Pub Date : 2024-01-01DOI: 10.1177/09603271231222873
Xiaoqin Wang, Song Qin, Yingcong Ren, Banghai Feng, Junya Liu, Kun Yu, Hong Yu, Zhenliang Liao, Hong Mei, Mei Tan
Background: Hyperoxia-induced acute lung injury (HALI) is a complication to ventilation in patients with respiratory failure, which can lead to acute inflammatory lung injury and chronic lung disease. The aim of this study was to integrate bioinformatics analysis to identify key genes associated with HALI and validate their role in H2O2-induced cell injury model.Methods: Integrated bioinformatics analysis was performed to screen vital genes involved in hyperoxia-induced lung injury (HLI). CCK-8 and flow cytometry assays were performed to assess cell viability and apoptosis. Western blotting was performed to assess protein expression.Results: In this study, glycoprotein non-metastatic melanoma protein B (Gpnmb) was identified as a key gene in HLI by integrated bioinformatics analysis of 4 Gene Expression Omnibus (GEO) datasets (GSE97804, GSE51039, GSE76301 and GSE87350). Knockdown of Gpnmb increased cell viability and decreased apoptosis in H2O2-treated MLE-12 cells, suggesting that Gpnmb was a proapoptotic gene during HALI. Western blotting results showed that knockdown of Gpnmb reduced the expression of Bcl-2 associated X (BAX) and cleaved-caspase 3, and increased the expression of Bcl-2 in H2O2 treated MLE-12 cells. Furthermore, Gpnmb knockdown could significantly reduce reactive oxygen species (ROS) generation and improve the mitochondrial membrane potential.Conclusion: The present study showed that knockdown of Gpnmb may protect against HLI by repressing mitochondrial-mediated apoptosis.
背景:高氧诱导的急性肺损伤(HALI)是呼吸衰竭患者通气的并发症,可导致急性炎症性肺损伤和慢性肺部疾病。本研究旨在整合生物信息学分析,找出与 HALI 相关的关键基因,并验证它们在 H2O2- 诱导的细胞损伤模型中的作用:方法:通过综合生物信息学分析筛选出参与高氧诱导肺损伤(HLI)的重要基因。采用 CCK-8 和流式细胞术测定评估细胞活力和凋亡。采用 Western 印迹法评估蛋白质表达:本研究通过对 4 个基因表达总库(GEO)数据集(GSE97804、GSE51039、GSE76301 和 GSE87350)进行综合生物信息学分析,发现糖蛋白非转移性黑色素瘤蛋白 B(Gpnmb)是 HLI 的关键基因。在H2O2处理的MLE-12细胞中,敲除Gpnmb增加了细胞活力,减少了细胞凋亡,这表明Gpnmb是HALI过程中的促凋亡基因。Western blotting结果显示,在H2O2处理的MLE-12细胞中,敲除Gpnmb会降低Bcl-2相关X(BAX)和裂解-天冬酶3的表达,增加Bcl-2的表达。此外,Gpnmb敲除可显著减少活性氧(ROS)的产生,并改善线粒体膜电位:本研究表明,敲除 Gpnmb 可抑制线粒体介导的细胞凋亡,从而预防 HLI。
{"title":"Gpnmb silencing protects against hyperoxia-induced acute lung injury by inhibition of mitochondrial-mediated apoptosis.","authors":"Xiaoqin Wang, Song Qin, Yingcong Ren, Banghai Feng, Junya Liu, Kun Yu, Hong Yu, Zhenliang Liao, Hong Mei, Mei Tan","doi":"10.1177/09603271231222873","DOIUrl":"10.1177/09603271231222873","url":null,"abstract":"<p><p><b>Background:</b> Hyperoxia-induced acute lung injury (HALI) is a complication to ventilation in patients with respiratory failure, which can lead to acute inflammatory lung injury and chronic lung disease. The aim of this study was to integrate bioinformatics analysis to identify key genes associated with HALI and validate their role in H<sub>2</sub>O<sub>2</sub>-induced cell injury model.<b>Methods:</b> Integrated bioinformatics analysis was performed to screen vital genes involved in hyperoxia-induced lung injury (HLI). CCK-8 and flow cytometry assays were performed to assess cell viability and apoptosis. Western blotting was performed to assess protein expression.<b>Results:</b> In this study, glycoprotein non-metastatic melanoma protein B (<i>Gpnmb</i>) was identified as a key gene in HLI by integrated bioinformatics analysis of 4 Gene Expression Omnibus (GEO) datasets (GSE97804, GSE51039, GSE76301 and GSE87350). Knockdown of <i>Gpnmb</i> increased cell viability and decreased apoptosis in H<sup>2</sup>O<sup>2</sup>-treated MLE-12 cells, suggesting that <i>Gpnmb</i> was a proapoptotic gene during HALI. Western blotting results showed that knockdown of <i>Gpnmb</i> reduced the expression of Bcl-2 associated X (BAX) and cleaved-caspase 3, and increased the expression of Bcl-2 in H<sub>2</sub>O<sub>2</sub> treated MLE-12 cells. Furthermore, <i>Gpnmb</i> knockdown could significantly reduce reactive oxygen species (ROS) generation and improve the mitochondrial membrane potential.<b>Conclusion:</b> The present study showed that knockdown of <i>Gpnmb</i> may protect against HLI by repressing mitochondrial-mediated apoptosis.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139081181","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}
Pub Date : 2024-01-01DOI: 10.1177/09603271241254338
Khatera Rahmani, Yen-Ching Wu, Neil R Buck, Alexandria Lau, Paul R Hanlon
Frameworks have been developed to standardize the assessment of carcinogenic potential in the pharmaceutical and agrochemical industries, building upon decades of research. Carcinogenicity is also evaluated during the safety evaluation of food substances, using a comprehensive approach unique to each substance. To better understand these approaches, a retrospective assessment was conducted on the publicly available database of substances notified to the United States Food and Drug Administration (US FDA) as being Generally Recognized As Safe (GRAS). The data contained within these GRAS notifications (GRNs) were reviewed for the methods used to evaluate carcinogenic potential (genotoxicity studies, 2-year bioassays, other pre-clinical animal studies) to identify patterns that could provide an understanding of how this assessment has been conducted for different categories of food substances. While different approaches to the safety evaluation were required to adapt to the unique food substances, the data in all notifications supported the conclusion of safety. The evaluation of food substances for carcinogenic potential must consider all available data, including identifying the need for when more data must be generated to support an evaluation. Due to the complexity of substances used in food, ranging from defined chemical entities to minimally processed agricultural commodities to live microorganisms, the approach to conducting the safety evaluation of food substances must be able to adapt to the most relevant scientifically supported approach. This paper illustrates the data commonly used to support the safety of different types of food substances and proposes an approach familiar to other product sectors.
{"title":"Retrospective analysis of carcinogenicity assessments within FDA-notified GRAS determinations.","authors":"Khatera Rahmani, Yen-Ching Wu, Neil R Buck, Alexandria Lau, Paul R Hanlon","doi":"10.1177/09603271241254338","DOIUrl":"https://doi.org/10.1177/09603271241254338","url":null,"abstract":"<p><p>Frameworks have been developed to standardize the assessment of carcinogenic potential in the pharmaceutical and agrochemical industries, building upon decades of research. Carcinogenicity is also evaluated during the safety evaluation of food substances, using a comprehensive approach unique to each substance. To better understand these approaches, a retrospective assessment was conducted on the publicly available database of substances notified to the United States Food and Drug Administration (US FDA) as being Generally Recognized As Safe (GRAS). The data contained within these GRAS notifications (GRNs) were reviewed for the methods used to evaluate carcinogenic potential (genotoxicity studies, 2-year bioassays, other pre-clinical animal studies) to identify patterns that could provide an understanding of how this assessment has been conducted for different categories of food substances. While different approaches to the safety evaluation were required to adapt to the unique food substances, the data in all notifications supported the conclusion of safety. The evaluation of food substances for carcinogenic potential must consider all available data, including identifying the need for when more data must be generated to support an evaluation. Due to the complexity of substances used in food, ranging from defined chemical entities to minimally processed agricultural commodities to live microorganisms, the approach to conducting the safety evaluation of food substances must be able to adapt to the most relevant scientifically supported approach. This paper illustrates the data commonly used to support the safety of different types of food substances and proposes an approach familiar to other product sectors.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763552","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}
Pub Date : 2024-01-01DOI: 10.1177/09603271241281159
Pengcheng Dou, Ruiping Song, Zhuangzhuang Feng, Bing Jiang, Xinyi Chen, Yuanbin Luo, Jiaojiao Zuo, Yi Gao, Jin Shu
Objective: Precancerous lesions of gastric cancer (PLGC) are key pathological stages in the transformation of gastric "inflammation-cancer", and timely and effective intervention at this stage is of great importance in the prevention and treatment of gastric cancer. Zhiwei Fuwei Pills (ZWFW), as a traditional Chinese medicine formulation, has been proven to have good clinical efficacy in the treatment of PLGC, but its specific mechanism of action has not been fully explained. Thus, this study validated the efficacy and explored the potential mechanisms of ZWFW in treating PLGC by integrating network pharmacology analyses and experimental verification.
Methods: The TCMSP database was used to obtain the active ingredients of ZWFW and their corresponding targets, and the GeneCards database was used to retrieve PLGC-related targets. The intersecting targets between ZWFW and PLGC were obtained through mapping, and protein-protein interaction (PPI) networks and "drug-active ingredient-target" networks were constructed by using Cytoscape software. The DAVID database was used for GO functional enrichment analysis and KEGG pathway enrichment analysis. AutoDockTools software was used for molecular docking of key active ingredients and key targets. In order to verify the analysis results of network pharmacology, TEM and H&E were used to observe the effects of different dosage groups of ZWFW on gastric mucosal microvasculature in PLGC rats. Subsequently, the ELISA, IF, IHC, RT-PCR and western blot were used to detected the expression levels of relevant targets in the tissues, so as to verify the potential mechanism of ZWFW in intervening PLGC.
Results: After the screening, 258 effective active ingredients and 325 targets were obtained, and 1294 disease-related targets were determined, resulting in 139 intersection targets through mapping. The KEGG enrichment results showed that PI3K/Akt and HIF-1 signaling pathway might play important roles in the treatment mechanism of PLGC. The molecular docking results showed that active ingredients of ZWFW all had a strong affinity and stable structure with key targets, including AKT1 and VEGF. In vivo experiments confirmed that ZWFW could improve gastric mucosal microvascular abnormalities in PLGC, effectively intervene in gastric mucosal pathological grading. Meanwhile, compared with the model group, this formulation could reduce the expression levels of PI3K, Akt, mTOR, HIF-1α, and VEGF in gastric mucosa, showing a dose-effect relationship.
Conclusion: ZWFW can intervene in the neovascularization and pathological evolution of PLGC, and this mechanism of action may be achieved by inhibiting abnormal activation of the PI3K/Akt/mTOR/HIF-1α/VEGF signaling pathway.
目的:胃癌癌前病变(PLGC)是胃 "炎-癌 "转化的关键病理阶段,在此阶段进行及时有效的干预对胃癌的防治具有重要意义。知味扶正丸作为一种传统的中药剂型,已被证实在治疗PLGC方面具有良好的临床疗效,但其具体的作用机制尚未完全阐明。因此,本研究通过网络药理学分析和实验验证,验证了紫花地丁在治疗PLGC方面的疗效,并探索了其潜在的作用机制:方法:利用TCMSP数据库获取ZWFW的有效成分及其相应靶点,利用GeneCards数据库检索PLGC相关靶点。绘制ZWFW和PLGC的交叉靶标图谱,利用Cytoscape软件构建蛋白质相互作用网络(PPI)和 "药物活性成分-靶标 "网络。利用 DAVID 数据库进行 GO 功能富集分析和 KEGG 通路富集分析。使用 AutoDockTools 软件对关键活性成分和关键靶点进行分子对接。为了验证网络药理学的分析结果,采用TEM和H&E观察不同剂量组ZWFW对PLGC大鼠胃黏膜微血管的影响。随后,采用ELISA、IF、IHC、RT-PCR和Western blot等方法检测相关靶点在组织中的表达水平,从而验证ZWFW干预PLGC的潜在机制:结果:经过筛选,获得了258种有效活性成分和325个靶点,确定了1294个疾病相关靶点,并通过图谱绘制获得了139个交叉靶点。KEGG富集结果显示,PI3K/Akt和HIF-1信号通路可能在PLGC的治疗机制中发挥重要作用。分子对接结果表明,ZWFW的有效成分均与AKT1和VEGF等关键靶点具有较强的亲和力和稳定的结构。体内实验证实,ZWFW能改善PLGC的胃黏膜微血管异常,有效干预胃黏膜病理分级。同时,与模型组相比,该制剂可降低胃黏膜中PI3K、Akt、mTOR、HIF-1α和VEGF的表达水平,呈现剂量效应关系:ZWFW可干预PLGC的新生血管形成和病理演变,其作用机制可能是通过抑制PI3K/Akt/mTOR/HIF-1α/VEGF信号通路的异常激活实现的。
{"title":"Network pharmacology and experimental verification: Unraveling Zhiwei Fuwei Pills's role and mechanism in angiogenesis of precancerous lesions of gastric cancer.","authors":"Pengcheng Dou, Ruiping Song, Zhuangzhuang Feng, Bing Jiang, Xinyi Chen, Yuanbin Luo, Jiaojiao Zuo, Yi Gao, Jin Shu","doi":"10.1177/09603271241281159","DOIUrl":"https://doi.org/10.1177/09603271241281159","url":null,"abstract":"<p><strong>Objective: </strong>Precancerous lesions of gastric cancer (PLGC) are key pathological stages in the transformation of gastric \"inflammation-cancer\", and timely and effective intervention at this stage is of great importance in the prevention and treatment of gastric cancer. Zhiwei Fuwei Pills (ZWFW), as a traditional Chinese medicine formulation, has been proven to have good clinical efficacy in the treatment of PLGC, but its specific mechanism of action has not been fully explained. Thus, this study validated the efficacy and explored the potential mechanisms of ZWFW in treating PLGC by integrating network pharmacology analyses and experimental verification.</p><p><strong>Methods: </strong>The TCMSP database was used to obtain the active ingredients of ZWFW and their corresponding targets, and the GeneCards database was used to retrieve PLGC-related targets. The intersecting targets between ZWFW and PLGC were obtained through mapping, and protein-protein interaction (PPI) networks and \"drug-active ingredient-target\" networks were constructed by using Cytoscape software. The DAVID database was used for GO functional enrichment analysis and KEGG pathway enrichment analysis. AutoDockTools software was used for molecular docking of key active ingredients and key targets. In order to verify the analysis results of network pharmacology, TEM and H&E were used to observe the effects of different dosage groups of ZWFW on gastric mucosal microvasculature in PLGC rats. Subsequently, the ELISA, IF, IHC, RT-PCR and western blot were used to detected the expression levels of relevant targets in the tissues, so as to verify the potential mechanism of ZWFW in intervening PLGC.</p><p><strong>Results: </strong>After the screening, 258 effective active ingredients and 325 targets were obtained, and 1294 disease-related targets were determined, resulting in 139 intersection targets through mapping. The KEGG enrichment results showed that PI3K/Akt and HIF-1 signaling pathway might play important roles in the treatment mechanism of PLGC. The molecular docking results showed that active ingredients of ZWFW all had a strong affinity and stable structure with key targets, including AKT1 and VEGF. In vivo experiments confirmed that ZWFW could improve gastric mucosal microvascular abnormalities in PLGC, effectively intervene in gastric mucosal pathological grading. Meanwhile, compared with the model group, this formulation could reduce the expression levels of PI3K, Akt, mTOR, HIF-1α, and VEGF in gastric mucosa, showing a dose-effect relationship.</p><p><strong>Conclusion: </strong>ZWFW can intervene in the neovascularization and pathological evolution of PLGC, and this mechanism of action may be achieved by inhibiting abnormal activation of the PI3K/Akt/mTOR/HIF-1α/VEGF signaling pathway.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142157049","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}
Objective of the research: Air pollution is a universal issue and has significant deleterious effects on both human health and also environment. The important indicators of air pollution include ozone (O3), particulate matter (PM), nitrogen dioxide (NO2), and sulfur dioxide (SO2). This research aims to investigate the impacts of ambient air pollution (AAP), SO2, and O3 on oxidative stress parameters, liver tissue histopathology, and expression of some carcinogenesis-related genes in the hepatic tissue of rats.
Materials and methods: 32 Wistar rats were randomly allocated to four groups: the control group, the AAP group, the SO2 group (10 ppm), and the ozone group (0.6 ppm). Over a period of five consecutive weeks, the rats were exposed to the specified pollutants for 3 h daily; liver tissues were harvested and instantly fixed with formalin. Pathological changes were assessed in the tissue samples. Additionally, the RT-qPCR technique was utilized to investigate Expression alterations of BAX, p-53, BCL2, caspase-3, caspase-8 and caspase-9. Furthermore, 30 milligrams of hepatic tissues were extracted to assess the activities of oxidative stress enzymes.
Results: The liver catalase and MDA activity were elevated in the air pollution (p < .05). Also, liver GPx activity in air pollution and ozone groups was significant in comparison to the control group (p < .05). The SO2 group exhibited severe lesions in histopathology examinations.
Conclusions: The findings revealed an alteration in liver histopathology, an induction of oxidative stress, and the expression of some apoptosis-related genes in hepatic tissues after exposure to AAP, SO2, and O3.
{"title":"The effects of short-time air pollution, SO2, and ozone on biochemical, histo-pathological, oxidative stress, and carcinogenesis related genes expressions in the liver of the rats.","authors":"Bita Sepehri, Roya Darbani, Mehran Mesgari-Abbasi, Sorayya Kheirouri, Dariush Shanehbandi, Monireh Khordadmehr, Mohammad Alizadeh","doi":"10.1177/09603271241263569","DOIUrl":"https://doi.org/10.1177/09603271241263569","url":null,"abstract":"<p><strong>Objective of the research: </strong>Air pollution is a universal issue and has significant deleterious effects on both human health and also environment. The important indicators of air pollution include ozone (O3), particulate matter (PM), nitrogen dioxide (NO2), and sulfur dioxide (SO2). This research aims to investigate the impacts of ambient air pollution (AAP), SO2, and O3 on oxidative stress parameters, liver tissue histopathology, and expression of some carcinogenesis-related genes in the hepatic tissue of rats.</p><p><strong>Materials and methods: </strong>32 Wistar rats were randomly allocated to four groups: the control group, the AAP group, the SO2 group (10 ppm), and the ozone group (0.6 ppm). Over a period of five consecutive weeks, the rats were exposed to the specified pollutants for 3 h daily; liver tissues were harvested and instantly fixed with formalin. Pathological changes were assessed in the tissue samples. Additionally, the RT-qPCR technique was utilized to investigate Expression alterations of BAX, p-53, BCL2, caspase-3, caspase-8 and caspase-9. Furthermore, 30 milligrams of hepatic tissues were extracted to assess the activities of oxidative stress enzymes.</p><p><strong>Results: </strong>The liver catalase and MDA activity were elevated in the air pollution (<i>p</i> < .05). Also, liver GPx activity in air pollution and ozone groups was significant in comparison to the control group (<i>p</i> < .05). The SO2 group exhibited severe lesions in histopathology examinations.</p><p><strong>Conclusions: </strong>The findings revealed an alteration in liver histopathology, an induction of oxidative stress, and the expression of some apoptosis-related genes in hepatic tissues after exposure to AAP, SO2, and O3.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141790628","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}
Pub Date : 2024-01-01DOI: 10.1177/09603271241256598
Carr J Smith, Thomas A Perfetti, Chirayu Chokshi, Chitra Venugopal, J Wesson Ashford, Sheila K Singh
Epidemiological evidence of an association between exposure to chemical carcinogens and an increased risk for development of glioblastoma (GBM) is limited to weak statistical associations in cohorts of firefighters, farmers, residents exposed to air pollution, and soldiers exposed to toxic chemicals (e.g., military burn pits, oil-well fire smoke). A history of ionizing radiation therapy to the head or neck is associated with an increased risk of GBM. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Data on 16 agents (15 chemicals and radio frequency radiation) that induced tumors in the rodent brain were extracted from 602 Technical Reports on 2-years cancer bioassays found in the National Toxicology Program database. Ten of the 15 chemical agents that induce brain tumors are alkylating agents. Three of the 15 chemical agents have idiosyncratic structures and might be alkylating agents. Only two of the 15 chemical agents are definitively not alkylating agents. The rat model is thought to be of possible relevance to humans suggesting that exposure to alkylating chemicals should be considered in epidemiology studies on GBM and other brain tumors.
{"title":"Alkylating agents are possible inducers of glioblastoma and other brain tumors.","authors":"Carr J Smith, Thomas A Perfetti, Chirayu Chokshi, Chitra Venugopal, J Wesson Ashford, Sheila K Singh","doi":"10.1177/09603271241256598","DOIUrl":"10.1177/09603271241256598","url":null,"abstract":"<p><p>Epidemiological evidence of an association between exposure to chemical carcinogens and an increased risk for development of glioblastoma (GBM) is limited to weak statistical associations in cohorts of firefighters, farmers, residents exposed to air pollution, and soldiers exposed to toxic chemicals (e.g., military burn pits, oil-well fire smoke). A history of ionizing radiation therapy to the head or neck is associated with an increased risk of GBM. Ionizing radiation induces point mutations, frameshift mutations, double-strand breaks, and chromosomal insertions or deletions. Mutational profiles associated with chemical exposures overlap with the broad mutational patterns seen with ionizing radiation. Data on 16 agents (15 chemicals and radio frequency radiation) that induced tumors in the rodent brain were extracted from 602 Technical Reports on 2-years cancer bioassays found in the National Toxicology Program database. Ten of the 15 chemical agents that induce brain tumors are alkylating agents. Three of the 15 chemical agents have idiosyncratic structures and might be alkylating agents. Only two of the 15 chemical agents are definitively not alkylating agents. The rat model is thought to be of possible relevance to humans suggesting that exposure to alkylating chemicals should be considered in epidemiology studies on GBM and other brain tumors.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961364","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}
Pub Date : 2024-01-01DOI: 10.1177/09603271241232609
Yonghong Tang, Guifang Ou, Ouyan Rang, Xu Liu, Xiaocheng Liu, Xinru Qin, Guojuan Li, Qing Yang, Mu Wang
Adipose tissue is the main organ that stores lipids and it plays important roles in metabolic balance in the body. We recently reported in Human and Experimental Toxicology that the combined exposure to BPA and fructose may interfere with energy metabolism of adipose tissue. However, it is still unclear whether the combined exposure to BPA and fructose has the possibility to induce lipid remodeling in adipose tissue. In the present study, we performed a widely targeted quantitative lipidomic analysis of the adipose tissue of rats after 6 months of BPA and fructose combined exposure. We totally determined 734 lipid molecules in the adipose tissue of rats. Principal component analysis (PCA) showed the group of the combined exposure to higher-dose (25 μg/kg every other day) BPA and fructose can be distinguished from the groups of control, higher-dose BPA exposure and fructose exposure clearly. Partial least squares-discriminant analysis (PLS-DA) and univariate statistical analysis displayed lipids of PC(18:0_ 20:3), TG(8:0_14:0_16:0), TG(12:0_14:0_16:1), TG(10:0_16:0_16:1), TG(12:0_ 14:0_18:1), TG(14:0_ 16:0_16:1), TG(14:0_14:1_16:1), TG(8:0_ 16:1_16:2), TG(14:1_16:1_ 16:1), TG(16:1_18:1_18:1), TG(16:0_16:1_20:4) and TG(15:0_18:1_ 24:1) may contributed the most to the discrimination. These findings indicated that combined exposure to BPA and fructose has the potential to cause lipid remodeling in adipose tissue.
脂肪组织是储存脂质的主要器官,在体内新陈代谢平衡中发挥着重要作用。我们最近在《人类与实验毒理学》(Human and Experimental Toxicology)杂志上报道,同时接触双酚 A 和果糖可能会干扰脂肪组织的能量代谢。然而,目前还不清楚双酚 A 和果糖的联合暴露是否有可能诱导脂肪组织的脂质重塑。在本研究中,我们对双酚 A 和果糖联合暴露 6 个月后的大鼠脂肪组织进行了广泛的定向定量脂质体分析。我们总共测定了大鼠脂肪组织中的 734 种脂质分子。主成分分析(PCA)结果表明,较高剂量(25 μg/kg,隔日一次)双酚A和果糖联合暴露组与对照组、较高剂量双酚A暴露组和果糖暴露组有明显的区别。偏最小二乘判别分析(PLS-DA)和单变量统计分析显示,PC(18:0_ 20:3)、TG(8:0_14:0_16:0)、TG(12:0_14:0_16:1)、TG(10:0_16:0_16:1)、TG(12:0_ 14:0_18:1)、TG(14:0_16:0_16:1)、TG(14:0_14:1_16:1)、TG(8:0_16:1_16:2)、TG(14:1_16:1_16:1)、TG(16:1_18:1_18:1)、TG(16:0_16:1_20:4)和 TG(15:0_18:1_24:1)可能对分辨作用最大。这些研究结果表明,同时接触双酚 A 和果糖有可能导致脂肪组织的脂质重塑。
{"title":"Widely targeted quantitative lipidomics reveal lipid remodeling in adipose tissue after long term of the combined exposure to bisphenol A and fructose.","authors":"Yonghong Tang, Guifang Ou, Ouyan Rang, Xu Liu, Xiaocheng Liu, Xinru Qin, Guojuan Li, Qing Yang, Mu Wang","doi":"10.1177/09603271241232609","DOIUrl":"10.1177/09603271241232609","url":null,"abstract":"<p><p>Adipose tissue is the main organ that stores lipids and it plays important roles in metabolic balance in the body. We recently reported in Human and Experimental Toxicology that the combined exposure to BPA and fructose may interfere with energy metabolism of adipose tissue. However, it is still unclear whether the combined exposure to BPA and fructose has the possibility to induce lipid remodeling in adipose tissue. In the present study, we performed a widely targeted quantitative lipidomic analysis of the adipose tissue of rats after 6 months of BPA and fructose combined exposure. We totally determined 734 lipid molecules in the adipose tissue of rats. Principal component analysis (PCA) showed the group of the combined exposure to higher-dose (25 μg/kg every other day) BPA and fructose can be distinguished from the groups of control, higher-dose BPA exposure and fructose exposure clearly. Partial least squares-discriminant analysis (PLS-DA) and univariate statistical analysis displayed lipids of PC(18:0_ 20:3), TG(8:0_14:0_16:0), TG(12:0_14:0_16:1), TG(10:0_16:0_16:1), TG(12:0_ 14:0_18:1), TG(14:0_ 16:0_16:1), TG(14:0_14:1_16:1), TG(8:0_ 16:1_16:2), TG(14:1_16:1_ 16:1), TG(16:1_18:1_18:1), TG(16:0_16:1_20:4) and TG(15:0_18:1_ 24:1) may contributed the most to the discrimination. These findings indicated that combined exposure to BPA and fructose has the potential to cause lipid remodeling in adipose tissue.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139699164","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}
Pub Date : 2024-01-01DOI: 10.1177/09603271231218707
Ru Yuan, Chunxia Wu
Background: Bupivacaine (BUP), a long-acting local anesthetic, has been widely used in analgesia and anesthesia. However, evidence strongly suggests that excessive application of BUP may lead to neurotoxicity in neurons. Sphingosine kinase 2 (SPHK2) has been reported to exert neuroprotective effects. In this study, we intended to investigate the potential role and mechanism of SPHK2 in BUP-induced neurotoxicity in dorsal root ganglion (DRG) neurons.
Methods: DRG neurons were cultured with BUP to simulate BUP-induced neurotoxicity in vitro. CCK-8, LDH, and flow cytometry assays were performed to detect the viability, LDH activity, and apoptosis of DRG neurons. RT-qPCR and western blotting was applied to measure gene and protein expression. Levels. MeRIP-qPCR was applied for quantification of m6A modification. RIP-qPCR was used to analyze the interaction between SPHK2 and YTHDF1.
Results: SPHK2 expression significantly declined in DRG neurons upon exposure to BUP. BUP challenge substantially reduced the cell viability and increased the apoptosis rate in DRG neurons, which was partly abolished by SPHK2 upregulation. YTHDF1, an N6-methyladenosine (m6A) reader, promoted SPHK2 expression in BUP-treated DRG neurons in an m6A-dependent manner. YTHDF1 knockdown partly eliminated the increase in SPHK2 protein level and the protection against BUP-triggered neurotoxicity in DRG neurons mediated by SPHK2 overexpression. Moreover, SPHK2 activated the PI3K/AKT signaling to protect against BUP-induced cytotoxic effects on DRG neurons.
Conclusions: In sum, YTHDF1-mediated SPHK2 upregulation ameliorated BUP-induced neurotoxicity in DRG neurons via promoting activation of the PI3K/AKT signaling pathway.
{"title":"YTHDF1-mediated sphingosine kinase 2 upregulation alleviates bupivacaine-induced neurotoxicity via the PI3K/AKT axis.","authors":"Ru Yuan, Chunxia Wu","doi":"10.1177/09603271231218707","DOIUrl":"10.1177/09603271231218707","url":null,"abstract":"<p><strong>Background: </strong>Bupivacaine (BUP), a long-acting local anesthetic, has been widely used in analgesia and anesthesia. However, evidence strongly suggests that excessive application of BUP may lead to neurotoxicity in neurons. Sphingosine kinase 2 (SPHK2) has been reported to exert neuroprotective effects. In this study, we intended to investigate the potential role and mechanism of SPHK2 in BUP-induced neurotoxicity in dorsal root ganglion (DRG) neurons.</p><p><strong>Methods: </strong>DRG neurons were cultured with BUP to simulate BUP-induced neurotoxicity <i>in vitro</i>. CCK-8, LDH, and flow cytometry assays were performed to detect the viability, LDH activity, and apoptosis of DRG neurons. RT-qPCR and western blotting was applied to measure gene and protein expression. Levels. MeRIP-qPCR was applied for quantification of m6A modification. RIP-qPCR was used to analyze the interaction between SPHK2 and YTHDF1.</p><p><strong>Results: </strong>SPHK2 expression significantly declined in DRG neurons upon exposure to BUP. BUP challenge substantially reduced the cell viability and increased the apoptosis rate in DRG neurons, which was partly abolished by SPHK2 upregulation. YTHDF1, an N6-methyladenosine (m6A) reader, promoted SPHK2 expression in BUP-treated DRG neurons in an m6A-dependent manner. YTHDF1 knockdown partly eliminated the increase in SPHK2 protein level and the protection against BUP-triggered neurotoxicity in DRG neurons mediated by SPHK2 overexpression. Moreover, SPHK2 activated the PI3K/AKT signaling to protect against BUP-induced cytotoxic effects on DRG neurons.</p><p><strong>Conclusions: </strong>In sum, YTHDF1-mediated SPHK2 upregulation ameliorated BUP-induced neurotoxicity in DRG neurons via promoting activation of the PI3K/AKT signaling pathway.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140133609","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}
Pub Date : 2024-01-01DOI: 10.1177/09603271241269024
Kwun Lok Cheung, Rex Pui Kin Lam, Chi Keung Chan, Man Li Tse, Matthew Sik Hon Tsui, Timothy Hudson Rainer
Introduction: Cocaine is commonly consumed with ethanol, which leads to the formation of cocaethylene through transesterification. Cocaethylene is an active metabolite of cocaine with a longer duration of action. Literature on the combined toxicity of cocaine, ethanol, and cocaethylene is conflicting. We aimed to compare the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone in Hong Kong.
Methods: This was a retrospective study on acute cocaine toxicities reported to the Hong Kong Poison Control Center from 1 January 2010 to 22 January 2023. Cocaine exposure was confirmed by urine immunoassays/laboratory tests and ethanol co-ingestion was confirmed by blood ethanol concentrations. A serious outcome was defined as a National Poison Data System outcome moderate or above. Univariate analyses and multivariable logistic regression were performed to compare the associations of clinical outcomes with and without ethanol, followed by subgroup analyses of cases with complete data.
Results: We analyzed 109 patients (median age 29 years, 71% men, 68% Chinese), of whom 20 had confirmed ethanol co-ingestion (mean blood ethanol concentration 1350 mg/L). Multivariable analysis showed that co-exposure to cocaine and ethanol was associated with a lower risk of serious outcomes (adjusted odds ratio 0.09, 95% confidence interval 0.01-0.77; p = 0.03) after adjusting for age, sex, ethnicity, route of cocaine administration, and physical health status. Subgroup analyses showed similar findings.
Conclusions: In contrast to previous studies, we did not identify a higher risk of serious outcomes after co-exposure to cocaine and ethanol compared to cocaine alone in a predominantly Chinese cohort.
{"title":"Comparing the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone.","authors":"Kwun Lok Cheung, Rex Pui Kin Lam, Chi Keung Chan, Man Li Tse, Matthew Sik Hon Tsui, Timothy Hudson Rainer","doi":"10.1177/09603271241269024","DOIUrl":"https://doi.org/10.1177/09603271241269024","url":null,"abstract":"<p><strong>Introduction: </strong>Cocaine is commonly consumed with ethanol, which leads to the formation of cocaethylene through transesterification. Cocaethylene is an active metabolite of cocaine with a longer duration of action. Literature on the combined toxicity of cocaine, ethanol, and cocaethylene is conflicting. We aimed to compare the acute toxicities of co-exposure to cocaine and ethanol versus cocaine alone in Hong Kong.</p><p><strong>Methods: </strong>This was a retrospective study on acute cocaine toxicities reported to the Hong Kong Poison Control Center from 1 January 2010 to 22 January 2023. Cocaine exposure was confirmed by urine immunoassays/laboratory tests and ethanol co-ingestion was confirmed by blood ethanol concentrations. A serious outcome was defined as a National Poison Data System outcome moderate or above. Univariate analyses and multivariable logistic regression were performed to compare the associations of clinical outcomes with and without ethanol, followed by subgroup analyses of cases with complete data.</p><p><strong>Results: </strong>We analyzed 109 patients (median age 29 years, 71% men, 68% Chinese), of whom 20 had confirmed ethanol co-ingestion (mean blood ethanol concentration 1350 mg/L). Multivariable analysis showed that co-exposure to cocaine and ethanol was associated with a lower risk of serious outcomes (adjusted odds ratio 0.09, 95% confidence interval 0.01-0.77; <i>p</i> = 0.03) after adjusting for age, sex, ethnicity, route of cocaine administration, and physical health status. Subgroup analyses showed similar findings.</p><p><strong>Conclusions: </strong>In contrast to previous studies, we did not identify a higher risk of serious outcomes after co-exposure to cocaine and ethanol compared to cocaine alone in a predominantly Chinese cohort.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141794318","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}
Pub Date : 2024-01-01DOI: 10.1177/09603271241282584
Hu Liu, Xing-Guo Peng, Ran Gao, Kai Yang, Yan-Bo Zhao
Objective: Environmental factors such as noise and music can significantly impact physiological responses, including inflammation. This study explored how environmental factors like noise and music affect lipopolysaccharide (LPS)-induced inflammation, with a focus on systemic and organ-specific responses.
Materials and methods: 24 Wistar rats were divided into four groups (n = 6 per group): Control group, LPS group, noise-exposed group, and music-exposed group. All rats, except for the Control group, received 10 mg/kg LPS intraperitoneally. The rats in the noise-exposed group were exposed to 95 dB noise, and the music-exposed group listened to Mozart's K. 448 music (65-75 dB) for 1 h daily over 7 days. An enzyme-linked immunosorbent assay was utilized to detect the levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in serum and tissues (lung, liver, and kidney). Western blot examined the phosphorylation levels of nuclear factor-κB (NF-κB) p65 in organ tissues.
Results: Compared with the Control group, LPS-induced sepsis rats displayed a significant increase in the levels of TNF-α and IL-1β in serum, lung, liver, and kidney tissues, as well as a remarkable elevation in the p-NF-κB p65 protein expression in lung, liver, and kidney tissues. Noise exposure further amplified these inflammatory markers, while music exposure reduced them in LPS-induced sepsis rats.
Conclusion: Noise exposure exacerbates inflammation by activating the NF-κB pathway, leading to the up-regulation of inflammatory markers during sepsis. On the contrary, music exposure inhibits NF-κB signaling, indicating a potential therapeutic effect in reducing inflammation.
{"title":"Comparative analysis of noise and music exposure on inflammatory responses on lipopolysaccharide-induced septic rats.","authors":"Hu Liu, Xing-Guo Peng, Ran Gao, Kai Yang, Yan-Bo Zhao","doi":"10.1177/09603271241282584","DOIUrl":"https://doi.org/10.1177/09603271241282584","url":null,"abstract":"<p><strong>Objective: </strong>Environmental factors such as noise and music can significantly impact physiological responses, including inflammation. This study explored how environmental factors like noise and music affect lipopolysaccharide (LPS)-induced inflammation, with a focus on systemic and organ-specific responses.</p><p><strong>Materials and methods: </strong>24 Wistar rats were divided into four groups (<i>n</i> = 6 per group): Control group, LPS group, noise-exposed group, and music-exposed group. All rats, except for the Control group, received 10 mg/kg LPS intraperitoneally. The rats in the noise-exposed group were exposed to 95 dB noise, and the music-exposed group listened to Mozart's K. 448 music (65-75 dB) for 1 h daily over 7 days. An enzyme-linked immunosorbent assay was utilized to detect the levels of inflammatory cytokines, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), in serum and tissues (lung, liver, and kidney). Western blot examined the phosphorylation levels of nuclear factor-κB (NF-κB) p65 in organ tissues.</p><p><strong>Results: </strong>Compared with the Control group, LPS-induced sepsis rats displayed a significant increase in the levels of TNF-α and IL-1β in serum, lung, liver, and kidney tissues, as well as a remarkable elevation in the p-NF-κB p65 protein expression in lung, liver, and kidney tissues. Noise exposure further amplified these inflammatory markers, while music exposure reduced them in LPS-induced sepsis rats.</p><p><strong>Conclusion: </strong>Noise exposure exacerbates inflammation by activating the NF-κB pathway, leading to the up-regulation of inflammatory markers during sepsis. On the contrary, music exposure inhibits NF-κB signaling, indicating a potential therapeutic effect in reducing inflammation.</p>","PeriodicalId":94029,"journal":{"name":"Human & experimental toxicology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143502","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}