Pub Date : 2026-02-01Epub Date: 2025-12-15DOI: 10.1016/j.taap.2025.117692
Zhe Wang , Le-hao Jin , Ni-hong Pang , Jun-er Xu , Xiao-yu Xu , Wei Sun , Xiao-dan Zhang , Jian-chang Qian
Apatinib is a tyrosine kinase inhibitor metabolized by hepatic cytochromes P450 (CYPs). This study investigated how CYP genetic variations affect apatinib metabolism and response. We employed a multi-scale approach including enzyme kinetic studies with recombinant human CYP variants (n = 3), cellular proliferation assays in CYP3A4-overexpressing A549 cells (n = 3), and pharmacokinetic studies in rats treated with CYP3A modulators (n = 6 per group). CYP3A4*18, CYP2D6*10, and CYP2C9*3 variants showed markedly reduced metabolic activity. CYP3A4*18 overexpression enhanced apatinib's anti-proliferative effect in A549 cells. In rats, dexamethasone decreased apatinib exposure by inducing CYP3A expression, while ketoconazole increased exposure without altering CYP3A levels. Both CYP genetic polymorphisms and drug interactions significantly influence apatinib metabolism, highlighting the importance of personalized dosing strategies for optimizing therapy.
{"title":"CYP genetic polymorphism, and CYP3A inducers and inhibitors regulate apatinib metabolism: Consequences for drug exposure and toxicity risks","authors":"Zhe Wang , Le-hao Jin , Ni-hong Pang , Jun-er Xu , Xiao-yu Xu , Wei Sun , Xiao-dan Zhang , Jian-chang Qian","doi":"10.1016/j.taap.2025.117692","DOIUrl":"10.1016/j.taap.2025.117692","url":null,"abstract":"<div><div>Apatinib is a tyrosine kinase inhibitor metabolized by hepatic cytochromes P450 (CYPs). This study investigated how CYP genetic variations affect apatinib metabolism and response. We employed a multi-scale approach including enzyme kinetic studies with recombinant human CYP variants (<em>n</em> = 3), cellular proliferation assays in CYP3A4-overexpressing A549 cells (n = 3), and pharmacokinetic studies in rats treated with CYP3A modulators (<em>n</em> = 6 per group). CYP3A4*18, CYP2D6*10, and CYP2C9*3 variants showed markedly reduced metabolic activity. CYP3A4*18 overexpression enhanced apatinib's anti-proliferative effect in A549 cells. In rats, dexamethasone decreased apatinib exposure by inducing CYP3A expression, while ketoconazole increased exposure without altering CYP3A levels. Both CYP genetic polymorphisms and drug interactions significantly influence apatinib metabolism, highlighting the importance of personalized dosing strategies for optimizing therapy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117692"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145775941","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 : 2026-02-01Epub Date: 2026-01-12DOI: 10.1016/j.taap.2026.117712
Min Hee Yang , Ducdat Le , Thinhulinh Dang , Vinhquang Truong , In Jin Ha , Mina Lee , Kwang Seok Ahn
Metastasis driven by epithelial-mesenchymal transition (EMT) remains a critical challenge in colorectal cancer treatment. This study investigated GKB7I-53, a saponin compound isolated through feature-based molecular networking, as a potential therapeutic agent targeting EMT pathways. GKB7I-53 demonstrated minimal cytotoxicity (>90% cell viability at 50 μM) while effectively inhibiting metastatic processes. The compound downregulated mesenchymal markers (CXCR4, CXCR7) and upregulated epithelial markers (E-cadherin, occludin), suppressing EMT progression. In CXCL12-stimulated cells, GKB7I-53 significantly reduced cell migration and invasion while decreasing MMP-2/9 activity, key enzymes facilitating metastatic spread. Mechanistically, GKB7I-53 suppressed MnSOD-induced STAT3 activation, thereby blocking the JAK/STAT3 signaling pathway crucial for metastasis. Molecular docking studies confirmed strong binding affinity to target proteins involved in EMT and cancer progression. These findings suggest that GKB7I-53 may serve as a potential lead compound with anti-metastatic properties in colorectal cancer. Rather than inducing general cytotoxicity, GKB7I-53 selectively modulates EMT-related pathways, indicating a mechanistic basis for its anti-metastatic effects. However, further in vivo validation and preclinical studies are required to determine its therapeutic relevance.
{"title":"GKB7I-53: A novel anti-metastatic agent for colorectal cancer","authors":"Min Hee Yang , Ducdat Le , Thinhulinh Dang , Vinhquang Truong , In Jin Ha , Mina Lee , Kwang Seok Ahn","doi":"10.1016/j.taap.2026.117712","DOIUrl":"10.1016/j.taap.2026.117712","url":null,"abstract":"<div><div>Metastasis driven by epithelial-mesenchymal transition (EMT) remains a critical challenge in colorectal cancer treatment. This study investigated GKB7I-53, a saponin compound isolated through feature-based molecular networking, as a potential therapeutic agent targeting EMT pathways. GKB7I-53 demonstrated minimal cytotoxicity (>90% cell viability at 50 μM) while effectively inhibiting metastatic processes. The compound downregulated mesenchymal markers (CXCR4, CXCR7) and upregulated epithelial markers (E-cadherin, occludin), suppressing EMT progression. In CXCL12-stimulated cells, GKB7I-53 significantly reduced cell migration and invasion while decreasing MMP-2/9 activity, key enzymes facilitating metastatic spread. Mechanistically, GKB7I-53 suppressed MnSOD-induced STAT3 activation, thereby blocking the JAK/STAT3 signaling pathway crucial for metastasis. Molecular docking studies confirmed strong binding affinity to target proteins involved in EMT and cancer progression. These findings suggest that GKB7I-53 may serve as a potential lead compound with anti-metastatic properties in colorectal cancer. Rather than inducing general cytotoxicity, GKB7I-53 selectively modulates EMT-related pathways, indicating a mechanistic basis for its anti-metastatic effects. However, further in vivo validation and preclinical studies are required to determine its therapeutic relevance.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117712"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145977776","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 : 2026-02-01Epub Date: 2025-12-08DOI: 10.1016/j.taap.2025.117682
Na Lu , Yuan-wen Cai , Qi-hai Cai , Xiu-wen Liang , Nuo Sun , On-kei Chan , Zi-jian Shi , Bo Hu , Xian-hui He , Qing-bing Zha , Dong-yun Ouyang
Andrographolide (Andro), the major bioactive component of Andrographis paniculata, exhibits potent anti-inflammatory properties but has raised safety concerns due to reported organ toxicity. This study aimed to investigate the mechanisms underlying Andro's in vitro and in vivo toxicity. In mice, single dose (≤100 mg/kg) Andro administration showed no acute toxicity, with no overt histopathological organ injury. But repeated administration of the same dose of Andro triggered damage in lung, liver, uterus, and kidney, characterized by pulmonary alveolar disruption, renal tubular edema, and elevated serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Concurrent with systemic injury, PANoptosis was induced by Andro in these organs, as evidenced by the activation of caspase-1/−8/−3 (apoptosis), gasdermin D/E (GSDMD/E, pyroptosis), and MLKL (necroptosis), indicating the correlation between PANoptosis and organ toxicity. In vitro, Andro caused lytic cell death in macrophages and other cells in a time- and dose-dependent manner. During this process, Andro induced rapid activation of caspase-8, followed by caspase-1/−3 and GSDME cleavage and phosphorylation of MLKL (p-MLKL), indicative of the activation of the PANoptosis signaling pathway. Consistent with this, Andro induced lytic cell death was markedly attenuated by caspase-1 inhibitor VX-765, pan-caspase inhibitors (IDN-6556, Z-VAD-FMK) and GSDMD/E inhibitor (disulfiram). In addition, RIPK1 inhibition (by Nec-1) partially reduced cell death, confirming RIPK1-dependent necroptosis as a minor contributor. In conclusion, our data establish PANoptosis as an important mechanism of Andro-induced organ injury, providing a mechanistic framework for Andro's dichotomous bioactivity, informing evidence-based dosing strategies to maximize therapeutic efficacy while mitigating toxicity risks in clinical practice.
{"title":"Andrographolide-induced PANoptosis underlies its multiple organ toxicity in mice","authors":"Na Lu , Yuan-wen Cai , Qi-hai Cai , Xiu-wen Liang , Nuo Sun , On-kei Chan , Zi-jian Shi , Bo Hu , Xian-hui He , Qing-bing Zha , Dong-yun Ouyang","doi":"10.1016/j.taap.2025.117682","DOIUrl":"10.1016/j.taap.2025.117682","url":null,"abstract":"<div><div>Andrographolide (Andro), the major bioactive component of <em>Andrographis paniculata</em>, exhibits potent anti-inflammatory properties but has raised safety concerns due to reported organ toxicity. This study aimed to investigate the mechanisms underlying Andro's <em>in vitro</em> and <em>in vivo</em> toxicity. In mice, single dose (≤100 mg/kg) Andro administration showed no acute toxicity, with no overt histopathological organ injury. But repeated administration of the same dose of Andro triggered damage in lung, liver, uterus, and kidney, characterized by pulmonary alveolar disruption, renal tubular edema, and elevated serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT). Concurrent with systemic injury, PANoptosis was induced by Andro in these organs, as evidenced by the activation of caspase-1/−8/−3 (apoptosis), gasdermin D/E (GSDMD/E, pyroptosis), and MLKL (necroptosis), indicating the correlation between PANoptosis and organ toxicity. <em>In vitro</em>, Andro caused lytic cell death in macrophages and other cells in a time- and dose-dependent manner. During this process, Andro induced rapid activation of caspase-8, followed by caspase-1/−3 and GSDME cleavage and phosphorylation of MLKL (p-MLKL), indicative of the activation of the PANoptosis signaling pathway. Consistent with this, Andro induced lytic cell death was markedly attenuated by caspase-1 inhibitor VX-765, pan-caspase inhibitors (IDN-6556, <em>Z</em>-VAD-FMK) and GSDMD/E inhibitor (disulfiram). In addition, RIPK1 inhibition (by Nec-1) partially reduced cell death, confirming RIPK1-dependent necroptosis as a minor contributor. In conclusion, our data establish PANoptosis as an important mechanism of Andro-induced organ injury, providing a mechanistic framework for Andro's dichotomous bioactivity, informing evidence-based dosing strategies to maximize therapeutic efficacy while mitigating toxicity risks in clinical practice.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117682"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726262","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 : 2026-02-01Epub Date: 2025-12-04DOI: 10.1016/j.taap.2025.117667
Giorgio Antoniolli , Gilberto Carlos Franchi Junior , Keli Lima , Rayssa de Mello Lopes , Euzebio Guimarães Barbosa , João Agostinho Machado-Neto , Carmen Silvia Passos Lima , Tiago Rodrigues , Fernando Coelho
This study reports the synthesis, physicochemical characterization, and preliminary pharmacological evaluation of a novel 2-substituted quinazolin-4(3H)-one, Qona11. The compound was synthesized from 2-aminobenzamide and 1H-benzo[d]imidazole-2-carbaldehyde in dimethyl sulfoxide with a 55 % yield, in a catalyst-free, atom-efficient process that adheres to Green Chemistry principles. Structural confirmation was achieved through IR (1667 cm−1, carbonyl), 1H NMR (13.50 and 12.50 ppm, NH protons), and 13C NMR (161.17 ppm, carbonyl carbon). In silico analysis suggested Qona11 possesses favorable oral bioavailability, high intestinal absorption, limited CYP450 inhibition, and predicted blood-brain barrier permeability. Toxicity predictions highlighted potential hepatotoxicity, neurotoxicity, and respiratory toxicity, while no significant risks for cardiotoxicity, carcinogenicity, immunotoxicity, or cytotoxicity were found. Comparative analysis with idelalisib revealed similar toxicity profiles to Qona11, distinct from vincristine. Biological evaluation in acute leukemia models demonstrated concentration- and time-dependent cytotoxicity, with Jurkat T-ALL cells being more sensitive (IC50 2.3 μM) than NB4 APL cells (IC50 12.7 μM). Flow cytometry confirmed apoptosis induction in Jurkat cells via mitochondrial permeabilization and caspase 3 activation. In vivo studies in NOD/SCID mice bearing Jurkat xenografts showed that Qona11 (100 mg.kg−1) was well tolerated with no systemic toxicity, although it did not inhibit leukemia cell proliferation in immune-independent models. Overall, Qona11 exhibits promising anticancer activity and low systemic toxicity, warranting further preclinical investigation in solid tumor models and combination therapies.
{"title":"In Silico, in vitro, and in vivo studies of a 2-substituted quinazolin-4(3H)-one in T-cell acute lymphoblastic leukemia","authors":"Giorgio Antoniolli , Gilberto Carlos Franchi Junior , Keli Lima , Rayssa de Mello Lopes , Euzebio Guimarães Barbosa , João Agostinho Machado-Neto , Carmen Silvia Passos Lima , Tiago Rodrigues , Fernando Coelho","doi":"10.1016/j.taap.2025.117667","DOIUrl":"10.1016/j.taap.2025.117667","url":null,"abstract":"<div><div>This study reports the synthesis, physicochemical characterization, and preliminary pharmacological evaluation of a novel 2-substituted quinazolin-4(3<em>H</em>)-one, Qona11. The compound was synthesized from 2-aminobenzamide and 1<em>H</em>-benzo[<em>d</em>]imidazole-2-carbaldehyde in dimethyl sulfoxide with a 55 % yield, in a catalyst-free, atom-efficient process that adheres to Green Chemistry principles. Structural confirmation was achieved through IR (1667 cm<sup>−1</sup>, carbonyl), <sup>1</sup>H NMR (13.50 and 12.50 ppm, NH protons), and <sup>13</sup>C NMR (161.17 ppm, carbonyl carbon). <em>In silico</em> analysis suggested Qona11 possesses favorable oral bioavailability, high intestinal absorption, limited CYP450 inhibition, and predicted blood-brain barrier permeability. Toxicity predictions highlighted potential hepatotoxicity, neurotoxicity, and respiratory toxicity, while no significant risks for cardiotoxicity, carcinogenicity, immunotoxicity, or cytotoxicity were found. Comparative analysis with idelalisib revealed similar toxicity profiles to Qona11, distinct from vincristine. Biological evaluation in acute leukemia models demonstrated concentration- and time-dependent cytotoxicity, with Jurkat T-ALL cells being more sensitive (IC<sub>50</sub> 2.3 μM) than NB4 APL cells (IC<sub>50</sub> 12.7 μM). Flow cytometry confirmed apoptosis induction in Jurkat cells <em>via</em> mitochondrial permeabilization and caspase 3 activation. <em>In vivo</em> studies in NOD/SCID mice bearing Jurkat xenografts showed that Qona11 (100 mg.kg<sup>−1</sup>) was well tolerated with no systemic toxicity, although it did not inhibit leukemia cell proliferation in immune-independent models. Overall, Qona11 exhibits promising anticancer activity and low systemic toxicity, warranting further preclinical investigation in solid tumor models and combination therapies.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117667"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145696370","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}
Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the cellular vital activities, has become a promising direction for HCC management. Celastrol is a terpenoids natural product isolated from the Tripterygium wilfordii Hook F. and catches attention for its multiple pharmacological activities including anti-HCC therapeutic potential. However, its effects in regulating glutamine metabolism to suppress HCC progression have not been investigated. In this study, Hep3B and HepG2 cells were used to investigate the inhibitory effects of celastrol on hepatoma cells. Subsequently, the biosafety and inhibitory effects of celastrol on tumor growth were investigated in a xenograft animal model of liver cancer. Our results showed that celastrol restrained the proliferation of hepatoma cells which was tightly associated with reduction of glutamine metabolic flux. Mechanistically, celastrol restricted glutamine uptake by inhibiting the SLC1A5 expression to reduce the content of glutamine metabolism intermediates in hepatoma cells thereby interrupting the energy source for cell proliferation. Consistently, similar results were observed in a transplanted HCC tumor mouse model. Interestingly, overexpression of SLC1A5 reversed the efficacy of celastrol in decreasing glutamine metabolic flux to suppress the malignant proliferation of hepatoma cells in vitro and in vivo. Overall, this study provides compelling evidence to demonstrate the efficacy of celastrol in inhibiting hepatocarcinogenesis by suppressing SLC1A5-mediated glutamine dependence, suggesting that celastrol as a natural active compound is expected to be developed as a therapeutic agent for HCC.
{"title":"Celastrol delays the progression of hepatocellular carcinoma by suppressing SLC1A5-mediated glutamine dependence","authors":"Simeng Xiao , Yun Zhao , Zhiguo Chen , Yangkun Xiong , Dingmei Zhang , Gang Zhou , Cong Zhang","doi":"10.1016/j.taap.2025.117690","DOIUrl":"10.1016/j.taap.2025.117690","url":null,"abstract":"<div><div>Hepatocellular carcinoma (HCC) is a serious public health problem worldwide due to its high mortality rate and specific therapeutic strategies with rare effective drugs. Glutamine, a critical nutrient for sustaining the cellular vital activities, has become a promising direction for HCC management. Celastrol is a terpenoids natural product isolated from the <em>Tripterygium wilfordii</em> Hook F. and catches attention for its multiple pharmacological activities including anti-HCC therapeutic potential. However, its effects in regulating glutamine metabolism to suppress HCC progression have not been investigated. In this study, Hep3B and HepG2 cells were used to investigate the inhibitory effects of celastrol on hepatoma cells. Subsequently, the biosafety and inhibitory effects of celastrol on tumor growth were investigated in a xenograft animal model of liver cancer. Our results showed that celastrol restrained the proliferation of hepatoma cells which was tightly associated with reduction of glutamine metabolic flux. Mechanistically, celastrol restricted glutamine uptake by inhibiting the SLC1A5 expression to reduce the content of glutamine metabolism intermediates in hepatoma cells thereby interrupting the energy source for cell proliferation. Consistently, similar results were observed in a transplanted HCC tumor mouse model. Interestingly, overexpression of SLC1A5 reversed the efficacy of celastrol in decreasing glutamine metabolic flux to suppress the malignant proliferation of hepatoma cells <em>in vitro</em> and <em>in vivo</em>. Overall, this study provides compelling evidence to demonstrate the efficacy of celastrol in inhibiting hepatocarcinogenesis by suppressing SLC1A5-mediated glutamine dependence, suggesting that celastrol as a natural active compound is expected to be developed as a therapeutic agent for HCC.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117690"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769301","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 : 2026-02-01Epub Date: 2026-01-08DOI: 10.1016/j.taap.2026.117708
Medine Akkan Öz , Hasan Şimşek , Selçuk Özdemir , Özge Kandemir , Sefa Küçükler , Hüseyin Mutlu , Ramiz Yazıcı , Fatih Mehmet Kandemir
The present study aimed to investigate the nephrotoxic effects of colistin (CS) in a rat model and to elucidate the potential renoprotective mechanisms of sinapic acid (SA) at biochemical, molecular, and metabolic levels. Colistin administration induced pronounced renal dysfunction, as evidenced by significant elevations in serum creatinine (Scr) and blood urea nitrogen (BUN), along with marked increases in kidney injury biomarkers, including KIM-1, NGAL, FABP, IL-18, MCP-1, and YKL-40. Metabolic disruption was further confirmed by reduced ATP levels and increased lactate dehydrogenase (LDH) and triacylglycerol (TAG) concentrations, indicating mitochondrial dysfunction and cytotoxicity. Serum proteomic profiling using proximity extension assay identified significant alterations in 22 of 43 proteins, with IL-1β, IL-2, CXCL2, CSF-1, CCL22, and IFN-α2 showing marked upregulation following CS exposure. These inflammatory and immune-related proteins were significantly attenuated by SA co-treatment. Molecular analyses revealed that CS activated the miR-21/NF-κB/CD68 axis while suppressing SIRT1 expression, reflecting enhanced inflammation and macrophage infiltration. Sinapic acid effectively normalized these molecular disturbances. Furthermore, CS significantly upregulated renal mRNA expression of Cst3, Timp2, Igfbp7, Hgf, IL9, and Dkk3—genes associated with renal stress, fibrosis, and inflammation—whereas SA treatment markedly reduced their expression. Collectively, these findings demonstrate that sinapic acid exerts renoprotective effects primarily through modulation of inflammatory signaling pathways, suppression of miR-21/NF-κB-mediated responses, restoration of SIRT1 activity, and improvement of metabolic homeostasis. The study confirms the therapeutic potential of SA against colistin-induced nephrotoxicity.
{"title":"Sinapic acid attenuates colistin-driven nephrotoxicity by targeting the miRNA-21/SIRT1/NF-κB pathway and facilitating tubular repair and inflammation in a rat model","authors":"Medine Akkan Öz , Hasan Şimşek , Selçuk Özdemir , Özge Kandemir , Sefa Küçükler , Hüseyin Mutlu , Ramiz Yazıcı , Fatih Mehmet Kandemir","doi":"10.1016/j.taap.2026.117708","DOIUrl":"10.1016/j.taap.2026.117708","url":null,"abstract":"<div><div>The present study aimed to investigate the nephrotoxic effects of colistin (CS) in a rat model and to elucidate the potential renoprotective mechanisms of sinapic acid (SA) at biochemical, molecular, and metabolic levels. Colistin administration induced pronounced renal dysfunction, as evidenced by significant elevations in serum creatinine (Scr) and blood urea nitrogen (BUN), along with marked increases in kidney injury biomarkers, including KIM-1, NGAL, FABP, IL-18, MCP-1, and YKL-40. Metabolic disruption was further confirmed by reduced ATP levels and increased lactate dehydrogenase (LDH) and triacylglycerol (TAG) concentrations, indicating mitochondrial dysfunction and cytotoxicity. Serum proteomic profiling using proximity extension assay identified significant alterations in 22 of 43 proteins, with IL-1β, IL-2, CXCL2, CSF-1, CCL22, and IFN-α2 showing marked upregulation following CS exposure. These inflammatory and immune-related proteins were significantly attenuated by SA co-treatment. Molecular analyses revealed that CS activated the miR-21/NF-κB/CD68 axis while suppressing SIRT1 expression, reflecting enhanced inflammation and macrophage infiltration. Sinapic acid effectively normalized these molecular disturbances. Furthermore, CS significantly upregulated renal mRNA expression of Cst3, Timp2, Igfbp7, Hgf, IL9, and Dkk3—genes associated with renal stress, fibrosis, and inflammation—whereas SA treatment markedly reduced their expression. Collectively, these findings demonstrate that sinapic acid exerts renoprotective effects primarily through modulation of inflammatory signaling pathways, suppression of miR-21/NF-κB-mediated responses, restoration of SIRT1 activity, and improvement of metabolic homeostasis. The study confirms the therapeutic potential of SA against colistin-induced nephrotoxicity.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117708"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948831","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 : 2026-02-01Epub Date: 2026-01-08DOI: 10.1016/j.taap.2026.117710
Jiajun Guo , Xiaoyan Feng , Yuankun Zhou , Tao You , Hengyi Xu
As an emerging category of environmental pollutants, microplastics (MPs) garner significant attention due to their exceptionally high exposure risk. Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer in the plastics industry, shares a similar trajectory of escalating risk as plastic pollution intensifies. MPs and DEHP are widely present in environments accessible to humans, exerting significant adverse effects on human health. The reproductive toxicity of both MPs and DEHP has been reported. However, their combined toxicity, particularly the damage to the male reproductive system, remains unclear. Here, we employed the C57BL/6 J mouse model for our experiments. The mice were continuously exposed to 10 mg/L MPs and 500 μg/L DEHP through free drinking water for two months to investigate the effects of these two pollutants on mouse testes. Our study found that mice co-exposed to MPs and DEHP experienced severe impairment of male reproductive system, manifested as disruption of testicular structure, decline in sperm quality, and dysregulation of sex hormone synthesis. Furthermore, the co-exposure to DEHP and MPs activated endoplasmic reticulum stress via the PERK-eIF2α-ATF4 pathway, and also induced excessive autophagy, contributing to reproductive damage. In summary, our findings highlight the significant risks of co-exposure to DEHP and MPs and provide new insights into their combined reproductive toxicity in male mammals.
{"title":"Synergistic assault of DEHP and MPs: Unmasking the ER stress-triggered autophagic injury male fertility","authors":"Jiajun Guo , Xiaoyan Feng , Yuankun Zhou , Tao You , Hengyi Xu","doi":"10.1016/j.taap.2026.117710","DOIUrl":"10.1016/j.taap.2026.117710","url":null,"abstract":"<div><div>As an emerging category of environmental pollutants, microplastics (MPs) garner significant attention due to their exceptionally high exposure risk. Di(2-ethylhexyl) phthalate (DEHP), a ubiquitous plasticizer in the plastics industry, shares a similar trajectory of escalating risk as plastic pollution intensifies. MPs and DEHP are widely present in environments accessible to humans, exerting significant adverse effects on human health. The reproductive toxicity of both MPs and DEHP has been reported. However, their combined toxicity, particularly the damage to the male reproductive system, remains unclear. Here, we employed the C57BL/6 J mouse model for our experiments. The mice were continuously exposed to 10 mg/L MPs and 500 μg/L DEHP through free drinking water for two months to investigate the effects of these two pollutants on mouse testes. Our study found that mice co-exposed to MPs and DEHP experienced severe impairment of male reproductive system, manifested as disruption of testicular structure, decline in sperm quality, and dysregulation of sex hormone synthesis. Furthermore, the co-exposure to DEHP and MPs activated endoplasmic reticulum stress <em>via</em> the PERK-eIF2α-ATF4 pathway, and also induced excessive autophagy, contributing to reproductive damage. In summary, our findings highlight the significant risks of co-exposure to DEHP and MPs and provide new insights into their combined reproductive toxicity in male mammals.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117710"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145948813","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 : 2026-02-01Epub Date: 2025-12-18DOI: 10.1016/j.taap.2025.117694
Sofia Jonasson, Åsa Gustafsson, Johanna Qvarnström, Marcus Carlsson, Nina Forsgren, Fredrik Ekström, Linda Elfsmark
Preclinical evaluation of oximes as antidotes for organophosphorus nerve agent (OPNAs) poisoning is predominantly based on protection ratio of the antidote against lethal doses. Developing protection indexes involves considerable animal distress and, due to the limited precision, requires large animal cohorts. This study aimed to establish an in vivo model for evaluating new therapeutic substances more aligned with the 3R principles that also enables detailed quantification of specific biological effects to better understand the impact of treatment.
Anesthetized Sprague-Dawley rats were tracheostomized and connected to a small animal ventilator allowing simultaneous registration of respiratory function. Rats were exposed to 1xLD50 VX or tabun, and progression of poisoning was monitored in real-time through measurements of respiratory resistance (RRS) over a 30-min period. Additional assessments included clinical symptoms and acetylcholine esterase (AChE) inhibition in blood. Pre-treatment with oxime (obidoxime, HI-6, RS194B) or atropine were used to validate the model.
Exposure to OPNAs resulted in rapid increases in RRS to 250–300 % above baseline. HI-6 and obidoxime were the most effective treatments, mitigating both respiratory and enzymatic effects of OPNA poisoning, while RS194B treatment delayed onset of symptoms but did not fully reverse toxicity. Tabun-inhibited AChE was generally more resistant to reactivation with oximes than VX- inhibited enzymes. The findings indicate that maintaining AChE activity above 15–20 % is sufficient to restore respiratory function and alleviate symptoms to levels comparable to unexposed controls.
This study highlights the value of high-sensitivity, real-time monitoring of physiological metrics like respiratory resistance in evaluating novel antidotes for OPNA poisoning.
{"title":"Establishment of a real-time monitored animal model to evaluate novel therapeutic strategies for organophosphorus nerve agent poisonings","authors":"Sofia Jonasson, Åsa Gustafsson, Johanna Qvarnström, Marcus Carlsson, Nina Forsgren, Fredrik Ekström, Linda Elfsmark","doi":"10.1016/j.taap.2025.117694","DOIUrl":"10.1016/j.taap.2025.117694","url":null,"abstract":"<div><div>Preclinical evaluation of oximes as antidotes for organophosphorus nerve agent (OPNAs) poisoning is predominantly based on protection ratio of the antidote against lethal doses. Developing protection indexes involves considerable animal distress and, due to the limited precision, requires large animal cohorts. This study aimed to establish an <em>in vivo</em> model for evaluating new therapeutic substances more aligned with the 3R principles that also enables detailed quantification of specific biological effects to better understand the impact of treatment.</div><div>Anesthetized Sprague-Dawley rats were tracheostomized and connected to a small animal ventilator allowing simultaneous registration of respiratory function. Rats were exposed to 1xLD<sub>50</sub> VX or tabun, and progression of poisoning was monitored in real-time through measurements of respiratory resistance (R<sub>RS</sub>) over a 30-min period. Additional assessments included clinical symptoms and acetylcholine esterase (AChE) inhibition in blood. Pre-treatment with oxime (obidoxime, HI-6, RS194B) or atropine were used to validate the model.</div><div>Exposure to OPNAs resulted in rapid increases in R<sub>RS</sub> to 250–300 % above baseline. HI-6 and obidoxime were the most effective treatments, mitigating both respiratory and enzymatic effects of OPNA poisoning, while RS194B treatment delayed onset of symptoms but did not fully reverse toxicity. Tabun-inhibited AChE was generally more resistant to reactivation with oximes than VX- inhibited enzymes. The findings indicate that maintaining AChE activity above 15–20 % is sufficient to restore respiratory function and alleviate symptoms to levels comparable to unexposed controls.</div><div>This study highlights the value of high-sensitivity, real-time monitoring of physiological metrics like respiratory resistance in evaluating novel antidotes for OPNA poisoning.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117694"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145800769","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 : 2026-02-01Epub Date: 2025-12-14DOI: 10.1016/j.taap.2025.117691
Victor Enrique Sarmiento-Ortega , Diana Moroni-González , José Everardo Avelino-Cruz , Miguel Garcia-Gonzalez , Rubén Vázquez-Roque , Eduardo Brambila , Samuel Treviño
Cadmium (Cd) is an environmental pollutant increasingly linked to cardiovascular morbidity. While its toxic effects have been well documented at high doses, the impact of chronic exposure to the minimal risk level remains underexplored. This study aimed to investigate the mechanistic basis of Cadmium-induced cardiotoxicity at low doses and to evaluate the cardioprotective potential of pioglitazone, a PPARγ agonist with anti-inflammatory and antioxidant properties. Male Wistar rats were exposed chronically to Cd in drinking water (Cd, 15 mg/L) for 3 and 5 months, with or without pioglitazone co-treatment (2.5 mg/kg bw/day). Hemodynamic parameters, serum biomarkers (hs-TnI, NT-proBNP, sST2, IL-6, TNF-α), ventricular morphometry, histology, and activation of MAPK signaling (p-ERK1/2, p-JNK, p-p38) were evaluated. At 5 months, Cd exposure significantly increased systolic and diastolic blood pressure, hs-TnI, and NT-proBNP, without affecting CK-MB or hs-PCR. Structural changes included selective left ventricular hypertrophy, increased cardiomyocyte size, and elevated HW/BW and LVW/BW ratios. Cadmium also disrupted the IL-33/sST2 axis, elevating IL-6 and TNF-α, which indicates the presence of chronic inflammation. Mechanistically, Cd activated the MAPK pathway, with marked increases in p-p38 and p-JNK. Pioglitazone partially reversed these alterations by reducing inflammatory cytokines, restoring IL-33 levels, downregulating MAPK activation, and attenuating cardiac remodeling. Chronic exposure to the minimal risk of cadmium dosage induces subclinical yet progressive cardiotoxicity through inflammatory and MAPK-dependent pathways. Pioglitazone confers partial protection by modulating these mechanisms, underscoring its therapeutic potential in mitigating environmentally induced cardiovascular injury.
{"title":"Pioglitazone attenuates cardiovascular remodeling cadmium-induced through the MAPK pathway","authors":"Victor Enrique Sarmiento-Ortega , Diana Moroni-González , José Everardo Avelino-Cruz , Miguel Garcia-Gonzalez , Rubén Vázquez-Roque , Eduardo Brambila , Samuel Treviño","doi":"10.1016/j.taap.2025.117691","DOIUrl":"10.1016/j.taap.2025.117691","url":null,"abstract":"<div><div>Cadmium (Cd) is an environmental pollutant increasingly linked to cardiovascular morbidity. While its toxic effects have been well documented at high doses, the impact of chronic exposure to the minimal risk level remains underexplored. This study aimed to investigate the mechanistic basis of Cadmium-induced cardiotoxicity at low doses and to evaluate the cardioprotective potential of pioglitazone, a PPARγ agonist with anti-inflammatory and antioxidant properties. Male Wistar rats were exposed chronically to Cd in drinking water (Cd, 15 mg/L) for 3 and 5 months, with or without pioglitazone co-treatment (2.5 mg/kg bw/day). Hemodynamic parameters, serum biomarkers (hs-TnI, NT-proBNP, sST2, IL-6, TNF-α), ventricular morphometry, histology, and activation of MAPK signaling (p-ERK1/2, p-JNK, p-p38) were evaluated. At 5 months, Cd exposure significantly increased systolic and diastolic blood pressure, hs-TnI, and NT-proBNP, without affecting CK-MB or hs-PCR. Structural changes included selective left ventricular hypertrophy, increased cardiomyocyte size, and elevated HW/BW and LVW/BW ratios. Cadmium also disrupted the IL-33/sST2 axis, elevating IL-6 and TNF-α, which indicates the presence of chronic inflammation. Mechanistically, Cd activated the MAPK pathway, with marked increases in p-p38 and p-JNK. Pioglitazone partially reversed these alterations by reducing inflammatory cytokines, restoring IL-33 levels, downregulating MAPK activation, and attenuating cardiac remodeling. Chronic exposure to the minimal risk of cadmium dosage induces subclinical yet progressive cardiotoxicity through inflammatory and MAPK-dependent pathways. Pioglitazone confers partial protection by modulating these mechanisms, underscoring its therapeutic potential in mitigating environmentally induced cardiovascular injury.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117691"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145769304","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 : 2026-02-01Epub Date: 2025-12-30DOI: 10.1016/j.taap.2025.117702
Mingkai Chang , Ye Shang , Jianing Zheng , Wenfei Wang , Tingting Zhao
Objective: This study evaluates the anti-sepsis efficacy and potential risks of the FGFR1 inhibitor PD-166866 by integrating network pharmacology, transcriptome sequencing, and network toxicology.Methods: In terms of druggability, network pharmacology was used to screen drug-disease common targets and conduct enrichment analysis. Meanwhile, transcriptome sequencing was performed on the LPS-induced Raw264.7 cell model for target validation. In terms of toxicology, network toxicology was applied to predict the potential toxicity of small molecules, which was further verified by gene expression and survival analysis using the TCGA and Kaplan-Meier Plotter databases.Results: A total of 39 common targets between PD-166866 and sepsis were identified. The core pathways include the Rap1 signaling pathway, and the core targets are SRC, EGFR, and CCND1; molecular docking showed stable binding between PD-166866 and these targets. Transcriptomic analysis confirmed that PD-166866 can significantly regulate the expression of inflammation-related genes and inhibit the Rap1 pathway. Network toxicology indicated a significant risk of hematological toxicity associated with this drug. Transcriptome sequencing revealed that PD-166866 treatment led to the downregulation of IRAK3 and IKBKE, and the low expression of these two genes was significantly associated with poor prognosis in leukemia patients, confirming the potential hematological toxicity of PD-166866.Conclusion: This study confirms that PD-166866 exerts anti-sepsis effects by regulating pathways such as Rap1, but it also has the potential risk of inducing leukemia. More importantly, this study successfully established a comprehensive evaluation framework integrating in silico and in vitro experiments. It provides a feasible methodological reference for systematically evaluating the dual attributes of “efficacy-risk” in the early stage of drug development and reducing the initial reliance on traditional animal models.
{"title":"Unveiling the therapeutic potential and leukemia risk of PD-166866 in sepsis via an integrated computational-experimental strategy","authors":"Mingkai Chang , Ye Shang , Jianing Zheng , Wenfei Wang , Tingting Zhao","doi":"10.1016/j.taap.2025.117702","DOIUrl":"10.1016/j.taap.2025.117702","url":null,"abstract":"<div><div>Objective: This study evaluates the anti-sepsis efficacy and potential risks of the FGFR1 inhibitor PD-166866 by integrating network pharmacology, transcriptome sequencing, and network toxicology.Methods: In terms of druggability, network pharmacology was used to screen drug-disease common targets and conduct enrichment analysis. Meanwhile, transcriptome sequencing was performed on the LPS-induced Raw264.7 cell model for target validation. In terms of toxicology, network toxicology was applied to predict the potential toxicity of small molecules, which was further verified by gene expression and survival analysis using the TCGA and Kaplan-Meier Plotter databases.Results: A total of 39 common targets between PD-166866 and sepsis were identified. The core pathways include the Rap1 signaling pathway, and the core targets are SRC, EGFR, and CCND1; molecular docking showed stable binding between PD-166866 and these targets. Transcriptomic analysis confirmed that PD-166866 can significantly regulate the expression of inflammation-related genes and inhibit the Rap1 pathway. Network toxicology indicated a significant risk of hematological toxicity associated with this drug. Transcriptome sequencing revealed that PD-166866 treatment led to the downregulation of IRAK3 and IKBKE, and the low expression of these two genes was significantly associated with poor prognosis in leukemia patients, confirming the potential hematological toxicity of PD-166866.Conclusion: This study confirms that PD-166866 exerts anti-sepsis effects by regulating pathways such as Rap1, but it also has the potential risk of inducing leukemia. More importantly, this study successfully established a comprehensive evaluation framework integrating in silico and in vitro experiments. It provides a feasible methodological reference for systematically evaluating the dual attributes of “efficacy-risk” in the early stage of drug development and reducing the initial reliance on traditional animal models.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"507 ","pages":"Article 117702"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889392","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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