Pub Date : 2022-04-11DOI: 10.1080/15376516.2022.2065226
Thalia Emmanoella Sebulsqui Saraiva, Gabriela Zimmermann Prado Rodrigues, Juliana Machado Kayser, E. Dallegrave, Nathália Pulz Maus, Andriele Veiverberg, Gabriel da Costa Berna, Andriéli Carolina Schuster, Maria Gabriela de Freitas, Marina Galdino da Rocha Pitta, I. da Rocha Pitta, G. Gehlen, A. H. Betti
Abstract Schizophrenia is a psychiatric disorder that affects 1% of the world population and is treated with antipsychotics, which may induce important biochemical and hematological alterations. Since it is necessary to verify the safety of new molecules with antipsychotic potential, the present study aimed to evaluate the oral toxicity of PT-31, a putative α2-adrenoreceptor agonist, after acute (2000 mg/kg) and repeated doses (28 days) gavage treatment, in three different doses: minimum effective dose in animal models (10 mg/kg), twice the dose (20 mg/kg), and four times the dose (40 mg/kg), as recommended by the OECD guidelines. Balb/C female adult mice were used, and biochemical, hematological, and histopathological analyses were performed. PT-31 10 and 20 mg/kg did not cause biochemical alterations related to hepatic and renal toxicity, and neither altered glycemic and lipid profiles. The preclinical dose of PT-31 also did not promote mice histopathological changes in the liver, kidney, and brain. In the hematimetric parameters, PT-31 only increased HGB at 20 mg/kg, and MCH and MCHC at 40 mg/kg. However, all the tested doses of PT-31 showed platelet increase, which must be better investigated. Therefore, further studies are needed to investigate the safety of PT-31 as a potential antipsychotic drug.
{"title":"Study of the acute and repeated dose 28-day oral toxicity in mice treated with PT-31, a molecule with a potential antipsychotic profile","authors":"Thalia Emmanoella Sebulsqui Saraiva, Gabriela Zimmermann Prado Rodrigues, Juliana Machado Kayser, E. Dallegrave, Nathália Pulz Maus, Andriele Veiverberg, Gabriel da Costa Berna, Andriéli Carolina Schuster, Maria Gabriela de Freitas, Marina Galdino da Rocha Pitta, I. da Rocha Pitta, G. Gehlen, A. H. Betti","doi":"10.1080/15376516.2022.2065226","DOIUrl":"https://doi.org/10.1080/15376516.2022.2065226","url":null,"abstract":"Abstract Schizophrenia is a psychiatric disorder that affects 1% of the world population and is treated with antipsychotics, which may induce important biochemical and hematological alterations. Since it is necessary to verify the safety of new molecules with antipsychotic potential, the present study aimed to evaluate the oral toxicity of PT-31, a putative α2-adrenoreceptor agonist, after acute (2000 mg/kg) and repeated doses (28 days) gavage treatment, in three different doses: minimum effective dose in animal models (10 mg/kg), twice the dose (20 mg/kg), and four times the dose (40 mg/kg), as recommended by the OECD guidelines. Balb/C female adult mice were used, and biochemical, hematological, and histopathological analyses were performed. PT-31 10 and 20 mg/kg did not cause biochemical alterations related to hepatic and renal toxicity, and neither altered glycemic and lipid profiles. The preclinical dose of PT-31 also did not promote mice histopathological changes in the liver, kidney, and brain. In the hematimetric parameters, PT-31 only increased HGB at 20 mg/kg, and MCH and MCHC at 40 mg/kg. However, all the tested doses of PT-31 showed platelet increase, which must be better investigated. Therefore, further studies are needed to investigate the safety of PT-31 as a potential antipsychotic drug.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"705 - 715"},"PeriodicalIF":3.2,"publicationDate":"2022-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44190544","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-11DOI: 10.1080/15376516.2022.2064257
A. Choudhary, Sanjiv Singh, V. Ravichandiran
Abstract Nanoparticles (range under 100 nm) prepared by different technology modes including physical, chemical, biological have many applications. Like in the same way silver nanoparticles are used for different beneficial actions like antimicrobial- antibacterial, antifungal and antiviral, anti-inflammatory, anticancer, water treatment, cosmetics, and in the textiles industry. As silver nanoparticles have shown wide application by different mechanisms against various pathophyisiological conditions. To maintain safety under their use, the study of the toxicity of silver nanoparticles has become more important. Health agencies like WHO, NIOSH, EPA, EFSA & EU have issued guidelines for unrisky exposure limit of silver nanopartricles in drinking water, food and breathing. The main purpose of this article is to summarize genotoxicity, cytotoxicity, neurotoxicity, reproductive toxicity of silver nanoparticles in both in vitro and in vivo studies focused on mechanism and methods of detection. The main mechanism of silver nanoparticles toxicity involves disruption of the mitochondrial respiratory chain, which results in the generation of ROS and the stoppage of ATP synthesis which further leads to a cascade of toxic events. ROS production measured by the technique like flow cytometry using DCFHDA dye and other method includes a confocal microscope, lipid peroxidation, etc. Different assay techniques used for evaluation of different kind of toxicities such as the comet assay, MTT assay, and histological assay, are also discussed.
{"title":"Toxicity, preparation methods and applications of silver nanoparticles: an update","authors":"A. Choudhary, Sanjiv Singh, V. Ravichandiran","doi":"10.1080/15376516.2022.2064257","DOIUrl":"https://doi.org/10.1080/15376516.2022.2064257","url":null,"abstract":"Abstract Nanoparticles (range under 100 nm) prepared by different technology modes including physical, chemical, biological have many applications. Like in the same way silver nanoparticles are used for different beneficial actions like antimicrobial- antibacterial, antifungal and antiviral, anti-inflammatory, anticancer, water treatment, cosmetics, and in the textiles industry. As silver nanoparticles have shown wide application by different mechanisms against various pathophyisiological conditions. To maintain safety under their use, the study of the toxicity of silver nanoparticles has become more important. Health agencies like WHO, NIOSH, EPA, EFSA & EU have issued guidelines for unrisky exposure limit of silver nanopartricles in drinking water, food and breathing. The main purpose of this article is to summarize genotoxicity, cytotoxicity, neurotoxicity, reproductive toxicity of silver nanoparticles in both in vitro and in vivo studies focused on mechanism and methods of detection. The main mechanism of silver nanoparticles toxicity involves disruption of the mitochondrial respiratory chain, which results in the generation of ROS and the stoppage of ATP synthesis which further leads to a cascade of toxic events. ROS production measured by the technique like flow cytometry using DCFHDA dye and other method includes a confocal microscope, lipid peroxidation, etc. Different assay techniques used for evaluation of different kind of toxicities such as the comet assay, MTT assay, and histological assay, are also discussed.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"650 - 661"},"PeriodicalIF":3.2,"publicationDate":"2022-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47891747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-07DOI: 10.1080/15376516.2022.2063095
C. Miao, Dandan Fan
Abstract Objective In this study, differentially expressed genes (DEGs) and signaling pathways involved in diquat (DQ) and paraquat (PQ) poisoning were identified via bioinformatics analysis, in order to inform the development of novel clinical treatments. Methods Raw data from GSE153959 were downloaded from the Gene Expression Omnibus database. DEGs of the DQ vs. control (CON) and PQ vs. CON comparison groups were identified using R, and DEGs shared by the two groups were identified using TBtools. Subsequently, the shared DEGs were searched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, using the Database for Annotation, Visualization, and Integrated Discovery. A protein–protein interaction (PPI) network was constructed, and hub genes were identified using the cytoHubba plug-in in Cytoscape software. Finally, circos and contrast plots showing the DEGs shared between mouse and human chromosomes were constructed using TBtools. Results Thirty-one DEGs shared by the DQ and PQ groups were identified. Enriched biological process terms included positive regulation of cell proliferation and translation. Enriched cellular component terms included extracellular region, intracellular membrane-bounded organelle and mitochondrion. Enriched molecular function terms included transcription factor activity and sequence-specific double-stranded DNA binding. Enriched KEGG pathways included the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and human T-cell leukemia virus 1 infection. The top 10 hub genes in the PPI network were prostaglandin-endoperoxide synthase 2 (Ptgs2), chemokine (C-X-C motif) ligand 2 (Cxcl2), colony-stimulating factor 2 (granulocyte-macrophage) (Csf2), matrix metallopeptidase 13 (Mmp13), amphiregulin (Areg), plasminogen activator, urokinase receptor (Plaur), fos-like antigen 1 (Fosl1), epiregulin (Ereg), activating transcription factor 3 (Atf3), and transferrin receptor (Tfrc). Cxcl2, Csf2, and Atf3 played important roles in the mitogen-activated protein kinase (MAPK) signaling pathway. Conclusions These pathways and DEGs may serve as targets for gene therapy.
【摘要】目的通过生物信息学分析，鉴定双甘菊(diquat, DQ)和百草枯(paraquat, PQ)中毒相关的差异表达基因(DEGs)和信号通路，为开发新的临床治疗方法提供依据。方法从Gene Expression Omnibus数据库下载GSE153959的原始数据。DQ组与对照组(CON)和PQ组与CON组的deg使用R进行鉴定，两组共有的deg使用TBtools进行鉴定。随后，使用Database for Annotation, Visualization, and Integrated Discovery在Gene Ontology和Kyoto Encyclopedia of Genes and Genomes (KEGG)数据库中检索共享的deg。构建蛋白-蛋白相互作用(PPI)网络，利用Cytoscape软件中的cytoHubba插件对枢纽基因进行鉴定。最后，使用TBtools构建显示小鼠和人类染色体之间共享的deg的环状图和对比图。结果DQ组和PQ组共鉴定出31个deg。丰富的生物过程术语包括细胞增殖和翻译的正调控。丰富的细胞成分包括胞外区、胞内膜结合细胞器和线粒体。富集的分子功能项包括转录因子活性和序列特异性双链DNA结合。富集的KEGG通路包括白细胞介素-17信号通路、肿瘤坏死因子信号通路和人t细胞白血病病毒1感染。PPI网络中排名前10位的枢纽基因分别是前列腺素内过氧化物合成酶2 (Ptgs2)、趋化因子(C-X-C基序)配体2 (Cxcl2)、集落刺激因子2(粒细胞-巨噬细胞)(Csf2)、基质金属肽酶13 (Mmp13)、双调节蛋白(Areg)、纤溶酶原激活剂、尿激酶受体(Plaur)、fos样抗原1 (Fosl1)、表调节蛋白(Ereg)、激活转录因子3 (Atf3)和转铁蛋白受体(Tfrc)。Cxcl2、Csf2和Atf3在丝裂原活化蛋白激酶(MAPK)信号通路中发挥重要作用。结论这些通路和deg可作为基因治疗的靶点。
{"title":"Identification of differentially expressed genes and pathways in diquat and paraquat poisoning using bioinformatics analysis","authors":"C. Miao, Dandan Fan","doi":"10.1080/15376516.2022.2063095","DOIUrl":"https://doi.org/10.1080/15376516.2022.2063095","url":null,"abstract":"Abstract Objective In this study, differentially expressed genes (DEGs) and signaling pathways involved in diquat (DQ) and paraquat (PQ) poisoning were identified via bioinformatics analysis, in order to inform the development of novel clinical treatments. Methods Raw data from GSE153959 were downloaded from the Gene Expression Omnibus database. DEGs of the DQ vs. control (CON) and PQ vs. CON comparison groups were identified using R, and DEGs shared by the two groups were identified using TBtools. Subsequently, the shared DEGs were searched in the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases, using the Database for Annotation, Visualization, and Integrated Discovery. A protein–protein interaction (PPI) network was constructed, and hub genes were identified using the cytoHubba plug-in in Cytoscape software. Finally, circos and contrast plots showing the DEGs shared between mouse and human chromosomes were constructed using TBtools. Results Thirty-one DEGs shared by the DQ and PQ groups were identified. Enriched biological process terms included positive regulation of cell proliferation and translation. Enriched cellular component terms included extracellular region, intracellular membrane-bounded organelle and mitochondrion. Enriched molecular function terms included transcription factor activity and sequence-specific double-stranded DNA binding. Enriched KEGG pathways included the interleukin-17 signaling pathway, tumor necrosis factor signaling pathway, and human T-cell leukemia virus 1 infection. The top 10 hub genes in the PPI network were prostaglandin-endoperoxide synthase 2 (Ptgs2), chemokine (C-X-C motif) ligand 2 (Cxcl2), colony-stimulating factor 2 (granulocyte-macrophage) (Csf2), matrix metallopeptidase 13 (Mmp13), amphiregulin (Areg), plasminogen activator, urokinase receptor (Plaur), fos-like antigen 1 (Fosl1), epiregulin (Ereg), activating transcription factor 3 (Atf3), and transferrin receptor (Tfrc). Cxcl2, Csf2, and Atf3 played important roles in the mitogen-activated protein kinase (MAPK) signaling pathway. Conclusions These pathways and DEGs may serve as targets for gene therapy.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"678 - 685"},"PeriodicalIF":3.2,"publicationDate":"2022-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48208284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-06DOI: 10.1080/15376516.2022.2063096
Jéssica Cristina Zoratto Romoli, Deborah Thais Palma Scanferla, Raul Gomes Aguera, Renata Sano Lini, G. C. Pante, C. B. Bueno Júnior, J. C. Castro, S. Mossini, C. Marchioni, M. M. Junior
Abstract Compilation studies related to toxicological aspects and also biological monitoring and analysis methods for specific fungicides and, mainly, those that belong to the class of the dithiocarbamates (DTCs) have not been carried out at least in the last ten years. DTCs – dimethyldithiocarbamates, ethylenebisditiocarbamates, propylenebisditiocarbamates – are organosulfur compounds that form complexes due to the presence of different chemical elements, which bind strongly and inhibit enzymes that are essential to the functioning of the organism, causing a serious proven adverse effect on biological systems, such as alteration of thyroid hormones, teratogenesis and neurotoxicity. It is still evident, as shown by world data, that the growing consumption of fungicides has increasingly exposed the population in general and, in particular, workers who deal with these substances. There is a scarcity of studies in the literature discussing the toxicological and analytical aspects that are important for understanding the real effects of DTCs and monitoring human exposure to them. Therefore, the aim of this work was to expose, in a comprehensive way and through a narrative review, gaps in research related to the fungicides of the DTCs class, their metabolites, as well as the toxicological and analytical aspects involved. The review is divided into two parts: (1) Toxicological aspects, including toxicokinetics, toxicodynamics and toxidromes; and (2) Analytical Toxicology, which comprises biomarkers, sample preparation and identification/quantification methods. Graphical Abstract
{"title":"Analytical and toxicological aspects of dithiocarbamates: an overview of the last 10 years","authors":"Jéssica Cristina Zoratto Romoli, Deborah Thais Palma Scanferla, Raul Gomes Aguera, Renata Sano Lini, G. C. Pante, C. B. Bueno Júnior, J. C. Castro, S. Mossini, C. Marchioni, M. M. Junior","doi":"10.1080/15376516.2022.2063096","DOIUrl":"https://doi.org/10.1080/15376516.2022.2063096","url":null,"abstract":"Abstract Compilation studies related to toxicological aspects and also biological monitoring and analysis methods for specific fungicides and, mainly, those that belong to the class of the dithiocarbamates (DTCs) have not been carried out at least in the last ten years. DTCs – dimethyldithiocarbamates, ethylenebisditiocarbamates, propylenebisditiocarbamates – are organosulfur compounds that form complexes due to the presence of different chemical elements, which bind strongly and inhibit enzymes that are essential to the functioning of the organism, causing a serious proven adverse effect on biological systems, such as alteration of thyroid hormones, teratogenesis and neurotoxicity. It is still evident, as shown by world data, that the growing consumption of fungicides has increasingly exposed the population in general and, in particular, workers who deal with these substances. There is a scarcity of studies in the literature discussing the toxicological and analytical aspects that are important for understanding the real effects of DTCs and monitoring human exposure to them. Therefore, the aim of this work was to expose, in a comprehensive way and through a narrative review, gaps in research related to the fungicides of the DTCs class, their metabolites, as well as the toxicological and analytical aspects involved. The review is divided into two parts: (1) Toxicological aspects, including toxicokinetics, toxicodynamics and toxidromes; and (2) Analytical Toxicology, which comprises biomarkers, sample preparation and identification/quantification methods. Graphical Abstract","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"637 - 649"},"PeriodicalIF":3.2,"publicationDate":"2022-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44524905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-04DOI: 10.1080/15376516.2022.2062271
T. R. R. Lima, Estela de Oliveira Lima, J. Delafiori, Rodrigo Ramos Catharino, J. L. Viana de Camargo, L. C. Pereira
Abstract Diuron, 3-(3,4-dichlorophenyl)-1,1-dimethylurea, is a worldwide used herbicide whose biotransformation gives rise to the metabolites, 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU) and 3,4-dichloroaniline (DCA). Previous studies indicate that diuron and/or its metabolites are toxic to the bladder urothelium of the Wistar rats where, under certain conditions of exposure, they may induce successively urothelial cell degeneration, necrosis, hyperplasia and eventually tumors. The hypothesis was raised that the molecular initiating event (MIE) of this Adverse Outcome Pathway is the mitochondrial toxicity of those compounds. Therefore, this study aimed to investigate in vitro the metabolic alterations resulting from urothelial mitochondria isolated from male Wistar rats exposure to diuron, DCPMU and DCA at 10 and 100 µM. A non-targeted metabolomic analysis using mass spectrometry showed discriminative clustering among groups and alterations in the intensity abundance of membrane-associated molecules phosphatidylcholine, phosphatidylinositol and phosphatidylserine, in addition to methylhexanoyl-CoA and, particularly for diuron 100 µM, dehydro-L-gulonate, all of them involved in critical mitochondrial metabolism. Collectively, these data indicate the mitochondrial dysfunction as an MIE that triggers cellular damage and death observed in previous studies.
{"title":"Molecular signatures associated with diuron exposure on rat urothelial mitochondria","authors":"T. R. R. Lima, Estela de Oliveira Lima, J. Delafiori, Rodrigo Ramos Catharino, J. L. Viana de Camargo, L. C. Pereira","doi":"10.1080/15376516.2022.2062271","DOIUrl":"https://doi.org/10.1080/15376516.2022.2062271","url":null,"abstract":"Abstract Diuron, 3-(3,4-dichlorophenyl)-1,1-dimethylurea, is a worldwide used herbicide whose biotransformation gives rise to the metabolites, 3-(3,4-dichlorophenyl)-1-methylurea (DCPMU) and 3,4-dichloroaniline (DCA). Previous studies indicate that diuron and/or its metabolites are toxic to the bladder urothelium of the Wistar rats where, under certain conditions of exposure, they may induce successively urothelial cell degeneration, necrosis, hyperplasia and eventually tumors. The hypothesis was raised that the molecular initiating event (MIE) of this Adverse Outcome Pathway is the mitochondrial toxicity of those compounds. Therefore, this study aimed to investigate in vitro the metabolic alterations resulting from urothelial mitochondria isolated from male Wistar rats exposure to diuron, DCPMU and DCA at 10 and 100 µM. A non-targeted metabolomic analysis using mass spectrometry showed discriminative clustering among groups and alterations in the intensity abundance of membrane-associated molecules phosphatidylcholine, phosphatidylinositol and phosphatidylserine, in addition to methylhexanoyl-CoA and, particularly for diuron 100 µM, dehydro-L-gulonate, all of them involved in critical mitochondrial metabolism. Collectively, these data indicate the mitochondrial dysfunction as an MIE that triggers cellular damage and death observed in previous studies.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"628 - 635"},"PeriodicalIF":3.2,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43716828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-04-04DOI: 10.1080/15376516.2022.2057264
H. Aboutalebi, F. Alipour, A. Ebrahimzadeh-Bideskan
Abstract Cyclophosphamide (CP), as an antineoplastic agent, causes premature ovarian failure (POF) due to ovarian toxicity and subsequent infertility in women. Platelet-rich plasma (PRP) has accumulated significant attention in regenerative medicine. Pentoxifylline (PTX) as a methylxanthine derivative has been shown to have antioxidant and antiapoptotic properties. The aim of this study was to evaluate the protective effect of PRP and PTX on CP-induced POF. Fifty mature and immature female rats were assigned into five groups: control, CP (75 mg/kg, intraperitoneal [ip] on days 1 and 10 to induce POF), CP + PRP (200 μl, ip, half an hour after CP injection on day 1 and 10), CP + PTX (50 mg/kg, orally, half an hour after CP injection daily for 21 day), and CP + PRP + PTX. At the end of experiments on day 21, measurement of body weight, ovarian parameters (ovarian volume, follicular granulosa cell layers diameter, oocyte diameter, and the number of granulosa cells), measurement of ovarian hormone in sera for estradiol (E2), and anti-Mullerian hormone (AMH), as well as biochemical assessment were performed. The results showed that CP significantly reduced the ovarian parameters, E2, AMH, superoxide dismutase (SOD) activity and increased Malondialdehyde (MDA) levels compared to the control group (p < 0.001). Our results also indicated that all histomorphometric parameters and biochemical markers in CP-induced POF, were preserved close to normal by PRP and PTX treatments in both mature and immature rats (p < 0.001). Therefore, it is concluded that the co-administration of PRP and PTX can protect the ovary from CP-induced POF. Graphical Abstract
{"title":"The protective effect of co-administration of platelet-rich plasma (PRP) and pentoxifylline (PTX) on cyclophosphamide-induced premature ovarian failure in mature and immature rats","authors":"H. Aboutalebi, F. Alipour, A. Ebrahimzadeh-Bideskan","doi":"10.1080/15376516.2022.2057264","DOIUrl":"https://doi.org/10.1080/15376516.2022.2057264","url":null,"abstract":"Abstract Cyclophosphamide (CP), as an antineoplastic agent, causes premature ovarian failure (POF) due to ovarian toxicity and subsequent infertility in women. Platelet-rich plasma (PRP) has accumulated significant attention in regenerative medicine. Pentoxifylline (PTX) as a methylxanthine derivative has been shown to have antioxidant and antiapoptotic properties. The aim of this study was to evaluate the protective effect of PRP and PTX on CP-induced POF. Fifty mature and immature female rats were assigned into five groups: control, CP (75 mg/kg, intraperitoneal [ip] on days 1 and 10 to induce POF), CP + PRP (200 μl, ip, half an hour after CP injection on day 1 and 10), CP + PTX (50 mg/kg, orally, half an hour after CP injection daily for 21 day), and CP + PRP + PTX. At the end of experiments on day 21, measurement of body weight, ovarian parameters (ovarian volume, follicular granulosa cell layers diameter, oocyte diameter, and the number of granulosa cells), measurement of ovarian hormone in sera for estradiol (E2), and anti-Mullerian hormone (AMH), as well as biochemical assessment were performed. The results showed that CP significantly reduced the ovarian parameters, E2, AMH, superoxide dismutase (SOD) activity and increased Malondialdehyde (MDA) levels compared to the control group (p < 0.001). Our results also indicated that all histomorphometric parameters and biochemical markers in CP-induced POF, were preserved close to normal by PRP and PTX treatments in both mature and immature rats (p < 0.001). Therefore, it is concluded that the co-administration of PRP and PTX can protect the ovary from CP-induced POF. Graphical Abstract","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"588 - 596"},"PeriodicalIF":3.2,"publicationDate":"2022-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45848105","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-30DOI: 10.1080/15376516.2022.2057267
Susan M. Britza, I. Musgrave, R. Byard
Abstract Hepatotoxicity is a well-known adverse effect of many substances, with toxicity often resulting from interactions of drugs with other drug-like substances. With the increased availability of complementary and alternative medicines, including herbal medicines, the likelihood of adverse interactions between drugs and drug-like substances in herbs increases. However, the impact of potential herb-herb interactions is little understood. To assess the potential of two cytochrome P450 enzyme modulating phytochemicals common to many herbal medicines, atractylenolide I (ATR-I) and astragaloside IV (AST-IV), to interact with coumarin, another phytochemical common in many foods, a hepatocyte function model with a liver carcinoma cell line, HepG2, was exposed to these agents. To determine the effects of cytochrome P450 modulation by these phytochemicals certain cells were induced with rifampicin to induce cytochrome P450. Increasing concentrations of ATR-I combined with a fixed, nontoxic concentration of coumarin (200 µM), demonstrated significant additive interactions. 300 µM ATR-I produced a 31% reduction in cell viability (p < 0.01) with coumarin in rifampicin uninduced cells. In rifampicin-induced cells, ATR-I (100–300 µM) produced a significant reduction in cell viability (p < 0.01) with coumarin (200 µM). AST-IV with fixed coumarin (200 µM) showed 27% toxicity at 300 µM AST-IV in rifampicin uninduced cells (p < 0.05) and 30% toxicity in rifampicin induced cells (p < 0.05). However, when fixed coumarin and AST-IV were combined with increasing concentrations of ATR-I no further significant increase in toxicity was observed (p > 0.05). These results demonstrate the potential toxic interactive capabilities of common traditional Chinese herbal medicine phytochemicals and underline the potential importance of coumarin-mediated toxicity.
{"title":"Implications for herbal polypharmacy: coumarin-induced hepatotoxicity increased through common herbal phytochemicals astragaloside IV and atractylenolide I","authors":"Susan M. Britza, I. Musgrave, R. Byard","doi":"10.1080/15376516.2022.2057267","DOIUrl":"https://doi.org/10.1080/15376516.2022.2057267","url":null,"abstract":"Abstract Hepatotoxicity is a well-known adverse effect of many substances, with toxicity often resulting from interactions of drugs with other drug-like substances. With the increased availability of complementary and alternative medicines, including herbal medicines, the likelihood of adverse interactions between drugs and drug-like substances in herbs increases. However, the impact of potential herb-herb interactions is little understood. To assess the potential of two cytochrome P450 enzyme modulating phytochemicals common to many herbal medicines, atractylenolide I (ATR-I) and astragaloside IV (AST-IV), to interact with coumarin, another phytochemical common in many foods, a hepatocyte function model with a liver carcinoma cell line, HepG2, was exposed to these agents. To determine the effects of cytochrome P450 modulation by these phytochemicals certain cells were induced with rifampicin to induce cytochrome P450. Increasing concentrations of ATR-I combined with a fixed, nontoxic concentration of coumarin (200 µM), demonstrated significant additive interactions. 300 µM ATR-I produced a 31% reduction in cell viability (p < 0.01) with coumarin in rifampicin uninduced cells. In rifampicin-induced cells, ATR-I (100–300 µM) produced a significant reduction in cell viability (p < 0.01) with coumarin (200 µM). AST-IV with fixed coumarin (200 µM) showed 27% toxicity at 300 µM AST-IV in rifampicin uninduced cells (p < 0.05) and 30% toxicity in rifampicin induced cells (p < 0.05). However, when fixed coumarin and AST-IV were combined with increasing concentrations of ATR-I no further significant increase in toxicity was observed (p > 0.05). These results demonstrate the potential toxic interactive capabilities of common traditional Chinese herbal medicine phytochemicals and underline the potential importance of coumarin-mediated toxicity.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"606 - 615"},"PeriodicalIF":3.2,"publicationDate":"2022-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"44260297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-27DOI: 10.1080/15376516.2022.2058898
M. Dey, R. Singh
Abstract Aluminum is an environmentally abundant potential neurotoxic agent that may result in oxidative damage to a range of cellular biomarkers. The potential sources of aluminum accumulation in the body include drinking water, food, medicines, vaccines, and aluminum cookware utensils, etc. The accumulation of aluminum in the brain is reported to be associated with cholinergic dysfunction, oxidative stress and neuronal damage, which may ultimately cause Alzheimer’s disease. Since chronic exposure to aluminum leads to its accumulation in the brain, so this study was done by a long-term (24 weeks) low dose (20 mg/kg) oral exposure of aluminum chloride in rats. In this chronic model, we have evaluated the major hallmarks of Alzheimer’s disease including amyloid-beta (Aβ1–42) and phosphorylated-tau (p231-tau) protein in brain tissue. Furthermore, we evaluated the level of acetyl cholinesterase activity, inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and oxidative stress biomarkers in the rat brain in this model. The neurobehavioral parameters were also assessed in animals by using spontaneous locomotor activity, passive avoidance, rotarod test and novel object recognition test to evaluate alteration in learning, memory and muscle co-ordination. We found that chronic oral exposure to aluminum chloride causes a significant increase in structural hallmarks such as Aβ1–42 and p231-tau levels along with pro-inflammatory cytokines (TNF-α and IL-6), oxidative stress, and a decrease in antioxidant markers such as GSH and catalase in the brain tissue. These biomarkers significantly affected neurobehavioral parameters in animals. This study provides a mechanistic understanding of chronic aluminum-induced neuronal toxicity in the brain with relevance to Alzheimer’s disease.
{"title":"Chronic oral exposure of aluminum chloride in rat modulates molecular and functional neurotoxic markers relevant to Alzheimer’s disease","authors":"M. Dey, R. Singh","doi":"10.1080/15376516.2022.2058898","DOIUrl":"https://doi.org/10.1080/15376516.2022.2058898","url":null,"abstract":"Abstract Aluminum is an environmentally abundant potential neurotoxic agent that may result in oxidative damage to a range of cellular biomarkers. The potential sources of aluminum accumulation in the body include drinking water, food, medicines, vaccines, and aluminum cookware utensils, etc. The accumulation of aluminum in the brain is reported to be associated with cholinergic dysfunction, oxidative stress and neuronal damage, which may ultimately cause Alzheimer’s disease. Since chronic exposure to aluminum leads to its accumulation in the brain, so this study was done by a long-term (24 weeks) low dose (20 mg/kg) oral exposure of aluminum chloride in rats. In this chronic model, we have evaluated the major hallmarks of Alzheimer’s disease including amyloid-beta (Aβ1–42) and phosphorylated-tau (p231-tau) protein in brain tissue. Furthermore, we evaluated the level of acetyl cholinesterase activity, inflammatory cytokines such as TNF-α, IL-6 and IL-1β, and oxidative stress biomarkers in the rat brain in this model. The neurobehavioral parameters were also assessed in animals by using spontaneous locomotor activity, passive avoidance, rotarod test and novel object recognition test to evaluate alteration in learning, memory and muscle co-ordination. We found that chronic oral exposure to aluminum chloride causes a significant increase in structural hallmarks such as Aβ1–42 and p231-tau levels along with pro-inflammatory cytokines (TNF-α and IL-6), oxidative stress, and a decrease in antioxidant markers such as GSH and catalase in the brain tissue. These biomarkers significantly affected neurobehavioral parameters in animals. This study provides a mechanistic understanding of chronic aluminum-induced neuronal toxicity in the brain with relevance to Alzheimer’s disease.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"616 - 627"},"PeriodicalIF":3.2,"publicationDate":"2022-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46410488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-17DOI: 10.1080/15376516.2022.2054749
Lakshmi Jaya Madhuri B, Neelima Ayyalasomayajula, Lokesh Murumulla, P. K. Dixit, C. Suresh
Abstract Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer’s Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/Parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and Parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and Parkin in cells exposed to Pb and β–amyloid peptides, both Aβ (25-35) and Aβ (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aβ peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and β–amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/Parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity.
{"title":"Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and Parkin in Pb and β-amyloid peptide induced toxicity","authors":"Lakshmi Jaya Madhuri B, Neelima Ayyalasomayajula, Lokesh Murumulla, P. K. Dixit, C. Suresh","doi":"10.1080/15376516.2022.2054749","DOIUrl":"https://doi.org/10.1080/15376516.2022.2054749","url":null,"abstract":"Abstract Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer’s Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/Parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and Parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and Parkin in cells exposed to Pb and β–amyloid peptides, both Aβ (25-35) and Aβ (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aβ peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and β–amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/Parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"559 - 568"},"PeriodicalIF":3.2,"publicationDate":"2022-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"59851344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-14DOI: 10.1080/15376516.2022.2053918
A. Toropov, A. Toropova, P. Achary, M. Rasková, I. Raška
Abstract Robust quantitative structure-activity relationships (QSARs) for hBACE-1 inhibitors (pIC50) for a large database (n = 1706) are established. New statistical criteria of the predictive potential of models are suggested and tested. These criteria are the index of ideality of correlation (IIC) and the correlation intensity index (CII). The system of self-consistent models is a new approach to validate the predictive potential of QSAR-models. The statistical quality of models obtained using the CORAL software (http://www.insilico.eu/coral) for the validation sets is characterized by the average determination coefficient R2 v= 0.923, and RMSE = 0.345. Three new promising molecular structures which can become inhibitors hBACE-1 are suggested.
{"title":"The searching for agents for Alzheimer’s disease treatment via the system of self-consistent models","authors":"A. Toropov, A. Toropova, P. Achary, M. Rasková, I. Raška","doi":"10.1080/15376516.2022.2053918","DOIUrl":"https://doi.org/10.1080/15376516.2022.2053918","url":null,"abstract":"Abstract Robust quantitative structure-activity relationships (QSARs) for hBACE-1 inhibitors (pIC50) for a large database (n = 1706) are established. New statistical criteria of the predictive potential of models are suggested and tested. These criteria are the index of ideality of correlation (IIC) and the correlation intensity index (CII). The system of self-consistent models is a new approach to validate the predictive potential of QSAR-models. The statistical quality of models obtained using the CORAL software (http://www.insilico.eu/coral) for the validation sets is characterized by the average determination coefficient R2 v= 0.923, and RMSE = 0.345. Three new promising molecular structures which can become inhibitors hBACE-1 are suggested.","PeriodicalId":49117,"journal":{"name":"Toxicology Mechanisms and Methods","volume":"32 1","pages":"549 - 557"},"PeriodicalIF":3.2,"publicationDate":"2022-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45725599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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