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Telmisartan potentiates the ITE-induced aryl hydrocarbon receptor activity in human liver cell line. 替米沙坦能增强 ITE 诱导的人肝细胞系芳香烃受体的活性。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-31 DOI: 10.1007/s00204-024-03901-4
Jiun Hsu, Hsiao-Ho Fang, Jyan-Gwo Joseph Su

Telmisartan is an angiotensin receptor blocker (ARB) approved by the Food and Drug Administration of the US for the treatment of hypertension. It possesses unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a 24-h sustained reduction of blood pressure. Besides well-known antihypertensive and cardioprotective effects, there is also strong clinical evidence that telmisartan confers renoprotection. Aryl hydrocarbon receptor (AhR) belongs to the steroid receptor family. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous ligand of AhR. Cytochrome P450 (CYP) 1A1 is an AhR-target gene. In this article, we demonstrated that telmisartan (2.5-60 μM) enhanced CYP1A1 promoter activity and expressions of mRNA and protein. Telmisartan-induced CYP1A1 expression was blocked by the AhR antagonist CH-223191 in liver cell lines and was negligible in the AhR signaling-deficient mutant cells. In addition, telmisartan induced transcriptional activity mediated by aryl hydrocarbon response element in both human and mouse cells, and was able to induce AhR translocation into the nucleus. Accordingly, telmisartan is an AhR agonist. It also acted synergistically with ITE to further enhance the expression of CYP1A1 mRNA and protein. This synergistic effect was more pronounced in cells with AhR overexpression compared to those without. AhR activity has strong association with the progression of chronic renal disease. Our study demonstrated that telmisartan is an AhR agonist and has synergistic effect with ITE, an indole derivative, to potentiate the effect on AhR. This finding may provide additional clues about the mechanism of the protective effect of telmisartan on the kidney.

替米沙坦是一种血管紧张素受体阻滞剂(ARB),已被美国食品药品管理局批准用于治疗高血压。它具有独特的药理特性,包括在所有血管紧张素受体阻滞剂中具有最长的半衰期,从而可实现 24 小时持续降压。除了众所周知的降压和心脏保护作用外,临床上也有确凿证据表明替米沙坦具有肾脏保护作用。芳基烃受体(AhR)属于类固醇受体家族。2-(1'H-吲哚-3'-羰基)-噻唑-4-羧酸甲酯(ITE)是AhR的内源性配体。细胞色素 P450(CYP)1A1 是 AhR 的靶基因。在本文中,我们证实替米沙坦(2.5-60 μM)可增强 CYP1A1 启动子的活性以及 mRNA 和蛋白质的表达。在肝细胞系中,替米沙坦诱导的CYP1A1表达被AhR拮抗剂CH-223191阻断,而在AhR信号缺失的突变细胞中则可忽略不计。此外,替米沙坦还能在人和小鼠细胞中诱导由芳基烃反应元件介导的转录活性,并能诱导 AhR 转位至细胞核。因此,替米沙坦是一种 AhR 激动剂。替米沙坦还与 ITE 起协同作用,进一步提高 CYP1A1 mRNA 和蛋白质的表达。与未表达 AhR 的细胞相比,这种协同作用在 AhR 过表达的细胞中更为明显。AhR 活性与慢性肾病的进展密切相关。我们的研究表明,替米沙坦是一种AhR激动剂,与吲哚衍生物ITE具有协同作用,可增强对AhR的影响。这一发现可能为替米沙坦对肾脏的保护作用机制提供了更多线索。
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引用次数: 0
Therapeutic potential of 4-phenylbutyric acid against methylmercury-induced neuronal cell death in mice. 4- 苯丁酸对甲基汞诱导的小鼠神经细胞死亡的治疗潜力。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-27 DOI: 10.1007/s00204-024-03902-3
Ryohei Miki, Ryosuke Nomura, Yuta Iijima, Sho Kubota, Nobumasa Takasugi, Takao Iwawaki, Masatake Fujimura, Takashi Uehara

Methylmercury (MeHg) is an environmental neurotoxin that induces damage to the central nervous system and is the causative agent in Minamata disease. The mechanisms underlying MeHg neurotoxicity remain largely unknown, and there is a need for effective therapeutic agents, such as those that target MeHg-induced endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), which is activated as a defense mechanism. We investigated whether intraperitoneal administration of the chemical chaperone, 4-phenylbutyric acid (4-PBA), at 120 mg/kg/day can alleviate neurotoxicity in the brains of mice administered 50 ppm MeHg in drinking water for 5 weeks. 4-PBA significantly reduced MeHg-induced ER stress, neuronal apoptosis, and neurological symptoms. Furthermore, 4-PBA was effective even when administered 2 weeks after the initiation of exposure to 30 ppm MeHg in drinking water. Our results strongly indicate that ER stress and the UPR are key processes involved in MeHg toxicity, and that 4-PBA is a novel therapeutic candidate for MeHg-induced neurotoxicity.

甲基汞(MeHg)是一种环境神经毒素,可诱发中枢神经系统损伤,是水俣病的致病因子。甲基汞的神经毒性机理在很大程度上仍然未知,因此需要有效的治疗药物,如针对甲基汞诱导的内质网(ER)应激和作为防御机制被激活的未折叠蛋白反应(UPR)的药物。我们研究了腹腔注射化学伴侣剂--4-苯基丁酸(4-PBA)120 毫克/千克/天是否能减轻在饮用水中添加 50 ppm MeHg 5 周的小鼠大脑的神经毒性。4-PBA 能明显减轻甲基汞引起的ER应激、神经细胞凋亡和神经症状。此外,即使在开始接触饮用水中的 30 ppm 甲基汞 2 周后施用 4-PBA 也是有效的。我们的研究结果有力地表明,ER应激和UPR是参与甲基汞毒性的关键过程,4-PBA是治疗甲基汞诱导的神经毒性的新型候选疗法。
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引用次数: 0
Biomarkers of genotoxic damage in pulmonary alveolar macrophages: a review. 肺泡巨噬细胞基因毒性损伤的生物标志物:综述。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-25 DOI: 10.1007/s00204-024-03894-0
Francesco D'Agostini, Sebastiano La Maestra

DNA damage is one of the primary mechanisms underlying cancer and other chronic degenerative diseases. Early evaluation of this damage in the affected cells and tissues is crucial for understanding pathogenesis and implementing effective prevention strategies. However, isolating target cells from affected organs, such as the lungs, can be challenging. Therefore, an alternative approach is to evaluate genotoxic damage in surrogate cells. Pulmonary alveolar macrophages are ideally suited for this purpose because they are in close contact with the target cells of the bronchial and alveolar epithelium, share the exact mechanisms and levels of exposure, and are easily recoverable in large numbers. This review comprehensively lists all studies using alveolar macrophages as surrogate cells to show genotoxic lung damage in humans or laboratory animals. These investigations provide fundamental information on the mechanisms of DNA damage in the lung and allow for better assessment and management of risk following exposure to inhalable genotoxic agents. Furthermore, they may be a valuable tool in cancer chemoprevention, helping the right choice of agents for clinical trials.

DNA 损伤是导致癌症和其他慢性退行性疾病的主要机制之一。及早评估受影响细胞和组织中的这种损伤对于了解发病机制和实施有效的预防策略至关重要。然而,从受影响器官(如肺部)中分离目标细胞是一项挑战。因此,另一种方法是评估代用细胞的基因毒性损伤。肺泡巨噬细胞非常适合这一目的,因为它们与支气管和肺泡上皮的靶细胞密切接触,具有确切的接触机制和水平,而且容易大量恢复。本综述全面列举了所有使用肺泡巨噬细胞作为替代细胞来显示人类或实验动物肺部基因毒性损伤的研究。这些研究提供了肺部 DNA 损伤机制的基本信息,有助于更好地评估和管理暴露于可吸入遗传毒性物质后的风险。此外,它们还是癌症化学预防的重要工具,有助于为临床试验正确选择药物。
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引用次数: 0
Evaluating the performance of multi-omics integration: a thyroid toxicity case study. 评估多组学整合的性能:甲状腺毒性案例研究。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-23 DOI: 10.1007/s00204-024-03876-2
Sebastian Canzler, Kristin Schubert, Ulrike E Rolle-Kampczyk, Zhipeng Wang, Stephan Schreiber, Hervé Seitz, Sophie Mockly, Hennicke Kamp, Volker Haake, Maike Huisinga, Martin von Bergen, Roland Buesen, Jörg Hackermüller

Multi-omics data integration has been repeatedly discussed as the way forward to more comprehensively cover the molecular responses of cells or organisms to chemical exposure in systems toxicology and regulatory risk assessment. In Canzler et al. (Arch Toxicol 94(2):371-388. https://doi.org/10.1007/s00204-020-02656-y ), we reviewed the state of the art in applying multi-omics approaches in toxicological research and chemical risk assessment. We developed best practices for the experimental design of multi-omics studies, omics data acquisition, and subsequent omics data integration. We found that multi-omics data sets for toxicological research questions were generally rare, with no data sets comprising more than two omics layers adhering to these best practices. Due to these limitations, we could not fully assess the benefits of different data integration approaches or quantitatively evaluate the contribution of various omics layers for toxicological research questions. Here, we report on a multi-omics study on thyroid toxicity that we conducted in compliance with these best practices. We induced direct and indirect thyroid toxicity through Propylthiouracil (PTU) and Phenytoin, respectively, in a 28-day plus 14-day recovery oral rat toxicity study. We collected clinical and histopathological data and six omics layers, including the long and short transcriptome, proteome, phosphoproteome, and metabolome from plasma, thyroid, and liver. We demonstrate that the multi-omics approach is superior to single-omics in detecting responses at the regulatory pathway level. We also show how combining omics data with clinical and histopathological parameters facilitates the interpretation of the data. Furthermore, we illustrate how multi-omics integration can hint at the involvement of non-coding RNAs in post-transcriptional regulation. Also, we show that multi-omics facilitates grouping, and we assess how much information individual and combinations of omics layers contribute to this approach.

多组学数据整合作为系统毒理学和监管风险评估中更全面地涵盖细胞或生物体对化学品暴露的分子反应的前进方向已被反复讨论。在 Canzler 等人(Arch Toxicol 94(2):371-388. https://doi.org/10.1007/s00204-020-02656-y )的文章中,我们回顾了在毒理学研究和化学品风险评估中应用多组学方法的最新进展。我们为多组学研究的实验设计、omics 数据采集以及后续的 omics 数据整合制定了最佳实践。我们发现,针对毒理学研究问题的多组学数据集通常很少见,没有一个数据集包含两个以上的 omics 层,且符合这些最佳实践。由于这些局限性,我们无法全面评估不同数据整合方法的益处,也无法定量评估不同omics层对毒理学研究问题的贡献。在此,我们报告了根据这些最佳实践进行的甲状腺毒性多组学研究。在一项为期 28 天加 14 天恢复期的大鼠口服毒性研究中,我们通过丙基硫脲嘧啶(PTU)和苯妥英分别诱导了直接和间接的甲状腺毒性。我们从血浆、甲状腺和肝脏中收集了临床和组织病理学数据以及六个组学层,包括长短转录组、蛋白质组、磷酸蛋白组和代谢组。我们证明,多组学方法在检测调控通路水平的反应方面优于单组学方法。我们还展示了将组学数据与临床和组织病理学参数相结合是如何促进数据解读的。此外,我们还说明了多组学整合如何暗示非编码 RNA 参与转录后调控。此外,我们还展示了多组学如何促进分组,并评估了单个组学层和组合组学层为这种方法贡献了多少信息。
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引用次数: 0
Metabolic dysfunction-associated steatotic liver disease-induced changes in the antioxidant system: a review. 代谢功能障碍相关脂肪肝诱发的抗氧化系统变化:综述。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-23 DOI: 10.1007/s00204-024-03889-x
Gabriela Svobodová, Martin Horní, Eva Velecká, Iva Boušová

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogeneous condition characterized by liver steatosis, inflammation, consequent fibrosis, and cirrhosis. Chronic impairment of lipid metabolism is closely related to oxidative stress, leading to cellular lipotoxicity, mitochondrial dysfunction, and endoplasmic reticulum stress. The detrimental effect of oxidative stress is usually accompanied by changes in antioxidant defense mechanisms, with the alterations in antioxidant enzymes expression/activities during MASLD development and progression reported in many clinical and experimental studies. This review will provide a comprehensive overview of the present research on MASLD-induced changes in the catalytic activity and expression of the main antioxidant enzymes (superoxide dismutases, catalase, glutathione peroxidases, glutathione S-transferases, glutathione reductase, NAD(P)H:quinone oxidoreductase) and in the level of non-enzymatic antioxidant glutathione. Furthermore, an overview of the therapeutic effects of vitamin E on antioxidant enzymes during the progression of MASLD will be presented. Generally, at the beginning of MASLD development, the expression/activity of antioxidant enzymes usually increases to protect organisms against the increased production of reactive oxygen species. However, in advanced stage of MASLD, the expression/activity of several antioxidants generally decreases due to damage to hepatic and extrahepatic cells, which further exacerbates the damage. Although the results obtained in patients, in various experimental animal or cell models have been inconsistent, taken together the importance of antioxidant enzymes in MASLD development and progression has been clearly shown.

代谢功能障碍相关性脂肪性肝病(MASLD)是一种以肝脏脂肪变性、炎症、随之而来的纤维化和肝硬化为特征的异质性疾病。脂质代谢的慢性损伤与氧化应激密切相关,导致细胞脂毒性、线粒体功能障碍和内质网应激。氧化应激的有害影响通常伴随着抗氧化防御机制的变化,许多临床和实验研究都报道了 MASLD 发生和发展过程中抗氧化酶表达/活性的改变。本综述将全面概述目前有关 MASLD 引起的主要抗氧化酶(超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶、谷胱甘肽 S-转移酶、谷胱甘肽还原酶、NAD(P)H:醌氧化还原酶)催化活性和表达变化以及非酶性抗氧化剂谷胱甘肽水平变化的研究。此外,还将概述维生素 E 在 MASLD 进展过程中对抗氧化酶的治疗作用。一般来说,在MASLD发展初期,抗氧化酶的表达/活性通常会增加,以保护生物体免受活性氧生成增加的影响。然而,在 MASLD 晚期,由于肝细胞和肝外细胞受损,几种抗氧化剂的表达/活性通常会下降,从而进一步加剧损伤。虽然在患者、各种实验动物或细胞模型中获得的结果并不一致,但综合来看,抗氧化酶在 MASLD 的发生和发展过程中的重要性已得到清楚的证明。
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引用次数: 0
Possum: identification and interpretation of potassium ion inhibitors using probabilistic feature vectors. Possum:利用概率特征向量识别和解释钾离子抑制剂。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-22 DOI: 10.1007/s00204-024-03888-y
Mir Tanveerul Hassan, Hilal Tayara, Kil To Chong

The flow of potassium ions through cell membranes plays a crucial role in facilitating various cell processes such as hormone secretion, epithelial function, maintenance of electrochemical gradients, and electrical impulse formation. Potassium ion inhibitors are considered promising alternatives in treating cancer, muscle weakness, renal dysfunction, endocrine disorders, impaired cellular function, and cardiac arrhythmia. Thus, it becomes essential to identify and understand potassium ion inhibitors in order to regulate the ion flow across ion channels. In this study, we created a meta-model, POSSUM, for the identification of potassium ion inhibitors. Two distinct datasets were used for training, testing, and evaluation of the meta-model. We employed seven feature descriptors and five distinctive classifiers to construct 35 baseline models. We used the mean Gini index score to select the optimal base models and classifiers. The POSSUM method was trained on the optimal probabilistic feature vectors. The proposed optimal model, POSSUM, outperforms the baseline models and the existing methods on both datasets. We anticipate POSSUM will be a very useful tool and will be essential in the process of finding and screening possible potassium ion inhibitors.

钾离子在细胞膜上的流动对促进激素分泌、上皮功能、维持电化学梯度和电脉冲形成等各种细胞过程起着至关重要的作用。钾离子抑制剂被认为是治疗癌症、肌无力、肾功能障碍、内分泌失调、细胞功能受损和心律失常的有前途的替代药物。因此,识别和了解钾离子抑制剂对调节离子通道中的离子流至关重要。在本研究中,我们创建了一个元模型 POSSUM,用于识别钾离子抑制剂。元模型的训练、测试和评估使用了两个不同的数据集。我们使用了七个特征描述和五个不同的分类器来构建 35 个基线模型。我们使用平均基尼指数得分来选择最佳基础模型和分类器。POSSUM 方法在最优概率特征向量上进行了训练。所提出的最优模型 POSSUM 在两个数据集上的表现都优于基准模型和现有方法。我们预计 POSSUM 将成为一个非常有用的工具,在寻找和筛选可能的钾离子抑制剂的过程中至关重要。
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引用次数: 0
In vivo pharmacokinetic, pharmacodynamic and brain concentration comparison of fentanyl and para-fluorofentanyl in rats. 芬太尼和对氟芬太尼在大鼠体内的药代动力学、药效学和脑浓度比较。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-17 DOI: 10.1007/s00204-024-03887-z
Jeremy R Canfield, Jon E Sprague

In 2022, para-fluorofentanyl (pFF) rose to the 6th most reported drug and the most reported fentanyl analog in the United States according to the Drug Enforcement Administration (DEA). pFF differs from fentanyl by the addition of a single fluorine group. To date, pFF has not been extensively evaluated in vivo and is frequently seen in combination with fentanyl. In the present study, the pharmacodynamic (PD) and pharmacokinetic (PK) properties and brain region-specific concentrations of pFF were evaluated in male Sprague-Dawley rats and compared to fentanyl. A 300 μg/kg subcutaneous dose of fentanyl or pFF was administered to assess PD and PK parameters as well as brain region concentrations. PD parameters were evaluated via a tail flick test to evaluate analgesia and core body temperature to measure hypothermia, a surrogate marker of overall opioid toxicity. Fentanyl and pFF were found to be equally active at the tested dose in terms of tail flick response with both compounds producing an analgesic response that lasted up to 240 min post-drug treatment. pFF induced a significantly greater hypothermic effect compared to fentanyl with a maximum temperature decrease of -5.6 ℃. Plasma PK parameters (T1/2, AUC, etc.) did not differ between fentanyl and pFF. However, pFF concentrations in the medulla, hippocampus, frontal cortex and striatum were more than two times the fentanyl concentrations. The increase in brain concentrations and greater hypothermic effect suggests that pFF is potentially more dangerous than fentanyl.

2022 年,根据美国缉毒署(DEA)的数据,对氟芬太尼(pFF)在美国报告最多的药物中排名第六,也是报告最多的芬太尼类似物。迄今为止,尚未对 pFF 进行广泛的体内评估,它经常与芬太尼混合使用。本研究评估了 pFF 在雄性 Sprague-Dawley 大鼠体内的药效学 (PD) 和药代动力学 (PK) 特性以及脑区特异性浓度,并与芬太尼进行了比较。大鼠皮下注射 300 μg/kg 芬太尼或 pFF,以评估 PD 和 PK 参数以及脑区浓度。通过甩尾试验评估镇痛和核心体温,以测量低体温(阿片类药物总体毒性的替代指标)。结果表明,在测试剂量下,芬太尼和对氟呋喃在尾弹反应方面具有相同的活性,两种化合物都能产生镇痛反应,并在用药后持续240分钟。与芬太尼相比,对氟呋喃诱导的体温降低效应明显更强,体温最高可降低-5.6 ℃。芬太尼和 pFF 的血浆 PK 参数(T1/2、AUC 等)没有差异。然而,髓质、海马、额叶皮层和纹状体中的 pFF 浓度是芬太尼浓度的两倍多。大脑浓度的增加和更大的低体温效应表明,pFF 可能比芬太尼更危险。
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引用次数: 0
Thiopurine S‑methyltransferase- and indolethylamine N‑methyltransferase-mediated formation of methylated tellurium compounds from tellurite. 硫代嘌呤 S-甲基转移酶和吲哚乙胺 N-甲基转移酶介导的亚碲酸盐甲基化碲化合物的形成。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-17 DOI: 10.1007/s00204-024-03890-4
Yu-Ki Tanaka, Ayuka Takata, Karin Takahashi, Yoshikazu Yamagishi, Yasunori Fukumoto, Noriyuki Suzuki, Yasumitsu Ogra

Tellurium (Te) is a metalloid widely used in various industries. However, its toxicological impact on humans is poorly understood. In this study, we investigated the role of two methyltransferases, thiopurine S‑methyltransferase (TPMT) and indolethylamine N‑methyltransferase (INMT), in the methylation of tellurite, an inorganic Te oxyanion. The products of the reaction of Te compounds catalyzed by recombinant human TPMT and/or INMT were analyzed by liquid chromatography hyphenated to inductively coupled plasma mass spectrometry (LC-ICP-MS) and gas chromatography mass spectrometry (GC-MS). We found that TPMT catalyzes the methylation of non-methylated Te and methanetellurol to generate dimethyltelluride. On the other hand, INMT catalyzes the methylation of methanetellurol and dimethyltelluride to produce trimethyltelluronium ion, a metabolite excreted into animal urine. We conclude that TPMT and INMT are cooperatively responsible for the detoxification of Te oxyanions through methylation to form trimethyltelluronium ions.

碲(Te)是一种广泛应用于各行各业的类金属。然而,人们对其对人体的毒理影响知之甚少。在这项研究中,我们研究了两种甲基转移酶(硫嘌呤 S-甲基转移酶(TPMT)和吲哚乙胺 N-甲基转移酶(INMT))在碲(一种无机碲氧阴离子)甲基化过程中的作用。通过液相色谱-电感耦合等离子体质谱(LC-ICP-MS)和气相色谱-质谱(GC-MS)分析了重组人 TPMT 和/或 INMT 催化的 Te 化合物反应产物。我们发现,TPMT 催化非甲基化碲和甲烷四氢呋喃的甲基化,生成二甲基四氢呋喃。另一方面,INMT 催化甲烷四呋喃和二甲基碲的甲基化,生成三甲基碲离子,这种代谢物排泄到动物尿液中。我们的结论是,TPMT 和 INMT 通过甲基化形成三甲基碲离子,共同负责碲氧阴离子的解毒。
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引用次数: 0
The current state of EVALI research (electronic cigarettes or vaping product use-associated lung injury) EVALI 研究现状(电子香烟或电子烟产品使用相关肺损伤)。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-16 DOI: 10.1007/s00204-024-03885-1
Hermann M. Bolt
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引用次数: 0
Innate immune regulation in inflammation resolution and liver regeneration in drug-induced liver injury. 药物性肝损伤中炎症消退和肝脏再生过程中的先天免疫调节。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-10-12 DOI: 10.1007/s00204-024-03886-0
Yihan Qian, Jie Zhao, Hailong Wu, Xiaoni Kong

Drug-induced liver injury (DILI) is an acute liver injury that poses a significant threat to human health. In severe cases, it can progress into chronic DILI or even lead to liver failure. DILI is typically caused by either intrinsic hepatotoxicity or idiosyncratic metabolic or immune responses. In addition to the direct damage drugs inflict on hepatocytes, the immune responses and liver inflammation triggered by hepatocyte death can further exacerbate DILI. Initially, we briefly discussed the differences in immune cell activation based on the type of liver cell death (hepatocytes, cholangiocytes, and LSECs). We then focused on the role of various immune cells (including macrophages, monocytes, neutrophils, dendritic cells, liver sinusoidal endothelial cells, eosinophils, natural killer cells, and natural killer T cells) in both the liver injury and liver regeneration stages of DILI. This article primarily reviews the role of innate immune regulation mediated by these immune cells in resolving inflammation and promoting liver regeneration during DILI, as well as therapeutic approaches targeting these immune cells for the treatment of DILI. Finally, we discussed the activation and function of liver progenitor cells (LPCs) during APAP-induced massive hepatic necrosis and the involvement of chronic inflammation in DILI.

药物性肝损伤(DILI)是一种急性肝损伤,对人类健康构成重大威胁。严重者可发展为慢性 DILI,甚至导致肝功能衰竭。DILI 通常是由内在肝毒性或特异性代谢或免疫反应引起的。除了药物对肝细胞造成的直接损伤外,肝细胞死亡引发的免疫反应和肝脏炎症也会进一步加剧 DILI。首先,我们简要讨论了肝细胞死亡类型(肝细胞、胆管细胞和LSECs)在免疫细胞激活方面的差异。然后,我们重点讨论了各种免疫细胞(包括巨噬细胞、单核细胞、中性粒细胞、树突状细胞、肝窦内皮细胞、嗜酸性粒细胞、自然杀伤细胞和自然杀伤 T 细胞)在 DILI 的肝损伤和肝再生阶段的作用。本文主要综述了这些免疫细胞介导的先天性免疫调节在 DILI 期间消除炎症和促进肝脏再生中的作用,以及针对这些免疫细胞治疗 DILI 的方法。最后,我们讨论了在 APAP 诱导的大量肝坏死过程中肝脏祖细胞(LPCs)的活化和功能,以及慢性炎症在 DILI 中的参与。
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引用次数: 0
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Archives of Toxicology
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