首页 > 最新文献

bioRxiv - Pharmacology and Toxicology最新文献

英文 中文
Enabling Transparent Toxicokinetic Modeling for Public Health Risk Assessment 为公共健康风险评估建立透明的毒物动力学模型
Pub Date : 2024-08-21 DOI: 10.1101/2024.08.19.608571
Sarah E. Davidson-Fritz, Caroline L. Ring, Celia M. Schacht, Marina V. Evans, Xiaoqing Chang, Miyuki Breen, Gregory S. Honda, Elaina Kenyon, Matthew W. Linakis, Annabel Meade, Robert G. Pearce, Mark A. Sfeir, James P. Sluka, Michael J. Devito, John F. Wambaugh
Toxicokinetics describes the absorption, distribution, metabolism, and elimination of chemicals by the body. Predictions from toxicokinetic models provide key information for chemical risk assessment. Traditionally, these predictions extrapolate from experimental animal species data (for example, in rats) to humans. More recently, toxicokinetics has been used for extrapolation from in vitro new approach methods (NAMs) for toxicology to in vivo. Chemical-specific in vivo toxicokinetic data are often unavailable for the thousands of chemicals in commerce. Therefore, large amounts of in vitro data measuring chemical-specific toxicokinetics have been collected. These data enable high-throughput toxicokinetic or HTTK modeling. The httk R package provides a library of chemical-specific data from peer-reviewed HTTK studies. httk further provides a suite of tools for parameterizing and evaluating toxicokinetic models. httk uses the open-source language MCSim to describe models for compartmental and physiologically based toxicokinetics (PBTK), MCSim can convert the model descriptions into a high-speed C code script. New models are integrated into httk using the open-source package development functionality in R, a model documentation file (R script), and the HTTK model description code file (C script). In addition to HTTK models, httk provides a series of functionalities such as unit conversion, model parameterization, Monte Carlo simulations for uncertainty propagation and biological variability, in vivo-derived data for evaluating model predictions, and other model utility functions. Here, we describe in detail how to add new HTTK models to httk and take advantage of the pre-existing data and functionality in the package. As a demonstration, we describe the integration of the gas inhalation PBTK model into httk. Modern modeling approaches, as exemplified by httk, allow for clear communication, reproducibility, and public scrutiny. The intention of httk is to provide a transparent, open-source tool for toxicokinetics, bioinformatics, and public health risk assessment.
毒物动力学描述了人体对化学品的吸收、分布、代谢和排出。毒物动力学模型的预测为化学品风险评估提供了关键信息。传统上,这些预测是从实验动物物种(如大鼠)的数据推断到人类。最近,毒物动力学已被用于从体外毒理学新方法(NAMs)外推至体内。对于成千上万的商业化学品来说,通常无法获得特定化学品的体内毒代动力学数据。因此,我们收集了大量测量特定化学品毒代动力学的体外数据。通过这些数据可以建立高通量毒代动力学或 HTTK 模型。httk 使用开源语言 MCSim 来描述分区和基于生理的毒物动力学(PBTK)模型,MCSim 可以将模型描述转换为高速 C 代码脚本。新模型可通过 R 的开源软件包开发功能、模型文档文件(R 脚本)和 HTTK 模型描述代码文件(C 脚本)集成到 httk 中。除了 HTTK 模型外,httk 还提供了一系列功能,如单位转换、模型参数化、用于不确定性传播和生物变异性的蒙特卡罗模拟、用于评估模型预测的体内衍生数据以及其他模型实用功能。在此,我们将详细介绍如何将新的 HTTK 模型添加到 httk 中,并利用软件包中已有的数据和功能。作为演示,我们介绍了如何将气体吸入 PBTK 模型集成到 httk 中。以 httk 为代表的现代建模方法可以实现清晰的交流、可重现性和公众监督。httk 的目的是为毒物动力学、生物信息学和公共健康风险评估提供一个透明、开源的工具。
{"title":"Enabling Transparent Toxicokinetic Modeling for Public Health Risk Assessment","authors":"Sarah E. Davidson-Fritz, Caroline L. Ring, Celia M. Schacht, Marina V. Evans, Xiaoqing Chang, Miyuki Breen, Gregory S. Honda, Elaina Kenyon, Matthew W. Linakis, Annabel Meade, Robert G. Pearce, Mark A. Sfeir, James P. Sluka, Michael J. Devito, John F. Wambaugh","doi":"10.1101/2024.08.19.608571","DOIUrl":"https://doi.org/10.1101/2024.08.19.608571","url":null,"abstract":"Toxicokinetics describes the absorption, distribution, metabolism, and elimination of chemicals by the body. Predictions from toxicokinetic models provide key information for chemical risk assessment. Traditionally, these predictions extrapolate from experimental animal species data (for example, in rats) to humans. More recently, toxicokinetics has been used for extrapolation from in vitro new approach methods (NAMs) for toxicology to in vivo. Chemical-specific in vivo toxicokinetic data are often unavailable for the thousands of chemicals in commerce. Therefore, large amounts of in vitro data measuring chemical-specific toxicokinetics have been collected. These data enable high-throughput toxicokinetic or HTTK modeling. The httk R package provides a library of chemical-specific data from peer-reviewed HTTK studies. httk further provides a suite of tools for parameterizing and evaluating toxicokinetic models. httk uses the open-source language MCSim to describe models for compartmental and physiologically based toxicokinetics (PBTK), MCSim can convert the model descriptions into a high-speed C code script. New models are integrated into httk using the open-source package development functionality in R, a model documentation file (R script), and the HTTK model description code file (C script). In addition to HTTK models, httk provides a series of functionalities such as unit conversion, model parameterization, Monte Carlo simulations for uncertainty propagation and biological variability, in vivo-derived data for evaluating model predictions, and other model utility functions. Here, we describe in detail how to add new HTTK models to httk and take advantage of the pre-existing data and functionality in the package. As a demonstration, we describe the integration of the gas inhalation PBTK model into httk. Modern modeling approaches, as exemplified by httk, allow for clear communication, reproducibility, and public scrutiny. The intention of httk is to provide a transparent, open-source tool for toxicokinetics, bioinformatics, and public health risk assessment.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"32 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Identification of Antiviral Drug Candidates Against Monkeypox DNA Polymerase and Profilin-like Protein A42R Utilizing an In-Silico Approach 利用内模拟方法鉴定针对猴痘 DNA 聚合酶和类 Profilin 蛋白 A42R 的抗病毒候选药物
Pub Date : 2024-08-21 DOI: 10.1101/2024.08.15.608157
Muhammad Amjid, Muhammad Maroof Khan, Stephen F Pastore, John B Vincent, Tahir Muhammad
Monkeypox virus (MPXV) is emerging as a major concern in the field of infectious diseases. Current treatments are limited, highlighting the need for new therapeutic options. The use of computational methods, such as molecular docking and molecular dynamic (MD) simulations, is a valuable approach in identifying potential compounds that can target specific proteins of the virus, like the DNA polymerase and profilin-like protein A42R in this case, with the aim of controlling the disease. Our study focused on screening various libraries of compounds for predicted binding to MPXV DPol and A42R proteins, with the top-performing molecules identified based on their docking scores. Among these, Dorsilurin K and Mangostin in complex with DPol , whereas [2-oxo-2-[3-(3,4,5,6-tetrahydro-2H-azepin-7-ylsulfamoyl)anilino]ethyl] 3,5-dimethylbenzoate and N-[4-[2-[4-(4-methylphenyl)sulfonylpiperazin-1-yl]-2-oxoethoxy]phenyl]furan-2-carboxamide in complex with A42R stand out with notably high docking scores, suggesting they may have a good affinity for binding to the DPol and A42R proteins of MPXV respectively. MD simulations confirmed the stability of these ligand-protein complexes followed by evaluation of the ADMET and oral bioavailability analysis. However, it is important that computational methods can suggest promising candidates, in vitro and eventually in vivo studies are essential to validate these therapeutic candidates. Further studies on these compounds will provide insights into their efficacy, safety, and potential side effects. In conclusion, this study offers promising avenues for developing potential treatments for Monkeypox. If the identified compounds prove effective in further studies, it could be a significant breakthrough in managing this zoonotic disease.
猴痘病毒(MPXV)正在成为传染病领域的一个主要问题。目前的治疗方法有限,因此需要新的治疗方案。使用计算方法,如分子对接和分子动力学(MD)模拟,是确定潜在化合物的重要方法,这些化合物可以靶向病毒的特定蛋白,如 DNA 聚合酶和 profilin-like 蛋白 A42R,从而达到控制疾病的目的。我们的研究重点是筛选预测与 MPXV DPol 和 A42R 蛋白结合的各种化合物库,并根据对接得分确定表现最佳的分子。其中,Dorsilurin K 和 Mangostin 与 DPol 复合物,而 [2-oxo-2-[3-(3,4,5,6-tetrahydro-2H-azepin-7-ylsulfamoyl)anilino]ethyl] 3、5-二甲基苯甲酸酯和 N-[4-[2-[4-(4-甲基苯基)磺酰基哌嗪-1-基]-2-氧代乙氧基]苯基]呋喃-2-甲酰胺与 A42R 复合物的对接得分明显较高,这表明它们可能分别与 MPXV 的 DPol 蛋白和 A42R 蛋白具有良好的亲和力。MD 模拟证实了这些配体-蛋白质复合物的稳定性,随后进行了 ADMET 评估和口服生物利用度分析。不过,重要的是,计算方法可以提出有希望的候选化合物,体外研究和最终的体内研究对于验证这些候选治疗药物至关重要。对这些化合物的进一步研究将有助于深入了解它们的疗效、安全性和潜在副作用。总之,这项研究为开发猴痘的潜在治疗方法提供了前景广阔的途径。如果已确定的化合物在进一步的研究中被证明有效,这将是治疗这种人畜共患病的重大突破。
{"title":"Identification of Antiviral Drug Candidates Against Monkeypox DNA Polymerase and Profilin-like Protein A42R Utilizing an In-Silico Approach","authors":"Muhammad Amjid, Muhammad Maroof Khan, Stephen F Pastore, John B Vincent, Tahir Muhammad","doi":"10.1101/2024.08.15.608157","DOIUrl":"https://doi.org/10.1101/2024.08.15.608157","url":null,"abstract":"Monkeypox virus (MPXV) is emerging as a major concern in the field of infectious diseases. Current treatments are limited, highlighting the need for new therapeutic options. The use of computational methods, such as molecular docking and molecular dynamic (MD) simulations, is a valuable approach in identifying potential compounds that can target specific proteins of the virus, like the DNA polymerase and profilin-like protein A42R in this case, with the aim of controlling the disease. Our study focused on screening various libraries of compounds for predicted binding to MPXV DPol and A42R proteins, with the top-performing molecules identified based on their docking scores. Among these, Dorsilurin K and Mangostin in complex with DPol , whereas [2-oxo-2-[3-(3,4,5,6-tetrahydro-2H-azepin-7-ylsulfamoyl)anilino]ethyl] 3,5-dimethylbenzoate and N-[4-[2-[4-(4-methylphenyl)sulfonylpiperazin-1-yl]-2-oxoethoxy]phenyl]furan-2-carboxamide in complex with A42R stand out with notably high docking scores, suggesting they may have a good affinity for binding to the DPol and A42R proteins of MPXV respectively. MD simulations confirmed the stability of these ligand-protein complexes followed by evaluation of the ADMET and oral bioavailability analysis. However, it is important that computational methods can suggest promising candidates, in vitro and eventually in vivo studies are essential to validate these therapeutic candidates. Further studies on these compounds will provide insights into their efficacy, safety, and potential side effects. In conclusion, this study offers promising avenues for developing potential treatments for Monkeypox. If the identified compounds prove effective in further studies, it could be a significant breakthrough in managing this zoonotic disease.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"66 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Impacts of Disinfection Methods in a Granular Activated Carbon (GAC) Treatment System on Disinfected Drinking Water Toxicity and Antibiotic Resistance Induction Potential 颗粒活性炭 (GAC) 处理系统中的消毒方法对消毒后饮用水毒性和抗生素耐药性诱导潜力的影响
Pub Date : 2024-08-21 DOI: 10.1101/2024.08.19.608195
Yinmei Feng, Stephanie Lau, William Mitch, Caroline Russell, Greg Pope, April Z Gu
Granular activated carbon (GAC) treatment followed by chlorination (GAC/Cl2) and chlorination followed by chloramination (Cl2/NH2Cl) are two methods utilized by drinking water treatment facilities to mitigate the formation of disinfection byproducts (DBPs) in treated water. However, the effectiveness of these methods in reducing the overall toxicity of drinking water, driven by DBPs, remains largely unknown. In this study, we evaluate the total toxicity of water samples from a pilot-scale GAC system with post-chlorination (GAC/Cl2), and occasionally pre-chlorination upstream of GAC (Cl2/GAC/Cl2), compared to water treated by chlorination followed by chloramination (Cl2/NH2Cl). The research was conducted at various bromide and iodide levels and across three GAC bed volumes. To assess DNA stress and oxidative stress in water extracts, we employed the yeast toxicogenomic assay and human cell RT-qPCR assay, along with the DBP analysis from in our previous study. Our results indicated that under environmental halogen conditions, GAC/Cl2 typically reduces both genotoxicity and oxidative stress in treated water more effectively than Cl2/NH2Cl and Cl2 treatment. However, Cl2/GAC/Cl2 does not consistently lower toxicity compared to GAC/Cl2. Notably, under high halogen conditions, Cl2/GAC/Cl2 fails to reduce genotoxicity and oxidative stress compared to samples without GAC treatment. Correlation analysis suggested that iodinated DBPs (I-DBPs) and nitrogenous DBPs (N-DBPs) were particularly associated with increased DNA stress and oxidative stress, indicating these classes of DBPs as significant contributors to the observed toxicity. While neither of these two categories of DBPs are regulated by the EPA, it appears that unregulated and unidentified DBPs significantly contribute to the genotoxicity and oxidative stress in drinking water. This research highlights the complex dynamics of water treatment processes and underscores the critical impact of unregulated DBPs on water toxicity.
颗粒活性炭 (GAC) 处理后加氯(GAC/Cl2)和加氯后加氯消毒(Cl2/NH2Cl)是饮用水处理设施用来减少处理过的水中形成消毒副产物 (DBP) 的两种方法。然而,这些方法在降低由 DBPs 导致的饮用水总体毒性方面的效果如何,在很大程度上仍是未知数。在本研究中,我们评估了来自中试规模 GAC 系统的水样的总毒性,该系统采用后氯化法(GAC/Cl2),偶尔也会在 GAC 上游进行预氯化(Cl2/GAC/Cl2),与采用氯化后再氯化法(Cl2/NH2Cl)处理的水样进行比较。这项研究是在不同的溴化物和碘化物水平以及三个 GAC 床体积下进行的。为了评估水提取物中的 DNA 压力和氧化压力,我们采用了酵母毒基因组分析法和人类细胞 RT-qPCR 分析法,以及之前研究中的 DBP 分析法。结果表明,在环境卤素条件下,GAC/Cl2 通常比 Cl2/NH2Cl 和 Cl2 处理能更有效地降低处理水的基因毒性和氧化应激。然而,与 GAC/Cl2 相比,Cl2/GAC/Cl2 并不能持续降低毒性。值得注意的是,在高卤素条件下,与未经 GAC 处理的样品相比,Cl2/GAC/Cl2 无法降低基因毒性和氧化应激。相关性分析表明,碘化 DBPs(I-DBPs)和氮化 DBPs(N-DBPs)与 DNA 压力和氧化压力的增加尤其相关,这表明这两类 DBPs 是造成所观察到的毒性的重要因素。虽然这两类 DBPs 都不受美国环保署的管制,但似乎未受管制和未确定的 DBPs 对饮用水中的遗传毒性和氧化应激起了重要作用。这项研究突出了水处理过程的复杂动态,并强调了未受管制的 DBPs 对水毒性的重要影响。
{"title":"Impacts of Disinfection Methods in a Granular Activated Carbon (GAC) Treatment System on Disinfected Drinking Water Toxicity and Antibiotic Resistance Induction Potential","authors":"Yinmei Feng, Stephanie Lau, William Mitch, Caroline Russell, Greg Pope, April Z Gu","doi":"10.1101/2024.08.19.608195","DOIUrl":"https://doi.org/10.1101/2024.08.19.608195","url":null,"abstract":"Granular activated carbon (GAC) treatment followed by chlorination (GAC/Cl2) and chlorination followed by chloramination (Cl2/NH2Cl) are two methods utilized by drinking water treatment facilities to mitigate the formation of disinfection byproducts (DBPs) in treated water. However, the effectiveness of these methods in reducing the overall toxicity of drinking water, driven by DBPs, remains largely unknown. In this study, we evaluate the total toxicity of water samples from a pilot-scale GAC system with post-chlorination (GAC/Cl2), and occasionally pre-chlorination upstream of GAC (Cl2/GAC/Cl2), compared to water treated by chlorination followed by chloramination (Cl2/NH2Cl). The research was conducted at various bromide and iodide levels and across three GAC bed volumes. To assess DNA stress and oxidative stress in water extracts, we employed the yeast toxicogenomic assay and human cell RT-qPCR assay, along with the DBP analysis from in our previous study. Our results indicated that under environmental halogen conditions, GAC/Cl2 typically reduces both genotoxicity and oxidative stress in treated water more effectively than Cl2/NH2Cl and Cl2 treatment. However, Cl2/GAC/Cl2 does not consistently lower toxicity compared to GAC/Cl2. Notably, under high halogen conditions, Cl2/GAC/Cl2 fails to reduce genotoxicity and oxidative stress compared to samples without GAC treatment. Correlation analysis suggested that iodinated DBPs (I-DBPs) and nitrogenous DBPs (N-DBPs) were particularly associated with increased DNA stress and oxidative stress, indicating these classes of DBPs as significant contributors to the observed toxicity. While neither of these two categories of DBPs are regulated by the EPA, it appears that unregulated and unidentified DBPs significantly contribute to the genotoxicity and oxidative stress in drinking water. This research highlights the complex dynamics of water treatment processes and underscores the critical impact of unregulated DBPs on water toxicity.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"454 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Optimising experimental designs for model selection of ion channel drug binding mechanisms 优化离子通道药物结合机制模型选择的实验设计
Pub Date : 2024-08-21 DOI: 10.1101/2024.08.20.608856
Frankie Patten-Elliott, Chon Lok R Lei, Simon P Preston, Richard D Wilkinson, Gary R Mirams
The rapid delayed rectifier current carried by the human Ether-à-go-go-Related Gene (hERG) channel is susceptible to drug-induced reduction which can lead to an increased risk of cardiac arrhythmia. Establishing the mechanism by which a specific drug compound binds to hERG can help to reduce uncertainty when quantifying pro-arrhythmic risk. In this study, we introduce a methodology for optimising experimental voltage protocols to produce data that enable different proposed models for the drug-binding mechanism to be distinguished. We demonstrate the performance of this methodology via a synthetic data study. If the underlying model of hERG current is known exactly, then the optimised protocols generated show noticeable improvements in our ability to select the true model when compared to a simple protocol used in previous studies. However, if the model is not known exactly, and we assume a discrepancy between the data-generating hERG model and the hERG model used in fitting the models, then the optimised protocols become less effective in determining the 'true' binding dynamics. While the introduced methodology shows promise, we must be careful to ensure that, if applied in a real data study, we have a well-calibrated model of hERG current gating.
人类ther-à-go-go-reelated基因(hERG)通道所携带的快速延迟整流电流容易受药物诱导而降低,从而导致心律失常的风险增加。确定特定药物化合物与 hERG 结合的机制有助于在量化促心律失常风险时减少不确定性。在本研究中,我们介绍了一种优化实验电压协议的方法,以产生能区分药物结合机制的不同建议模型的数据。我们通过一项合成数据研究展示了该方法的性能。如果 hERG 电流的基本模式是已知的,那么生成的优化方案与之前研究中使用的简单方案相比,在我们选择真实模式的能力方面就会有明显改善。但是,如果模型并不准确,而且我们假定数据生成的 hERG 模型与拟合模型时使用的 hERG 模型之间存在差异,那么优化方案在确定 "真实 "结合动态方面就会变得不那么有效。虽然引入的方法很有希望,但我们必须小心谨慎,以确保在实际数据研究中应用时,我们有一个校准良好的 hERG 电流门控模型。
{"title":"Optimising experimental designs for model selection of ion channel drug binding mechanisms","authors":"Frankie Patten-Elliott, Chon Lok R Lei, Simon P Preston, Richard D Wilkinson, Gary R Mirams","doi":"10.1101/2024.08.20.608856","DOIUrl":"https://doi.org/10.1101/2024.08.20.608856","url":null,"abstract":"The rapid delayed rectifier current carried by the human Ether-à-go-go-Related Gene (hERG) channel is susceptible to drug-induced reduction which can lead to an increased risk of cardiac arrhythmia. Establishing the mechanism by which a specific drug compound binds to hERG can help to reduce uncertainty when quantifying pro-arrhythmic risk. In this study, we introduce a methodology for optimising experimental voltage protocols to produce data that enable different proposed models for the drug-binding mechanism to be distinguished. We demonstrate the performance of this methodology via a synthetic data study. If the underlying model of hERG current is known exactly, then the optimised protocols generated show noticeable improvements in our ability to select the true model when compared to a simple protocol used in previous studies. However, if the model is not known exactly, and we assume a discrepancy between the data-generating hERG model and the hERG model used in fitting the models, then the optimised protocols become less effective in determining the 'true' binding dynamics. While the introduced methodology shows promise, we must be careful to ensure that, if applied in a real data study, we have a well-calibrated model of hERG current gating.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
ER stress-induced TREM2 downregulation exacerbates platelet activation and myocardial infarction in patients with coronary artery disease ER应激诱导的TREM2下调会加剧冠心病患者的血小板活化和心肌梗死
Pub Date : 2024-08-21 DOI: 10.1101/2024.08.20.608887
Xiaowen Wu, Guanxing Pan, Lin Chang, Yulong Zhang, Yangyang Liu, Wei Zhang, Yifan Guo, Ge Zhang, Haoxuan Zhong, Zhiyong Qi, Jianjun Zhang, Ruyi Xue, She Chen, Hu Hu, Jianzeng Dong, Si Zhang, Zhongren Ding
Coronary artery disease (CAD) is characterized by the chronic immune-inflammation, excessive endoplasmic reticulum (ER) stress, and platelet hyperactivity; however, whether there is a signaling hub linking these events remains unclear. Here, we identified that triggering receptor expressed on myeloid cells 2 (TREM2), an important pattern recognition receptor of the innate immune system, may serve as one such hub. We found that platelets expressed TREM2 and platelets from CAD patients had decreased TREM2 expression compared to healthy subjects. Decreased TREM2 is associated with platelet hyperactivity in CAD patients. This decrease could be due to excessive ER stress, which downregulated TREM2 through the CHOP-C/EBPα axis. Loss of TREM2 not only enhanced platelet activation in response to ADP, collagen, and collagen-related peptide (CRP), but also amplified the platelet inflammatory response. Loss of TREM2 exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction (MI). Moreover, a TREM2-activating antibody inhibited platelet activation, alleviated arterial thrombosis and pulmonary embolism. In addition, TREM2-activating antibody exhibited cardioprotective roles against experimental MI and reduced the inflammatory burden. Mechanistically, TREM2/DAP12/SHIP1 axis negatively regulated platelet activation through reducing PIP3 levels and inhibiting Akt phosphorylation. We also provided evidence supporting sphingosine-1-phospage (S1P) as a physiological agonist of TREM2. In summary, we find that TREM2 connects chronic immune-inflammation, excessive ER stress, and platelet hyperactivity in CAD patients. Downregulating TREM2 by ER stress exacerbates platelet activation and amplifies inflammation response in patients with CAD. TREM2-activating antibodies may have therapeutic potential for CAD patients.
冠状动脉疾病(CAD)的特点是慢性免疫炎症、过度的内质网(ER)应激和血小板活性亢进;然而,是否有一个信号枢纽将这些事件联系起来仍不清楚。在这里,我们发现髓系细胞上表达的触发受体 2(TREM2)--一种先天性免疫系统的重要模式识别受体--可能就是这样一个枢纽。我们发现血小板表达 TREM2,与健康人相比,CAD 患者血小板的 TREM2 表达减少。TREM2 的减少与 CAD 患者血小板的过度活跃有关。这种减少可能是由于过度的ER应激通过CHOP-C/EBPα轴下调了TREM2。TREM2的缺失不仅增强了血小板对ADP、胶原蛋白和胶原蛋白相关肽(CRP)的活化反应,还扩大了血小板的炎症反应。失去 TREM2 会加剧小鼠肠系膜动脉血栓形成,并加重实验性心肌梗塞(MI)。此外,TREM2 激活抗体可抑制血小板活化,缓解动脉血栓和肺栓塞。此外,TREM2-激活抗体对实验性心肌梗死具有心脏保护作用,并能减轻炎症负担。从机制上讲,TREM2/DAP12/SHIP1 轴通过降低 PIP3 水平和抑制 Akt 磷酸化负向调节血小板活化。我们还提供了支持鞘磷脂-1-磷酸(S1P)作为 TREM2 生理激动剂的证据。总之,我们发现 TREM2 将慢性免疫炎症、过度的 ER 应激和 CAD 患者的血小板过度活跃联系在一起。通过ER应激下调TREM2会加剧CAD患者的血小板活化和炎症反应。激活 TREM2 的抗体可能对 CAD 患者有治疗潜力。
{"title":"ER stress-induced TREM2 downregulation exacerbates platelet activation and myocardial infarction in patients with coronary artery disease","authors":"Xiaowen Wu, Guanxing Pan, Lin Chang, Yulong Zhang, Yangyang Liu, Wei Zhang, Yifan Guo, Ge Zhang, Haoxuan Zhong, Zhiyong Qi, Jianjun Zhang, Ruyi Xue, She Chen, Hu Hu, Jianzeng Dong, Si Zhang, Zhongren Ding","doi":"10.1101/2024.08.20.608887","DOIUrl":"https://doi.org/10.1101/2024.08.20.608887","url":null,"abstract":"Coronary artery disease (CAD) is characterized by the chronic immune-inflammation, excessive endoplasmic reticulum (ER) stress, and platelet hyperactivity; however, whether there is a signaling hub linking these events remains unclear. Here, we identified that triggering receptor expressed on myeloid cells 2 (TREM2), an important pattern recognition receptor of the innate immune system, may serve as one such hub. We found that platelets expressed TREM2 and platelets from CAD patients had decreased TREM2 expression compared to healthy subjects. Decreased TREM2 is associated with platelet hyperactivity in CAD patients. This decrease could be due to excessive ER stress, which downregulated TREM2 through the CHOP-C/EBPα axis. Loss of TREM2 not only enhanced platelet activation in response to ADP, collagen, and collagen-related peptide (CRP), but also amplified the platelet inflammatory response. Loss of TREM2 exacerbated mouse mesenteric arterial thrombosis and aggravated experimental myocardial infarction (MI). Moreover, a TREM2-activating antibody inhibited platelet activation, alleviated arterial thrombosis and pulmonary embolism. In addition, TREM2-activating antibody exhibited cardioprotective roles against experimental MI and reduced the inflammatory burden. Mechanistically, TREM2/DAP12/SHIP1 axis negatively regulated platelet activation through reducing PIP3 levels and inhibiting Akt phosphorylation. We also provided evidence supporting sphingosine-1-phospage (S1P) as a physiological agonist of TREM2. In summary, we find that TREM2 connects chronic immune-inflammation, excessive ER stress, and platelet hyperactivity in CAD patients. Downregulating TREM2 by ER stress exacerbates platelet activation and amplifies inflammation response in patients with CAD. TREM2-activating antibodies may have therapeutic potential for CAD patients.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"34 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Title: 4-week GLP immunotoxicity assessment of lactoferrin alpha produced by Komagataella phaffii in Sprague Dawley rats 标题: 在 Sprague Dawley 大鼠体内对 Komagataella phaffii 产生的乳铁蛋白 alpha 进行为期 4 周的 GLP 免疫毒性评估
Pub Date : 2024-08-19 DOI: 10.1101/2024.08.16.608335
Ross Peterson, Robert B Crawford, Lance K Blevins, Norbert E Kaminski, Anthony J Clark, Carrie-Anne Malinczak
Oral toxicity and toxicokinetic properties of human lactoferrin (LF) alpha produced in Komagataella Phaffii (effera™) were investigated in adult Sprague-Dawley rats over a 28-day period under good laboratory practice conditions. Main study dosing used groups of 10 rats/sex/dose, and a secondary study evaluating toxicokinetic parameters used 6 rats/sex/dose. The vehicle control group received sodium citrate buffer, test groups received daily doses of 200, 600, and 2000 mg of effera™ per kg body weight, and the comparative control group received 2000 mg bovine LF (bLF)/kg body weight per day. T-cell dependent antibody response against keyhole limpet hemocyanin and immunophenotyping of the spleen were performed as measures of immunotoxicity. Clinical observations, body weight, hematology, coagulation, clinical chemistry, urinalysis, immunotoxicity, gross necropsy, and histopathology were assessed. Toxicokinetic parameters were analyzed as an indication of LF bioavailability, and anti-LF antibody assays were conducted to detect antibodies produced against LF to measure immunogenicity. No treatment related toxicologically significant changes were observed. Based on the absence of toxicologically relevant changes, effera™ is well tolerated in rats at doses up to 2000 mg rhLF/kg/day, an amount ~400 times that of the estimated daily intake at the 90th percentile proposed for human adult use.
在良好实验室规范条件下,对 Komagataella Phaffii(effera™)生产的人乳铁蛋白(LF)α的口服毒性和毒代动力学特性进行了为期 28 天的研究。主要研究剂量为每组 10 只大鼠/性别/剂量,评估毒物动力学参数的辅助研究剂量为每组 6 只大鼠/性别/剂量。载体对照组使用柠檬酸钠缓冲液,试验组每天每公斤体重使用 200、600 和 2000 毫克 effera™,对比对照组每天每公斤体重使用 2000 毫克牛 LF (bLF)。作为免疫毒性的测量指标,进行了针对匙孔帽贝血蓝蛋白的 T 细胞依赖性抗体反应和脾脏免疫分型。对临床观察、体重、血液学、凝血、临床化学、尿液分析、免疫毒性、大体尸检和组织病理学进行了评估。对毒物动力学参数进行了分析,以显示 LF 的生物利用度,并进行了抗 LF 抗体检测,以检测针对 LF 产生的抗体,从而衡量免疫原性。没有观察到与治疗有关的毒理学上的重大变化。根据未发现的毒理学相关变化,effera™在大鼠体内的耐受性良好,剂量最高可达2000毫克rhLF/公斤/天,约为建议人类成人使用的第90百分位数估计日摄入量的400倍。
{"title":"Title: 4-week GLP immunotoxicity assessment of lactoferrin alpha produced by Komagataella phaffii in Sprague Dawley rats","authors":"Ross Peterson, Robert B Crawford, Lance K Blevins, Norbert E Kaminski, Anthony J Clark, Carrie-Anne Malinczak","doi":"10.1101/2024.08.16.608335","DOIUrl":"https://doi.org/10.1101/2024.08.16.608335","url":null,"abstract":"Oral toxicity and toxicokinetic properties of human lactoferrin (LF) alpha produced in Komagataella Phaffii (effera™) were investigated in adult Sprague-Dawley rats over a 28-day period under good laboratory practice conditions. Main study dosing used groups of 10 rats/sex/dose, and a secondary study evaluating toxicokinetic parameters used 6 rats/sex/dose. The vehicle control group received sodium citrate buffer, test groups received daily doses of 200, 600, and 2000 mg of effera™ per kg body weight, and the comparative control group received 2000 mg bovine LF (bLF)/kg body weight per day. T-cell dependent antibody response against keyhole limpet hemocyanin and immunophenotyping of the spleen were performed as measures of immunotoxicity. Clinical observations, body weight, hematology, coagulation, clinical chemistry, urinalysis, immunotoxicity, gross necropsy, and histopathology were assessed. Toxicokinetic parameters were analyzed as an indication of LF bioavailability, and anti-LF antibody assays were conducted to detect antibodies produced against LF to measure immunogenicity. No treatment related toxicologically significant changes were observed. Based on the absence of toxicologically relevant changes, effera™ is well tolerated in rats at doses up to 2000 mg rhLF/kg/day, an amount ~400 times that of the estimated daily intake at the 90th percentile proposed for human adult use.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21 临床抗原虫药物卤夫酮通过提高 GDF15 和 FGF21 促进减肥
Pub Date : 2024-08-19 DOI: 10.1101/2024.08.18.608423
Suowen Xu, Zhenghong Liu, Tian Tian, Wenqi Zhao, Zhihua Wang, Monan Liu, Mengyun Xu, Fanshun Zhang, Zhidan Zhang, Meijie Chen, Yanjun Yin, Meiming Su, Wenhao Pan, Shiyong Liu, Min-dian Li, Peter Little, Danielle Danielle Kamato, Song-yang Zhang, Dongdong Wang, Stefan Offermanns, John Speakman, Jianping Weng
Obesity is a debilitating disease with increasing worldwide prevalence. Despite its high prevalence, specific pharmacologic intervention for obesity is challenging. Here, we report that halofuginone, an FDA-approved anti-scleroderma and anti-protozoal drug, is a promising anti-obesity agent in rodent models. Halofuginone suppressed food intake, increased energy expenditure, and resulted in weight loss in preclinical diet-induced obese mouse models, while also decreasing insulin resistance and hepatic steatosis. By combining genetic and pharmacological tools with transcriptomics, we identified that halofuginone increases FGF21 and GDF15 levels via ATF4. Using knockout mice, we show these hormones are both necessary for its anti-obesity effects. Thus, our study first reports the beneficial metabolic effects of halofuginone and underscores its utility to treat obesity and its associated metabolic complications.
肥胖症是一种使人衰弱的疾病,在全球的发病率越来越高。尽管肥胖症的发病率很高,但针对肥胖症的特殊药物干预却很有挑战性。在此,我们报告了经美国食品及药物管理局批准的一种抗硬皮病和抗原虫药物--卤夫酮,它在啮齿动物模型中是一种很有前景的抗肥胖药物。在临床前饮食诱导的肥胖小鼠模型中,卤夫酮可抑制食物摄入、增加能量消耗并减轻体重,同时还能降低胰岛素抵抗和肝脏脂肪变性。通过将遗传学和药理学工具与转录组学相结合,我们发现卤夫酮可通过 ATF4 提高 FGF21 和 GDF15 的水平。通过使用基因敲除小鼠,我们发现这些激素对哈洛芬酮的抗肥胖作用都是必需的。因此,我们的研究首次报道了卤夫酮对代谢的有益影响,并强调了其治疗肥胖症及其相关代谢并发症的作用。
{"title":"The clinical antiprotozoal drug halofuginone promotes weight loss by elevating GDF15 and FGF21","authors":"Suowen Xu, Zhenghong Liu, Tian Tian, Wenqi Zhao, Zhihua Wang, Monan Liu, Mengyun Xu, Fanshun Zhang, Zhidan Zhang, Meijie Chen, Yanjun Yin, Meiming Su, Wenhao Pan, Shiyong Liu, Min-dian Li, Peter Little, Danielle Danielle Kamato, Song-yang Zhang, Dongdong Wang, Stefan Offermanns, John Speakman, Jianping Weng","doi":"10.1101/2024.08.18.608423","DOIUrl":"https://doi.org/10.1101/2024.08.18.608423","url":null,"abstract":"Obesity is a debilitating disease with increasing worldwide prevalence. Despite its high prevalence, specific pharmacologic intervention for obesity is challenging. Here, we report that halofuginone, an FDA-approved anti-scleroderma and anti-protozoal drug, is a promising anti-obesity agent in rodent models. Halofuginone suppressed food intake, increased energy expenditure, and resulted in weight loss in preclinical diet-induced obese mouse models, while also decreasing insulin resistance and hepatic steatosis. By combining genetic and pharmacological tools with transcriptomics, we identified that halofuginone increases FGF21 and GDF15 levels via ATF4. Using knockout mice, we show these hormones are both necessary for its anti-obesity effects. Thus, our study first reports the beneficial metabolic effects of halofuginone and underscores its utility to treat obesity and its associated metabolic complications.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tanshinone IIA potentiates the therapeutic efficacy of glucocorticoid in lipopolysaccharide-treated HEI-OC1 cells through modulation of Foxp3/Nrf2 signaling pathway 丹参酮 IIA 通过调节 Foxp3/Nrf2 信号通路增强糖皮质激素对脂多糖处理的 HEI-OC1 细胞的疗效
Pub Date : 2024-08-19 DOI: 10.1101/2024.08.19.608552
Jie Li, Xiaoyan Zhu, Shiming Ye, Qi Dong, Jie Hou, Jing Liu, Wandong She
Glucocorticoids (GC) are commonly used to treat sudden sensorineural hearing loss (SSNHL) , although some patients show resistance to this therapeutic approach. Clinical studies demonstrate the efficacy of tanshinone IIA (TA) in combination with GC for managing various human ailments. However, it remains unclear whether TA can mitigate GC resistance in SSNHL.Aim of the study: Our aim is to elucidate the role of NRF2-induced transcriptional regulation of HDAC2 in influencing GC resistance and investigate the involvement of TA-related molecular pathways in GC resistance.Materials and Methods: HEI-OC1 cells are treated with lipopolysaccharide (LPS) to establish an in vitro model for SSNHL. Subsequently, the cells are treated with dexamethasone (DXE) or DXE+TA. RT-qPCR and western blot analyses are employed to measure mRNA and protein levels of Forkhead box P3 (FOXP3), nuclear factor erythroid 2-related factor 2 (NRF2), and histone deacetylase 2 (HDAC2). Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays are conducted to assess cell proliferation. Flow cytometry analysis is performed for apoptosis evaluation. Mechanistic studies involve Chromatin immunoprecipitation (ChIP), luciferase reporter, and DNA pull-down assays.Results: Treatment with TA+DEX significantly enhances proliferation and suppresses apoptosis in LPS-treated HEI OC1 cells. TA upregulates HDAC2 expression by activating NRF2-mediated transcription of HDAC2, with the NRF2-HDAC2 binding site located at bases 419-429 (ATGACACTCCA) in the promoter sequence of HDAC2. Furthermore, TA upregulates FOXP3 expression to activate NRF2 transcription, with the predicted FOXP3-binding site located at bases 864-870 (GCAAACA) in the promoter sequence of NRF2.Conclusion: This study's findings suggest that TA enhances the therapeutic effects of GC on proliferation and apoptosis in HEI OC1 cells by up-regulating FOXP3/Nrf2 expression. These results indicate that TA may be promising in ameliorating GC resistance in patients with SSNHL.
糖皮质激素(GC)是治疗突发性感音神经性听力损失(SSNHL)的常用药物,但有些患者对这种治疗方法表现出抗药性。临床研究表明,丹参酮 IIA(TA)与糖皮质激素联用可有效治疗各种人类疾病。然而,目前仍不清楚丹参酮 IIA 能否减轻 SSNHL 患者对 GC 的耐药性:材料与方法:用脂多糖(LPS)处理 HEI-OC1 细胞,建立 SSNHL 体外模型。随后,用地塞米松(DXE)或 DXE+TA 处理细胞。采用 RT-qPCR 和 Western 印迹分析法检测叉头盒 P3(FOXP3)、核因子红细胞 2 相关因子 2(NRF2)和组蛋白去乙酰化酶 2(HDAC2)的 mRNA 和蛋白水平。细胞计数试剂盒-8(CCK-8)和 5-乙炔基-2-脱氧尿苷(EdU)检测用于评估细胞增殖。流式细胞术分析用于细胞凋亡评估。机理研究包括染色质免疫沉淀(ChIP)、荧光素酶报告和 DNA 下拉试验:结果:TA+DEX能明显增强LPS处理的HEI OC1细胞的增殖并抑制其凋亡。TA通过激活NRF2介导的HDAC2转录上调HDAC2的表达,NRF2-HDAC2结合位点位于HDAC2启动子序列中的419-429碱基(ATGACACTCCA)。此外,TA 还能上调 FOXP3 的表达以激活 NRF2 的转录,预测的 FOXP3 结合位点位于 NRF2 启动子序列中的 864-870 碱基(GCAAACA):本研究结果表明,TA通过上调FOXP3/Nrf2的表达,增强了GC对HEI OC1细胞增殖和凋亡的治疗效果。这些结果表明,TA 在改善 SSNHL 患者对 GC 的耐药性方面可能大有可为。
{"title":"Tanshinone IIA potentiates the therapeutic efficacy of glucocorticoid in lipopolysaccharide-treated HEI-OC1 cells through modulation of Foxp3/Nrf2 signaling pathway","authors":"Jie Li, Xiaoyan Zhu, Shiming Ye, Qi Dong, Jie Hou, Jing Liu, Wandong She","doi":"10.1101/2024.08.19.608552","DOIUrl":"https://doi.org/10.1101/2024.08.19.608552","url":null,"abstract":"Glucocorticoids (GC) are commonly used to treat sudden sensorineural hearing loss (SSNHL) , although some patients show resistance to this therapeutic approach. Clinical studies demonstrate the efficacy of tanshinone IIA (TA) in combination with GC for managing various human ailments. However, it remains unclear whether TA can mitigate GC resistance in SSNHL.\u0000Aim of the study: Our aim is to elucidate the role of NRF2-induced transcriptional regulation of HDAC2 in influencing GC resistance and investigate the involvement of TA-related molecular pathways in GC resistance.\u0000Materials and Methods: HEI-OC1 cells are treated with lipopolysaccharide (LPS) to establish an in vitro model for SSNHL. Subsequently, the cells are treated with dexamethasone (DXE) or DXE+TA. RT-qPCR and western blot analyses are employed to measure mRNA and protein levels of Forkhead box P3 (FOXP3), nuclear factor erythroid 2-related factor 2 (NRF2), and histone deacetylase 2 (HDAC2). Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays are conducted to assess cell proliferation. Flow cytometry analysis is performed for apoptosis evaluation. Mechanistic studies involve Chromatin immunoprecipitation (ChIP), luciferase reporter, and DNA pull-down assays.\u0000Results: Treatment with TA+DEX significantly enhances proliferation and suppresses apoptosis in LPS-treated HEI OC1 cells. TA upregulates HDAC2 expression by activating NRF2-mediated transcription of HDAC2, with the NRF2-HDAC2 binding site located at bases 419-429 (ATGACACTCCA) in the promoter sequence of HDAC2. Furthermore, TA upregulates FOXP3 expression to activate NRF2 transcription, with the predicted FOXP3-binding site located at bases 864-870 (GCAAACA) in the promoter sequence of NRF2.\u0000Conclusion: This study's findings suggest that TA enhances the therapeutic effects of GC on proliferation and apoptosis in HEI OC1 cells by up-regulating FOXP3/Nrf2 expression. These results indicate that TA may be promising in ameliorating GC resistance in patients with SSNHL.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Endoplasmic reticulum stress inhibition preserves mitochondrial function and cell survival during early onset of isoniazid-induced oxidative stress 抑制内质网应激可在异烟肼诱发氧化应激的早期阶段保护线粒体功能和细胞存活
Pub Date : 2024-08-17 DOI: 10.1101/2024.08.12.607527
Truong Thi My Nhung, Nguyen Ky Phat, Trinh Tam Anh, Tran Diem Nghi, Nguyen Quang Thu, Ara Lee, Nguyen Tran Nam Tien, Nguyen Ky Anh, Kimoon Kim, Duc Ninh Nguyen, Dong Hyun Kim, Sang Ki Park, Nguyen Phuoc Long
A comprehensive understanding of isoniazid (INH)-mediated hepatotoxic effects is essential for developing strategies to predict and prevent severe liver toxicity in tuberculosis treatment. Our study utilized multi-omics profiling to investigate the toxic effects of INH, revealing significant involvement of endoplasmic reticulum (ER) stress, mitochondrial impairment, redox imbalance, and altered metabolism. Followed-up mechanistic studies revealed that INH triggered the generation of cytosolic reactive oxygen species (ROS) and the activation of the Nrf2 signaling pathway prior to mitochondrial ROS accumulation. Subsequently, INH disrupted mitochondrial function by impairing respiratory complexes I-IV and caused mitochondrial membrane proton leaks without affecting ATP synthase activity, together leading to mitochondrial depolarization and reduced ATP production. These disturbances enhanced mitochondrial fission and mitophagy. While much attention has been given to mitochondrial dysfunction and oxidative stress in INH-induced hepatotoxicity, our findings highlight the potential of inhibiting ER stress during early INH exposure to mitigate cytosolic and mitochondrial oxidative stress. We further revealed the critical role of Nrf2 signaling in protecting liver cells under INH-induced oxidative stress by maintaining redox homeostasis and enabling metabolic reprogramming via regulating the expression of antioxidant genes and cellular lipid abundance. We also identified other antioxidant pathways (e.g., selenocompound metabolism, HIF-1 signaling pathway, and pentose phosphate pathway) as potential alternative mechanisms besides Nrf2 signaling in response to INH-induced oxidative stress. In conclusion, our research emphasizes the importance of ER stress, redox imbalance, metabolic changes, and mitochondrial dysfunction underlying INH-induced hepatotoxicity.
全面了解异烟肼(INH)介导的肝毒性效应对于制定预测和预防结核病治疗中严重肝毒性的策略至关重要。我们的研究利用多组学分析方法研究了 INH 的毒性效应,发现内质网(ER)应激、线粒体损伤、氧化还原失衡和新陈代谢改变的显著参与。后续机理研究发现,INH 会在线粒体 ROS 积累之前引发细胞膜活性氧(ROS)的生成和 Nrf2 信号通路的激活。随后,INH 通过损害呼吸复合体 I-IV 破坏线粒体功能,并在不影响 ATP 合成酶活性的情况下造成线粒体膜质子泄漏,从而导致线粒体去极化和 ATP 生成减少。这些干扰增强了线粒体分裂和有丝分裂。尽管线粒体功能障碍和氧化应激在 INH 诱导的肝毒性中的作用已引起了广泛关注,但我们的研究结果强调了在 INH 暴露早期抑制 ER 应激以减轻细胞膜和线粒体氧化应激的潜力。我们进一步揭示了Nrf2信号在INH诱导的氧化应激条件下保护肝细胞的关键作用,它通过调节抗氧化基因的表达和细胞脂质丰度来维持氧化还原平衡和实现代谢重编程。我们还发现了其他抗氧化通路(如硒化合物代谢、HIF-1 信号通路和磷酸戊糖通路),它们是 Nrf2 信号通路之外应对 INH 诱导的氧化应激的潜在替代机制。总之,我们的研究强调了ER应激、氧化还原失衡、代谢变化和线粒体功能障碍在INH诱导的肝毒性中的重要性。
{"title":"Endoplasmic reticulum stress inhibition preserves mitochondrial function and cell survival during early onset of isoniazid-induced oxidative stress","authors":"Truong Thi My Nhung, Nguyen Ky Phat, Trinh Tam Anh, Tran Diem Nghi, Nguyen Quang Thu, Ara Lee, Nguyen Tran Nam Tien, Nguyen Ky Anh, Kimoon Kim, Duc Ninh Nguyen, Dong Hyun Kim, Sang Ki Park, Nguyen Phuoc Long","doi":"10.1101/2024.08.12.607527","DOIUrl":"https://doi.org/10.1101/2024.08.12.607527","url":null,"abstract":"A comprehensive understanding of isoniazid (INH)-mediated hepatotoxic effects is essential for developing strategies to predict and prevent severe liver toxicity in tuberculosis treatment. Our study utilized multi-omics profiling to investigate the toxic effects of INH, revealing significant involvement of endoplasmic reticulum (ER) stress, mitochondrial impairment, redox imbalance, and altered metabolism. Followed-up mechanistic studies revealed that INH triggered the generation of cytosolic reactive oxygen species (ROS) and the activation of the Nrf2 signaling pathway prior to mitochondrial ROS accumulation. Subsequently, INH disrupted mitochondrial function by impairing respiratory complexes I-IV and caused mitochondrial membrane proton leaks without affecting ATP synthase activity, together leading to mitochondrial depolarization and reduced ATP production. These disturbances enhanced mitochondrial fission and mitophagy. While much attention has been given to mitochondrial dysfunction and oxidative stress in INH-induced hepatotoxicity, our findings highlight the potential of inhibiting ER stress during early INH exposure to mitigate cytosolic and mitochondrial oxidative stress. We further revealed the critical role of Nrf2 signaling in protecting liver cells under INH-induced oxidative stress by maintaining redox homeostasis and enabling metabolic reprogramming via regulating the expression of antioxidant genes and cellular lipid abundance. We also identified other antioxidant pathways (e.g., selenocompound metabolism, HIF-1 signaling pathway, and pentose phosphate pathway) as potential alternative mechanisms besides Nrf2 signaling in response to INH-induced oxidative stress. In conclusion, our research emphasizes the importance of ER stress, redox imbalance, metabolic changes, and mitochondrial dysfunction underlying INH-induced hepatotoxicity.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Novel Computational Machine Learning Pipeline to Quantify Similarities in Three-Dimensional Protein Structures 量化三维蛋白质结构相似性的新型计算机器学习管道
Pub Date : 2024-08-17 DOI: 10.1101/2024.08.14.607969
Shreyas U Hirway, Xiao Xu, Fan Fan
Animal models are widely used during drug development. The selection of suitable animal model relies on various factors such as target biology, animal resource availability and legacy species. It is imperative that the selected animal species exhibit the highest resemblance to human, in terms of target biology as well as the similarity in the target protein. The current practice to address cross-species protein similarity relies on pair wise sequence comparison using protein sequences, instead of the biologically relevant 3-dimensional (3D) structure of proteins. We developed a novel quantitative machine learning pipeline using 3D structure-based feature data from the Protein Data Bank, nominal data from UNIPROT and bioactivity data from ChEMBL, all of which were matched for human and animal data. Using the XGBoost regression model, similarity scores between targets were calculated and based on these scores, the best animal species for a target was identified. For real-world application, targets from an alternative source, i.e., AlphaFold, were tested using the model, and the animal species that had the most similar protein to the human counterparts were predicted. These targets were then grouped based on their associated phenotype such that the pipeline could predict an optimal animal species.
动物模型在药物研发过程中被广泛使用。选择合适的动物模型取决于多种因素,如目标生物学、动物资源可用性和遗留物种。就目标生物学以及目标蛋白质的相似性而言,所选动物物种必须与人类具有最高的相似性。目前解决跨物种蛋白质相似性的方法依赖于使用蛋白质序列进行成对序列比较,而不是蛋白质的生物相关三维(3D)结构。我们利用蛋白质数据库中基于三维结构的特征数据、UNIPROT 的标称数据和 ChEMBL 的生物活性数据,开发了一种新型定量机器学习管道,所有这些数据都与人类和动物数据相匹配。利用 XGBoost 回归模型计算目标之间的相似性得分,并根据这些得分确定目标的最佳动物物种。在实际应用中,使用该模型测试了来自其他来源(即 AlphaFold)的靶标,并预测了与人类对应蛋白最相似的动物物种。然后根据相关的表型对这些靶标进行分组,这样管道就能预测出最佳的动物物种。
{"title":"A Novel Computational Machine Learning Pipeline to Quantify Similarities in Three-Dimensional Protein Structures","authors":"Shreyas U Hirway, Xiao Xu, Fan Fan","doi":"10.1101/2024.08.14.607969","DOIUrl":"https://doi.org/10.1101/2024.08.14.607969","url":null,"abstract":"Animal models are widely used during drug development. The selection of suitable animal model relies on various factors such as target biology, animal resource availability and legacy species. It is imperative that the selected animal species exhibit the highest resemblance to human, in terms of target biology as well as the similarity in the target protein. The current practice to address cross-species protein similarity relies on pair wise sequence comparison using protein sequences, instead of the biologically relevant 3-dimensional (3D) structure of proteins. We developed a novel quantitative machine learning pipeline using 3D structure-based feature data from the Protein Data Bank, nominal data from UNIPROT and bioactivity data from ChEMBL, all of which were matched for human and animal data. Using the XGBoost regression model, similarity scores between targets were calculated and based on these scores, the best animal species for a target was identified. For real-world application, targets from an alternative source, i.e., AlphaFold, were tested using the model, and the animal species that had the most similar protein to the human counterparts were predicted. These targets were then grouped based on their associated phenotype such that the pipeline could predict an optimal animal species.","PeriodicalId":501518,"journal":{"name":"bioRxiv - Pharmacology and Toxicology","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142184299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
bioRxiv - Pharmacology and Toxicology
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1