4 组每天只服用金丝桃素(100 毫克/千克):结果:镉暴露会明显增加肾功能障碍指标(血尿素氮、肌酐)和氧化应激(活性氧、丙二醛)。相反,镉会降低抗氧化酶活性(谷胱甘肽过氧化物酶、过氧化氢酶)和谷胱甘肽水平。核因子红细胞 2 相关因子 2 和抗氧化基因的表达量减少,而 Kelch 样 ECH 相关蛋白 1 的表达量增加。此外,镉暴露还增加了炎症介质(核因子卡巴 B、肿瘤坏死因子α、白细胞介素-1β、环氧化酶-2)和凋亡标志物(Bax、Caspase-3),同时降低了 Bcl-2 的表达和肾组织异常。线粒体功能障碍表现为克雷布斯循环和呼吸链酶活性降低,线粒体膜电位降低。金丝桃素具有抗凋亡、抗氧化和抗炎特性,与金丝桃素联合治疗可显著减轻这些有害影响:结论:金丝桃素联合治疗可明显减轻氯化镉2-诱导的小鼠肾损伤,这表明金丝桃素具有保护镉诱导的肾毒性的潜力。
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引用次数: 0
Mass spectrometric methods for evaluation of voriconazole avian pharmacokinetics and the inhibition of its cytochrome P450-induced metabolism. 评估伏立康唑禽药代动力学及其细胞色素 P450 诱导的代谢抑制的质谱方法。
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-07-01 Epub Date: 2024-02-29 DOI: 10.1080/15376516.2024.2322675
Andreas F Lehner, Sharmie D Johnson, Levent Dirikolu, Margaret Johnson, John P Buchweitz

Invasive fungal aspergillosis is a leading cause of morbidity and mortality in many species including avian species such as common ravens (Corvus corax). Methods were developed for mass spectral determination of voriconazole in raven plasma as a means of determining pharmacokinetics of this antifungal agent. Without further development, GC/MS/MS (gas chromatography-tandem quadrupole mass spectrometry) proved to be inferior to LC/MS/MS (liquid chromatography-tandem quadrupole mass spectrometry) for measurement of voriconazole levels in treated raven plasma owing to numerous heat-induced breakdown products despite protection of voriconazole functional groups with trimethylsilyl moieties. LC/MS/MS measurement revealed in multi-dosing experiments that the ravens were capable of rapid or ultrarapid metabolism of voriconazole. This accounted for the animals' inability to raise the drug into the therapeutic range regardless of dosing regimen unless cytochrome P450 (CYP) inhibitors were included. Strategic selection of CYP inhibitors showed that of four selected compounds including cimetidine, enrofloxacin and omeprazole, only ciprofloxacin (Cipro) was able to maintain voriconazole levels in the therapeutic range until the end of the dosing period. The optimal method of administration involved maintenance doses of voriconazole at 6 mg/kg and ciprofloxacin at 20 mg/kg. Higher doses of voriconazole such as 18 mg/kg were also tenable without apparent induction of toxicity. Although most species employ CYP2C19 to metabolize voriconazole, it was necessary to speculate that voriconazole might be subject to metabolism by CYP1A2 in the ravens to explain the utility of ciprofloxacin, a previously unknown enzymatic route. Finally, despite its widespread catalog of CYP inhibitions including CYP1A2 and CYP2C19, cimetidine may be inadequate at enhancing voriconazole levels owing to its known effects on raising gastric pH, a result that may limit voriconazole solubility.

侵袭性真菌曲霉病是导致许多物种发病和死亡的主要原因,其中包括普通乌鸦(Corvus corax)等禽类物种。我们开发了通过质谱测定乌鸦血浆中伏立康唑含量的方法,以此来确定这种抗真菌药物的药代动力学。尽管伏立康唑的官能团受到三甲基硅基的保护,但在测量处理过的乌鸦血浆中伏立康唑的含量时,GC/MS/MS(气相色谱-串联四极杆质谱法)仍比 LC/MS/MS(液相色谱-串联四极杆质谱法)差,原因是热引起的分解产物较多。LC/MS/MS 测量显示,在多次给药实验中,乌鸦能够快速或超速代谢伏立康唑。这就是为什么无论采用何种给药方案,除非加入细胞色素 P450 (CYP) 抑制剂,否则乌鸦都无法将药物提升到治疗范围。对细胞色素 P450(CYP)抑制剂的策略性选择表明,在所选的四种化合物(包括西米替丁、恩诺沙星和奥美拉唑)中,只有环丙沙星(Cipro)能够将伏立康唑的水平维持在治疗范围内,直到给药期结束。最佳给药方法是将伏立康唑的维持剂量定为 6 毫克/千克,环丙沙星的维持剂量定为 20 毫克/千克。更高的伏立康唑剂量(如每公斤 18 毫克)也可以承受,但不会产生明显的诱导毒性。虽然大多数物种使用 CYP2C19 代谢伏立康唑,但有必要推测伏立康唑在乌鸦体内可能通过 CYP1A2 代谢,以解释环丙沙星的效用,这是一种以前未知的酶解途径。最后,尽管西咪替丁对包括 CYP1A2 和 CYP2C19 在内的 CYP 有广泛的抑制作用,但它可能不足以提高伏立康唑的水平,因为它具有已知的提高胃 pH 值的作用,而这种作用可能会限制伏立康唑的溶解度。
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引用次数: 0
Modulating oxidative stress, apoptosis, and mitochondrial dysfunctions on cardiotoxicity induced by aluminum phosphide pesticide using resveratrol. 利用白藜芦醇调节氧化应激、细胞凋亡和线粒体功能障碍对磷化铝农药诱发的心脏毒性的影响
IF 3.2 4区 医学 Q1 Pharmacology, Toxicology and Pharmaceutics Pub Date : 2024-07-01 Epub Date: 2024-03-27 DOI: 10.1080/15376516.2024.2331768
Deema K Sabir, Abeer Al-Masri, Munirah F Aldayel, Abeer A Sharaf

The agricultural fumigant pesticide aluminum phosphide (AlP) is cardiotoxic. Water causes AlP to emit phosphine gas, a cardiac toxin that affects heart function and causes cardiogenic shock. AlP poisoning's high fatality rate is due to cardiotoxicity. This study examines how resveratrol reduces oxidative stress, mitochondrial activity, and apoptosis in human cardiac myocyte (HCM) cells. After determining the optimal doses of resveratrol using the MTT test, HCM cells were subjected to a 24-h treatment of resveratrol following exposure to AlP (2.36 μM). The levels of reactive oxygen species (ROS), superoxide dismutase (SOD) activity, mitochondrial swelling, mitochondrial cytochrome c release, and mitochondrial membrane potential (MMP) in HCM cells were investigated. Also, the expression of Bax and Bcl-2, caspace-3 activity, and apoptosis were assessed. The present investigation revealed that AlP substantially increased the level of ROS and decreased SOD activation, which were significantly modulated by resveratrol in a dose-dependent manner. Moreover, AlP induced an elevation of mitochondrial swelling, cytochrome c release, and MMP collapse. Co-administration of resveratrol significantly reduced above mitochondrial markers. AlP also significantly upregulated BAX and downregulated Bcl-2 expression, elevated caspace-3 activity, and apoptosis. Resveratrol co-administration was able to meaningfully modulate the mentioned parameters and finally reduce apoptosis. In conclusion, resveratrol, via its pleotropic properties, significantly demonstrated cytoprotective effects on HCM cytotoxicity induced by AlP.

农用熏蒸剂杀虫剂磷化铝(AlP)具有心脏毒性。水会使 AlP 放出磷化氢气体,这是一种心脏毒素,会影响心脏功能并导致心源性休克。AlP 中毒的高致死率是由于心脏毒性造成的。本研究探讨了白藜芦醇如何降低氧化应激、线粒体活性和人心肌细胞(HCM)凋亡。在使用 MTT 试验确定白藜芦醇的最佳剂量后,HCM 细胞在暴露于 AlP(2.36 μM)后接受了 24 小时的白藜芦醇处理。研究了 HCM 细胞中活性氧(ROS)水平、超氧化物歧化酶(SOD)活性、线粒体肿胀、线粒体细胞色素 c 释放和线粒体膜电位(MMP)。此外,还评估了 Bax 和 Bcl-2 的表达、caspace-3 活性和细胞凋亡。本研究发现,AlP 能显著增加 ROS 水平并降低 SOD 的活化,而白藜芦醇能以剂量依赖的方式显著调节 ROS 水平。此外,AlP 还诱导线粒体肿胀、细胞色素 c 释放和 MMP 崩溃。同时服用白藜芦醇可显著降低上述线粒体指标。AlP 还能明显上调 BAX,下调 Bcl-2 的表达,提高 caspace-3 的活性,促进细胞凋亡。同时服用白藜芦醇能有效调节上述参数,最终减少细胞凋亡。总之,白藜芦醇通过其多方面的特性,对 AlP 诱导的 HCM 细胞毒性具有显著的细胞保护作用。
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引用次数: 0
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Toxicology Mechanisms and Methods
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