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Hypertension toxicity of VEGFR-TKIs in cancer treatment: incidence, mechanisms, and management strategies. 癌症治疗中 VEGFR-TKIs 的高血压毒性:发生率、机制和管理策略。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-30 DOI: 10.1007/s00204-024-03874-4
Yan-Xi Du, Xu Li, Si-Wen Ji, Na Niu

Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are a class of targeted anticancer agents that include pazopanib, sunitinib, axitinib, and others. Currently, VEGFR-TKIs are widely used in the clinical treatment of various tumors, which can prolong patients' survival and even cure tumors. However, the use of VEGFR-TKIs is frequently associated with the occurrence of cardiovascular adverse events, with hypertension being the most prevalent. Hypertension and its complications can significantly impact the prognosis of patients, potentially jeopardizing their lives and resulting in the reduction or even cessation of treatment in severe cases. This review addresses the incidence of hypertension due to VEGFR-TKIs, mechanisms of toxicity, management strategies, and future research directions. In addition, hypertension due to VEGFR-TKIs may be associated with salt sensitivity, and possible mechanisms of hypertensive side effects are vasodilator imbalance, decreased capillary density, renal injury, impaired endothelial function due to oxidative stress, decreased lymphatic vascular density, and "off-target effect". A comprehensive understanding of hypertension toxicity due to cancer treatment with VEGFR-TKIs, can enhance clinical practice, thereby improving the prognostic outcomes of VEGFR-TKIs in oncology patients.

血管内皮生长因子受体酪氨酸激酶抑制剂(VEGFR-TKIs)是一类靶向抗癌药,包括帕唑帕尼、舒尼替尼、阿西替尼等。目前,VEGFR-TKIs 已广泛应用于各种肿瘤的临床治疗,可延长患者生存期,甚至治愈肿瘤。然而,VEGFR-TKIs 的使用常常伴随着心血管不良事件的发生,其中以高血压最为常见。高血压及其并发症会严重影响患者的预后,可能危及患者的生命,严重者会导致减少甚至停止治疗。本综述探讨了 VEGFR-TKIs 引起的高血压发病率、毒性机制、管理策略和未来研究方向。此外,VEGFR-TKIs 引起的高血压可能与盐敏感性有关,高血压副作用的可能机制包括血管扩张失衡、毛细血管密度降低、肾损伤、氧化应激导致的内皮功能受损、淋巴管密度降低以及 "脱靶效应"。全面了解VEGFR-TKIs治疗癌症引起的高血压毒性,可以促进临床实践,从而改善肿瘤患者VEGFR-TKIs的预后。
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引用次数: 0
Development of two ultra-sensitive UHPLC–QqQ-MS/MS methods for the simultaneous determination of hydroxyzine and its active metabolite (cetirizine) in human blood: applications to real cases of forensic toxicology 开发两种超灵敏 UHPLC-QqQ-MS/MS 方法,用于同时测定人体血液中的羟嗪及其活性代谢物(西替利嗪):在法医毒理学实际案例中的应用。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-28 DOI: 10.1007/s00204-024-03867-3
Agnieszka Chłopaś-Konowałek, Paweł Szpot, Marcin Zawadzki, Wirginia Kukula-Koch, Ewa Dudzińska

Both postmortem toxicological and medical-forensic examinations are very important in the case of analyzing various types of chemical substances. Hydroxyzine (HZ) is a first-generation antihistamine drug with a sedative effect that disrupts cognitive function and affects the ability to drive motor vehicles. Enzymatic oxidation of the hydroxy-methyl group to the carboxyl group leads to the formation of its main metabolite—cetirizine (CZ). CZ is the active substance of antiallergic drugs. Because it does not cross the BBB (blood–brain barrier) easily, it is less likely to cause drowsiness or affect memory and impair cognitive function. Therefore, in criminal studies, it is often important what medication had been taken by a person involved, e.g., in a car accident, HZ or CZ. The analysis of both antihistamine drugs is challenging, as usually very low concentrations of the compound of interest need to be determined. Thus, an ultra-sensitive UHPLC–QqQ-MS/MS method was developed for simultaneous determination of HZ and CZ in biological fluid samples. The lower limit of quantification (LOQ) for HZ and CZ was calculated as 0.345 and 0.3696 ng/mL, respectively. Together with a reduced sample volume to 200 μL, it makes the developed method suitable for a sensitive multidrug forensic toxicological analysis. Samples were extracted with simple and fast liquid–liquid extraction (ethyl acetate, pH 9). The present method for the determination of HZ and CZ in human blood proved to be simple, fast, selective, and sensitive. The quantification by LC–MS/MS was successfully applied to the samples coming from 28 authentic biological fluids (blood, urine, vitreous humor, bile and stomach content), both antemortem and postmortem. The performed studies confirm that the developed method is characterized by a high extraction efficiency. Its accuracy, reproducibility, simplicity, and selectivity suggest its application in clinical, toxicological, and forensic laboratories.

在分析各类化学物质时,尸体毒理学检查和医学法医学检查都非常重要。羟嗪(HZ)是第一代抗组胺药物,具有镇静作用,会扰乱认知功能,影响驾驶机动车辆的能力。羟甲基被酶促氧化为羧基后,会形成其主要代谢产物--西替利嗪(CZ)。CZ 是抗过敏药物的活性物质。由于它不容易通过 BBB(血脑屏障),因此不容易引起嗜睡或影响记忆和损害认知功能。因此,在刑事研究中,涉案人员服用了什么药物往往很重要,例如在车祸中服用的是 HZ 还是 CZ。这两种抗组胺药物的分析都具有挑战性,因为通常需要测定极低浓度的相关化合物。因此,我们开发了一种超灵敏的 UHPLC-QqQ-MS/MS 方法,用于同时测定生物液体样品中的 HZ 和 CZ。经计算,HZ 和 CZ 的定量下限(LOQ)分别为 0.345 和 0.3696 ng/mL。该方法样品量减少至 200 μL,适用于灵敏的多种药物法医毒理学分析。样品采用简单快速的液液萃取(乙酸乙酯,pH 9)。本方法简便、快速、选择性强、灵敏度高,可用于人体血液中 HZ 和 CZ 的检测。LC-MS/MS 方法成功地应用于 28 种真实生物液体(血液、尿液、玻璃体、胆汁和胃内容物)样品的生前和死后定量分析。研究证实,所开发的方法具有提取效率高的特点。该方法的准确性、可重复性、简便性和选择性表明它可应用于临床、毒理学和法医实验室。
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引用次数: 0
Multi-step gene set analysis identified HTR3 family genes involving childhood acute lymphoblastic leukemia susceptibility. 多步骤基因组分析确定了涉及儿童急性淋巴细胞白血病易感性的 HTR3 家族基因。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-25 DOI: 10.1007/s00204-024-03881-5
Xiao Liu, Honghao Guo, Meiyun Kang, Wenfeng Fu, Huiqin Li, Hongsheng Ji, Jiou Zhao, Yongjun Fang, Mulong Du, Yao Xue

In our previous conventional genome-wide association study (GWAS), WWOX was a susceptibility gene associated with acute lymphoblastic leukemia (ALL) development. Nowadays, advancements in genetic association analyses promote an in-depth exploration of ALL genomics. We conducted a two-step enrichment analysis at both gene and pathway levels based on ALL GWAS data including 269 cases and 1039 controls of Chinese descent. The following functional prediction and experiments were used to evaluate the genetic biology of candidate variants and genes. The serotonin-activated cation-selective channel complex gene-set was a potential biological pathway involved in ALL occurrence. Of which, individuals carrying the T allele of rs33940208 exhibited a prominent reduced risk of ALL [odds ratio (OR) = 0.71, 95% confidence interval (CI) = 0.53 to 0.96, P = 2.81 × 10-2], whereas those with the A allele of rs6779545 demonstrated an increased risk (OR = 1.23, 95% CI = 1.01 to 1.51, P = 4.11 × 10-2). Notably, the two variants displayed a better prediction capability when combined, that the risk of developing childhood ALL increased by 131% in subjects with 2-4 risk alleles compared to those with 0-1 risk alleles (Ptrend = 2.05 × 10-3). In addition, the T allele of rs33940208 could reduce HTR3A mRNA level, while the A allele of rs6779545 increased HTR3D mRNA expression. In this study, we identified HTR3A rs33940208 and HTR3D rs6779545 as potential susceptibility loci for ALL in Chinese children. Future validation and functional research will elucidate the underlying molecular processes, refining preventive strategies for this disease.

在我们之前的传统全基因组关联研究(GWAS)中,WWOX 是与急性淋巴细胞白血病(ALL)发病相关的易感基因。如今,遗传关联分析的进步促进了对 ALL 基因组学的深入探索。我们基于包括 269 例病例和 1039 例华裔对照在内的 ALL GWAS 数据,从基因和通路两个层面进行了两步富集分析。我们采用了以下功能预测和实验来评估候选变体和基因的遗传生物学特性。5-羟色胺激活阳离子选择性通道复合物基因组是参与ALL发生的潜在生物学通路。其中,携带rs33940208的T等位基因的个体患ALL的风险显著降低[几率比(OR)=0.71,95%置信区间(CI)=0.53至0.96,P=2.81×10-2],而携带rs6779545的A等位基因的个体患ALL的风险增加(OR=1.23,95%CI=1.01至1.51,P=4.11×10-2)。值得注意的是,当这两个变异结合在一起时,其预测能力更强,与具有 0-1 个风险等位基因的受试者相比,具有 2-4 个风险等位基因的受试者罹患儿童 ALL 的风险增加了 131%(Ptrend = 2.05 × 10-3)。此外,rs33940208的T等位基因可降低HTR3A mRNA水平,而rs6779545的A等位基因可增加HTR3D mRNA表达。本研究发现,HTR3A rs33940208和HTR3D rs6779545是中国儿童ALL的潜在易感位点。未来的验证和功能研究将阐明其潜在的分子过程,从而完善该疾病的预防策略。
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引用次数: 0
In vitro assessment of emerging mycotoxins co-occurring in cheese: a potential health hazard 奶酪中新出现的霉菌毒素的体外评估:对健康的潜在危害。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-25 DOI: 10.1007/s00204-024-03872-6
Nadia Pérez-Fuentes, Rebeca Alvariño, Amparo Alfonso, Jesús González-Jartín, Mercedes R. Vieytes, Luis M. Botana

Some Penicillium strains used in cheese ripening produce emerging mycotoxins, notably roquefortine C (ROQC) and cyclopiazonic acid (CPA), as well as enniatins (ENNs) and beauvericin (BEA). Co-occurrence of these mycotoxins in natural samples has been reported worldwide, however, most studies focus on the toxicity of a single mycotoxin. In the present study, the effects of ROQC and CPA alone and in combination with BEA and ENNs A, A1, B, and B1 were analysed in human neuroblastoma cells. ROQC and CPA reduced cell viability, with IC50 values of 49.5 and 7.3 µM, respectively, and induced caspase-8-mediated apoptosis. When ROQC and CPA were binary combined with ENNs, an enhancement of their individual effects was observed. Furthermore, a clear synergism was produced when ROQC and CPA were mixed with the four ENNs. An additive effect was also described for the combination of CPA + ENNs (A, A1, B, B1) + BEA. Finally, the effects of commercial cheese extracts containing the mentioned mycotoxins were evaluated, finding a strong reduction in cell viability. These results suggest that the co-occurrence of emerging mycotoxins in natural matrices could pose a potential health risk.

奶酪成熟过程中使用的一些青霉菌株会产生新的霉菌毒素,特别是洛古福丁 C (ROQC) 和环茴香酸 (CPA),以及烯萘菌素 (ENNs) 和贝维菌素 (BEA)。世界各地都有关于这些霉菌毒素同时出现在天然样本中的报道,但大多数研究都集中在单一霉菌毒素的毒性上。本研究分析了 ROQC 和 CPA 单独使用或与 BEA 和 ENNs A、A1、B 和 B1 合用对人类神经母细胞瘤细胞的影响。ROQC 和 CPA 能降低细胞活力,IC50 值分别为 49.5 µM 和 7.3 µM,并能诱导 caspase-8 介导的细胞凋亡。当 ROQC 和 CPA 与 ENNs 进行二元组合时,可以观察到它们各自的作用得到了增强。此外,当 ROQC 和 CPA 与四种 ENNs 混合使用时,会产生明显的协同作用。CPA + ENNs(A、A1、B、B1)+ BEA 的组合也产生了叠加效应。最后,还对含有上述霉菌毒素的商业奶酪提取物的效果进行了评估,结果发现细胞活力大大降低。这些结果表明,天然基质中新出现的霉菌毒素可能会对健康造成潜在威胁。
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引用次数: 0
An integrated multi-omics analysis of the effects of the food processing-induced contaminant 2-monochloropropane-1,3-diol (2-MCPD) in rat heart 食品加工过程中产生的污染物 2-单氯丙烷-1,3-二醇(2-MCPD)对大鼠心脏影响的多组学综合分析。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-24 DOI: 10.1007/s00204-024-03856-6
Lucien G. J. Cayer, Thorsten Buhrke, Jennifer Roberts, Andrée Nunnikhoven, Katharina Sommerkorn, Anna Reinhold, Albert Braeuning, Jayadev Raju, Harold M. Aukema, Tobias Karakach

Many foods including edible oils contain 2-monochloropropane-1,3-diol (2-MCPD), a processing-induced chemical contaminant. Cardiotoxic effects have been shown to result from oral 2-MCPD exposure in rodents, but the underlying mechanisms of action remain poorly understood. We undertook a comprehensive multi-omics approach to assess changes at the transcriptomic, proteomic, and oxylipin levels in heart tissues from male F344 rats that were exposed to 0 or 40 mg/kg BW/day of 2-MCPD in the diet for 90 days, in a regulatory compliant rodent bioassay. Heart tissues were collected for RNA sequencing, quantitative PCR analysis, proteomic analysis via two-dimensional gel electrophoresis and mass spectrometry, and targeted lipidomic profiling by high-performance liquid chromatography–tandem mass spectrometry (HPLC–MS/MS). Transcriptomic and proteomic data analyses revealed upregulation of immune/inflammatory response processes and downregulation of energy metabolism and cardiac structure and functions. Among differentially expressed gene–protein pairs, coronin-1A, a key leukocyte-regulating protein, emerged as markedly up-regulated. Oxylipin profiling highlighted a selective suppression of docosahexaenoic acid-derived metabolites, suggesting a disruption in cardioprotective lipid pathways. These findings suggest that 2-MCPD disrupts homeostasis through inflammatory activation and suppression of metabolic and cardiac function. This research provides insights into 2-MCPD's cardiotoxicity, emphasizing the need for further studies to support hazard characterization.

包括食用油在内的许多食品都含有 2-氯丙二醇(2-MCPD),这是一种由加工过程引起的化学污染物。啮齿类动物经口摄入 2-MCPD 已被证明会产生心脏毒性效应,但人们对其潜在的作用机制仍知之甚少。在一项符合法规要求的啮齿动物生物测定中,雄性 F344 大鼠每天从食物中摄入 0 或 40 毫克/千克体重的氯丙二醇,持续 90 天,我们采用了一种全面的多组学方法来评估其心脏组织在转录组、蛋白质组和氧脂水平上的变化。收集的心脏组织用于核糖核酸(RNA)测序、定量 PCR 分析、通过二维凝胶电泳和质谱进行蛋白质组分析,以及通过高效液相色谱-串联质谱(HPLC-MS/MS)进行有针对性的脂质组分析。转录组和蛋白质组数据分析显示,免疫/炎症反应过程上调,能量代谢和心脏结构与功能下调。在差异表达的基因-蛋白质对中,coronin-1A(一种关键的白细胞调节蛋白)明显上调。氧脂分析显示,二十二碳六烯酸衍生代谢物受到了选择性抑制,这表明心脏保护脂质途径受到了干扰。这些研究结果表明,2-氯丙二醇会通过炎症激活和抑制代谢及心脏功能来破坏体内平衡。这项研究深入揭示了 2-MCPD 的心脏毒性,强调有必要开展进一步研究,以支持危害特征描述。
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引用次数: 0
Revisiting cadmium-induced toxicity in the male reproductive system: an update 重新审视镉对男性生殖系统的毒性:最新进展。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-24 DOI: 10.1007/s00204-024-03871-7
Jitender Kumar Bhardwaj, Anshu Siwach, Drishty Sachdeva, Som Nath Sachdeva

Heavy metals like cadmium (Cd) are one of the main environmental pollutants, with no biological role in the human body. Cd has been well-documented to have disastrous effects on both plants and animals. It is known to accumulate in kidneys, lungs, liver, and testes and is thought to affect these organs' function over time, which is linked to a very long biological half-life and a very poor rate of elimination. According to recent researches, the testes are extremely vulnerable to cadmium. The disruption of the blood–testis barrier, seminiferous tubules, Sertoli cells, and Leydig cells caused by cadmium leads to the loss of sperm through various mechanisms, such as oxidative stress, spermatogenic cell death, testicular swelling, dysfunction in androgen-producing cells, interference with gene regulation, disruption of ionic homeostasis, and damage to the vascular endothelium. Additionally, through epigenetic control, cadmium disrupts the function of germ cells and somatic cells, resulting in infertile or subfertile males. A full grasp of the mechanisms underlying testicular toxicity caused by Cd is very important to develop suitable strategies to ameliorate male fertility. Therefore, this review article outlines cadmium’s impact on growth and functions of the testicles, reviews therapeutic approaches and protective mechanisms, considers recent research findings, and identifies future research directions.

镉(Cd)等重金属是主要的环境污染物之一,对人体没有任何生物作用。镉对植物和动物的灾难性影响已有大量记载。众所周知,镉会在肾脏、肺部、肝脏和睾丸中蓄积,并随着时间的推移影响这些器官的功能,这与镉的生物半衰期很长、消除率很低有关。根据最新研究,睾丸极易受到镉的影响。镉对血睾屏障、曲细精管、Sertoli 细胞和 Leydig 细胞造成的破坏,会通过多种机制导致精子损失,如氧化应激、生精细胞死亡、睾丸肿胀、雄激素生成细胞功能障碍、基因调控干扰、离子平衡破坏和血管内皮损伤等。此外,镉还会通过表观遗传学控制,破坏生殖细胞和体细胞的功能,导致男性不育或弱精症。全面掌握镉导致睾丸毒性的机制,对于制定改善男性生育能力的适当策略非常重要。因此,这篇综述文章概述了镉对睾丸生长和功能的影响,回顾了治疗方法和保护机制,探讨了最新的研究成果,并确定了未来的研究方向。
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引用次数: 0
Neutralizing chimeric heavy-chain antibody targeting the L-HN domain of Clostridium botulinum neurotoxin type F 针对 F 型肉毒杆菌神经毒素 L-HN 结构域的中和嵌合重链抗体。
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-23 DOI: 10.1007/s00204-024-03869-1
Kaiyue Sun, Shudi Luo, Yujia Jiang, Jiazheng Guo, Xi Wang, Kexuan Cheng, Changyan Xu, Yixiao Zhang, Chen Gao, Jiansheng Lu, Peng Du, Yunzhou Yu, Rong Wang, Zhixin Yang, Chunyang Zhou

Botulinum toxin (BoNT) from Clostridium botulinum is the most toxic biotoxin known and is also an important bioterrorism agent. After poisoning, the only effective treatment is injection of antitoxin. However, neutralizing nanoantibodies are safer and more effective, representing a promising therapeutic approach. Therefore, it is important to obtain effective neutralizing nanoantibodies. Hence, the present study aimed to construct a phage antibody library by immunizing a camel and screening specific clones that bind to the L-HN domain of BoNT/F and constructing chimeric heavy-chain antibodies by fusing them with a human Fc fragment. The antibodies’ affinity and in vivo neutralizing activities were evaluated. The results showed that 2 µg of F20 antibody could completely neutralize 20 × the median lethal dose (LD50) of BoNT/F in vitro. Injection of 5 mg/kg F20 at 1 h, 2 h, 3 h, and 4 h into mice after BoNT/F challenge resulted in complete survival in vivo. Overall, the antibody might be a candidate for the development of new drugs to treat botulism.

来自肉毒梭状芽孢杆菌的肉毒毒素(BoNT)是已知毒性最强的生物毒素,也是一种重要的生物恐怖剂。中毒后,唯一有效的治疗方法是注射抗毒素。然而,中和纳米抗体更安全、更有效,是一种很有前景的治疗方法。因此,获得有效的中和纳米抗体非常重要。因此,本研究旨在通过对骆驼进行免疫来构建噬菌体抗体库,筛选出与 BoNT/F 的 L-HN 结构域结合的特异克隆,并通过将其与人类 Fc 片段融合来构建嵌合重链抗体。对抗体的亲和力和体内中和活性进行了评估。结果表明,2 µg 的 F20 抗体可在体外完全中和 20 倍中位致死剂量(LD50)的 BoNT/F。在小鼠接受 BoNT/F 挑战后的 1 小时、2 小时、3 小时和 4 小时内注射 5 毫克/千克 F20,可使小鼠在体内完全存活。总之,该抗体可能是开发治疗肉毒中毒新药的候选药物。
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引用次数: 0
Research advances on CaMKs-mediated neurodevelopmental injury 有关 CaMKs 介导的神经发育损伤的研究进展
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-18 DOI: 10.1007/s00204-024-03865-5
Lingxu Kong, Jing Yang, Huajie Yang, Bin Xu, Tianyao Yang, Wei Liu

Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca2+/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury.

钙/钙调蛋白依赖性蛋白激酶(CaMKs)是钙信号级联反应途径中的重要蛋白,可广泛调控体内生物功能。多功能 CaMKs 在神经发育过程中发挥着关键作用,包括神经元回路构建、突触可塑性建立和神经营养因子分泌。目前,人们认为在神经发育过程中对钙/钙调蛋白依赖性蛋白激酶 I(CaMKI)、钙/钙调蛋白依赖性蛋白激酶 II(CaMKII)、真核延伸因子 2 激酶(eEF2K,俗称 CaMKIII)和钙/钙调蛋白依赖性蛋白激酶 IV(CaMKIV)这四种家族蛋白的研究最为广泛。虽然它们的空间结构以及激活的初始起点极为相似,但都需要钙和钙调素(CaM)复合物的激活才能参与这一过程,而且每个成员的磷酸化位点和模式也不尽相同。此外,由于 CaMK 的结构高度相似,其成员可能在神经发育调控中发挥协同作用,但不同的 CaMK 也有各自的神经发育调控手段。在这篇综述中,我们首先描述了 CaMKI、CaMKII、eEF2K 和 CaMKIV 的可视化蛋白结构形式,然后描述了每种激酶在神经发育中的功能。之后,我们将重点介绍 CaMKs 造成神经发育损伤的四种主要机制:CaMKI/ERK/CREB通路抑制导致树突棘结构损伤;Ca2+/CaM/CaMKII通过诱导线粒体动力学紊乱导致神经发育损伤;CaMKIII/eEF2过度磷酸化影响突触可塑性的建立;CaMKIV/JNK/NF-κB通过诱导炎症反应导致神经发育损伤。最后,我们简要讨论了神经发育障碍中 CaMK 家族表达异常的病理生理学意义,以及传统 CaMKII 和 CaMKIII 拮抗剂对神经发育损伤的保护作用。
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引用次数: 0
FGTN: Fragment-based graph transformer network for predicting reproductive toxicity FGTN:用于预测生殖毒性的片段图转换器网络
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-18 DOI: 10.1007/s00204-024-03866-4
Jia-Nan Ren, Qiang Chen, Hong-Yu-Xiang Ye, Cheng Cao, Ya-Min Guo, Jin-Rong Yang, Hao Wang, Muhammad Zafar Irshad Khan, Jian-Zhong Chen

Reproductive toxicity is one of the important issues in chemical safety. Traditional laboratory testing methods are costly and time-consuming with raised ethical issues. Only a few in silico models have been reported to predict human reproductive toxicity, but none of them make full use of the topological information of compounds. In addition, most existing atom-based graph neural network methods focus on attributing model predictions to individual nodes or edges rather than chemically meaningful fragments or substructures. In current studies, we develop a novel fragment-based graph transformer network (FGTN) approach to generate the QSAR model of human reproductive toxicity by considering internal topological structure information of compounds. In the FGTN model, the compound is represented by a graph architecture using fragments to be nodes and bonds linking two fragments to be edges. A super molecule-level node is further proposed to connect all fragment nodes by undirected edges, obtaining global molecular features from fragment embeddings. The FGTN model achieved an accuracy (ACC) of 0.861 and an area under the receiver operating characteristic curve (AUC) value of 0.914 on nonredundant blind tests, outperforming traditional fingerprint-based machine learning models and atom-based GCN model. The FGTN model can attribute toxic predictions to fragments, generating specific structural alerts for the positive compound. Moreover, FGTN may also have the capability to distinguish various chemical isomers. We believe that FGTN can be used as a reliable and effective tool for human reproductive toxicity prediction in contribution to the advancement of chemical safety assessment.

生殖毒性是化学品安全的重要问题之一。传统的实验室测试方法成本高、耗时长,且存在伦理问题。据报道,目前只有少数硅学模型可以预测人类生殖毒性,但这些模型都没有充分利用化合物的拓扑信息。此外,大多数现有的基于原子的图神经网络方法侧重于将模型预测归因于单个节点或边,而不是具有化学意义的片段或子结构。在目前的研究中,我们开发了一种新颖的基于片段的图转换器网络(FGTN)方法,通过考虑化合物的内部拓扑结构信息来生成人类生殖毒性的 QSAR 模型。在 FGTN 模型中,化合物由图结构表示,以片段为节点,连接两个片段的键为边。此外,还提出了一个超级分子级节点,通过无向边连接所有片段节点,从而从片段嵌入中获取全局分子特征。在非冗余盲测中,FGTN 模型的准确度(ACC)达到了 0.861,接收者工作特征曲线下面积(AUC)达到了 0.914,优于传统的基于指纹的机器学习模型和基于原子的 GCN 模型。FGTN 模型可将毒性预测归因于片段,为阳性化合物生成特定的结构警报。此外,FGTN 还具有区分各种化学异构体的能力。我们相信,FGTN 可以作为一种可靠而有效的工具,用于人类生殖毒性预测,为推进化学品安全评估做出贡献。
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引用次数: 0
Interactions between polycyclic aromatic hydrocarbons and genetic variants in the cGAS–STING pathway affect the risk of colorectal cancer 多环芳烃与 cGAS-STING 通路中的遗传变异之间的相互作用会影响罹患结直肠癌的风险
IF 4.8 2区 医学 Q1 TOXICOLOGY Pub Date : 2024-09-17 DOI: 10.1007/s00204-024-03862-8
Jieyu Zhou, Dongzheng Li, Menghuan Xu, Tianru Zhu, Zhengyi Li, Zan Fu, Meilin Wang, Shuwei Li, Dongying Gu

The cGAS–STING pathway plays an essential role in the activation of tumor immune cells. Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants with potential carcinogenicity, and their exposure is associated with the development of colorectal cancer. However, the impacts of genetic factors in the cGAS‒STING pathway and gene‒environment interactions on colorectal cancer remain understudied. We used logistic regression models and interaction analysis to evaluate the impact of genetic variants on colorectal cancer risk and gene‒environment interactions. We analysed the expression patterns of candidate genes based on the RNA-seq data. Molecular biology experiments were performed to investigate the impact of PAHs exposure on candidate gene expression and the progression of colorectal cancer. We identified the susceptibility locus rs3750511 in the cGAS‒STING pathway, which is associated with colorectal cancer risk. A negative interaction between TRAF2 rs3750511 and PAHs exposure was also identified. Single-cell RNA-seq analysis revealed significantly elevated expression of TRAF2 in colorectal cancer tissues compared with normal tissues, especially in T cells. BPDE exposure increased TRAF2 expression and the malignant phenotype of colorectal cancer cells. The treatment also further increased the expression of the TRAF2 downstream gene NF-κB and decreased the expression of Caspase8. Our results suggest that the genetic variant of rs3750511 affects the expression of TRAF2, thereby increasing the risk of colorectal cancer through interaction with PAHs. Our study provides new insights into the influence of gene‒environment interactions on the risk of developing colorectal cancer.

cGAS-STING 通路在激活肿瘤免疫细胞方面起着至关重要的作用。多环芳烃(PAHs)是具有潜在致癌性的环境污染物,暴露于这种物质与结直肠癌的发生有关。然而,cGAS-STING 通路中的遗传因素以及基因与环境的相互作用对结直肠癌的影响仍未得到充分研究。我们使用逻辑回归模型和交互分析来评估遗传变异对结直肠癌风险和基因-环境交互作用的影响。我们根据 RNA-seq 数据分析了候选基因的表达模式。我们进行了分子生物学实验,研究多环芳烃暴露对候选基因表达和结直肠癌进展的影响。我们在 cGAS-STING 通路中发现了与结直肠癌风险相关的易感位点 rs3750511。我们还发现 TRAF2 rs3750511 与多环芳烃暴露之间存在负交互作用。单细胞RNA-seq分析显示,与正常组织相比,TRAF2在结直肠癌组织中的表达明显升高,尤其是在T细胞中。暴露于 BPDE 会增加 TRAF2 的表达和结直肠癌细胞的恶性表型。处理还进一步增加了 TRAF2 下游基因 NF-κB 的表达,降低了 Caspase8 的表达。我们的研究结果表明,rs3750511 基因变异会影响 TRAF2 的表达,从而通过与多环芳烃的相互作用增加罹患结直肠癌的风险。我们的研究为基因-环境相互作用对结直肠癌发病风险的影响提供了新的见解。
{"title":"Interactions between polycyclic aromatic hydrocarbons and genetic variants in the cGAS–STING pathway affect the risk of colorectal cancer","authors":"Jieyu Zhou,&nbsp;Dongzheng Li,&nbsp;Menghuan Xu,&nbsp;Tianru Zhu,&nbsp;Zhengyi Li,&nbsp;Zan Fu,&nbsp;Meilin Wang,&nbsp;Shuwei Li,&nbsp;Dongying Gu","doi":"10.1007/s00204-024-03862-8","DOIUrl":"10.1007/s00204-024-03862-8","url":null,"abstract":"<div><p>The cGAS–STING pathway plays an essential role in the activation of tumor immune cells. Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants with potential carcinogenicity, and their exposure is associated with the development of colorectal cancer. However, the impacts of genetic factors in the cGAS‒STING pathway and gene‒environment interactions on colorectal cancer remain understudied. We used logistic regression models and interaction analysis to evaluate the impact of genetic variants on colorectal cancer risk and gene‒environment interactions. We analysed the expression patterns of candidate genes based on the RNA-seq data. Molecular biology experiments were performed to investigate the impact of PAHs exposure on candidate gene expression and the progression of colorectal cancer. We identified the susceptibility locus rs3750511 in the cGAS‒STING pathway, which is associated with colorectal cancer risk. A negative interaction between <i>TRAF2</i> rs3750511 and PAHs exposure was also identified. Single-cell RNA-seq analysis revealed significantly elevated expression of <i>TRAF2</i> in colorectal cancer tissues compared with normal tissues, especially in T cells. BPDE exposure increased <i>TRAF2</i> expression and the malignant phenotype of colorectal cancer cells. The treatment also further increased the expression of the <i>TRAF2</i> downstream gene <i>NF-κB</i> and decreased the expression of <i>Caspase8</i>. Our results suggest that the genetic variant of rs3750511 affects the expression of <i>TRAF2</i>, thereby increasing the risk of colorectal cancer through interaction with PAHs. Our study provides new insights into the influence of gene‒environment interactions on the risk of developing colorectal cancer.</p></div>","PeriodicalId":8329,"journal":{"name":"Archives of Toxicology","volume":"98 12","pages":"4117 - 4129"},"PeriodicalIF":4.8,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142265429","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}
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Archives of Toxicology
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