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Short-term repeated oral intake of low dose cannabidiol: effects on liver enzyme activity and creatinine concentration during intense exercise 短期反复口服低剂量大麻二酚:对剧烈运动期间肝酶活性和肌酐浓度的影响。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-12-04 DOI: 10.1007/s00204-024-03904-1
Eduard Isenmann, Dirk W. Lachenmeier, Ulrich Flenker, Alessio Lesch, Sebastian Veit, Patrick Diel

The side effects and safety of cannabidiol (CBD) products are currently discussed in different contexts. Of all adverse effects, hepatotoxic effects have been reported most frequently in previous studies. However, the threshold for liver toxicity of CBD in humans is uncertain due to the lack of adequately designed studies in humans below the lowest observed adverse effect level (LOAEL) of 300 mg/day. In a randomised, three-arm, double-blind, crossover study, the effects of two CBD products (oil and solubilisate (solu) containing 60 mg CBD) were investigated during a high-intensity exercise protocol. Seventeen well-trained subjects (26±4 years, 181±5 cm, 85.6±9.4 kg) participated in the intervention. All subjects were healthy and had no physiological or psychological injuries. Participants were divided into advanced (Ad) and highly advanced (Hi) athletes … They consumed 60 mg of the compound in each microcycle over 7 days. To evaluate possible effects of short-term repeated use of 60 mg CBD on oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT), gamma-glutamyl transferase (GGT) and creatinine (CREA) were analysed before and after each microcycle. GOT increased significantly in both performance levels of the placebo groups (Ad: p≤0.001; Hi: p=0.003). This increase was significantly reduced in the Ad group by both CBD oil (p=0.050, ES=0.66) and CBD solu (p=0.027; ES=0.75). GPT also increased significantly in both placebo groups (Ad: p≤0.001; Hi: p=0.032). This increase was significantly reduced in the Ad group by both CBD oil (p=0.027; ES=0.75) and CBD solu (p=0.023; ES=0.77). These effects were not observed in the Hi group for either parameter. Our results show that short-term repeated use of 60 mg CBD can inhibit exercise-induced liver activity. Furthermore, under the conditions of the present study, there was no evidence for hepatotoxic effects of oral intake of CBD at 60 mg for seven days. Nevertheless, despite the inhibitory effect on exercise-induced liver activity, the study provides evidence for the pharmacological effects of CBD on the liver even at low CBD dose and does not exclude adverse effects in sensitive individuals.

大麻二酚(CBD)产品的副作用和安全性目前在不同的背景下进行了讨论。在所有的不良反应中,肝毒性反应在以前的研究中报道得最多。然而,由于缺乏充分设计的人体研究,CBD对人体的肝毒性阈值低于300毫克/天的最低观察到的不良反应水平(LOAEL),因此尚不确定。在一项随机、三组、双盲、交叉研究中,研究人员在高强度运动方案中研究了两种CBD产品(含有60毫克CBD的油和可溶物(溶质))的效果。17名训练有素的受试者(26±4岁,181±5 cm, 85.6±9.4 kg)参加了干预。所有受试者均健康,无生理或心理损伤。参与者被分为高级运动员(Ad)和高级运动员(Hi),在7天的时间里,他们在每个微循环中摄入60毫克的化合物。为评价短期重复使用60 mg CBD对草酰乙酸转氨酶(GOT)、谷氨酸丙酮酸转氨酶(GPT)、γ -谷氨酰转移酶(GGT)和肌酐(CREA)在每个微循环前后的可能影响。在安慰剂组的两种表现水平中,GOT均显著增加(Ad: p≤0.001;嗨:p = 0.003)。CBD油(p=0.050, ES=0.66)和CBD溶液(p=0.027;ES = 0.75)。两组安慰剂组GPT均显著升高(Ad: p≤0.001;嗨:p = 0.032)。在Ad组中,CBD油显著降低了这种增加(p=0.027;ES=0.75)和CBD浓度(p=0.023;ES = 0.77)。在Hi组中没有观察到这些影响。我们的研究结果表明,短期重复使用60毫克CBD可以抑制运动诱导的肝脏活性。此外,在本研究条件下,没有证据表明口服摄入CBD 60mg,连续7天有肝毒性作用。然而,尽管对运动诱导的肝脏活性有抑制作用,该研究为CBD在低剂量下对肝脏的药理作用提供了证据,并且不排除对敏感个体的不良影响。
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引用次数: 0
Does a carboxamide moiety alter the toxicokinetics of synthetic cannabinoids? A study after pulmonary and intravenous administration of cumyl-5F-P7AICA to pigs 甲酰胺片段是否会改变合成大麻素的毒性动力学?猪经肺和静脉给药cumyl-5F-P7AICA后的研究。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-12-04 DOI: 10.1007/s00204-024-03906-z
Nadja Walle, Christiane Dings, Omar Zaher, Adrian A. Doerr, Benjamin Peters, Matthias W. Laschke, Thorsten Lehr, Michael D. Menger, Peter H. Schmidt, Markus R. Meyer, Nadine Schaefer

Synthetic cannabinoids (SCs) are consumed as an alternative to cannabis. Novel compounds are developed by minor modifications in their chemical structure, e.g. insertion of a carboxamide moiety as a linker, which can potentially lead to altered toxicokinetics (TK). Knowledge on the TK data of SCs, especially structural modified substances, is scarce. Hence, interpretation of toxicological results is challenging. Therefore, the aim of the present study was to evaluate the TK of cumyl-5F-P7AICA in a pig model, which was shown to be suitable for TK studies of SCs. A 200 µg/kg body weight dose of cumyl-5F-P7AICA was administered intravenously (n = 6) or inhalatively (n = 10) via an ultrasonic nebulizer to pigs. Blood specimens were repeatedly drawn over 6 h and the concentrations of cumyl-5F-P7AICA as well as its N-pentanoic acid (NPA) metabolite were determined using a fully validated LC–MS/MS method. Based on the concentration–time profiles, a population TK analysis yielded a three-compartment model for the TK of cumyl-5F-P7AICA, whilst a two-compartment model described the NPA best. The incorporation of transit compartments accounts for the time delay between the appearance of cumyl-5F-P7AICA and NPA in serum. Finally, the model was upscaled to humans using allometric scaling. In comparison to older SCs, a higher volume of distribution was determined for cumyl-5F-P7AICA. No further relevant differences of the TK properties were observed. Insertion of a carboxamide moiety into the chemical structure of SCs does not appear to have only minor influence on the TK.

合成大麻素(SCs)是大麻的替代品。新化合物是通过对其化学结构进行微小修改而开发的,例如插入一个羧胺片段作为连接物,这可能导致毒性动力学(TK)的改变。关于SCs,特别是结构修饰物质的TK数据的知识很少。因此,毒理学结果的解释是具有挑战性的。因此,本研究的目的是在猪模型中评估cumyl-5F-P7AICA的TK,该模型被证明适合于SCs的TK研究。将200µg/kg体重剂量的cumyl-5F-P7AICA通过超声雾化器静脉注射(n = 6)或吸入(n = 10)给猪。在6小时内反复抽取血液标本,使用完全验证的LC-MS/MS方法测定cumyl-5F-P7AICA及其n -戊酸(NPA)代谢物的浓度。基于浓度-时间分布,群体TK分析得出cumyl-5F-P7AICA的TK为三室模型,而两室模型最能描述NPA。血清中cumyl-5F-P7AICA和NPA出现之间的时间延迟是由于转运隔室的存在。最后,采用异速缩放法将模型扩展到人体。与较老的sc相比,cumyl-5F-P7AICA的分布体积更大。未观察到TK特性的进一步相关差异。在SCs的化学结构中插入一个羧酰胺片段似乎对TK的影响并不大。
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引用次数: 0
Effects of carbon black particles on human monocyte-derived macrophages: type-dependent pro-inflammatory activation in vitro 炭黑颗粒对人单核细胞源性巨噬细胞的影响:体外类型依赖性促炎激活。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-11-29 DOI: 10.1007/s00204-024-03909-w
Justina Pajarskienė, Agnė Vailionytė, Ieva Uogintė, Steigvilė Byčenkienė, Ugnė Jonavičė, Ilona Uzielienė, Edvardas Bagdonas, Rūta Aldonytė

Carbon black is a key component of air-borne particulate matter, linked to adverse health outcomes, such as increased susceptibility to respiratory infections and chronic pulmonary disease exacerbations. Fine and ultrafine particles can penetrate the lungs, enter the bloodstream, and induce pathogenetic events. Macrophages play a crucial role in responding to inhaled particles, including carbon black, by initiating an innate immune response and upregulating pro-inflammatory cytokines and anti-oxidative enzymes. This study investigates the effects of carbon black particles on human monocyte-derived macrophages in vitro at a concentration of 10 µg/ml, offering insights into their potential role in disease pathogenesis. We have compared two commercially available carbon black particle types using various physicochemical techniques and assessed their biological effects on monocyte-derived macrophages. We have evaluated changes in cell viability, morphology, and particle uptake/phagocytosis. Western blot, ELISA, and RT-qPCR measured inflammatory and oxidative stress biomarkers. Both types of carbon black particles induced similar responses in macrophages, including particle uptake, cytokine production, and oxidative stress-related protein expression. The observed changes suggest activation of the Nrf2-mediated antioxidant response, impaired autophagy, and decreased cellular defense against oxidative stress, indicating potential pathways for chronic inflammatory lung disease development.

炭黑是空气传播颗粒物的关键成分,与呼吸道感染易感性增加和慢性肺部疾病加重等不良健康后果有关。细颗粒和超细颗粒可穿透肺部,进入血液,诱发发病事件。巨噬细胞通过启动先天免疫反应和上调促炎细胞因子和抗氧化酶,在吸入颗粒(包括炭黑)的反应中起着至关重要的作用。本研究探讨了炭黑颗粒在体外浓度为10 μ g/ml时对人单核细胞源性巨噬细胞的影响,为其在疾病发病机制中的潜在作用提供见解。我们使用不同的物理化学技术比较了两种市售的炭黑颗粒类型,并评估了它们对单核细胞来源的巨噬细胞的生物学效应。我们评估了细胞活力、形态和颗粒摄取/吞噬的变化。Western blot、ELISA和RT-qPCR检测炎症和氧化应激生物标志物。两种类型的炭黑颗粒在巨噬细胞中诱导相似的反应,包括颗粒摄取,细胞因子产生和氧化应激相关蛋白表达。观察到的变化表明nrf2介导的抗氧化反应被激活,自噬受损,细胞对氧化应激的防御能力下降,提示慢性炎症性肺病发展的潜在途径。
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引用次数: 0
Toxicokinetics of benzotriazole UV stabilizer UV-P in humans after single oral administration 单次口服苯并三唑紫外线稳定剂UV- p在人体内的毒性动力学。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-11-29 DOI: 10.1007/s00204-024-03907-y
Corinna Fischer, Julia Hiller, Edgar Leibold, Thomas Göen

UV-P (2-(2H-Benzotriazol-2-yl)-p-cresol) is used as an ultraviolet (UV) light absorber in coating products, paints, adhesives, and sealants. Due to its widespread industrial and consumer uses, human exposure to UV-P is conceivable. In the study presented herein, initial data on its human in vivo metabolism were obtained for three study participants after single oral administration of 0.3 mg of UV-P/kg body weight. Urine and blood samples of two volunteers were collected up to 48 h after exposure. The third study participant donated urine and blood samples up to 72 h. Maximum levels of UV-P in blood of 184 ± 36 µg/l (85 ± 3% as conjugates) were reached 2.4 ± 1.2 h post-exposure. Maximum excretion rates of UV-P in urine of 2896 ± 884 µg/h (completely conjugated) were reached 3.5 ± 1.1 h post-exposure. 37.2 ± 5.4% of the orally administered dose of UV-P was recovered in urine within 48 h post-exposure. The present study provides insight into the complex absorption, distribution, metabolism, and elimination (ADME) processes of benzotriazole UV stabilizers (BUVS). The study also demonstrates differences in the ADME between sterically hindered BUVS, such as UV-327 and UV-328, and sterically unhindered BUVS, such as UV-P, in which the phenolic hydroxyl group is readily accessible for conjugation with glucuronic acid or sulfate.

UV- p (2-(2h -苯并三唑-2-基)-对甲酚)在涂料产品、油漆、粘合剂和密封剂中用作紫外线吸收剂。由于其广泛的工业和消费用途,人类暴露于UV-P是可以想象的。在本文提出的研究中,获得了3名研究参与者在单次口服0.3 mg UV-P/kg体重后的人体体内代谢的初步数据。两名志愿者在接触后48小时内收集尿液和血液样本。第三个研究参与者捐献尿液和血液样本长达72小时。暴露后2.4±1.2小时,血液中UV-P的最高水平达到184±36µg/l(85±3%为结合物)。暴露后3.5±1.1 h,尿液中UV-P的最大排泄率达到2896±884µg/h(完全偶联)。37.2±5.4%的口服剂量的UV-P在暴露后48 h内从尿液中回收。本研究揭示了苯并三唑类紫外线稳定剂(BUVS)的复杂吸收、分布、代谢和消除过程。该研究还证明了空间阻碍BUVS(如UV-327和UV-328)和空间无阻碍BUVS(如UV-P)之间ADME的差异,其中酚羟基很容易与葡萄糖醛酸或硫酸盐结合。
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引用次数: 0
High molecular weight polycyclic aromatic hydrocarbon (HMW-PAH) isomers: unveiling distinct toxic effects from cytotoxicity to oxidative stress-induced DNA damage 高分子量多环芳烃(HMW-PAH)异构体:揭示从细胞毒性到氧化应激诱导的DNA损伤的独特毒性作用。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-11-29 DOI: 10.1007/s00204-024-03917-w
Lara Ferreira Azevedo, Cecilia Cristina de Souza Rocha, Marília Cristina Oliveira Souza, Ana Rita Thomazela Machado, Paula Pícoli Devóz, Bruno Alves Rocha, Lusania Maria Greggi Antunes, Fernando J. Uribe-Romo, Andres D. Campiglia, Fernando Barbosa Jr.

Polycyclic aromatic hydrocarbons (PAHs) represent one of the most extensive classes of known carcinogenic and genotoxic compounds widely distributed across the globe. Particularly relevant to ecotoxicological studies is the possible presence of PAHs with molecular weight (MW) 302 Da. Since the toxicity of 302 Da PAHs differs significantly from isomer to isomer, understanding their relative toxicity is essential for assessing their potential risks to human health. This study investigates the toxic effects of micromolar concentrations of four HMW-PAHs isomers of MW = 302 Da, namely dibenzo(b,l)fluoranthene (DB(b,l)F), dibenzo(a,j)fluoranthene (DB(a,j)F), dibenzo(a,l)fluoranthene (DB(a,l)F) and naphtho(1-2j)fluoranthene (N(1-2j)F), upon exposure and metabolic activation in HepG2 cells. Appropriate assays were selected to investigate their potential to disrupt cellular viability and to induce cytotoxicity, apoptosis/necrosis, genotoxicity, and oxidative stress with DNA damage. After 48 h of exposure time, DB(a,l)F was the only isomer to reduce cellular viability in a concentration-dependent manner. In all cases, apoptosis was the main mechanism of HepG2 cell death, which could be induced by the significant DNA damage and an increase in 8-hydroxy-2′-deoxyguanosine (8-OHdG) adduct level formation. The highest concentrations of DB(a,l)F tested exhibited the greatest potential to induce HepG2 DNA damage and 8-OHdG formation. Altogether, these facts demonstrate that the distinct arrangements of the atoms in HMW-PAHs isomers can impact on their toxic potential and that DB(a,l)F was the most toxic isomer evaluated in this study. These results shed light on the importance to thoroughly characterize MW302 PAHs to substantiate their human and environmental risk assessments.

多环芳烃(PAHs)是广泛分布在全球的已知致癌物和遗传毒性化合物中最广泛的一类。与生态毒理学研究特别相关的是可能存在分子量(MW)为302 Da的多环芳烃。由于302da多环芳烃的毒性因异构体而异,因此了解其相对毒性对于评估其对人类健康的潜在风险至关重要。本研究研究了MW = 302 Da的四种HMW-PAHs异构体,即二苯并(b,l)荧光蒽(DB(b,l)F),二苯并(a,j)荧光蒽(DB(a,j)F),二苯并(a,l)荧光蒽(DB(a,l)F)和萘(1-2j)荧光蒽(N(1-2j)F)的微摩尔浓度对HepG2细胞暴露和代谢激活的毒性作用。选择适当的检测方法来研究它们破坏细胞活力、诱导细胞毒性、细胞凋亡/坏死、遗传毒性和DNA氧化应激损伤的可能性。暴露48 h后,DB(a,l)F是唯一以浓度依赖性方式降低细胞活力的异构体。凋亡是HepG2细胞死亡的主要机制,细胞凋亡可通过DNA损伤和8-羟基-2′-脱氧鸟苷(8-OHdG)加合物水平的增加引起。最高浓度的DB(a,l)F诱导HepG2 DNA损伤和8-OHdG形成的潜力最大。总之,这些事实表明,HMW-PAHs异构体中不同的原子排列方式会影响其毒性潜力,并且DB(a,l)F是本研究中评估的毒性最大的异构体。这些结果阐明了彻底表征MW302多环芳烃以证实其人类和环境风险评估的重要性。
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引用次数: 0
Sepsis-induced cardiomyopathy: understanding pathophysiology and clinical implications 败血症诱发的心肌病:了解病理生理学和临床意义。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-11-27 DOI: 10.1007/s00204-024-03916-x
Haoran Liu, Chaoqun Xu, Qin Hu, Yang Wang

Sepsis is a life-threatening form of organ dysfunction resulting from a dysregulated response to infection. The complex pathogenesis of sepsis poses challenges because of the lack of reliable biomarkers for early identification and effective treatments. As sepsis progresses to severe forms, cardiac dysfunction becomes a major concern, often manifesting as ventricular dilation, a reduced ejection fraction, and a diminished contractile capacity, known as sepsis-induced cardiomyopathy (SIC). The absence of standardized diagnostic and treatment protocols for SIC leads to varied criteria being used across medical institutions and studies, resulting in significant outcome disparities. Despite the high prevalence of SIC, accurate statistical data are lacking. To understand how SIC affects sepsis prognosis, a thorough exploration of its pathophysiological mechanisms, including systemic factors and complex signalling within myocardial and immune cells, is required. Identifying the factors influencing SIC occurrence and progression is crucial and must be conducted within specific clinical contexts. In this review, the clinical manifestations, pathophysiological mechanisms, and treatment strategies for SIC are discussed, along with the clinical background. We aim to connect current practices with future research challenges, providing clear guidance for clinicians and researchers.

败血症是一种危及生命的器官功能障碍,由对感染的反应失调引起。败血症的发病机制复杂,由于缺乏可靠的生物标志物来进行早期识别和有效治疗,因此给治疗带来了挑战。当败血症发展到严重程度时,心脏功能障碍成为一个主要问题,通常表现为心室扩张、射血分数降低和收缩能力减弱,即败血症诱发的心肌病(SIC)。由于缺乏针对 SIC 的标准化诊断和治疗方案,各医疗机构和研究采用的标准不尽相同,导致结果差异显著。尽管 SIC 的发病率很高,但却缺乏准确的统计数据。要了解 SIC 如何影响脓毒症的预后,需要对其病理生理机制进行深入探讨,包括系统因素以及心肌细胞和免疫细胞内的复杂信号传导。确定影响 SIC 发生和发展的因素至关重要,而且必须在特定的临床环境中进行。在这篇综述中,我们将结合临床背景,讨论 SIC 的临床表现、病理生理机制和治疗策略。我们旨在将当前的实践与未来的研究挑战联系起来,为临床医生和研究人员提供明确的指导。
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引用次数: 0
Heavy metals: toxicity and human health effects 重金属:毒性和对人类健康的影响。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-11-20 DOI: 10.1007/s00204-024-03903-2
Klaudia Jomova, Suliman Y. Alomar, Eugenie Nepovimova, Kamil Kuca, Marian Valko
<div><p>Heavy metals are naturally occurring components of the Earth’s crust and persistent environmental pollutants. Human exposure to heavy metals occurs via various pathways, including inhalation of air/dust particles, ingesting contaminated water or soil, or through the food chain. Their bioaccumulation may lead to diverse toxic effects affecting different body tissues and organ systems. The toxicity of heavy metals depends on the properties of the given metal, dose, route, duration of exposure (acute or chronic), and  extent of bioaccumulation. The detrimental impacts of heavy metals on human health are largely linked to their capacity to interfere with antioxidant defense mechanisms, primarily through their interaction with intracellular glutathione (GSH) or sulfhydryl groups (R-SH) of antioxidant enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and other enzyme systems. Although arsenic (As) is believed to bind directly to critical thiols, alternative hydrogen peroxide production processes have also been postulated. Heavy metals are known to interfere with signaling pathways and affect a variety of cellular processes, including cell growth, proliferation, survival, metabolism, and apoptosis. For example, cadmium can affect the BLC-2 family of proteins involved in mitochondrial death via the overexpression of antiapoptotic Bcl-2 and the suppression of proapoptotic (BAX, BAK) mechanisms, thus increasing the resistance of various cells to undergo malignant transformation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an important regulator of antioxidant enzymes, the level of oxidative stress, and cellular resistance to oxidants and has been shown to act as a double-edged sword in response to arsenic-induced oxidative stress. Another mechanism of significant health threats and heavy metal (e.g., Pb) toxicity involves the substitution of essential metals (e.g., calcium (Ca), copper (Cu), and iron (Fe)) with structurally similar heavy metals (e.g., cadmium (Cd) and lead (Pb)) in the metal-binding sites of proteins. Displaced essential redox metals (copper, iron, manganese) from their natural metal-binding sites can catalyze the decomposition of hydrogen peroxide via the Fenton reaction and generate damaging ROS such as hydroxyl radicals, causing damage to lipids, proteins, and DNA. Conversely, some heavy metals, such as cadmium, can suppress the synthesis of nitric oxide radical (NO<sup>·</sup>), manifested by altered vasorelaxation and, consequently, blood pressure regulation. Pb-induced oxidative stress has been shown to be indirectly responsible for the depletion of nitric oxide due to its interaction with superoxide radical (O<sub>2</sub><sup>·−</sup>), resulting in the formation of a potent biological oxidant, peroxynitrite (ONOO<sup>−</sup>). This review comprehensively discusses the mechanisms of heavy metal toxicity and their health effects. Aluminum (Al), cadmium (
重金属是地壳中天然存在的成分,也是持久性环境污染物。人类通过各种途径接触重金属,包括吸入空气/粉尘颗粒、摄入受污染的水或土壤,或通过食物链。重金属的生物累积可能导致不同的毒性效应,影响不同的人体组织和器官系统。重金属的毒性取决于特定金属的特性、剂量、途径、接触时间(急性或慢性)以及生物累积程度。重金属对人体健康的有害影响主要与它们干扰抗氧化防御机制的能力有关,主要是通过与细胞内谷胱甘肽(GSH)或抗氧化酶(如超氧化物歧化酶(SOD)、过氧化氢酶、谷胱甘肽过氧化物酶(GPx)、谷胱甘肽还原酶(GR)和其他酶系统)的巯基(R-SH)相互作用。虽然砷(As)被认为会直接与关键的硫醇结合,但也有人推测会产生其他的过氧化氢。众所周知,重金属会干扰信号传导途径并影响多种细胞过程,包括细胞生长、增殖、存活、新陈代谢和凋亡。例如,镉可通过过度表达抗凋亡的 Bcl-2 和抑制促凋亡(BAX、BAK)机制,影响参与线粒体死亡的 BLC-2 家族蛋白,从而增加各种细胞的抗恶性转化能力。核因子红细胞 2 相关因子 2(Nrf2)是抗氧化酶、氧化应激水平和细胞抗氧化能力的重要调节因子,已被证明在应对砷诱导的氧化应激方面起着双刃剑的作用。对健康构成重大威胁和重金属(如铅)毒性的另一个机制是,蛋白质的金属结合位点中的基本金属(如钙、铜和铁)被结构相似的重金属(如镉和铅)取代。从天然金属结合位点置换出来的必需氧化还原金属(铜、铁、锰)可通过芬顿反应催化过氧化氢的分解,并产生有害的 ROS(如羟自由基),从而对脂质、蛋白质和 DNA 造成破坏。相反,一些重金属(如镉)会抑制一氧化氮自由基(NO-)的合成,表现为血管舒张功能的改变,进而影响血压调节。铅诱导的氧化应激已被证明是一氧化氮耗竭的间接原因,这是因为铅与超氧自由基(O2--)相互作用,形成了一种强效生物氧化剂--过氧化亚硝酸盐(ONOO-)。这篇综述全面讨论了重金属毒性的机理及其对健康的影响。其中讨论了铝(Al)、镉(Cd)、砷(As)、汞(Hg)、铅(Pb)和铬(Cr)及其在胃肠道、肺、肾、生殖、神经退行性疾病(阿尔茨海默氏症和帕金森氏症)、心血管和癌症(如肾、肺、皮肤和胃)等疾病中的作用。还简要介绍了通过使用乙二胺四乙酸(EDTA)、二巯基丙醇(BAL)、2,3-二巯基丁二酸(DMSA)、2,3-二巯基-1-丙烷磺酸(DMPS)和青霉胺螯合剂进行螯合的重金属解毒方法。
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引用次数: 0
Design of optimal concentrations for in vitro cytotoxicity experiments 设计体外细胞毒性实验的最佳浓度。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-11-16 DOI: 10.1007/s00204-024-03893-1
Leonie Schürmeyer, Chen Peng, Wiebke Albrecht, Tim Brecklinghaus, Pauline Baur, Jan G. Hengstler, Kirsten Schorning

Concentration-dependent cytotoxicity experiments are frequently used in toxicology. Although it has been reported that an adequate choice of concentrations improves the quality of the statistical inference substantially, a recent literature review of three major toxicological journals has shown that the corresponding methods are rarely used in toxicological practice. In this study the performance of different sets of concentrations, also called designs, are analyzed, while the overall goal is to promote the advantages of optimal design procedures and to present a user-friendly guideline for planning new cytotoxicity concentration-response experiments. We compare the frequently used log-equidistant design to a Bayesian design, which is constructed by methods of optimum design theory. Using both a dense data set of concentration-cytotoxicity data of valproic acid (VPA) and regular assay data of 104 substances, the performance of the different designs is analyzed in two scenarios, where detailed previous knowledge on VPA is available or not. The results show that it is critical to apply a specific design strategy to determine optimal concentrations for cytotoxicity testing. In particular, the Bayesian design technique with and without incorporating pre-existing knowledge of a specific test substance resulted in a more precise statistical inference than the other used designs. Finally, we present a guideline for upcoming experiments and an accessible user-friendly Shiny app (see http://shiny.statistik.tu-dortmund.de:8080/app/occe).

浓度依赖性细胞毒性实验经常用于毒理学研究。尽管有报告称,适当选择浓度可大幅提高统计推断的质量,但最近对三大毒理学期刊的文献综述显示,毒理学实践中很少使用相应的方法。本研究分析了不同浓度组(也称为设计)的性能,其总体目标是宣传优化设计程序的优势,并为规划新的细胞毒性浓度-反应实验提供用户友好型指南。我们将常用的对数不等式设计与贝叶斯设计进行了比较,后者是通过最优设计理论方法构建的。利用丙戊酸(VPA)浓度-毒性数据的密集数据集和 104 种物质的常规检测数据,在两种情况下分析了不同设计的性能,即是否有关于 VPA 的详细前人知识。结果表明,采用特定的设计策略来确定细胞毒性测试的最佳浓度至关重要。特别是,采用贝叶斯设计技术并结合或不结合特定试验物质的已有知识,比其他设计方法得出的统计推断更为精确。最后,我们为即将进行的实验提供了指导,并提供了一个方便用户使用的 Shiny 应用程序(见 http://shiny.statistik.tu-dortmund.de:8080/app/occe )。
{"title":"Design of optimal concentrations for in vitro cytotoxicity experiments","authors":"Leonie Schürmeyer,&nbsp;Chen Peng,&nbsp;Wiebke Albrecht,&nbsp;Tim Brecklinghaus,&nbsp;Pauline Baur,&nbsp;Jan G. Hengstler,&nbsp;Kirsten Schorning","doi":"10.1007/s00204-024-03893-1","DOIUrl":"10.1007/s00204-024-03893-1","url":null,"abstract":"<div><p>Concentration-dependent cytotoxicity experiments are frequently used in toxicology. Although it has been reported that an adequate choice of concentrations improves the quality of the statistical inference substantially, a recent literature review of three major toxicological journals has shown that the corresponding methods are rarely used in toxicological practice. In this study the performance of different sets of concentrations, also called designs, are analyzed, while the overall goal is to promote the advantages of optimal design procedures and to present a user-friendly guideline for planning new cytotoxicity concentration-response experiments. We compare the frequently used log-equidistant design to a Bayesian design, which is constructed by methods of optimum design theory. Using both a dense data set of concentration-cytotoxicity data of valproic acid (VPA) and regular assay data of 104 substances, the performance of the different designs is analyzed in two scenarios, where detailed previous knowledge on VPA is available or not. The results show that it is critical to apply a specific design strategy to determine optimal concentrations for cytotoxicity testing. In particular, the Bayesian design technique with and without incorporating pre-existing knowledge of a specific test substance resulted in a more precise statistical inference than the other used designs. Finally, we present a guideline for upcoming experiments and an accessible user-friendly Shiny app (see http://shiny.statistik.tu-dortmund.de:8080/app/occe).</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 1","pages":"357 - 376"},"PeriodicalIF":4.8,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00204-024-03893-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Drug-induced cholestasis (DIC) predictions based on in vitro inhibition of major bile acid clearance mechanisms 根据体外对主要胆汁酸清除机制的抑制作用预测药物诱导胆汁淤积症(DIC)。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-11-14 DOI: 10.1007/s00204-024-03895-z
Vlasia Kastrinou-Lampou, Raquel Rodríguez-Pérez, Birk Poller, Felix Huth, Heiko S. Schadt, Gerd A. Kullak-Ublick, Michael Arand, Gian Camenisch

Drug-induced cholestasis (DIC) is recognized as a major safety concern in drug development, as it represents one of the three types of drug-induced liver injury (DILI). Cholestasis is characterized by the disruption of bile flow, leading to intrahepatic accumulation of toxic bile acids. Bile acid regulation is a multifarious process, orchestrated by several hepatic mechanisms, namely sinusoidal uptake and efflux, canalicular secretion and intracellular metabolism. In the present study, we developed a prediction model of DIC using in vitro inhibition data for 47 marketed drugs on nine transporters and five enzymes known to regulate bile acid homeostasis. The resulting model was able to distinguish between drugs with or without DILI concern (p-value = 0.039) and demonstrated a satisfactory predictive performance, with the area under the precision–recall curve (PR AUC) measured at 0.91. Furthermore, we simplified the model considering only two processes, namely reversible inhibition of OATP1B1 and time-dependent inhibition of CYP3A4, which provided an enhanced performance (PR AUC = 0.95). Our study supports literature findings suggesting a contribution not only from a single process inhibition, but a rather synergistic effect of the key bile acid clearance processes in the development of cholestasis. The use of a quantitative model in the preclinical investigations of DIC is expected to reduce attrition rate in advanced development programs and guide the discovery and development of safe medicines.

药物诱导胆汁淤积症(DIC)是药物开发中的一个主要安全问题,因为它是三种药物诱导肝损伤(DILI)之一。胆汁淤积症的特点是胆汁流动受阻,导致有毒胆汁酸在肝内蓄积。胆汁酸的调节是一个多元过程,由几种肝脏机制协调,即窦状吸收和流出、管状分泌和细胞内代谢。在本研究中,我们利用 47 种已上市药物对已知调节胆汁酸平衡的九种转运体和五种酶的体外抑制数据,建立了一个 DIC 预测模型。所建立的模型能够区分是否存在 DILI 问题的药物(p 值 = 0.039),并显示出令人满意的预测性能,精确-召回曲线下面积(PR AUC)为 0.91。此外,我们简化了模型,只考虑了两个过程,即 OATP1B1 的可逆抑制和 CYP3A4 的时间依赖性抑制,从而提高了预测效果(PR AUC = 0.95)。我们的研究支持文献中的结论,即胆汁淤积症的发生不仅与单一过程的抑制有关,还与关键胆汁酸清除过程的协同作用有关。在 DIC 临床前研究中使用定量模型有望降低高级开发项目的损耗率,并指导安全药物的发现和开发。
{"title":"Drug-induced cholestasis (DIC) predictions based on in vitro inhibition of major bile acid clearance mechanisms","authors":"Vlasia Kastrinou-Lampou,&nbsp;Raquel Rodríguez-Pérez,&nbsp;Birk Poller,&nbsp;Felix Huth,&nbsp;Heiko S. Schadt,&nbsp;Gerd A. Kullak-Ublick,&nbsp;Michael Arand,&nbsp;Gian Camenisch","doi":"10.1007/s00204-024-03895-z","DOIUrl":"10.1007/s00204-024-03895-z","url":null,"abstract":"<div><p>Drug-induced cholestasis (DIC) is recognized as a major safety concern in drug development, as it represents one of the three types of drug-induced liver injury (DILI). Cholestasis is characterized by the disruption of bile flow, leading to intrahepatic accumulation of toxic bile acids. Bile acid regulation is a multifarious process, orchestrated by several hepatic mechanisms, namely sinusoidal uptake and efflux, canalicular secretion and intracellular metabolism. In the present study, we developed a prediction model of DIC using in vitro inhibition data for 47 marketed drugs on nine transporters and five enzymes known to regulate bile acid homeostasis. The resulting model was able to distinguish between drugs with or without DILI concern (<i>p</i>-value = 0.039) and demonstrated a satisfactory predictive performance, with the area under the precision–recall curve (PR AUC) measured at 0.91. Furthermore, we simplified the model considering only two processes, namely reversible inhibition of OATP1B1 and time-dependent inhibition of CYP3A4, which provided an enhanced performance (PR AUC = 0.95). Our study supports literature findings suggesting a contribution not only from a single process inhibition, but a rather synergistic effect of the key bile acid clearance processes in the development of cholestasis. The use of a quantitative model in the preclinical investigations of DIC is expected to reduce attrition rate in advanced development programs and guide the discovery and development of safe medicines.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"99 1","pages":"377 - 391"},"PeriodicalIF":4.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Antineoplastic therapy affects the in vitro phenotype and functionality of healthy human bone marrow-derived mesenchymal stromal cells 抗肿瘤疗法会影响健康人骨髓间充质基质细胞的体外表型和功能。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-11-12 DOI: 10.1007/s00204-024-03898-w
Bo Scherer, Lucienne Bogun, Annemarie Koch, Paul Jäger, Uwe Maus, Laura Schmitt, Karina S. Krings, Sebastian Wesselborg, Rainer Haas, Thomas Schroeder, Stefanie Geyh

While antineoplastic therapies aim to specifically target cancer cells, they may also exert adverse effects on healthy tissues, like healthy hematopoietic stem and progenitor cells (HSPC), leading to hematotoxicity as a common side effect. Mesenchymal stromal cells (MSC) are a major component of the bone marrow (BM) microenvironment, regulating normal hematopoiesis, while their susceptibility to anticancer therapies and contribution to therapy-related hematotoxicity remains largely unexplored. To address this, we investigated the effects of etoposide, temozolomide, 5-azacitidine, and venetoclax on healthy BM-derived MSC functionality. Doses below therapeutic effects of etoposide (0.1–0.25 µM) inhibited cellular growth and induced cellular senescence in healthy MSC, accompanied by an increased mRNA expression of CDKN1A, decreased trilineage differentiation capacity, and insufficient hematopoietic support. Pharmacological doses of 5-azacitidine (2.5 µM) shifted MSC differentiation capacity by inhibiting osteogenic capacity but enhancing the chondrogenic lineage, as demonstrated by histochemical staining and on mRNA level. At the highest clinically relevant dose, neither venetoclax (40 nM) nor temozolomide (100 µM) exerted any effects on MSC but clearly inhibited cellular growth of cancer cell lines and primary healthy HSPC, pointing to damage to hematopoietic cells as a major driver of hematotoxicity of these two compounds. Our findings show that besides HSPC, also MSC are sensitive to certain antineoplastic agents, resulting in molecular and functional alterations that may contribute to therapy-related myelosuppression. Understanding these interactions could be helpful for the development of strategies to preserve BM MSC functionality during different kinds of anticancer therapies.

虽然抗肿瘤疗法旨在专门针对癌细胞,但它们也可能对健康组织产生不利影响,如健康的造血干细胞和祖细胞(HSPC),从而导致血液毒性这一常见的副作用。间充质基质细胞(MSC)是骨髓(BM)微环境的主要组成部分,调节正常的造血,但它们对抗癌疗法的易感性以及对治疗相关血液毒性的贡献在很大程度上仍未得到研究。为了解决这个问题,我们研究了依托泊苷、替莫唑胺、5-氮胞苷和 Venetoclax 对健康间充质干细胞功能的影响。依托泊苷的剂量低于治疗效果(0.1-0.25 µM)会抑制健康间充质干细胞的细胞生长并诱导细胞衰老,同时CDKN1A的mRNA表达增加,三系分化能力下降,造血支持不足。药理剂量的 5-azacitidine (2.5 µM)改变了间充质干细胞的分化能力,通过组织化学染色和 mRNA 水平证明,它抑制了成骨能力,但增强了软骨细胞系。在最高临床相关剂量下,venetoclax(40 nM)和替莫唑胺(100 µM)对间充质干细胞均无任何影响,但却明显抑制了癌细胞系和原代健康造血干细胞的细胞生长,这表明对造血细胞的损伤是这两种化合物血液毒性的主要驱动因素。我们的研究结果表明,除了 HSPC 外,间充质干细胞对某些抗肿瘤药物也很敏感,从而导致分子和功能的改变,这些改变可能会造成与治疗相关的骨髓抑制。了解这些相互作用可能有助于制定策略,在不同类型的抗癌疗法中保护骨髓间充质干细胞的功能。
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引用次数: 0
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Archives of Toxicology
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