Pub Date : 2024-11-22DOI: 10.1016/j.taap.2024.117163
Lo-Wei Lin, Allison K. Ehrlich, Robert H. Rice
Serially passaged rat keratinocytes exhibit dramatically attenuated induction of Cyp1a1 by aryl hydrocarbon receptor ligands such as TCDD. However, the sensitivity to induction can be restored by protein synthesis inhibition. Previous work revealed that the functionality of the receptor was not affected by passaging. The present work explored the possibility of epigenetic silencing on CYP1A1 inducibility in both rat and human cells. Use of an array of small molecule epigenetic modulators demonstrated that inhibition of histone deacetylases mimicked the effect of protein synthesis inhibition. Consistent with this finding, cycloheximide treatment also reduced histone deacetylase activity. More importantly, when compared to human CYP1A1, rat Cyp1a1 exhibited much greater sensitivity toward epigenetic modulators, particularly inhibitors of histone deacetylases. Other genes in the aryl hydrocarbon receptor domain showed variable and less dramatic responses to histone deacetylase inhibitors. These findings highlight a potential species difference in epigenetics that must be considered when extrapolating results from rodent models to humans and has implications for xenobiotic- or drug-drug interactions where CYP1A1 activity plays an important role.
{"title":"Epigenetic modifications control CYP1A1 Inducibility in human and rat keratinocytes","authors":"Lo-Wei Lin, Allison K. Ehrlich, Robert H. Rice","doi":"10.1016/j.taap.2024.117163","DOIUrl":"10.1016/j.taap.2024.117163","url":null,"abstract":"<div><div>Serially passaged rat keratinocytes exhibit dramatically attenuated induction of <em>Cyp1a1</em> by aryl hydrocarbon receptor ligands such as TCDD. However, the sensitivity to induction can be restored by protein synthesis inhibition. Previous work revealed that the functionality of the receptor was not affected by passaging. The present work explored the possibility of epigenetic silencing on CYP1A1 inducibility in both rat and human cells. Use of an array of small molecule epigenetic modulators demonstrated that inhibition of histone deacetylases mimicked the effect of protein synthesis inhibition. Consistent with this finding, cycloheximide treatment also reduced histone deacetylase activity. More importantly, when compared to human <em>CYP1A1</em>, rat <em>Cyp1a1</em> exhibited much greater sensitivity toward epigenetic modulators, particularly inhibitors of histone deacetylases. Other genes in the aryl hydrocarbon receptor domain showed variable and less dramatic responses to histone deacetylase inhibitors. These findings highlight a potential species difference in epigenetics that must be considered when extrapolating results from rodent models to humans and has implications for xenobiotic- or drug-drug interactions where CYP1A1 activity plays an important role.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117163"},"PeriodicalIF":3.3,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142695807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bisphenol-A (BPA) analogues seem inevitable components of numerous domestic products, but these have been identified as agents of teratogenic disorders. This study, therefore, investigated the effect of thymoquinone (TMQ) on the striatum of hypertensive female rats and their F1 male offsprings, on exposure to a mixture of Bisphenol-B, Bisphenol-F and Bisphenol-S (MBFS). Female rats were divided into normotensive and hypertensive groups; and both were treated with MBFS only, MBFS + TMQ, and TMQ only. Exposure to MBFS and co-treatment with TMQ lasted at least 63 days. Neurobehavioural assessments were conducted using Open Field (OF). A spectrophotometer was used for cholinergic, dopaminergic and adenosinergic enzyme assays; Real-Time PCR for gene expression; and immunohistochemistry for protein quantification; while H&E, cresyl fast violent, and congo red stains were used for histological assessments. From the results, maternal exposure to MBFS mediated striatal dysfunction via p53 and NF-kB upregulation; decreased BCl-2, Ki-67 and NeuN; increased GFAP, nissl bodies and β-amyloid. Dysregulation of cholinergic, dopaminergic and adenosinergic enzymes in addition to decreased nitric oxide levels were also associated with MBFS toxicity. Hypertension was found to exacerbate MBFS toxicity. From OF test; increased anxiety and decreased psychomotor activity were associated with maternal exposure to MBFS. However, co-treatment with thymoquinone prevented striatal dysfunction in hypertensive dams and their F1 male offspring. In conclusion, disruption of the delicate balance between apoptosis and cell proliferation culminating in the reduction of mature neurons is responsible for neurodegeneration and neuropathy associated with MBFS exposure. However, these can be prevented through regular consumption of natural products and supplements rich in thymoquinone.
{"title":"Thymoquinone inhibits Neuroinflammatory mediators and vasoconstriction injury via NF-κB dependent NeuN/GFAP/Ki-67 in hypertensive Dams and F1 male pups on exposure to a mixture of Bisphenol-A analogues","authors":"O.S. Okoh , J.K. Akintunde , A.J. Akamo , Ubong Akpan","doi":"10.1016/j.taap.2024.117162","DOIUrl":"10.1016/j.taap.2024.117162","url":null,"abstract":"<div><div>Bisphenol-A (BPA) analogues seem inevitable components of numerous domestic products, but these have been identified as agents of teratogenic disorders. This study, therefore, investigated the effect of thymoquinone (TMQ) on the striatum of hypertensive female rats and their F1 male offsprings, on exposure to a mixture of Bisphenol-B, Bisphenol-F and Bisphenol-S (MBFS). Female rats were divided into normotensive and hypertensive groups; and both were treated with MBFS only, MBFS + TMQ, and TMQ only. Exposure to MBFS and co-treatment with TMQ lasted at least 63 days. Neurobehavioural assessments were conducted using Open Field (OF). A spectrophotometer was used for cholinergic, dopaminergic and adenosinergic enzyme assays; Real-Time PCR for gene expression; and immunohistochemistry for protein quantification; while H&E, cresyl fast violent, and congo red stains were used for histological assessments. From the results, maternal exposure to MBFS mediated striatal dysfunction via p53 and NF-kB upregulation; decreased BCl-2, Ki-67 and NeuN; increased GFAP, nissl bodies and β-amyloid. Dysregulation of cholinergic, dopaminergic and adenosinergic enzymes in addition to decreased nitric oxide levels were also associated with MBFS toxicity. Hypertension was found to exacerbate MBFS toxicity. From OF test; increased anxiety and decreased psychomotor activity were associated with maternal exposure to MBFS. However, co-treatment with thymoquinone prevented striatal dysfunction in hypertensive dams and their F1 male offspring. In conclusion, disruption of the delicate balance between apoptosis and cell proliferation culminating in the reduction of mature neurons is responsible for neurodegeneration and neuropathy associated with MBFS exposure. However, these can be prevented through regular consumption of natural products and supplements rich in thymoquinone.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117162"},"PeriodicalIF":3.3,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1016/j.taap.2024.117161
Chaocheng Wang , Hui Hu , Junzhao Liu , Xia Rong , Jing Zhang , Yu Du
Brain injury following acute diquat poisoning has become increasingly common in moderate to severe cases, with unclear pathogenesis and high mortality. To investigate this, we conducted metabolomics on brain tissue from poisoned rats, combined with clinical biochemical and pathological analyses. In the high-dose group, 24 metabolites showed significant differences compared to the control group: 18 were upregulated, including cytosine, sedoheptulose-7-phosphate, indole, 3-dehydroshikimate, etc.; 6 were downregulated, including 6-phosphogluconic acid, 3-hydroxybenzoic acid, dAMP, etc. In the low-dose group, 10 metabolites showed significant differences: 4 were upregulated, including pentamidine, γ-tocotrienol, benzoylecgonine, etc.; and 6 were downregulated, including dAMP, glutathione, 3-hydroxybenzoic acid, etc. Enrichment analysis identified two key pathways—phenylalanine, tyrosine, and tryptophan biosynthesis, and the pentose phosphate pathway—as involved in brain injury. ROC analysis of six differential metabolites showed that sedoheptulose-7-phosphate, (2R)-2-hydroxy-3-(phosphonatooxy)propanoate, and 3-hydroxybenzoic acid had AUC values above 0.8. These findings suggest that these three metabolites demonstrate strong diagnostic potential for brain injury induced by diquat poisoning. Correlation analysis linked these biomarkers to clinical indicators such as neutrophil count and the eutrophil to lymphocyte ratio, supporting their relevance. This study provides insights into the mechanisms and biomarkers of diquat-induced brain injury, offering a foundation for future treatment and rapid detection.
{"title":"Study on the mechanism of brain injury caused by acute diquat poisoning based on metabolomics","authors":"Chaocheng Wang , Hui Hu , Junzhao Liu , Xia Rong , Jing Zhang , Yu Du","doi":"10.1016/j.taap.2024.117161","DOIUrl":"10.1016/j.taap.2024.117161","url":null,"abstract":"<div><div>Brain injury following acute diquat poisoning has become increasingly common in moderate to severe cases, with unclear pathogenesis and high mortality. To investigate this, we conducted metabolomics on brain tissue from poisoned rats, combined with clinical biochemical and pathological analyses. In the high-dose group, 24 metabolites showed significant differences compared to the control group: 18 were upregulated, including cytosine, sedoheptulose-7-phosphate, indole, 3-dehydroshikimate, etc.; 6 were downregulated, including 6-phosphogluconic acid, 3-hydroxybenzoic acid, dAMP, etc. In the low-dose group, 10 metabolites showed significant differences: 4 were upregulated, including pentamidine, γ-tocotrienol, benzoylecgonine, etc.; and 6 were downregulated, including dAMP, glutathione, 3-hydroxybenzoic acid, etc. Enrichment analysis identified two key pathways—phenylalanine, tyrosine, and tryptophan biosynthesis, and the pentose phosphate pathway—as involved in brain injury. ROC analysis of six differential metabolites showed that sedoheptulose-7-phosphate, (2<em>R</em>)-2-hydroxy-3-(phosphonatooxy)propanoate, and 3-hydroxybenzoic acid had AUC values above 0.8. These findings suggest that these three metabolites demonstrate strong diagnostic potential for brain injury induced by diquat poisoning. Correlation analysis linked these biomarkers to clinical indicators such as neutrophil count and the eutrophil to lymphocyte ratio, supporting their relevance. This study provides insights into the mechanisms and biomarkers of diquat-induced brain injury, offering a foundation for future treatment and rapid detection.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117161"},"PeriodicalIF":3.3,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142688570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-17DOI: 10.1016/j.taap.2024.117158
Zhicheng Deng , Mengdie Ou , Yonghui Shi , Guocheng Li , Li Lv
Ginsenoside Rg3 (Rg3), a bioactive compound from ginseng, is gaining attention for its potential in targeting cancer stem cells in cancer therapy. The therapeutic effect of Rg3 on breast cancer stem cells (BCSCs) has not been systematically explored using a suitable approach. Our study leverages a multi-faceted strategy, including network pharmacology, molecular docking, and in vitro experiments validation, to explore the effect of Rg3 against BCSCs. We identified 38 common targets of Rg3 and BCSCs through public databases mining. The analysis of protein-protein interaction network revealed Myc, Stat3, Bcl2, Cdh1, Egf, Il6, Egfr, Nfkb1, Sox2 and Sirt1 as the top 10 potential targets. Molecular docking further validated Rg3 has robust binding potential with these targets. Utilizing the BCSC-enriched MCF-7 and MDA-MB-231 mammosphere model, in vitro experiments substantiated Rg3's ability to induce apoptosis, suppress proliferation, and inhibit mammospheres formation of BCSCs. Rg3 also decreased the ALDHhigh and CD44+/CD24−/low subpopulations and downregulated the expression of cancer stem cell markers such as c-MYC, ALDH1A1, NANOG in BCSCs. After Rg3 treatment, most of the top 10 genes in BCSC-enriched MCF-7 mammospheres showed a significant reduction in expression, with Cdh1 (E-cadherin) being the most markedly downregulated. The E-cadherin/catenin complex acts as an upstream regulator of the Hippo signaling pathway, which is crucial for BCSC function and is among the top 20 enriched pathways identified by KEGG analysis. Mechanistically, Rg3 attenuates the stemness of BCSCs by activating the Hippo signaling pathway. This study provides a comprehensive evaluation of Rg3 as a promising therapeutic agent against BCSCs.
{"title":"Ginsenoside Rg3 attenuates the stemness of breast cancer stem cells by activating the hippo signaling pathway","authors":"Zhicheng Deng , Mengdie Ou , Yonghui Shi , Guocheng Li , Li Lv","doi":"10.1016/j.taap.2024.117158","DOIUrl":"10.1016/j.taap.2024.117158","url":null,"abstract":"<div><div>Ginsenoside Rg3 (Rg3), a bioactive compound from ginseng, is gaining attention for its potential in targeting cancer stem cells in cancer therapy. The therapeutic effect of Rg3 on breast cancer stem cells (BCSCs) has not been systematically explored using a suitable approach. Our study leverages a multi-faceted strategy, including network pharmacology, molecular docking, and <em>in vitro</em> experiments validation, to explore the effect of Rg3 against BCSCs. We identified 38 common targets of Rg3 and BCSCs through public databases mining. The analysis of protein-protein interaction network revealed <em>Myc</em>, <em>Stat3</em>, <em>Bcl2</em>, <em>Cdh1</em>, <em>Egf</em>, <em>Il6</em>, <em>Egfr</em>, <em>Nfkb1</em>, <em>Sox2</em> and <em>Sirt1</em> as the top 10 potential targets. Molecular docking further validated Rg3 has robust binding potential with these targets. Utilizing the BCSC-enriched MCF-7 and MDA-MB-231 mammosphere model, <em>in vitro</em> experiments substantiated Rg3's ability to induce apoptosis, suppress proliferation, and inhibit mammospheres formation of BCSCs. Rg3 also decreased the ALDH<sup>high</sup> and CD44<sup>+</sup>/CD24<sup>−/low</sup> subpopulations and downregulated the expression of cancer stem cell markers such as c-MYC, ALDH1A1, NANOG in BCSCs. After Rg3 treatment, most of the top 10 genes in BCSC-enriched MCF-7 mammospheres showed a significant reduction in expression, with <em>Cdh1</em> (E-cadherin) being the most markedly downregulated. The E-cadherin/catenin complex acts as an upstream regulator of the Hippo signaling pathway, which is crucial for BCSC function and is among the top 20 enriched pathways identified by KEGG analysis. Mechanistically, Rg3 attenuates the stemness of BCSCs by activating the Hippo signaling pathway. This study provides a comprehensive evaluation of Rg3 as a promising therapeutic agent against BCSCs.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117158"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-17DOI: 10.1016/j.taap.2024.117157
Eduardo Makiyama Klosowski , Byanca Thais Lima de Souza , Letícia Fernanda Nanami , Paulo Francisco Veiga Bizerra , Márcio Shigueaki Mito , Giovana Natiele Machado Esquissato , Renato Polimeni Constantin , Breno Miguel Joia , Paulo Vinicius Moreira da Costa Menezes , Wilker Caetano , Paulo Cesar de Souza Pereira , Renato Sonchini Gonçalves , Francielle Pelegrin Garcia , Danielle Lazarin Bidoia , Tânia Ueda Nakamura , Celso Vataru Nakamura , Emy Luiza Ishii-Iwamoto , Wanderley Dantas dos Santos , Osvaldo Ferrarese-Filho , Rogério Marchiosi , Rodrigo Polimeni Constantin
Previous research has revealed that mitochondria are an important target for photodynamic therapy (PDT), which might be employed as a therapeutic approach for several malignancies, including hepatocellular carcinoma (HCC). In this study, we investigated both intrinsic toxicity and photodynamic effects of the photosensitizer (PS) aluminum chloride phthalocyanine (AlClPc) on mitochondrial functions. Several aspects of mitochondrial bioenergetics, structure, and oxidative state were investigated in the isolated mitochondria obtained from rat liver by differential centrifugation. Additionally, experiments were conducted to demonstrate the intrinsic and photodynamic effects of AlClPc on the viability of HepG2 cells. AlClPc interacted with mitochondria regardless of photostimulation; however, at the maximum utilized concentration (40 μM), photostimulation reduced its interaction with mitochondria. Although AlClPc hindered catalase (CAT) and glutathione reductase (GR) activities intrinsically, it had no discernable capacity to generate oxidative stress or impact bioenergetics in mitochondria without photostimulation, as one would anticipate from an ideal PS. When exposed to light, however, AlClPc had a substantially unfavorable influence on mitochondrial function, strengthening its intrinsic inhibitory action on CAT, producing oxidative stress, and jeopardizing mitochondrial bioenergetics. In terms of oxidative stress parameters, AlClPc induced lipid peroxidation and decreased the level of reduced glutathione (GSH) in mitochondria. Regarding bioenergetics, AlClPc promoted oxidative phosphorylation uncoupling and photodynamic inactivation of complex I, complex II, and the FoF1–ATP synthase complex, lowering mitochondrial ATP production. Lastly, AlClPc exhibited a concentration-dependent decrease in the viability of HepG2 cells, regardless of the presence or absence of photostimulation. While the harmful photodynamic effects of AlClPc on mitochondrial bioenergetics hold promise for treating HCC and other malignancies, the inherent toxic impacts on HepG2 cells underscore the need for caution in its application for this purpose.
{"title":"Unraveling the intrinsic and photodynamic effects of aluminum chloride phthalocyanine on bioenergetics and oxidative state in rat liver mitochondria","authors":"Eduardo Makiyama Klosowski , Byanca Thais Lima de Souza , Letícia Fernanda Nanami , Paulo Francisco Veiga Bizerra , Márcio Shigueaki Mito , Giovana Natiele Machado Esquissato , Renato Polimeni Constantin , Breno Miguel Joia , Paulo Vinicius Moreira da Costa Menezes , Wilker Caetano , Paulo Cesar de Souza Pereira , Renato Sonchini Gonçalves , Francielle Pelegrin Garcia , Danielle Lazarin Bidoia , Tânia Ueda Nakamura , Celso Vataru Nakamura , Emy Luiza Ishii-Iwamoto , Wanderley Dantas dos Santos , Osvaldo Ferrarese-Filho , Rogério Marchiosi , Rodrigo Polimeni Constantin","doi":"10.1016/j.taap.2024.117157","DOIUrl":"10.1016/j.taap.2024.117157","url":null,"abstract":"<div><div>Previous research has revealed that mitochondria are an important target for photodynamic therapy (PDT), which might be employed as a therapeutic approach for several malignancies, including hepatocellular carcinoma (HCC). In this study, we investigated both intrinsic toxicity and photodynamic effects of the photosensitizer (PS) aluminum chloride phthalocyanine (AlClPc) on mitochondrial functions. Several aspects of mitochondrial bioenergetics, structure, and oxidative state were investigated in the isolated mitochondria obtained from rat liver by differential centrifugation. Additionally, experiments were conducted to demonstrate the intrinsic and photodynamic effects of AlClPc on the viability of HepG2 cells. AlClPc interacted with mitochondria regardless of photostimulation; however, at the maximum utilized concentration (40 μM), photostimulation reduced its interaction with mitochondria. Although AlClPc hindered catalase (CAT) and glutathione reductase (GR) activities intrinsically, it had no discernable capacity to generate oxidative stress or impact bioenergetics in mitochondria without photostimulation, as one would anticipate from an ideal PS. When exposed to light, however, AlClPc had a substantially unfavorable influence on mitochondrial function, strengthening its intrinsic inhibitory action on CAT, producing oxidative stress, and jeopardizing mitochondrial bioenergetics. In terms of oxidative stress parameters, AlClPc induced lipid peroxidation and decreased the level of reduced glutathione (GSH) in mitochondria. Regarding bioenergetics, AlClPc promoted oxidative phosphorylation uncoupling and photodynamic inactivation of complex I, complex II, and the F<sub>o</sub>F<sub>1</sub>–ATP synthase complex, lowering mitochondrial ATP production. Lastly, AlClPc exhibited a concentration-dependent decrease in the viability of HepG2 cells, regardless of the presence or absence of photostimulation. While the harmful photodynamic effects of AlClPc on mitochondrial bioenergetics hold promise for treating HCC and other malignancies, the inherent toxic impacts on HepG2 cells underscore the need for caution in its application for this purpose.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117157"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-17DOI: 10.1016/j.taap.2024.117160
Muhammad Arif Asghar , Shixin Tang , Bing Wan , Ying Chen , Xiao Zhang , Qinjian Zhao
Valproic acid (VPA) is a widely used antiepileptic drug, but its effects on oxidative stress in rodent models have not been systematically reviewed. This meta-analysis aimed to evaluate the impact of VPA on oxidative stress markers in rodents and explore underlying mechanisms through network pharmacology. A systematic search of PubMed, Web of Science, and PsycINFO (2010–2024) was conducted, following PRISMA and CAMARADES guidelines. Forty-two studies involving 639 rodents were included. Meta-analysis and meta-regression were performed using SPSS and R, and network pharmacology identified key pathways. From 1802 studies, 42 met the criteria, involving 639 rodents. VPA treatment was associated with a significant increase in malondialdehyde (MDA) levels (SMD = 30.45, 95 % CI: 17.64–43.25, P < 0.001) and a decrease in clinically relevant biomarkers, such as superoxide dismutase (SOD) (SMD = −13.22, 95 % CI: −19.39–-7.04, P < 0.001), glutathione (GSH) (SMD = −16.97, 95 % CI: −28.13–-5.82, P < 0.001), catalase (CAT) (SMD = −9.24, 95 % CI: −13.85–-4.62, P < 0.001), glutathione S-transferases (GST) (SMD = −8.82, 95 % CI: −17.40–-0.24, P = 0.040), and glutathione peroxidase (GPx) (SMD = −36.05, 95 % CI: −60.72–-11.37, P < 0.001). Meta-regression analysis suggested that dosing periods and doses significantly impacted oxidative stress markers. Network pharmacology analysis identified 33 key targets and significant pathways, including MAPK signaling, Toll-like receptor signaling, and TNF signaling. VPA induces oxidative stress in rodent models by increasing MDA and reducing antioxidants, suggesting potential oxidative stress-related side effects in patients.
{"title":"Valproic acid-induced oxidative stress: Systematic review, meta-analysis and network pharmacology highlights disruption in antioxidant pathways in rodents","authors":"Muhammad Arif Asghar , Shixin Tang , Bing Wan , Ying Chen , Xiao Zhang , Qinjian Zhao","doi":"10.1016/j.taap.2024.117160","DOIUrl":"10.1016/j.taap.2024.117160","url":null,"abstract":"<div><div>Valproic acid (VPA) is a widely used antiepileptic drug, but its effects on oxidative stress in rodent models have not been systematically reviewed. This meta-analysis aimed to evaluate the impact of VPA on oxidative stress markers in rodents and explore underlying mechanisms through network pharmacology. A systematic search of PubMed, Web of Science, and PsycINFO (2010–2024) was conducted, following PRISMA and CAMARADES guidelines. Forty-two studies involving 639 rodents were included. Meta-analysis and meta-regression were performed using SPSS and R, and network pharmacology identified key pathways. From 1802 studies, 42 met the criteria, involving 639 rodents. VPA treatment was associated with a significant increase in malondialdehyde (MDA) levels (SMD = 30.45, 95 % CI: 17.64–43.25, <em>P</em> < 0.001) and a decrease in clinically relevant biomarkers, such as superoxide dismutase (SOD) (SMD = −13.22, 95 % CI: −19.39–-7.04, <em>P</em> < 0.001), glutathione (GSH) (SMD = −16.97, 95 % CI: −28.13–-5.82, <em>P</em> < 0.001), catalase (CAT) (SMD = −9.24, 95 % CI: −13.85–-4.62, P < 0.001), glutathione S-transferases (GST) (SMD = −8.82, 95 % CI: −17.40–-0.24, <em>P</em> = 0.040), and glutathione peroxidase (GPx) (SMD = −36.05, 95 % CI: −60.72–-11.37, <em>P</em> < 0.001). Meta-regression analysis suggested that dosing periods and doses significantly impacted oxidative stress markers. Network pharmacology analysis identified 33 key targets and significant pathways, including MAPK signaling, Toll-like receptor signaling, and TNF signaling. VPA induces oxidative stress in rodent models by increasing MDA and reducing antioxidants, suggesting potential oxidative stress-related side effects in patients.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117160"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-17DOI: 10.1016/j.taap.2024.117159
Choon-Myung Lee , Ho Young Lee , Zachery R. Jarrell , M. Ryan Smith , Dean P. Jones , Young-Mi Go
Cadmium (Cd) is a toxic environmental metal that occurs naturally in food and drinking water. Cd is of increasing concern to human health due to its association with age-related diseases and long biological half-life. Previous studies show that low-dose Cd exposure via drinking water induces mechanistic target of rapamycin complex 1 (mTORC1) signaling in mice; however, the role of mTORC1 pathway in Cd-induced pro-fibrotic responses has not been established. In the present study, we used human lung fibroblasts to examine whether inhibiting the mTORC1 pathway prevents lung fibrosis signaling induced by low-dose Cd exposure. Results show that rapamycin, a pharmacological inhibitor of mTORC1, inhibited Cd-dependent phosphorylation of ribosomal protein S6, a downstream marker of mTORC1 activation. Rapamycin also decreased Cd-dependent increases in pro-fibrotic markers, α-smooth muscle actin, collagen 1α1 and fibronectin. Cd activated mitochondrial spare respiratory capacity in association with increased cell proliferation. Rapamycin decreased these responses, showing that mTORC1 signaling supports mitochondrial energy supply for cell proliferation, an important step in fibroblast trans-differentiation into myofibroblasts. Collectively, these results establish a key mechanistic role for mTORC1 activation in environmental Cd-dependent lung fibrosis.
{"title":"Mechanistic role for mTORC1 signaling in profibrotic toxicity of low-dose cadmium","authors":"Choon-Myung Lee , Ho Young Lee , Zachery R. Jarrell , M. Ryan Smith , Dean P. Jones , Young-Mi Go","doi":"10.1016/j.taap.2024.117159","DOIUrl":"10.1016/j.taap.2024.117159","url":null,"abstract":"<div><div>Cadmium (Cd) is a toxic environmental metal that occurs naturally in food and drinking water. Cd is of increasing concern to human health due to its association with age-related diseases and long biological half-life. Previous studies show that low-dose Cd exposure via drinking water induces mechanistic target of rapamycin complex 1 (mTORC1) signaling in mice; however, the role of mTORC1 pathway in Cd-induced pro-fibrotic responses has not been established. In the present study, we used human lung fibroblasts to examine whether inhibiting the mTORC1 pathway prevents lung fibrosis signaling induced by low-dose Cd exposure. Results show that rapamycin, a pharmacological inhibitor of mTORC1, inhibited Cd-dependent phosphorylation of ribosomal protein S6, a downstream marker of mTORC1 activation. Rapamycin also decreased Cd-dependent increases in pro-fibrotic markers, α-smooth muscle actin, collagen 1α1 and fibronectin. Cd activated mitochondrial spare respiratory capacity in association with increased cell proliferation. Rapamycin decreased these responses, showing that mTORC1 signaling supports mitochondrial energy supply for cell proliferation, an important step in fibroblast trans-differentiation into myofibroblasts. Collectively, these results establish a key mechanistic role for mTORC1 activation in environmental Cd-dependent lung fibrosis.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"494 ","pages":"Article 117159"},"PeriodicalIF":3.3,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acute lung injury (ALI) is a common complication of sepsis and a leading cause of mortality in septic patients. Studies indicate that STING may play a crucial role in the pathogenesis of sepsis-induced ALI by interacting with the PARP-1/NLRP3 pathway. Therefore, targeting STING inhibition has potential as a novel therapeutic strategy for ALI. However, effective inhibition remains challenging due to the widespread expression of STING across various tissues. In this study, we developed a nanozyme-based drug delivery system, DSPE-TK-mPEG-MnO2@siSTING (abbreviated as DTmM@siSTING), using DSPE-TK-mPEG-MnO2 as the carrier, and characterized it via scanning electron microscopy, dynamic light scattering, nanoparticle size analysis, and gel electrophoresis. To evaluate the therapeutic effects of DTmM@siSTING, an in vitro ALI cell model and an in vivo ALI mouse model were established, assessing the nanozyme's impact on ROS levels, inflammatory responses, and the PARP-1/NLRP3 pathway in sepsis-induced ALI. Results demonstrated that DTmM@siSTING exhibited good physiological stability. In vitro, DTmM@siSTING significantly reduced ROS levels, myeloperoxidase activity, and expression of inflammatory cytokines, while also inhibiting PARP-1/NLRP3 pathway activation. In vivo experiments further revealed that DTmM@siSTING effectively delivered siSTING to the lungs, mitigating sepsis-induced ALI and associated inflammatory responses. Additionally, DTmM@siSTING displayed excellent biocompatibility. In summary, our findings suggest that DTmM@siSTING significantly enhances the therapeutic efficacy of siSTING, alleviating ALI by inhibiting ROS production, inflammatory responses, and activation of the PARP-1/NLRP3 pathway. This novel approach presents a promising therapeutic avenue for sepsis-induced ALI.
急性肺损伤（ALI）是脓毒症的常见并发症，也是脓毒症患者死亡的主要原因。研究表明，STING 可通过与 PARP-1/NLRP3 通路相互作用，在脓毒症诱发的 ALI 的发病机制中发挥关键作用。因此，靶向抑制 STING 有可能成为 ALI 的一种新型治疗策略。然而，由于 STING 在不同组织中的广泛表达，有效抑制 STING 仍具有挑战性。在本研究中，我们以 DSPE-TK-mPEG-MnO2 为载体，开发了一种基于纳米酶的给药系统 DSPE-TK-mPEG-MnO2@siSTING（简称 DTmM@siSTING），并通过扫描电镜、动态光散射、纳米颗粒粒度分析和凝胶电泳对其进行了表征。为了评估 DTmM@siSTING 的治疗效果，研究人员分别建立了体外 ALI 细胞模型和体内 ALI 小鼠模型，评估纳米酶对 ROS 水平、炎症反应以及 PARP-1/NLRP3 通路在败血症诱导的 ALI 中的影响。结果表明，DTmM@siSTING 具有良好的生理稳定性。在体外，DTmM@siSTING 能显著降低 ROS 水平、髓过氧化物酶活性和炎症细胞因子的表达，同时还能抑制 PARP-1/NLRP3 通路的激活。体内实验进一步表明，DTmM@siSTING 能有效地将 siSTING 运送到肺部，减轻败血症引起的 ALI 及相关炎症反应。此外，DTmM@siSTING 还具有良好的生物相容性。总之，我们的研究结果表明，DTmM@siSTING 能显著增强 siSTING 的疗效，通过抑制 ROS 生成、炎症反应和 PARP-1/NLRP3 通路的激活来缓解 ALI。这种新方法为脓毒症诱发的 ALI 提供了一条前景广阔的治疗途径。
{"title":"ROS responsive nanozyme loaded with STING silencing for the treatment of sepsis-induced acute lung injury","authors":"Yin-jin Zhang , Ling-yang Chen , Feng Lin , Xia Zhang , Hai-fei Xiang , Qing Rao","doi":"10.1016/j.taap.2024.117155","DOIUrl":"10.1016/j.taap.2024.117155","url":null,"abstract":"<div><div>Acute lung injury (ALI) is a common complication of sepsis and a leading cause of mortality in septic patients. Studies indicate that STING may play a crucial role in the pathogenesis of sepsis-induced ALI by interacting with the PARP-1/NLRP3 pathway. Therefore, targeting STING inhibition has potential as a novel therapeutic strategy for ALI. However, effective inhibition remains challenging due to the widespread expression of STING across various tissues. In this study, we developed a nanozyme-based drug delivery system, DSPE-TK-mPEG-MnO<sub>2</sub>@siSTING (abbreviated as DTmM@siSTING), using DSPE-TK-mPEG-MnO<sub>2</sub> as the carrier, and characterized it via scanning electron microscopy, dynamic light scattering, nanoparticle size analysis, and gel electrophoresis. To evaluate the therapeutic effects of DTmM@siSTING, an in vitro ALI cell model and an in vivo ALI mouse model were established, assessing the nanozyme's impact on ROS levels, inflammatory responses, and the PARP-1/NLRP3 pathway in sepsis-induced ALI. Results demonstrated that DTmM@siSTING exhibited good physiological stability. In vitro, DTmM@siSTING significantly reduced ROS levels, myeloperoxidase activity, and expression of inflammatory cytokines, while also inhibiting PARP-1/NLRP3 pathway activation. In vivo experiments further revealed that DTmM@siSTING effectively delivered siSTING to the lungs, mitigating sepsis-induced ALI and associated inflammatory responses. Additionally, DTmM@siSTING displayed excellent biocompatibility. In summary, our findings suggest that DTmM@siSTING significantly enhances the therapeutic efficacy of siSTING, alleviating ALI by inhibiting ROS production, inflammatory responses, and activation of the PARP-1/NLRP3 pathway. This novel approach presents a promising therapeutic avenue for sepsis-induced ALI.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"493 ","pages":"Article 117155"},"PeriodicalIF":3.3,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
CDGSH iron‑sulfur domain 2 (CISD2) is recognized as a ferroptosis-related gene that has potential as a target for cancer treatment. However, it is still uncertain whether targeting CISD2 can modulate ferroptosis in diffuse large B-cell lymphoma (DLBCL) cells and exhibit cancer-suppressing effects. The present study thoroughly investigated the role of CISD2 in DLBCL. CISD2 was found to be overexpressed in DLBCL, and its inhibition resulted in substantial growth inhibition in DLBCL cells. The growth inhibition effect resulting from CISD2 silencing could be reversed by a ferroptosis inhibitor, whereas inhibitors of apoptosis and necrosis did not yield the same reversal. CISD2-silenced DLBCL cells exhibited increased sensitivity to growth inhibition induced by ferroptosis suppressors. The inhibition of CISD2 induced ferroptotic cell death in DLBCL cells, which was supported by the overproduction of lipid peroxides, depletion of glutathione, accumulation of iron, and increased presence of shrunken mitochondria. Further investigation revealed reduced levels of NRF2, GPX4, and SLC7A11 in CISD2-silenced DLBCL cells. The overexpression of NRF2 significantly reduced the occurrence of ferroptotic cell death in DLBCL cells in which CISD2 was silenced. Furthermore, CISD2 inhibition exhibited tumor-suppressing effects in vivo associated with the induction of ferroptotic cell death in xenografts. These findings suggest that CISD2inhibition has tumor-suppressing effects on DLBCL by promoting ferroptotic cell death via the NRF2/SLC7A11/GPX4 pathway. Therefore, CISD2 holds promise as a viable candidate target for treating DLBCL.
{"title":"Inhibition of CDGSH iron‑sulfur domain 2 exhibits tumor-suppressing effects on diffuse large B-cell lymphoma (DLBCL) by inducing ferroptosis through the regulation of the NRF2/SLC7A11/GPX4 pathway","authors":"Jingjing Zhang, Ting Wang, Hui Zhang, Na Li, Bailing Liu, Ling Fang","doi":"10.1016/j.taap.2024.117148","DOIUrl":"10.1016/j.taap.2024.117148","url":null,"abstract":"<div><div>CDGSH iron‑sulfur domain 2 (CISD2) is recognized as a ferroptosis-related gene that has potential as a target for cancer treatment. However, it is still uncertain whether targeting CISD2 can modulate ferroptosis in diffuse large B-cell lymphoma (DLBCL) cells and exhibit cancer-suppressing effects. The present study thoroughly investigated the role of CISD2 in DLBCL. CISD2 was found to be overexpressed in DLBCL, and its inhibition resulted in substantial growth inhibition in DLBCL cells. The growth inhibition effect resulting from CISD2 silencing could be reversed by a ferroptosis inhibitor, whereas inhibitors of apoptosis and necrosis did not yield the same reversal. CISD2-silenced DLBCL cells exhibited increased sensitivity to growth inhibition induced by ferroptosis suppressors. The inhibition of CISD2 induced ferroptotic cell death in DLBCL cells, which was supported by the overproduction of lipid peroxides, depletion of glutathione, accumulation of iron, and increased presence of shrunken mitochondria. Further investigation revealed reduced levels of NRF2, GPX4, and SLC7A11 in CISD2-silenced DLBCL cells. The overexpression of NRF2 significantly reduced the occurrence of ferroptotic cell death in DLBCL cells in which CISD2 was silenced. Furthermore, CISD2 inhibition exhibited tumor-suppressing effects in vivo associated with the induction of ferroptotic cell death in xenografts. These findings suggest that CISD2inhibition has tumor-suppressing effects on DLBCL by promoting ferroptotic cell death via the NRF2/SLC7A11/GPX4 pathway. Therefore, CISD2 holds promise as a viable candidate target for treating DLBCL.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"493 ","pages":"Article 117148"},"PeriodicalIF":3.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07DOI: 10.1016/j.taap.2024.117145
Jing Kong , Yan Dong , Mengxuan Li , Jing Fan , Ting Wang
Chemotherapy remains the major strategy for treating triple-negative breast cancer (TNBC); however, frequently acquired chemoresistance greatly limits the treatment outcomes. Protein arginine methyltransferase 5 (PRMT5), which modulates arginine methylation, is important in chemoresistance acquisition across various cancers. The function of PRMT5 in the development of chemoresistance in TNBC is still not well understood. This work focused on defining PRMT5's function in contributing to the chemoresistance in TNBC and demonstrating the possible mechanisms involved. Two TNBC cell lines resistant to nanoparticle albumin-bound paclitaxel (Nab-PTX), designated MDA-MB-231/R and MDA-MB-468/R, were developed. The expression of PRMT5 was markedly elevated in the cytoplasm of Nab-PTX-resistant cells accompanied with enhanced autophagy. The depletion of PRMT5 rendered these cells sensitive to Nab-PTX-evoked cytotoxicity. The autophagic flux was upregulated in Nab-PTX-resistant cells, which was markedly repressed by PRMT5 depletion. The dimethylation of ULK1 was markedly elevated in Nab-PTX-resistant cells, which was decreased by silencing PRMT5. Re-expression of PRMT5 in PRMT5-depleted cells restored the dimethylation and activation of ULK1 as well as the autophagic flux, while the catalytically-dead PRMT5 (R368A) mutant showed no significant effects. The depletion of PRMT5 rendered the subcutaneous tumors formed by Nab-PTX-resistant TNBC cells sensitive to Nab-PTX. The findings of this work illustrate that PRMT5 confers chemoresistance of TNBC by enhancing autophagy through dimethylation and the activation of ULK1, revealing a novel mechanism for understanding the acquisition of chemoresistance in TNBC. Targeting PRMT5 could be a viable approach for overcoming chemoresistance in the treatment of TNBC.
{"title":"Protein arginine methyltransferase 5 confers the resistance of triple-negative breast cancer to nanoparticle albumin-bound paclitaxel by enhancing autophagy through the dimethylation of ULK1","authors":"Jing Kong , Yan Dong , Mengxuan Li , Jing Fan , Ting Wang","doi":"10.1016/j.taap.2024.117145","DOIUrl":"10.1016/j.taap.2024.117145","url":null,"abstract":"<div><div>Chemotherapy remains the major strategy for treating triple-negative breast cancer (TNBC); however, frequently acquired chemoresistance greatly limits the treatment outcomes. Protein arginine methyltransferase 5 (PRMT5), which modulates arginine methylation, is important in chemoresistance acquisition across various cancers. The function of PRMT5 in the development of chemoresistance in TNBC is still not well understood. This work focused on defining PRMT5's function in contributing to the chemoresistance in TNBC and demonstrating the possible mechanisms involved. Two TNBC cell lines resistant to nanoparticle albumin-bound paclitaxel (Nab-PTX), designated MDA-MB-231/R and MDA-MB-468/R, were developed. The expression of PRMT5 was markedly elevated in the cytoplasm of Nab-PTX-resistant cells accompanied with enhanced autophagy. The depletion of PRMT5 rendered these cells sensitive to Nab-PTX-evoked cytotoxicity. The autophagic flux was upregulated in Nab-PTX-resistant cells, which was markedly repressed by PRMT5 depletion. The dimethylation of ULK1 was markedly elevated in Nab-PTX-resistant cells, which was decreased by silencing PRMT5. <em>Re</em>-expression of PRMT5 in PRMT5-depleted cells restored the dimethylation and activation of ULK1 as well as the autophagic flux, while the catalytically-dead PRMT5 (R368A) mutant showed no significant effects. The depletion of PRMT5 rendered the subcutaneous tumors formed by Nab-PTX-resistant TNBC cells sensitive to Nab-PTX. The findings of this work illustrate that PRMT5 confers chemoresistance of TNBC by enhancing autophagy through dimethylation and the activation of ULK1, revealing a novel mechanism for understanding the acquisition of chemoresistance in TNBC. Targeting PRMT5 could be a viable approach for overcoming chemoresistance in the treatment of TNBC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"493 ","pages":"Article 117145"},"PeriodicalIF":3.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142628758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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